Journal of Pharmaceutical Sciences & Emerging Drugs ISSN: 2380-9477

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Review Article, J Pharm Sci Emerg Drugs Vol: 5 Issue: 1

Bioprospecting of Marine Bioactive Compounds: A Boon towards Developing Therapeutic Molecules to Curb Multifoliated Human Ailments

Amitha Kurian1, Ajith J Nair2, Prasitha K1, Rubeena KA1 and Preetham Elumalai1*

1Department of Biochemistry, School of Aquatic Food Products and Technology, Kerala University of Fisheries and Ocean Studies (KUFOS), Panangad, Kerala 682 506, India

2Centre for Bioactive Substances, Kerala University of Fisheries and Ocean Studies, Panangad, Kerala, India

*Corresponding Author : Preetham Elumalai
Department of Biochemistry, School of Aquatic Food Products and Technology, Kerala University of Fisheries and Ocean Studies (KUFOS), Panangad, Kerala 682 506, India
E-mail:
[email protected]

Received: December 27, 2016 Accepted: January 31, 2017 Published: February 07, 2017

Citation: Kurian A, Nair AJ, Prasitha K, Rubeena KA, Elumalai P (2017) Bioprospecting of Marine Bioactive Compounds: A Boon Towards Developing Therapeutic Molecules to Curb Multifoliated Human Ailments. J Pharm Sci Emerg Drugs 5:1. doi:10.4172/2380-9477.1000120

Abstract

Marine world comprises of varied fauna and flora. They are of immense utility to humans and related organism. Large number of bioactive compounds have been elucidated and studied so far. Most of the compounds are bioactive and are proved to have anti-cancer, anti- bacterial and anti-fungal properties. Some of them are also effective in curing diabetes and autoimmune diseases. The mechanism of action of these compounds is still under investigation. However, several potent drugs are isolated from marine organisms. Clinical trials have shown that they have good results of success as compared to contemporary drugs available in the market. Today marine bioactive compounds pave way to studies at molecular level in understanding drug action in organism. This is a yet to be explored area of study. Improved methodology and instrumentation help studies to be carried out in a more co-ordinated and time bound fashion. In this context, the present article provides an update on the plethora of natural marine compounds, their source and also their potential application in healing diseases.

Keywords: Bioactive compounds; Chemical structure; Marine organisms; Health; Disease; Therapeutic agents; Immunomodulation; Antiinflammatory;Cytotoxic; Anti-cancer

Introduction

The marine habitat has been considered as a source of potentially useful bioactive compounds [1]. More than 70% of earth’s surface is covered by oceans. Hence marine life is a rich source of bioactive compounds. It has been estimated that more than 2,30,000 known species of marine organisms exist and the number of undiscovered marine species would be more than 2 million [2]. A wide variety of bioactive compounds have been discovered from the marine organisms in the past few decades. They have become the current interest of industry for the development of new drugs and their application. Several bioactive compounds isolated from the marine life have proved to produce promising therapeutic applications. Marine environment is a rich source of plants, animals and microorganisms. It has been suggested that the marine natural products have the potential to be used against a wide range of diseases like cancer, autoimmune diseases, viral diseases etc. Marine organisms are sources of bioactive compounds such as antibiotics, anti-tumour, anticoagulants, antiviral, antiulcer, analgesic, antifungal, insecticides and pharmaceutical supplements and stabilizers [3]. All these findings attract the pharmaceutical field to involve in marine drug research. Today scientists engage in studying the mode of action of these compounds from marine habitat at molecular level and also their possible role in treating diseases. So far more than 20,000 compounds have been derived from marine organisms such as algae, sponges, corals, sea weeds and microorganisms [4,5].

Marine world comprises a treasure of biotic universe comprising of diverse flora and fauna. They include microorganism and unclassified species of living forms interacting in a neat fashion to keep the environment safe and steady. Marine or aquatic world is prone to a multitude of human invasion. So also is the contribution of marine world towards the human race in fighting thrift situation, mainly when new microorganism goes mad against its human host or when grave disease breakout engulfing human and animal life.

