Marine bioactives: pharmacological properties and potential applications against inflammatory diseases

Inflammation is a hot topic in medical research, because it plays a key role in inflammatory diseases: rheumatoid arthritis (RA) and other forms of arthritis, diabetes, heart diseases, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, allergies, asthma, even cancer and many others. Over the past few decades, it was realized that the process of inflammation is virtually the same in different disorders, and a better understanding of inflammation may lead to better treatments for numerous diseases. Inflammation is the activation of the immune system in response to infection, irritation, or injury, with an influx of white blood cells, redness, heat, swelling, pain, and dysfunction of the organs involved. Although the pathophysiological basis of these conditions is not yet fully understood, reactive oxygen species (ROS) have often been implicated in their pathogenesis. In fact, in inflammatory diseases the antioxidant defense system is compromised, as evidenced by increased markers of oxidative stress, and decreased levels of protective antioxidant enzymes in patients with rheumatoid arthritis (RA). An enriched diet containing antioxidants, such as vitamin E, vitamin C, β-carotene and phenolic substances, has been suggested to improve symptoms by reducing disease-related oxidative stress. In this respect, the marine world represents a largely untapped reserve of bioactive ingredients, and considerable potential exists for exploitation of these bioactives as functional food ingredients. Substances such as n-3 oils, carotenoids, vitamins, minerals and peptides provide a myriad of health benefits, including reduction of cardiovascular diseases, anticarcinogenic and anti-inflammatory activities. New marine bioactives are recently gaining attention, since they could be helpful in combating chronic inflammatory degenerative conditions. The aim of this review is to examine the published studies concerning the potential pharmacological properties and application of many marine bioactives against inflammatory diseases.     

Benefits under the Sea: The Role of Marine Compounds in Neurodegenerative Disorders

Marine habitats offer a rich reservoir of new bioactive compounds with great pharmaceutical potential; the variety of these molecules is unique, and its production is favored by the chemical and physical conditions of the sea. It is known that marine organisms can synthesize bioactive molecules to survive from atypical environmental conditions, such as oxidative stress, photodynamic damage, and extreme temperature. Recent evidence proposed a beneficial role of these compounds for human health. In particular, xanthines, bryostatin, and 11-dehydrosinulariolide displayed encouraging neuroprotective effects in neurodegenerative disorders. This review will focus on the most promising marine drugs’ neuroprotective potential for neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. We will describe these marine compounds’ potential as adjuvant therapies for neurodegenerative diseases, based on their antioxidant, anti-inflammatory, and anti-apoptotic properties.     

Marine carotenoids and oxidative stress

Oxidative stress induced by reactive oxygen species plays an important role in the etiology of many diseases. Dietary phytochemical products, such as bioactive food components and marine carotenoids (asthaxantin, lutein, β-carotene, fucoxanthin), have shown an antioxidant effect in reducing oxidative markers stress. Scientific evidence supports the beneficial role of phytochemicals in the prevention of some chronic diseases. Many carotenoids with high antioxidant properties have shown a reduction in disease risk both in epidemiological studies and supplementation human trials. However, controlled clinical trials and dietary intervention studies using well-defined subjects population have not provided clear evidence of these substances in the prevention of diseases. The most important aspects of this special issue will cover the synthesis, biological activities, and clinical applications of marine carotenoids, with particular attention to recent evidence regarding anti-oxidant and anti-inflammatory properties in the prevention of cardiovascular disease.     

