Journal of Ethnopharmacology 142 (2012) 591–619
Contents lists available at SciVerse ScienceDirect
Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep
Review
Towards a better understanding of medicinal uses of the brown seaweed Sargassum in Traditional Chinese Medicine: A phytochemical and pharmacological review Lei Liu a,n, Michael Heinrich a,b, Stephen Myers a, Symon A. Dworjanyn c a
Southern Cross Plant Science, Southern Cross University, PO Box 157, Lismore, NSW 2480, Australia Centre for Pharmacognosy and Phytotherapy, UCL School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK c National Marine Science Centre, Southern Cross University, Coffs Harbour, NSW 2450, Australia b
a r t i c l e i n f o
abstract
Article history: Received 29 February 2012 Received in revised form 18 April 2012 Accepted 25 May 2012 Available online 6 June 2012
Ethnopharmacological relevance: For nearly 2000 years Sargassum spp., a brown seaweed, has been used in Traditional Chinese Medicine (TCM) to treat a variety of diseases including thyroid disease (e.g. goitre). Aims of the review: To assess the scientific evidence for therapeutic claims made for Sargassum spp. in TCM and to identify future research needs. Background and methods: A systematic search for the use of Sargassum in classical TCM books was conducted and linked to a search for modern phytochemical and pharmacological data on Sargassum spp. retrieved from PubMed, Web of Knowledge, SciFinder Scholar and CNKI (in Chinese). Results and discussion: The therapeutic effects of Sargassum spp. are scientifically plausible and may be explained partially by key in vivo and in vitro pharmacological activities of Sargassum, such as anticancer, antiinflammatory, antibacterial and antiviral activities. Although the mechanism of actions is still not clear, the pharmacological activities could be mainly attributed to the major biologically active metabolites, meroterpenoids, phlorotanins and fucoidans. The contribution of iodine in Sargassum for treating thyroid related diseases seem to have been over estimated. Conclusions: The bioactive compounds in Sargassum spp. appear to play a role as immunomodulators and could be useful in the treatment of thyroid related diseases such as Hashimoto’s thyroiditis. Further research is required to determine both the preventative and therapeutic role of Sargassum spp. in thyroid health. & 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Sargassum Traditional Chinese Medicine (TCM) Thyroid Meroterpenoids Phlorotanin Fucoidan Immunomodulator Hashimoto’s thyroiditis
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592 Botany and taxonomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592 Traditional uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594 Phytochemistry and pharmacological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594 4.1. Meroterpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595 4.2. Phlorotanins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
Abbreviations: AAPT, activated partial thromboplastin time; ABTS, 2,20 -azinobis-3-ethylbenzo thizoline-6-sulphonate; BT, bleeding time; BuOH, butanol; CCl4, carbon tetrachloride; COX, cyclooxygenase; CPR, C-reactive protein; CT, coagulation time; DCM, dichloromethane; DIT, diiodotyrosine; DPPH, 1,1-diphenyl-2-picrylhydrazyl; EtOAc, ethyl acetate; ET, endothelin; HCMV, human cytomegalovirus; GC, gas chromatography; GOT, glutamic oxaloacetic transminase; GPT, glutamic pyruvic transaminase; GSH, glutathione; HAV, Hepatitis A Virus; HCMV, human cytomegalovirus; HDL, high-density lipoprotein; HIV-1, Human Immunodeficiency Virus Type 1; H2O2, hydrogen peroxide; HPLC, high performance liquid chromatography; HSV-1, Herpes Simplex Virus Type 1; HSV-2, Herpes Simplex Virus Type 2; HTLV-1, Human T-cell Lymphotropic Virus Type 1; IgE, Immunoglobulin E; IL, interleukin; INF-b, interferon b; iNOS, inducible nitric oxide synthase; LDL, Low-density lipoprotein; LPO, lipid peroxidation; MeOH, methanol; MIT, monoiodotyrosine; M/G, mannuronic acid/guluronic acid; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NMR, nuclear magnetic resonance; NGF, nerve growth factor; NO, nitric oxide; PARP, poly ADP-ribose polymerase; PG, prostaglandin; PPAR, peroxisome proliferatoractivated receptors; PT, prothrombin time; ROS, reactive oxygen species; Seq., Sequential (extraction); SOD, superoxide dismutase; T3, triiodothyronine; T4, thyroxine; TCM, traditional Chinese medicine; Tg, thyroglobulin; TgAb, thyroglobulin antibody; TNF-a, tumour necrosis factor-alpha; TPO, thyroperoxidase; TPOAb, thyroperoxidase antibody; TT, thrombin time; UVB, ultraviolet B; VLDL, very low-density lipoprotein n Corresponding author. Tel.: þ61 2 66223211; fax: þ61 2 66223459. E-mail addresses:
[email protected],
[email protected] (L. Liu),
[email protected] (M. Heinrich),
[email protected] (S. Myers),
[email protected] (S.A. Dworjanyn). 0378-8741/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jep.2012.05.046
592
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
4.3.
5.
6. 7. 8.
Polysaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595 4.3.1. Fucoidans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595 4.3.2. Alginates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599 4.4. Other compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603 4.4.1. Phytosterols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603 4.4.2. Bisnorditerpenens and farnesylacetones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603 4.4.3. Polyunsaturated fatty acids and glycolipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 4.4.4. Arsenosugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 4.4.5. Iodoamino acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 4.4.6. Dipeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 4.4.7. Flavonoids and coumarins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 4.4.8. Miscellaneous compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 Pharmacological properties of Sargassum extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 5.1. Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 5.2. Anti-allergic activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 5.3. Antimicrobial, antiviral and antiplasmodial activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 5.4. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 5.5. Liver and bone protective activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 5.6. Other pharmacological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 Safety, traditional and modern issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 Future research for Sargassum with focus on thyroid health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
1. Introduction Sargassum, a genus of brown seaweed (Phaeophyceae) in the Sargassaceae family, contains approximately 400 species (Mattio and Payri, 2011). Sargassum is found throughout all oceans and consumed as food and medicines in many cultures. Bioactive compounds (currently about 200), such as meroterpenoids, phlorotanins, fucoidans, sterols and glycolipids, have been identified from this genus. A wide range of pharmacological properties of the Sargassum spp. extracts or isolated pure components have been recognised. These include anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, anticoagulant, antioxidant, hypoglycaemic, hypolipidemic, antimelanogenic, anti-bone loss, hepatoprotective and neuroprotective activities; which suggests that Sargassum is a rich source of health maintaining and promoting agents. However, the numerous species, complex chemistry and various pharmacological properties of Sargassum necessitate a systematic and critical assessment of the future directions of research and application. The English common names for Sargassum spp. (in the following called ‘Sargassum’) is gulfweed or sea holly. In Asia, where the majority of ethnopharmacological knowledge is found, Sargassum species have numerous common names like ‘‘Hai Zao’’ ( ) or ‘‘Hai Qian’’ ( ) in Chinese, ‘‘Hondawara’’ ( ) in Japanese, and ‘‘Mojaban’’ ( ) in Korean. Traditional Chinese Medicine (TCM) contains valuable information for the uses of Sargassum, which have been recorded in ancient manuscripts and summarised in recently published books such as Chinese Pharmacopoeias, Compendium of Materia Medica (‘‘Ben Cao Gang Mu’’, ), ‘‘Zhong Hua Ben Cao’’ ( ), and ‘‘Zhong Hua Hai Yang Ben Cao’’ ( ). The biomedical literatures on modern phytochemical and pharmacological studies of Sargassum have increased dramatically (30 articles in the 1980s, 78 articles in the 1990s and 386 articles in 2000–2011 cited in PubMed, Web of Knowledge and SciFinder Scholar). Search of the China Knowledge Resource Integrated Database (CNKI, http://eng.cnki.net/ last accessed at 29/02/2012), a Chinese publication database, suggested there have been 136 peer-reviewed reports (in Chinese) on the chemistry and medicinal property of Sargassum since 1979. Although most of these studies were initiated according to traditional knowledge of Sargassum, the connections between the traditional
uses and modern scientific studies have not been systematically examined. The aim of this review was to assess the scientific evidence for the therapeutical claims for Sargassum used in TCM and provide the opportunity for future research, for a more evidence-based approach to the species use and potentially to the development of novel supplements or herbal medicines (Uzuner et al., 2012).
2. Botany and taxonomy Sargassum was first described nearly 200 years ago by Agardh (1820). It is from the order Fucales or rockweeds and in temperate regions it can be common but is less conspicuous than the kelps. In tropical seas it is the dominant most conspicuous upright macroalgae and plays a major role in structuring ecosystems. Sargassum often detaches from reefs and forms vast pelagic mats and some species have a solely pelagic life cycle. It is these large floating masses of Sargassum that gives the Sargasso Sea its name. The genus, with complex and variable morphology, has been estimated to be the most species rich genus of the marine macrophytes with 400 species being identified to date (Mattio and Payri, 2011). Sargassum is characterised by holdfast that attaches to the substrate, a short stipe that differentiates into numerous primary branches that mostly have many leaf like laterals. Spherical vesicles that aid floatation are often present and reproductive structures are contained in specialised laterals called receptacles. The shape of the leaf like thallus, vesicles and receptacles are highly diversified. Even within the same species, Sargassum morphology significantly varies under different environmental conditions and at different seasons (Kilar et al., 1992). Due to these variations, it is often a difficult task to identify Sargassum species especially from the diverse tropical flora. Only 78 Sargassum species (less than 20% of all identified Sargassum species) have been investigated for their phytochemical and pharmacological properties. The majority of studies concentrated on 18 species, of which 11 have been frequently used in TCM (Table 1). When used in TCM, Sargassum seaweeds are dried for easy storage and transportation. Once dried it is more difficult to distinguish the specific Sargassum species. Little research has been carried out on the comparative chemistry,
Table 1 Sargassum used in Traditional Chinese Medicine (TCM). Sargassum used in TCM ‘‘Hai Zao’’
Species S. pallidum (Turner) C. Agardh
a
Traditional use
‘‘Hai Hao Zi’’
Used to treat (a) Goitre, scrofula, swelling and pain of testes, oedema due to retention of phlegm and morbid fluids; (b) arteriosclerosis, skin diseases; (c) high blood pressure, hepatolienomegaly, neurosis; (d) angina pectoris; (e) acute esophagitis; (f) chronic bronchitis.
or S. confusum, C. Agardhb S. fusiforme (Harvey) Setchell
‘‘Hai Qian’’
Other Sargassum species used in China (unofficially)c
‘‘Yang Xi Cai’’
S. fulvellum (Turner) C. Agardh
‘‘Wu Lei Ma Wei Zao’’
S. henslowianum, C. Agardh
‘‘Heng Shi Ma Wei Zao’’
S. thunbergii (Mertens ex Roth) Kuntze S. horneri (Turner) C. Agardh
‘‘Shu Wei Zao’’ ‘‘Tong Zao’’
S. siliquastrum (Turner) C. Agardh
‘‘Lie Ye Ma Wei Zao’’
S. muticum (Yendo) Fensholt
‘‘Hai Shu Zi’’
S. hemiphyllum (Turner) var. Chinense J. Agardh S. polycystum C. Agardh
‘‘Ban Ye Ma Wei Zao’’ ‘‘Pu Zhi Ma Wei Zao’’
S.vachellianum Greville
‘‘Wa Shi Ma Wei Zao’’
Reference (a) ‘‘Zhong Hua Ben Cao’’, (b) ‘‘Zhong Guo Yao Yong Zhi Wu Tu Jian’’, (c) ‘‘Qing Dao Zhong Yao Shou Ce’’, (d) ‘‘Zhong Guo Yao Yong Bao Zi Zhi Wu’’, (e) ‘‘Fu Jian Yao Wu Zhi’’, (f) ‘‘Xian Dai Shi Yong Zhong Yao’’,
Used to treat scrofula, goitre, sore throat, cough and phlegm stasis, angina pectoris, dropsy, dysuria and furuncle
‘‘Zhong Hua Ben Cao’’, and ‘‘Guang Dong Zhong Yao Zhi’’, .
Similar use as ‘‘Hai Zao’’ and ‘‘Hai Qian’’
‘‘Zhong Hua Ben Cao’’,
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Chinese name for the species
a
Name used in Chinese pharmacopeia (2010 version). Name used in ‘‘Zhong Hua Hai Yang Ben Cao’’( ) (Guan and Wang, 2009). In this book, S. pallidum C. Agardh and S. confusum C. Agardh are considered as same seaweed used in TCM. But, according to AlgaeBase (http://www.algaebase.org, last access 29/02/2012), the taxonomic names of these two species are accepted separately. c There are another 8 species listed at ‘‘Zhong Huan Hai Yang Ben Cao’’ , but little chemical and pharmacological information has been found for these species. Therefore, these species have not been listed here. b
593
594
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
especially the secondary metabolites profiles, between different Sargassum species (Liu et al., 2009). Chemotaxonomic studies of this genus would be extremely useful to authenticate the species and control the quality of products manufactured from Sargassum.
3. Traditional uses The ‘‘Shen Nong Ben Cao Jing’’ ( ) or ‘‘Ben Jing’’ ( ) provides a summary of early Chinese medicinal knowledge before 25–220 AD, and is the first known record of Sargassum seaweed used to treat goitre or ‘‘Ying Liu’’ ( ) in traditional Chinese medicine. Sargassum has been continuously described as ‘‘Hai Zao’’ ( ) for its therapeutic uses in ancient Chinese books, such as ‘‘Ming Yi Bie Lu’’ ( ) or ‘‘Bie Lu’’ ( , written in 220–450 AD), ‘‘Ben Cao Shi Yi’’ ( , written in 741 AD) and ‘‘Ben Cao Tu Jing’’ ( , written in 1061 AD). Although the complete original copies of these ancient books have long been lost, the medicinal uses of Sargassum seaweeds have been re-examined and written into one of the most quoted and well kept ancient Chinese medicinal books, the ‘‘Ben Cao Gang Mu’’ ( ) or ‘‘Compendium of Materia Medica’’ which was written by Shizhen Li in 1578. The Compendium states that Sargassum can soften hard lumps, dispel nodes, eliminate phlegm and induce urination in humans. The Sargassum seaweeds or ‘‘Hai Zao’’ ( ) recorded in the Compendium are believed to be S. pallidum (Turner) C. Agardh (‘‘Hai Hao Zi’’, ) and S. fusiforme (Harvey) Setchell (‘‘Yang Xi Cai’’, ). These two specific species have been listed as ‘‘Hai Zao’’ ( ) in the every version of Chinese Pharmacopoeia since 1953 and indicate confidence in their use as medicinal ingredients. According to the modern Chinese pharmacopoeia, ‘‘Hai Zao’’ ( ) can be used to treat goitre, scrofula, swelling and pain of testes, oedema due to retention of phlegm and morbid fluids. In modern Chinese medical practise, ‘‘Hai Zao’’ ( ) has also been used to treat arteriosclerosis, skin diseases, high blood pressure, hepatolienomegaly, neurosis, angina pectoris, acute esophagitis, chronic bronchitis (Table 1) (Editorial Board of Zhong Hua Ben Cao, 1999). Another four Sargassum species, S. fulvellum (Turner) C. Agardh, S. henslowianum C. Agardh, S. thunbergii (Mertens ex Roth) Kuntze, S. horneri (Turner) C. Agardh, commonly named as ‘‘Hai Qian’’ ( ) have been used as popular medicines and food ingredients in the south east region of China (Guang Dong province, ) (Editorial Board of Zhong Hua Ben Cao, 1999). Similar to the ‘‘Hai Zao’’ ( ), these seaweeds have been used to treat various diseases such as goitre (Table 1). Unofficially, another five species listed in Table 1 may also be used for similar therapeutical purposes as ‘‘Hai Zao’’ ( ) and ‘‘Hai Qian’’ ( ). Although these 11 Sargassum species are used interchangeably,
without comparative chemical and pharmacological profiles it is uncertain that these species can be exchanged. According to the Chinese Pharmacopeia, a dose of ‘‘Hai Zao’’ ( ) should be 6–12 g (dry weight) when used as medicine. In TCM, Sargassum seaweeds can be ingested as water decoction or alcoholic tincture, or ground into powder and applied topically (Editorial Board of Zhong Hua Ben Cao, 1999). Sargassum seaweeds can also be eaten as foods using a small serving. In Japan, S. fusiforme (or Hijiki), named as ‘‘vegetable for longevity’’, is a popular side dish and often prepared by soaking and boiling the dried seaweeds with water and served with soy sauce. The popularity of S. fusiforme is spreading to Korea, China, Europe and North America, despite recent warnings for the arsenic content from several authorities, such as the Government of the Hong Kong Special Adminstrative Region (http://www.cfs.gov.hk/, last accessed at 29/02/2012). Most of Chinese traditional medicines are used in combination with other herbs to enrich or enhance the therapeutic function and reduce side effects. Sargassum seaweeds have been used in more than 226 prescriptions to treat various diseases in China (http://www.zysj.com.cn, last accessed at 29/02/2012). As most of Chinese traditional medicines, these prescriptions have not been evaluated using modern evidence-based approaches. Among them, ‘‘Xiao Ying Wu Hai Wan’’ ( ) or ‘‘Xiao Ying Wan’’ ( ) (Table 2) is a prescription having similarity with Sargassum’s own traditional therapeutical claims (to treat thyroid related diseases) and has been accredited by China State Food and Drug Administration (http://www.sfda.gov.cn/, last accessed at 29/02/2012), commercially manufactured and sold in China as a medicine. An opportunity exists to research this prescription using modern scientific methods. Treating thyroid related diseases, such as simple goitre, is one of most important traditional uses for Sargassum seaweed. The iodine in Sargassum seaweed was believed to play an important role in the therapeutical function. However the role of iodine may have been overestimated and other bioactive metabolites may have more significant contribution towards Sargassum’s therapeutic claims. Recent research on modified decoction of ‘‘Hai Zao Yu Hu Tang’’ ( ) (Table 2) suggested that Sargassum may play a role as an immunomodulator (Song et al., 2011). The bioactive metabolites in Sargassum may inhibit thyroid growth induced by excessive iodine intake and improve immune function, which may be useful in treating Hashimoto’s thyroiditis.
