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Review

Metabolites with Antioxidant Activity from Marine Macroalgae

by
Leto-Aikaterini Tziveleka
1,
Mohamed A. Tammam
1,2,
Olga Tzakou
1,
Vassilios Roussis
1 and
Efstathia Ioannou
1,*
1
Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
2
Department of Biochemistry, Faculty of Agriculture, Fayoum University, Fayoum 63514, Egypt
*
Author to whom correspondence should be addressed.
Antioxidants 2021, 10(9), 1431; https://doi.org/10.3390/antiox10091431
Submission received: 3 August 2021 / Revised: 30 August 2021 / Accepted: 3 September 2021 / Published: 8 September 2021
(This article belongs to the Section Natural and Synthetic Antioxidants)
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Abstract

:
Reactive oxygen species (ROS) attack biological molecules, such as lipids, proteins, enzymes, DNA, and RNA, causing cellular and tissue damage. Hence, the disturbance of cellular antioxidant homeostasis can lead to oxidative stress and the onset of a plethora of diseases. Macroalgae, growing in stressful conditions under intense exposure to UV radiation, have developed protective mechanisms and have been recognized as an important source of secondary metabolites and macromolecules with antioxidant activity. In parallel, the fact that many algae can be cultivated in coastal areas ensures the provision of sufficient quantities of fine chemicals and biopolymers for commercial utilization, rendering them a viable source of antioxidants. This review focuses on the progress made concerning the discovery of antioxidant compounds derived from marine macroalgae, covering the literature up to December 2020. The present report presents the antioxidant potential and biogenetic origin of 301 macroalgal metabolites, categorized according to their chemical classes, highlighting the mechanisms of antioxidative action when known.

1. Introduction

In all aerobic organisms, oxygen is a crucial element in their metabolic pathways. A high redox potential milieu stimulates the production of free radicals, defined as chemical species with unpaired valence electrons [1]. The most common reactive species in biological systems are oxygen radicals or oxygen-derived species, such as superoxide anion (O2−), hydrogen peroxide (H2O2), and hydroxyl radicals (·OH) [2,3], collectively named reactive oxygen species (ROS). Still, other forms of radicals, such as nitric oxide (NO·) and transition metal ions, can also be produced. ROS are generated as products of normal cellular functioning and oxygen metabolism and have essential functions in various important biochemical processes, such as the defense against infections, vasodilation, neurotransmission, gene regulation, and oxidative signaling [3,4].
Disturbance of the equilibria of prooxidant/antioxidant reactions in cells can lead to redox imbalance and oxidative stress, which causes an excessive generation of ROS and free radicals, in turn resulting in severe cellular damage (Figure 1) [3,5,6,7,8,9]. These molecules further react with key organic substrates, such as DNA, RNA, proteins, and lipids, leading to disruption of their structure or function, and consequently to the onset of diseases, such as atherosclerosis [10], diabetes [11], rheumatoid arthritis [12], inflammatory diseases [13], neurodegenerative diseases [14,15], aging, immune system disorders, and cancer [16,17].
The defense system of living organisms against free radicals comprises both enzymatic and non-enzymatic antioxidants [18]. Enzymes either prevent the formation of or neutralize free radicals (e.g., superoxide dismutases (SOD), catalases (CAT), lactoperoxidases, and glutathione peroxidases (GPx)), or indirectly neutralize free radicals by supporting the activity of other endogenous antioxidants (e.g., glutathione reductase (GR) and glucose-6-phosphate dehydrogenase) [19]. On the other hand, non-enzymatic antioxidants are compounds, other than enzymes, that act on free radicals and can be either produced by the stressed living organism or delivered through the diet, e.g., via the consumption of ascorbic acid (vitamin C), tocopherol (vitamin E), β-carotene, flavonoids, and polyphenols [20]. The most effective and extensively used strategy to diminish oxidative stress is the supplementation of exogenous antioxidants [21]. In recent years, safety and health concerns have been raised for synthetic antioxidants. Therefore, natural antioxidants have attracted attention and are being widely used [1]. Since 2007, antioxidants have been defined as “any substance that delays, prevents or removes oxidative damage to a target molecule’’ [2].
Oceans, covering about 70% of Earth’s surface and hosting an immense array of macro- and microorganisms, constitute a renewable resource of potential therapeutic agents. The diverse and antagonistic marine environment triggers the production of a wide variety of bioactive compounds. Marine organisms have adapted remarkably to extreme environmental conditions, such as high salinity, low or high temperature, high pressure, low availability of nutrients, and low or high exposure to sunlight [22], and can, therefore, provide an outstanding reservoir of bioactive compounds, many of which are unprecedented in terrestrial organisms [23,24,25,26,27].
Marine algae constitute a rich source of structurally diverse natural products, often exhibiting significant biological activities [28,29]. Algae are growing in ecosystems with intense exposure to sunlight and high concentrations of oxygen, conditions that favor the production of free radicals. However, the absence of oxidative damage in structural fatty acid membranes suggests that these organisms synthesize compounds with antioxidant activity [30]. In recent years, several studies highlight the antioxidant potential of seaweeds, attributed to natural products belonging to different structural classes [31,32,33,34,35,36].
A high number of compounds isolated from green, brown, and red algae (Chlorophyta, Ochrophyta, and Rhodophyta, respectively) have been proven to exert prominent antioxidant activity. This review compiles the progress made concerning the discovery of antioxidant compounds derived from marine macroalgae, covering the literature up to December 2020. Following a brief overview of the most commonly used methods for the evaluation of antioxidant activity, algal metabolites with antioxidant activity are presented according to their chemical classification in five main groups, namely (1) phenolic compounds, including bromophenols, phlorotannins, and flavonoids, (2) terpenoids, including steroids & carotenoids, (3) meroterpenoids, (4) nitrogenous compounds, including peptides, alkaloids and chlorophyll-related pigments, and (5) carbohydrates and polysaccharides. Their structural characteristics, the assays used to evaluate their activity, and the measured antioxidant activity levels (when reported in numerical form) are presented, while the mechanisms of antioxidative action are discussed when known.

2. Brief Overview of the Methods Employed for the Evaluation of Antioxidant Activity

Efficient antioxidants typically have high redox potential that allows them to act as reducing agents, hydrogen donors, or singlet oxygen quenchers. There are many techniques for evaluating the antioxidant activity, including free radical scavenging, oxygen scavenging, singlet oxygen quenching, metal chelation and inhibition of oxidative enzymes [37]. Overall, in vitro antioxidant tests using free radical traps are relatively straightforward to perform. However, antioxidant activity cannot be securely proposed based on the results from a single assay due to the differences observed between the various test systems [38]. Huang et al. (2005) roughly classified the most important antioxidant capacity assays, according to the reactions involved, into two types: (a) the hydrogen atom transfer (HAT)-based reactions which quantify hydrogen atom donating capacity, and (b) the electron transfer (ET)-based reactions which measure the reducing capacity of antioxidants [39] (Table 1). In HAT-based assays, the antioxidant and the substrate compete for peroxyl radicals. The most commonly used HAT-based assays include the oxygen radical absorbance capacity (ORAC) [40] and the total radical trapping antioxidant potential (TRAP) [41] assays. On the other hand, in ET-based assays the capacity of an antioxidant to reduce an oxidant is measured. The most common ET-based assays include the determination of the total phenolics content (TPC) using the Folin–Ciocalteu reagent [42], the trolox equivalence antioxidant capacity (TEAC)/2,2-azino-bis(3-ethyl benzothiazoline-6-sulfonic acid) diammonium salt (ABTS+) radical scavenging [43], the ferric reducing antioxidant power (FRAP) [44,45], and 1,1-diphenyl-2-picrylhydrazyl (DPPH) [46,47] assays.
Antioxidant activity evaluation can also be performed in vivo in animal models, such as in Wistar rats or mice. SOD, CAT, glutathione (GSH), GPx, oxidized low-density lipoprotein (LDL), malondialdehyde (MDA), and GR are the major in vivo indicators of oxidative stress that are usually monitored [48,49].

