Anti-Inflammatory Activities of Natural Products Isolated from Soft Corals of Taiwan between 2008 and 2012

This review reports details on the natural products isolated from Taiwan soft corals during the period 2008–2012 focusing on their in vitro and/or in vivo anti-inflammatory activities. Chemical structures, names, and literature references are also reported. This review provides useful and specific information on potent anti-inflammatory marine metabolites for future development of immune-modulatory therapeutics.


Introduction
Marine natural products, especially those from stationary or slow moving marine organisms, are used naturally as a chemical defense to protect the organisms from dangerous predators, stressful local environments, and/or the encroachment of competitors. Due to the biological and chemical diversity of marine habitats, and the identification and greater understanding of marine secondary metabolites with unique chemical structures and biological activities, natural products from marine organisms are increasingly being considered as a major source of new therapeutics [1][2][3]. More than 20,000 novel compounds have been isolated and identified from marine organisms since the 1960s [4]. At least two current drugs and a series of anti-tumor drug candidates in preclinical or clinical trials have been developed from marine natural products [2][3][4]. The soft corals or Alcyonacea, an order of Anthozoa widely distributed in warm seawaters, have been a particular focus of attention. An abundance of unique secondary metabolites including sesquiterpenoids, diterpenoids, steroids and other chemical compounds have been isolated and identified from various species of soft corals [5][6][7]. It has been estimated that the percentage of new metabolites discovered from soft corals represents up to 22% of the total new marine natural products reported from 2010 to 2011 [5,6]. Importantly, many of the natural products discovered from soft corals have been demonstrated to exhibit a spectrum of biological activities such as anti-tumor, antiviral, antifouling and anti-inflammatory [5][6][7][8].
Inflammation processes often constitute an initial activation of the mammalian immune system, and the body's normal defense or protective mechanisms in response to microbial infection or irritation or injury of tissues/organs. Increasing evidence suggests a critical link between inflammation and the chronic promotion/progression of various human diseases, including atherosclerosis, diabetes, arthritis, inflammatory bowel disease, cancer and Alzheimer. Proinflammatory enzymes, particularly the inducible nitric oxide synthase (iNOS) for nitric oxide production and cyclooxygenase (COX-2) for prostaglandin production, have been demonstrated to play central roles in the development of inflammatory diseases. In addition, it is also known that during the initial phase of acute inflammation, neutrophils are one of the first leukocyte populations to migrate towards the damaged tissue sites [9]. Neutrophils play a key role in the pathogenesis of various chronic inflammation diseases such as rheumatoid arthritis [10,11]. Activated neutrophils can secrete the superoxide anion, reactive oxygen species (ROS) and enzymes that are associated with the killing of invading pathogens [12]. Furthermore, elastase secreted by stimulated neutrophils has been recognized to play a key contribution in the demolition of tissues affected by chronic inflammatory disease [13]. Therefore, evaluation of the inhibition of iNOS and COX-2 expression, the production of superoxide anion, and the release of elastase in inflammatory cells/tissues by various natural products have been extensively employed in a spectrum of in vitro preliminary screening systems for lead compound or drug discovery. Recently, a number of marine biology and chemistry researchers in Taiwan (including our laboratory) have systematically screened several marine natural products isolated from soft corals for such in vitro anti-inflammatory activities, mainly by measuring the inhibition of iNOS, COX-2, superoxide anion or elastase in murine immune cells. Animal models were further used to evaluate the potential therapeutic activities of candidate compounds in specific disease models. This report reviews some recent representative studies and examples of marine natural products with anti-inflammatory and other related bioactivities that have been isolated from soft corals of Taiwan. Soft corals are abundant in the off-shore environment of the island of Taiwan, and have hence become a focus of local studies of marine nature products. We hope that this review will provide a useful data for the further study of marine natural products.

Triquinane-Type Sesquiterpenoids
Intraperitoneal administration of GB9 reduced CCI-induced thermal hyperalgesia, suppressed microglial cells activation and COX-2 upregulation in the dorsal horn of the lumbar spinal cord, ipsilateral to the injury. Also, intrathecal administration of GB9 and GB10 suppressed activities of CCl-induced nociceptive sensitization and thermal hyperalgesia [26]. The above findings suggest that some of these compounds may warrant systematic investigation for future development as immune-modifiers. Table 8    Culobophylin B Lobophytum crassum [43] 122

Conclusions
Marine invertebrates, particularly octocorals, are rich potential sources of drug leads. Most of our own and other studies on anti-inflammatory activities of natural products from soft corals have been focused on "screening-like" assays using COX-2 and iNOS as target markers. These assay studies have been useful in generating small libraries of anti-oxidant and anti-inflammatory activities from a broad spectrum of soft corals. These results, however, apparently have limitations. For example, the findings are usually generic in nature, and there is often difficulty in immediate or specific application of such results to drug/pharmaceutical discovery, as compared to the existing synthetic chemicals or phytochemicals or those being developed for clinical use. We [45,57,88] and others [25,26] have recently initiated a number of cross-disciplinary studies, employing bio-organic chemistry, cellular immunology and animal disease models for systematic and in-depth studies. As a result, we believe that useful information on the possible application of specific natural products from soft corals for future clinical studies have been obtained. We consider such approaches [57] may need to be encouraged and organized at the international level, and hopefully be integrated into systematic studies, aiming to create translational research of marine natural products for pharmaceuticals/nutraceuticals. Special emphasis may need to be placed on new or specific cell biological/disease model systems.
In terms of evaluating marine natural products for future pharmaceutical application, despite the abundance of unique marine natural products identified, the extremely low quantity of a given compound of interest that can be isolated from marine organisms may be a big hurdle for evaluation of in vivo bioactivities and development for pharmaceutical applications.
Fortunately, due to the recent advancement in aquaculture technologies, aquacultural cultivation of various types of specific soft corals is becoming possible. Our team has successfully cultured a number of species of soft corals, including Klyxum simplex and Briareum excavatum [47,91]. As a result, more abundant and routine preparations of experimental materials will become available for global distribution and collaborative research purposes. Nonetheless, the vast volume of marine organisms and the small base of knowledge so far assembled on soft coral-derived marine chemicals calls for increased international cooperation in this field.