4. Phytochemistry and pharmacological activity Approximately 80 of the 400 known Sargassum species have been analysed for their phytochemical compounds. Although the
Table 2 Examples of classical Chinese prescriptions containing Sargassum. Preparation name
Main composition
‘‘Xiao Ying Laminariae Thallus, Sargassum, Meretricis Concha, Fritillariae Wu Hai Wan’’ Thunbergii Bulbus, Platycodonis Radix, Prunellae Spica, Citri Rticulatae Pericarpium, Semen Arecae
Traditional and clinical uses
Reference
Resolve hard mass and eliminate goitre, used to treat simple goitre
Chinese Pharmacopoeia
Chinese Pharmacopoeia Disperse stagnated liver qi for relieve qi ‘‘Ru Ji Ling Ke Radix Bupleuri, Rhizoma Cyperi, Pericarpium Citri Reticulatae stagnation, reduce swelling and resolve mass, used Li’’ Viride, Radix Paeoniae Rubra, Salviae Miltiorrhizae Radix Et to treat mammary gland hyperplasia Rhizoma, Vaccariae Semen, Caulis Spatholobi, Concha Ostreae, Sargassum, Laminariae Thallus, Herba Epimedii, Semen Cuscutae ‘‘Hai Zao Yu Hu Tang’’
Sargassum fusiforme, Rhizoma pinellia ternate, Fructus Forsythis suspense, Pericarpium Citrus reticulate, Radix Angelicae sinesis, Bulbus Fritillariae thunbergii, Rhizoma Ligustici Chuanxiong and Radix Glycyrrhiza
Remove phlegm, relieve qi stagnation, and resolve ‘‘Wai Ke Zheng Zong’’ hard mass, used to treat goitre (Summary of Surgical Medicine) (Song et al., 2011)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
major constituents of the species traditionally used are known, the bioactive secondary metabolites have not been thoroughly studied. From a chemical prospective, there have been a number of successful attempts to isolate novel compounds which are abundant in species that are rarely used in traditional medicine (Table 3). These novel compounds may also be present in small quantities in the species commonly used traditionally but have so far not been investigated. There is still a lack of effective GC or LC methods for the phytochemical analysis of Sargassum, which is important for the identification of Sargassum species and the effective quantification of the bioactive compounds. Diverse pharmacological properties and structurally novel compounds have been found for the meroterpenoids, pholorotanins and fucoidans in Sargassum, suggesting that these compounds may be the major contributors for the traditional therapeutical effects of Sargassum (Table 4). Other compounds such as arsenosugars, phytosterols, sulphonoglycolipids, and polyunsaturated fatty acids have been also reported in the genus (Table 3). 4.1. Meroterpenoids Meroterpenoids are a class of compounds containing terpenoid elements along with structures of other biosynthetic origin (Cornforth, 1968). Meroterpenoids are particularly abundant in Sargassum, which often possess a polyprenyl chain attached to a hydroquinone or similar aromatic ring moiety (Fig. 1). These compounds account for nearly half ( 80) of the compounds identified in this genus (Table 3). With diverse structures, this group of compounds could be the best candidate for future chemotaxonomic studies. d-Tocotrenol, and its 110 ,120 -epoxide were the first meroterpenoids isolated from Sargassum (S. tortile) (Kato et al., 1975). Later many of the meroterpenoids, such as plastoquinones, chromanols and chromenes, were isolated from various species (Table 3 and Fig. 1). Interestingly, the plastoquinones can be easily converted into the corresponding chromenes by treating them with pyridine at room temperature under N2 atmosphere (Iwashima et al., 2005). These meroterpenoids are structurally related to vitamin E and have similar biological activities such as antioxidant and anticancer activities (Table 4). The meroterpenoids have also been found to have in vitro bioactivity such as neuroprotective, antimalarial and antiviral agents (Tsang and Kamei, 2004; Iwashima et al., 2005; Afolayan et al., 2008) (Table 4). Recently some in vivo studies revealed that meroterpenoids in Sargassum may also be used to treat hyperproliferative skin disease, gastric ulcer and cerebral vascular disease (Mori et al., 2006; Hur et al., 2008; Park et al., 2008b) (Table 4). Although meroterpenoids are important in the context of the medicinal properties of Sargassum, there has been no quantification for these compounds reported in literature. The type and quantity of meroterpenoids in Sargassum may have significant impact on the quality of its role as a medicinal ingredient. An effective quantification method for the meroterpenoids in Sargassum needs to be developed to better understand these compounds and their pharmacological role. 4.2. Phlorotanins Phlorotanins are tannins found in brown algae that are oligomers of phloroglucinol (1,3,5-trihydroxybenzene). A large number (69) of phlorotanins (Table 3) have been identified in Sargassum including phlorethols, fuhalols and fucophlorethols (Fig. 2). Although most of these phlorotanins were identified in S. spinuligerum, other species of Sargassum may also contain these polyphenols. The size of identified phlorotanins in Sargassum
595
ranges between 250 (2,30 ,4,50 ,6-pentahydroxydiphenyl ether, containing 2 phloroglucinol units) and 2644 (eicosafuhalol A, containing 20 phloroglucinol units) Daltons, although there must be larger ones that are still unidentified (Glombitza and Keusgen, 1995). When isolating these phlorotainins, the enriched fraction was often acetylated immediately with acetic anhydride-pyridine to stabilise the phenols (Glombitza and Keusgen, 1995). For bioactivity testing of the isolated pholortainins, a desacetylation can be carried out (Keusgen and Glombitza, 1997). The HPLC method developed for the isolation of acetylated phlorotainins uses a silica gel column and normal phase solvents, which could be applied to the analysis and quantification of the phlorotainins in Sargassum (Keusgen and Glombitza, 1995). However, an up to date reversed phase HPLC method may be easier and could be developed for the analysis of these polyphenols. Although the biological activity of individual phlorotanins have not been studied, the phlorotanins fractions were reported to have anticoagulant and antioxidant activities (Nakai et al., 2006; Li et al., 2007; Wei et al., 2007, 2003, 2008). Phlorotanins separated from S. thunbergii could significantly increase coagulation time (in vivo), bleeding time (in vivo), activated partial thromboplastin time (in vitro), prothrombin time (in vitro) and thrombin time (in vitro) and the larger molecular weight phlorotanins fraction ( 41 105 Da) have a similar degree of in vivo and in vitro activity as Aspirin, an antiplatelet drug inhibiting the production of thromboxane (Li et al., 2007; Wei et al., 2007). Recent study of the mechanism demonstrated that the anticoagulant activity of phlorotanins may relate to its ability to reduce the cytosolic calcium level in platelets (Wei et al., 2008). 4.3. Polysaccharides Polysaccharides are macromolecules with polymeric carbohydrate structures. The polysaccharides in Sargassum belong to three major groups, fucoidan, alginate and laminaran. Generally, Sargassum contains more alginate, and less fucodian and laminaran. However, a large number of bioactive polysaccharides found in Sargassum have not been characterised. Both fucoidans and alginates obtained from various Sargassum species were found to have significantly different mass (8–627 kDa) and, due to their complexity, the exact structures of bioactive polysaccharides have not been fully elucidated. 4.3.1. Fucoidans Fucoidans, or fucans, are bioactive polysaccharides containing fucose and sulphate which have been mainly identified in brown seaweed (Fig. 3). Diverse fucoidans have been isolated from Sargassum with molecular weight ranging from 5 to 627 kDa. Modern pharmacological research has found that Sargassum fucoidans have antiviral, anticancer, antioxidant, anti-inflammatory, antimicrobial, anticoagulant, hypolipidemic, antivasculogenic, and liver and renal protective activities (Table 5). In general, the biological activity of sulphated polysaccharide are related to the molecular size, type of sugar and sulphate content and sulphate position. The type of linkage and molecular geometry are also known to have a role in its activity. The fucoidan from Sargassum were found to have antiviral activity against Herpes Simplex Virus Type 1 (HSV-1), Type 2 (HSV-2), Hepatitis A Virus (HAV), coxsackie virus (CVB 3), human cytomegalovirus (HCMV) and Human Immunodeficiency Virus Type 1 (HIV-1). The fucoidan can inhibit the initial stages of viral infection, attachment to and penetration into host cells (Sinha et al., 2010), and replication stages after virus penetration (Preeprame et al., 2001), however, the exact mechanism remains
596
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Table 3 Compounds found in Sargassum seaweed. Compounds Meroterpenoids Chromequinolide 11-Hydroxysargachromelide 150 -Hydroxysargaquinolide 150 -Hydroxysargaquinolide; 150 -Deoxy, 150 ,160 -didehydro 2-Methyl-6-(3-methyl-7-oxo-2,5-octadienyl)-1,4-benzoquinone; (E,E)-form Nahocol A 100 ,110 -Didehydronahocol A Nahocol A; 130 -Ketone, 120 R-alcohol Nahocol A; 130 -Ketone, 120 S-alcohol Nahocol A; 130 -Deoxy, 140 ,150 -dihydro, 130 ,140 ,150 ,160 -tetradehydro, 120 x-alcohol Nahocol A; 100 ,110 -Didehydro(E-), 130 -ketone, 120 S-alcohol Nahocol A; 100 ,110 -Didehydro(Z-), 130 -ketone, 120 S-alcohol Nahocol A1 Nahocol B Nahocol C Nahocol D1 Nahocol D2 Isonahocol D1 Isonahocol D2 Isonahocol D1; 120 -Ketone Isonahocol D1; 20 E-Isomer, 120 -ketone Isonahocol D1; 20 E-Isomer, 100 ,110 -dihydro, 120 -ketone Isonahocol D1; 130 -Epimer, 60 ,70 -dihydro, 60 -oxo, 120 -deoxy 9,13-Cyclo-3-hydroxy-1,6,10,14-phytatetraen-12-one; [4-Hydroxy-2(methoxycarbonylmethyl) phenyl] ether 2-(12,13-Dihydroxytetraprenyl)-2-(methoxycarbonylmethyl)-5-cyclohexene-1, 4-dione Fallachromenoic acid Fallahydroquinone Fallahydroquinone; 1,4-Quinone Mojabanchromanol Sargachromenol Sargachromanol A Sargachromanol B Sargachromanol C Sargachromanol D Sargachromanol E Sargachromanol F Sargachromanol G Sargachromanol H Sargachromanol I Sargachromanol J Sargachromanol K Sargachromanol L Sargachromanol M Sargachromanol N Sargachromanol O Sargachromanol P Sargatriol Sargadiol I Sargadiol II Sargathunbergol A Thunbergol A Thunbergol B Sargaquinone Sargaquinal Sargaquinoic acid Sargahydroquinoic acid 140 ,150 -Dihydroxysargahydroquinone Sargahydroquinone; 120 -Oxo, 20 ,30 -dihydro, 30 ,130 -dihydroxy Sargaol Sargaol; 110 ,120 -Dihydro, 110 R,120 -dihydroxy Sargaol; 90 -Oxo, 3,4-dihydro Sargaol; 90 -Oxo, 3,4,70 ,80 b-tetrahydro 140 ,150 -Dihydroxysargaquinone. 80 ,90 -Dihydroxysargaquinone 90 -Hydroxysargaquinone 110 -Methoxysargaquinone 90 -Methoxysargaquinone 80 ,90 -Dihydroxy-5-methylsargaquinone. Sargasal II Sargasal I Sargatetraol d-Tocotrienol
Species
Reference
S. sagamianum S. sagamianum S. sagamianum S. sagamianum S. sagamianum S.autumnale S.autumnale S.autumnale S.autumnale S.autumnale S.autumnale S.autumnale S.autumnale S.autumnale S.autumnale S.autumnale S.autumnale S. autumnale S. siliquastrum S. siliquastrum S. siliquastrum S. siliquastrum S. siliquastrum S. siliquastrum
Horie et al. (2008) Horie et al. (2008) Horie et al. (2008) Horie et al. (2008) Horie et al. (2008) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Tsuchiya et al. (1998) Jung et al. (2008) Jung et al. (2008) Jung et al. (2008) Jung et al. (2008) Jung et al. (2008) Jung et al. (2008)
S. siliquastrum
Jung et al. (2008)
S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S.
Reddy and Urban (2009) Reddy and Urban (2009) Reddy and Urban (2009) Cho et al. (2008) Kusumi et al. (1979b) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Jang et al. (2005) Kikuchi et al. (1983) Numata et al. (1992) Numata et al. (1992) Seo et al. (2007) Seo et al. (2006) Seo et al. (2006) Ishitsuka et al. (1979) Kusumi et al. (1979b) Kusumi et al. (1979b) Segawa and Shirahama (1987) Iwashima et al. (2005) Jung et al. (2008) Numata et al. (1992) Iwashima et al. (2005) Iwashima et al. (2008) Iwashima et al. (2008) Iwashima et al. (2005) Ishitsuka et al. (1979) Numata et al. (1992) Ishitsuka et al. (1979) Ishitsuka et al. (1979) Ishitsuka et al. (1979) Numata et al. (1992) Numata et al. (1992) Ishitsuka et al. (1979) Kato et al. (1975)
fallax fallax fallax siliquastrum serratifolium siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum siliquastrum tortile tortile tortile thunbergii thunbergii thunbergii tortile serratifolium serratifolium sagamianum micracanthum siliquastrum tortile micracanthum micracanthum micracanthum micracanthum tortile tortile tortile tortile tortile tortile tortile tortile tortile
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
597
Table 3 (continued ) Compounds
Species
Reference
d -Tocotrienol; 110 ,120 -Epoxide Yezoquinolide 2,5-Cyclohexadiene-1,4-dione, 2-[(2E,6E,10E)-15-hydroxy-3,7,11,15-tetramethyl14-oxo-2,6,10-hexadecatrien-1-yl]-6-methyl1,4-Benzenediol, 2-[(2E,6E,10E,14R)-14,15-dihydroxy-3,7,11,15-tetramethyl2,6,10-hexadecatrien-1-yl]-6-methyl6,10,14-Hexadecatrien-3-one, 16-(2,5-dihydroxy-3-methylphenyl)-2-hydroxy2,6,10,14-tetramethyl-, (6E,10E,14E)9-Octadecenoic acid (9Z)-, 3-[(2E,6E,10E,14R)-14,15-dihydroxy-3,7,11,15tetramethyl-2,6,10-hexadecatrien-1-yl]-4-hydroxy-5-methylphenyl ester Octadecanoic acid, 3-[(2E,6E,10E,14R)-14,15-dihydroxy-3,7,11,15-tetramethyl2,6,10-hexadecatrien-1-yl]-4-hydroxy-5-methylphenyl ester 13-(3,4-dihydro-6-hydroxy-2,8-dimethy-2H-1-benzopyran-2-yl)-2,6,10trimethyl-trideca-(2E,6E)-diene-4,5,10-triol. 9-(3,4-dihydro-6-hydroxy-2,8-dimethy-2H-1-benzopyran-2-yl)-2,6-dimethyl(6E)-nonenoic acid.
S. tortile S. sagamianum S. micracanthum
Kato et al. (1975) Segawa and Shirahama (1987) Mori et al. (2005)
S. micracanthum
Mori et al. (2005)
S. micracanthum
Mori et al. (2005)
S. micracanthum
Mori et al. (2005)
S. micracanthum
Mori et al. (2005)
S. siliquastrum
Lee and Seo (2011)
S. siliquastrum
Lee and Seo (2011)
S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S. S.
Glombitza et al. (1997) Glombitza et al. (1997) Glombitza et al. (1997) Glombitza et al. (1997) Glombitza and Keusgen Glombitza et al. (1997) Glombitza et al. (1997) Glombitza et al. (1997) Glombitza and Keusgen Glombitza and Keusgen Glombitza et al. (1997) Glombitza et al. (1997) Glombitza et al. (1997) Glombitza et al. (1997) Glombitza et al. (1997) Glombitza et al. (1997) Glombitza et al. (1997) Glombitza et al. (1997) Glombitza and Keusgen Glombitza and Keusgen Keusgen and Glombitza Keusgen and Glombitza Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen
Phlorotanins Bisfucopentaphlorethol A, 4D-Chloro (or Chlorobisfucopentaphlorethol A) Bisfucotriphlorethol A Bisfucotriphlorethol A; 4D-Hydroxy (or Hydroxybisfucotriphlorethol A) Chlorobisfucopentaphlorethol B Decafuhalol A Difucodiphlorethol A Dihydroxyfucotriphlorethol A Dihydroxyfucotriphlorethol B Dodecafuhalol A Eicosafuhalol A Fucodifucotetraphlorethol A Fucodiphlorethol D Fucodiphlorethol D; 400 0 -Hydroxy Fucodiphlorethol E Fucodiphlorethol F Fucophlorethol B Fucophlorethol B; 400 0 -Hydroxy Fucotriphlorethol B; 4C,4D-Dihydrox Heptafuhalol A Heptafuhalol A; 2G-Hydroxy Heptafuhalol B Heptafuhalol B; 4B-Hydroxy Hexadecafuhalol A Hexafuhalol A Hexafuhalol A; 4B-Deoxy Hexafuhalol A; 4C-Deoxy Hexafuhalol A; 4E-Deoxy Hexafuhalol A; 4F-Deoxy Hydroxypentafuhalol A Nonafuhalol A Nonafuhalol B Octadecafuhalol A Octafuhalol A Octafuhalol A; 4H-Deoxy Octafuhalol B Octafuhalol C; 4-Deoxy Pentafuhalol A Pentafuhalol A; 2C-Hydroxy Pentafuhalol B 2,30 ,4,50 ,6-Pentahydroxydiphenyl ether Pentaphlorethol A Phloroscorbinol Pseudoheptafuhalol A Pseudoheptafuhalol B Pseudoheptafuhalol C Pseudoheptafuhalol D Pseudohexafuhalol A Pseudohexafuhalol B Pseudohexafuhalol C Pseudooctafuhalol B Pseudooctafuhalol C Pseudooctafuhalol D Pseudopentafuhalol A Pseudopentafuhalol B Pseudopentafuhalol C Pseudopentafuhalol D
spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum muticum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum muticum thunbergii spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum
(1995)
(1995) (1995)
(1995) (1995) (1995) (1995) (1995) (1995) (1995) (1995) (1995) (1995) (1995) (1995)
Keusgen and Glombitza Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza and Keusgen Glombitza et al. (1978)
(1995) (1995) (1995) (1995) (1995) (1995) (1995) (1995) (1995)
Glombitza and Keusgen Keusgen et al. (1997) Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza Keusgen and Glombitza
(1995) (1997) (1997) (1997) (1997) (1997) (1997) (1997) (1997) (1997) (1997) (1997) (1997) (1997) (1997)
598
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Table 3 (continued ) Compounds
Species
Reference
Pseudotetrafuhalol A Pseudotrifuhalol A Tetradecafuhalol A Tetrafuhalol A; 4B-Deoxy Tetrafuhalol A; 4C-Deoxy Tetrafuhalol A; 4D-Deoxy Tetraphlorethol C Tetraphlorethol C; 200 ,4000 -Dihydroxy Tetraphlorethol C; 20 ,4000 -Dihydroxy Trifuhalol A Trifuhalol A; 4-Hydroxy Trifuhalol B Trifuhalol B; 50 -Hydroxy Undecafuhalol A
S. S. S. S. S. S. S. S. S. S. S. S. S. S.
Keusgen and Glombitza (1997) Keusgen and Glombitza (1997) Glombitza and Keusgen (1995) Keusgen and Glombitza (1997) Keusgen and Glombitza (1997) Keusgen and Glombitza (1997) Keusgen and Glombitza (1995) Keusgen and Glombitza (1995) Keusgen and Glombitza (1995) Keusgen and Glombitza (1995) Keusgen and Glombitza (1995) Keusgen and Glombitza (1995) Keusgen and Glombitza, (1995) Glombitza and Keusgen (1995)
spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum spinuligerum
Phytosterols 4(3-2)-Abeo-4-hydroxy-2-oxostigmasta-5,24(28)-dien-3-oic acid; Et ester 3-Hydroxycholest-5-en-24-one; 3b-form, Vinyl enol ether (23Z-) 5-Hydroxy-3,4-dinor-2,3-secostigmast-24(28)-en-2,5-olide; (5aOH,24(28)E)form 24-Hydroxystigmasta-4,28-dien-3-one; (24x)-form(Saringosterone) Stigmasta-5,23-diene-3,28-diol; (3b,23Z,28x)-form Stigmasta-5,28-diene-3,24-diol; (3b,24x)-form(Saringosterol) Stigmasta-5,22-dien-3-ol; (3b,22E,24S)-form (Stigmasterol) Stigmasta-5,24(28)-dien-3-ol; (3b,24(28)E)-form (Fucosterol) Stigmasta-5,24(28)-dien-3-ol; (3b,20S,24(28)E)-form. (20S- Fucosterol) Stigmasta-5,23,25-trien-3-ol; (3b,23E)-form
S. carpophyllum S. thumbergii S. carpophyllum
Tang et al. (2003) Kobayashi et al. (1985) Tang et al. (2002)
S. S. S. S. S. S. S.
Ayyad et al. (2003) Tang et al. (2002) Ayyad et al. (2003) Ayyad et al. (2003) Wang et al. (1997) Ayyad et al. (2003) Xu et al. (2002b)
Bisnorditerpenes Hedaol A Hedaol B Hedaol C 14-Hydroxy-2,6,10-trimethyl-10-pentadecen-4-one 14-Hydroxy-2,6,10-trimethyl-10-pentadecen-4-one; 5,6-Didehydro
Not specified Not specified Not specified S. micracanthum S. micracanthum
Takada et al. (2001) Takada et al. (2001) Takada et al. (2001) Kusumi et al. (1979a) Kusumi et al. (1979a)
Farnesylacetones 6,10,14-Trimethyl-5,10-pentadecadiene-2,12-dione; (E, E)-form 6,10,14-Trimethyl-5,10-pentadecadiene-2,12-dione; (E, Z)-form 6,10,14-Trimethyl-5,9-pentadecadiene-2,12-dione; (E, E)-form 6,10,14-Trimethyl-5,10,13-pentadecatriene-2,12-dione; (E, E)-form 6,10,14-Trimethyl-5,9,13-pentadecatriene-2,12-dione; (E, E)-form 6,10,14-Trimethyl-5,9,13-pentadecatrien-2-one; (5E, 9E)-form 6,10,14-Trimethyl-5-pentadecene-2,12-dione; (E)-form
