Marine bioactive compounds and health promoting perspectives; innovation pathways for drug discovery

Accepted Manuscript Marine Bioactive Compounds and Health Promoting Perspectives; Innovation Pathways for Drug Discovery Hafiz Ansar Rasul Suleria, RHD Fellow, Glenda Gobe, Paul Masci, Simone A. Osborne PII:

S0924-2244(16)00022-4

DOI:

10.1016/j.tifs.2016.01.019

Reference:

TIFS 1761

To appear in:

Trends in Food Science & Technology

Received Date: 11 May 2015 Revised Date:

13 January 2016

Accepted Date: 26 January 2016

Please cite this article as: Rasul Suleria, H.A., Gobe, G., Masci, P., Osborne, S.A., Marine Bioactive Compounds and Health Promoting Perspectives; Innovation Pathways for Drug Discovery, Trends in Food Science & Technology (2016), doi: 10.1016/j.tifs.2016.01.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Marine Bioactive Compounds and Health Promoting Perspectives; Innovation

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Pathways for Drug Discovery

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Hafiz Ansar Rasul Suleria1, 2*, Glenda Gobe1, Paul Masci1 and Simone A. Osborne2

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School of Medicine, The University of Queensland, Translational Research Institute, Kent Street, Woolloongabba, Brisbane, 4102, Australia

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CSIRO Agriculture, 306 Carmody Road, St Lucia, QLD, 4067, Australia

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Hafiz Ansar Rasul Suleria, ([email protected])

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Corresponding Author

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Hafiz Ansar Rasul Suleria

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RHD Fellow

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School of Medicine

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The University of Queensland

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Brisbane QLD 4072, Australia

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Phone: +61 7 321 42207; +61 470 439 670 (Mobile)

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Email: [email protected]

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Marine Bioactive Compounds and Health Promoting Perspectives; Innovation

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Pathways for Drug Discovery

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Hafiz Ansar Rasul Suleria1, 2*, Glenda Gobe1, Paul Masci1 and Simone A. Osborne2

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School of Medicine, The University of Queensland, Translational Research Institute, Kent Street, Woolloongabba, Brisbane, 4102, Australia

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CSIRO Agriculture, 306 Carmody Road, St Lucia, QLD, 4067, Australia

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ABSTRACT

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Background

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Marine organisms are one of the most important sources of bioactive compounds for the food

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and pharmaceutical industries. Bioactive compounds can be isolated from various sources

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including marine plants, animals and microorganisms.

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Scope and approach

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Marine bioactive compounds exhibit significant and biological properties contributing to their

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nutraceutical and pharmaceutical potential and are also considered to be safer alternatives to

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some existing synthetic drugs. As such, some marine bioactive compounds are currently

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under investigation at an advanced stage of clinical trials with a few of them already being

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marketed as safer drugs.

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Key findings and conclusions

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Marine bioactive compounds that have been the most extensively studied include

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carbohydrates, pigments, polyphenols, peptides, proteins and essential fatty acids. These

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compounds have rheological properties, deeming them useful in the food industry, as well as

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various biological functions like anti-oxidant, anti-thrombotic, anti-coagulant, anti-

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inflammatory, anti-proliferative, anti-hypertensive, anti-diabetic and cardio-protection

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activities making them attractive nutraceuticals and pharmaceutical compounds. This review

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summarises current research on bioactive compounds from different marine sources and

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brings into focus the potential use of these compounds in the food industry and in drug

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discovery to treat and prevent various chronic diseases.

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Keywords: Marine bioactive compounds, drug discovery, nutraceuticals, health perspectives

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BACKGROUND

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Marine bioactive compounds Marine flora and fauna are excellent sources of bioactive compounds with therapeutic

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benefits that represent a valuable source of new compounds. The biodiversity of the marine

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environment and its associated chemical diversity contribute to an almost unlimited resource

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of new bioactive compounds (Pihlanto-Leppälä, 2000). Bioactive compounds can be isolated

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from various sources including marine plants, animals, microorganisms and sponges with

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unique set of molecules (Rasmussen & Morrissey, 2007). Bioactive compounds extracted

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from these organisms are effective against different infectious and non-infectious diseases.

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Six hundred and fifty new marine compounds were isolated in 2003 from the marine

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environment (Kim & Wijesekara, 2010) highlighting the great potential of marine sources.

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Therefore, the following review presents current knowledge that demonstrates the suitability

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of marine bioactive compounds in drug discovery to treat and prevent various chronic

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diseases.

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Marine Bioactive Molecules and the Food Industry

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Numerous marine bioactive compounds are utilized in different food products at

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industrial scale. Marine products are rich in proteins containing both essential and non-

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essential amino acids, polysaccharides, polyunsaturated fatty acids (PUFAs), vitamins,

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minerals and many other nutrients (Venugopal, 2005). These compounds can be isolated from

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fish, shellfish, molluscs (including mussel, oyster, scallop, abalone, snail and conch),

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cephalopods (including squid, cuttlefish and octopus), crustaceans (including crayfish, crab,

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shrimp and lobster), echinoderms, seaweeds and microalgae (Kannan, Hettiarachchy,

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Marshall, Raghavan & Kristinsson, 2011). Marine organisms are able to provide different

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types of bioactive compounds at different quantities—an appealing attribute to the food

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industry.

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Proteins from marine sources are used in food products because of their unique

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properties such as film foaming capacity and gel forming ability (Rasmussen & Morrissey,

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2007). Marine gelatin is formed during the partial hydrolysis of collagen and is used as a food

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additive because of its gel forming ability, texture improvement, water holding capacity and

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food product stability (Rustad, 2003).

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Marine polysaccharides are sourced from a variety of organisms and display several

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properties making them suitable for inclusion in food products, in particular marine 3

ACCEPTED MANUSCRIPT polysaccharides are able to bind large amounts of water and disperse it in food products

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(Berna, Cirik, Turan, Tekogul & Koru, 2013). For example, agar can be used in confectionery

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industries because of high sugar content, bland taste and does not impart flavour in jellies,

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jams, fruit candies, puddings, and custards. Carrageenans are used to modify the textures of

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diverse food products through changes in water binding, foaming and emulsifying attributes.

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Textural modifications of food are influenced by the interactions of these polysaccharides

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with other food components (Yu et al., 2002). Other marine polysaccharides such as alginate,

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chitosan and fucoidan are also ideal raw materials for edible, biodegradable films because of

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their gel forming ability. Chitin, chitosan and their derivatives also have variety of food

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applications including use as antimicrobial agents, edible films, additives, nutraceuticals (e.g.,

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increasing dietary fibre, reducing lipid absorption) and water purifiers (Fiszman & Salvador,

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2003).