It is worth noting here that the last year Nobel Prize in Physiology was awarded to therapeutic studies of “Artemisinin”, a Chinese herbal drug that is found to be an excellent cure for malaria. So is the effect of plant extracts on humans. Marine flora and fauna is a treasure house of such molecules or extracts which can curb many incurable human pathologies including cancer, Alzheimer’s disease, autoimmune disease etc.

Many of marine drugs are extracts of metabolites or secondary metabolites or compounds extracted and purified from waste treated or toxins. These compounds are isolated, purified and characterized and tested to see whether it suits the said purpose. Then it is tried in animal models and finally its clinical and therapeutic trials are done.

Marine algae- Marine algae are one of the largest producers of biomass in the marine environment [6]. Algae produce many biogenic compounds such as halogenated compounds, aldehydes, terpenoids which have antibacterial, anti-algal, anti-macrofouling and anti-fungal properties which are effective in the prevention of bio-fouling and have other expected uses, as in therapeutics [7].

Seaweeds- Seaweeds are the eukaryotic organism that live in salty water and recognized as a potential source of bioactive natural products. Seaweeds have been used since ancient times as food, fodder, fertilizers as source of medicine. Today, seaweeds are the raw materials for industrial production of agar, algin and carrageenan but they continue to be widely consumed as food in Asian countries [8].

In the sea, three types of plants occur. They are phytoplanktons, seaweeds or marine algae and sea grasses. Phytoplanktons are the primary producers of the sea and are microscopic and free-floating forms. Seaweeds or marine algae are attached or freely floating plants and are macroscopic. They form one of the important massive living renewable resources. They are primitive plants without any root, stem and leaves. They are the members of the division Thallophyta in plant kingdom and are classified in to four groups namely: Chlorophyceae (green algae), cyanophyceae (blue- green algae), Phaeophyceae (brown algae) and Rhodophyceae (Red algae); based on the type of pigments, morphological, anatomical and reproductive structures. Humans now pose the problem of microorganism turning resistant to antibiotics [9] and these have necessitated the development of new alternative [10]. Moreover, the drugs can cause adverse drug reaction (ADR) on the host, which include hypersensitivity and depletion of beneficial microbes in the gut [11]. The pharmaceutical companies and the researchers are now searching for new antibacterial agents, to treat infectious disease caused by different pathogenic bacteria which have developed antibiotic resistance [12].

Natural products are those compounds produced by living organisms. They can be categorized into primary and secondary metabolites. Primary metabolites such as proteins and carbohydrates act as energy source of the organism. Secondary metabolites of marine organisms are the compounds such as terpenes, polyketides, and alkaloids etc that are obtained by solvent extraction. Secondary metabolites are derived from the primary metabolites like amino acids, proteins, fats and polysaccharides of the organism. The secondary metabolites are not required for the cell metabolism whereas the primary metabolites are essential for the basic cell metabolic processes. The exact role of secondary metabolites is still unclear. It is believed that secondary metabolites are the chemicals produced by the organism in response to environmental stress to serve as defence agents against predators. Marine organisms provide home to several symbiotic micro-organisms and they may occupy up to 40% of the tissue volume. The micro-organisms exhibit very specific relationship with corals, ascidians, sponges, marine plants etc. [13]. The realization that ocean can serve as the potential source of bioactive compounds and new drugs have obtained stimulated research activities in laboratories and clinics throughout the world. This review aims at covering the new developments in the field of marine drug research and of bioactive compound discovery from marine origin and their potential uses in health and diseases. It’s difficult to summarize the whole ocean wealth of life in one review hence, some of the marine organisms widely investigated are described below.

Marine sponges

Sponges are considered as the world’s simplest multi-cellular organisms. They belong to the phylum Porifera which means pore bearing. A marine sponge is a filter feeding, sedentary metazoan that possesses a single layer of flagellated cells which helps in driving a unidirectional current of water. Sponges are considered as an ancient and highly successful group of animals that can thrive well in a variety of oceanic climates and can also survive at all latitudes.

The three main classes of sponges are Calcarea, Demospongiae and Hexactinellida. Sponges are well known hosts for a large community of microorganisms. Marine sponges have been associated with microbial communities such as bacteria, fungi, microalgae etc. These symbionts comprise more than 40% of sponge body and are involved in producing primary and secondary metabolites. Bacteria and fungi are the common symbionts in sponges [14].

