Marine Algal Phlorotannins As Potential Mmpis

It is a well-understood fact that marine flora harbors a wide range of biologically active compounds that are reported to have an outstanding prospective in the medicinal, nutraceutical, and cosmeceutical applications. Natural metabolites obtained from marine seaweeds prove to be abundant resources with chemical diversity, and among them, phloro-tannins are studied most for their biological activities. These phlorotan-nins (Fig. 10.1) are derived from tannins and are composed of several phloroglucinol units linked to each other in different ways and mostly

Phloroglucinol

Phloroglucinol

2-Phloroeckol

FIGURE 10.1

7-Phloroeckol

2-Phloroeckol

FIGURE 10.1

7-Phloroeckol

(Continued)

OH O

OH

Fucofuroeckol-A

Fucofuroeckol-A

OH O

Eckol

OH O

OH O

Dioxynodehydroeckol

OH O

OH O

O OH

O OH

6,6'-Bieckol

HO OH

HO OH

Phlorofucofuroeckol-A

Phlorofucofuroeckol-B

FIGURE 10.1 (Continued)

OH Dieckol

8,8'-Bieckol

FIGURE 10.1 Phlorotannins derived from brown seaweeds and their chemical structures.

OH Dieckol

8,8'-Bieckol

FIGURE 10.1 Phlorotannins derived from brown seaweeds and their chemical structures.

distributed in marine brown algae (Singh and Bharate, 2006). It is suggested that formation of phlorotannins is by polymerization of phloro-glucinol (1,3,5-trihydroxybenzene) monomer units and biosynthesized through the acetate-malonate pathway, also known as polyketide pathway. Usually, their molecular sizes range from 126 to 650 kDa (Ragan and Glombitza, 1986). Recent studies recommend that the polyphenolic compounds derived from marine algae have preventive properties against human diseases including cancer, coronary heart diseases, and other allergies (Shibata et al., 2003), hence suggesting the brown algae as potential medicinal food.

Based on substrate specificity, the MMPs are categorized into three major functional groups. The main three groups include interstitial col-lagenases that have affinities toward collagen types I, II, and III (MMP-1, MMP-8, and MMP-13); the stromelysins with specificity for laminin, fibronectin, and proteoglycans (MMP-3, MMP-10, and MMP-11); and the gelatinases that effectively cleave type IV and type V collagen (MMP-2 and MMP-9; Nelson et al., 2000). Two phlorotannins namely dieckol and 1-(3',5'-dihydroxyphenoxy)-7-(2',4' ,6'-trihydroxyphenoxy) 2,4,9-trihydroxydibenzo-1,4,-dioxin isolated from the methanol extract of marine brown alga, Ecklonia cava, have been reported to suppress both the protein and gene expression levels of MMP-1, MMP-3, and MMP-13 in human osteosarcoma cells (MG-63). This in vitro study also reports that these phlorotannins were able to promote osteosarcoma differentiation by increasing alkaline phosphatase (ALP) activity, mineralization, total protein, and collagen synthesis (Ryu et al., 2009b). Similarly, dieckol and eckol isolated from Ecklonia stolonifera have inhibited the expression of MMP-1 in human dermal fibroblast (HDF) cell, in vitro (Joe et al., 2006). More precisely, this investigation suggested that these phlorotannins interfere with the expressions of NF-kB and activator protein-1 (AP-1) which in turn enhances the MMP-1 expression that leads to skin-related damages. Hence, brown algae can be recommended as foods with medicinal values that can aid for skin care.