3. Phenolic Compounds

Phenols comprise a class of chemical compounds containing an aromatic ring bearing a hydroxyl group. Phenolic compounds are classified either as simple phenols or polyphenols based on the number of phenol units in their molecule. Bromophenols (BPs) are marine secondary metabolites containing one or several phenols with one or more bromine atoms in their molecule. Many BPs have been isolated and identified from a variety of marine species, including red, brown, and green algae, as well as ascidians and sponges [73]. Phlorotannins constitute another important and diverse group of naturally occurring polyphenolic secondary metabolites, restricted though to marine algae. Table 2 presents the phenolic compounds, including BPs, phlorotannins, and flavonoids (Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7 and Figure 8), isolated so far from marine macroalgae that exhibit significant antioxidant activities.
Recent studies reveal BPs to be one of the most promising candidates in the prevention of diseases associated with free radical attack [73]. Hitherto, more than 60 BPs, mainly isolated from marine red algae, have been reported to exert antioxidant activity in vitro. Their antioxidant activity has been primarily determined by the DPPH radical scavenging method. In general, the BPs shown in Table 2 exhibited better activity than that of butylated hydroxytoluene (BHT, IC50 = 82.1 µM), a synthetic antioxidant often used as positive control, with BPs isolated from the red algae Polysiphonia urceolata, Rhodomela confervoides and Symphyocladia latiuscula, as well as the green alga Avrainvillea sp. possessing the highest activities in the DPPH assay (IC50 < 10.0 µM).
Previous studies have shown that the non-brominated phenolic compounds 5-(hydroxylmethyl)-2-methoxybenzene-1,3-diol (2) and 3,4-dihydroxy-benzoic acid (DBA, 26) exert antioxidant activity [75,77,87]. Specifically, DBA (26) was found to reduce the levels of intracellular ROS generated by H2O2 or UVB treatment of the human HaCaT keratinocytes cells, thus protecting the cells from UVB-induced oxidative stress [87].
A series of BPs (3, 4, 6, 9–11, 13–16, 18, 19, 21, 22, 24, 27–32, 34–39, 42, 45, 47, 50–52, 56, 65) have been isolated from the red alga R. confervoides [76,77,81,83,85]. Among them, compounds 10, 15, 16, 18, 19, 37, 38, 39, 42, and 65 exerted the highest antioxidant activity with IC50 values of 7.43, 5.43, 5.70, 3.82, 9.52, 8.72, 9.40, 7.62, 5.22, and 8.90 µM, respectively, with all but 37 and 38 bearing a 2,3-dibromo-4,5-dihydroxy-benzyl skeleton. In particular, rhodomelin A (18) displayed the highest scavenging activity towards DPPH radical with an IC50 value of 3.82 µM. The 2,3-dibromo-4,5-dihydroxy-benzyl unit appears to be a structural element positively influencing antioxidant activity. Moreover, it seems that the antioxidant activity may have a close connection to the number of hydroxyl groups in the molecule [74]. Additionally, the presence of two successive hydroxyl groups in the benzene ring appears to be necessary for increased levels of antioxidant activity to be displayed. This conclusion is supported by the higher IC50 values exerted by BPs lacking the second free hydroxyl group by having a methoxyl group instead (e.g., 3, 22, 27, and 36 with IC50 values of 50.6, 58.2, 50.3 and 50.9 µM, respectively). For example, compound 22, with an IC50 value of 58.2 µM, bearing only one hydroxyl substituent, is less active than 21 (IC50 = 20.3 µM) that possesses the characteristic 4,5-dihydroxy-benzyl group [84,88]. On the other hand, a short and hydrophilic side chain leads to lower activities (e.g., compounds 4, 6, 9, and 11 with IC50 values of 42.3, 40.5, 38.4, and 22.5 µM, as compared to compounds 10, 13, 14, 15, 16, 18, and 19 with IC50 values of 7.43, 12.4, 14.6, 5.43, 5.70, 3.82, and 9.52 µM, respectively).
Ryu et al. (2019) found that 3-bromo-4,5-dihydroxy-benzaldehyde (21) protects human keratinocytes from oxidative stress by upregulating extracellular signal-regulated kinase (ERK) and protein kinase B (Akt), which allows nuclear factor erythroid 2-related factor 2 (Nrf2) to induce the transcription of the antioxidant enzyme heme oxygenase (HO-1) [85].
BPs 8 and 41, as well as the biphenyl BPs 46, 48, 53, and 59, isolated from the red alga S. latiuscula, all being fully substituted, showed particularly high radical scavenging activity, with IC50 values of 7.5, 8.5, 8.5, 8.1, 10.5, and 10.2 µM, respectively, significantly higher than that of L-ascorbic acid (IC50 = 15.3 µM), employed as positive control [74,79]. The structurally similar avrainvilleol (49), isolated from the green alga Avrainvillea sp., also exerted high antioxidant activity with an IC50 value of 6.1 µM [91]. The DPPH radical-scavenging activities of the bis-phenols 46, 48, 53, and 59 are noticeably higher than those of the mono-phenols 1, 7, 8, 12, 20, 25, and 41 with IC50 values of 14.0, 15.5, 7.5, 14.4, 24.0, 24.7, and 8.5 µM, respectively. Apparently, DPPH scavenging activity is directly related to the overall number of phenol units in the molecules (e.g., 45 and 47 vs. 65 and 14 vs. 56, with IC50 values of 17.6 and 16.9 vs. 8.90, and 18.5 vs. 13.6 μM, respectively). Compounds having the same number of phenolic hydroxyl groups, such as compounds 28 and 34, or 45 and 47 exhibit similar DPPH radical scavenging activity (23.6 and 20.8, or 17.6 and 16.9 μM, respectively) [76,81].
Furthermore, a series of BPs isolated from the red alga P. urceolata (23, 33, 38, 57, 58, 60–64) was shown to exhibit significant DPPH radical scavenging activity [84,88,92]. Among them, compounds 60, 62, 63, and 64, bearing four hydroxyl groups in their molecules, were the most active with IC50 values of 8.1, 6.8, 6.1, and 7.9 µM, respectively. Moreover, in this case, the necessity for the presence of two successive hydroxyl groups in the benzene ring is evident for the display of enhanced antioxidant activity. Another important factor for enhanced activity is the conjugation of the benzene rings, as evidenced by comparing compounds 57 and 63. The conjugation in the dihydrophenanthrene skeleton results to a reduction in the IC50 values from 19.6 µM for 57 to 6.1 µM for 63.
The degree of bromination does not appear to affect the antioxidant activity in a consistent manner. For example, in the case of BPs 12 and 13 the IC50 values were comparable (14.4 and 12.4 µM, respectively). In the case of 19 and 20 (IC50 values 9.52 and 24.0 μM, respectively), it appears that the extra bromine atom in 20 reduces the antioxidant activity, while in the cases of 24 and 25, 45, and 46, as well as 47 and 48 it appears that the presence of an additional bromine atom increases the activity. Moreover, by comparing the IC50 values of 37 and 38 (8.72 and 9.40 µM, respectively), it appears that the site of bromination is of no decisive importance.
Choi et al. (2018) showed that bis (3-bromo-4,5-dihydroxybenzyl) ether (BDDE, 44), isolated from Polysiphonia morrowii, suppresses the lipopolysaccharide (LPS)-induced ROS generation in RAW 264.7 macrophage cells. In turn, inhibition of LPS-induced ROS generation by BDDE (44) caused ERK inactivation and an inflammatory reaction [90]. Therefore, BBDE (44) inhibits LPS-induced inflammation by inhibiting the ROS-mediated ERK signaling pathway in RAW 264.7 macrophage cells and thus can be useful for the treatment of inflammatory diseases [90].
Phlorotannins, exclusively found in macroalgae, are oligomers or polymers of phloroglucinol (1,3,5-trihydroxybenzene, PGU, 66) that can be classified according to the linkage of PGU units [125,126]. Park et al. (2019) suggested that PGU (66) is able to protect HaCaT keratinocytes against oxidative stress-induced DNA damage and apoptosis through the activation of the Nrf2/HO-1 signaling pathway [96].
Until now, numerous phlorotannins purified from brown seaweeds, especially from Ecklonia sp., have been proven to exert antioxidant activities and protective effects against H2O2-induced cell damage [93,95,104,105,106,108,110]. In particular, eckol (71), eckstolonol (72), diphlorethohydroxycarmalol (DPHC, 73), 7-phloroglucinol-eckol (74), dieckol (75), fucodiphloroethol G (77), phlorofucofuroeckol-A (79) 6,6′-bieckol (80), 6,8′-bieckol (81), 8,8′-bieckol (82), 974-B (83), and 2,7″-phloroglucinol-6,6′-bieckol (84), isolated from Eisenia bicyclis, Ecklonia cava, Ecklonia stolonifera, and Ishige okamurae, have shown potent antioxidant activity as determined by the DPPH radical scavenging method, with IC50 values of 11.5, 8.8, 10.5, 18.6, 6.2, 0.60, 4.7, 8.69, 15.0, 0.86, and 0.51 μM, respectively [95,97,104,108,109,115,122,123]. Among them, fucodiphloroethol G (77), compound 83, and 2,7″-phloroglucinol-6,6′-bieckol (84) are the most effective, with IC50 values in the nanomolar range [115,122,123].
Eckol (71) suppresses the production of intracellular ROS and increases GSH levels in HepG2 cells [103], while dieckol (75) induces apoptosis in human hepatocellular carcinoma Hep3B cells via the activation of both death receptor and mitochondrial-dependent pathways, by activating caspases-3, -7, -8, -9, and poly(ADP-ribose) polymerase (PARP) [113]. Moreover, eckol (71), phlorofucofuroeckol A (79), dieckol (75), and 8,8′-bieckol (82) have shown potent inhibition of phospholipid peroxidation at a concentration of 1 μM in a liposome system [108]. Lee et al. (2018) showed that both eckol (71) and dieckol (75) attenuated PM10 (particulate matter of less than 10 mm) -induced lipid peroxidation and cytokine expression in human epidermal keratinocytes [107]. Similarly, Zhen et al. (2019) showed that DPHC (73) blocked PM2.5 (fine particulate matter with a diameter ≤2.5 μm) -induced ROS generation in human keratinocytes [111]. Specifically, DPHC (73) protected cells against PM2.5-induced DNA damage, endoplasmic reticulum stress, and autophagy, and inhibited lipid peroxidation, protein carbonylation, and increased epidermal height in HR-1 hairless mice exposed to PM2.5. Moreover, DPHC (73) attenuated PM2.5-induced apoptosis and mitogen-activated protein kinase (MAPK) protein expression [111]. In the study of Heo et al. (2012), the neuroprotective effect of DPHC (73) against H2O2-induced oxidative stress in murine hippocampal neuronal cells HT22 was investigated and it was found that DPHC protected cells from H2O2-induced neurotoxicity by restoring cell viability [110]. Specifically, DPHC (73) slightly reduced the expression of Bax induced by H2O2, but recovered the expression of Bcl-xL, as well as caspase-9 and -3 mediated PARP cleavage by H2O2, while it effectively inhibited intracellular ROS and lipid peroxidation in a dose-dependent manner and suppressed the elevation of H2O2-induced Ca2+ release [110].
On the other hand, the protective effects of 6,6′-bieckol (80) against high-glucose-induced oxidative stress were investigated using human umbilical vein endothelial cells (HUVECs) susceptible to oxidative stress [121]. It was found that 6,6′-bieckol (80) significantly inhibited the high-glucose treatment-induced HUVECs’ cell death. Moreover, compound 80 dose-dependently decreased thiobarbituric acid reactive substances (TBARS), intracellular ROS generation, and nitric oxide levels that were increased by high glucose. High glucose levels induced the overexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and nuclear factor-kappa B (NF-κB) proteins in HUVECs, but treatment with 6,6′-bieckol (80) reduced their overexpression.
The structure–activity relationship of phlorotannins, although not fully elucidated, suggests that the hydroxyl group availability influences phlorotannins’ antioxidant capacity to a far greater extent than polymerization and the size of the molecule.
Flavonoids are another important class of polyphenolic secondary metabolites often exhibiting potent antioxidant activity, found predominantly in plants and fungi, but also to a lesser degree in algae. The flavonoids acanthophorin A (88) and acanthophorin B (89), isolated from the red alga Acanthophora spicifera, were shown to exert significant antioxidant activity by preventing lipid peroxidation and inhibiting the generation of MDA in liver homogenates of rat in vitro. Compounds 88 and 89, with IC50 values 1.0 × 10−2 and 1.5 × 10−2 µM, respectively, displayed almost 10,000 times higher activity than vitamin E (IC50 = 160 µM) [124].

4. Terpenoids

Terpenoids, also called isoprenoids, represent a diverse class of naturally occurring secondary metabolites composed of isoprene units. Terpenoids, often possessing multicyclic structures with various functional groups [127], are ubiquitous, found in almost all classes of living organisms, including macroalgae. Table 3 presents the terpenoids possessing significant antioxidant activities isolated so far from marine macroalgae (Figure 9, Figure 10, Figure 11 and Figure 12).
Compared to phenolic compounds, as presented in Table 2, it is evident that terpenoids are less active, since their IC50 values in the DPPH radical scavenging assay are mostly within the mM range. The most active compounds reported are the halogenated monoterpene (1E,3R,4S,5E,7Z)-1-bromo-3,4,8-trichloro-7-(dichloro-methyl)-3-methyl- octa-1,5,7-triene (90), isolated from the red alga Plocamium sp., and the carotenoids fucoxanthin (118) and violaxanthin (122), isolated from various macroalgae, with IC50 values of 50.0, 19.6, and 68.9 μM, respectively [128,159,163].
Alarif et al. (2015) isolated a series of C-29 steroids (102–106), along with fucoxanthin (118), from the brown alga Cystoseira trinodis and all compounds were evaluated for their antioxidant activity [135]. Steroids 102–106 showed moderate antioxidant activity (20.4 to 27.5%) in the ABST assay, while compound 118 exhibited significant levels of activity (72.1%).
Fucosterol (104), frequently isolated from brown algae, was confirmed to exert antioxidant activity on hepatic cells via an increase in the hepatic levels of GSH and a decrease in ROS production, therefore preventing hepatic damage and the resultant increase in alanine transaminase and aspartate transaminase activities [136]. Hence, fucosterol is considered an effective hepatoprotective agent that could be useful for preventive therapies against oxidative stress-related hepatotoxicity.
Moreover, the abeo-oleanenes 110 and 111 were isolated from the red alga Gracilaria salicornia and their antioxidant activity was evaluated employing the DPPH and ABTS+ radical scavenging assays [138]. Compound 110 exhibited higher radical scavenging activities (DPPH IC50 = 1.33 mM; ABTS+ IC50 = 1.09 mM), when compared to those displayed by compound 111 (DPPH IC50 = 1.56 mM; ABTS+ IC50 = 1.24 mM) and α-tocopherol that was used as positive control (DPPH IC50 = 1.46 mM; ABTS+ IC50 = 1.72 mM).
Among terpenoids, carotenoids, a family of lipophilic pigments synthesized by plants, algae, fungi, and microorganisms, but not animals, exhibit high levels of antioxidant activity. In red, brown, and green algae, carotenoids play a key role in their protection against photo-oxidative processes [6]. Their antioxidant action is based on their singlet oxygen quenching properties and their free radicals scavenging ability, which mainly depends on the number of conjugated double bonds, the nature of substituents and the end groups of the carotenoids [6].
In marine macroalgae, β-carotene (113), lutein (114), zeaxanthin (115), astaxanthin (116), neoxanthin (117), fucoxanthin (118), and violaxanthin (122) are known to be among the major carotenoids encountered [167]. Astaxanthin (116) acts as a safeguard against oxidative damage through various mechanisms, such as singlet oxygen quenching, radical scavenging, inhibition of lipid peroxidation, and regulation of gene expression related to oxidative stress [144,148,168,169,170,171]. The exact mechanisms of action of astaxanthin have been extensively studied, since it has been proven to confer protective effects against neurological diseases, as well as in treating and preventing skin diseases [171,172,173].
Specifically, astaxanthin (116) activates the phosphatidylinositol 3-kinase (PI3K)/Akt and ERK signaling pathways, and thus facilitates the dissociation and nuclear translocation of Nrf2, which leads to upregulation of the expression of Nrf2-regulated enzymes (e.g., HO-1, NQO-1, and GST-α1) [147]. Astaxanthin (116) inhibits the production of intracellular ROS by negatively regulating the Sp1/NR1 signaling pathway [149,150] and modulating the expression of oxidative stress-responsive enzymes, such as HO-1, which is a marker of oxidative stress and a regulatory mechanism involved in cell adaptation against oxidative damage [143]. In addition, astaxanthin activates the Nrf2/HO-1 antioxidant pathway by generating small amounts of ROS [145,146]. In agreement with these studies, Xue et al. (2017) observed that astaxanthin upregulated Nrf2 expression, as well as Nrf2-targeted proteins HO-1 and antioxidative enzymes SOD2, CAT, and GPx1 in irradiated cells [151]. Thus, astaxanthin (116) exerts noteworthy antioxidant activities via both direct radical scavenging, and activation of the cellular antioxidant defense system through modulation of the Nrf2 pathway. Furthermore, a recent study in a rat deep-burn model demonstrated astaxanthin’s protective role in early burn-wound progression by controlling ROS-induced oxidative stress. In that case, the regulation of free radical production is due to the influence of xanthine oxidase and the reduced form of nicotinamide adenine dinucleotide phosphate oxidase, both contributing to the generation of ROS [144].
Fucoxanthin (118), often isolated from brown algae, is an oxo-carotenoid with an allenic carbon moiety and a 5,6-monoepoxide in its structure, acknowledged as an efficient quencher of singlet oxygen in photooxidation [174,175,176]. The antioxidant activity of fucoxanthin (118) is mediated through various mechanisms, such as singlet oxygen quenching, radical scavenging, and inhibition of lipid peroxidation. Fucoxanthin (118) has been shown to exert the best in vitro bioactivities among carotenoids in inhibiting overexpression of vascular endothelial growth factor, resisting senescence, improving phagocytic function, and clearing intracellular ROS in retinal pigment epithelium cells, protecting the retina against photoinduced damage [156].
The study of Taira et al. (2017) demonstrated that fucoxanthin (118), through the Nrf2 activation, exerts either cytoprotective activity or induction of apoptosis, depending on the concentrations employed [153]. At a low concentration range (1–4 µM), fucoxanthin provides a cytoprotective effect due to its antioxidant activity, as exerted by its peroxyl radical scavenging capacity, involving the antioxidant HO-1 protein expression increase through the activation of the Nrf2/ARE pathway. On the other hand, high concentration (>10µM) treatment of cells induces apoptosis with caspase -3/7 activation during the suppression of anti-apoptotic proteins, such as Bcl-xL and pAkt.
Besides, the cytoprotective effect of fucoxanthin (118) has been investigated against H2O2-induced cell damage [154,158]. It was shown that fucoxanthin effectively inhibited intracellular ROS formation, DNA damage, and apoptosis induced by H2O2. Finally, the protective effect of fucoxanthin was investigated against UVB-induced cell injury in human fibroblasts and showed significant decrease in intracellular ROS formation and increase in cell survival rate in a dose-dependent manner [155].
Comparative studies of the radical scavenging efficiency of fucoxanthin (118) and its stereoisomers (119–121) isolated from Laminaria japonica have also been conducted [162]. All three stereoisomers had stronger hydroxyl radical scavenging activities than α-tocopherol but showed weaker scavenging activities toward DPPH and superoxide radical, while their radical scavenging activities were not remarkably different, indicating that the differences in the geometry of the double bonds had very little effect on their activity.
Recently, the monoterpenoid (−)-loliolide (124) was proven to effectively reduce 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced ROS, cell death, and lipid peroxidation in Vero cells and zebrafish embryos in a dose-dependent manner [165]. Moreover, a study conducted by Jayawardena et al. (2019) elaborated the anti-inflammatory effect of Sargassum horneri ethanolic extract containing (−)-loliolide on LPS-stimulated RAW 264.7 macrophages via suppression of NF-κB and MAPK and reduction of oxidative stress through the Nrf2/HO-1 pathway [166].