S. S. S. S. S. S. S.
Park et al. (2008a) Park et al. (2008a) Shizuri et al. (1982) Kusumi et al. (1979a) Kusumi et al. (1979a) Kusumi et al. (1979a) Kusumi et al. (1979a)
Glycolipids 1-O-(6-Deoxy-6-sulphoglucopyranosyl)glycerol; a-D-form, 3-Hexadecanoyl 1-O-(6-Deoxy-6-sulphoglucopyranosyl)glycerol; a-D-form, 3-Octadecanoyl Glycerol 1,2-dialkanoates; Glycerol 1,2-dihexadecanoate, 3-O-(6-Deoxy-6sulpho-a-D-glucopyranoside) Glycerol 1,2-dialkanoates; Glycerol 1-(5Z,8Z,11Z,14Z,17Z-eicosapentaenoate) 2-(9Z,12Z,15Z-octadecatrienoate), 3-O-b-D-Galactopyranoside Glycerol 1,2-dialkanoates; Glycerol 1-hexadecanoate 2-(9Z-octadecenoate), 3-O-a-D-Glucopyranoside Glycerol 1,2-dialkanoates; Glycerol 1-(9Z,12Z,15Z-octadecatrienoate) 2-(6Z,9Z,12Z,15Z-octadecatetraenoate), 3-O-b-D-Galactopyranoside Glycerol 1,2-dialkanoates; Glycerol 1-tetradecanoate 2-(9Z-octadecenoate), 3-O-a-D-Glucopyranoside Arsenosugars 2-Amino-3-[[5-deoxy-5-(dimethylarsinoyl)ribofuranosyl]oxy]-1propanesulphonic acid; (2S)-b-D-form Sargassum lacerifolium Arsenomethionine 1-O-[5-Deoxy-5-(dimethylarsinoyl)-b-D-ribofuranosyl]-D-mannitol 3-[5-Deoxy-5-(dimethylarsinoyl)ribofuranosyloxy]-2-hydroxy-1propanesulphonic acid; (2S-b-D)-form 5-Deoxy-5-(dimethylarsinoyl)ribose; b-D-Furanose-form, Me glycoside 3-[[(2,3-Dihydroxypropoxy) hydroxyphosphinyl] oxy]-2-hydroxypropyl 5-deoxy5-(dimethylarsinoyl) -b-D-ribofuranoside 2,3-Dihydroxypropyl [5-deoxy-5-(dimethylarsino)] ribofuranoside; As-Oxide, O30 -sulphate 2-Hydroxy-3-(sulphooxy)propyl 5-[[2-carboxy-3-(2,3dihydrooxypropoxy)propyl]dimethylarsonio]-5-deoxy-b-D-ribofuranoside inner salt 2-Hydroxy-3-(sulphooxy)propyl-5-deoxy-5-(trimethylarsonio)b-D-ribofuranoside; (20 R-b-D)-form Iodoamino acids 3-Iodotyrosine (S)-form
asperifolium carpophyllum asperifolium asperifolium carpophyllum asperifolium polycystum
siliquastrum siliquastrum micracanthum micracanthum micracanthum micracanthum micracanthum
S. wightii S. thunbergii S. parvivesiculosum
Arunkumar et al. (2005) Son et al. (1992) Qi et al. (2004)
S. thunbergii
Kim et al. (2007b)
S. fulvellum
Wu et al. (2009)
S. thunbergii
Kim et al. (2007b)
S.fulvellum
Wu et al. (2009)
S.lacerifolium
Francesconi et al. (1991)
S.lacerifolium S.lacerifolium S.lacerifolium
Edmonds (2000) Francesconi et al. (1991) Francesconi et al. (1991)
S.lacerifolium S.latifolia
Francesconi et al. (1991) Francesconi et al. (1991)
S.lacerifolium
Francesconi et al. (1991)
S.lacerifolium
Francesconi et al. (1991)
S. thunbergii
Shibata and Morita (1988)
S. thunbergii
Ito et al. (1976)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
599
Table 3 (continued ) Compounds
Species
Reference
3,5-Diiodotyrosine; (S)-form 3,5,30 -Triiodothyronine; (S)-form Thyroxine; (S)-form
S. thunbergii S. thunbergii S. thunbergii
Ito et al. (1976) Ito et al. (1976) Ito et al. (1976)
Dipeptides Aurantiamide Aurantiamide acetate Dia-aurantiamide acetate
S. pallidum S. pallidum S. pallidum
Liu et al. (2009) Liu et al. (2009) Liu et al. (2009)
Coumarins Melanettin Stevenin
S. pallidum S. pallidum
Liu et al. (2009) Liu et al. (2009)
Flavonoids Calycosin Liquiritigenin
S. pallidum S. pallidum
Liu et al. (2009) Liu et al. (2009)
Diterpenes Sargassinone Crinitol
S. crispum S. tortile
Ayyad et al. (2001) Kubo et al. (1985)
Loliolide Loliolide; (6S,7aR)-form Loliolide; (6S,7aS)-form
S. crassifolium S. crassifolium
Kuniyoshi (1985) Kuniyoshi (1985)
Octatriene 1,3,5-Octatriene; (3E,5E)-form 1,3,5-Octatriene; (3Z,5E)-form 2,4,6-Octatriene; (2E,4Z,6Z)-form
S. horneri S. horneri S. horneri
Kajiwara et al. (1980) Kajiwara et al. (1980) Kajiwara et al. (1980)
S. S. S. S. S. S. S. S. S. S. S. S. S. S.
Nakayama et al. (1980) Ehrhardt and Knap (1989) Mooney and Van (1987) Mooney and Van (1987) Xu et al. (1999) Kamei et al. (2009) Nozaki et al. (1995) Nozaki et al. (1980) Qi et al. (2004) Zubia et al. (2008) Terasaki et al. (2009)
Others Kjellmanianone; (S)-form 1,2-Benzenedicarboxylic acid; Dioctyl ester (Dioctyl phthalate) Zeatin; (E)-form, Deoxy Zeatin; (E)-form, 20 ,30 S-Dihydro 4-Methyl-1,2,6,8-tetraazacycloundeca-4,9-diene-3,7,11-trione Sargafuran Sargassumketone Sargassumlactam Vernoniether S Mannitol Fucoxanthin
unknown. In addition, the fucoidan isolated from Sargassum have been found to have low cytotoxicity ( 41000 mg/mL) to virus host cell lines such as normal Vero cells (African green monkey kidney cells) (Sinha et al., 2010), suggesting the potential for development of safe antiviral drugs based on these fucoidans. Since 1970s, a number of animal studies showed fucoidan from Sargassum had considerable in vivo anticancer activity and could significant reduce tumour weight and prolong survival time of tumour bearing animals (Table 5). However, in vitro experiments revealed that Sargassum fucoidans had very limited cytotoxicity (IC50 E0.1–1 mg/mL). Based on the available in vivo and in vitro studies, the anticancer action of Sargassum fucoidans is suspected to be a host-mediated immune mechanism (Itoh et al., 1993; Ale et al., 2011). Most of Sargassum fucoidans had weaker anticoagulant activity than heparin, which is a highly sulphated glycosaminoglycan similar to the structures of fucoidans and widely used as an injectable anticoagulant. Only Abdel-Fattah et al. (1974) reported that fucoidan isolated from S. linifolium had significant higher anticoagulant activity than heparin. Li and Xu (2004) suggested the anticoagulant activity of fucoidan isolated from S. fusiforme had positive correlation with the degree of sulphation, but not with the molecular weight. Fucoidans isolated from S. wightii and S. henslowianum were found to have hypolipidemic effects, reducing serum total cholesterol and triglyceride, low-density lipoprotein, and increase
kjellmanianum wightii heterophyllum heterophyllum vachellianum macrocarpum kjellmanianum, S. thunbergii jellmanianum parvivesiculosum mangarevense horneri thunbergii fusiforme confusum
high-density lipoprotein, for mice and rats with the diet-induced hyperlipidemia (Chen et al., 2010; Preetha and Devaraj, 2010). Interestingly, the fucodians introduced to the animals by subcutaneous injection (Preetha and Devaraj, 2010) and gastric perfusion (Chen et al., 2010) both exerted hypolipidemic effects. In vivo and in vitro anti-inflammatory activity has been identified for the fucoidan isolated from S. hemiphyllum and S. wightii (Preetha and Devaraj, 2010; Hwang et al., 2011). Preetha and Devaraj (2010) found the fucoidan isolated from S. wightii could restore inflammatory complications in rats with diet-induced hyperlipidemia. The levels of plasma tumour necrosis factor-alpha (TNF-a), C-reactive protein (CRP), fibrinogen, inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-II (COX-2) and lysosomal enzymes could be reduced by treatment with fucoidan in animal models. Later, Hwang et al. (2011) found fucoidan isolated from S. hemiphyllum could reduce interleukin (IL)-1b, IL-6, TNF-a, and NO, inhibit mRNA expressions of IL-b, iNOS, and COX-2, and down-regulate of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) in nucleus for the mouse macrophage cells (RAW 264.7) activated by lipopolysaccharide.
4.3.2. Alginates Alginates are mainly of linear polymers consisting of b-Dmannuronic (M) and a-L-guluronic (G) acids with different M/G
600
Table 4 Major phytochemicals in Sargassum and their pharmacological activities. Compounds
Meroterpenoids Sargaquinoic acid
Biological activity
in vivo/ Model in vitro
Active Concentration
Comment
0 and1.5
1.5 mg/mL
Compared in the presence of Tsang and 0–50 ng/mL NGF in serum free Kamei (2004) medium
3 mg/mL 3 mg/mL
Through two separated signalling pathway
in vitro
Inhibitory activity against butyrylcholinesterase
–
–
IC50 ¼ 26nM
–
in vitro
–
1–5 mg/mL
2 and 5 mg/mL
–
in vivo
Synergistic effect with UVB irradiation on the apoptosis of human keratinocyte HaCaT cells On hairless mice with UVB irradiation
Topical
0 and 100 mg –
in vitro
Cytotoxicity against P388 Murine Leukaemia cell line
–
–
IC50 ¼ 17 mM
Antimalar-ial activity
in vitro
antiplasmodial activity toward a chloroquine-sensitive strain (D10) of Plasmodium falciparum
–
–
IC50 ¼ 12.0 mM or 5.1 mg/mL
–
Potential treatment of metabolic disorders Antioxidant activity
in vitro
Increased peroxisome proliferator-activated receptors (PPAR) a/g transcriptional activity in 3T3-L1 cells
–
1–30mM
3–30 mM for PPARa 1–30 mM for PPARg
–
in vitro
1,1-Diphenyl-2-picrylhydrazyl (DPPH) stable free radical scavenging activity
–
–
EC50 ¼ 27 mg/mL
Similar as a-tocopherol with EC50 of 23 mg/mL
Selective vasodilation effect on the basilar arteries Promote neurite outgrowth Antioxidant activity
in vivo
Selectively accelerate cerebral blood flow through dilatation of not specified the basilar artery without lowering systemic blood pressure
10 5.5– 10 4 M
EC50 ¼ 11.8mM
in vitro
Showed nerve growth factor (NGF)-dependent neurite outgrowth promoting activity against PC12D cells
–
in vitro
– Scavenging effects on generation of intracellular reactive oxygen species (ROS), increments of intracellular glutathione (GSH) level, and inhibitory effects on lipid peroxidation (LPO) in human fibrosarcoma HT 1080 cells (a) Na þ /K þ ATPase and (b) isocitrate lyase inhibitory assay –
5 mg/mL for ROS and GSH, 50 mg/ mL for LPO –
– (a) Inhibited the proliferation of HL-60 cells, and induced apoptosis, (b) induced apoptosis and (c) downregulated Bcl-xL, upregulated Bax, activated caspase-3, and cleaved poly (ADPribose) polymerase (PARP) Inhibition of endothelin (ET-1) binding to its receptors –
a &b: 12.5– (a and b) 50mM and Sargachromanol E isolated 50mM c:12.5 (c) 25 mM through bioassay-guided & 25 mM fraction
Inhibit Na þ /K þ ATPase and isocitrate lyase Anticancer activity
Nahocol A (most active among Endothelin nahocols and isonahocols) antagonistic activity
in vitro
in vitro
in vitro
in vitro
–
mg/mL
–
Applied 100 mL of 1 mg/mL sample –
For carotid artery, EC50 ¼140mM Selective index (SI, EC50 for carotid/EC50 for basilar): 11.9 ED50 ¼9mM Promotes neuronal differentiation and survival of PC12D cells. 5 mg/mL for ROS and Most active sargachromanol E 87.2% for ROS GSH, 50 mg/mL for LPO (a) IC50 ¼2.0 mg/ml Most active (b) IC50 ¼ 48.4 mg/ml (a) Sargachromanol M (b) Sargachromanol H
IC50 ¼ 76.1mM for ETA, bovine aorta;IC50 ¼ 21.6mM for ETB, porcine lung
Potential to treat acute renal insufficiency, acute myocardial infarction, hypertensi-on and arteriosclerosis.
Reference
Kamei and Tsang (2003) Choi et al. (2007) Hur et al. (2008)
Reddy and Urban (2009) Afolayan et al. (2008) Kim et al. (2008a)
Seo et al. (2007) Park et al. (2008b)
Tsang et al. (2005) Lee and Seo (2011)
Chung et al. (2011)
Heo et al. (2011)
Tsuchiya et al. (1998)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
0 and 3 mg/ mL 0 and 3 mg/ mL
Promote neurite outgrowth AntiAlzheimer’s Treat hyperproliferative skin disease Anticancer activity
Sargachromenol (similar activities as sargaquinoic acid not listed) Sargachromanols
Dose range
– Promoted the nerve growth factor (NGF)-induced survival support on neuronal PC12D cells and abated neuronal PC12D cell death even in the absence of NGF Enhanced neurite-regeneration and protected PC12D cells – from hydrogen peroxide (H2O2)-induced oxidative stress Mechanism study for the neurite outgrowth promotive activity – of Sargaquinoic acid
Neuroprotin vitro ective activity in vitro
Sargahydroquinoic acid (similar activities as sargaquinoic acid not listed)
Administration (in vivo)
IC50 ¼ 0.11 mg/mL for LPO IC50 ¼ 11.0 mg/mL for DPPH
–
Iwashima et al. (2005)
0–10 mM
(a) 3, 6, 10 mM (b) 6, 10 mM (c) 6, 10 mM
Potential for prevention of osteoporosis
Komai et al. (2006)
–
CC50 ¼ 32 mM (a) IC50¼ 2.0 mM (b) IC50 ¼2.6 mM 3–30 mg/kg
a: CC50/IC50 ¼ 16 a: CC50/IC50 ¼ 12 CC for cytotoxic A decrease in the hexosamine level of the gastric mucosa was slightly improved Only one dose reported Mode of action was evaluated. Synergistic inhibitors with ganciclovir, an anti-HCMV drug
Iwashima et al. (2005) Mori et al. (2006)
Most active among the isolated thunbergols
Seo et al. (2006)
Most active within the isolated compounds
Horie et al. (2008)
Antioxidant activity
in vitro
Antioxidant activities against lipid peroxidation (LPO) and radical scavenging effect on DPPH
140 ,150 -dihydroxysargahydroquinone
Prevention of bone diseases
in vitro
140 ,150 dihydroxysargaquinone (similar activities as 140 ,150 dihydroxysargahydroquinone not listed)
Antiviral activity
in vitro
Antiulcer effects (Gastric)
in vivo
– (a) inhibition on the differentiation of osteoclast progenitors into osteoclast-like cells, (b) inhibition of pit formation, (c) inhibitory effects on the survival of osteoclast-like cells – Antiviral against human cytomegalovirus (HCMV); (a) the compound was added to the medium during viral infection and (b) through the incubation hydrochloric acid/ethanol induced rat ulcer Oral
Antiviral activity
in vitro
(a) inhibited early events of human cytomegalovirus (HCMV) replication including the virus (b) adsorption and (c) penetration, (d)virucidal action on the virus particles exposure for 3 h
Antioxidant activity
in vitro
–
Antibacter-ial activity
in vitro
(a) DPPH radical scavenge activity, (b) scavenging activity on authentic ONOO , (c) inhibition against the generation of ONOO from morpholinosydnonimine Antibacterial activities against Staphylococcus aureus
30 mg/kg (a) 1 and 10 mM (b) 0–10 mM (c) 0–10 mM (d) 0–10 mM –
–
–
Anti-diabetic (Type 2)
in vitro
Induced transcriptional activation of peroxisome proliferatoractivated receptor gamma (PPARg)
–
0–5 mg/mL
5 mg/mL (active as the positive control)
Anticoagulant activity
in vitro
Prolonged activated partial thromboplastin time (APTT), – prothrombin time (PT) and thrombin time (TT) Increase coagulation time (CT) and bleeding time (BT) in mice Gastric perfusion Reduced the elevated platelet cytosolic calcium level induced – by ADP Prolonged APTT, PT, and TT in rats Gastric perfusion Scavenging activity against superoxide anion radicals –
0–2 mg/mL
0.5–2 mg/mL
0–40 mg/kg
10–40 mg/kg
0–2 mg/mL
1 and 2 mg/mL
0–40 mg/kg
10–40 mg/kg
–
IC50 ¼ 1.0 mg/mL
110 ,120 -Dihydro-110 ,120 dihydroxysargaol (similar activities as 140 ,150 dihydroxysargahydroquinone not listed) Thunbergol A
2-Methyl-6-(3-methyl-7-oxo2,5-octadienyl)-1,4benzoqui-none Meroterphenols A-D
Phlorotanins phlorotanin fraction from S. thunbergii (MW410,000)
in vivo in vitro in vivo Phlorotanin fraction from S. kjellmanianum
Phytosterols Fucosterol (most abundant in Sargassum)
Antioxidant activity
in vitro
–
Intraduodenal –
0–30 mg/kg
30 mg/kg (a) 1 and 10 mM (b) 0.2 and 1 mM (c) 0.2 and 1 mM (d) 0.2–10 mM (a) EC50 ¼ 30 mg/mL (b) 5 mg/mL (c) 5 mg/mL MIC ¼ 2 mg/mL MBC¼ 64 mg/mL
Kim et al. (2011)
Large phlorotanins are active (in vitro and in vivo).
Li et al. (2007)
Wei et al. (2008)
Inhibited the generation of malondialdehyde in mouse liver and decreased membrane swelling of mouse liver mitochondria
Oral
5 g/kg
5 g/kg
Inhibiting mouse liver lipid peroxidation. Only single concentration tested.
Cholesterol lowing activity
in vivo
Inhibited the lymphatic absorption of cholesterol in rats
Intragastric
25 mg per rat
Only one dose tested
in vitro
Displace cholesterol from bile salt (taurocholate) micelles.