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Marine pigments such as carotenoid and chlorophyll molecules are used as natural

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colorants and antioxidants in different food products (Schoefs, 2002). Beta-carotene can be

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extracted from Dunaliella salina, one of the most suitable sources producing up to 14% of

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beta-carotene of its dry weight (Metting, 1996). Moreover, Dharmaraj, Ashokkumar &

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Dhevendaran (2009) confirmed the production of food grade carotenoids from Callyspongia

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diffusa, marine sponge. Beta-carotene is one of the leading food colorants in the world and

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has been applied to a range of food and beverage products to improve their appearance to

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consumers (Dufossé et al., 2005). Chlorophylls are also used as natural colorants in food and

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beverage industries. Furthermore, phycobiliproteins can be derived from marine blue–green

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and red algae, which also have potential as natural food colorants. Therefore, marine

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bioactive compounds have important functional properties that could be scaled up and

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economically favorable as ingredients for the food industry (Park, Jung, Nam, Shahidi &

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Kim, 2001).

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Place Table 1 here

An extensive array of various compounds are added into food products in order to

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produce desirable characteristics in finished products. Accordingly, marine bioactive

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compounds are capable of improving the texture, appearance, quality and stability of finished

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food products. Marine bioactive compounds also appear to be suitable and attractive to the

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food industry owing to their natural availability, relatively cost effective extraction methods

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and biological activities that can promote health and reduce the burden of various diseases.

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MARINE BIOACTIVE COMPOUNDS AND HEALTH BENEFITS The incidence of chronic diseases such as cancer, cardiovascular disease, diabetes and

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obesity is rapidly increasing (Nugent, 2008), as such there is a need for the development of

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new and safe therapeutics to meet the growing health needs of the global population. Marine

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organisms are valuable sources of bioactive compounds that can be used as food additives,

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nutraceuticals or pharmaceuticals. It has been reported that consumption of marine foods and

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marine bioactive compounds can reduce the burden of diseases (Lordan, Ross & Stanton,

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2011). Some of the major health effects and therapeutic uses of marine sources and their

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bioactive compounds are illustrated in the following sections. Place Table 2 here Anti-oxidant activity

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Food industries are working towards the development of anti-oxidants from natural

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sources that offer safer alternatives to many synthetic commercial anti-oxidants. Food

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deterioration occurs because of the oxidation of lipids and results in production of

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undesirable compounds leading to the spoilage of food commodities. Lipid oxidation by

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reactive oxygen species (ROS) like hydroxyl radicals, hydrogen peroxide and superoxide

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anions decrease the nutritional properties of lipid enriched food. In order to reduce the lipid

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peroxidation several synthetic anti-oxidants are used such as propyl gallate, butylated

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hydroxytoluene, butylated hydroxytoluene and tert-butylhydroquinone. The use of synthetic

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anti-oxidants are tightly regulated in some countries because of their health related issues (Je,

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Park, & Kim, 2005); for this reason, researchers are investigating natural anti-oxidants as

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safer alternatives with marine organisms providing many candidate bioactive compounds

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(Pena-Ramos & Xiong, 2001).

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Aside from the role of ROS in the deterioration of food products, excessive ROS are

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also associated with various diseases such as neurodegenerative, inflammatory diseases and

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cancer (Cornish & Garbary 2010). The reaction of ROS with biomolecules like proteins,

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membrane lipids and DNA results in cellular or tissue level injuries. Equilibrium between

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endogenous anti-oxidant systems and oxidant formation protects cellular biomolecules,

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however a disturbance in this balance can lead to oxidative stress. Therefore, anti-oxidants

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play a vital role in maintaining the cellular redox state and protecting the body against

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damage caused by ROS (Ngo, Wijesekara, Vo, Ta, & Kim, 2011).

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Marine sourced bioactive compounds with anti-oxidant activity fall into several

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categories including proteins, peptides, carbohydrates, pigments and polyphenols. Examples

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from each category are discussed in the following sections.

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1. Marine peptides and phycobiliproteins The beneficial effects of marine bioactive peptides include scavenging ROS and

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preventing lipid peroxidation (Qian, Jung, Byun & Kim, 2008). In the last few years,

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different studies have isolated, characterized and purified bioactive peptides from different

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marine sources with anti-oxidant potential. Some of the major marine sources are Pacific

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hake (Samaranayaka & Li-Chan, 2008), cod (Slizyte et al., 2009), hoki (Kim, Je & Kim,

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2007), mackerel (Wu, Chen & Shiau, 2003), jumbo squid (Mendis, Rajapakse, Byun & Kim,

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2005), Alaska pollack (Cho et al., 2008), blue mussel (Rajapakse, Jung, Mendis, Moon &

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Kim, 2005a), conger eel (Ranathunga, Rajapakse & Kim, 2006), oyster (Qian, Jung, Byun &

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Kim, 2008), scad (Thiansilakul, Benjakul & Shahidi, 2007), yellow stripe trevally (Klompong

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et al., 2009), tuna (Je, Qian, Lee, Byun & Kim, 2008), yellow fin sole (Jun, Park, Jung &

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Kim, 2004), capelin (Amarowicz & Shahidi, 1997), and microalgae (Sheih, Wu & Fang,

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2009a).

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Mendis, Rajapakse, Byun & Kim, (2005b) isolated bioactive peptides from jumbo

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squid and demonstrated inhibition of lipid peroxidation by these peptides using a linoleic acid

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model system. The anti-oxidant activity of the isolated peptides was found to be comparable

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to the synthetic anti-oxidant butylated hydroxytoluene. It was further deduced that anti-

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oxidant activity could be attributed to the presence of particular hydrophobic amino acids in

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the isolated peptides. In another study, one of the anti-oxidant peptides (Leu-Lys-Gln-Glu-

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Leu-Glu-Asp-Leu-Leu-Glu-Lys-Gln-Glu) isolated from oyster (Crassostrea gigas), showed

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higher anti-oxidant activity than the synthetic anti-oxidant α-tocopherol in polyunsaturated

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fatty acid peroxidation (Qian, Jung, Byun & Kim, 2008). Other studies have also suggested

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that peptides derived from marine fish have greater anti-oxidant potential than α-tocopherol

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in different oxidative settings (Rajapakse, Jung, Mendis, Moon & Kim, 2005a). The precise

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mechanisms involved in the anti-oxidant activities are not known, however some aromatic

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amino acids, such as histidine, and some hydrophobic amino acids are reported to play an

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important role in the observed activity.