Several examples of bioactive compounds that were tested for the potential of antitumor, anti malarial, antiviral, antibiotic, immunosuppressive, neurosuppresive, anti-inflammatory and antifouling properties from marine sponges have been cited in scientific literatures.

Marine microalgae

Due to the photosynthetic activity, marine microalgae play a crucial role in marine ecosystems. They are considered as the biomass producers in the ocean and have been classified into five groups such as Chlorophyta (green algae), Chrysophyta (golden-brown, yellow algae, and diatoms), Pyrrhophyta (dinoflagellates), Euglenophyta, and Cyanophyta (blue-green algae). Compounds produced by marine algal species are beneficial to human health as these compounds are produced as secondary metabolites. These compounds may include polyunsaturated fatty acids, carotenoids, alkaloids, terpenes etc. [15]. They are highly branched polycyclic aromatic and aliphatic compounds for therapeutic properties such as anti-tumor, anticancer, anti-viral as well as cosmetic applications. Many of them are now under clinical trials.

Marine microalgae has the potential to produce long chain PUFAs including docosahexaenoic acid (DHA) and eicosapentanoic acid (EPA). DHA is essential for brain development in infants and can provide protection to the brain whereas EPA has important roles in the immune system, and cell communication and cardiovascular function [16]. Microalgae belonging to the genera Phaeodatylum and Monodus are considered as good sources of EPA; whereas Schizotrychium species are sources of DHA.

Marine macroalgae

Marine macroalgae, or seaweeds, have been used as medicines, vegetables and fertilizers and have been considered as a rich source of bioactive compounds [17]. Gelling polysaccharides agar and carrageenan extracted from the Rhodophyta and alginate from members of the Phaeophyta are some of the natural products derived from seaweeds. These are referred to as hydrocolloids or phycocolloids that has application in the food industry. Similarly, alginates are used in wound dressings, drug delivery systems and tissue engineering, in the biomedical and pharmaceutical industry. Anticoagulant polysaccharides isolated from marine algae exert their anticoagulant activity through potentiating antithrombin III or heparin cofactor II [18]. Novel anticoagulant compounds have been isolated from red alga Pachymeniopsis elliptica and red seaweed Lomentaria catenata [19].

Marine bacteria and fungi

Marine fungi often live as symbionts in invertebrates, especially sponges. Polyketides, alkaloids, sesquiterpenes and aromatic compounds are isolated from marine fungi that belong to the phyla Chytridiomycota, Oomycota, Ascomycota, Bacidomycota, Deuteromycota, and Zygomycota. Marine fungus-based drugs have different properties like neuroactive, cytotoxic, antibacterial, antiviral, and antifungal activities [20,21].

Marine bacteria include archaea and eubacteria. Many of the archaea are extremophiles. Archaea are organisms that live in extreme conditionshence got the name extremophiles. They are considered as a potential source for pharmaceutical applications as well as industrial purposes. Marine eubacteria consist of Grampositive bacilli, actinomycetes, Gram-negative α-proteobacteria and γ-proteobacteria and anaerobes. Compounds such as polyketides, alkaloids, fatty acids, peptides and terpenes are isolated from several species of marine bacteria. Salinosporamide A (marizomib), a compound isolated from actinomycete Salinospora acts as a proteosome inhibitor for multiple myeloma. Another compound, Anthracetin, isolated from Streptomyces species is an antibiotic against Bacillus anthracis and methicillin-resistant Staphylococcus aureus (MRSA). Thiazolyl cyclic-peptide is another antibiotic isolated from sponge-associated actinobacterium strain of genus Kocuria which acts against vancomycin-resistant enterococci [22,23].

Molluscs, echinoderms and crustaceans

Another important category of marine natural products include molluscs, crustaceans and echinoderms. Several bioactive molecules have been obtained from these sources. Many Cuttlefish, squid, octopus and nautiloids possess therapeutic effects. Bones of cuttlefish, have been found to have therapeutic effects against rickets and gastrointestinal disorders [24]. Similarly, peptides from oyster and mussel have been found effective against hypertension [25]. Crustaceans like crabs, prawns and shrimps are most economically important class of marine arthropods. One of the major structural components of their shell is chitin, a linear polymer of N-acetyl-D glucosamine [26].