–
25 mg per rat 0.1–2.0 mM
0.1–2.0 mM
Anti-diabetic activity
in vivo
Decrease serum glucose concentrations and inhibited of sorbitol accumulations in the lenses in (a) streptozotocin or (b) epinephrine-induced diabetic rats
Oral
Equimolar binary mixture with cholesterol –
Anticancer activity Antioxidant activity
in vitro
Cytotoxicity against P388 cell line
in vitro
DPPH radical scavenging activity
in vivo
Increased activity of antioxidant enzymes, hepatic cytosolic Oral superoxide dismutase, catalase and glutathione peroxidase by in CCl4-intoxicated rats
–
(a) 30 30mg/kg (b) 0–300 mg/kg –
IC50 ¼ 0.7 mg/mL
–
–
–
IC50 4250 mM
Low in vitro activity
30 mg/kg
30 mg/kg
Only one dose tested
Nakai et al. (2006) Wei et al. (2003)
Ikeda et al. (1988)
Lee et al. (2004)
Tang et al. (2002) Ham et al. (2010) Lee et al. (2003)
601
in vivo
(a) 30 mg/kg (b) 300 mg/kg
Hayashi et al. (2006)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
–
140 ,150 -dihydroxysargahydroquinone
602
Table 4 (continued ) Compounds
Bisnorditerpenes Hedaol B
Farnesylacetones 6,10,14-Trimethyl-5,10pentadecadiene-2,12-dione; (E,E)-form and (E,Z)-form
6,10,14-Trimethyl-5,10,13pentadecatriene-2,12-dione; (E,E)-form
Miscellaneous compounds Loliolides
Sargafuran
Miscellaneous compounds Fucoxanthin(FC)
in vivo/ Model in vitro
Administration (in vivo)
Dose range
Active Concentration
Comment
Reference
Anticancer
in vitro
Cytotoxicity against P388 cells
–
–
IC50 ¼ 2.2 mg/mL
–
Takada et al. (2001)
Vasodilatation effect
in vivo
Vasodilatation effect on the (a) basilar and (b) carotid arteries Not specified of rabbits
EC50, (a) 1.22 mM (b) 13.7 mM
–
Park et al. (2008a)
–
(E,E): 10 6– 10 5 M (E,Z):10 5.5– 10 4.5 M –
–
Ryu et al. (2003)
EC50, (a) 3.72 mM (b) 14.5 mM (a) IC50 ¼ 48 mM (b) IC50 ¼ 23 mM
AntiAlzheimer’s
in vitro
Fibrinolytic activity
in vitro
Shortened the initiation time of single chain urokinase-type plasminogen activator activation and increased the rate of activation,
–
0–15.9 mM
Half-maximal effect at 0.85 mM
more active than the other glycolipids tested in this paper
Wu et al. (2009)
Antimicrobial activity
in vitro
Antibiotic against (a) Staphylococcus aureus, (b) S. epidermidis and (c) Pseudomonas aeruginosa
–
0–0.5 mg/ mL
MIC (a) 0.1 mg/mL (b) 0.5 mg/mL (c) 0.5 mg/mL
Concentrations may not be the final concentration in the test
Ferreira et al. (2004)
Antioxidant activity
in vitro
(a) DPPH, (b) H2O2 radical and (c) intracellular reactive oxygen – species scavenging, protect H2O2-induced cell damage
Active on high concentrations
No EC50 caculated
Yang et al. (2011)
Antibacterial activity
in vitro
Antibacterial activity against Propionibacterium acnes
–
(a, c and d) 0–500 mM, (b) 0– 250 mM –
MIC ¼ 15 mg/mL
Low cytotoxic to skin cells, maybe useful for skin care
Kamei et al. (2009)
Anti infamma-tory
in vitro
Decease the expression of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) protein in RAW264.7cells Reduce the concentrations of nitric oxide (NO), prostaglandin (PG)-E2 and tumour necrosis factor (TNF)-a Antiinflammation on endotoxin-induced uveitis in rats, leucocyte and protein infiltration, NO, PGE2 and TNF-a concentrations in rat aqueous humour Decreases the blood glucose and plasma insulin concentrations of diabetic/obese KK-Ay mice, down-regulate TNF-a and mRNA in white adipose tissue
–
0–100 mg/ mL
10 and 100 mg/mL
Dose-dependent
Shiratori et al. (2005)
Intravenous injection
0–10 mg/kg
0.1–10 mg/kg
No dose-reponse
Oral
Diets with 0.1% FC, 0.2% FC, 0.1% FC þfish oil
Diets with 0.1% FC, 0.2% FC, 0.1% FCþ fish oil
The combination use of fucoxanthin and fish oil was more effective
in vitro in vivo
Antidiabetic activities and anti-obesity
in vivo
(a) Acetylcholinesterase inhibitory activity (b) Butyrylcholinesterase inhibitory activity
–
Maeda et al. (2007)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Glycolipids Glycerol 1,2-dialkanoates; Glycerol 1-hexadecanoate 2(9Z-octadecenoate), 3-O-a-DGlucopyranoside Dipeptides aurantiamide acetate
Biological activity
Sachindra et al. (2007)
(c) 0.14 mg/mL (d) 2.5 mg/mL
(b) 13.5 times more active than a-tocopherol EC50 (a) 164.6mM (b) 8.94mM (e) 50 mM Antioxidant
in vitro
– For HL-60, HepG-2 and Ht-29 cells, induction on the accumulation of reactive oxygen species (ROS), and induce the cleavage of caspases -3 and -7, and poly-ADP-ribose polymerase (PARP) and decrease of Bcl-xL levels (a) DPPH, (b) 2,20 -azinobis-3-ethylbenzo thizoline-6– sulphonate (ABTS); hydroxyl radical scavenging activity by (c) chemiluminescence assay and (d) electron spin resonance assay; (e) singlet oxygen quenching in vitro
(mM) (a) 0–100 (b) 0–5 (e) 5–50 (mg/mL) (c) 0.1–2.5 (d) 0.25–0.5
HL-60 are more sensitive to FC Kim et al. than HepG-2, HCT-15 and Ht- (2010) 29 cells 15 and 30 mM
(a) Reduce viability of human colon cancer cells, Caco-2, HT-29 – and DLD-1, (b) induce DNA fragmentation,(c) suppress Bcl-2 protein in Caco-2 cells and (d) decrease Caco-2 cells viability together with troglitazone Anticancer
in vitro
(a) 0–15.2 (b) 0–22.6 (c) 22.6 (d) FC 3.8 þTG 10 (mM for all) 0–30 mM
(a) more active in Caco-2 cells Hosokawa (a) 7.6 and 15.2 et al. (b) 11.3 and 22.6 (2004) (c) 22.6 (d) FC 3.8 þTG 10 for 48 h (mM for all)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
603
ratios and linear arrangements (Fig. 3). As alginates can absorb water and form viscous gum, they have been used as thickeners, stabilisers and gelling agents in the food and pharmaceutical industries. Alginates have been considered to be without any nutritional value, however, modern pharmacological research found alginates isolated from Sargassum had anticancer (in vivo), antiviral (in vitro) and hypolipidemic (in vivo) activity (Table 5). It is important not to overlook these pharmacological effects, as these bioactive alginates may confer health benefits or risks to the many people who consumed them regularly as food additives. The alginates from the genus Sargassum were found to have a wide range of molecular weights (13–330 kDa) (Table 4), which may depend upon the species, season, age, part of plant used for extraction and the extraction method. Alginates are water soluble, so they can be extracted directly by hot water. Sodium alginates form insoluble precipitates at acidic pH and with calcium salts, but they are stable in solution between pHs 6 and 9. Therefore, the alginates were often extracted with K2CO3, which can significantly increase the yield. Interestingly, the alginates directly extracted from Sargassum species using hot water often had lower molecular weights (13–33.4 kDa) (Fujihara et al., 1984a, 1984b; Gu et al., 1998; Mao et al., 2004). While the base digestion often yielded significantly larger alginates (194– 330 kDa) (Fujihara and Nagumo, 1992; Sousa et al., 2008, 2007). Therefore, we suspect that the small MW alginates may be in the intercellular space and relatively easy to extract compared to the large alginates, which form parts of the cell walls of the brown algae. Comparison of the biological activity between these small and large alginates requires investigation and details about the extract’s composition need to be included in such studies. 4.4. Other compounds Other compounds reported in Sargassum include phytosterols, bisnorditerpenes, farnesylacetones, polyunsaturated fatty acids, glycolipids, arsenosugars, dipeptides, iodoamino acids, loliolides, octatrienes, etc. (Table 3). Compared to the meroterpenoids, phlorotanins, polysaccharides in Sargassum, there are fewer reports on these constituents.
4.4.1. Phytosterols Phytosterols such as saringosterol and fucosterol have been identified in some species (Wang et al., 1997; Ayyad et al., 2003). Fucosterol, a characteristic component of brown seaweeds, was found to be the major phytosterols (485%) in S. despiense, S. latifolium and S. carpophyllum (Karawya et al., 1987; Wang et al., 1997). Fucosterol could inhibit the cholesterol absorption in rats by displacing cholesterol from bile salt micelles (Ikeda et al., 1988) (Table 4). Although fucosterol had very low in vitro antioxidant activity (Ham et al., 2010), it exhibited in vivo antioxidant activity by increasing activity of antioxidant enzymes such as hepatic cytosolic superoxide dismutase, catalase and glutathione peroxidase in CCl4intoxicated rats (Lee et al., 2003). Fucosterol was also identified as an antidiabetic compound (Lee et al., 2004). When administered orally, fucosterol decreased serum glucose concentrations and inhibited sorbitol accumulations in the lenses of diabetic rats.
4.4.2. Bisnorditerpenens and farnesylacetones With similar structures, some bisnorditerpenes and farnesylacetones have been identified in Sargassum (Kusumi et al., 1979a; Shizuri et al., 1982; Takada et al., 2001) (Fig. 4). So far, only cytotoxicity has been reported for the bisnorditerpenes such as hedaols A, B, and C in Sargassum (Takada et al., 2001). Farnesylacetones in Sargassum showed a moderate in vivo vasodilatation effect on the basilar arteries of rabbits (Park et al., 2008a) and
604
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
O
O
HO
OH
O Sargaquinoic acid
δ-Tocotrienol
O HO
O
OH
O
OH
OH
O Sargahydroquinoic acid
Sargachromenol OH HO
OH
OH
OH
O
OH
OH Sargachromanol E
14', 15'- dihydroxysargahydroquinone
OH
HO OH O
O
O OH
HO
11', 12'-Dihydro-11',12'-dihydroxysargaol OH
O HO
OH
O
OH O
Nahocol A O Thunbergol A Fig. 1. Structures of meroterpenoids.
HO
O HO
OH
HO
HO
HO
HO
OH
O
O OH
HO
HO
OH OH O OH HO
OH
HO HO
HO O
HO
HO
HO O HO
HO O
O OH
HO
OH HO
HO
HO
OH OH HO
Fig. 2. Structures of simple phlorotanins.
some potential to treat Alzheimer’s disease with in vitro cholinesterase inhibitory activity (Ryu et al., 2003).
4.4.3. Polyunsaturated fatty acids and glycolipids Sargassum is also a rich source of polyunsaturated fatty acids and glycolipids, which are functional lipids with proven nutritional
significance (Sanina et al., 2004). Long-chain omega-3 and -6 fatty acids such as eicosapentaenoicacid (EPA, 20:5n-3), arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3) are particularly rich in some Sargassum species (Terasaki et al., 2009; van Ginneken et al., 2011). Glycolipids in Sargassum includes glucosylglycerols, galactosylglycerols and sulphonoglycolipids (Son et al., 1992; Qi et al., 2004; Arunkumar et al., 2005; Kim et al., 2007b;
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
605
L-guluronic acids
CH
O COOH OH OH
O O O COOH
O3SO OH
O OH
OH
O3SO OH
O
O O OH
COOH
O CH
O
O COOH OH OH
O
O O OH D-mannuronic acids
Fig. 3. Structures of fucoidan and alginate.
Wu et al., 2009). Some glucosyldiacylglycerols in S. fulvellum showed fibrinolytic activity in the reaction system of single chain urokinasetype plasminogen activator and plasminogen (Wu et al., 2009). To date, the understanding of the pharmacological activity of the glycolipids in Sargassum is limited. 4.4.4. Arsenosugars Like many marine algae, Sargassum seaweeds contain arsenosugars that are arsenic-containing ribofuranosides (Fig. 4) (Table 3). As arsenosugars may be hazardous to human health (Andrewes et al., 2004), the level of arsenosugars in different Sargassum species used in TCM needs to be further studied and appropriately quantified. 4.4.5. Iodoamino acids Iodoamino acids such as monoiodotyrosine (MIT), diiodotyrosine (DIT), triiodothyronine (T3) and thyroxine (T4) have been identified in S. thunbergii (Ito et al., 1976). The level of MIT and DIT was much higher than T3 and T4 in S. thunbergii. T3 and T4 are the same hormones produced by the thyroid gland central to metabolic regulation, which are also clinically significant for Grave’s disease and Hashimoto’s thyroiditis (Michelangeli et al., 2000). In human thyroid, T4 is produced by combining two moieties of DIT, and T3 is produced by combining one molecule of MIT and one molecule of DIT. MIT and DIT were formed by covalently bound iodine to tyrosine residues in thyroglobulin (Tg) molecules via a reaction with the thyroperoxidase (TPO) (Ekholm and Bjorkman, 1997). It is possible that some compounds mediating the iodoamino acids in Sargassum may affect human thyroid metabolism, and contribute to a traditionally observed pharmacological effect in thyroid disease.
4.4.8. Miscellaneous compounds Loliolides (2), octatrienes (3), kjellmanianone, zeatins (2), 4-methyl-1,2,6,8-tetraazacycloundeca-4,9-diene-3,7,11-trione, sargafuran, sargassumketone, sargassumlactam, vernoniether S, mannitol, fucoxanthin have been also identified in Sargassum (Fig. 4). Loliolides have been identified in S. crassifolium (Kuniyoshi, 1985) and they had moderate in vitro antioxidant activity and showed protective effect for cells against H2O2induced cell damage or apoptosis (Yang et al., 2011). Sargafuran was identified in S. macrocarpum with antibacterial activity against Propionibacterium acnes, which can be developed into new skin care cosmetics to prevent or treat acne (Kamei et al., 2009). Mannitol is commonly found in brown seaweeds, where it is the primary product from photosynthesis (Zubia et al., 2008). Sargassum contains very high level of mannitol, e.g. 12.2% dry weight in S. mangarevense. This polyol has osmotic diuretic effect and is a weak renal vasodilator (Better et al., 1997). The high mannitol content may induce urination and reduce oedema, which are part of the traditional claims for Sargassum. Fucoxanthin is a carotenoid in the chloroplasts of brown algae and has been identified in several Sargassum species (Terasaki et al., 2009). Recent pharmacological research indicates that fucoxanthin had anticancer, anti-inflammatory, antioxidant, antiobesity and antidiabetic activities (Hosokawa et al., 2004; Shiratori et al., 2005; Maeda et al., 2007; Sachindra et al., 2007; Kim et al., 2010). Sargassum contain 1–8 mg of fucoxanthin per g of dry weight with seasonal variation (Terasaki et al., 2009). This compound may make a significant contribution to the traditionally observed therapeutical effects of Sargassum.
5. Pharmacological properties of Sargassum extracts 4.4.6. Dipeptides Three dipeptides, aurantiamide, aurantiamide acetate and diaaurantiamide have been isolated from S. pallidum (Liu et al., 2009). Although aurantiamide acetate was found to have antibiotic activity against Staphylococcus aureus, S. epidermidis and Pseudomonas aeruginosa (Ferreira et al., 2004), little pharmacological study has been done on these dipeptides from Sargassum. 4.4.7. Flavonoids and coumarins Two flavonoids, calycosin and liquiritigenin and two coumarins, melanettin and stevenin have been isolated from S. pallidum (Liu et al., 2009). The levels of these compounds in Sargassum may be very low and the exact values are unknown. Flavonoids and coumarins are commonly known as bioactive compounds (Mabry and Ulubelen, 1980) but their contribution to pharmacological activity of Sargassum may be very limited due to their low concentrations.
The extracts of many seaweeds species have been screened for their pharmacological activity. Among them, Sargassum spp. extracted using various solvents showed anti-inflammatory, anti-allergic, antimicrobial, antiviral, antiplasmodial, anticancer, hypoglycaemic, liver protective, gastric protective, bone protective, skin-whitening, anti-Alzheimer’s and antioxidant activities (Table 6). In these reports, the bioactive compounds responsible for these effects have not been identified. We have examined the activities of these extracts against the bioactive metabolites outlined in Section 4 and extrapolate likely responsible compounds and make suggestions for further investigation. 5.1. Anti-inflammatory activity The relatively lipophilic extracts such as hexane, dichloromethane and 95% ethanol extracts of Sargassum showed in vitro and in vivo anti-inflammatory activity (Dar et al., 2007; Kang
606
Table 5 Bioactive alginates and fucoidan from Sargassum. Polysaccharides
Biological activity
in vivo/in vitro
Model
Administration (in vivo)
Dose range
Active Concentration
Comment
MW
Reference
Anticancer activity
in vivo
Inhibited growth of sarcoma 180 in mice, led to acute tubular necrosis and cause the enlargement of the white pulp of the spleen Prolonged the survival duration of mice suffering from ascetic Sarcome 180 through intraperitoneal injection Increase life span for mice with sarcoma-180 and Ehrlich ascites carcinoma or IMC carcinoma. Reduced size of subcutaneous Sarcoma180 carcinoma tumour in mice antiviral against Herpes Simplex Virus Type 1. Decreased total cholesterol, triglyceride and low density lipoprotein-cholesterol and increase the high density lipoprotein-cholesterol. Increased perfusion pressure, renal vascular resistance, glomerular filtration rate, urinary flow and sodium, potassium and chloride excretion and by reduction of chloride tubular transport.
intraperitoneally or orally
0–100 m/m2/day
50 and 100 m/m2/day
Alginates with different viscosity tested
194, 330 kDa
Sousa et al. (2007)
Intraperitoneal injection
0, 75 mg/kg
75 mg/kg
Only one dose tested
13 kDa
Gu et al. (1998)
Intraperitoneal injection
0–100 mg/kg
12.5–100 mg/kg
–
29kDa
Fujihara et al. (1984b)
Intraperitoneal injection –
0–50 mg/kg
10–50 mg/kg
–
33.4 kDa
–
IC50 ¼ 15 mg/mL
–
26 7 5 kDa
Gastrointestinal injection
0, 200 mg/kg
200 mg/kg
Only one dose tested
16 kDa
Fujihara et al. (1984a) Sinha et al. (2010) Mao et al. (2004)
–
10 mg/mL
10 mg/mL
Alginates with different viscosity tested
194, 330 kDa
Sousa et al. (2008)
Only 28% inhibiton at 200 mg/mL Low cytotoxicity found Mechanism study, only one concentration tested.
n/a
Sokolova et al. (2011)
n/a
Ermakova et al. (2011)
n/a
Costa et al. (2011b)
Five fucoidan fractions tested
n/a
Costa et al. (2011a)
Only one dose test –
n/a
Ale et al. (2011)
Alginates
in vivo
in vivo Antiviral activity Hypolipid-emic activity
in vitro in vivo
Renal effect
in vitro
Anticancer activity
in vitro
Inhibited the growth of RPMI-7951 human melanoma cells
–
0–200 mg/mL
200 mg/mL.
in vitro
Inhibited (a) colony formation in human melanoma (SK-MEL-28) and (b) colon cancer cells (DLD-1) Induced apoptosis by mitochondrial release of apoptosis-inducing factor into cytosol in HeLa cells, decreased the expression of anti-apoptotic protein Bcl-2 and increased expression of apoptogenic protein Bax Inhibited (a) HepG2, (b) PC3 and (c) Hela cells
–
100 mg/mL
–
1.5 mg/mL
100 mg/mL (a) 15–32% (b) 32%–44% 1.5 mg/mL
–
0.1–2.0 mg/mL
Induced enhanced natural killer cell activity in mice Reduced (a) Lewis Lung Carcinoma cell and (b) melanoma B16 cells cell viability
Intraperitoneal injection –
0, 50 mg/kg
Fucoidans
Anticancer activity
in vitro
in vitro
in vivo in vitro
0–1 mg/mL
a: 38%&b: 31% at 2 mg/mL c:IC50 ¼13mM 50 mg/kg (a) 40%, 1 mg/ mL (b) 20%, 1 mg/ mL
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
in vivo
Antiproliferative activity on Hela cells
–
0–2 mg/mL
in vitro
Inhibited growth of HepG2 cells, A549 cells, and MGC-803 cells Inhibited the growth of (a) human Rhabdosarcoma cells and (b) lung cancer cells by fucoidan fraction 20. Inhibited lung cancer cells by fucoidan fraction 25 Inhibited the growth of S180 tumor in mice and enhanced the functions of the immune organs, increase SOD content and glutathione peroxidase activity, decrease malondialdehyde content Inhibited the growth of SPCA-I lung cancer cell, Promoted accentuated morphologic modifications in HeLa cells, caused alterations in the cellular morphology and reduction of the growth, increased in the number of condensed cells, atypical nuclei, number of clusters and blebs at Prolonged the survival duration of mice with Ehrlich carcinoma transplanted Inhibited lung metastases induced by Lewis lung carcinoma
–
0–1 mg/mL
in vitro
in vivo
in vitro in vitro
Anticancer activity
in vivo in vivo
in vivo
in vivo in vivo in vivo
in vivo
Anticoagul-ant activity
in vitro in vivo in vitro in vitro
Anti-inflammatory activity
in vitro
in vivo
Activated the reticuloendothelial system, enhanced the phagocytosis and chemiluminescence of macrophages in mice Prolonged the survival duration mice with Sarcoma-180 ascites tumor. Prolonged the survival duration mice with Sarcoma-180 ascites tumor Fucoidan and sulphated fucoidan fraction enhance antitumor activity against L-1210 leukemia, increase life span Reduced Sarcoma-180 tumor
Anticoagulant with relative clotting factor of 27.47 for the fucoidan Anticoagulant with when in mice
–
n/a
Low in vitro activity
o50 kDa 4100 kDa
Costa et al. (2010) Ye et al. (2008) Nguyen et al. (2008)
Intraperitoneal injection
0, 75, 150 mg/kg
150 mg/kg
–
n/a
Liu and Meng (2004)
–
0–1.2 mg/mL 1.25–160 mg/mL
Low in vitro activity –
n/a
–
IC50 ¼ 423 mg/mL 40 mg/mL
n/a
Liu et al. (2003) Stevan et al. (2001)
Intraperitoneal injection Intraperitoneal injection
0, 20 mg/kg
20 mg/kg
–
19,13.5 kDa
0–50 mg/kg
20 mg/kg
19 kDa
Intraperitoneal injection
0, 20 mg/kg
20 mg/kg
when using with 5-fluorouracil Only one dose tested
Intraperitoneal injection Intraperitoneal injection Intraperitoneal injection
0–50 mg/kg
50 mg/kg
0–250 mg/kg
25 mg/kg
0–300 mg/kg
300 mg/kg
Intraperitoneal injection
50 mg/kg for the active Fr.
50 mg/kg
–
0–180 mg/mL
180 mg/mL
Intravenous injection –
10 mg/ mL 0.1 mL/g 0–100 mg/mL
10 mg/ mL 0.1 mL/g 5–100 mg/mL
–
1%
1%
–
0–5 mg/mL
5 mg/mL
Subcutaneous injection
0, 5 mg/kg
5 mg/kg
Zhuang et al. (1995) Itoh et al. (1995)
19 kDa
Itoh et al. (1993)
–
n/a
Toxic at high concentration Sulphated fucoidan more active
n/a
Nagumo et al. (1988) Iizima-Mizui et al. (1985) Yamamoto et al. (1984)
Only one concentration tested Activity weaker than heparin. 76% of heparin equivalents weaker than heparin Fucoidan 72h, Heparin: 1 h. Active at high concentration
n/a
n/a
Yamamoto et al. (1977)
8–20 kDa
De et al. (2008) Liu et al. (2004) Li and Xu (2004) Abdel-Fattah et al. (1974) Hwang et al. (2011)
n/a 25–950 kDa n/a n/a
n/a 607
Prolonged activated partial thromboplastin time The required time for the clotting of blood plasma of the isolated fucoidan Reduced IL-1beta, IL-6, TNF-a, and NO in the mouse macrophage cell line (RAW 264.7) activated by lipopolysaccharide. Inhibited mRNA expressions of IL-beta, iNOS, and COX-2. Down-regulated of NF-kB in nucleus Restore inflammatory complications in rats with diet-induced hyperlipidemia.