5. Meroterpenoids

Meroterpenoids are natural products of mixed biosynthesis containing a terpenoid part that exhibit a variety of biological activities. Metabolites belonging to this class that display antioxidant activity have been isolated from various macroalgae (Table 4, Figure 13, Figure 14, Figure 15, Figure 16, Figure 17, Figure 18 and Figure 19), the majority of which belong to the phylum Ochrophyta, and especially to the genera Cystoseira and Sargassum.
Overall, meroterpenoids from marine macroalgae have exhibited moderate to remarkable antioxidant activity. Specifically, the brominated compound cymopol (125), isolated from the green alga Cymopolia barbata, exerted noticeably high DPPH scavenging activity with an IC50 value of 4.0 μM [91].
De los Reyes et al. (2013, 2016) described the isolation of meroditerpenoids 129–132 and 156–173 that have shown radical scavenging activity from the brown alga Cystoseira usneoides [178,186]. The most active compounds were cystodiones A (173), B (172), G (162), and H (158), cystomexicone B (129), amentadione (156), amentadione 1′-methyl ether (157), 6-cis-amentadione 1′-methyl ether (159), and 11-hydroxyamentadione (160), which exhibited antioxidant activity in the ABTS assay in the range of 77–115% compared to Trolox that was used as a standard.
Additionally, Fisch et al. (2003) reported a number of triprenyltoluquinol derivatives (127, 128, 146–155), isolated from the brown alga Cystoseira crinita, that showed very high levels of radical scavenging at a concentration of 230 μM (92.5–96.7% as compared to 95.2% scavenging for α-tocopherol) [177]. In contrast, the co-occurring quinones 197 and 198 showed DPPH radical scavenging activities significantly less than that of α-tocopherol and the hydroquinones, but still comparable to that of BHT, i.e., 29.0% for 197 and 38.6% for 198 as compared to 35.6% scavenging observed for BHT at a concentration of 230 μM. The observed differences in the values obtained in the DPPH assay for the tested compounds were attributed to the existence of small impurities in the samples (e.g., due to autoxidation) and the handling of small amounts rather than to structural variations. On the other hand, in the TBARS assay, potent inhibition of linolenic acid methyl ester peroxidation was observed for all hydroquinones, i.e., 66.5–74.9% inhibition for compounds 127, 128, and 146–155 at a concentration of 164 μM. These activities were comparable to those of α-tocopherol (72.7%) and BHT (69.3%). Additionally, these compounds showed activities between 13% (153) and 59% (149) of α-tocopherol in the TEAC test and between 40% (152) and 112% (198) of α-tocopherol in the PCL assay [177].
Jung et al. (2008) isolated an array of meroterpenoids (174, 175, 178–194) from the brown alga Sargassum siliquastrum which exhibited moderate to significant radical scavenging activity in the DPPH assay with IC50 values ranging from 0.21 to 47.9 μM (for compounds 183 and 192, respectively) [187]. The observed more than 200-fold increase in the radical scavenging activity of the isonahocols (174, 175, 178–183 with IC50 values of 0.54, 0.40, 0.27, 0.25, 0.64, 0.68, 0.62, and 0.21 μM, respectively) in comparison to that of the nahocols (184–194 with IC50 values of 23.3, 26.1, 25.4, 37.9, 35.4, 18.7, 25.9, 30.4, 47.9, 26.3, and 25.1 μM, respectively) indicated the pivotal role of the second free hydroxyl group in the phenol ring for enhanced radical scavenging activity. Along this trend, the absence of a free phenolic hydroxyl group resulted in lack of scavenging activity [187].
Another investigation conducted by Jang et al. (2005) reported the isolation of meroterpenoids belonging to the subclasses of chromenes and chromenols (201, 202, 204–212, 218, 221–224) from the brown alga S. siliquastrum that exhibited over 87% radical scavenging activity at a concentration of 0.23 to 0.29 mM (0.1 mg/mL) [191]. Moreover, the antioxidant activity of compounds 205, 206, and 209, along with that of 203, 216, and 217, was evaluated in various assays, including scavenging effects on the generation of intracellular ROS, increments of intracellular GSH levels, and inhibitory effects on lipid peroxidation in human fibrosarcoma HT 1080 cells [192]. All tested compounds significantly decreased the generation of intracellular ROS, while increasing the levels of intracellular GSH at a concentration of 5 μg/mL, and inhibited H2O2-induced lipid peroxidation at a concentration of 50 μg/mL.
In an effort to elucidate the mechanism of antioxidant activity of zonarol (134), Shimizu et al. (2015) studied its effect on neuronal cells and proved that zonarol protects them from oxidative stress by activating the Nrf2/ARE pathway and inducing phase-2 enzymes [180].
Moreover, Yoon et al. (2013) elucidated the role of sargachromanol G (208), isolated from the brown alga S. siliquastrum, in receptor activator of NF-κB ligand (RANKL)-induced osteoclast formation [193]. Compound 208 was found to inhibit RANKL-induced osteoclast differentiation from RAW264.7 cells without signs of cytotoxicity. Additionally, the expression of osteoclastic marker genes, such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase 9 (MMP9), and calcitonin receptor (CTR), was also strongly inhibited. It was concluded that sargachromanol G inhibits RANKL-induced activation of NF-κB by suppressing RANKL-mediated IκB-α protein degradation, and therefore the phosphorylation of mitogen activated protein kinases (p38, JNK, and ERK).

6. Nitrogenous Compounds

So far, a number of nitrogenous compounds, including peptides, alkaloids, and chlorophyll-related pigments (Figure 20 and Figure 21), isolated from marine macroalgae have shown antioxidant activity (Table 5).
Peptides and alkaloids 225–239, isolated from Gloiopeltis furcata, Porphyra sp., and Martensia fragilis, have demonstrated moderate to significant antioxidant activity [91,196,197,198,199,200]. Specifically, mycosporine-like amino acids 225–227 exhibited markedly lower free radical scavenging activities compared to those of ascorbic acid and Trolox [196,197], although heat treatment of porphyra 334 (225) at temperatures over 100 °C afforded its dehydrated form (227) and resulted in more than a 100-fold increase in the DPPH radical scavenging activity (IC50 =10.1 μg/mL for 227 vs. >1000 μg/mL for 225) [197].
The histidine-related dipeptides carnosine (228) and anserine (229) were shown to exert comparable antioxidant activities, as measured by ferric thiocyanate and TBARS (85.2% and 84.1% inhibition for 228 and 94.4% and 89.1% inhibition for 229, respectively), to those of α-tocopherol (88.2% and 86.7%, respectively) and BHT (99.8% and 98.2%, respectively) [198]. Moreover, Cermeno et al. (2019) isolated a series of bioactive peptides (232–238) from Porphyra dioica that displayed significant antioxidant activity as assessed using the ORAC assay [200]. It appears that peptides containing tyrosine in their structure (compounds 232, 233, 235, and 237) possessed higher levels of antioxidant activity.
In an effort to elucidate the mechanism of action of dictyospiromide (231), neuron-like PC12 cells were treated with H2O2, and its cytoprotective effect against the induced oxidative damage was evaluated [199]. Treatment with dictyospiromide increased cell survival in a dose-dependent manner and reduced H2O2-induced lactate dehydrogenase (LDH) production at a concentration as low as 0.5 μM. Additionally, compound 231 was investigated regarding its implication in the Nrf2/ARE signaling pathway, which regulates the expression of genes involved in cellular antioxidant defense. It was found that dictyospiromide (231) exhibited a cytoprotective antioxidant effect in PC12 cells that involved activation of the Nrf2/ARE signaling pathway and enhanced expression of HO-1.
Chlorophylls are natural pigments with a well-known antioxidant activity. Although their radical scavenging activities are reported to be low [203], their inhibitory action in lipid peroxidation was found to be 95% at concentrations as low as 100 μM [204]. However, knowledge is limited regarding the yield of chlorophyll metabolites, their absorption and transportation processes, their metabolic pathways, and their precise oxidation mechanisms. At the in vitro level, only few researchers have studied the stability of chlorophylls during digestion and subsequent absorption through intestinal cells. The major outcome is that chlorophylls α and β are transformed into their corresponding pheophorbides and pheophytins and are absorbed at similar rates to those of carotenoids. Further, it has been shown that pheophorbide a is transported at the intestinal level by a protein-mediated mechanism, with scavenger receptor class B type 1 (SR-BI) being a plausible transporter. These results have been confirmed at the in vivo level, using mice as the experimental model, showing a preferential accumulation of pheophorbide in the liver along with multiple other chlorophyll compounds [205].
The characteristic pigments of the light harvesting proteins phycoerythrobilin (239), pheophorbide a (240), chlorophyll β (241) and pyropheophytin α (242) have been found to exert antioxidant activity [141,201,202,203,204,205,206]. It seems that the porphyrin ring system is important for the expression of antioxidative activity in the dark. Indeed, phycoerythrobilin (239) showed potent antioxidant activity in in vitro experiments and significantly inhibited the release of β-hexosaminidase in rat basophilic leukemia cells [207], suggesting that phycoerythrobilin exhibits anti-inflammatory activity. Pheophorbide a (240) demonstrated antioxidant activity (88.6 ± 1.3% DPPH scavenging) higher than that of α-tocopherol, and comparable to that of butylated hydroxyanisol (BHA, 85.3 ± 0.2% DPPH scavenging) at a concentration of 0.1 mg/mL [202], while pyropheophytin α (242) demonstrated antioxidant activity higher than that of α-tocopherol [206].