Potential Anti-Aging Substances Derived from Seaweeds

Aging is a major risk factor for many chronic diseases, such as cancer, cardiovascular disease, and diabetes. The exact mechanisms underlying the aging process are not fully elucidated. However, a growing body of evidence suggests that several pathways, such as sirtuin, AMP-activated protein kinase, insulin-like growth factor, autophagy, and nuclear factor erythroid 2-related factor 2 play critical roles in regulating aging. Furthermore, genetic or dietary interventions of these pathways can extend lifespan by delaying the aging process. Seaweeds are a food source rich in many nutrients, including fibers, polyunsaturated fatty acids, vitamins, minerals, and other bioactive compounds. The health benefits of seaweeds include, but are not limited to, antioxidant, anti-inflammatory, and anti-obese activities. Interestingly, a body of studies shows that some seaweed-derived extracts or isolated compounds, can modulate these aging-regulating pathways or even extend lifespans of various animal models. However, few such studies have been conducted on higher animals or even humans. In this review, we focused on potential anti-aging bioactive substances in seaweeds that have been studied in cells and animals mainly based on their anti-aging cellular and molecular mechanisms.     

Bioactive Lipids of Marine Microalga Chlorococcum sp. SABC 012504 with Anti-Inflammatory and Anti-Thrombotic Activities

Microalgae are at the start of the food chain, and many are known producers of a significant amount of lipids with essential fatty acids. However, the bioactivity of microalgal lipids for anti-inflammatory and antithrombotic activities have rarely been investigated. Therefore, for a sustainable source of the above bioactive lipids, the present study was undertaken. The total lipids of microalga Chlorococcum sp., isolated from the Irish coast, were fractionated into neutral-, glyco-, and phospho-lipids, and were tested in vitro for their anti-inflammatory and antithrombotic activities. All tested lipid fractions showed strong anti-platelet-activating factor (PAF) and antithrombin activities in human platelets (half maximal inhibitory concentration (IC₅₀) values ranging ~25–200 μg of lipid) with the highest activities in glyco- and phospho-lipid fractions. The structural analysis of the bioactive lipid fraction-2 revealed the presence of specific sulfoquinovosyl diacylglycerols (SQDG) bioactive molecules and the HexCer-t36:2 (t18:1/18:1 and 18:2/18:0) cerebrosides with a phytosphingosine (4-hydrosphinganine) base, while fraction-3 contained bioactive phosphatidylcholine (PC) and phosphatidylethanolamine (PE) molecules. These novel bioactive lipids of Chlorococcum sp. with putative health benefits may indicate that marine microalgae can be a sustainable alternative source for bioactive lipids production for food supplements and nutraceutical applications. However, further studies are required towards the commercial technology pathways development and biosafety analysis for the use of the microalga.     

Marine Alkaloids: Compounds with In Vivo Activity and Chemical Synthesis

Marine alkaloids comprise a class of compounds with several nitrogenated structures that can be explored as potential natural bioactive compounds. The scientific interest in these compounds has been increasing in the last decades, and many studies have been published elucidating their chemical structure and biological effects in vitro. Following this trend, the number of in vivo studies reporting the health-related properties of marine alkaloids has been increasing and providing more information about the effects in complex organisms. Experiments with animals, especially mice and zebrafish, are revealing the potential health benefits against cancer development, cardiovascular diseases, seizures, Alzheimer’s disease, mental health disorders, inflammatory diseases, osteoporosis, cystic fibrosis, oxidative stress, human parasites, and microbial infections in vivo. Although major efforts are still necessary to increase the knowledge, especially about the translation value of the information obtained from in vivo experiments to clinical trials, marine alkaloids are promising candidates for further experiments in drug development.     

Marine Carotenoids against Oxidative Stress: Effects on Human Health

Carotenoids are lipid-soluble pigments that are produced in some plants, algae, fungi, and bacterial species, which accounts for their orange and yellow hues. Carotenoids are powerful antioxidants thanks to their ability to quench singlet oxygen, to be oxidized, to be isomerized, and to scavenge free radicals, which plays a crucial role in the etiology of several diseases. Unusual marine environments are associated with a great chemical diversity, resulting in novel bioactive molecules. Thus, marine organisms may represent an important source of novel biologically active substances for the development of therapeutics. In this respect, various novel marine carotenoids have recently been isolated from marine organisms and displayed several utilizations as nutraceuticals and pharmaceuticals. Marine carotenoids (astaxanthin, fucoxanthin, β-carotene, lutein but also the rare siphonaxanthin, sioxanthin, and myxol) have recently shown antioxidant properties in reducing oxidative stress markers. This review aims to describe the role of marine carotenoids against oxidative stress and their potential applications in preventing and treating inflammatory diseases.     