–
61% inhibition 100 mg/mL 1 mg/mL (50%– 81.4%) IC50, a:16.6, b:13.4, c:13.8 (mg/mL)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
in vitro
608
Table 5 (continued ) Polysaccharides
Biological activity Antiinflammatory activity Antioxidant activity
in vivo/in vitro
Model
in vitro
Reduced levels of plasma TNF-a, C-reactive protein, fibrinogen, iNOS, NO, COX-2 and lysosomal enzymes (a) Total antioxidant capacity, scavenging (b) hydroxyl and (c) superoxide radicals, (d) reducing power and (e) ferrous ion chelating
in vitro
Antiviral activity
in vitro
in vitro in vitro
–
(a) n/a (b and c) 0.05– 0.5 (d) 0.01–0.5 (e) 0.1–2.0 mg/mL) (a) 10 mg/mL (b) 0–10 mg/mL 1–5 mg/mL
–
–
–
0–100 mg/mL
–
0–40 mg/mL
40 mg/mL, a:81%, b:85%
–
(b and c) 0.5 (d) 0.5
Kim et al. (2007a)
–
low activity
o50 kDa
IC50 (a) 18 mg/mL (b) 410 mg/mL IC50 ¼ 1.4 mg/mL
CC50/IC50 (a) 4280 (b) 412
19.8 kDa
Ye et al. (2008) Lee et al. (2011)
CC50 41000 mg/mL Active depends on degree of sulphation and MW Inhibit attachment of virus to cells Inhibit virus adsorption
30 7 5 kDa
in vitro
Antiviral against HSV-2, against HSV-2 strain 8702 and clinical strain for virus adsorption Kill HSV-1 and coxsackie virus (CVB 3)
–
0–100 mg/mL
EC50 ¼ 1.85 and 3.5 mg/mL
–
–
–
–
–
–
–
–
Subcutaneous injection
0, 5 mg/kg
IC50 ¼0.8– 50 mg/mL 1.3, 5.5, and 4.1 mg/mL CC50/IC50 (a) 11,000 and (b) 7100 IC50, (a) 1.0,1.4; (b) 3.3, 8.5; (c) 1.2, 5.4 (mg/mL) 5 mg/kg
Gastric perfusion
0–200 mg/kg
50–200 mg/kg
in vivo
in vivo
Preetha and Devaraj (2010) Costa et al. (2011a)
529 kDa
EC50 ¼ 1.5–5.3 mg/mL
in vitro
n/a
Reference
low activity
0–25 mg/mL
Antiviral against HSV-2, HSV-1, and HSV-1 acyclovir resistant strain Antiviral against HSV-1, added to the medium (a) at the same time as the viral infection, (b) after viral infection Antiviral against (a) HSV-1, (b) human cytomegalovirus (HCMV) and (c) Human Immunodeficiency Virus Type 1 (HIV-1) Reduced total cholesterol and triglyceride, reduce LDL and VLDL, elevate HDL in mice Reduce total cholesterol and triglyceride, reduce LDL and VLDL, elevate HDL in mice
Only one concentration tested (a) 90.7 ascorbic acid equivalents
MW
(a) 10 mg/mL (b) 5 mg/mL
–
in vitro
Comment
(e) 2.0 mg/mL
Antiviral against HSV-1
in vitro
Hyoplipid-emic
Active Concentration
in vitro
in vitro Antiviral activity
Antiviral against Herpes Simplex Virus Type 2 (HSV-2) (a) during infection and throughout the incubation; (b) immediately after viral infection Antiviral against Herpes Simplex Virus Type 1 (HSV-1) Inhibition against (a) HSV-1 and (b) Hepatitis A Virus (HAV)
–
Dose range
70–130 kDa
Sinha et al. (2010) Asker et al. (2007)
424 kDa
Zhu et al. (2006)
n/a
Zhu et al. (2004)
CC50 45000 mg/mL CC50 44000 mg/mL –
n/a
Cen et al. (2004) Zhu et al. (2003) Preeprame et al. (2001)
CC50 42440– 6200 mg/mL
229 kDa
Hoshino et al. (1998)
Only one dose tested
n/a
–
n/a
Preetha and Devaraj (2010) Chen et al. (2010)
424 kDa 270 kDa
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
in vitro
Antioxidant with (a) DPPH, H2O2, NO radical scavenging activity and (b) H2O2 scavenging activity in V79-4 cells DPPH radical scavenging activity
Administration (in vivo)
n/a
Josephine et al. (2007) Dias et al. (2008) n/a
at 96–1500
mg/implant
0–1500
mg/implant
5 mg/kg 0, 5 mg/kg
Subcutaneous injection –
200 mg/kg 0–750 mg/kg for dose fixation
Only one dose tested in vitro and in vivo both active
n/a
n/a
Only one dose tested Only one dose tested 5 mg/kg 0, 5 mg/kg
in vitro and in vivo Antivasculogenic effect
in vivo
in vivo
Therapeutic effect on cyclosporine A-induced oxidative liver injury in rat Protection against paracetamol-induced DNA fragmentation and modulation of membrane-bound phosphatases during toxic hepatitis in rats Protection against cyclosporine A-induced renal injury in rats Decreased the vitelline vessel number in implant in chick embryo in vivo
Subcutaneous injection Oral
200 mg/kg Protection against acetaminopheninduced abnormality in rats Liver and renal protection
in vivo
Oral
0, 200 mg/kg
Only one dose tested
n/a
Raghavendran and Srinivasan (2008) Josephine et al. (2008) Raghavendran et al. (2007)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
609
et al., 2008; Lee et al., 2008). The in vivo anti-inflammatory activity can be observed through both topical application and intraperitoneal injection of the extracts. Although fucoidan from Sargassum showed in vivo and in vitro anti-inflammatory activity (Preetha and Devaraj, 2010; Hwang et al., 2011), this hydrophilic polysaccharide is unlikely to be responsible for the anti-inflammatory activity of the lipophilic extracts. The anti-inflammatory activity in these lipophilic extracts is more likely to be attributed to the liopophilic components such as phytosterols, polyunsaturated fatty acids, fucoxanthin and meroterpenoids. The constituents need to be evaluated in further anti-inflammatory research. 5.2. Anti-allergic activity In vitro studies on mast cells indicated the anti-allergic potential of Sargassum extracts (Na et al., 2004, 2005; Lee et al., 2006), which might be useful to allergic diseases like atopic dermatitis. Sargasssum extracts (at a relatively high concentration of 100 mg/mL) exerted moderate inhibitory activity (about 50%) against compound 48/80-induced histamine and b-hexosaminidase release from rat peritoneal mast cells (Na et al., 2004; Lee et al., 2006). In vivo study suggested that oral administration of Sargassum extract could protect mice from the IgE-mediated local allergic reaction (Na et al., 2005). NMR analysis suggested that the active compounds had sugar moieties and long aliphatic chains like glycolipids (Na et al., 2005), which requires further investigation. 5.3. Antimicrobial, antiviral and antiplasmodial activities Sargassum extracts have broad antimicrobial activities against bacteria and fungi (Morales et al., 2006). The lipophilic fraction (ethyl acetate) of extracts showed stronger antimicrobial activity than the hydrophilic components (water). The activity may be attributed to meroterpenoids such as 2-methyl-6-(3-methyl-7oxo-2,5-octadienyl)-1,4-benzoquinone (Horie et al., 2008). Sargassum extracts exerted in vitro antiviral activities against Human T-cell Lymphotropic Virus Type 1 (HTLV-1) (Romanos et al., 2002), Human Immunodeficiency Virus Type 1 (HIV-1) (Ahn et al., 2002) and vaccinia virus (Premanathan et al., 1994). The antiviral activity of HTLV-1 by S. vulgare water extract is likely to be linked to the fucoidan (Table 5). The antiviral activity against HIV-1 and vaccinia virus need to be further researched and the potential for novel antivirals from Sargassum determined. In vitro screening of seaweeds for promoting production of interferon b (INF-b), which has strong antiviral effect by inducing antiviral action in cells susceptible to viruses, suggested methanol extract of S. hemiphyllum had antiviral activity (Nakano et al., 1997). Two active substances with less than 3000 molecular weight, heat stable and noncytotoxic characters were identified but the structures were not elucidated. The more active compound showed in vivo antiviral activity for mice infected with Aujeszky’s disease virus (Nakano and Kamei, 2005), which now needs to be characterised. The dichloromethane fraction of a dicholormethane/methanol extract of S. hemiphyllum exerted potent in vitro antiplasmodial activity (IC50 ¼2.8 mg/mL) against Plasmodium falciparum (Lategan et al., 2009). The activity of this lipophilic fraction is likely due to the bioactive meroterpenoids like sargaquinoic acid (Afolayan et al., 2008). In vivo studies are required to evaluate the antiplasmodial potential of Sargassum. 5.4. Anticancer activity In vitro and in vivo studies suggested Sargassum extracts had anticancer activity (Table 6). Khanavi et al. (2010) found the
610
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Fig. 4. Structures of other compounds in Sargassum.
hexane fraction of methanol extract of S. swartzii had in vitro cytotoxicity against Caco-2 and T47D cells and increased the percentage of apoptotic cells among these cells. The activity of
this lipophilic fraction may in part be due to the meroterpenoids (Table 4), which needs to be investigated further. Most anticancer studies were carried out using the Sargassum water extracts
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
611
(Yamamoto et al., 1981, 1974; Matsuda et al., 2005; Zandi et al., 2010). which exerted in vitro and in vivo anticancer activities and in vivo activity can be observed in both oral administration and intraperitoneal injection of Sargassum water extracts. The in vivo anticancer activity may be attributed to active polysaccharides (Table 5), but there may be other smaller active constituents, as the intact polysaccharides are poorly absorbed through oral administration.
rat liver (Table 6). The antioxidant activity may also play an important role for the protective activity against HCl–ethanol induced gastric mucosal injury in rats (Raghavendran et al., 2004a). A number of compounds in Sargassum summarised in Tables 4 and 5 such as meroterpenoids, phlorotanins and fucoidans may all contribute to the antioxidant activity of Sargassum extracts.
5.5. Liver and bone protective activities
6. Safety, traditional and modern issues
Sargassum extracts have potential to protect vital organs such as liver and bone. In vivo studies suggested oral administration of Sargassum ethanol or water extracts can protect rat liver from acetaminophen induced toxic hepatitis and hepatic oxidative stress, and reduced CCl4 induced acute elevation of serum glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transminase (GOT) in rats (Wong et al., 2000; Raghavendran et al., 2006, 2004b). The doses ranges tested in these studies were very limited and the active dose reported was very high (200–600 mg/ kg). More recently, Raghavendran et al. (2007) researched the polysaccharides fraction of Sargassum extract and suggested the hepatoprotective activity was due to the bioactive fucoidan. A series of in vitro and in vivo studies suggested S. horneri water extracts has anabolic effects on bone calcification in rat femoral tissues (Yamaguchi et al., 2001; Uchiyama and Yamaguchi, 2002a, 2002b, 2003; Uchiyama et al., 2004). Oral administration of S. horneri water extracts could prevent bone loss and stimulate bone calcification in rats (Yamaguchi et al., 2001; Uchiyama and Yamaguchi, 2003). In vitro study of S. horneri water extracts revealed two active components promoting bone protection (Uchiyama et al., 2004). One active component increasing calcium content was identified with approximate molecular weight of 1000 but this compound was not heat stable (80 1C for 30 min) and its structure has not been elucidated. The other heat stable component suppressing osteoclastic bone resorption (molecular weight more than 50,000) was speculated to be a peptide. Further research is needed to elucidate the structures of these compounds. To date, 140 ,150 -dihydroxysargahydroquinone and other meroterpenoids have been identified in Sargassum suppressing bone resorption (Komai et al., 2006), which may contribute the bone protective activity of Sargassum extracts.
For ‘‘Hai Zao’’ ( , Sargassum), it has been clearly stated ‘‘Not to be used with licorice ( , Glycyrrhizae Radix et Rhizoma)’’ in traditional and modern TCM documents such as ‘‘Compendium of Materia Medica’’ ( ) and the Chinese pharmacopeia (cited in the 1963 version). In most cases, the combination of these two medicines is forbidden due to possible adverse effects. However there is little reported clinical evidence and no biochemical support for these purported adverse effects. Interestingly, ‘‘Hai Zao Yu Hu Tang’’ (Table 2), a classical Chinese prescription formally recorded in Summary of Surgical Medicine ( ) in 1617, have used licorice, Sargassum and other six ingredients together. This prescription has been used continuously for centuries to treat diseases such as goitre and scrofula. Similar warnings of adverse effects with licorice are not found for another brown seaweed, Kun Bu ( ), traditionally used in TCM (also named as Laminaria Thallus or Ecklonia Thallus in Chinese Pharmacopeia). This traditional caution regarding the use of licorice and Sargassum together may be explained by opposing effects on immune function and needs to be investigated in more detail. Sargassum should be generally recognised as non toxic. The estimated LD50 of oral administration of seven Sargassum species including S. pallidum, S. fusiforme, S. thunbergii, S. horneri, S. polycystum, S. hemiphyllum, and S. kjellmanianum for mice was more than 40 g/kg of body weight (Cui et al., 1997). No acute toxicity in mice was observed after oral administration of 5 g/kg of body weight of dichloromethane, ethanol and boiling water extracts of S. fulvellum and S. thunbergii (Kang et al., 2008). No acute toxicity in mice was observed for intraperitoneal injection of 500 mg/kg of body weight of hexane, sequential methanol and butanol extracts of S. wightii (Dar et al., 2007). Seafood may contain high level of arsenic and arsenosugar is a major form of arsenic in Sargassum. Arsenosugar is not acutely toxic, but there is a possibility of slight chronic toxicity (Andrewes et al., 2004). Most of the arsenic in Sargassum could be removed by soaking in warm water for more than 30 min and discarding the water extracts (Katayama and Sugawa-Katayama, 2007). An in vitro study suggested after soaking with warm water the remaining arsenic could mostly be excreted without being absorbed via digestive tract (Sugawa-Katayama et al., 2010).
5.6. Other pharmacological activity Other pharmacological activity of Sargassum extracts include skin-whitening, anti-Alzheimer’s, hypoglycaemic, gastric protective and antioxidant activities (Table 6). Sargassum extract exerted in vitro inhibitory activity against tyrosinase and melanin production (Cha et al., 2011; Chan et al., 2011), which could be developed to a skinwhitening agent in cosmetics industry. An in vivo study suggested 95% ethanol extract of S. fusiforme (through gastric perfusion) could reduce blood glucose in diabetes mice (Zhang, 2006), however the concentration test was extremely high (350–700 mg/kg). Fucosterol, the major phytosterol in Sargassum, may have some contribution to this anti-diabetic activity (Lee et al., 2004). A number of reports suggested both lipophilic and hydrophilic Sargassum extracts had in vitro and in vivo antioxidant activity. The in vitro antioxidant activity against DPPH radical and lipid peroxidation have been reported for different Sargassum extracts such as 0.5% Na2CO3, enzymatic, methanol, ethyl acetate and dichloromethane extracts (Mori et al., 2003; Park et al., 2005; Shanab, 2007; Han et al., 2008). In vivo study suggested oral pretreatment with Sargassum extracts could inhibit reduction of free radical scavenger enzymes in acetaminophen induced lipid peroxidation in rats and lower the CCl4 induced lipid peroxidation in
7. Future research for Sargassum with focus on thyroid health The pharmacological activity of Sargassum extracts and research of its bioactive constituents provide scientific evidence which underpins the traditional therapeutical claims made for Sargassum, such as treating scrofula, sore throat, cough and phlegm stasis, dropsy, furuncle (anti-microbial, antiviral and anti-inflammatory activities), hepatolienomegaly (liver protection) and induce urination (possibly due to high mannitol content) (Fig. 5). However, to-date one of the most important TCM claims for Sargassum, treating thyroid related diseases (e.g. goitre), has not been sufficiently researched. Thyroid is one of the largest endocrine glands in human body. Importantly, by producing thyroid hormones it controls how quickly
612
Table 6 Pharmacological activities of Sargassum extracts. Type of extract
Species
in vivo/ Model in vitro
Administration (in vivo)
Dose Rang
Antiinflammatory activity
95% Ethanol Ext.
S. horneri, and S. yezoense
in vitro
Inhibition of NO and PG-E2 in RAW264.7 cells
–
DCM Ext.
S. fulvellum
in vivo
Inhibition of an inflammatory symptom of mouse ear oedema
Topical
5–20 mg/mL 20 mg/mL NO for NO 50 mg/ 50 mg/mL, PGE2 mL for PGE2 0.4 mg/ear 79.1%.
DCM Ext. Hexane Ext.
S. thunbergii S. wightii
in vivo in vivo
Anti-inflammatory against paw oedema in rats.
S. thunbergii
in vitro
S. hemiphyllum
in vitro
Topical Intraperitoneal injection
0.4 mg/ear 100 mg/kg
72.1%. 80% for summer collection 34–59% for winter collection
Inhibition of histamine release in rat peritoneal mast cells –
100 mg/mL
49.8% inhbition
Inhibited histamine and b-hexosaminidase release from – rat peritoneal mast cells. Inhibited interleukin (IL)-8 and TNF-a release from HMC-1 cells, inhibited the increase of NF-kB protein levels, transcription factor of TNF-a from 293T cells. Inhibition of passive cutaneous anaphylaxis reaction in Oral mice induced by IgE Inhibited the histamine release from rat peritoneal mast – cells Reduced IL-8 in the human mast cell line
10–1000 mg/ mL
active on the high concentration tested
10–1000 mg/ mL 100 mg/mL
100 and 1000 mg/mL (1) Inhibited histamine, 49.85%; IL4, 6, 8. (4) Inhibited histamine, 59.62%; IL4, 6, 8
–
–
–
32 mg/mL
Seq. MeOH Ext. Seq. BuOH Ext. Anti-allergic activity
DCM & MeOH Ext. MeOH Ext.
in vivo S. thunbergii (1) Acetone/ DCM and MeOH Ext.; (2) Hexane Fr.; (3) 85% MeOH Fr. (4) BuOH Fr. (5) H2O Fr.
Antimicrobial
Antiviral activity
in vitro
EtOAc Fr. of MeOH Ext.
S. hystrix and S. filipendula
EtOAc Fr. of 95% EtOH Ext. MeOH:H2O:HCl (1:10:0.15) Ext
S. in vitro kjelimanianum S. filipendula in vitro
Benzene Ext./ Seq. CHCl3 Ext./ MeOH Ext.
S. wightii
MeOH Ext.
S. hemiphyllum in vitro
Active Fr. of above
Water Ext.
S.vulgare
in vitro
Active Concentration
Staphylococcus aureus, Bacillus subtilis, Streptococcus agalactiae, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Shigella flexneri, Candida albicans, Saccharomyces cerevisae, Aspergillus niger, and Trichophyton mentagrophytes Antibacterial against Staphylococcus aurens
Comment
Reference
Only one concentration for PGE2 Only one concentration tested
Kang et al. (2008)
Only one concentration tested to compare seasonal variation
Dar et al. (2007)
Only one concentration tested –
Lee et al. (2006) Na et al. (2005)
Only one concentration tested
Na et al. (2004)
3.13–6.25 mg/mL
–
Morales et al. (2006)
32 mg/mL
Only one concentration tested Very high concentration tested
Xu et al. (2002a) MartinezLozano et al. (2000) Sastry and Rao (1994)
– Antifungal against Aspergillus niger, A. flavus, A. parasiticum, Penicillum spp., Fusarium oxysporum, Candida albicans, C. rugosa. – Staphylococcus aureus, Escherichia coli, Proteus vulgaris, Psedomonas aeruginosa, Salmonella paratyphi A., S. typhi, S. typhimurium
30ug of extract on 6 mm discs
CHCl3 extract exhibited the greatest antibacterial activity
–
Promote production of interferon b (IFN-b) in MG-63 cells –
–
in vivo
Mice infected with Aujeszky’s disease virus
Not stated
6.3–100 mg/ kg
11.25 for IFN-b relative productivity 100 mg/mL, 7 out of 10 mice survived
in vitro
Antiviral in HeLa cells co-cultured with Human T-cell Lymphotropic Virus Type 1 (HTLV-1) infected T-cell line
–
0–5%
Concentration used not stated Antiviral activity by modulating host immunodefense system –
in vitro
22.5 200mg/ 200mg/mL mL
78.8% syncytium inhibition at 5% concentration
Nakano et al. (1997) Nakano and Kamei (2005)
Romanos et al. (2002)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Pharmacological activity
MeOH Ext.
S. connfusum and S. hemiphyllum
in vitro
Inhibition of HIV-1 (a) integrase, (b) reverse transcriptase. –
a: 200 mg/mL b: 10, 25, 100 mg/mL
a: 200 mg/mL b: 100 mg/mL
70% EtOH Ext.
S. wightii
in vitro
Reduce plaques formed by vaccinia virus in chick embryo – fibroblast cell culture
–
CC50 ¼ 132 mg/mL EC50 ¼ 38 mg/mL Selective index ¼3.44
EtOAc Fr. most potent Ahn et al. (2002) inhibitory activity, indicate activity not from polysaccharides – Premanathan et al. (1994)
Antiplasmodial activity
DCM Fr. of MeOH S. heterophyand DCM Ext. llum
in vitro
Antiplasmodial activity against Plasmodium falciparum
–
–
IC50 ¼2.8 mg/mL
Anticancer
Water Ext.
S. oligocystum
in vitro
K562 and Daudi human cancer cell lines
–
0–500 mg/mL
Hexane Fr.of MeOH Ext.
