**1. Introduction**

Marine macroalgae, popularly known as seaweeds, have emerged as one of the contributors to achieve United Nations sustainable development goals (SDG) [1]. Indeed, algae can be used in healthy and sustainable diets, thereby meeting the farm to fork strategy, which is the core of the European Green Deal [2,3]. Moreover, they are a rich source of nutrients and valuable bioactive phytochemicals that act as preventive agents against non-communicable diseases [4] and that can contribute to overcome multiple societal challenges, such as the ongoing fight on obesity [5] and on the issues caused by antimicrobial resistance in microorganisms [6,7]. Additionally, their chemical diversity can also be paramount to fight infectious viral diseases and allow a higher efficiency when tackling future pandemic situations [7,8]. The exploitation of seaweeds as marine resources for new high value-added products thus contributes to increase their economic relevance on multiple niche markets [9].

**Citation:** Lopes, D.; Rey, F.; Leal, M.C.; Lillebø, A.I.; Calado, R.; Domingues, M.R. Bioactivities of Lipid Extracts and Complex Lipids from Seaweeds: Current Knowledge and Future Prospects. *Mar. Drugs* **2021**, *19*, 686. https://doi.org/ 10.3390/md19120686

Academic Editor: Bill J. Baker

Received: 5 November 2021 Accepted: 28 November 2021 Published: 30 November 2021

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Seaweeds, have been used since earliest times as a source of food and in traditional medicine in Asian and other seacoast countries around the world [1]. Although their generalized value for human nutrition and health is already recognized, it is mostly based on empirical knowledge. Seaweeds are reservoirs of bioactive compounds [10] yet to be fully used in a plethora of blue biotechnology applications [11], such as functional foods and feeds, pharmaceutical, nutraceutical [12], cosmeceutical [13], and other high-end uses.

Well-known phytochemicals have already been recorded from seaweeds, including polysaccharides, proteins, pigments, and other minor compounds such as phenolics and vitamins [14]. Seaweed lipids are a less abundant fraction of such bioactive phytochemicals that, despite their great value, remain largely over-looked, likely because of their lower content, high structural diversity, and complexity, along with a rather poorly understood biological activity. They are mainly known as reservoirs of omega-3 polyunsaturated fatty acids (PUFA) with well-recognized health benefits [15]. Nevertheless, seaweeds also have complex lipids, such as phospholipids (PLs) and glycolipids (GLs), which display unique features that are not found in terrestrial plants, such as being esterified with omega-3 fatty acids (FA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [16,17]. Marine PLs have better bioavailability, resistance to oxidation, and higher content of omega-3 PUFA than lipids from other sources. Moreover, they are better at delivering dietary omega-3 PUFA than terrestrial PLs, as already demonstrated in several comparative studies [18–21]. On the other hand, and unlike their terrestrial analogues, GLs from seaweeds contain long chain PUFA (20 or more carbon atoms) with potential biotechnological applications [22]. PLs and GLs play a structural role in biological systems, representing the major building blocks of cytoplasmatic and chloroplast membranes [23]. They are also the main carriers of PUFA [24,25].

Recently, complex lipids are being considered, promising phytochemicals with intrinsic bioactive properties, including antioxidant, antitumor, anti-inflammatory, and antimicrobial [7,26,27], fostering potential applications in pharmaceutical, nutraceutical, and cosmeceutical fields (Figure 1) [28]. However, the complexity and structural diversity of complex lipids are hindering their detailed characterization and exploitation. Most published works describing seaweed bioactive lipids refer to assays of total lipid extracts or enriched fractions [29–31], and few studies are focused on the identification and characterization of complex lipids, making it difficult to establish a clear structure–activity relationship. Nevertheless, the rapid development of modern -omics approaches and bioinformatic tools in recent years have been contributing to achieve a detailed mapping of the lipidome of seaweeds from different phyla. Selected species to date include *Ulva rigida* and *Codium tomentosum* from Chlorophyta phylum [32,33]; *Chondrus crispus*, *Palmaria palmata*, *Porphyra dioica*, *Gracilaria* sp. from Rhodophyta phylum [27,34–36]; and *Fucus vesiculosus*, *Saccharina latissima*, *Sargassum muticum*, and *Bifurcaria bifurcata* from Ochrophyta phylum [37–39]. The comparison of seaweeds lipidome revealed unique lipid signatures [40]. While some phylum-specific trends could perceived, lipidomic signatures were rather species-specific [40]. More work is needed to achieve a larger coverage of seaweeds lipidome to fully unravel the specificity of their signatures and support value added uses of these marine bioresources.

Despite its biotechnological potential, our knowledge on naturally occurring bioactive complex lipids from seaweeds is still in its infancy. Only recently sustainably farmed seaweeds have emerged in Europe [41]. The production of seaweeds biomass under controlled conditions has promoted the safeguarding of high food safety standards, and subsequently generated interest in the bioprospecting for new compounds, namely complex lipids, for high-end biotechnological uses. For now, questions such as the relationship between bioactivities already detected and complex lipid structures and their specificity remain to be answered.

The authors have performed a systematic review of scientific literature to establish the state of the art of our knowledge on naturally occurring bioactive complex lipids from seaweeds. The information here assembled provides new insights on how studies are being

performed and allows the identification of gaps in knowledge that still need attention in upcoming years.

**Figure 1.** Complex lipids from seaweeds as bioactive compounds with reported bioactivities.