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Phycobiliproteins (PBPs) are a class of marine proteins with anti-oxidant activity that

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are found in very high abundance in cyanobacteria (Soni, Trivedi & Madamwar, 2008). 6

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hypothesized to be associated with the different side chains of constituent amino acids

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(Sonani, Singh, Kumar, Thakar & Madamwar, 2014). For example, amino acids in PBPs with

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hydrophobic side chains are good proton donors and metal ion chelators whereas acidic, basic

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and aromatic amino acids are thought to sequesters metal ion (Sarmadi & Ismail, 2010).

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Taken together, variations in the distribution of amino acids on the outer surface of PBPs may

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favour one anti-oxidant activity over another contributing to the diverse anti-oxidant activity

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associated with PBPs. Phycobiliproteins are also utilised as natural dyes in the food and

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cosmetic industry where they are used as colorants in many food products such as desserts,

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ice creams, fermented milk and milk shakes (Santiago-Santos, Ponce-Noyola, Olvera-

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Ramıŕ ez, Ortega-López & Cañizares-Villanueva, 2004). Even though PBPs are relatively

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unstable at higher temperatures and light, PBPs are considered more versatile than the

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commonly used colorants indigo and gardenia, producing a bright blue color in products such

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as coated soft candies and jelly gum (Sekar & Chandramohan, 2008).

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Overall, potent anti-oxidant activity has been displayed by several marine-derived

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bioactive peptides and proteins demonstrating a huge potential to be utilized in nutraceuticals

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and pharmaceuticals industries.

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2. Marine polysaccharides

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Polysaccharides derived from marine organisms have anti-oxidant capacity via their

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scavenging effect on ROS. Fucoidans from the edible seaweed F. vesiculosus have been

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shown to prevent the generation of superoxide and hydroxyl radicals and decrease lipid

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peroxidation (Micheline et al., 2007). Specific fucoidan fractions prepared from L. japonica

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using gel-permeation chromatography exhibited excellent superoxide radical scavenging

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capacities with low molecular weight fucoidin fractions in particular possessing greater

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inhibitory effects on low-density lipoprotein (LDL) oxidation induced by Cu2+ (Zhao, Xue,

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Cai, Wang & Fang, 2005). The superoxide radical scavenging ability of fucoidan obtained

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from L. japonica has also been confirmed by other studies (Wang, Zhang, Zhang, & Li, 2008)

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and Zhao, Wang, and Xue (2011) where low molecular weight fucoidin oligosaccharides

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(2000–8000 Da) from L. japonica with a sulfate content of 24.3% had a strong protective

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effect against both hydrophilic radical 2, 2'-azobis (2, 4-amidinopropane) dihydrochloride

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(AAPH) and lipophilic radical 2 ,2'-azobis (2, 4-dimethylvaleronitrile)-induced (AMVN)

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LDL oxidation. Furthermore, a highly sulfated and lower molecular weight (20 kDa) fucoidin

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fraction effectively suppressed AMVN-induced LDL oxidation. In an in vivo experiment,

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fucoidan from L. japonica prevented an increase in lipid peroxide in the serum, spleen and

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liver of diabetic mice (Li et al., 2002). Collectively, these results illustrate the beneficial

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effect of algal fucoidans as anti-oxidants and highlight the great potential of these molecules

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for alleviating oxidative stress associated with disease. Other studies have shown that sulfated polysaccharides slightly different to fucoidins

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are also potent anti-oxidants. For example, sulfated polysaccharides isolated from brown

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algae, Sargassum fulvellum have more potential to scavenge nitric oxide (NO) compared to

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commercial synthetic anti-oxidants like butylated hydroxyanisole and tocophorol (Kim et al.

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2009). The anti-oxidant capacity of these sulfated polysaccharides was found to depend upon

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the molecular weight, degree of sulfation, major saccharide unit and glycosidic branching

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(Zhang et al., 2003). For example, the lower molecular weight sulfated polysaccharides

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displayed more anti-oxidant activity than higher molecular weight (Sun, Wang, Shi, & Ma,

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2009). In another study, different molecular weight ulvans prepared from (Ulva pertusua) by

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H2O2 degradation and their anti-oxidant activities were investigated, showing that lower

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molecular weight ulvans have stronger anti-oxidant activity, compared to intact ulvans (Qi et

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al., 2005). The reason for this may be that lower molecular weight polysaccharides are more

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easily incorporated into cells donating protons more effectively compared to higher

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molecular weight polysaccharides. This evidence suggests that sulfated polysaccharides with

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different degrees of sulfation, glycosidic branching and molecular weight may prove to be the

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more useful candidates in the search for effective, non-toxic substances with anti-oxidant

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activity.

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3. Marine pigments and polyphenols

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Marine algae are one of the richest sources of anti-oxidants in marine biota (Cornish

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& Garbary, 2010). Microalgae and macroalage (seaweed) have been shown to decrease ROS

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due to their abundance in bioactive compounds such as pigments, polyphenols and vitamins.

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Le Tutour et al. (1998) reported that chlorophyll a and related compounds derived

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from brown algae have anti-oxidant activities in methyl linolenate systems. Likewise, Endo,

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Usuki & Kaneda (1985a) also demonstrated that chlorophyll a exhibits anti-oxidant activity

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and that a porphyrin ring present in chlorophyll a was an essential structure for activity. More

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recently, it has been suggested that chlorophyll a reacts with peroxyl radicals to form a charge

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transfer complex. The charge transfer complex reacts with and sequesters peroxyl radicals 8

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prepared different chlorophyll derivatives and investigated their anti-oxidant activities.

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Among the natural products assayed, chlorophyll b derivatives showed stronger anti-oxidant

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activity than chlorophyll a derivatives, suggesting that the presence of an aldehyde group in

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chlorophyll b in place of a methyl group in chlorophyll a provides better anti-oxidant activity,

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however the mechanism involved remains unknown.

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Yan, Chuda, Suzuki, & Nagata (1999) investigated the anti-oxidant activity in Hijikia

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fusiformis and showed that fucoxanthin was one of the major anti-oxidant molecules with

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potential to scavenge free radicals. Fucoxanthin has a strong radical scavenging activity that

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appeared to correlate with the presence of unusual double allenic bonds at the C-70 position

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(Sachindra et al. 2007). Fucoxanthin was also isolated from Undaria pinnatifida and used to

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prepare two metabolites, fucoxanthinol and halocynthiaxanthin, with antioxidant potential.