Skin wrinkling is normally attributed by the reactive oxygen species (ROS) which is caused by the oxidative stress. ROS stimulates mitogen-activated protein kinases that phosphorylate transcription factor AP-1, which in turn results in upregulation of MMPs that contribute for the degradation of skin collagen ultimately leading to skin ageing (Fisher et al., 1996; Rittie and Fisher, 2002). The gelatinases that include MMP-2 and MMP-9 promote UV-induced skin damage. It is reported that sun-damaged skin shows significantly elevated levels of active gelatinases (MMP-2 and MMP-9) than intrinsically aged skin (Chung et al., 2001). In vitro studies on methanol extract from marine alga Corallina pilulifera (CPM) have revealed that CPM has the ability to prevent UV-induced oxidative stress and also the expressions of MMP-2 and MMP-9 in HDF cells. This clearly suggests the role of phenolic compounds from marine algae as potential MMPIs (Ryu et al., 2009a). As it is evident that unregulated expression of MMPs leads to the photoaging, many research groups are emphasizing their research goals to check the ability of marine-derived phlorotannins as potential antiphotoaging agents. Moreover, the ROS that includes hydrogen peroxide, hydroxyl radical, and superoxide anion is involved in metabolic diseases, especially chronic inflammation. In chronic inflammation, proinflammatory cytokines induce MMPs that degrade the extracellular matrix and contribute for several inflammatory disorders. In this process of screening the medicinally valuable agents from marine seaweeds, phloroglucinol, a monomer of phlorotan-nins, is reported to exhibit anti-inflammatory effect in addition to free radical scavenging activity. This in vitro study has revealed the MMP-2 and MMP-9 inhibitory activities in HT1080 cells, thus suggesting the potentiality of phloroglucinol as an antimetastatic compound. Moreover, the phloroglucinol has exhibited anti-inflammatory activity by expression levels of TNF-a, IL-1p, IL-6, and PGE2 in macrophages RAW264.7 (Kim and Kim, 2010). These in vitro studies bring front the scientific proof that phloroglucinol from marine algae can be recommended as a medicinal agent to reduce the risk of metastasis and inflammation-related diseases. On the other hand, reports suggest that some other brown alga contain higher amount of phloroglucinol (Koivikko et al., 2005) and have exhibited several medicinally beneficial effects in vitro. Hence, members of brown seaweeds can be recommended as medicinal foods because of the abundant presence of polyphenolic compounds that aids for the betterment of human health.

The species Ecklonia and Eisenia are the mostly studied brown algae for the biological activities associated with phlorotannins. The E. cava extract has the capability to reduce the expression of MMP-2 and MMP-9. An in vitro study on the effect of E. cava extract in HDF cells (HT1080) has revealed that the extract which was rich in phlorotannins has attenuated the expression of MMP-2 and MMP-9 expression (Kim et al., 2006). Interestingly, this in vitro study has revealed that the phlorotannis did not exhibit any cytotoxicity on the cells and has the MMP inhibitory effect almost same to that of doxycyclin (a commercial MMP inhibitor). Similarly, phlorotannins namely fucofuroeckol-A and eckol that are derived from Eisenia bicyclis had shown MMP-2 and MMP-9 inhibitory activities in HT1080 cells. In this study, it has been suggested that fucofuroeckol-A and eckol exhibited a significant inhibitory activity on the NF-kB expression and also they had a considerable inhibitory effect on AP-1 expression, thus inhibiting the expression of MMP-2 and MMP-9 via blocking the transcription of both NF-kB and AP-1 (Lee, 2010). As the investigations suggest that MMP-2 (Gelatinase-A) and MMP-9 (Gelatinase-B) can degrade type IV collagen of base membranes and are known to play a crucial role in cancer invasion such as oral carcinoma and other cancers (Ikebe et al., 1999) and that these enzymes play a major role in cancer metastasis (Nagase et al., 1998), the MMP downregulation effect of phlor-otannins and polyphenolic compounds from marine brown algae stands more promising and recommending them as potential medicinal foods to combat metastasis.

The phlorotannins eckol and dieckol that were first isolated from Ecklonia species possess oligomeric polyphenol of phloroglucinol unit. Dieckol from marine brown alga, E. cava, has been reported to suppress LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) and expression of inducible nitric oxide synthase (iNOS) and cyclooxy-genase-2 (COX-2) in murine BV2 microglia, thus establishing dieckol as a potent anti-inflammatory and neuroprotective agent (Jung et al., 2009). A detailed account of the various biological activities including free radical scavenging activity of phlorotannins from Ecklonia species has been reported earlier.

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