7. Carbohydrates and Polysaccharides

Carbohydrates ranging in size from simple monosaccharides to high molecular weight polysaccharides isolated from marine macroalgae often exert antioxidant activities [208,209] (Table 6, Figure 22).
The simplest sugar alcohol isolated from a plethora of macroalgae is mannitol (243), representing up to 9%, 47%, and 59% of the dry algal weight in Chlorophyta, Rhodophyta and Ochrophyta, respectively [210]. Antioxidant activity evaluation by enzymes (α-glucosidase, acetyl (AChE) and butyrylcholinesterase (BuChE)) and free radicals (DPPH, NO, OH, and O2−) revealed that higher contents of mannitol are closely related with cholinesterases and DPPH radical scavenging, and to a lesser extent are responsible for α-glucosidase inhibition, OH, O2−, and NO scavenging.
Two simple glucosides, floridoside (244) and D-isofloridoside (245), have been isolated from the red alga Laurencia undulata and their free radical scavenging activity, inhibition of intracellular ROS levels, the level of membrane protein oxidation, myeloperoxidase (MPO) activity inhibition, gene expression levels of GSH and SOD, and protein expression of MMP2 and MMP9 have been determined [211]. It was found that both floridoside (244) and D-isofloridoside (245) possess significant antioxidant capacity and are potential inhibitors of MMP2 and MMP9.
Marine macroalgae are the most important source of non-animal sulfated polysaccharides (SPs), with the main categories being fucoidans isolated from brown algae, carrageenans and porphyrans isolated from red algae and ulvans isolated from green algae. SPs possess excellent in vitro antioxidant activity, including both radical scavenging capacity and metal chelating ability [212,227,228]. The antioxidant activity of SPs directly related to their structural features, such as degree of sulfation, molecular weight (MW), type of major sugar, and glycosidic branching [212,225,229]. For example, low MW SPs have shown potent antioxidant activity, stronger than that of high MW SPs [230]. The rationale for this is that low MW SPs may be incorporated into the cells more efficiently and donate proton effectively compared to high MW SPs.
Alginate oligosaccharide (AO, 246) and fucoidan oligosaccharide (FO, 247) were enzymatically produced from commercially available polysaccharides and their antioxidant activity was studied [212]. AO (246) had the highest hydroxyl radical scavenging activity as compared to FO (247), while in the Fe2+ chelation assay, FO exhibited good chelation in contrast to AO that hardly displayed any activity.
Fucoidans of diverse MW and sulfation degree (247–264) have been isolated from various brown algae and/or chemically modified and their antioxidant activity has been tested employing OH and O2− scavenging, erythrocyte hemolysis inhibition, metal chelation, and anti-lipid peroxidation assays [212,213,214,215]. In the study of Zhao et al. (2008) two fractions of different MW, namely 742 kDa (254) and 175.9 kDa (255), were obtained from fucoidans extracted from L. japonica and evaluated for their OH and O2− scavenging activity, with the higher MW fraction exhibiting higher levels of activity [215]. Following radical process degradation, an ascophyllan-like fraction rich in glucuronic acid and a fraction rich in galactose and mannose were confirmed as responsible for the oxygen free radical scavenging activity [215]. On the contrary, Koh et al. (2019) reported on the higher antioxidant capacity of low MW (10 kDa) fucoidan (256) from Undaria pinnatifida (close to that of BHA) as compared to a high MW (300 kDa) fucoidan (257) [216].
Additionally, Rodriguez-Jasso et al. (2014) isolated fucose-containing sulfated polysaccharides from Fucus vesiculosus using either microwave-assisted extraction (258) or autohydrolysis (259) and their antioxidant activity was determined [217]. Both samples presented similar sulfate contents (~21%), as well as comparable antioxidant potential as evaluated by DPPH and ABTS+ scavenging, and lipid oxidation inhibition methods. Differences in the antioxidant potential could be observed only when using a differential pulse voltammetry technique, pointing to structural variations of the fucans obtained by the two different methods.
Several studies have reported the in vitro and in vivo antioxidant efficacy of fucoidan [231]. Kim et al. (2012) have demonstrated that low MW fucoidan (262) might block NO, as well as ROS production, suppressing therefore oxidative stress and MAPKs in RAW264.7 cells [220]. Additionally, fucoidan (263) was found to reduce the oxidative stress through Nrf2/ERK signaling mediated regulation of HO-1 and SOD1 expression in human keratinocytes [221]. More recently, Phull et al. (2017) have demonstrated that fucoidans derived from U. pinnatifida (264) exhibit significant in vitro and in vivo anti-arthritic responses in rabbit articular chondrocytes and rats, respectively. Moreover, administration of fucoidan to arthritic rats ameliorated the clinical symptoms and led to the overall improvement of their health [222].
Rocha de Souza et al. (2007) reported on the isolation of iota (ι)- (265), kappa (κ)- (266), and lambda (λ)- (267) carrageenans from various red algae and their antioxidant activity as evaluated by the scavenging of OH and O2− radicals, and lipid peroxidation assays [213]. The results of the study indicated that, among the different carrageenans, λ-carrageenan (267) exhibited the highest antioxidant and free radical scavenging activity. Thus, a positive correlation between sulfate content and antioxidant activity was evidenced.
Acetylation, phosphorylation and benzoylation of porphyran (268) extracted from the red alga Porphyra haitanensis afforded derivatives with improved antioxidant activity, as evaluated in superoxide radical, hydroxyl radical and reducing power assays [223]. In a previous study, Zhang et al. (2003) obtained through anion-exchange column chromatography three sulfated polysaccharide fractions with variable sulfate content (17.4%, 20.5% and 33.5%) from the same red algal species and investigated their in vitro antioxidant activities [229]. All three showed strong scavenging effect on superoxide radical and much weaker effect on hydroxyl free radical, while lipid peroxide in the rat liver microsome was significantly inhibited. In two subsequent studies the fractions with sulfate contents 17.4% and 20.5% were evaluated in vivo in aging mice [48,49]. In both cases, intraperitoneal administration significantly decreased lipid peroxidation in a dose-dependent manner, while at the same time increasing total antioxidant capacity and the activity of SOD and GPx in all organs of the aging mice.
Ulvans of diverse sulfation degree and MW (269–271) have been isolated from the green alga Ulva pertusa and/or chemically modified and their antioxidant activity was tested employing OH and O2− radical scavenging, reducing power and metal chelating assays [224,225,226]. Specifically, Qi et al. (2005) extracted ulvan (269) with 19.5% sulfate content and chemically prepared derivatives of higher sulfate content ranging from 23.5% to 32.8%. Upon evaluation of their O2− radical and OH radical scavenging activity, it was observed that the derivatives displayed higher levels of activity, ranging from 91.7% to 95.5% at a concentration as low as 23.0 μg/mL for O2− radical scavenging and with IC50 values ranging from 0.46 to 1.43 mg/mL for OH radical scavenging [224].
In another study, Qi et al. (2005) initially extracted ulvan (270) from U. pertusa, and subsequently, three derivatives of different MW were prepared by H2O2 degradation and their antioxidant activities, including OH and O2− radical scavenging activity, reducing power and metal chelating ability, were investigated [225]. The MW of the natural and degraded ulvans were calculated at 151.7, 28.2, 58.0, and 64.5, kDa, respectively. All polysaccharides exhibited significant OH and O2− radical scavenging capacity at all concentrations tested with similar IC50 values at about >1 mg/mL and 22.1 μg/mL, respectively. Among the natural ulvan and the obtained derivatives, the lowest MW one showed the strongest reducing power and metal chelating ability. The results indicated that MW had a significant effect on the antioxidant activity of ulvan, with low MW ulvan exerting the strongest antioxidant activity. In a further study, Qi et al. (2006) prepared derivatives of ulvan (262) after acetylation and benzoylation, which exhibited higher levels of antioxidant activity, as determined using in vitro assays, including scavenging activity against superoxide and hydroxyl radicals, reducing power, and chelating ability [226].

8. Miscellaneous Compounds

A number of compounds (272–301, Figure 23 and Figure 24) isolated from marine macroalgae, displaying various structures that do not belong to the previously described classes, have also exhibited levels of antioxidant activity worth mentioning (Table 7).
Among these, the most active compounds, exerting significant DPPH radical scavenging capacity, were compounds 278 (5-hydroxymethyl-2-furfural, 5-HMF), 291 (Z-4′-chloroaurone), and 297, with IC50 values at 27.1, 22.2, and 25.0 μM, respectively [233,239,241]. In particular, 5-HMF (278), isolated from L. undulata, exhibited significant antioxidant activities, as evaluated by its in vitro free radical species (including alkyl, DPPH, OH, and O2− radicals) scavenging, intracellular ROS scavenging, membrane protein oxidation, MPO inhibition, as well as gene expression of the antioxidative enzymes GSH and SOD [233]. Overall, 5-HMF (278) displayed antioxidant activity, by scavenging overproducing free radicals and decreasing the activity of MPO or increasing the activity of GSH and SOD antioxidant enzymes in certain biological pathways.
Fang et al. (2010) isolated the non-polar compounds 272–274, 276, 277, and 279 from the red alga G. furcata and evaluated their antioxidant activities as inhibitors of AChE and BChE and as scavengers of DPPH radical and ONOO⁻ [75]. All isolated compounds exhibited moderate AChE inhibitory activity with IC50 values ranging between 13.6 and 94.4 μM, whereas compounds 276 and 277 showed mild BChE inhibitory activity with IC50 values 57.1 and 21.7 μM, respectively. Only compound 272 showed substantial DPPH radical scavenging activity, while compounds 272 and 274 showed potent ONOO⁻ scavenging activity.
Compounds 280–286, 288–290, 292–296, and 298–301 exhibited moderate DPPH radical scavenging capacities, with IC50 values in the mM range, with activities comparable to either α-tocopherol (IC50 = 1.46 mM), or BHT and BHA (IC50 ~ 1.30–1.54 mM) [234,235,236,237,238,240,241,242]. Structure–activity relationship analysis revealed that the antioxidant activities of compounds 293, 297, and 298 were directly proportional to their steric freedom and hydrophobicity [241].

9. Conclusions

The marine environment harbors diverse biological species that can provide a vast repertoire of molecules with therapeutic properties. Forced to tolerate extreme environmental conditions, marine organisms produce structurally unique molecules as an adaptive strategy to survive in their biotopes. In particular, macroalgae contain a plethora of antioxidative compounds, such as bromophenols, phlorotannins, pigments, terpenoids, and polysaccharides, in order to protect themselves from free radicals, the production of which is favored in sublittoral zones with intense exposure to sunlight and high concentrations of oxygen.
Structural elements, such as the number of phenol rings, the number of free hydroxyl groups and conjugated systems, are in general accepted as enhancing the antioxidant activity observed. Among the metabolites presented in the current review, the most active belong to the classes of phenols and polyphenols, as well as meroterpenoids, with bromophenols and phlorotannins exerting the highest activities. In particular, the bromophenol rhodomelin A (18) isolated from the red alga R. confervoides, the phlorotannins fucodiphloroethol G (77), phlorofucofuroeckol-A (79), 974-B (83), and 2,7″-phloroglucinol-6,6′-bieckol (84) purified from brown seaweeds especially of the genus Ecklonia, as well as the meroterpenoids 174, 175, and 178–183 isolated from brown algae of the genus Sargassum exerted noticeably high DPPH scavenging activity.
Nevertheless, the most studied antioxidant compounds are the natural pigments astaxanthin (116) and fucoxanthin (118), belonging to the class of carotenoids, ubiquitous in marine macroalgae. Their antioxidant action is based on their singlet oxygen quenching properties and their free radicals scavenging ability, which mainly depends on the number of conjugated double bonds and end groups. The antioxidant activity of fucoxanthin (118) has also been evaluated in vivo. Dietary intake of fucoxanthin significantly reduced lipid hydroperoxide levels of liver and abdominal white adipose tissue of obese/diabetes KK-Ay mice [243]. Fucoxanthin supplementation also significantly reduced the blood glucose level and hepatic lipid contents of the mice. Promising results were also observed in experiments on rats fed a high fat diet supplemented with fucoxanthin that improved the antioxidant capacity, depleted by a high fat diet, by activating the Nrf2 pathway and its downstream target gene NQO1 [244]. Therefore, supplementation of the diet with fucoxanthin, especially of those who consume high fat in their diet, may benefit them by reducing the risk of oxidative stress.
Although emerging evidence points to a diversity of actions and effects, which are intricate and independent from any antioxidant chemical nature, there is an urgent need for deciphering the role of chemical structure on the antioxidant behavior of molecules. Moreover, constraints imposed by experimental protocols should always be taken into consideration when dealing with a lack of biological context in regard to results, so as to discriminate between the in vitro and in vivo scenarios. In this regard, the development of novel antioxidant activity detecting protocols prompts further investigations.

Author Contributions

Conceptualization, O.T., V.R. and E.I.; methodology, L.-A.T., V.R. and E.I.; investigation, L.-A.T. and M.A.T.; resources, V.R. and E.I.; writing—original draft preparation, L.-A.T. and M.A.T.; writing—review and editing, O.T., V.R. and E.I.; supervision, V.R. and E.I.; funding acquisition, V.R. and E.I. All authors have read and agreed to the published version of the manuscript.

Funding

This research has been co-financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation under the call SPECIAL ACTIONS “AQUACULTURE—INDUSTRIAL MATERIALS—OPEN INNOVATION IN CULTURE” (project code: Τ6ΥBΠ-00474, project acronym: ALGOSMETIC). The authors thank the Special Account for Research Grants of the National and Kapodistrian University of Athens for funding to cover the publication costs.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