Importance of Marine Bioactive Compounds

Anti-viral and anti-malarial activity

Each and every day we come across with millions of microbes and most of them are pathogenic or opportunistic pathogens. The diseases caused by them vary from mild infections to fatal diseases. In spite of the tireless efforts made by the scientists to formulate drugs and to find out cure, several new diseases, which are resistant to many antibiotic drugs, are reported on different parts of the world. Hence there is a need for more pharmacological agents, especially against viral infections.

Researchers are concentrating in screening marine life forms for finding antiviral activity against viruses such as HIV, HCMV, and HSV (1 and 2) [27,28]. Carrageenan is used as a potential pharmaceutical adjuvant as it has anti-tumor, anti-viral, anticoagulant and immunomodulation activity. Recent investigations have shown that carrageenan gel from C. crispus may block the transmission of the herpes simplex viruses (HSV), HIV and viruses of sexually transmitted diseases such as gonorrhea, genital warts. There are many types of carrageenan like μ-carrageenan, λ-carrageenan, κ-carrageenan and ı-carrageenan.

It is found that some sulphated polysaccharide from red algae, Aghardhiella tenera and Nothogenia fastigiata exhibit remarkable antiviral activity against those viruses causing some infections in humans. The polysaccharides galactan sulphate and xylomannan sulphate present in the seaweeds Aghardhiella tenera and Nothogenia fastigiata show antiviral activity against the highly infectious human viruses like human immunodeficiency virus or HIV, herpes simplex viruses types 1, 2, respiratory syncytial virus or RSV [29,30]. The galactan sulphate also known as agaroids from Gracilaria corticata can inhibit the initial attachment of the HSV type 1 and 2 to the host cell. They are considered as antiviral agents [31]. Also Fucoidan shows antiviral property by inhibiting the binding of viral particle to host cell [32]. It inhibits HSV type 1 and 2, human cytomegalovirus [33] and HIV [34,35].

Ara-A (vidarabine) isolated from sponge Tethya crypta has been considered as one of the most important antiviral agents that can inhibit DNA synthesis of herpes, vaccinia and varicella viruses. Such compounds are produced by enzyme clusters in sponges [36].

The extracts from sponge Petromica citrina produced by the Bacillus species give promising results for the treatment of hepatitis C [37]. Derivatives of Psammaplysin were identified in the Indonesian marine sponge Aplysinella strongylata which exhibitted antimalarial activity [38]. Diterpenes from the sponge Stylissa also exhibit antimalarial activity [39].

Some of the bromotyrosine derived compounds isolated from the marine sponge Verongula rigida showed potent and selective antiparasitic activity, when screened for in vitro activity against parasitic protozoa such as Leishmania panamensis, Plasmodium falciparum and Trypanosoma cruzi [40]. A diterpenoid showing potent antimalarial activity was isolated from the marine sponge Hymeniacidon sp [28].

Anti-bacterial and anti-fungal activity

The bioactive compounds from symbiotic microbial consortia are found to be of antibiotic in nature and have antitumor and antiinflammatory compounds [41,42,43]. There are many structurally diverse bioactive substances derived from marine Pseudomonas including pyrroles, pyrrolidinedione, phloroglucinol, pseudopeptide phenazine, benzaldehyde, quinolone, phenanthren, quinoline, phthalate, andrimid, moiramides, zafrin and bushrin [44] and some of these are antimicrobial agents [45]. Methicillin resistant Staphylococcus aureus strains can be inhibited by the marine species of Pseudoalteromonas phenolica due to the presence of a brominated biphenyl compound, 3,3‟,5,5‟-tetrabromo-2,2‟-diphenyldiol in this bioactive substance [46]. Bacillus amyloliquefaciens SCSIO 00856 isolated from the South China Sea gorgonian, Junceella juncea exhibited strong antibacterial activity towards Escherichia coli, Bacillus subtilis, and Staphyloccocus aureus [47].