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The anti-oxidant activity of these three carotenoids derived from Undaria pinnatifida was

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quantified by hydroxyl radical scavenging activity, singlet oxygen quenching activity and

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DPPH. It was concluded that the highest anti-oxidant activity was found in fucoxanthin

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followed by fucoxanthinol and halocynthiaxanthin due to the presence of an allenic bond in

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fucoxanthin and fucoxanthinol (Sachindra et al., 2007). Heo et al. (2008) also investigated the

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cytoprotective effect (in vitro) of fucoxanthin against ROS induced by H2O2 and observed

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that inhibition of these ROS formation is due to the presence of two hydroxyl groups in the

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fucoxanthin structure.

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Phlorotannins derived from marine brown algae have also been found to exhibit

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strong anti-oxidant activities against free radical mediated oxidation (Shibata, Ishimaru,

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Kawaguchi, Yoshikawa, & Hama, 2008). Phlorotannins have been purified from the brown

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algae E. bicyclis, E. kurome, H. fusiformis and E. cava and all have displayed potent anti-

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oxidant and protective effects against H2O2-induced cell damage (Kang et al., 2006). In

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particular, phlorotannins like eckol, phlorofucofuroeckol A, dieckol, and 8, 8-bieckol have

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shown anti-oxidant capacity in phospholipid peroxidation (Shibata, Ishimaru, Kawaguchi,

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Yoshikawa, & Hama, 2008). Phlorotannins also have strong anti-oxidant activity against

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DPPH and superoxide comparable to anti-oxidants such as ascorbic acid and tocopherol.

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Therefore, phlorotannins in E. cava are potential natural anti-oxidants for the food and

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pharmaceutical industries (Kim et al., 2006).

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oxidant activities (Yoon, Eom, Kim, & Kim, 2009). These anti-oxidant compounds have

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potential as therapeutics in nutraceutical and pharmaceutical industries and as preservatives

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in food industry.

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Anti-thrombin and Anti-coagulant Activity

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Coagulation is a complex process involved in the formation of clots and is an important part

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of haemostasis; the cessation of blood loss from a damaged vessel following injury (David,

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Nigel, Michael, & Denise, 2009). Anti-coagulants are therapeutics that have the ability to

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prevent blood coagulation or stop the formation of blood clots (Desai, 2004). For example,

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they provide immediate therapeutic anti-coagulation in life threatening conditions like deep

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vein thrombosis and pulmonary embolisms; they are also used to reduce the risk of blood

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clots post-surgery.

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Heparin, a sulfated polysaccharide found in most mammalian tissues, one of the most

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common anti-coagulant drugs in the world and has been used for last fifteen years as a

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commercial anti-coagulant against thromboembolic disorders (Fan et al., 2011). However,

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there are several sides effect associated with heparin treatment including thrombocytopenia,

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inability to inhibit thrombin bound to fibrin, ineffectiveness in acquired anti-thrombin

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deficiencies and unwanted bleeding (Pereira, Melo, & Mourao, 2002). Currently, most of the

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commercial heparin is isolated from pig intestine and bovine lungs with considerable efforts

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made to extract it from safer sources that minimize the hemorrhagic risk, while retaining an

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efficacious anti-thrombotic activity (Mansour et al., 2010). Therefore, heparin alternatives are

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in high demand (Mauro, Pavão, & Mourão, 2012). Marine organisms are being investigated

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as a source of heparin alternatives and have recently provided many new anti-thrombotic and

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anti-coagulant therapeutic candidates. These molecules range from sulfated polysaccharides

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to peptides and are derived from a variety of marine sources.

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Marine algae are abundant in sulfated polysaccharides that have anti-thrombotic and anti-

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coagulant activities. Sulfated polysaccharides with anti-thrombotic and anti-coagulant

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activities have been extracted from different marine algae including red and brown seaweeds.

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Anti-coagulant fucoidans from different brown algae species have been identified showing

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variations in structure and biological activity (Boisson-Vidal et al., 2000). Fucoidins have

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been well characterised and studies have shown that anti-coagulant activity is related to

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sulfate content and position as well as monosaccharide content. For example, characterization

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gymnospora, revealed that 3-O-sulfation at C-3 of 4-α-l-fucose-1→unit was responsible for

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anti-coagulant activity (Silva et al., 2005). Nishino & Nagumo (1992) have also revealed that

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the higher content of fucose and sulfate groups present in fucoidins from E. kurome, the

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higher the anti-coagulant activity. Moreover, position of sulfated groups within carbohydrate

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molecules is also one of the prime factors for the anti-coagulant activity in fucoidan. It was

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further identified that the content of C-2 sulfate and C-2, 3 disulfate in fucoidans is associated

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with anti-coagulant activity (Chevolot, Mulloy, & Racqueline, 2001). With respect to

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mechanism, heparin cofactor II-mediated anti-thrombin activity increases with an increasing

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sulfate content in fucoidan (Qui, Amarasekara, & Doctor, 2006). It has also been found that

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fucoidans enhance anti-thrombin-mediated coagulation factor inhibition (Ustyuzhanina et al.,

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2013).

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Other studies involving fucoidin have investigated the relevance of molecular weight to anti-

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coagulant activity indicating that a higher molecular weight is more consistent with activity.

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In one study higher molecular weight fucoidans, such as 27 and 58 kDa, exhibited stronger

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anti-coagulant effects than a lower molecular weight 10 kDa fucoidan (Nishino, Aizu, &

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Nagumo, 1991b). In another study, native fucoidan isolated from Lessonia vadose, (MW 320,

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kDa) showed better anti-coagulant activity than a lower molecular fraction (MW 32, kDa)

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obtained by radical depolymerisation (Chandı´a & Matsuhiro, 2008).

