1. Introduction

The oceans are home to many biological and chemical compounds and have enormous biodiversity globally, with about 80% of the world’s animal and plant species [58,59]. The oceanic environment is hostile and competitive, conditioning marine organisms to develop adaptive mechanisms through biochemical compounds to resist various types of stressors. Thus, the metabolites produced give these organisms unique structural and functional characteristics [60,61]. As Halvey [62] points out, life originated in the sea and adapted to the terrestrial environment throughout evolution. Despite intense structural changes, many molecules continue to have the same physiological functions. Therefore, several bioactive compounds of marine organisms have therapeutic potential and may be candidates for developing drugs and products for the treatment of human diseases [63].

Discoveries and studies of marine bioactive compounds are still recent compared to other areas of knowledge. In recent decades, numerous new molecules have been documented, patented, and already tested in clinical trials [61,64]. Approximately 25,000 marine chemical compounds have been reported [65]. With the improvement of the technologies of exploitation and extraction of these compounds and the undeniable therapeutic potential, the trend is that in the coming years many drugs, supplements, and natural products with marine derivatives will emerge to treat a multitude of diseases [63]. Several studies have shown that bioactive marine compounds have significant antitumor and anticancer activities [66]. Jimenez et al. [67] analyzed five marine-derived drugs successfully against cancer, and several other diseases in clinical trials. The literature also reports the association of these compounds with several other therapeutic effects such as treatment of diabetes, chronic pain, and cardiovascular diseases, and antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activity [68]. Finally, marine-derived biologically active compounds can be used in immunotherapies. They can act by inducing, increasing, or reducing the immune response, therefore, with enormous potential for therapeutic use [60]. In this context, evidence and findings have pointed out several marine derivatives with immunomodulatory and anti-inflammatory properties [60,69,70,71], which represents new sources for the treatment, damage control, and prevention of rheumatologic diseases whose etiopathogenesis involves inflammatory pathway disorders, such as RA.

2.Examples of Marine-Derived Biologically Active Compounds

2.1. Glycosaminoglycans—Chondroitin Sulfate and Hyaluronic Acid

Glycosaminoglycan (GAGs) are multifunctional polysaccharides composed of repeating disaccharide units that may change the form of sulfation and epimerization, which determines different functions of protein recognition and biological activities of these compounds [72,73]. Two important groups of complex heteropolysaccharides belonging to the class of GAGs are chondroitin sulfate (CS) and hyaluronic acid (HA). CS is formed by repeated disaccharides N-acetyl-d-galactosamine (GalNAc) and d-glucuronic acid (GlcA) with sulfate groups allocated in different numbers and positions, which makes this polymer extremely heterogeneous in terms of length and structure [74,75]. Around 16 various disaccharides can be formed depending on the position of sulfation [76], and there are differences in concentration and composition between land and marine source SC. It is a biomolecule present in virtually all vertebrate organisms and invertebrates, mostly marine organisms, because they present unusual sulfation patterns. Consequently, it is involved in many biological processes at the molecular, cellular, and tissue levels [75,77,78]. They play an essential structural role in the composition of extracellular matrix and formation of tissues such as cartilage and bones, abundant in mammals’ connective tissue [73,79]. Some studies have revealed that CS has immunomodulatory and anti-inflammatory properties in several diseases [80,81], highlighting the promising effects of CS reducing symptoms and improving function in osteoarthritis patients, which is one of the consequences of RA in advanced phases [82,83]. According to Abdallah et al. [72] compiled in a recent review, CS can be extracted from cartilage, head, skeleton, fins, and skin from different marine animals such as sharks, salmon, zebrafish, and other species of fish, squid, ray, and octopus. Still, the primary marine source in commercial terms is shark cartilage. Therefore, they are valuable compounds that can be collected to optimize the use of marine waste.

HA consists of units of disaccharides N-acetyl-d-glucosamine (GalNAc) and d-glucuronic acid (GlcA) [84], is an unbranched high molecular weight linear polysaccharide, the only nonsulfated GAGs that is not bound to proteins [85,86]. It is widely distributed in the conjunctive as an essential component of the extracellular matrix, playing a vital role in controlling tissue permeability and hydration, macromolecular transport between cells, and bacterial invasion control [85,87]. The human body is found in higher concentrations in connective tissues such as synovial fluid, the vitreous humor of the eyeball, and the umbilical cord [87]. HA from marine sources can be extracted mainly from the eyeball and liver of swordfish, shark, mollusk bivalves, stingray, and tuna [72,87]. HA is widely used in the biomedical sector for the production of hydrogels that can be used as long-term low-dose drug delivery vehicles [88,89], with an input for the development of new biomaterials applied to wound healing [90] and tissue culture scaffolds [88,91,92]. Evidence has revealed that HA has anti-inflammatory properties and has been used in RA treatment for decades [89,91,93].