M.A.T. acknowledges support by the non-profit organization “Kleon Tsetis”.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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Antioxidants 10 01431 g001 550
Figure 1. Causes and effects of oxidative stress (adapted from [6]).
Figure 1. Causes and effects of oxidative stress (adapted from [6]).
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Figure 2. Chemical structures of compounds 1–32.
Figure 2. Chemical structures of compounds 1–32.
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Figure 3. Chemical structures of compounds 33–54.
Figure 3. Chemical structures of compounds 33–54.
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Figure 4. Chemical structures of compounds 55–65.
Figure 4. Chemical structures of compounds 55–65.
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Figure 5. Chemical structures of compounds 66–70.
Figure 5. Chemical structures of compounds 66–70.
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Figure 6. Chemical structures of compounds 71–76.
Figure 6. Chemical structures of compounds 71–76.
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Figure 7. Chemical structures of compounds 77–82.
Figure 7. Chemical structures of compounds 77–82.
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Figure 8. Chemical structures of compounds 83–89.
Figure 8. Chemical structures of compounds 83–89.
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Figure 9. Chemical structures of compounds 90–101.
Figure 9. Chemical structures of compounds 90–101.
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Figure 10. Chemical structures of compounds 102–111.
Figure 10. Chemical structures of compounds 102–111.
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Figure 11. Chemical structures of compounds 112–115.
Figure 11. Chemical structures of compounds 112–115.
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Figure 12. Chemical structures of compounds 116–124.
Figure 12. Chemical structures of compounds 116–124.
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Figure 13. Chemical structures of compounds 125–139.
Figure 13. Chemical structures of compounds 125–139.
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Figure 14. Chemical structures of compounds 140–157.
Figure 14. Chemical structures of compounds 140–157.
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Figure 15. Chemical structures of compounds 158–171.
Figure 15. Chemical structures of compounds 158–171.
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Figure 16. Chemical structures of compounds 172–183.
Figure 16. Chemical structures of compounds 172–183.
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Figure 17. Chemical structures of compounds 184–199.
Figure 17. Chemical structures of compounds 184–199.
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Figure 18. Chemical structures of compounds 200–215.
Figure 18. Chemical structures of compounds 200–215.
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Figure 19. Chemical structures of compounds 216–224.
Figure 19. Chemical structures of compounds 216–224.
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Figure 20. Chemical structures of compounds 225–237.
Figure 20. Chemical structures of compounds 225–237.
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Figure 21. Chemical structures of compounds 238–242.
Figure 21. Chemical structures of compounds 238–242.
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Figure 22. Chemical structures of compounds 243–271.
Figure 22. Chemical structures of compounds 243–271.
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Figure 23. Chemical structures of compounds 272–288.
Figure 23. Chemical structures of compounds 272–288.
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Figure 24. Chemical structures of compounds 289–301.
Figure 24. Chemical structures of compounds 289–301.
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Table
Table 1. A list of the most commonly used in vitro assays for the determination of antioxidant activity (adapted from [50]).
Table 1. A list of the most commonly used in vitro assays for the determination of antioxidant activity (adapted from [50]).
Hydrogen atom transfer (HAT)-based assays2,2-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid) diammonium salt (ABTS+) radical scavenging [51]
β-carotene bleaching [52]
crocin bleaching [53]
hydrogen peroxide (H2O2) scavenging [54]
hydroxyl radical averting capacity (HORAC) [55]
hydroxyl scavenging [56]
inhibited oxygen uptake (IOU) [57]
lipid peroxidation inhibition capacity (LPIC) [58]
oxygen radical absorbance capacity (ORAC) [40]
photochemiluminescence (PCL) [59]
total radical trapping antioxidant parameter (TRAP) [41]
Electron transfer (ET)-based assays1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging [46,47]
cupric reducing antioxidant capacity (CUPRAC) [60]
ferric reducing antioxidant power (FRAP) [44,45]
ferric thiocyanate (FTC) [61]
nitric oxide radical scavenging [62]
N,N-dimethyl-p-phenylene diamine (DMPD) radical scavenging [63]
peroxyl radical scavenging [64]
potassium ferricyanide reducing power (PFRAP) [65]
superoxide anion radical scavenging [66]
thiobarbituric acid reactive substances (TBARS) [67]
total phenolics content (TPC) using Folin-Ciocalteu reagent [42]
trolox equivalence antioxidant capacity (TEAC) using ABTS [43]
Other in vitro methodsascorbic acid content [68]
cellular antioxidant activity (CAA) [69]
metal chelating activity [70]
scavenging of phosphomolybdenum [71]
scavenging of xanthine oxidase [72]
Table
Table 2. Phenolic compounds from macroalgae with antioxidant activity.
Table 2. Phenolic compounds from macroalgae with antioxidant activity.
CompoundIsolation SourceAssay/ActivityReference
1Symphyocladia latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 14.0 μM[74]
2Gloiopeltis furcata
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 = 86.2 μΜ
ONOO− scavenging: 4.58 ± 0.01 μM		[75]
3Rhodomela confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 1.60 ± 0.04 μM
DPPH scavenging: IC50 = 50.6 ± 0.2 μM		[76]
4R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 1.56 ± 0.02 μM
DPPH scavenging: IC50 = 42.3 ± 0.2 μM; 67%		[76,77]
5S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		bleomycin-dependent DNA damage deoxyribose assay[78]
6R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 1.62 ± 0.03 μM
DPPH scavenging: IC50 = 40.5 ± 0.2 μM; 30% 		[76,77]
7S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 15.5 μM[74]
8S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 7.5 µM[79]
9R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 1.36 ± 0.01 μM
DPPH scavenging: IC50 = 38.4 ± 0.2 μM		[76]
10R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 2.11 ± 0.04 μM
DPPH scavenging: IC50 = 7.43 ± 0.10 μM		[76]
11R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 1.87 ± 0.02 μM
DPPH scavenging: IC50 = 20.5 ± 0.1 μM		[76]
12S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 71.0 μM
DPPH scavenging: IC50 = 14.4; 18.5 μM
CUPRAC
Fe2+ chelation: IC50 = 44.7 μM
FRAP
AChE inhibition: IC50 = 13.85 nM
BChE inhibition: IC50 = 38.22 nM		[74,80]
13R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 8.07 μM; TEAC = 2.68 mM
DPPH scavenging: IC50 = 12.4; 15.9 μM
CUPRAC
Fe2+ chelation: IC50 = 65.2 μM
FRAP
AChE inhibition: IC50 = 17.10 nM
BChE inhibition: IC50 = 40.57 nM		[80,81]
14R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 8.1 μM; TEAC = 2.21 mM
DPPH scavenging: IC50 = 14.6; 18.5 μM
CUPRAC
Fe2+ chelation: IC50 = 54.6 μM
FRAP
AChE inhibition: IC50 = 29.88 nM
BChE inhibition: IC50 = 46.51 nM		[80,81]
15R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.31 mM
DPPH scavenging: IC50 = 5.43 μM		[81]
16R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.14 mM
DPPH scavenging: IC50 = 5.70 μM		[81]
17S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 27.9 μM[82]
18R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 4.37 ± 0.24 mM
DPPH scavenging: IC50 = 3.82 ± 0.01 μM		[83]
19R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.06 ± 0.08 mM
DPPH scavenging: IC50 = 9.52 ± 0.04 μM		[76]
20S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 24.0 μM[74]
21Polysiphonia morrowii, Polysiphonia urceolata, R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 20.3 μM
cytoprotective effect against cellular oxidative stress
HO-1 activity and expression in keratinocytes
Nrf2 expression
Nrf2 nuclear translocation		[84,85]
22R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 1.32 ± 0.02 mM
DPPH scavenging: IC50 = 58.2 ± 0.4 μM		[76]
23P. urceolata
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 35.8 μM[84]
24R. confervoides, Vertebrata lanosa
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 1.09 ± 0.01 mM
CAA
CLPAA
DPPH scavenging: IC50 = 32.0 ± 0.1 μM
ORAC		[76,86]
25S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 24.7 μM[74]
26Cladophora wrightiana
(Chlorophyta, Ulvophyceae, Cladophorales)		DPPH scavenging: 69% at 160 μM
OH scavenging
O2− scavenging
protective effect against UVB-induced apoptosis and DNA damage in HaCaT cells
scavenging activity against H2O2- or UVB-generated intracellular ROS in HaCaT cells		[87]
27R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 1.86 ± 0.02 mM
DPPH scavenging: IC50 = 50.3 ± 0.3 μM		[76]
28R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.11 mM
DPPH scavenging: IC50 = 23.6 μM		[81]
29R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 1.98 ± 0.01 mM
DPPH scavenging: IC50 = 30.9 ± 0.1 μM		[76]
30R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.35 ± 0.02 mM
DPPH scavenging: IC50 = 26.3 ± 0.2 μM		[76]
31R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.87 ± 0.11 mM
DPPH scavenging: IC50 = 19.8 ± 0.1 μM 		[76]
32R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.07 ± 0.12 mM
DPPH scavenging: IC50 = 30.2 ± 0.2 μM		[76]
33P. urceolata
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 16.1 ± 0.1 μM[88]
34R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.36 mM
DPPH scavenging: IC50 = 20.8 μM		[81]
35R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.11 ± 0.11 mM
DPPH scavenging: IC50 = 18.6 ± 0.1 μM		[76]
36R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 1.63 ± 0.01 mM
DPPH scavenging: IC50 = 50.9 ± 0.3 μM		[76]
37R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 3.68 ± 0.12 mM
DPPH scavenging: IC50 = 8.72 ± 0.05 μM		[76]
38P. urceolata, R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 3.10 ± 0.13 mM
DPPH scavenging: IC50 = 9.40 ± 0.05; 9.67 ± 0.04 μM		[76,88]
39R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 3.45 ± 0.12 mM
DPPH scavenging: IC50 = 7.62 ± 0.01 μM		[76]
40S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 43.8 μM[82]
41S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 8.5 µM[79]
42R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.87 mM
DPPH scavenging: IC50 = 5.22 μM		[81]
43Odonthalia corymbifera
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 17.3 ± 0.1 μM
Cu2+-chelation: IC50 = 61.9 ± 0.1 μM
CUPRAC: ECA0.50 = 13.6 ± 0.1 μM
DPPH scavenging: IC50 = 24.7 ± 0.0 μM
FRAP: ECA0.50 = 11.1 ± 0.1 μM
tyrosinase inhibition: IC50 = 17.3 ± 0.1 μM		[89]
44P. morrowii
(Rhodophyta, Florideophyceae, Ceramiales)		LPS-induced ROS generation and ROS-mediated ERK signaling in RAW 264.7 macrophages[90]
45R. confervoides, V. lanosa
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 3.05 mM
CAA
CLPAA
DPPH scavenging: IC50 = 17.6 μM
ORAC		[81,86]
46S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 8.5 μM[74]
47R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 3.18 mM
DPPH scavenging: IC50 = 16.9 μM; 27%		[77,81]
48S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 8.1 μM[74]
49Avrainvillea sp.
(Chlorophyta, Ulvophyceae, Bryopsidales)		DPPH scavenging: strong
exogenous ROS scavenging in TPA-treated HL-60 cells (DCFH-DA): IC50 = 6.1 μM		[91]
50R. confervoides, V. lanosa
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 3.16 mM
CAA
CLPAA
DPPH scavenging: IC50 = 19.6 μM
ORAC		[81,86]
51R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 3.00 mM
DPPH scavenging: IC50 = 14.3 μM		[81]
52R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 2.78 mM