Extract from the Zooxanthellate Jellyfish Cotylorhiza tuberculata Modulates Gap Junction Intercellular Communication in Human Cell Cultures

On a global scale, jellyfish populations in coastal marine ecosystems exhibit increasing trends of abundance. High-density outbreaks may directly or indirectly affect human economical and recreational activities, as well as public health. As the interest in biology of marine jellyfish grows, a number of jellyfish metabolites with healthy potential, such as anticancer or antioxidant activities, is increasingly reported. In this study, the Mediterranean “fried egg jellyfish” Cotylorhiza tuberculata (Macri, 1778) has been targeted in the search forputative valuable bioactive compounds. A medusa extract was obtained, fractionated, characterized by HPLC, GC-MS and SDS-PAGE and assayed for its biological activity on breast cancer cells (MCF-7) and human epidermal keratinocytes (HEKa). The composition of the jellyfish extract included photosynthetic pigments, valuable ω-3 and ω-6 fatty acids, and polypeptides derived either from jellyfish tissues and their algal symbionts. Extract fractions showed antioxidant activity and the ability to affect cell viability and intercellular communication mediated by gap junctions (GJIC) differentially in MCF-7and HEKa cells. A significantly higher cytotoxicity and GJIC enhancement in MCF-7 compared to HEKa cells was recorded. A putative action mechanism for the anticancer bioactivity through the modulation of GJIC has been hypothesized and its nutraceutical and pharmaceutical potential was discussed.     

Marine carotenoids and cardiovascular risk markers

Marine carotenoids are important bioactive compounds with physiological activities related to prevention of degenerative diseases found principally in plants, with potential antioxidant biological properties deriving from their chemical structure and interaction with biological membranes. They are substances with very special and remarkable properties that no other groups of substances possess and that form the basis of their many, varied functions and actions in all kinds of living organisms. The potential beneficial effects of marine carotenoids have been studied particularly in astaxanthin and fucoxanthin as they are the major marine carotenoids. Both these two carotenoids show strong antioxidant activity attributed to quenching singlet oxygen and scavenging free radicals. The potential role of these carotenoids as dietary anti-oxidants has been suggested to be one of the main mechanisms for their preventive effects against cancer and inflammatory diseases. The aim of this short review is to examine the published studies concerning the use of the two marine carotenoids, astaxanthin and fucoxanthin, in the prevention of cardiovascular diseases.     

Prospects of Marine Sterols against Pathobiology of Alzheimer’s Disease: Pharmacological Insights and Technological Advances

Alzheimer’s disease (AD) is a degenerative brain disorder characterized by a progressive decline in memory and cognition, mostly affecting the elderly. Numerous functional bioactives have been reported in marine organisms, and anti-Alzheimer’s agents derived from marine resources have gained attention as a promising approach to treat AD pathogenesis. Marine sterols have been investigated for several health benefits, including anti-cancer, anti-obesity, anti-diabetes, anti-aging, and anti-Alzheimer’s activities, owing to their anti-inflammatory and antioxidant properties. Marine sterols interact with various proteins and enzymes participating via diverse cellular systems such as apoptosis, the antioxidant defense system, immune response, and cholesterol homeostasis. Here, we briefly overview the potential of marine sterols against the pathology of AD and provide an insight into their pharmacological mechanisms. We also highlight technological advances that may lead to the potential application of marine sterols in the prevention and therapy of AD.     