2.2. Chitin and Chitosan

Chitin or poly (β-(1→4)-N-acetyl-d-glucosamine) is a polysaccharide synthesized by numerous living organisms and one of the most abundant natural biopolymers on earth. It is found in the exoskeleton of crustaceans and cell walls of marine fungi [94], but is extracted mainly from the shell of the crab, shrimp, and lobster [95]. Due to its characteristics of high strength, biocompatibility, high biodegradability, and low toxicity, it is a biopolymer with numerous applications in the biomedical field, for example, gene delivery, target drug delivery, surgical sutures, and tissue engineering products [96,97,98].

Chitosan is the direct derivative of chitin obtained by partial deacetylation under alkaline conditions [95], shares characteristics similar to its precursor. Still, chitosan has more applications in the chemical areas, nutraceutical, and pharmaceutical industries [73,99]. It has hydrophilic and antimicrobial properties, being necessary for the production of biomaterials [95]. It is interesting for application in drug delivery systems, emphasizing the development of chitosan-based nanosystems to treat inflammatory diseases such as RA [100]. Studies have pointed out that chitosan exerts anti-inflammatory, antioxidant, antimicrobial, antitumor, and hypocholesterolemic activity [101,102,103,104].

2.3. Alginate—Polysaccharides

Alginate is a natural polysaccharide composed of building blocks of 1,4-linked (-d-mannuronic acid) (M) and (-l-guluronic acid) (G), which vary in proportion forming alginate compounds with different chemical and physical characteristics [105,106]. The primary sources of Alginate are brown seaweed such as Ascophyllum nodosum, Laminaria hyperborea, Saccharina japonica, Macrocystis pyrifera, and Laminaria digitata [107]. It is bioactive with biocompatibility, low cost, low toxicity, gelling agent, and stabilizer of solutions, which make it interesting for various biomedical applications [108], nutraceuticals, and cosmetics [109]. It is used to treat wounds, and there are already at least 12 commercially available alginate-based dressings with promising results due to its immunogenic, antibacterial, and procoagulant activities [107,110].

2.4. Peptides

Peptides play numerous bioregulatory roles of extreme importance. Those of marine origin stand out for having unique molecular mechanisms [111]. They offer enormous possibilities for the study of several secondary metabolites, which have high specificity and low toxicity. Therefore, they constitute an opportunity to identify new prototypes of drugs and products, expanding their applications in the pharmaceutical and biomedical industry [111,112]. Bioactive peptides usually have 3–20 amino acid residues organized in different sequences, determining distinct structures and properties [113]. Given the various possible compositions, they can perform different biological activities such as antiviral, antifungal, anticancer, antidiabetic, antioxidant, anticoagulant, antihypertensive, immunomodulatory, analgesic, and calcium-binding properties, and most marine peptides have antimicrobial activity [114,115]. The extraction of marine bioactive peptides is made from bacteria, mainly marine cyanobacteria, microalgae such as Chlorella vulgaris (green algae), marine sponges, and their associated microorganisms [114,116].

2.5. Fatty Acids

Fatty acids (FA) are carboxylic acids with different carbon numbers and double bonds. According to the structure and biochemical properties they are classified into two broad groups, saturated FAs that do not contain double bonds in their carbon structure and unsaturated FAs that include double bonds in their composition and are subdivided into monounsaturated FAs (MUFAs) or polyunsaturated FAs (PUFAs) [117,118]. PUFAs are classified into two categories: (i) Omega-3 (n-3 PUFAs), which mainly includes α-Linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA); (ii) Omega-6 (n-6 PUFAs), which includes linoleic acid (LA); y-linoleic acid (GLA) and arachidonic acid (AA) [119,120]. They are synthesized by the human organism but need to be also ingested through diet, being classified as essential FAs due to their enormous importance participating in various metabolic processes throughout human life [120] and constitute the phospholipids that form the cell membrane [121]. They act significantly in inflammatory responses with participation as substrates for the biosynthesis of inflammatory mediators, cellular receptors’ activation, and modulation of membrane fluidity to alter cell function [122,123,124]. Omega-3 rich oils, especially DHA and EPA, can be extracted from seafood such as algae and fatty fish, the best are salmon, sardines, tuna, herring, and trout [119,125]. Marine fatty acids play essential anti-inflammatory activities and studies have pointed out that they can be used in the treatment of RA, promoting clinical improvements [126,127,128,129].

For References - please visit: Bilal, M., Qindeel, M., Nunes, L. V., Duarte, M. T. S., Ferreira, L. F. R., Soriano, R. N., & Iqbal, H. (2021). Marine-Derived Biologically Active Compounds for the Potential Treatment of Rheumatoid Arthritis. Marine Drugs, 19(1), 10. https://doi.org/10.3390/md19010010

This entry is adapted from the peer-reviewed paper 10.3390/md19010010