The bioactive compounds derived from marine fungi were reported as a rich source of novel antiplasmodial, antiviral, antibacterial, anti-inflammatory and anticancer agents [48,49]. The larval settlement of the tubeworm Hydroides elegans and of cyprids of the barnacle Balanus Amphitrite were inhibited by 3-chloro-2, 5-dihydroxybenzyl alcohol which was isolated by Kwong et al. [50] This suggests its potent antifoulant and/or antibiotic activity. These authors also reported that Cladosporium sp. F14 strain produced antibiotic and antifouling compounds in the presence of glucose or xylose in the media.

A series of chlorinated bis-indole pyrroles, Lynamicins A-E isolated from a marine actinomycete, Marinispora demonstrated broad-spectrum activity against both Gram-positive and Gramnegative organisms. Pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium are susceptible to these compounds [51]. In 2009 Carlson et al. [52] isolated two new dienoyl tetramic acids- tirandamycin C and tirandamycin D from the marine environmental isolate Streptomyces sp. 307-9 which exhibited activity against vancomycin-resistant Enterococcus faecalis.

An antibacterial agent, Fimbrolide was isolated from Delisea pulchara which can used for the treatment for chronic Pseudomonas aeruginosa infection [53] and is also effective against bio-fouling [54]. The antibiotic property of compounds like sterols heterocyclic and phenolic compounds may be made use in antiseptics and cleansing agent but the antibiotic property in vivo is only achieved at a minimum toxic concentration.

Halogenated alkaloids from the marine sponge Lotrochota purpurea is found to be effective against many diseases caused by fungi and Shen et al. [55]. Alkaloids isolated from the marine sponge Agelas mauritiana showed antifungal activity against Cryptococcus neoformans, antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus, in vitro and also antileishmanial activity in vitro [56]. Diterpene isonitriles isolated from the marine sponge Cymbastela hooperi, and the sesquiterpene axisonitrile-3, isolated from the sponge Acanthella kletra, were evaluated in a series of bioassays including anti-algal, anti-photosynthetic, anti-bacterial, anti-fungal, and anti-tubercular and it was proved that most of the tested compounds were active in at least two of the applied test systems [57].

In another study, the bioactive metabolites were isolated from marine sponge’s sediments and sponge-derived actinomycetes and tested for their antimicrobial and antifungal activity. Out of the fifteen extracts, 9 were active against multi-resistant indicator organisms, including vancomycin-resistant Enterococcus faecium and multidrug-resistant Candida albicans [58].

Anti-oxidant property

Free radicals are atoms or groups of atoms with unpaired electrons. The ability of organism to use oxygen has led to the development of reactive oxygen species (ROS). ROS are by-products of normal metabolic processes and include hydrogen peroxide, hydroxyl radical, superoxide anions etc. Although ROS are involved in several beneficial functions like apoptosis, higher level of free radicals may cause severe damage to DNA. They also alter the biochemical compounds and disintergrates the cell membrane [59] and produce DNA adducts leading to cancerous mutations and cell death [60]. To counter their effect, cells contain large number of antioxidants which helps in preventing or repairing the damage caused by ROS. Polyphenolic compounds isolated from marine microalgae and macroalgae are one class of compounds which show antioxidant property. Nutraceutical supplements from sea weeds have been gaining wide popularity. More than 8000 compounds are thought to be of bioactive polyphenolic origin [61]. Polypehenols are classified into 10 classes on the basis of their structural characteristics and it includes hydroxycinnamic acids, simple phenols, coumarins, xanthones, naphthoquinones, flavonoids, stilbenes, anthraquinones, and lignins [62]. Pholorotannin (Figures 1 and 2) isolated from brown algae is one of the polyphenolic compounds which exhibits antioxidant activity [63]. They also have other properties such as antibacterial, chemopreventive, UV-protective, antiproliferative effects and are also involved in detoxifying metals (Table 1) [62].