S. swartzii
in vitro
Cytotoxicity against HT-29, Caco-2, T47D, MDA-MB468 and NIH 3T3 cell lines
–
–
Hot water Ext.
S. horneri
in vitro
Meth-A cell line
–
5–25 mg/mL
about 60% inhibition at – 500 mg/mL Apoptosis observed IC50 o 100 mg/mL for Caco-2 cells and T47D cells 25 mg/mL –
in vivo
Meth-A tumor bearing BALB/c female mice
Oral
Anticancer against the growth of subcutaneously implanted sarcoma-180 solid tumor in mice Anticancer on the growth of sarcoma-180 cells subcutaneously implanted into mice
Intraperitoneal injection Intraperitoneal injection Intraperitoneal injection
0.01% or 0.05% 105 mL/mouse 0.1 and 0.5 mg/mouse 10 mg/kg
Bone protection
S. fulvellum
in vivo
Water Ext.
S. kjellmanianum
in vivo
EtOH Ext.
S. polycystum
in vivo
Protection against acetaminophen induced toxic hepatitis Oral in rats
200 mg/kg
EtOH Ext.
S. polycystum
in vivo
Protection against acetaminophen induced hepatic oxidative stress in rats
Oral
200 mg/kg
Water Ext.
S. henslowianum and S. siliquastrum
in vivo
Reduced CCl4-induced acute elevation of serum glutamic Oral pyruvic transaminase (GPT) and glutamic oxaloacetic transminase (GOT) in rats.
150, 300, 600 mg/kg
Water Ext.
S. horneri
in vitro
Rat femoral-diaphyseal and –metaphyseal tissue
25 mg/mL
–
Skin-whitening agent
10 mg/kg
Only one concentration tested –
Yamamoto et al. (1974) Yamamoto et al. (1981)
Only one concentration tested
Raghavendran et al. (2006)
Inhibition of TNF-a Protected the liver structural integrity Reduced biochemical changes in the serum and liver tissue 150, 300, 600 mg/kg
Only one concentration tested
Raghavendran et al. (2004b)
–
Wong et al. (2000)
Stimulate bone formation Suppress osteoclastic bone resorption Prevent effect on bone loss
Only one concentration tested Only one concentration tested Only one concentration tested
Uchiyama et al. (2004)
S. horneri
in vivo
Reduce bone loss in streptozotocin-Diabetic rats
–
10 mg/100 g
Water Ext.
S. horneri
in vitro
Rat femoral-diaphyseal and –metaphyseal tissue
–
10, 25, 50 mg/mL
Inhibitory effect on bone resorption
–
Water Ext.
S.horneri
in vivo
In femoral-diaphyseal and –metaphyseal tissues of Rats
Oral
2.5, 5, 10 mg/100 g
10 mg/100 g
–
Water Ext.
S.horneri
in vivo
Bone calcification content and bone alkaline phosphatise Oral activity in rat Enhance alkaline phosphatise in rat femoral-metaphyseal tissues
5%, 1 mL/ 100 g 25, 50 mg/mL
5%, 1 mL/100 g
Only one concentration tested
B16F10 murine melanoma cells Test for inhibition on melanin production. Zebrafish embryo, inhibited both tyrosinase activity and total melanin contents Tyrosinase inhibitory activity against mushroom tyrosinase
100, 250 and 500 mg/mL 100 mg/mL
15.13, 28.71 and 39.93% inhibition 50% inhibition for both in vivo model need further development IC50 ¼19.85 mg/mL
Hexane Fr. of S. polycystum EtOH Ext. o Water Ext. (20 C) S. silquastrum
in vitro in vivo
–
Uchiyama and Yamaguchi (2003) Uchiyama and Yamaguchi (2002b) Uchiyama and Yamaguchi (2002a) Yamaguchi et al. (2001)
50 mg/mL Chan et al. (2011) Cha et al. (2011) 613
in vitro
–
Matsuda et al. (2005)
0.1 mg/mouse
Water Ext.
in vitro
Zandi et al. (2010) Khanavi et al. (2010)
0.05% 105 mL/mouse
50, 100 mg/kg 93.7% for 100 mg/mL
1.0 mg/mL
Mouse marrow cells
Lategan et al. (2009)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Liver protection
Hot water Ext.
–
614
Table 6 (continued ) Pharmacological activity
Type of extract
Species
in vivo/ Model in vitro
Administration (in vivo)
Dose Rang
Treat Alzheimer’s disease
MeOH Ext.
S. macrocarpum
in vitro
Hypoglycemic effect
95% EtOH
S. fusiforme
in vivo
Neurite outgrowth promoting activity in a rat adrenal medulla pheochromocytoma cell line, PC12D
–
1.5–200 mg/ mL
3–12.5 mg/mL
Cytotoxicity observed Kamei and at greater than 25 mg/ Sagara (2002) mL
Reduce blood glucose in diabetes mice
Gastric perfusion
350 mg/kg
reduce from 28 to 23 mmol/L reduce from 26 to 18 mmol/L
–
Zhang (2006)
Maintain the volume/ acidity of gastric juice and improve the gastric mucosa antioxidant
Only one concentration tested
Raghavendran et al. (2004a)
Only one concentration tested
Kim et al. (2008b)
–
Han et al. (2008) Shanab (2007)
700 mg/kg
Reference
S. polycystum
in vivo
Induced gastric mucosal injury in rats
Oral
100 mg/kg
Antioxidant
S.horneri
in vitro
Intracellular reactive oxygen species (ROS) scavenging effect, NO reduction, and increase GSH (glutathione) in mouse macrophage Raw 264.7 cells.
–
20 mg/mL for ROS, 50 mg/ mL for NO and GSH
0.5% Na2CO3 Ext. S. fusiforme
in vitro
DPPH radical scavenging activity
–
DCM Ext.
S. dentifolium
in vitro
DPPH radical scavenging and inhibition of lipid peroxidation (LPO)
–
Inhibit the reduction of free radical scavenger enzymes in acetaminophen induced lipid peroxidation in rats Hydroxyl, DPPH, alkyl radicals scavenging activity and DNA damage protective activity. Hydroxyl, DPPH, alkyl radicals scavenging activity
Oral pretreatment –
Seq. MeOH Ext. of above
70% EtOH Ext.
47%-ROS 47.5%-NO 11%-GSH 3%-ROS 63.5%-NO 23%-GSH 0.3–10 mg/mL About 93% at 10 mg/mL 86%-DPPH 10, 50, 83%-LPO 100 mg/mL100 mg/mL-DCM DPPH 100 mg/mL-EtOH 0.25, 0.5, 82%-DPPH 1 mg/mL-LPO 69%-LPO 100 and active for both 200 mg/kg concentration 5–25 mg/mL Significant activity seen at 25 mg/mL 5–25 mg/mL Significant activity seen at 25 mg/mL
Water Ext. and EtOH Ext. Enzymatic Ext.
S. polycystum
in vivo
S. thunbergii
in vitro
Enzymatic Ext.
S. horneri
in vitro
MeOH Ext.
S. micracanth-
in vitro
–
–
CHCl3/ MeOH Ext. EtOAc Ext. MeOH Ext.
um
Inhibition of lipid peroxidation (LPO) in rat liver homogenates DPPH radical scavenging activity
IC50 ¼0.7, 0.7, 0.37 mg/ mL-LPO IC50 ¼34, 37, 11 mg/ mL-DPPH
in vivo
Lower lipid peroxidation in rat liver
Oral
in vitro
DPPH radical scavenging activity
–
120–1200 mg/kg not stated clearly
14.7% inhibition for 1200 mg/kg 10% (CHCl3) o 10%(EtOAc) 10% (Acetone) 30% (MeOH)
–
–
– – Spin-trapping electron spin resonance spectrophotometer method developed –
Concentration tested not stated
Raghavendran et al. (2005) Park et al. (2005) Park et al. (2004)
Mori et al. (2003)
Yan et al. (1999)
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Gastric protection Hot water Ext.
CHCl3 Ext./Seq. S. thunbergii EtOAc Ext. /Seq. acetone Ext. /Seq. MeOH Ext.
Comment
IC50 ¼72.68 mg/mL
Melanin synthesis inhibitory activity on B-16 cell line
Acetone and DCM Ext.
Active Concentration
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
615
Pharmacological activity
Therapeutical effects in TCM Soften Hard Lumps Dispel Nodes Eliminate Phlegm Induce Urination.
Treat Goitre Scrofula Edema
Hai Zao
Anticancer Anti-inflammatory Antibacterial Antiviral activities
Anticoagulant Antimelanogenic Hepatoprotective Neuroprotective
Traditional Chinese Medicine (TCM)
Future Research
Immunomodulators Treat Thyroid Diseases Hashimoto’s thyroiditis Graves' disease
Sargassum
Bioactive Phytochemicals Polyunsaturated fatty acids Fucoxanthin Phytosterols Meroterpenoids Phlorotanins Fucoidans
Fig. 5. Research of Sargassum past, present and future.
the body uses energy, synthesises proteins, and controls how sensitive the body is to other hormones (Michelangeli et al., 2000). Thyroid disease, is a highly prevalent disease, effecting one in seven people around the world. Goitre, referred to a disease with enlargement of thyroid, can associate with both hypothyroidism and hyperthyroidism (Abraham-Nordling et al., 2005; Babademez et al., 2010). The iodine in Sargassum may help to control or treat endemic goitre, a type of goitre that is associated with dietary iodine deficiency. TCM claims Sargassum can resolve ‘‘hard mass’’ such as goitre. The goitre treated by Sargassum in TCM may be not limited to endemic goitre, but little research has been done in this area. Elevated level of thyroid peroxidise antibody (TPOAb) and thyroglobulin antibody (TgAb) can often be observed in autoimmune disorders such as Hashimoto’s thyroiditis and Graves’ disease (Shivaraj et al., 2009). The high levels of these antibodies often involved with chronic inflammation of the thyroid gland that, eventually, causes the gland to become underactive and sometimes leads to thyroid cancer. Besides iodine, bioactive phytochemicals in Sargassum may play a more important role in treating thyroid diseases. Resent research suggested Sargassum could reduce the levels of TPOAb and TgAb in rats (Song et al., 2011), which could be attributed to the immunomodulatory activity such as antiinflammatory and anti-allergic activities of Sargassum. The pathogenesis of autoimmune disorders of thyroid such as Hashimoto’s thyroiditis and Graves’ disease are still not clear. The antimicrobial and antiviral activities may also contribute to the therapeutic effects of Sargassum on thyroid related diseases. Sargassum has a considerable potential for improving thyroid health, but further biochemical and clinical research are required to understand the function of Sargassum for treating thyroid diseases. At this stage developing preventive uses seem to be the more appropriate strategy.
8. Conclusion Sargassum is a rich source of bioactive compounds with wide range of health benefits. However, the difference between the
bioactive compounds of Sargassum species has not been studied. Although only two species of Sargassum, S. pallidum and S. fusiforme have been listed in Chinese Pharmacopeia (2010 version), other species such as S. fulvellum, S. henslowianum, S. thunbergii and S. horneri may be used for similar medical treatments. A systemic phytochemical study of these Sargassum species could help to determine the biological activity of each species for medicinal uses and assist the taxonomic study of this genus. A large number of studies suggested that Sargassum has antiinflammatory, anticancer, antimicrobial, antiviral, liver protective and antioxidant activity. This pharmacological activity and identified bioactive compounds provides solid scientific evidence for some of the traditional therapeutical claims of Sargassum. However in many studies there is a general lack of proper phytochemical characterisation of the extracts used. Future research will need to incorporate such a profiling. As discussed above, priority should be given to investigating Sargassum’s potential for preventing and treating thyroid diseases.
Acknowledgements S. A. Dworjanyn and L. Liu were supported by the Australian Centre for International Agricultural Research. References Abdel-Fattah, A.F., Hussein, M.M.D., Salem, H.M., 1974. Studies of the purification and some properties of sargassan, a sulphated heteropolysaccharide from Sargassum linifolium. Carbohydrate Research 33, 9–17. Abraham-Nordling, M., Torring, O., Hamberger, B., Lundell, G., Tallstedt, L., Calissendorff, J., Wallin, G., 2005. Graves’ disease: a long-term quality-of-life follow up of patients randomized to treatment with antithyroid drugs, radioiodine, or surgery. Thyroid 15, 1279–1286. Afolayan, A.F., Bolton, J.J., Lategan, C.A., Smith, P.J., Beukes, D.R., 2008. Fucoxanthin, tetraprenylated toluquinone and toluhydroquinone metabolites from Sargassum heterophyllum inhibit the in vitro growth of the malaria parasite Plasmodium ¨ Naturforschung C: Journal of Biosciences 63, 848–852. falciparum. Zeitschrift fur
616
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Agardh, C.A., 1820. Species algarum rite cognitae, cum synonymis, differentiis specificis et descriptionibus succinctis. Lund, Berling. Ahn, M.J., Yoon, K.D., Kim, C.Y., Min, S.Y., Kim, Y.U., Kim, H.J., Kim, J.H., Shin, C.-G., Lee, C.-K., Kim, T.G., Kim, S.H., Huh, H., Kim, J., 2002. Inhibition of HIV-1 reverse transcriptase and HIV-1 integrase and antiviral activity of Korean seaweed extracts. Journal of Applied Phycology 14, 325–329. Ale, M.T., Maruyama, H., Tamauchi, H., Mikkelsen, J.D., Meyer, A.S., 2011. Fucoidan from Sargassum sp. and Fucus vesiculosus reduces cell viability of lung carcinoma and melanoma cells in vitro and activates natural killer cells in mice in vivo. International Journal of Biological Macromolecules 49, 331–336. Andrewes, P., Demarini, D.M., Funasaka, K., Wallace, K., Lai, V.W., Sun, H., Cullen, W.R., Kitchin, K.T., 2004. Do arsenosugars pose a risk to human health? The comparative toxicities of a trivalent and pentavalent arsenosugar. Environmental Science & Technology 38, 4140–4148. Arunkumar, K., Selvapalam, N., Rengasamy, R., 2005. The antibacterial compound sulphoglycerolipid 1-0 palmitoyl-3-0(60 -sulpho-a-quinovopyranosyl)-glycerol from Sargassum wightii greville (Phaeophyceae). Botanica Marina 48, 441–445. Asker, M.M.S., Mohamed, S.F., Ali, F.M., El-Sayed, O.H., 2007. Chemical structure and antiviral activity of water-soluble sulfated polysaccharides from Sargassum latifolium. Journal of Applied Sciences Research 3, 1178–1185. Ayyad, S.E., Slama, M.O., MoKhtar, A.H., Anter, A.F., 2001. Cytotoxic bicyclic diterpene from the brown alga Sargassum crispum. Bollettino Chimico Farmaceutico 140, 155–159. Ayyad, S.E., Sowellim, S.Z., el-Hosini, M.S., Abo-Atia, A., 2003. The structural determination of a new steroidal metabolite from the brown alga Sargassum ¨ Naturforschung C: Journal of Biosciences 58, asperifolium. Zeitschrift fur 333–336. Babademez, M.A., Tuncay, K.S., Zaim, M., Acar, B., Karasen, R.M., 2010. Hashimoto thyroiditis and thyroid gland anomalies. Journal of Craniofacial Surgery 21, 1807–1809. Better, O.S., Rubinstein, I., Winaver, J.M., Knochel, J.P., 1997. Mannitol therapy revisited (1940–1997). Kidney International 52, 886–894. Cen, Y., Wang, L., Ma, X., Xu, S., Zhang, M., Wang, Y., 2004. Antivirus effects of polysaccharides from Sargassum fusiforme in vitro. Zhongguo Bingli Shengli Zazhi 20, 765–768. Cha, S.H., Ko, S.C., Kim, D., Jeon, Y.J., 2011. Screening of marine algae for potential tyrosinase inhibitor: those inhibitors reduced tyrosinase activity and melanin synthesis in zebrafish. Journal of Dermatology 38, 354–363. Chan, Y.Y., Kim, K.H., Cheah, S.H., 2011. Inhibitory effects of Sargassum polycystum on tyrosinase activity and melanin formation in B16F10 murine melanoma cells. Journal of Ethnopharmacology 137, 1183–1188. Chen, S., Wang, W., Liu, H., Li, C., Liu, C., 2010. Purification and lowing hyperlipidemia activity of fucoidan from Sargassum henslowianum. Shipin Yu Fajiao Gongye 36, 28–31. Cho, S.H., Cho, J.Y., Kang, S.E., Hong, Y.K., Ahn, D.H., 2008. Antioxidant activity of mojabanchromanol, a novel chromene, isolated from brown alga Sargassum siliquastrum. Journal of Environmental Biology 29, 479–484. Choi, B.W., Ryu, G., Park, S.H., Kim, E.S., Shin, J., Roh, S.S., Shin, H.C., Lee, B.H., 2007. Anticholinesterase activity of plastoquinones from Sargassum sagamianum: lead compounds for Alzheimer’s disease therapy. Phytotherapy Research 21, 423–426. Chung, S.C., Jang, K.H., Park, J., Ahn, C.H., Shin, J., Oh, K.B., 2011. Sargachromanols as inhibitors of Naþ /Kþ ATPase and isocitrate lyase. Bioorganic & Medicinal Chemistry Letters 21, 1958–1961. Cornforth, J.W., 1968. Terpenoid biosynthesis. Chemistry in Britain 4, 102–106. Costa, L.S., Fidelis, G.P., Cordeiro, S.L., Oliveira, R.M., Sabry, D.A., Camara, R.B., Nobre, L.T., Costa, M.S., Almeida-Lima, J., Farias, E.H., Leite, E.L., Rocha, H.A., 2010. Biological activities of sulfated polysaccharides from tropical seaweeds. Biomedicine & Pharmacotherapy 64, 21–28. Costa, L.S., Fidelis, G.P., Telles, C.B., Dantas-Santos, N., Camara, R.B., Cordeiro, S.L., Pereira Costa, M.S., Almeida-Lima, J., Melo-Silveira, R.F., Oliveira, R.M., Albuquerque, I.R., Andrade, G.P., Rocha, H.A., 2011a. Antioxidant and antiproliferative activities of heterofucans from the seaweed Sargassum filipendula. Marine Drugs 9, 952–966. Costa, L.S., Telles, C.B., Oliveira, R.M., Nobre, L.T., Dantas-Santos, N., Camara, R.B., Costa, M.S., Almeida-Lima, J., Melo-Silveira, R.F., Albuquerque, I.R., Leite, E.L., Rocha, H.A., 2011b. Heterofucan from Sargassum filipendula induces apoptosis in HeLa Cells. Marine Drugs 9, 603–614. Cui, Z., Li, Y., Zhao, W., Ding, W., Dong, Y., Liu, D., Chen, H., 1997. Pharmacological study of crude drugs prepared from Sargassum and same genus plants. Zhongguo Haiyang Yaowu 16, 5–8. Dar, A., Baig, H.S., Saifullah, S.M., Ahmad, V.U., Yasmeen, S., Nizamuddin, M., 2007. Effect of seasonal variation on the anti-inflammatory activity of Sargassum wightii growing on the N. Arabian Sea coast of Pakistan. Journal of Experimental Marine Biology and Ecology 351, 1–9. De, Z.M., Nikapitiya, C., Jeon, Y.J., Jee, Y., Lee, J., 2008. Anticoagulant activity of sulfated polysaccharide isolated from fermented brown seaweed Sargassum fulvellum. Journal of Applied Phycology 20, 67–74. Dias, P.F., Siqueira Jr, J.M., Maraschin, M., Ferreira, A.G., Gagliardi, A.R., Ribeiro-doValle, R.M., 2008. A polysaccharide isolated from the brown seaweed Sargassum stenophyllum exerts antivasculogenic effects evidenced by modified morphogenesis. Microvascular Research 75, 34–44. EditorialBoardofZhongHuaBenCao, 1999. Zhong Hua Ben Cao (China Herbal). Shanghai Science and Technology Publishing House, Shanghai. Edmonds, J.S., 2000. Diastereoisomers of an ‘arsenomethionine’-based structure from Sargassum lacerifolium: the formation of the arsenic-carbon bond in
arsenic-containing natural products. Bioorganic & Medicinal Chemistry Letters 10, 1105–1108. Ehrhardt, M., Knap, A., 1989. A direct comparison of UV fluorescence and GC/MS data of lipophilic open-ocean seawater extracts. Marine Chemistry 26, 179–188. Ekholm, R., Bjorkman, U., 1997. Glutathione peroxidase degrades intracellular hydrogen peroxide and thereby inhibits intracellular protein iodination in ¨ thyroid epithelium. Ekholm and Bjorkman 138, 2871–2878. Ermakova, S., Sokolova, R., Kim, S.M., Um, B.H., Isakov, V., Zvyagintseva, T., 2011. Fucoidans from brown seaweeds Sargassum horneri, Eclonia cava, Costaria costata: structural characteristics and anticancer activity. Applied Biochemistry and Biotechnology 164, 841–850. Ferreira, E.O., Salvador, M.J., Pral, E.M.F., Alfieri, S.C., Ito, I.Y., Dias, D.A., 2004. A new heptasubstituted (E)-aurone glucoside and other aromatic compounds of gomphrena agrestis with biological activity. Zeitschrift fur Naturforschung Teil C: Biochemie Biophysik Biologie Virologie 59, 499–505. Francesconi, K.A., Edmonds, J.S., Stick, R.V., Skelton, B.W., White, A.H., 1991. Arsenic-containing ribosides from the brown alga Sargassum lacerifolium X-ray molecular structure of 2-amino-3-[50 -deoxy-50 -(dimethylarsinoyl)ribosyloxy]propane-1-sulphonic acid. Journal of the Chemical Society— Perkin Transactions 1, 2707–2716. Fujihara, M., Iizima, N., Yamamoto, I., Nagumo, T., 1984a. Purification and chemical and physical characterisation of an antitumour polysaccharide from the brown seaweed Sargassum fulvellum. Carbohydrate Research 125, 97–106. Fujihara, M., Komiyama, K., Umezawa, I., Nagumo, T., 1984b. Antitumor activity and action-mechanisms of sodium alginate isolated from the brown seaweed Sargassum fulvellum. Chemotherapy 32, 1004–1009. Fujihara, M., Nagumo, T., 1992. The effect of the content of D-mannuronic acid and L-guluronic acid blocks in alginates on antitumor activity. Carbohydrate Research 224, 343–347. ¨ Glombitza, K.W., Forster, M., Eckhardt, G., 1978. Polyhydroxyphenylather aus der phaeophycee Sargassum muticum. Phytochemistry 17, 579–580. Glombitza, K.W., Keusgen, M., 1995. Fuhalols and deshydroxyfuhalols from the brown alga Sargassum spinuligerum. Phytochemistry 38, 987–995. Glombitza, K.W., Keusgen, M., Hauperich, S., 1997. Fucophlorethols from the brown algae Sargassum spinuligerum and Cystophora torulosa. Phytochemistry 46, 1417–1422. Gu, Q., Fang, Y., Wang, C., Li, B., Mao, W., 1998. Studies on the chemical composition and antitumor activity of the acid polysaccharide from alga Sargassum fusiforme. Natural Product Sciences 4, 88–90. Guan, H.S., Wang, S.G., 2009. Hai Yang Kuang Wu Yao Yu Hai Yang Zhi Wu Yao, Zhong Hua Hai Yang Ben Cao. Shanghai Ke Xue Ji Shu Chu Ban She, Shanghai. (pp. 232–274). Ham, Y.M., Kim, K.N., Lee, W.J., Lee, N.H., Hyun, C.G., 2010. Chemical constituents from Sargassum micracanthum and antioxidant activity. International Journal of Pharmacology 6, 147–151. Han, H., Zhan, S., Shan, L., Wang, C., 2008. Studies on the free radical scavenging activity of bioactive substances from Sargassum fusiforme. Zhongguo Haiyang Yaowu 27, 31–34. Hayashi, K., Mori, J., Saito, H., Hayashi, T., 2006. Antiviral targets of a chromene derivative from Sargassum micracanthum in the replication of human cytomegalovirus. Biological & Pharmaceutical Bulletin 29, 1843–1847. Heo, S.J., Kim, K.N., Yoon, W.J., Oh, C., Choi, Y.U., Affan, A., Lee, Y.J., Lee, H.S., Kang, D.H., 2011. Chromene induces apoptosis via caspase-3 activation in human leukemia HL-60 cells. Food and Chemical Toxicology 49, 1998–2004. Horie, S., Tsutsumi, S., Takada, Y., Kimura, J., 2008. Antibacterial quinone metabolites from the brown alga, Sargassum sagamianum. Bulletin of the Chemical Society of Japan 81, 1125–1130. Hoshino, T., Hayashi, T., Hayashi, K., Hamada, J., Lee, J.B., Sankawa, U., 1998. An antivirally active sulfated polysaccharide from Sargassum horneri (TURNER) C. AGARDH. Biological & Pharmaceutical Bulletin 21, 730–734. Hosokawa, M., Kudo, M., Maeda, H., Kohno, H., Tanaka, T., Miyashita, K., 2004. Fucoxanthin induces apoptosis and enhances the antiproliferative effect of the PPARg ligand, troglitazone, on colon cancer cells. Biochimica et Biophysica Acta (BBA)—General Subjects 1675, 113–119. Hur, S., Lee, H., Kim, Y., Lee, B.H., Shin, J., Kim, T.Y., 2008. Sargaquinoic acid and sargachromenol, extracts of Sargassum sagamianum, induce apoptosis in HaCaT cells and mice skin: Its potentiation of UVB-induced apoptosis. European Journal of Pharmacology 582, 1–11. Hwang, P.A., Chien, S.Y., Chan, Y.L., Lu, M.K., Wu, C.H., Kong, Z.L., Wu, C.J., 2011. Inhibition of lipopolysaccharide (LPS)-induced inflammatory responses by Sargassum hemiphyllum sulfated polysaccharide extract in RAW 264.7 macrophage cells. Journal of Agricultural and Food Chemistry 59, 2062–2068. Iizima-Mizui, N., Fujihara, M., Himeno, J., Komiyama, K., Umezawa, I., Nagumo, T., 1985. Antitumor activity of polysaccharide fractions from the brown seaweed Sargassum kjellmanianum. Kitasato Archives of Experimental Medicine 58, 59–71. Ikeda, I., Tanaka, K., Sugano, M., Vahouny, G.V., Gallo, L.L., 1988. Inhibition of cholesterol absorption in rats by plant sterols. Journal of Lipid Research 29, 1573–1582. Ishitsuka, M., Kusumi, T., Nomura, Y., Konno, T., Kakisawa, H., 1979. New geranylgeranylbenzoquinone derivatives from Sargassum tortile. Chemistry Letters 8, 1269–1272. Ito, K., Ishikawa, K., Tsuchiya, Y., 1976. Studies on the depressive factors in Heterochordaria abietina affecting the blood cholesterol level in rats. III. Quantitative determination of iodoamino acids in marine algae and their effects of depressing the blood cholesterol level in rats. Tohoku Journal of Agricultural Research 27, 53–61.