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Sources other than algae have also provided sulfated polysaccharides with the potential to

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become new therapeutic candidates. Sulfated polysaccharides, such as a glycosaminoglycan-

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like molecule or fucosylated chondroitin sulfate (FCS), have been isolated from Sea

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cucumber (Ludwigothurea grisea). This molecule contains a chondroitin sulfate-like core

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with side chains of sulfated α-L-fucose attached to β-D-glucuronic acid at C-3 position

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(Mourao et al., 1996). Several studies have demonstrated potent anti-thrombotic and anti-

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coagulant activity from FCS in vitro and in vivo. Mulloy, Mourão, & Gray (2000)

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investigated FCS isolated from Ludwigothurea grisea and found the fractions have ability to

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increase the APTT. Lu & Wang, (2009) also investigated the anti-coagulant activity of FCS

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and modified chemical FCS derivatives from sea cucumber (Stichopus japonicus) in a stasis

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thrombosis model in rabbits revealing that both desulfation of FCS and partial defucosylation

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reduced its anti-coagulant activities. Furthermore, FCS isolated from Stichopus japonicus

341

also has ability to initiate thrombin inhibition through both anti-thrombin and heparin

342

cofactor II. Comparisons between native and chemically modified (desulfated, partial

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ACCEPTED MANUSCRIPT defucosylated and carboxyl-reduced) polysaccharides also showed that sulfated fucose-side

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chains play a vital role in anti-coagulant properties (Zancan & Mourao, 2004).

345

Marine peptides with potent anti-coagulant properties have also been isolated from marine

346

sources such as starfish (Koyama, Noguchi, Aniya, & Sakanashi, 1998), marine echiuroid

347

worm (Jo, Jung, & Kim, 2008), blood ark shells (Jung, Je, & Kim, 2001), blue mussel (Jung

348

& Kim, 2009) and yellow fin sole (Rajapakse, Jung, Mendis, Moon, & Kim, 2005a). Jo, Jung,

349

& Kim (2008) isolated an anti-coagulant peptide (Gly-Glu-Leu-Thr-Pro-Glu-Ser-Gly-Pro-

350

Asp-Leu-Phe-Val-His-Phe-Leu-Asp-Gly-Asn-Pro-Ser-Tyr-Ser-Leu-Tyr-Ala-Asp-Ala-Val-

351

Pro-Arg) from marine echiuroid worm (Urechis caupo). The isolated peptide prolonged

352

normal clotting time from 32.3 ± 0.9 s to 192.2 ± 2.1 s in APTT assays in a dose-dependent

353

manner. This peptide also bound specifically with clotting factor FIXa, and inhibited

354

molecular interactions between FIXa and FX in a dose-dependent manner. Moreover, another

355

anti-coagulant peptide isolated from blue mussel (Glu-Ala- Asp-Ile-Asp-Gly-Asp-Gly-Gln-

356

Val-Asn-Tyr-Glu-Glu-Phe-Val-Ala-Met-Met-Thr-Ser-Lys), prolonged the clotting time in a

357

TT assay from 11.6 ± 0.4 s (control) to 81.3 ± 0.8 s and 35.3 ± 0.5 s (control) to of 321±2.1 s,

358

in an APTT assay (Jung & Kim, 2009).

359

Overall, many studies have proposed marine bioactive compounds such as fucoidan and

360

fucosylated chondroitin sulfates as alternatives to heparin; one study has even suggested that

361

certain fractions of fucoidan with potent anti-coagulant activity should qualify as heparinoids

362

(i.e. molecules derived from heparin) (Mourao, 2004).

363

Anti-inflammatory effect

364

Inflammation, a critically important part of host responses to various stimuli including injury,

365

microbial invasion and immune reactions (Vo, Ngo, & Kim, 2012), involves various

366

biological pathways that can be directed by external and internal stimuli. These biological

367

pathways can be modulated, reduced or inhibited by compounds known as anti-

368

inflammatories. These anti-inflammatories mainly modulate macrophages; one of the key

369

players in the inflammation process (Nagatoshi & Kazuo, 2005). In the innate immune

370

system, macrophages play a significant role in homeostasis as they are the predominant

371

source of inflammatory mediators such as prostaglandin E2 (PGE2), interleukin-6 (IL-6) and

372

interleukin-1β (IL-1β)], nitric oxide (NO), pro-inflammatory cytokines like tumour necrosis

373

factor-α (TNF-α) and a few other types of ROS (Block, Zecca, & Hong, 2007). Excessive or

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prolonged inflammation can be harmful and cause other diseases, including chronic asthma,

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ACCEPTED MANUSCRIPT rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis and cancer. It

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has been reported in recent years that synthetic anti-inflammatory drugs can cause

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gastrointestinal irritations; therefore the search for safer alternatives from natural sources is

378

ongoing (Nguemfo et al., 2007).

379

Many bioactive compounds isolated and purified from natural sources are capable of boosting

380

immunity (Li, Lu, Wei, & Zhao, 2008). Sulfated polysaccharides from algae have effects on

381

innate immunity modulating the ability of immune cells to produce nitric oxide ultimately

382

reducing inflammation (Leiro, Castro, Arranz, & Lamas, 2007). Fucoidans from marine algae

383

have been shown to inhibit inflammatory responses in in vitro studies. Investigations in the

384

immunomodulating effects of fucoidan and arabinogalactan demonstrated that both

385

molecules are activators of macrophages and lymphocytes (Choi, Kim, Kim, & Hwang,

386

2005). According to Yang et al. (2008), fucoidan may be used for cancer immunotherapy

387

because it can influence the activation and maturation of human monocyte-derived dendritic

388

cells. The effect of fucoidin on the production of NO induced by IFN-α was reported using

389

two cells lines; macrophages (RAW264.7) and glial cells (C6, BV-2). It was further shown

390

that fucoidan effects inducible Nitric Oxide Synthase (iNOS) expression through IFN-Ɣ-

391

mediated signalling in the same cell lines indicating that it is not only an anti-inflammatory

392

candidate, but also an immune-modulating compound.

393

In another study fucoidan from Fucus vesiculosus significantly inhibited NO production in

394

BV2 microglia induced by LPS. Inhibition of NO production was due to down regulation of

395

iNOS expression, cyclooxygenase (COX-2), monocyte chemoattractant protein-1 (MCP-1)

396

and interleukin-1β (IL-1β) and (TNF)-α (Park et al., 2011a). Interestingly, the anti-

397

inflammatory properties exhibited by fucoidin acted by suppressing nuclear factor-kappa B

398

(NF-κB) activation and through the down regulation of c-Jun N-terminal kinase (JNK), p38

399

mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase (ERK) and

400

AKT pathways. In short, fucoidin has considerable potential as a therapeutic in

401

neurodegenerative and inflammatory diseases (Park et al., 2011a).

402

Fucoxanthin is another marine bioactive compound with both in vitro and in vivo anti-

403

inflammatory activities. Fucoxanthin is comparable with predinisolone, a commercially

404

available steroidal anti-inflammatory drug (Shiratori et al. 2005). Furthermore, Heo et al.