Compound Structure Biological activity Reference
Cyanobacteria
Dolastatin 10 image Antimicrotubule; and the synthetic analogue, TZT-1027, as antitumor Tan et al.[111]
Dolastatin 15 image Antimicrotubule; and the synthetic analogue, ILX-651, as antitumor Tan et al. [111]
Curacin A image Antimicrotubule Burja et al.[112]
Toyocamycin image Antifungal Burja et al. [112]
Actinomycetes
Resistoflavine image Anticancerous and antibacterial Gorajana et al. [113]
Marinomycin A image Antitumor and antibiotic Kwon et al.[114]
Daryamide C image Anti-tumor Asolkar et al.[115]
Violacein image Anti-protozoal Matz et al. [116]
Bacteria
Macrolactin S image Antibacterial Lu et al.[117]
Pyrone I and II image Antibacterial Maya et al.[118]
MC21-B image Antibacterial Isnansetyo et al.[119]
Fungi
Meleagrin image Antitumor Du et al.[120]
Oxaline image Antitumor Koizumi et al. [27]
Alternaramide image Antibacterial Kim et al. [121]
Algae
Norharman image Enzyme inhibitor Volk et al.[122]
Calothrixin-A image Antimalarial and anticancerous Rickards et al. [123]
Eicosapentanoic acid (EPA) image Treats heart disease, Anti-inflammatory agent (rheumatoid arthritis and immunodeficiency diseases) Singh et al. [124]
Symbiotic microbes
Macrolactin V image Antibacterial and antilarval Gao et al. [48]
DAPG image Antibacterial (anti-MRSA, anti-VRSA and anti-VRE) Kamei et al. [125]
BE-43472B image Antibacterial (anti-MRSA and anti-VRE) Nicolaou et al. [126]

Table 1: Structure and biological activity of some of the marine microbial metabolites [127] .

Figure 1: β- carotene.

Figure 2: Phlorotannin.

Carotenoids are another group of compounds which shows antioxidative property [64]. They are produced by algae, fungi, plants, and certain microorganisms. Humans and animals get these through their diet [65]. β-carotene (Figure 1) is formed in high concentration in microalgae and is more biologically active than synthetic β-carotene [66]. Hence are now used in food and drinks. β-carotene with its capacity to curb the ill effects of free radicals, thus helps in preventing cancer [67], premature aging, [68] and arthritis [69]. Romay et al., [70] worked on phycocyanin (found in blue-green algae) for its activity against ROS by Luminol enhanced Chemiluminescence (LCL) and found that phycocyanin can scavenge OH• and RO•. Apart from the use in neutraceutical industry, antioxidants of algal origin have wide use in cosmetic industry. Another microalgae-derived carotenoid pigment astaxathin (Figure 3) also contains antioxidant properties [71]. Lutein is one of the most important carotenoids and is used for the treatment of diseases including macular degeneration, cataracts and in early stages of atherosclerosis. Strains of the green microalga Muriellopsis is a good source of Lutein [72].

Figure 3: Astaxanthin [51].

The polysaccharides from Hyriopsis cumingii (HCPS) was proven to scavenge superoxide, hydrogen peroxide and 2,2-diphenyl-1- picrylhydrazyl (DPPH). The in vivo effect of this isolate was carried out on D-galactose induced mouse model. Oral administration of HCPS inhibited the formation of malondialdehyde in serum and liver and enhanced the activity of antioxidant enzymes [36,73]. Floridoside and D-isofloridoside isolated from marine red algae inhibited the pro-inflammatory matrix metalloproteinases-MMP2 and MMP 9 [74].

Chitin, a positively charged polymer of N-acetylglucosamine (GlcNAc) units. Chitosan is a deacylated derivative of chitin. Chitosan and its oligomers of marine crustaceans like shrimp and krill have been found to be effective in reducing the LDL-cholesterol level in humans, and can also improve levels of vitamin A. The immunestimulation property of chitin and chitosan has been utilized in wound healing and also they can scavenge oxygen free radicals. A scientific study reported that sponge Pandaros acanthifolium showed cytoprotective as well as antioxidant properties [75] while another study proved the presence of metabolites like phenolic compounds, alkaloids and polyketides that exhibited antioxidant properties [76].