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Itoh, H., Noda, H., Amano, H., Ito, H., 1995. Immunological analysis of inhibition of lung metastases by fucoidan (GIV-A) prepared from brown seaweed Sargassum thunbergii. Anticancer Research 15, 1937–1947. Itoh, H., Noda, H., Amano, H., Zhuaug, C., Mizuno, T., Ito, H., 1993. Antitumor activity and immunological properties of marine algal polysaccharides, especially fucoidan, prepared from Sargassum thunbergii of Phaeophyceae. Anticancer Research 13, 2045–2052. Iwashima, M., Mori, J., Ting, X., Matsunaga, T., Hayashi, K., Shinoda, D., Saito, H., Sankawa, U., Hayashi, T., 2005. Antioxidant and antiviral activities of plastoquinones from the brown alga Sargassum micracanthum, and a new chromene derivative converted from the plastoquinones. Biological & Pharmaceutical Bulletin 28, 374–377. Iwashima, M., Tako, N., Hayakawa, T., Matsunaga, T., Mori, J., Saito, H., 2008. New chromane derivatives isolated from the brown alga, Sargassum micracanthum. Chemical & Pharmaceutical Bulletin 56, 124–128. Jang, K.H., Lee, B.H., Choi, B.W., Lee, H.S., Shin, J., 2005. Chromenes from the brown alga Sargassum siliquastrum. Journal of Natural Products 68, 716–723. Josephine, A., Nithya, K., Amudha, G., Veena, C.K., Preetha, S.P., Varalakshmi, P., 2008. Role of sulphated polysaccharides from Sargassum Wightii in Cyclosporine A-induced oxidative liver injury in rats. BMC Pharmacology 8, 4. Josephine, A., Veena, C.K., Amudha, G., Preetha, S.P., Varalakshmi, P., 2007. Protective role of sulphated polysaccharides in abating the hyperlipidemic nephropathy provoked by cyclosporine A. Archives of Toxicology 81, 371–379. Jung, M., Jang, K.H., Kim, B., Lee, B.H., Choi, B.W., Oh, K.B., Shin, J., 2008. Meroditerpenoids from the brown alga Sargassum siliquastrum. Journal of Natural Products 71, 1714–1719. Kajiwara, T., Kodama, K., Hatanaka, A., 1980. Attractants of male-gamete from a marine brown alga Sargassum horneri. Nippon Suisan Gakkaishi 46, 555–557. Kamei, Y., Sagara, A., 2002. Neurite outgrowth promoting activity of marine algae from Japan against rat adrenal medulla pheochromocytoma cell line, PC12D. Cytotechnology 40, 99–106. Kamei, Y., Sueyoshi, M., Hayashi, K.-i., Terada, R., Nozaki, H., 2009. The novel antiPropionibacterium acnes compound, sargafuran, found in the marine brown alga Sargassum macrocarpum. Journal of Antibiotics 62, 259–263. Kamei, Y., Tsang, C.K., 2003. Sargaquinoic acid promotes neurite outgrowth via protein kinase A and MAP kinases-mediated signaling pathways in PC12D cells. International Journal of Developmental Neuroscience 21, 255–262. Kang, J.Y., Khan, M.N.A., Park, N.H., Cho, J.Y., Lee, M.C., Fujii, H., Hong, Y.K., 2008. Antipyretic, analgesic, and anti-inflammatory activities of the seaweed Sargassum fulvellum and Sargassum thunbergii in mice. Journal of Ethnopharmacology 116, 187–190. Karawya, M.S., Abdel-Wahab, S.M., Sallam, L.A., El-Refai, A.M.H., Hamdy, A.H.A., 1987. Study of lipid content of certain Red Sea algae. Egyptian Journal of Pharmaceutical Sciences 28, 247–254. Katayama, M., Sugawa-Katayama, Y., 2007. Effect of temperature on the diminution of retained arsenic in dried Hijiki, Sargassum fusiforme (Harvey) Setchell, by water-soaking. Nippon Kasei Gakkaishi 58, 75–80. Kato, T., Kumanireng, A.S., Ichinose, I., Kitahara, Y., Kakinuma, Y., Kato, Y., 1975. Structure and synthesis of active component from a marine alga, Sargassum tortile, which induces the settling of swimming larvae of Coryne uchidai. Chemistry Letters 4, 335–338. Keusgen, M., Falk, M., Walter, J.A., Glombitza, K.W., 1997. A phloroglucinol derivative from the brown alga Sargassum spinuligerum. Phytochemistry 46, 341–345. Keusgen, M., Glombitza, K.W., 1995. Phlorethols, fuhalols and their derivatives from the brown alga Sargassum spinuligerum. Phytochemistry 38, 975–985. Keusgen, M., Glombitza, K.W., 1997. Pseudofuhalols from the brown alga Sargassum spinuligerum. Phytochemistry 46, 1403–1415. Khanavi, M., Nabavi, M., Sadati, N., Shams Ardekani, M., Sohrabipour, J., Nabavi, S.M., Ghaeli, P., Ostad, S.N., 2010. Cytotoxic activity of some marine brown algae against cancer cell lines. Biological Research 43, 31–37. Kikuchi, T., Mori, Y., Yokoi, T., Nakazawa, S., Kuroda, H., Masada, Y., Kitamura, K., Kuriyama, K., 1983. Structure and absolute-configuration of sargatriol, a new isopenoid chromenol from a brown alga, Sargassum tortile Agardh, C. Chemical & Pharmaceutical Bulletin 31, 106–113. Kilar, J.A., Hanisak, M.D., Yoshida, T., 1992. On the expression of phenotypic variability: why is Sargassum so taxonomically difficult?. In: Abbott, I.A. (Ed.), Taxonomy of Economic Seaweed with Reference to Some Pacific and Western Atlantic Species. California Sea Grant College Program, La Jolla, California, pp. 95–117. Kim, K.N., Heo, S.J., Kang, S.M., Ahn, G., Jeon, Y.J., 2010. Fucoxanthin induces apoptosis in human leukemia HL-60 cells through a ROS-mediated Bcl-xL pathway. Toxicology in Vitro 24, 1648–1654. Kim, M.C., Kwon, H.C., Kim, S.N., Kim, H.S., Um, B.H., 2011. Plastoquinones from Sargassum yezoense: chemical structures and effects on the activation of peroxisome proliferator-activated receptor gamma. Chemical & Pharmaceutical Bulletin 59, 834–838. Kim, S.H., Choi, D.S., Athukorala, Y., Jeon, Y.J., Senevirathne, M., Rha, C.K., 2007a. Antioxidant activity of sulfated polysaccharides isolated from Sargassum fulvellum. Journal of Food Science and Nutrition 12, 65–73. Kim, S.N., Choi, H.Y., Lee, W., Park, G.M., Shin, W.S., Kim, Y.K., 2008a. Sargaquinoic acid and sargahydroquinoic acid from Sargassum yezoense stimulate adipocyte differentiation through PPARalpha/gamma activation in 3T3-L1 cells. FEBS Letters 582, 3465–3472. Kim, Y.A., Kong, C.S., Um, Y.R., Lee, J.I., Nam, T.J., Seo, Y., 2008b. Antioxidant efficacy of extracts from a variety of seaweeds in a cellular system. Ocean Science Journal 43, 31–37.
617
Kim, Y.H., Kim, E.H., Lee, C., Kim, M.H., Rho, J.R., 2007b. Two new monogalactosyl diacylglycerols from brown alga Sargassum thunbergii. Lipids 42, 395–399. Kobayashi, M., Hasegawa, A., Mitsuhashi, H., 1985. Marine sterols. 15. Isolation of 24-vinyloxycholesta-5,23-dien-3-beta-ol from the brown alga Sargassum thumbergii. Chemical & Pharmaceutical Bulletin 33, 4012–4013. Komai, E., Miyahara, T., Mori, J., Obi, N., Ochiai, H., Saito, H., Hayashi, T., 2006. Inhibitory activities of plastoquinones and chromene derivative from a brown alga Sagassum micracanthum on bone resorption. Biological & Pharmaceutical Bulletin 29, 1980–1982. Kubo, I., Matsumoto, T., Ichikawa, N., 1985. Absolute configuration of crinitol, an acyclic diterpene insect growth inhibitor from the brown algae Sargassum tortile. Chemistry Letters 14, 249–252. Kuniyoshi, M., 1985. Germination inhibitors from the brown alga Sargassum crassifolium (Phaeophyta, Sargassaceae). Botanica Marina 28, 501–503. Kusumi, T., Ishitsuka, M., Nomura, Y., Konno, T., Kakisawa, H., 1979a. New farnesylacetone derivatives from Sargassum micracanthum. Chemistry Letters, 1181–1184. Kusumi, T., Shibata, Y., Ishitsuka, M., Kinoshita, T., Kakisawa, H., 1979b. Structures of new plastoquinones from the brown alga Sargassum serratifolium. Chemistry Letters 8, 277–278. Lategan, C., Kellerman, T., Afolayan, A.F., Mann, M.G., Antunes, E.M., Smith, P.J., Bolton, J.J., Beukes, D.R., 2009. Antiplasmodial and antimicrobial activities of South African marine algal extracts. Pharmaceutical Biology 47, 408–413. Lee, H.J., Kim, Y.A., Ahn, J.W., Na, H.J., Kim, H.M., Seo, Y., 2006. Screening of Korean marine plants for their inhibitory effect on histamine release from RPMC in vitro. Biotechnology and Bioprocess Engineering 11, 80–83. Lee, J.B., Takeshita, A., Hayashi, K., Hayashi, T., 2011. Structures and antiviral activities of polysaccharides from Sargassum trichophyllum. Carbohydrate Polymers 86, 995–999. Lee, J.I., Seo, Y., 2011. Chromanols from Sargassum siliquastrum and their antioxidant activity in HT 1080 cells. Chemical & Pharmaceutical Bulletin 59, 757–761. Lee, S., Lee, Y.S., Jung, S.H., Kang, S.S., Shin, K.H., 2003. Anti-oxidant activities of fucosterol from the marine algae Pelvetia siliquosa. Archives of Pharmacal Research 26, 719–722. Lee, S.B., Lee, J.Y., Song, D.G., Pan, C.H., Nho, C.W., Kim, M.C., Lee, E.H., Jung, S.H., Kim, H.S., Kim, Y.S., Um, B.H., 2008. Cancer chemopreventive effects of Korean seaweed extracts. Food Science and Biotechnology 17, 613–622. Lee, Y.S., Shin, K.H., Kim, B.K., Lee, S., 2004. Anti-diabetic activities of fucosterol from Pelvetia siliquosa. Archives of Pharmacal Research 27, 1120–1122. Li, B., Xu, S., 2004. Anticoagulant activity of fucoidan from the brown seaweed Sargassum fusiform. Tianran Chanwu Yanjiu Yu Kaifa 16, 431–434. Li, J., Wei, Y., Du, G., Hu, Y., Li, L., 2007. Anticoagulant activities of phlorotannins from Sargassum thunbergii. Zhongyao Xinyao Yu Linchuang Yaoli 18, 191–194. Liu, C., Zhou, Y., Wu, Y., Gan, J., Zhou, P., 2004. Primary screening of the components with blood-anticoagulant activity from marine algae Sargassum fusiforme and Undaria pinnatifida. Shuichan Xuebao 28, 473–476. Liu, Q., Meng, Q., Liu, Z., 2003. Extraction and measurement of two kinds of seaweed polysaccharides and their antitumor effect in vitro. Guangdong Yaoxueyuan Xuebao 19, 336–337. Liu, Q.Y., Meng, Q.Y., 2004. In vivo anti-tumor effect of polysaccharide from Sargassum confusum and the mechanisms. Di Yi Jun Yi Da Xue Xue Bao 24, 434–436. Liu, X., Wang, C.Y., Shao, C.L., Wei, Y.X., Wang, B.G., Sun, L.L., Zheng, C.J., Guan, H.S., 2009. Chemical constituents from Sargassum pallidum (Turn.) C. Agardh. Biochemical Systematics and Ecology 37, 127–129. Mabry, T.J., Ulubelen, A., 1980. Chemistry and utilization of phenylpropanoids including flavonoids, coumarins, and lignans. Journal of Agricultural and Food Chemistry 28, 188–196. Maeda, H., Hosokawa, M., Sashima, T., Miyashita, K., 2007. Dietary combination of fucoxanthin and fish oil attenuates the weight gain of white adipose tissue and decreases blood glucose in obese/diabetic KK-Ay mice. Journal of Agricultural and Food Chemistry 55, 7701–7706. Mao, W., Li, B., Gu, Q., Fang, Y., Xing, H., 2004. Preliminary studies on the chemical characterization and antihyperlipidemic activity of polysaccharide from the brown alga Sargassum fusiforme. Hydrobiologia 512, 263–266. Martinez-Lozano, S.J., Garcia, S., Heredia, N., Villarreal-Rivera, L., Garcia-Padilla, C.A., 2000. Antifungal activity of extract of Sargassum filipendula. Phyton— International Journal of Experimental Botany 66, 179–182. Matsuda, T., Sasaki, J., Kurihara, H., Hatano, M., Takahashi, K., 2005. Anticancer benefit of Sargassum horneri extract. Hokkaido Daigaku Suisan Kagaku Kenkyu Iho 56, 75–86. Mattio, L., Payri, C., 2011. 190 years of Sargassum taxonomy, facing the advent of DNA phylogenies. Botanical Review 77, 31–70. Michelangeli, V., Morris, H.A., Topliss, D., 2000. Current issues in thyroid disease: laboratory and clinical developments: In: Proceedings of a Conjoint Symposium Organised by the Australasian Association of Clinical Biochemists and the Endocrine Society of Australia. The Australasian Association of Clinical Biochemists, Mt. Lawley, WA, Australia. Mooney, P.A., Van, S.J., 1987. Tentative identification of cytokinins in Sargassum heterophyllum (Phaeophyceae). Botanica Marina 30, 323–325. Morales, J.L., Cantillo-Ciau, Z.O., Sanchez-Molina, I., Mena-Rejon, G.J., 2006. Screening of antibacterial and antifungal activities of six marine macroalgae from coasts of Yucatan peninsula. Pharmaceutical Biology 44, 632–635. Mori, J., Hayashi, T., Iwashima, M., Matsunaga, T., Saito, H., 2006. Effects of plastoquinones from the brown alga Sargassum micracanthum and a new chromene derivative converted from the plastoquinones on acute gastric lesions in rats. Biological & Pharmaceutical Bulletin 29, 1197–1201.