Polar Lipids Composition,Antioxidant and Anti-Inflammatory Activities of the Atlantic Red Seaweed Grateloupia turuturu

Grateloupia turuturu Yamada, 1941, is a red seaweed widely used for food in Japan and Korea which was recorded on the Atlantic Coast of Europe about twenty years ago. This seaweed presents eicosapentaenoic acid (EPA) and other polyunsaturated fatty acids (PUFAs) in its lipid fraction, a feature that sparked the interest on its potential applications. In seaweeds, PUFAs are mostly esterified to polar lipids, emerging as healthy phytochemicals. However, to date, these biomolecules are still unknown for G. turuturu. The present work aimed to identify the polar lipid profile of G. turuturu, using modern lipidomics approaches based on high performance liquid chromatography coupled to high resolution mass spectrometry (LC–MS) and gas chromatography coupled to mass spectrometry (GC–MS). The health benefits of polar lipids were identified by health lipid indices and the assessment of antioxidant and anti-inflammatory activities. The polar lipids profile identified from G. turuturu included 205 lipid species distributed over glycolipids, phospholipids, betaine lipids and phosphosphingolipids, which featured a high number of lipid species with EPA and PUFAs. The nutritional value of G. turuturu has been shown by its protein content, fatty acyl composition and health lipid indices, thus confirming G. turuturu as an alternative source of protein and lipids. Some of the lipid species assigned were associated to biological activity, as polar lipid extracts showed antioxidant activity evidenced by free radical scavenging potential for the 2,2′-azino-bis-3-ethyl benzothiazoline-6-sulfonic acid (ABTS^●+) radical (IC₅₀ ca. 130.4 μg mL⁻¹) and for the 2,2-diphenyl-1-picrylhydrazyl (DPPH^●) radical (IC₂₅ ca. 129.1 μg mL⁻¹) and anti-inflammatory activity by inhibition of the COX-2 enzyme (IC₅₀ ca. 33 µg mL⁻¹). Both antioxidant and anti-inflammatory activities were detected using a low concentration of extracts. This integrative approach contributes to increase the knowledge of G. turuturu as a species capable of providing nutrients and bioactive molecules with potential applications in the nutraceutical, pharmaceutical and cosmeceutical industries.     

Penicillinolide A: A New Anti-Inflammatory Metabolite from the Marine Fungus Penicillium sp. SF-5292

In the course of studies on bioactive metabolites from marine fungi, a new 10-membered lactone, named penicillinolide A (1) was isolated from the organic extract of Penicillium sp. SF-5292 as a potential anti-inflammatory compound. The structure of penicillinolide A (1) was mainly determined by analysis of NMR and MS data and Mosher’s method. Penicillinolide A (1) inhibited the production of NO and PGE₂ due to inhibition of the expression of iNOS and COX-2. Penicillinolide A (1) also reduced TNF-α, IL-1β and IL-6 production, and these anti-inflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of IκB-α, NF-κB nuclear translocation, and NF-κB DNA binding activity. In addition, using inhibitor tin protoporphyrin (SnPP), a competitive inhibitor of HO activity, it was verified that the inhibitory effects of compound 1 on the production of pro-inflammatory mediators and NF-κB DNA binding activity were partially associated with HO-1 expression through Nrf2 nuclear translocation.     

Stereochemical Determination of Fistularins Isolated from the Marine Sponge Ecionemia acervus and Their Regulatory Effect on Intestinal Inflammation