405

(2010) also screened for the in vitro inhibitory effect of fucoxanthin from nine different

406

species of brown algae and correlated fucoxanthin contents with inhibition of NO production.

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The decrease in NO production correlated with a decrease in the expression of COX-2 and

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ACCEPTED MANUSCRIPT iNOS as well as a decrease in TNF-α, IL-6 and IL-1β (Heo et al., 2010). The mechanism

409

involved in the fucoxanthin anti-inflammatory activities was similar to that reported for

410

fucoidin; phosphorylation of mitogen-activated protein kinases (MAPKs) and suppression of

411

NF-κB (Kim et al., 2010).

412

Polyunsaturated fatty acids (PUFAs), especially omega-3 and omega-6 fatty acid isolated

413

from different marine sources have anti-inflammatory effects and are capable of modulating,

414

suppressing and inhibiting various inflammatory mediators (Calder, 2006). It has also been

415

shown that by incorporating specific ratios of the omega fatty acids in the diet, inflammation

416

may be reduced. Furthermore, eicosanoids derived from omega-3 fatty acids like

417

docosahexaenoic acid and eicosapentaenoic acid (DHA and EPA) have anti-inflammatory

418

activities while eicosanoids derived from omega-6 fatty acids such as arachidonic acid (AA)

419

have immune-active functions and pro-inflammatory properties. Some clinical studies have

420

also shown that both DHA and EPA have positive effect on inflammation. Moreillon,

421

Bowden, & Shelmadine, (2012) reported that leukotrienes and the prostaglandins derived

422

from EPA by lipoxygenases (LOXs) and cyclooxygenases (COXs) are less pro-inflammatory

423

as compared to AA (omega-6). For that reason when there is a higher ratio of (DHA +

424

EPA)/AA, there is a lower index of inflammatory mediators. Moreover, various fish oils have

425

been evaluated as an alternative therapy for nonsteroidal anti-inflammatory drugs (NSAID).

426

Research conducted on rheumatoid arthritis (RA) patients in an informed dietary intervention

427

showed that an anti-inflammatory diet containing omega-3 fatty acids alleviated

428

inflammation and the symptoms of RA more than a placebo, indicating that fish oil has anti-

429

inflammatory properties for RA patients. In short, Omega-3 fatty acids are considered to be a

430

safer alternative to NSAID to reduce rheumatoid arthritis (Galarraga et al., 2007).

431

Hyaluronidase enzyme (EC 3.2.1.35) depolymerizes hyaluronic acid, a non-sulfated

432

glycsoaminoglycan mostly present in the extra cellular matrix of connective tissue.

433

Hyaluronidase is considered to be involved in allergic responses, inflammation and migration

434

of cancer cells. Phlorotannins isolated from different marine sources have a strong inhibitory

435

effect against hyaluronidase. Some of the phlorotannins like phlorofucofuroeckol A, eckol, 8,

436

80-bieckol and dieckol have shown more inhibition than the known hyaluronidase inhibitors,

437

catechin and sodium cromoglycate (Shibata, Fujimoto, Nagayama, Yamaguchi, & Nakamura,

438

2002). Moreover, Phlorofucofuroekol A showed anti-inflammatory activities by inhibiting

439

LPS-induced production of prostaglandin E2 and NO via the suppression of COX-2 and

440

iNOS in different cellular models (Kim et al., 2009). Moreover, phlorotannins are also potent

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inhibitors of histamine release (Le, Li, Qian, Kim, & Kim, 2009). Considering these facts,

442

phlorotannins could become one of the leading candidate compounds in the development of

443

new anti-inflammatory or anti-cancer drugs.

444

Anti-tumor Effects Cancer is a serious disease where uncontrolled growth of abnormal cells occurs due to

446

intrinsic factors like inherited mutations and extrinsic factors such as smoking, pathogens,

447

malnutrition and certain chemicals and radiation (American Cancer Society, 2006). Almost

448

six million cancer causalities are reported worldwide each year (Dikshit et al., 2012). It is

449

important to find an effective, safe and easily available medicine at low cost to treat these

450

cancers. Marine algae possess an extensive array of bioactive compounds that can be used to

451

cure various types of cancers (Frestedt, Kuskowski & Zenk, 2009). Various studies have

452

highlighted the anti-tumor potential of water-soluble bioactive compounds from marine

453

algae, but attempts at human clinical trials are limited due to risk-associated factors (Harada,

454

Noro & Kamei, 1997). These molecules have been found to destroy tumor cells by initiating

455

apoptosis or instigating signalling enzymes that affect cell metabolism and lead to cell death

456

(Sithrangaboopathy & Kathiresan, 2010). Apoptosis is the sequential death of cells induced

457

by extrinsic or intrinsic stimuli in multicellular organisms to maintain tissue homeostasis (Ker

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& Wyllie, 1972); some other factors like enzymes, signalling sensors and transcription factors

459

also induce apoptotic cell death. Apoptosis occurs in three distinct phases: activation;

460

execution; and cell deletion.

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Extracts of Nostocmuscorum and Oscillatoria spp. have shown anti-tumor activity in

462

vitro due to their inhibitory effect on the human hepatocellular cancer cell line (HepG2) and

463

Ehrlich’s Ascites Carcinoma Cells (EACC) (Tripathi, Fang, Leong, & Tan, 2012).

464

Serine/threonine kinase inhibition was also reported in response to scytonemin extracted from

465

Stigonema spp (Tripathi, Fang, Leong, & Tan, 2012). In vitro growth inhibition of

466

Plasmodium falciparum, a malarial parasite resistant to chloroquine, and human HeLa cancer

467

cells, was reported following treatment with extracts from Calothrix (Rickards, Rothschild,

468

Willis, 1999). Some other growth inhibitors like pentacyclic metabolites with an indole (3, 2-

469

j) phenanthridine alkaloids and calothrixin A (I) and B (II) have been isolated by

470

fractionation of extracts by Soxhlet solvent extraction method. Microcolin-A, extracted from

471

Lyngbya majuscule, is a linear peptide and immunosuppressant (Koehn, Longley, & Reed,

472

1992). Curacin-A, another peptide isolated from L. majuscule is also known for its anti-

473

proliferative properties in various tumor cell lines like renal, colon and breast (Carte, 1996).