618
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
Mori, J., Iwashima, M., Wakasugi, H., Saito, H., Matsunaga, T., Ogasawara, M., Takahashi, S., Suzuki, H., Hayashi, T., 2005. New plastoquinones isolated from the brown alga, Sargassum micracanthum. Chemical & Pharmaceutical Bulletin 53, 1159–1163. Mori, J., Matsunaga, T., Takahashi, S., Hasegawa, C., Saito, H., 2003. Inhibitory activity on lipid peroxidation of extracts from marine brown alga. Phytotherapy Research 17, 549–551. Na, H.J., Seo, Y., Lee, E.H., Kim, H.M., Hong, S.H., 2004. Regulatory effect of Th-2 cytokine production in mast cells by 02PS15. Journal of Applied Pharmacology 12, 79–84. Na, H.J., Moon, P.D., Ko, S.G., Lee, H.J., Jung, H.A., Hong, S.H., Seo, Y., Oh, J.M., Lee, B.H., Choi, B.W., Kim, H.M., 2005. Sargassum hemiphyllum inhibits atopic allergic reaction via the regulation of inflammatory mediators. Journal of Pharmacological Sciences 97, 219–226. Nagumo, T., Iizima-Mizui, N., Fujihara, M., Himeno, J., Komiyama, K., Umezawa, I., 1988. Separation of sulfated, fucose-containing polysaccharides from the brown seaweed Sargassum kjellmanianum and their heterogeneity and antitumor activity. Kitasato Archives of Experimental Medicine 61, 59–67. Nakai, M., Kageyama, N., Nakahara, K., Miki, W., 2006. Phlorotannins as radical scavengers from the extract of Sargassum ringgoldianum. Marine Biotechnology 8, 409–414. Nakano, T., Kamei, Y., 2005. In vivo antiviral activity of an interferon beta production-promoting fraction from the marine brown alga, Sargassum hemiphyllum (Turner) C. Agardh. Botanica Marina 48, 84–86. Nakano, T., Noro, T., Kamei, Y., 1997. In vitro promoting activity of human interferon b production by extracts of marine algae from Japan. Cytotechnology 25, 239–241. Nakayama, M., Fukuoka, Y., Nozaki, H., Matsuo, A., Hayashi, S., 1980. Structure of (þ)-kjellmanianone, a highly oxygenated cyclopentenone from the marine alga, Sargassum kjellmanianum. Chemistry Letters, 1243–1246. Nguyen, D.N., Bui, M.L., Nguyen, M.C., Tran, V.S., 2008. Fucoidans from brown seaweed Sargassum swartzii: extraction method, cytotoxic activity and structural studies. Tap Chi Hoa Hoc 46, 52–56. Nozaki, H., Fukuoka, Y., Matsuo, A., Soga, O., Nakayama, M., 1980. Structure of Sargassumlactam: a new b, g-unsaturated-g-lactam, from the marine alga, Sargassum kjellmanianum. Chemistry Letters 9, 1453–1454. Nozaki, H., Ohira, S., Takaoka, D., Senda, N., Nakayama, M., 1995. Structure of Sargassumketone, a novel highly oxygenated ketone from Sargassum kjellmanianum. Chemistry Letters 24, 331. Numata, A., Kanbara, S., Takahashi, C., Fujiki, R., Yoneda, M., Usami, Y., Fujita, E., 1992. A cytotoxic principle of the brown alga Sargassum tortile and structures of chromenes. Phytochemistry 31, 1209–1213. Park, B.G., Kwon, S.C., Park, G.M., Ham, J., Shin, W.S., Lee, S., 2008a. Vasodilatation effect of farnesylacetones, active constituents of Sargassum siliquastrum, on the basilar and carotid arteries of rabbits. Bioorganic & Medicinal Chemistry Letters 18, 6324–6326. Park, B.G., Shin, W.S., Um, Y., Cho, S., Park, G.M., Yeon, D.S., Kwon, S.C., Ham, J., Choi, B.W., Lee, S., 2008b. Selective vasodilatation effect of sargahydroquinoic acid, an active constituent of Sargassum micracanthum, on the basilar arteries of rabbits. Bioorganic & Medicinal Chemistry Letters 18, 2624–2627. Park, P.J., Shahidi, F., Jeon, Y.J., 2004. Antioxidant activities of enzymatic extracts from an edible seaweed Sargassum horneri using ESR spectrometry. Journal of Food Lipids 11, 15–27. Park, P.J., Heo, S.J., Park, E.J., Kim, S.K., Byun, H.G., Jeon, B.T., Jeon, Y.J., 2005. Reactive oxygen scavenging effect of enzymatic extracts from Sargassum thunbergii. Journal of Agricultural and Food Chemistry 53, 6666–6672. Preeprame, S., Hayashi, K., Lee, J.B., Sankawa, U., Hayashi, T., 2001. A novel antivirally active fucan sulfate derived from an edible brown alga, Sargassum horneri. Chemical & Pharmaceutical Bulletin 49, 484–485. Preetha, S.P., Devaraj, H., 2010. Role of sulphated polysaccharides from Sargassum wightii in the control of diet-induced hyperlipidemia and associated inflammatory complications in rats. European Journal of Inflammation 8, 23–30. Premanathan, M., Kathiresan, K., Chandra, K., Bajpai, S.K., 1994. In vitro antivaccinia virus activity of some marine plants. Indian Journal of Medical Research 99, 236–238. Qi, S.H., Zhang, S., Huang, J.S., Xiao, Z.H., Wu, J., Long, L.J., 2004. Glycerol derivatives and sterols from Sargassum parvivesiculosum. Chemical & Pharmaceutical Bulletin 52, 986–988. Raghavendran, H.B., Sathivel, A., Devaki, T., 2006. Defensive nature of Sargassum polycystum (Brown alga) against acetaminophen-induced toxic hepatitis in rats: role of drug metabolizing microsomal enzyme system, tumor necrosis factor-alpha and fate of liver cell structural integrity. World Journal of Gastroenterology 12, 3829–3834. Raghavendran, H.B., Sathivel, A., Yogeeta, R.S., Devaki, T., 2007. Efficacy of Sargassum polycystum (Phaeophyceae) sulphated polysaccharide against paracetamol-induced DNA fragmentation and modulation of membrane-bound phosphatases during toxic hepatitis. Clinical and Experimental Pharmacology & Physiology 34, 142–147. Raghavendran, H.R., Sathivel, A., Devaki, T., 2004a. Efficacy of brown seaweed hot water extract against HCl–ethanol induced gastric mucosal injury in rats. Archives of Pharmacal Research 27, 449–453. Raghavendran, H.R., Sathivel, A., Devaki, T., 2005. Protective effect of Sargassum polycystum (brown alga) against acetaminophen-induced lipid peroxidation in rats. Phytotherapy Research 19, 113–115. Raghavendran, H.R., Srinivasan, P., 2008. Effect of crude sulphated polysaccharide from brown algae against acetaminophen-induced toxicity in rats. Canadian Journal of Physiology and Pharmacology 86, 660–666.
Raghavendran, H.R.B., Sathivel, A., Devaki, T., 2004b. Hepatoprotective nature of seaweed alcoholic extract on acetaminophen induced hepatic oxidative stress. Journal of Health Science 50, 42–46. Reddy, P., Urban, S., 2009. Meroditerpenoids from the southern Australian marine brown alga Sargassum fallax. Phytochemistry 70, 250–255. Romanos, M., Andrada-Serpa, M.J., Dos, S., Ribeiro, A., Yoneshigue-Valentin, Y., Costa, S.S., Wigg, M.D., 2002. Inhibitory effect of extracts of Brazilian marine algae on human T-cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation in vitro. Cancer Investigation 20, 46–54. Ryu, G., Park, S.H., Kim, E.S., Choi, B.W., Ryu, S.Y., Lee, B.H., 2003. Cholinesterase inhibitory activity of two farnesylacetone derivatives from the brown alga Sargassum sagamianum. Archives of Pharmacal Research 26, 796–799. Sachindra, N.M., Sato, E., Maeda, H., Hosokawa, M., Niwano, Y., Kohno, M., Miyashita, K., 2007. Radical scavenging and singlet oxygen quenching activity of marine carotenoid fucoxanthin and its metabolites. Journal of Agricultural and Food Chemistry 55, 8516–8522. Sanina, N.M., Goncharova, S.N., Kostetsky, E.Y., 2004. Fatty acid composition of individual polar lipid classes from marine macrophytes. Phytochemistry 65, 721–730. Sastry, V.M.V.S., Rao, G.R.K., 1994. Antibacterial substances from marine algae: Successive extraction using benzene, chloroform and methanol. Botanica Marina 37, 357–360. Segawa, M., Shirahama, H., 1987. New plastoquinones from the brown alga Sargassum sagamianum var. yezoense. Chemistry Letters 16, 1365–1366. Seo, Y., Park, K.E., Kim, Y.A., Lee, H.J., Yoo, J.S., Ahn, J.W., Lee, B.J., 2006. Isolation of tetraprenyltoluquinols from the brown alga Sargassum thunbergii. Chemical & Pharmaceutical Bulletin 54, 1730–1733. Seo, Y., Park, K.E., Nam, T.J., 2007. Isolation of a new chromene from the Brown Alga Sargassum thunbergii. Bulletin of the Korean Chemical Society 28, 1831–1833. Shanab, S.M.M., 2007. Antioxidant and antibiotic activities of some seaweeds (Egyptian isolates). International Journal of Agriculture & Biology 9, 220–225. Shibata, Y., Morita, M., 1988. A novel, trimethylated arseno-sugar isolated from the brown alga Sargassum thunbergii. Agricultural and Biological Chemistry 52, 1087–1089. Shiratori, K., Ohgami, K., Ilieva, I., Jin, X.-H., Koyama, Y., Miyashita, K., Yoshida, K., Kase, S., Ohno, S., 2005. Effects of fucoxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Experimental Eye Research 81, 422–428. Shivaraj, G., Desai Prakash, B., Sonal, V., Shruthi, K., Vinayak, H., Avinash, M., 2009. Thyroid function tests: a review. European Review for Medical and Pharmacological Sciences 13, 341–349. Shizuri, Y., Matsukawa, S., Ojika, M., Yamada, K., 1982. Two new farnesylacetone derivatives from the brown alga Sargassum micracanthum. Phytochemistry 21, 1808–1809. Sinha, S., Astani, A., Ghosh, T., Schnitzler, P., Ray, B., 2010. Polysaccharides from Sargassum tenerrimum: structural features, chemical modification and antiviral activity. Phytochemistry 71, 235–242. Sokolova, R.V., Ermakova, S.P., Awada, S.M., Zvyagintseva, T.N., Kanaan, H.M., 2011. Composition, structural characteristics, and antitumor properties of polysaccharides from the brown algae Dictyopteris polypodioides and Sargassum sp. Chemistry of Natural Compounds 47, 329–334. Son, B.W., Cho, Y.J., Kim, N.K., Choi, H.D., 1992. New glyceroglycolipids from the brown alga Sargassum thunbergii. Bulletin of the Korean Chemical Society 13, 584–586. Song, X.H., Zan, R.Z., Yu, C.H., Wang, F., 2011. Effects of modified Haizao Yuhu Decoction in experimental autoimmune thyroiditis rats. Journal of Ethnopharmacology 135, 321–324. Sousa, A.d.P.A., Barbosa, P.S.F., Torres, M.R., Martins, A.M.C., Martins, R.D., Alves, R.d.S., Freire, d.S.D., Alves, C.D., Costa-Lotufo, L.V., Monteiro, H.S.A., 2008. The renal effects of alginates isolated from brown seaweed Sargassum vulgare. Journal of Applied Toxicology 28, 364–369. Sousa, A.d.P.A., Torres, M.R., Pessoa, C., Moraes, M.O.d., Filho, F.D.R., Alves, A.P.N.N., Costa-Lotufo, L.V., 2007. In vivo growth-inhibition of Sarcoma 180 tumor by alginates from brown seaweed Sargassum vulgare. Carbohydrate Polymers 69, 7–13. Stevan, F.R., Oliveira, M.B., Bucchi, D.F., Noseda, Iacomini, M., Duarte, M.E., 2001. Cytotoxic effects against HeLa cells of polysaccharides from seaweeds. Journal of Submicroscopic Cytology and Pathology 33, 477–484. Sugawa-Katayama, Y., Katayama, M., Imanishi, H., Tomita, K., 2010. Effects of digestive enzymes on the retained arsenic in dried Hijiki, Sargassum fusiforme. Trace Nutrients Research 27, 84–87. Takada, N., Watanabe, R., Suenaga, K., Yamada, K., Uemura, D., 2001. Isolation and structures of hedaols A, B, and C, new bisnorditerpenes from a Japanese brown alga. Journal of Natural Products 64, 653–655. Tang, H.F., Yang-Hua, Y., Yao, X.S., Xu, Q.Z., Zhang, S.Y., Lin, H.W., 2002. Bioactive steroids from the brown alga Sargassum carpophyllum. Journal of Asian Natural Products Research 4, 95–101. Tang, H.F., Yi, Y.H., Yao, X.S., 2003. A novel steroid for Sargassum carpophyllum. Zhonggu Haiyang Yaowu 22, 28–30. Terasaki, M., Hirose, A., Narayan, B., Baba, Y., Kawagoe, C., Yasui, H., Saga, N., Hosokawa, M., Miyashita, K., 2009. Evaluation of recoverable functional lipid components of several brown seaweeds (Phaeophyta) from Japan with special reference to fucoxanthin and fucosterol contents. Journal of Phycology 45, 974–980. Tsang, C.K., Ina, A., Goto, T., Kamei, Y., 2005. Sargachromenol, a novel nerve growth factor-potentiating substance isolated from Sargassum macrocarpum,
L. Liu et al. / Journal of Ethnopharmacology 142 (2012) 591–619
promotes neurite outgrowth and survival via distinct signaling pathways in PC12D cells. Neuroscience 132, 633–643. Tsang, C.K., Kamei, Y., 2004. Sargaquinoic acid supports the survival of neuronal PC12D cells in a nerve growth factor-independent manner. European Journal of Pharmacology 488, 11–18. Tsuchiya, N., Sato, A., Haruyama, H., Watanabe, T., Iijima, Y., 1998. Nahocols and isonahocols, endothelin antagonists from the brown alga, Sargassum autumnale. Phytochemistry 48, 1003–1011. Uchiyama, S., Hashizume, M., Hokari, Y., Nakagawa, T., Igarashi, A., Yamaguchi, M., 2004. Characterization of active component in marine alga Sargassum horneri extract in stimulating bone calcification in vitro. Journal of Health Science 50, 634–639. Uchiyama, S., Yamaguchi, M., 2002a. Anabolic effect of marine alga Sargassum horneri extract on bone components in the femoral-diaphyseal and -metaphyseal tissues of young and aged rats in vivo. Journal of Health Science 48, 325–330. Uchiyama, S., Yamaguchi, M., 2002b. Inhibitory effect of marine alga Sargassum horneri extract on bone resorption in tissue culture in vitro. Journal of Health Science 48, 154–160. Uchiyama, S., Yamaguchi, M., 2003. Preventive effect of marine alga Sargassum horneri extract on bone loss in streptozotocin-diabetic rats in vivo. Journal of Health Science 49, 149–155. Uzuner, H., Bauer, R., Fan, T.-P., Guo, D.A., Dias, A., El-Nezami, H., Efferth, T., Williamson, E.M., Heinrich, M., Robinson, N., Hylands, P.J., Hendry, B.M., Cheng, Y.-C., Xu, Q., 2012. Traditional Chinese medicine research in the post-genomic era: good practice, priorities, challenges and opportunities. Journal of Ethnopharmacology 140, 458–468. van Ginneken, V.J., Helsper, J.P., de Visser, W., van Keulen, H., Brandenburg, W.A., 2011. Polyunsaturated fatty acids in various macroalgal species from North Atlantic and tropical seas. Lipids in Health and Disease 10, 104. Wang, C., Yan, S., Zeng, L., Su, J., 1997. Studies on the chemical constituents of the alga Sargassum carpophyllum J. Agardh. Se Pu 15, 396–399. Wei, Y., Li, J., Wang, J., Qi, H., 2007. Screening of different fractions of phlorotannins from Sargassum thunbergii Kuntze for anticoagulant activity. Zhongguo Shenghua Yaowu Zazhi 28, 227–229. Wei, Y., Li, Z.e., Hu, Y., Xu, Z., 2003. Inhibition of mouse liver lipid peroxidation by high molecular weight phlorotannins from Sargassum kjellmanianum. Journal of Applied Phycology 15, 507–511. Wei, Y., Wang, C., Li, J., Qi, H., Guo, Q., 2008. Effects of high-molecular-weight phlorotannins from Sargassum thunbergii Kuntze on anticoagulation activity and platelet cytosolic calcium level. Zhongguo Yaoke Daxue Xuebao 39, 257–261. Wong, C.K., Ooi, V.E., Ang, P.O., 2000. Protective effects of seaweeds against liver injury caused by carbon tetrachloride in rats. Chemosphere 41, 173–176. Wu, W., Hasumi, K., Peng, H., Hu, X., Wang, X., Bao, B., 2009. Fibrinolytic compounds isolated from a brown alga Sargassum fulvellum. Marine Drugs 7, 85–94. Xu, N., Fan, X., Han, L., Lin, W., Zeng, C., 2002a. Study on antibacterial activity of ethanol extract of seaweed. Haiyang Yu Huzhao 33, 265–270. Xu, S.H., Cen, Y.Z., Li, Y.L., Xu, S.Y., 1999. A novel eleven-membered heterocyclic compound from algae Sargassum vachellianum. Chinese Chemical Letters 10, 401–402.
619
Xu, S.H., Ding, L.S., Wang, M.K., Peng, S.L., Liao, X., 2002b. Studies on the chemical constituents of the algae Sargassum polycystcum. Chinese Journal of Organic Chemistry 22, 138–140. Yamaguchi, M., Hachiya, S., Hiratuka, S., Suzuki, T., 2001. Effect of marine algae extract on bone calcification in the femoral–metaphyseal tissues of rats: anabolic effect of Sargassum horneri. Journal of Health Science 47, 533–538. Yamamoto, I., Nagumo, T., Fujihara, M., Takahashi, M., Ando, Y., Okada, M., Kawai, K., 1977. Antitumor effect of seaweeds. II. Fractionation and partial characterization of the polysaccharide with antitumor activity from Sargassum fulvellum. Japanese Journal of Experimental Medicine 47, 133–140. Yamamoto, I., Nagumo, T., Takahashi, M., Fujihara, M., Suzuki, Y., Iizima, N., 1981. Antitumor effect of seaweeds. III. Antitumor effect of an extract from Sargassum kjellmanianum. Japanese Journal of Experimental Medicine 51, 187–189. Yamamoto, I., Nagumo, T., Yagi, K., Tominaga, H., Aoki, M., 1974. Antitumor effect of seaweeds. I. Antitumor effect of extracts from Sargassum and Laminaria. Japanese Journal of Experimental Medicine 44, 543–546. Yamamoto, I., Takahashi, M., Suzuki, T., Seino, H., Mori, H., 1984. Antitumor effect of seaweeds. IV. Enhancement of antitumor activity by sulfation of a crude fucoidan fraction from Sargassum kjellmanianum. Japanese Journal of Experimental Medicine 54, 143–151. Yan, X.J., Fang, G.M., Lou, Q.X., 1999. Studies on free radical scavenging activity in Chinese seaweeds Part I. Screening results. Chinese Journal of Oceanology and Limnology 17, 240–246. Yang, X., Kang, M.C., Lee, K.W., Kang, S.M., Lee, W.W., Jeon, Y.J., 2011. Antioxidant activity and cell protective effect of loliolide isolated from Sargassum ringgoldianum subsp. coreanum. Algae 26, 201–208. Ye, H., Wang, K., Zhou, C., Liu, J., Zeng, X., 2008. Purification, antitumor and antioxidant activities in vitro of polysaccharides from the brown seaweed Sargassum pallidum. Food Chemistry 111, 428–432. Zandi, K., Ahmadzadeh, S., Tajbakhsh, S., Rastian, Z., Yousefi, F., Farshadpour, F., Sartavi, K., 2010. Anticancer activity of Sargassum oligocystum water extract against human cancer cell lines. European Review for Medical and Pharmacological Sciences 14, 669–673. Zhang, H., 2006. The hypoglycemic effect of the extract of Sargassum fusiforme. Shizhen Guoyi Guoyao 17, C3–C4. Zhu, W., Chiu, L.C.M., Ooi, V.E.C., Chan, P.K.S., Ang, J.P.O., 2006. Antiviral property and mechanisms of a sulphated polysaccharide from the brown alga Sargassum patens against Herpes simplex virus type 1. Phytomedicine 13, 695–701. Zhu, W., Chiu, L.C.M., Ooi, V.E.C., Chan, P.K.S., Ang, P.O., 2004. Antiviral property and mode of action of a sulphated polysaccharide from Sargassum patens against herpes simplex virus type 2. International Journal of Antimicrobial Agents 24, 279–283. Zhu, W., Ooi, V.E., Chan, P.K., Ang Jr., P.O., 2003. Isolation and characterization of a sulfated polysaccharide from the brown alga Sargassum patens and determination of its anti-herpes activity. Biochemistry and Cell Biology 81, 25–33. Zhuang, C., Itoh, H., Mizuno, T., Ito, H., 1995. Antitumor active fucoidan from the brown seaweed, umitoranoo (Sargassum thunbergii). Bioscience, Biotechnology, and Biochemistry 59, 563–567. Zubia, M., Payri, C., Deslandes, E., 2008. Alginate, mannitol, phenolic compounds and biological activities of two range-extending brown algae, Sargassum mangarevense and Turbinaria ornata (Phaeophyta: Fucales), from Tahiti (French Polynesia). Journal of Applied Phycology 20, 1033–1043.