By activity-guided fractionation based on inhibition of nitric oxide (NO) and prostaglandin E2 (PGE₂), six fistularin compounds (1–6) were isolated from the marine sponge Ecionemia acervus (order Astrophorida). Based on stereochemical structure determination using Mosher’s method, fistularin-3 was assigned as a new stereoisomer. On the basis of the stereochemistry of fistularin-3, the stereochemical homogeneity of all six compounds was established by comparing carbon and proton chemical shifts. For fistularin-1 (1) and -2 (2), quantum calculations were performed to confirm their stereochemistry. In a co-culture system of human epithelial Caco-2 cells and THP-1 macrophages, all six isolated compounds showed potent anti-inflammatory activities. These bioactive fistularins inhibited the production of NO, PGE₂, TNF-α, IL-1β, and IL-6 induced by lipopolysaccharide and interferon gamma. Inducible NO synthase and cyclooxygenase-2 expression and MAPK phosphorylation were downregulated in response to the inhibition of NF-κB nuclear translocation. Among the compounds tested, fistularin-1 (1) and 19-deoxyfistularin-3 (4) showed the highest activity. These findings suggest the potential use of the marine sponge E. acervus and its metabolites as pharmaceuticals for the treatment of inflammation-related diseases including inflammatory bowel disease.     

Overview on Biological Activities and Molecular Characteristics of Sulfated Polysaccharides from Marine Green Algae in Recent Years

Among the three main divisions of marine macroalgae (Chlorophyta, Phaeophyta and Rhodophyta), marine green algae are valuable sources of structurally diverse bioactive compounds and remain largely unexploited in nutraceutical and pharmaceutical areas. Recently, a great deal of interest has been developed to isolate novel sulfated polysaccharides (SPs) from marine green algae because of their numerous health beneficial effects. Green seaweeds are known to synthesize large quantities of SPs and are well established sources of these particularly interesting molecules such as ulvans from Ulva and Enteromorpha, sulfated rhamnans from Monostroma, sulfated arabinogalactans from Codium, sulfated galacotans from Caulerpa, and some special sulfated mannans from different species. These SPs exhibit many beneficial biological activities such as anticoagulant, antiviral, antioxidative, antitumor, immunomodulating, antihyperlipidemic and antihepatotoxic activities. Therefore, marine algae derived SPs have great potential for further development as healthy food and medical products. The present review focuses on SPs derived from marine green algae and presents an overview of the recent progress of determinations of their structural types and biological activities, especially their potential health benefits.     

Unravelling the Dermatological Potential of the Brown Seaweed Carpomitra costata

The ever-increasing interest in keeping a young appearance and healthy skin has leveraged the skincare industry. This, coupled together with the increased concern regarding the safety of synthetic products, has boosted the demand for new and safer natural ingredients. Accordingly, the aim of this study was to evaluate the dermatological potential of the brown seaweed Carpomitra costata. The antioxidant, anti-enzymatic, antimicrobial, photoprotective and anti-inflammatory properties of five C. costata fractions (F1–F5) were evaluated. The ethyl acetate fraction (F3) demonstrated the most promising results, with the best ability to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals (EC₅₀ of 140.1 µg/mL) and the capacity to reduce reactive oxygen species (ROS) production promoted by UVA and UVB radiation in 3T3 cells, revealing its antioxidant and photoprotective potential. This fraction also exhibited the highest anti-enzymatic capacity, inhibiting the activities of collagenase, elastase and tyrosinase (IC₅₀ of 7.2, 4.8 and 85.9 µg/mL, respectively). Moreover, F3 showed anti-inflammatory potential, reducing TNF-α and IL-6 release induced by LPS treatment in RAW 264.7 cells. These bioactivities may be related to the presence of phenolic compounds, such as phlorotannins, as demonstrated by NMR analysis. The results highlight the potential of C. costata as a source of bioactive ingredients for further dermatological applications.     

Guava (<Emphasis Type="Italic">Psidium guajava L</Emphasis>. cv. Red Suprema) Crude Extract Protect Human Dermal Fibroblasts against Cytotoxic Damage Mediated by Oxidative Stress