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Recently, the most important discoveries are of cyanovirin, cryptophycin 1 & 8 and

475

borophycin. Borophycin is actually a boron-containing metabolite and normally purified from

476

marine cyanobacterial strains of N. spongiaeforme and Nostoc linckia having cytotoxic

477

effects against human colorectal cells (Banker, & Carmeli, 1999). Some algae are also noted for their inter-conversion of fatty acids from their simple

479

arachidonic acid form, to complex eicosanoids that can play a significant role in maintaining

480

homeostasis and curing ailments like cancer, heart disease, asthma, psoriasis, arteriosclerosis

481

and ulcers (Carte, 1996). There are different mechanisms that have been reported from

482

marine algae regarding the capacity of bioactive molecules to promote anti-cancer activity

483

like anti-oxidation, immune stimulation and apoptotic cell death (Sithrangaboopathy &

484

Kathiresan, 2010).

485

Anti-hypertensive effects and cardio-protection perspectives

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Hypertension, commonly known as high blood pressure, is more common in

487

developed countries and is associated with other diseases like cardiovascular diseases

488

(CVDs). Cardiovascular diseases are a group of illnesses related to heart and blood vessels

489

and include hypertension, coronary heart disease/myocardial infarction, stroke, heart failure

490

and peripheral vascular disorders (Masley, 1998). Coronary heart disease proceeds in three

491

distinct phases. In the first phase, atherosclerotic plaques high in lipid content grow along

492

with the propagation of smooth muscle cells as well as monocytes and macrophages that are

493

attracted to the plaque site. In the second stage, coronary arteries are obstructed with the

494

plaques and blood flow reduced. In the third phase, ulceration of the endothelial lining occurs

495

with the possible development of thrombi (blood clots) which may lead to myocardial

496

infarction (Connor, & Connor, 1997). Some of the major risk factors linked with

497

atherosclerosis are high plasma cholesterol levels, low levels of high density lipoprotein

498

(HDL), high levels of low density lipoprotein (LDL) very low density lipoprotein (VLDL)

499

and elevated levels of triglycerides. Nutraceuticals in the form of anti-oxidants, dietary fibres,

500

omega-3 PUFAs, vitamins and minerals obtained from fruits and vegetables, fish and their

501

products, algae, marine invertebrates and some microbes could be used for prevention and

502

treatment of CVDs (Mayakrishnan, Kannappan, Abdullah, & Ahmed, 2013).

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Marine fish are rich in bioactive peptides and omega-3 PUFAs that may act as anti-

504

hypertensives and can decrease systolic and diastolic blood pressure of patients with mild

505

hypertension (Deckere, Korver, Verschuren, & Katan, 1998). Similarly marine fish-derived

16

ACCEPTED MANUSCRIPT angiotensin-converting enzyme ACE inhibitory peptides have therapeutic properties to treat

507

CVDs especially hypertension (Kobayashi, Yamauchi, Katsuda, Yamaji, & Katoh, 2008).

508

Chlorella, a well-known microalga, is thought to lower the blood pressure by regulating the

509

renin-angiotensin-aldosterone system in hypertensive rat model (Ko et al., 2012). A relation

510

between risk factors and fish oil consumption was reported by various researchers (Olsen, &

511

Secher 2002). Fish oil is rich in omega-3 PUFAs that can decrease plasma cholesterol,

512

VLDL, LDL, and triglycerides whilst improving HDL levels (Connor & Connor, 1997).

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A number of epidemiological researchers have established a relationship between fish

514

oil consumption and the reduced incidence of stroke, hypertension, cardiac arrhythmias,

515

diabetes mellitus, rheumatoid arthritis and cancer (Albert et al., 2002). Recent studies

516

reported that polysaccharides from marine algae, especially fucoidan and chitin have

517

medicinal benefits and could be used for their cardioprotective activity (Mayakrishnan,

518

Kannappan, Abdullah, & Ahmed, 2013). It was also found that chitosan, derived from chitin

519

with varying degrees of N-deacetylation, has anti-oxidant, hypo-lipidemic, hypo-

520

cholesterolemic and hypo-triglyceridemic effects (Lamiaa, & Barakat, 2011).

521

Anti-diabetic effects

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The significance of omega-3 dietary inclusions has also been investigated in the

523

treatment or prevention of diabetes. Studies have shown that the incidence of type 2 diabetes

524

was lower in populations consuming fish and fish products and that the consumption of

525

omega-3 PUFAs from different marine sources can improve insulin sensitivity and lower the

526

risk of diabetes (Kromann, & Green, 1980). Deckere, Korver, Verschuren, & Katan, (1998)

527

also suggested that n-3 PUFA consumption has a crucial role in the improvement of insulin

528

sensitivity. Consumption of these PUFAs is important in the treatment of type 2- diabetes by

529

exerting positive effect on insulin resistance in obese patients (Taranathan, & Kittur, 2003).

530

Some epidemiological studies conducted on lean fish consumers proposed that there are

531

bioactive compounds other than n-3 PUFAs that may prevent impaired glucose tolerance and

532

type 2-diabetes (Feskens, Bowles, & Kromhout, 1991).

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Cod protein has also been found to provide many health benefits by improving

534

glucose tolerance. It was found that, the amino acids in cod protein have a direct effect on

535

insulin stimulated transport of glucose in muscles. VonPost-Skagegard, Vessby, & Karlstrom,

536

(2006) investigated the effects of dietary protein on insulin and glucose response in healthy

537

women, cod protein meal can lower the insulin level, reduce the insulin to glucose ratio and

17

ACCEPTED MANUSCRIPT insulin to C-peptide ratio. Ouellet, Marois, Weisnagel, & Jacques, (2007) also reported that

539

cod protein improves the insulin sensitivity in insulin resistant men and women more than

540

other animal proteins. Cod protein includes higher arginine content and lower branched chain

541

amino acid (isoleucine, leucine and valine) as compare to other animal proteins. Taurine can

542

also improve insulin sensitivity; white fish contains 3-4 times greater taurine content

543

compared with beef and pork. Mollsten, Dahlquist, Stattin, & Rudberg, (2001) studied the

544

effect of dietary intake of difference sources of protein on microalbuminuria in patients with

545

type 1 diabetes and highlighted that a diet high in fish protein decreased the chance of

546

microalbuminuria in young patients with type1 diabetes compared with other protein sources.