Anti-diabetic property

Several compounds isolated from marine organisms show antidiabetic property [77] Sesquiterpenes from sponges have proven to be antidiabetic by inhibition of glycogen synthase kinase 3β (GSK-3β) [78]. The effect of methanolic extracts of brown algae Ecklonia cava was studied by Kang et al. [79]. They concluded that the extract had reduced the concentration of plasma glucose and increased the concentration of insulin in rats which were induced with type 1 diabetes mellitus. Euryspongins (Figure 4) isolated from marine sponge (Euryspongia sp.) act as inhibitors of the enzyme protein tyrosine phosphatase 1 B [80]. The antidiabetic property of α-galactosylceramide, a glycolipid was tested in nude mice. This glycolipid is produced by a marine sponge Agelas mauritianus. This compound exert its antidiabetic effect by stimulating the Natural Killer cells, by selectively suppressing those pathogenic T cells that destroy pancreatic β (insulin producing) cells [81]. Phlorotannins from brown algae also show antidiabetic effect by several mechanisms like inhibition of α-glucosidase and α-amylase, inhibiting protein tyrosine phosphatase 1B (PTP 1B) enzyme, increasing skeletal muscle glucose uptake and increasing sensitivity of insulin [82].

Figure 4: Rel-Euryspongin-A.

Hepato-protective property

Liver disease can be caused by a series of factors like intake of alcohol, metabolic dysfunction, viral infections, toxin intoxication, or genetic. According to Karthikeyan et al. [83] carotenoids exert hepatoprotective effect through cellular membrane stanilization or antiperoxidase activity, but the compound responsible is yet to be isolated. The ethanolic extract from red algae Hypnea muciformis is showed to exhibit protective action against CCL4-induced liver damage in male albino rats [84]. Zhao et al. [85] worked on mice induced with liver injury. They concluded that treatment of mice with Low Molecular Fucoidan oligosaccharides (LMFO) had protective effect on liver cells because of their antioxidant property. Makhmoor et al.,[86] studied on bioactive compound from brown algae, Spatoglossum variabile on animal models with induced liver damage showed hepato-protective role. These studies show that marine organisms offer a wide niche of bioactive compounds that has potent use in treating liver diseases.

Anticancer property

Cancer is characterized by angiogenesis (birth of new blood vessels). Angiogenesis cause abnormal growth of cells then causing cancer. Dercitin (Figure 5), an aminoacridine alkaloid isolated form marine sponge, Dercitus spp. has been shown cytotoxic effects in low concentrations and also increases the life span of mice models with ascitic P388 Tumours, B16 melanoma cells and small cell Lewis carcinoma [87]. Microbes living in the mollusc Elysia rubefescens are believed to synthesize a compound called Kahalalide F (Figure 6), which causes cell toxicity and thus inhibit the cell cycle in G1 phase. In vitro studies have shown activity against prostate cancer cell lines and in vivo study reports that it has activity in breast and colon cancers [88]. Varitriol, isolated from sponge is produced by a fungus called Emericella variecolor and show activity against breast cancer cell-lines, renal and central nervous system [89]. A bioactive pepetide thiocoraline from actinomycetes (Micromonospora) inhibits RNA synthesis and exhibit antitumour property by selective cytotoxicity against melanoma, lung and colon cancer with defective p53 system [90]. Scytonemin is a serine/threonine kinase inhibitor [91] isolated from Stigonema sp. It is reported to control the mitotic spindle formation. Kinases involved in control of cell cycle prevent the uncontrolled growth of human fibroblasts and endothelial cells [92].

Figure 5: Dercitin.

Figure 6: Kahalalide F.

Curacin-A from Lyngbya majuscula is an anti-tumour agent that acts selectively on colon, renal, and breast cancer derived cell lines and it acts by inhibiting the polymerization of tubulin [93]. Likewise bioactive compound Condriamide –A from Chondria sp. shows cytotoxicity to human nasopharyngeal and colorectal cancer cells [94].

Kahalalide F has undergone clinical trials upto phase IV but yet to be released in the market.

A derivative of the nucleosides spongothymidine and spongouridine isolated from Tectitethya crypta, known as Ara-C is considered as the pioneer anticancer agent that can be used against leukemia [95-97]. It has been currently used in clinical trials against myeloid neoplasms along other anticancer drugs [96,97].