We analyzed guava fruits (Psidium guajava L. cv. Red Suprema) from Cuba to determine their chemical composition, total antioxidant capacity, as well as their protective effect against oxidative damage using an in vitro model of human dermal fibroblasts. The guava fruit is a natural source of bioactive compounds, such as polyphenols, vitamin C, folates and beta carotenes with proven health benefits. Human dermal fibroblasts were pre-incubated with different concentrations of guava crude extract and then subjected to oxidative stress using the AAPH stressor. The number of apoptotic and dead cells, as well as the markers of oxidative damage such as lipid and protein oxidation significantly decreased when cells were pre-incubated with guava crude extract and then exposed to the stressor. The activity of antioxidant enzymes also improved when cells were pre-incubated with guava crude extract in comparison to cells subjected to stress without prior pre-incubation with the guava extract. The results obtained in this study highlight the health benefits of guava regarding oxidative stress, proving it to be an important source of bioactive compounds associated with important biological properties.     

Antioxidant and Anti-Inflammatory Activities of Barettin

In this paper, we present novel bioactivity for barettin isolated from the marine sponge Geodia barretti. We found that barettin showed strong antioxidant activity in biochemical assays as well as in a lipid peroxidation cell assay. A de-brominated synthetic analogue of barettin did not show the same activity in the antioxidant cell assay, indicating that bromine is important for cellular activity. Barettin was also able to inhibit the secretion of the inflammatory cytokines IL-1β and TNFα from LPS-stimulated THP-1 cells. This combination of anti-inflammatory and antioxidant activities could indicate that barettin has an atheroprotective effect and may therefore be an interesting product to prevent development of atherosclerosis.     

Screening of Marine Bioactive Antimicrobial Compounds for Plant Pathogens

Plant diseases have been threatening food production. Controlling plant pathogens has become an important strategy to ensure food security. Although chemical control is an effective disease control strategy, its application is limited by many problems, such as environmental impact and pathogen resistance. In order to overcome these problems, it is necessary to develop more chemical reagents with new functional mechanisms. Due to their special living environment, marine organisms have produced a variety of bioactive compounds with novel structures, which have the potential to develop new fungicides. In the past two decades, screening marine bioactive compounds to inhibit plant pathogens has been a hot topic. In this review, we summarize the screening methods of marine active substances from plant pathogens, the identification of marine active substances from different sources, and the structure and antibacterial mechanism of marine active natural products. Finally, the application prospect of marine bioactive substances in plant disease control was prospected.     

Fish Sidestream-Derived Protein Hydrolysates Suppress DSS-Induced Colitis by Modulating Intestinal Inflammation in Mice

Inflammatory bowel disease is characterized by extensive intestinal inflammation, and therapies against the disease target suppression of the inflammatory cascade. Nutrition has been closely linked to the development and suppression of inflammatory bowel disease, which to a large extent is attributed to the complex immunomodulatory properties of nutrients. Diets containing fish have been suggested to promote health and suppress inflammatory diseases. Even though most of the health-promoting properties of fish-derived nutrients are attributed to fish oil, the potential health-promoting properties of fish protein have not been investigated. Fish sidestreams contain large amounts of proteins, currently unexploited, with potential anti-inflammatory properties, and may possess additional benefits through bioactive peptides and free amino acids. In this project, we utilized fish protein hydrolysates, based on mackerel and salmon heads and backbones, as well as flounder skin collagen. Mice fed with a diet supplemented with different fish sidestream-derived protein hydrolysates (5% w/w) were exposed to the model of DSS-induced colitis. The results show that dietary supplements containing protein hydrolysates from salmon heads suppressed chemically-induced colitis development as determined by colon length and pro-inflammatory cytokine production. To evaluate colitis severity, we measured the expression of different pro-inflammatory cytokines and chemokines and found that the same supplement suppressed the pro-inflammatory cytokines IL-6 and TNFα and the chemokines Cxcl1 and Ccl3. We also assessed the levels of the anti-inflammatory cytokines IL-10 and Tgfb and found that selected protein hydrolysates induced their expression. Our findings demonstrate that protein hydrolysates derived from fish sidestreams possess anti-inflammatory properties in the model of DSS-induced colitis, providing a novel underexplored source of health-promoting dietary supplements.