DPPH scavenging: IC50 = 13.8 μM		[81]
53S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: ΙC50 = 10.5 μM[74]
54O. corymbifera
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: IC50 = 6.7 ± 0.1 μM
Cu2+-chelation: IC50 = 74.3 ± 0.1 μM
CUPRAC: ECA0.50 = 7.8 ± 0.1 μM
DPPH scavenging: IC50 = 13.5 ± 0.0 μM
FRAP: ECA0.50 = 10.8 ± 0.1 μM
tyrosinase inhibition: ΙC50 = 31.0 ± 0.1 μM		[90]
55V. lanosa
(Rhodophyta, Florideophyceae, Ceramiales)		CAA
CLPAA
ORAC		[86]
56R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 3.21 mM
DPPH scavenging: IC50 = 13.6 μM		[81]
57P. urceolata
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 19.6 ± 0.1 μM[88]
58P. urceolata
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 21.9 ± 0.1 μM[88]
59S. latiuscula
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 10.2 μM[74]
60P. urceolata
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 8.1 μM[84]
61P. urceolata
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 15.1 μM[84]
62P. urceolata
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 6.8 μM[84]
63P. urceolata
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 6.1 μM[84]
64P. urceolata
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: IC50 = 7.9 μM[92]
65R. confervoides
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: TEAC = 3.58 mM
DPPH scavenging: IC50 = 8.90 μM		[81]
66Sargassum wightii, Sargassum tenerrimum, Turbinaria conoides
(Ochrophyta, Phaeophyceae, Fucales)
Ishige okamurae
(Ochrophyta, Phaeophyceae, Ishigeales)
Ecklonia cava
(Ochrophyta, Phaeophyceae, Laminariales)		alkyl scavenging: IC50 = 103.5 ± 1.9 μM
DPPH scavenging: 64.71–71.07% at 200 μg/mL
H2O2 scavenging: 88.33–89.7% at 200 μg/mL
OH scavenging: IC50 = 392.5 ± 2.8; 408.5 ± 3.7 μM
O2− scavenging: IC50 = 115.2 ± 2.5; 124.7 ± 2.4 μM
ROO scavenging: IC50 = 128.9 ± 2.2 μM
metal chelating activity: 11.40–14.38% at 200 μg/mL
H2O2-induced apoptosis, cytotoxicity, DNA damage, mitochondrial dysfunction and ROS generation in HaCaT keratinocytes
intracellular ROS generation (DCFH-DA) in RAW 264.7 macrophages/V79-4 cells
Nrf2/HO-1 signaling pathway in HaCaT keratinocytes		[93,94,95,96,97]
67Gracilaria sp.
(Rhodophyta, Florideophyceae, Gracilariales)		DPPH scavenging: 83.8 ± 2.6%
XO inhibition: 64.7 ± 0.7%		[98]
68Sargassum micracanthum
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 47 μM[99]
69E. cava
(Ochrophyta, Phaeophyceae, Laminariales)		oxidative stress-induced DNA damage in V79-4 cells[100]
70Ishige foliacea
(Ochrophyta, Phaeophyceae, Ishigeales)		enzyme activity (SOD, CAT, GPx)
intracellular ROS generation and lipid peroxidation in HUVEC/pancreatic β cells
oxidative stress-induced cell death in zebrafish embryo
streptozotocin-induced pancreatic β cell damage in rat insulinoma cell line 		[101,102]
71E. cava, Ecklonia kurome, Ecklonia stolonifera, Eisenia bicyclis
(Ochrophyta, Phaeophyceae, Laminariales)		DPPH scavenging: IC50 = 11.5; 22.9 ± 0.52; 26 µM
OH scavenging: IC50 = 51.8 ± 2.5 µM
O2− scavenging: IC50 = 26.5 ± 1.25; 107 µM
ROO scavenging: IC50 = 28.4 ± 1.5 µM
inhibitory effect on total ROS: IC50 = 4.04 ± 0.04 µM
cellular membrane protein oxidation in RAW 264.7 macrophages
GSH levels in HepG2 cells/RAW 264.7 macrophages
HO-1 expression
H2O2-induced lipid peroxidation (TBARS) in V79-4 cells
intracellular ROS generation (DCFH-DA) and oxidative stress induced cell damage in lung fibroblast cells
MPO activity in HL60 cells
Nrf2 nuclear translocation and activation
PM10 (particulate matter of less than 10 mm) -induced lipid peroxidation and cytokine expression in human epidermal keratinocytes		[95,103,104,105,106,107,108]
72E. stolonifera
(Ochrophyta, Phaeophyceae, Laminariales)		DPPH scavenging: IC50 = 8.8 ± 0.4 μM
intracellular ROS scavenging		[109]
73I. okamurae
(Ochrophyta, Phaeophyceae, Ishigeales)		alkyl scavenging: IC50 = 18.8 ± 1.2 μM
DPPH scavenging: IC50 = 10.5 ± 0.5 μM
OH scavenging: IC50 = 27.1 ± 0.9 μM
O2− scavenging: IC50 = 16.7 ± 0.6 μM
H2O2-induced oxidative stress-induced ROS generation (DCFH-DA) in murine hippocampal neuronal cells
intracellular Ca2+ level
lipid peroxidation assay (TBARS)
membrane protein oxidation
MPO activity
PM2.5 (fine particulate matter with a diameter ≤2.5 μm) -induced ROS generation in human keratinocytes
PM2.5-induced DNA damage, endoplasmic reticulum stress and autophagy, mitochondrial damage, apoptosis via MAPK signaling pathways		[97,110,111]
74E. cava
(Ochrophyta, Phaeophyceae, Laminariales)		DPPH scavenging: IC50 = 18.6 ± 1.0 μM
OH scavenging: IC50 = 39.6± 2.1 μM
O2− scavenging: IC50 = 21.9 ± 1.8 μM
ROO scavenging: IC50 = 22.7 ± 1.5 μM
cellular membrane protein oxidation in RAW 264.7 cells
GSH levels in RAW 264.7 cells
intracellular ROS generation (DCFH-DA)
MPO activity in HL60 cells		[95]
75E. cava, E. kurome, E. stolonifera, E. bicyclis
(Ochrophyta, Phaeophyceae, Laminariales)		DPPH scavenging: IC50 = 6.2 ± 0.4; 8.28 ± 0.45; 13 μM
OH scavenging: IC50 = 28.6 ±2.5 μM
O2− scavenging: IC50 = 7.6; 16.2 ±1.0 μM
ROO scavenging: IC50 = 14.5 ±1.8 μM
apoptosis in Hep3B cells
cellular membrane protein oxidation in RAW 264.7 cells
detection of apoptosis-related proteins
GSH levels in RAW 264.7 cells
intracellular ROS generation (DCFH-DA) in RAW 264.7 cells
MPO activity in HL60 cells
PM10 (particulate matter of less than 10 mm) -induced lipid peroxidation and cytokine expression in human epidermal keratinocytes
rotenone-induced oxidative stress in SH-SY5Y cells		[95,107,108,109,112,113]
76Fucus spiralis
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: Q50 = 0.090 ± 0.002 μmol[114]
77E. cava
(Ochrophyta, Phaeophyceae, Laminariales)		DPPH scavenging: IC50 = 0.60; 14.7 ± 1.2 μM
OH scavenging: IC50 = 3.5 ± 1.55 μM
O2− scavenging: IC50 = 18.6 ± 1.5 μM
ROO scavenging: IC50 = 18.1 ± 1.0 μM
cellular membrane protein oxidation in RAW 264.7 cells
GSH levels in RAW 264.7 cells
intracellular ROS generation (DCFH-DA)
intracellular ROS detection in UVB-irradiated HaCaT keratinocytes
MPO activity in HL60 cells		[95,115,116]
78Fucus vesiculosus
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: ΙC50 = 16.1 ± 1.0 μM
O2− scavenging: ΙC50 > 401.6 μM
ORAC: 3.3 ± 0.3 units at 1 μg/mL		[117]
79E. cava, E. kurome, E. stolonifera, E. bicyclis
(Ochrophyta, Phaeophyceae, Laminariales)		alkyl scavenging: IC50 = 3.9 μM
DPPH scavenging: IC50 = 4.7 ± 0.3; 10.3; 12; 17.7 ± 0.8 μM
OH scavenging: IC50 = 21.4; 39.2± 1.8 μM
O2− scavenging: IC50 = 8.4 μM; IC50 = 21.6 ± 2.2 μM
ROO scavenging: IC50 = 21.4 ± 2.1 μM
total ROS generation: IC50 = 3.80 ± 0.09 μM
intracellular ROS generation (DCFH-DA) in RAW 264.7 macrophages/Vero cells/zebrafish system		[95,105,108,109,118]
80I. okamurae
(Ochrophyta, Phaeophyceae, Ishigeales)
E. cava, E. bicyclis
(Ochrophyta, Phaeophyceae, Laminariales)
Grateloupia elliptica
(Rhodophyta, Florideophyceae, Halymeniales)		ABTS+ scavenging: IC50 = 37.1 ± 2.8 μΜ
alkyl scavenging: IC50 = 17.3 ± 1.0 μM
DPPH scavenging: IC50 = 8.69 ± 0.35; 9.1 ± 0.4; 28; 66.5 ± 0.5 μΜ
OH scavenging: IC50 = 28.7 ± 1.1; 29.7 ± 1.5 μM
O2− scavenging: IC50 = 15.4 ± 0.9; 15.9 ± 1.3 μM
ROO scavenging: IC50 = 17.1 ± 2.2 μM
singlet oxygen (1O2) quenching: QC50 = 30.7 ± 2.4 μM
cellular membrane protein oxidation in RAW 264.7 macrophages
GSH levels in RAW 264.7 macrophages
high-glucose-induced oxidative stress intracellular ROS generation (DCFH-DA) in UVB-irradiated HaCaT keratinocytes
MPO activity in HL60 cells		[95,97,119,120,121]
81E. bicyclis
(Ochrophyta, Phaeophyceae, Laminariales)		ABTS+ scavenging: IC50 = 43.3 ± 2.3 μΜ
DPPH scavenging: IC50 = 103.0 ± 3.5 μM
singlet oxygen (1O2) quenching: QC50 = 35.7 ± 2.4 μM		[119]
82E. cava, E. kurome, E. bicyclis
(Ochrophyta, Phaeophyceae, Laminariales)		ABTS+ scavenging: IC50 = 43.4 ± 2.0 μΜ
DPPH scavenging: IC50 = 15.0; 95.9 ± 3.2 μΜ
O2− scavenging: IC50 = 6.5 μM
singlet oxygen (1O2) quenching: QC50 = 49.4 ± 1.7 μM
H2O2-induced DNA damage
intracellular ROS generation in Vero cells		[108,119]
83E. bicyclis
(Ochrophyta, Phaeophyceae, Laminariales)		DPPH scavenging: IC50 = 0.86 ± 0.02 μM
ONOO− scavenging: 1.80 ± 0.01 μM
total ROS: 6.45 ± 0.04 μM		[122]
84E. cava
(Ochrophyta, Phaeophyceae, Laminariales)		alkyl scavenging: IC50 = 2.07 ± 1.00 μM
DPPH scavenging: IC50 = 0.51 μM
OH scavenging: IC50 = 75.6μM
O2− scavenging: IC50 = 57.2 μM
intracellular ROS generation (DCFH-DA) in H2O2-treated Vero cells		[123]
85F. spiralis
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: Q50 = 0.087 ± 0.004 μmol[114]
86F. vesiculosus
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: ΙC50 = 19.3 ± 2.7 μM
O2− scavenging: ΙC50 > 334.9 μM
ORAC: 3.5 ± 0.2 units at 1 μg/mL		[117]
87F. vesiculosus
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 15.8 ± 1.5 μM
O2− scavenging: IC50 > 175.6 μM
ORAC: 3.2 ± 0.2 units at 1 μg/mL		[117]
88Acanthophora spicifera
(Rhodophyta, Florideophyceae, Ceramiales)		lipid peroxidation and inhibition of the generation of MDA in rat liver: IC50 = 1.0 × 10−2 μM[124]
89A. spicifera
(Rhodophyta, Florideophyceae, Ceramiales)		lipid peroxidation and inhibition of the generation of MDA in rat liver: IC50 = 1.5 × 10−2 μM[124]
ABTS+: 2,2’-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid) diammonium salt; AChE: acetylcholinesterase; BChE: butyrylcholinesterase; CAA: cellular antioxidant activity; CAT: catalase; CLPAA: cellular lipid peroxidation antioxidant activity; CUPRAC: cupric reducing antioxidant capacity; DCFH-DA: cell-based 2′,7′-dichlorodihydrofluorescein diacetate antioxidant assay; DPPH: 1,1-diphenyl-2-picrylhydrazyl free radical; ECA0.50: effective concentration for absorbance of 0.50; FRAP: ferric reducing antioxidant power; GSH: glutathione; GPx: glutathione peroxidase; HO-1: heme oxygenase-1; H2O2: hydrogen peroxide; IC50: half maximal inhibitory concentration; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; MPO: myeloperoxidase; Nrf2: nuclear factor erythroid 2-related factor 2; OH: hydroxyl; ONOO−: peroxynitrite; O2−: superoxide anion; ORAC: oxygen radical absorbance capacity; Q50: amount of phenolics (in μg) necessary to obtain 50% of inhibition in the DPPH assay; QC50: half maximal quenching concentration; ROO: peroxyl; ROS: reactive oxygen species; SH-SY5Y: human dopaminergic neuronal cell line; SOD: superoxide dismutase; TBARS: thiobarbituric acid reactive substances; TEAC: trolox equivalence antioxidant capacity; TPA: 12-O-tetradecanoylphorbol 13-acetate; V79-4: Chinese hamster lung fibroblast cell line; XO: xanthine oxidase.
Table
Table 3. Terpenoids from macroalgae with antioxidant activity.
Table 3. Terpenoids from macroalgae with antioxidant activity.
CompoundIsolation SourceAssay/ActivityReference
90Plocamium sp.
(Rhodophyta, Florideophyceae, Plocamiales)		DPPH scavenging: IC50 = 0.05 ± 0.01 mM
H2O2 scavenging: IC50 = 5.58 ± 1.11 mM
NO scavenging: IC50 = 4.18 ± 0.22 mM
reducing power (Fe3+ to Fe2+ reduction)		[128]
91Ulva fasciata
(Chlorophyta, Ulvophyceae, Ulvales)		ABTS+ scavenging: 66.8 ± 1.5% at 50 μM
DPPH scavenging: IC50 = 13.74 ± 1.38 mM		[129]
92Pyropia orbicularis
(Rhodophyta, Bangiophyceae, Bangiales)		activation of antioxidant responses during desiccation[130]
93U. fasciata
(Chlorophyta, Ulvophyceae, Ulvales) 		ABTS+ scavenging
DPPH scavenging: IC50 = 80.56 ± 2.43 mM		[129]
94U. fasciata
(Chlorophyta, Ulvophyceae, Ulvales) 		ABTS+ scavenging
DPPH scavenging: IC50 = 23.60 ± 1.15 mM		[129]
95U. fasciata
(Chlorophyta, Ulvophyceae, Ulvales) 		ABTS+ scavenging
DPPH scavenging: IC50 = 20.83 ± 0.92 mM		[129]
96U. fasciata
(Chlorophyta, Ulvophyceae, Ulvales) 		ABTS+ scavenging: 78 ± 1.9% at 50 μM
DPPH scavenging: IC50 = 10.24 ± 0.98 mM		[129]
97Laurencia tristicha
(Rhodophyta, Florideophyceae, Ceramiales)		alcohol-induced oxidative injury in rats
enzyme activity (SOD, CAT, GPx)
D-galactose-induced oxidation in mice
endogenous apoptosis-related genes’ expression (BAX, cytochrome c, cytochrome P450, BCL-2, Caspase-9 and Caspase-3)
GSH content
lipid peroxidation		[131,132]
98Laurencia dendroidea
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: 30.3% at 2.12 mM
H2O2 scavenging		[133]
99L. dendroidea
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: 27.5% at 2.12 mM
H2O2 scavenging		[133]
100S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging IC50 = 1.18 ± 0.07 mM