Almost 39 compounds from sponges that can induce apoptosis and that can act as anticancer agents have been identified [98]. Renieramycin isolated from the sponge genera Reniera has shown to induce apoptosis in lung cancer cells [99]. Researchers have reported that a lectin from the sponge Cinachyrella apion has the ability to induce cell death in tumour cells [100].

.From the marine sponge Monanchora pulchra, a novel polycyclic guanidine alkaloid, Monanchocidin is isolated that induced cell death in human monocytic leukemia, human cervical cancer (HeLa) and mouse epidermal cells [101] (Figure 7).

Figure 7: Principal mechanisms of action of marine antitumor alkaloids .

Immunosuppressive activity

In the cases of hypersensitivity to certain antigens or organ transplantations, suppression of immune system is required. Immunomodulatory potential shown by the marine sponge Aurora globostellata was proven by oral administration to Wistar rats. The results obtained indicated that extracts possesses immunosuppressant activity [102]. Since nearly 10 marine bacterial strains that showed antagonistic activity against clinical bacterial pathogens were isolated from the marine sponge Callyspongia difusa, researchers suggest that the bacterial strain Virgibacillus species associated with sponge may contribute to the discovery of novel antibiotics against infections and also for the production of potential immuno modulators [103].

Anti-Inflammatory activity

Macro algae are a rich source of polyunsaturated fatty acids also known as PUFA’s [104]. The metabolic products of PUFA’s in red algae are called as oxylipins which resembles eicosanoid hormone in higher plant and animals and the uncontrolled production of these compounds may cause several inflammatory disorders [105]. Eicosanoid and its derivatives exhibit anti-inflammatory activity and other properties like chemical attraction of neutrophils or smooth muscle cell, the muscle contraction and have role in several diseases in mammals.

Several bioactive compounds from marine sponges that possess anti-inflammatory, antioxidant and radical scavenging properties have been discovered in the last few years. The extracts of sponges Callyspongia, Niphates and Stylissa collected from the Red sea showed potent reducing power and inhibitory effects on oxidative stress [106].

Treatment of Cardiovascular diseases

Cardiovascular diseases are the diseases involving heart or blood vessels. It is one among the lifestyle diseases that is responsible for increasing mortality rate. High blood pressure is a major risk factor in CVD. Due to the antioxidant properties Astaxanthin is thought to have benefits in treating CVD. Studies show that consumption of astaxanthin can prevent atherosclerosis. A study by Hussain et al. [107] revealed that oral administration of this compound showed a reduction in blood pressure in hypertensive rats. Astaxanthin can also improve elastin and thickness of arterial wall in hypertension [108]. Ethanolic extract of Caulerpa racemosa , Colpomenia sinuosa, Iyengaria stellata, Spatoglossum asperum and Solieria robusta show hypolipidemic activities, resulting in decrease of total cholesterol, triglycerides and LDL in the serum of rats [109]. Peptides from macroalgae have shown to reduce blood pressure who act by inhibiting Angiotensin Converting Enzyme 1 [110,127]. In earlier days the main source of bioactive peptides were dairy products. But today macroalgae is another important reservoir of peptides which help in the treatment of CVD.

Conclusion

Marine bioactive substances are numerous in number. They are found to be potent enough to cure human ailments. Most plant extracts and products cure a variety of diseases in humans. Also bioactive compounds from various marine organisms, marine algae are potentially good curative agents of diseases and a much better adjunct in bringing down the symptoms and difficulties arising due to drug use. Most of the drugs derived from marine sources are highly effective and risk free with less side-effects. However, the important difficulty is the high cost of production and collection to rawmaterials. These are present in very low concentration and have to be synthesized for commercial supply. Many of them are now under clinical trials in several countries. Investments costs are heavy. But some of their drugs are going to be potentially most effective against incurable diseases like HIV and cancer.

Acknowledgements

The authors wish to thank Prof. (Dr).A. Ramachandran, Vice Chancellor and Dr. V.M Victor George, Registrar, Kerala University of Fisheries and Ocean Studies, Panangad, Kerala, India for encouraging and supporting us.

References

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