547

CONCLUSION

548

Marine organisms are important sources of bioactive compounds that are used in the food and

549

pharmaceutical industries. Marine sources are considered to be one of the most important

550

natural bioactive reservoirs that may be used as ingredients in the food industry and as active

551

ingredients in the nutraceutical and pharmaceutical industries. In the food industry, these

552

compounds can be used as natural preservatives, colorants, stabilizers, gelling agents etc. In

553

the nutraceutical and pharmaceutical industries marine bioactive compounds can be used as

554

actives in pharmaceuticals, nutraceuticals, dietary supplements and prebiotics because of

555

their anti-oxidant, anti-thrombotic, anti-coagulant, anti-inflammatory, anti-proliferative, anti-

556

hypertensive, anti-diabetic and cardio-protective activity.

557

ACKNOWLEDGMENTS

558

Hafiz Ansar Rasul Suleria has been awarded an International Postgraduate Research

559

Scholarship (IPRS) and Australia Postgraduate Award (APA) from Australian Government at

560

University of Queensland, Australia.

561

AUTHOR CONTRIBUTIONS

562

All authors contributed equally to the concept for this manuscript. Hafiz Ansar Rasul Suleria

563

was the principal author. All authors contributed equally to the editing.

564

CONFLICTS OF INTEREST

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The authors declare no conflict of interest.

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ACCEPTED MANUSCRIPT 567

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Table 1: Marine bioactive molecules, functional properties and their food application Sources

Functional properties

Marine polysaccharides Mainly extracted from Gelidium, Pterocladia, and Gracilaria

Rheological properties

Alginate and Alginic acid

Large brown seaweeds, such as Laminaria hyperborea, Ascophyllum nodosum, and Macrocystis spp. Mainly extracted from Eucheuma, Betaphycus, Kappaphycus, and Chondrus crispus Crustaceans, principally crabs, shrimps and shellfish

Thickening agent, viscosity improver and stabilizing agent

Marine proteins Gelatin and Collagen

M AN U

Chidanandaiah et al., 2009

Gel-forming and Water holding capacity

Form gel networks that absorb water and solutes in food and beverages

Vazhiyil, 2011

Edible films for food packaging

Krishna et al., 2012

TE D

Increases surface hydrophobicity and oil-binding properties

EP

Chitosan, and pectin

Cod, haddock and Pollock, Cuttlefish (Sepia pharaonis), Giant squid (Dosidicus gigas)

Texture improvement, stabilization Brownlee et al., characteristics, reduction in pasting 2005 properties and control of phase separation Foam stabilizer in beer, provides Vazhiyil, 2011 thermostability and desired consistency. A thickening agent and increases the viscosity of various food

Oil binding properties or Emulsifier

AC C

Carrageenans including furcellaran

References

SC

Agar

Food Application

RI PT

Marine Bioactives

Plasticizer

ACCEPTED MANUSCRIPT

Marine pigments Food colorants in different products to improve their appearance

Dufossé et al., 2005

Natural food colorants

Food colorants especially for food and beverage products

Park et al., 2001

AC C

EP

TE D

M AN U

Phycobiliprotein Blue–green and red algae and chlorophyll

Colouring agent

RI PT

Dunaliella salina and Callyspongia diffusa

SC

Carotenoid, Beta- carotene

ACCEPTED MANUSCRIPT

No.

Bioactive compound

RI PT

Table 2: Marine bioactive molecules and health promoting perspectives

Structure

Marine Sources

References

2.

Phycoerythrobilin

3

Fucoidans

Leu-Lys-Gln-Glu-Leu-Glu-Asp-Leu-Leu-GluLys-Gln-Glu

M AN U

Peptide

Crassostrea gigas

Qian et al., 2008

Porphyra sp.

Yabuta et al., 2010

Fucus vesiculosus and L.

Micheline et al., 2007

japonica

and Zhao et al., 2005

AC C

EP

TE D

1

SC

Anti-oxidative Perspectives

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6.

Fucoxanthinol

7

Phlorotannins

RI PT

Fucoxanthin

SC

5.

Epiactis prolifera

M AN U

Chlorophyll a

Cho et al., 2011

Turbinaria ornata

Dovi Kelman et al., 2012

Undaria pinnatifida

Sachindra et al., 2007

Hyaleucerea fusiformis

Kyoung et al., 2009

AC C

EP

TE D

4.

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Eisenia bicyclis

RI PT

Phlorofucofuroeckol A

Kwon et al., 2013

SC

8

Fucoidans

Fucus vesiculosus

Mourao, 2004

Ludwigothurea grisea

Mulloy et al., 2000

2

Fucosylated Chondroitin Sulfate

AC C

EP

TE D

1

M AN U

Anti-thrombin Perspectives

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Gly-Glu-Leu-Thr-Pro-Glu-Ser-Gly-Pro-AspAnticoagulant peptide

Tyr-Ser-Leu-Tyr-Ala-Asp-Ala-Val-Pro-Arg

4

Anticoagulant peptide

Urechis caupo

Leu-Phe-Val-His-Phe-Leu-Asp-Gly-Asn-Pro-

Glu-Ala-Asp-Ile-Asp-Gly-Asp-Gly-Gln-Val-

Mytilus edulis

SC

Asn-Tyr-Glu-Phe-Val-Ala-Met-Met-Thr-Ser-

Jung & Kim, 2009

M AN U

Lys

Jo et al., 2008

RI PT

3

EP

Fucoidans

AC C

1

TE D

Anti-inflammatory Perspectives

Fucus vesiculosus

Kim and Joo, 2008

ACCEPTED MANUSCRIPT

3

Fucose

4

Fucoxanthin

5

Carrageenan

Fucus vesiculosus

RI PT

Arabinogalactan

Choi et al., 2005

Ecklonia cava

Kang et al. 2011

Myagropsis myagroides

Heo et al. 2010

Turbinaria ornate

Ananthi et al., 2010

AC C

EP

TE D

M AN U

SC

2

Omega 3 and Omega 6

7

Phlorotannins

Most of marine sources

Wall et al., 2010

AC C

EP

TE D

M AN U

SC

6

RI PT

ACCEPTED MANUSCRIPT

Ecklonia cava

Kim et al. 2009

ACCEPTED MANUSCRIPT

Highlights of Manuscripts •

This review highlights latest research on bioactive compounds from different

RI PT

marine sources and brings into focus the potential use of these compounds in the field of drug discovery to treat and prevent various chronic diseases •

Marine bioactive compounds exhibit significant nutraceutical and pharmaceutical potential and are also considered to be safer alternatives to some existing synthetic drugs

It reflects the potential scope and utilization of marine bioactive compounds in food and pharmaceutical industry

It also highlights the bioactivity of marine bioactives, standard methods, mode of

M AN U

•

SC

•

AC C

EP

TE D

action and mechanism involved to prevent and cure different disease