DPPH scavenging: IC50 = 1.08 ± 0.07 mM		[134]
101S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 0.72 ± 0.09 mM
DPPH scavenging: IC50 = 0.75 ± 0.03 mM		[134]
102Cystoseira trinodis
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 24.19 ± 1.15% inhibition at 2 mM[135]
103C. trinodis
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 27.50 ± 1.30% inhibition at 2 mM[135]
104C. trinodis
(Ochrophyta, Phaeophyceae, Fucales)
E. stolonifera, E. bicyclis
(Ochrophyta, Phaeophyceae, Laminariales)		ABTS+ scavenging: 24.05 ± 2.38% inhibition at 2 mM
intracellular ROS generation (DCFH-DA)
intracellular GSH levels in t-BHP- and tacrine-treated HepG2 cells
t-BHP- and tacrine-induced oxidative stress in HepG2 cells		[135,136]
105C. trinodis
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 26.37 ± 0.20% inhibition at 2 mM[135]
106C. trinodis
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 20.41 ± 0.13% inhibition at 2 mM[135]
107Caulerpa racemosa
(Chlorophyta, Ulvophyceae, Bryopsidales)		Alkyl scavenging: IC50 = 0.66 ± 0.05 mM
OH scavenging: IC50 = 0.29 ± 0.05 mM		[137]
108S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging IC50 = 0.37 ± 0.02 mM
DPPH scavenging: IC50 = 0.31 ± 0.02 mM		[134]
109S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 0.37 ± 0.02 mM
DPPH scavenging: IC50 = 0.34 ± 0.06 mM		[134]
110Gracilaria salicornia
(Rhodophyta, Florideophyceae, Gracilariales)		ABTS+ scavenging: IC50 = 1.09 mM
DPPH scavenging: IC50 = 1.33 mM		[138]
111G. salicornia
(Rhodophyta, Florideophyceae, Gracilariales)		ABTS+ scavenging: IC50 = 1.24 mM
DPPH scavenging: IC50 = 1.56 mM		[138]
112from plants and microalgae, but also from macroalgaeenzyme activity (CAT, SOD, GPx and GSH reductase)
GSH and TBARS levels in hepatic tissue of lycopene-treated rats		[139]
113from plants and microalgae, but also from macroalgaeintracellular ROS generation in LPS-stimulated RAW 264.7 macrophages
LPS- and IFN-γ-induced NO generation in RAW 264.7 macrophages
TPA-induced O2− generation in differentiated human promyelocytic HL-60 cells		[140,141,142]
114from plants and microalgae, but also from macroalgaeLPS- and IFN-γ-induced NO generation in RAW 264.7 macrophages
TPA-induced O2− generation in differentiated human promyelocytic HL-60 cells		[141,142]
115from plants and microalgae, but also from macroalgaeLPS- and IFN-γ-induced NO generation in RAW 264.7 macrophages
TPA-induced O2− generation in differentiated human promyelocytic HL-60 cells		[141,142]
116from plants and microalgae, but also from macroalgaeradical scavenging
enzyme (SOD2, CAT, and GPx1) regulation in irradiated cells
intracellular ROS generation (DCFH-DA) in acetaldehyde-treated SH-SY5Y cells
LPS- and IFN-γ-induced NO generation in RAW 264.7 macrophages
Nrf2/HO-1 antioxidant pathway
Nrf2 dissociation and nuclear translocation
Nrf2 expression regulation in irradiated cells
Nrf2-regulated enzymes expression (HO-1, NQO-1, and GST-α1)
PI3K/Akt and ERK signaling pathway regulation
ROS-induced oxidative stress in a rat deep-burn model
regulation of free radical production (XO/reduced form of Nox)
Sp1/NR1 signaling pathway regulation
TPA-induced O2− generation in differentiated human promyelocytic HL-60 cells Akt/CREB and p38 kinase/MAPK signaling pathway in acetaldehyde-treated SH-SY5Y cells		[141,142,143,144,145,146,147,148,149,150,151,152]
117from plants and microalgae, but also from macroalgaeROO scavenging (ORAC/ESR)
caspase-3/7 activation
Nrf2/ARE signaling in RAW 264.7 macrophages		[153]
118from various species of OchrophytaABTS+ scavenging: 72.06 ± 0.70% inhibition at 2 mM
β-carotene bleaching: 95% inhibition at 150 μg/mL
DPPH scavenging: IC50 = 19.6, 206.4 μM
Fe2+ chelation: IC50 = 1.52 mM
FRAP: 15.2 μg TE; 24.62 mg ascorbic acid eqs/g at 1.5 mM
OH scavenging: IC50 = 51.6 μM
O2− scavenging
ROO scavenging (ORAC/ESR)
caspase-3/7 activation
high glucose-induced oxidative stress in HUVEC and zebrafish model
H2O2-induced intracellular ROS and cytotoxicity in fibroblast cells
H2O2-induced neuronal apoptosis in SH-SY5Y cells
intracellular ROS generation in SH-SY5Y cells (DCFH-DA)
LPS- and IFN-γ-induced NO generation and Nrf2/ARE signaling in RAW 264.7 macrophages
oxidative DNA damage
PI3-K/Akt cascade/ERK signaling
square wave voltammetry
TPA-induced O2− generation in differentiated HL-60 cells		[142,153,154,155,156,157,158,159,160,161,162]
119Laminaria japonica
(Ochrophyta, Phaeophyceae, Laminariales)		ABTS+ scavenging
DPPH scavenging
OH scavenging
O2− scavenging		[162]
120L. japonica
(Ochrophyta, Phaeophyceae, Laminariales)		ABTS+ scavenging
DPPH scavenging
OH scavenging
O2− scavenging		[162]
121L. japonica
(Ochrophyta, Phaeophyceae, Laminariales)		ABTS+ scavenging
DPPH scavenging
OH scavenging
O2− scavenging		[162]
122from plants and microalgae, but also from macroalgaeABTS+ scavenging: IC50 = 25.4 μM
DPPH scavenging: IC50 = 68.9 μM		[163]
123Undariopsis peterseniana
(Ochrophyta, Phaeophyceae, Laminariales)		oxidative stress-mediated apoptosis[164]
124Sargassum horneri
(Ochrophyta, Phaeophyceae, Fucales)		alkyl scavenging (ESR): IC50: 0.22 ± 0.02 mM
AAPH-induced intracellular ROS in Vero cells
AAPH-induced lipid peroxidation in zebrafish models in vivo
NF-κB, MAPK and oxidative stress regulation in RAW 264.7 macrophages
Nrf2/HO-1 pathways regulation		[165,166]
AAPH: 2,2′-azobis(2-amidinopropane) dihydrochloride; ABTS+: 2,2’-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid) diammonium salt; Akt: protein kinase B; ARE: antioxidant response element; CAT: catalase; DCFH-DA: cell-based 2′,7′-dichlorodihydrofluorescein diacetate antioxidant assay; DPPH: 1,1-diphenyl-2-picrylhydrazyl free radical; ESR: electron spin resonance; FRAP: ferric reducing antioxidant power; GSH: glutathione; GPx: glutathione peroxidase; HO-1: heme oxygenase-1; H2O2: hydrogen peroxide; HUVEC: human umbilical vein endothelial cells; OH: hydroxyl; IC50: half maximal inhibitory concentration; IFN-γ: interferon γ; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinase; NADPH: nicotinamide adenine dinucleotide phosphate; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, NO.: nitric oxide; Nox: NADPH oxidase; Nrf2: nuclear factor erythroid 2-related factor 2; O2−: superoxide anion; ORAC: oxygen radical absorbance capacity; PI3-K: phosphatidylinositol 3-kinase; ROS: reactive oxygen species; SH-SY5Y: human dopaminergic neuronal cell line; SOD: superoxide dismutase; TBARS: thiobarbituric acid reactive substances; t-BHP: tert-butyl hydroperoxide; TE: trolox equivalents; TPA: 12-O-tetradecanoylphorbol 13-acetate; XO: xanthine oxidase.
Table
Table 4. Meroterpenoids from macroalgae with antioxidant activity.
Table 4. Meroterpenoids from macroalgae with antioxidant activity.
CompoundIsolation SourceAssay/ActivityReference
125Cymopolia barbata
(Chlorophyta, Ulvophyceae, Dasycladales)		DPPH scavenging: strong
exogenous ROS scavenging in TPA-treated HL-60 cells (DCFH-DA): IC50 = 4.0 μM		[91]
126C. barbata
(Chlorophyta, Ulvophyceae, Dasycladales)		DPPH scavenging: strong
exogenous ROS scavenging in TPA-treated HL-60 cells (DCFH-DA): IC50 >14.6 μM		[91]
127Cystoseira crinita
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging
DPPH scavenging: 94.1% at 230 μM
O2− generation (PCL assay)
TBARS assay: 66.8% inhibition at 164 μM		[177]
128C. crinita
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging
DPPH scavenging activity: 92.5% at 230 μM
O2− generation (PCL assay)
TBARS assay: 66.5% inhibition at 164 μM 		[177]
129Cystoseira usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 33.3 ± 2.3 μM; 0.78 TE[178]
130C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 51.6 ± 4.8 μM; 0.50 TE [178]
131C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 44.7 ± 1.1 μM; 0.58 TE[178]
132C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 55.9 ± 9.9 μM; 0.46 TE[178]
133Dictyopteris undulata
(Ochrophyta, Phaeophyceae, Dictyotales)		DPPH scavenging: IC50 = 71 μM[179]
134D. undulata
(Ochrophyta, Phaeophyceae, Dictyotales)		expression of phase-2 enzymes (i.e., NQO1, GSH S-transferase, HO-1 and PRDX4)
Nrf2/ARE signaling pathway
oxidative stress in HT22 hippocampal neuronal cells		[180]
135D. undulata
(Ochrophyta, Phaeophyceae, Dictyotales)		DPPH scavenging: IC50 = 121 μM[179]
136G. salicornia
(Rhodophyta, Florideophyceae, Gracilariales)		ABTS+ scavenging: IC50 = 1.88 ± 0.02 mM
DPPH scavenging: IC50 = 1.51 ± 0.01 mM		[181]
137G. salicornia
(Rhodophyta, Florideophyceae, Gracilariales)		ABTS+ scavenging: IC50 = 1.96 ± 0.01 mM
DPPH scavenging: IC50 = 1.85 ± 0.02 mM		[181]
138G. salicornia
(Rhodophyta, Florideophyceae, Gracilariales)		ABTS+ scavenging: IC50 = 1.57 ± 0.02 mM
DPPH scavenging: IC50 = 1.33 ± 0.01 mM		[181]
139D. undulata
(Ochrophyta, Phaeophyceae, Dictyotales)		DPPH scavenging: IC50 = 145 μM[179]
140G. salicornia
(Rhodophyta, Florideophyceae, Gracilariales)		ABTS+ scavenging: IC50 = 1.50 mM
DPPH scavenging: IC50 = 1.40 mM		[182]
141G. salicornia
(Rhodophyta, Florideophyceae, Gracilariales)		ABTS+ scavenging: IC50 = 1.33 mM
DPPH scavenging: IC50 = 1.17 mM		[182]
142S. micracanthum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 25.5 μM
lipid peroxidation in rat liver: IC50 = 0.26 μM		[183]
143S. micracanthum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 3.0% at 0.23 mM
lipid peroxidation in rat liver: IC50 = 2.22 μM		[184]
144Cystoseira abies-marina
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 29% at 1.06 mM[185]
145C. abies-marina
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 30% at 1.02 mM[185]
146C. crinita
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging
DPPH scavenging: 94.4% at 230 μM
O2− radical generation (PCL assay)
TBARS: 70.8% inhibition at 164 μM		[177]
147C. crinita
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: TEAC = 0.14 mM
DPPH scavenging: 95.4% at 230 μM
O2− radical generation (PCL assay): 1.35
TBARS: 71.8% inhibition at 164 μM		[177]
148C. crinita
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging
DPPH scavenging: 96.1% at 230 μM
O2− radical generation (PCL assay)
TBARS: 68.9% inhibition at 164 μM		[177]
149C. crinita
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging
DPPH scavenging: 95.5% at 230 μM
O2− radical generation (PCL assay)
TBARS: 70.3% inhibition at 164 μM		[177]
150C. crinita
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: TEAC = 0.37 mM
DPPH scavenging: 95.5% at 230 μM
O2− radical generation (PCL assay): 1.39
TBARS: 72.2% inhibition at 164 μM		[177]
151C. crinita 
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: TEAC = 0.09 mM
DPPH scavenging: 95.7% at 230 μM
O2− radical generation (PCL assay): 0.72
TBARS: 71.1% inhibition at 164 μM		[177]
152C. crinita 
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: TEAC = 0.09 mM
DPPH scavenging: 96.4% at 230 μM
O2− radical generation (PCL assay): 0.59
TBARS: 73.7% inhibition at 164 μM		[177]
153C. crinita 
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: TEAC = 0.09 mM
DPPH scavenging: 96.7% at 230 μM
O2− radical generation (PCL assay): 0.51
TBARS: 73.4% inhibition at 164 μM		[177]
154C. crinita 
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: TEAC = 0.08 mM
DPPH scavenging: 65.4% at 230 μM
O2− radical generation (PCL assay): 1.06
TBARS: 74.9% inhibition at 164 μM		[177]
155C. crinita 
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: TEAC = 0.28 mM
DPPH scavenging: 95.8% at 230 μM
O2− radical generation (PCL assay): 0.79
TBARS: 74.6% inhibition at 164 μM		[177]
156C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.77 TE[186]
157C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 24.5 ± 1.6 μM; 1.06 TE[178]
158C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.77 TE[186]
159C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 26.3 ± 2.3 μM; 0.98 TE[178]
160C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.87 TE[186]
161C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 33.1 ± 5.1 μM; 0.78 TE[178]
162C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.67 TE[186]
163C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.81 TE[186]
164C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 43.1 ± 3.1 μM; 0.60 TE[178]
165C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.53 TE[186]
166C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.37 TE[186]
167C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.66 TE[186]
168C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.45 TE[186]
169C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.65 TE[186]
170C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.50 TE[186]
171C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: 0.62 TE[186]
172C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 24.4 ± 0.9 μM; 1.06 TE[178]
173C. usneoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 22.5 ± 2.1 μM; 1.15 TE[178]
174Sargassum siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 0.54 μM[187]
175Sargassum elegans, S. siliquastrum, Sargassum thunbergii
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 0.40; 46.9 μM
ONOO scavenging: 78.03% at 23.4 μM
ONOO− derived from SIN-1 scavenging: 100% at 23.4 μM
electrochemistry-guided isolation of antioxidant metabolites (using square wave and cyclic voltammetry methods)		[157,187,188,189]
176S. micracanthum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 52.6% inhibition at 143.6 μM
lipid peroxidation in rat liver: IC50 = 63.6 μM		[184]
177S. micracanthum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 32.3% inhibition at 144.0 μM
lipid peroxidation in rat liver: IC50 = 1.66 μM		[184]
178S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 0.27 μM[187]
179S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 0.25 μM[187]
180S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 0.68 μM[187]
181S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 0.64 μM[187]
182S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 0.62 μM[187]
183S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 0.21 μM[187]
184S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 23.3 μM[187]
185S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 26.1 μM[187]
186S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 25.4 μM[187]
187S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 37.9 μM[187]
188S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 35.4 μM[187]
189S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 18.7 μM[187]
190S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 25.9 μM[187]
191S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 30.4 μM[187]
192S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 47.9 μM[187]
193S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 26.3 μM[187]
194S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 25.1 μM[187]
195S. micracanthum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 933.3 μM
lipid peroxidation in rat liver: IC50 = 2.33 μM		[183]
196S. elegans
(Ochrophyta, Phaeophyceae, Fucales)		electrochemistry-guided isolation of antioxidant metabolites (using square wave and cyclic voltammetry methods)[157]
197S. elegans, S. micracanthum, S. thunbergii
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 63.6; 100.2 μM; 69.82% at 250 μM
ONOO scavenging: 64.18% at 23.6 μM
ONOO− derived from SIN-1 scavenging activity: 75.39% at 23.6 μM
electrochemistry-guided isolation of antioxidant metabolites (using square wave and cyclic voltammetry methods)		[157,188,189,190]
198C. crinita
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging
DPPH scavenging: 29.0% at 230 μM
O2− generation (PCL assay)
TBARS: 43.3% inhibition at 164 μM		[177]
199C. crinita
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: TEAC = 0.30 mM
DPPH scavenging: 38.6% at 230 μM
O2− generation (PCL assay): 1.41
TBARS: 54.4% inhibition at 164 μM		[177]
200C. barbata
(Ochrophyta, Phaeophyceae, Fucales)		antioxidant activity against ROS and reactive nitrogen species[141,183,184,189]
201S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 90.0% at 0.29 mM[191]
202S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 87.4% at 0.29 mM[191]
203S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		H2O2-induced lipid peroxidation in HT 1080 cells
intracellular GSH level in HT 1080 cells
intracellular ROS generation (DCFH-DA) in HT 1080 cells		[192]
204S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 90.5% at 0.24 mM[191]
205S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 89.6% at 0.23 mM
H2O2-induced lipid peroxidation in HT 1080 cells
intracellular GSH level in HT 1080 cells
intracellular ROS generation (DCFH-DA) in HT 1080 cells: 67.2% decrease at 11.7 μM		[191,192]
206S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 87.3% at 0.23 mM
H2O2-induced lipid peroxidation in HT 1080 cells
intracellular GSH level in HT 1080 cells
intracellular ROS generation (DCFH-DA) in HT 1080 cells: 87.2% decrease at 11.7 μM		[191,192]
207S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 88.2% at 0.23 mM[191]
208S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 90.4% at 0.23 mM
expression of osteoclastic marker gene in RANKL-stimulated RAW264.7 cells (TRAP, CTSK, MMP9 and CTR)
NF-κB activation in RANKL-stimulated RAW264.7 cells
osteoclast differentiation in RANKL-stimulated RAW264.7 cells
phosphorylation of MAPKs in RANKL-stimulated RAW264.7 cells		[191,193]
209S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 89.2% at 0.23 mM
H2O2-induced lipid peroxidation in HT 1080 cells
intracellular GSH level in HT 1080 cells
intracellular ROS generation (DCFH-DA assay) in HT 1080 cells		[191,192]
210S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 87.8% at 0.23 mM[191]
211S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 90.4% at 0.23 mM[191]
212S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 89.1% at 0.23 mM[191]
213S. micracanthum
(Ochrophyta, Phaeophyceae, Fucales)		NADPH-dependent lipid peroxidation in rat microsomes: IC50 = 0.65 μM[194]
214S. micracanthum, S. thunbergii
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 75.4 μM; 78.85% at 250 μM
ONOO scavenging: 92.69% at 23.6 μM
ONOO− derived from SIN-1 scavenging: 99.51% at 23.6 μM		[188,189,190]
215S. thunbergii
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 82.9 μM[189]
216S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		H2O2-induced lipid peroxidation in HT 1080 cells: 43.2% at 112.0 μM
intracellular GSH level in HT 1080 cells
intracellular ROS generation (DCFH-DA) in HT 1080 cells		[192]
217S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		H2O2-induced lipid peroxidation in HT 1080 cells: 38.9% at 112.0 μM
intracellular GSH level in HT 1080 cells
intracellular ROS generation (DCFH-DA) in HT 1080 cells		[192]
218S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 88.8% at 0.24 mM[191]
219S. thunbergii
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 67.8 μM
ONOO scavenging: 60.0% at 11.3 μM
ONOO− derived from SIN-1 scavenging: 98.6% at 11.3 μM		[195]
220S. thunbergii
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: IC50 = 70.0 μM
ONOO scavenging: 57.1% at 11.3 μM
ONOO− derived from SIN-1 scavenging: 90.6% at 11.3 μM		[195]
221S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 90.1% at 0.24 mM[191]
222S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 88.7% at 0.23 mM[191]
223S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 89.2% at 0.24 mM[191]
224S. siliquastrum
(Ochrophyta, Phaeophyceae, Fucales)		DPPH scavenging: 88.7% at 0.24 mM[191]
ABTS+: 2,2’-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid) diammonium salt; ARE: antioxidant response element; CTR: calcitonin receptor; CTSK: cathepsin K; DCFH-DA: cell-based 2′,7′-dichlorodihydrofluorescein diacetate antioxidant assay; DPPH: 1,1-diphenyl-2-picrylhydrazyl free radical; GSH: glutathione; HO-1: heme oxygenase-1; HT 1080: human fibrosarcoma cell line; IC50: half maximal inhibitory concentration; MMP9: matrix metalloproteinase 9; NADPH: nicotinamide adenine dinucleotide phosphate; NQO1: NADPH quinone oxidoreductase 1; Nrf2: nuclear factor erythroid 2-related factor 2; ONOO−: peroxynitrite; O2−: superoxide anion; PCL: photochemiluminescence; PRDX4: peroxyredoxin 4; RANKL: receptor activator of NF-κB ligand; ROS: reactive oxygen species; SIN-1: 3-morpholinosydnonimine; SOD: superoxide dismutase; TBARS: thiobarbituric acid reactive substances; TE: trolox equivalents; TEAC: trolox equivalence antioxidant capacity; TPA: 12-O-tetradecanoylphorbol 13-acetate; TRAP: tartrate-resistant acid phosphatase.
Table
Table 5. Nitrogenous compounds from macroalgae with antioxidant activity.
Table 5. Nitrogenous compounds from macroalgae with antioxidant activity.
CompoundIsolation SourceAssay/ActivityReference
225Porphyra yezoensis
(Rhodophyta, Bangiophyceae, Bangiales)		DPPH scavenging: IC50 = 185.2 ± 3.2 μM
ORAC: 51 ± 7% TE
Nrf2-regulated antioxidant response in UVA-treated fibroblasts (1BR)		[196,197]
226G. furcata
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 = 399.0 ± 1.1 μM
ORAC: 17 ± 7% TE
Nrf2-regulated antioxidant response in UVA-treated fibroblasts (1BR)		[196]
227P. yezoensis
(Rhodophyta, Bangiophyceae, Bangiales)		DPPH scavenging: IC50 = 30.8 μM[197]
228P. yezoensis
(Rhodophyta, Bangiophyceae, Bangiales)		TBARS: 85.2% inhibition
FTC: 84.1% inhibition		[198]
229P. yezoensis
(Rhodophyta, Bangiophyceae, Bangiales)		TBARS: 94.4% inhibition
FTC: 89.1% inhibition		[198]
230Martensia fragilis
(Rhodophyta, Florideophyceae, Ceramiales)		DPPH scavenging: moderate
exogenous ROS scavenging in TPA-treated HL-60 cells (DCFH-DA): IC50 = 11 μM		[91]
231Dictyota coriacea
(Ochrophyta, Phaeophyceae, Dictyotales)		H2O2-induced oxidative damage and toxicity in neuron-like PC12 cell
Nrf2/ARE signaling pathway		[199]
232Porphyra dioica
(Rhodophyta, Bangiophyceae, Bangiales)		ORAC: 3.79 ± 0.11 μmol TE/μM[200]
233P. dioica
(Rhodophyta, Bangiophyceae, Bangiales)		ORAC: 3.14 ± 0.32 μmol TE/μM[200]
234P. dioica
(Rhodophyta, Bangiophyceae, Bangiales)		ORAC: 0.09 ± 0.00 μmol TE/μM[200]
235P. dioica
(Rhodophyta, Bangiophyceae, Bangiales)		ORAC: 2.85 ± 0.42 μmol TE/μM[200]
236P. dioica
(Rhodophyta, Bangiophyceae, Bangiales)		ORAC: 2.50 ± 0.16 μmol TE/μM[200]
237P. dioica
(Rhodophyta, Bangiophyceae, Bangiales)		ORAC: 4.27 ± 0.15 μmol TE/μM[200]
238P. dioica
(Rhodophyta, Bangiophyceae, Bangiales)		ORAC: 0.92 ± 0.10 μmol TE/μM[200]
239Porphyra sp.
(Rhodophyta, Bangiophyceae, Bangiales)		ROO scavenging (CBA): 0.048 ± 0.003 mmol TE/g[201]
240Enteromorpha prolifera
(Chlorophyta, Ulvophyceae, Ulvales)		DPPH scavenging: 88.6 ± 1.3% at 168.7 μM
reducing power: 60% at 843.6 μM
ROO scavenging: 50% at 843.6 μM
TPC: 21.4 ± 0.1 mg GAE/g		[202]
241from plants and microalgae, but also from macroalgaeβ-carotene bleaching: 49.63% at 56.0 μM
DPPH scavenging: 13.89% at 56.0 μM
Fe2+ chelation: 55% at 200 μM
lipid peroxidation: 95% at 100 μM
ROO scavenging capacity: 308		[141,203,204,205]
242E. bicyclis
(Ochrophyta, Phaeophyceae, Laminariales)		FTC
TBARS		[206]
CBA: crocin bleaching activity; DPPH: 1,1-diphenyl-2-picrylhydrazyl free radical; FTC: ferric thiocyanate; GAE: gallic acid equivalents; Nrf2: nuclear factor erythroid 2-related factor 2; ORAC: oxygen radical absorbance capacity; ROO: peroxyl; TBARS: thiobarbituric acid reactive substances; TE: trolox equivalents; TPC: total phenolics content.
Table
Table 6. Carbohydrates and polysaccharides from macroalgae with antioxidant activity.
Table 6. Carbohydrates and polysaccharides from macroalgae with antioxidant activity.
CompoundIsolation SourceMW/Sulfate ContentAssay/ActivityReference
243from a plethora of macroalgae-free radicals (DPPH, OH, NO, O2,) scavenging
enzyme activity (a-glucosidase, AChE, BChE)		[210]
244Laurencia undulata
(Rhodophyta, Florideophyceae, Ceramiales)		-alkyl scavenging: IC50 = 43.7 μM
DPPH scavenging: IC50 = 39.3 μM
OH scavenging: IC50 = 27.4 μM
O2− scavenging: IC50 = 39.4 μM
gene expression levels of GSH and SOD
intracellular ROS levels (DCFH-DA) in RAW264.7 cells
membrane protein oxidation
MPO activity
protein expression of MMP2 and MMP9		[211]
245L. undulata
(Rhodophyta, Florideophyceae, Ceramiales)		-alkyl scavenging: IC50 = 32.3 μM
DPPH scavenging: IC50 = 41.8μM
OH scavenging: IC50 = 22.7 μM
O2− scavenging: IC50 = 33.6 μM
gene expression levels of GSH and SOD
intracellular ROS levels (DCFH-DA) in RAW264.7 cells
membrane protein oxidation
MPO activity
protein expression of MMP2 and MMP9		[211]
246enzymatically produced from commercially available polysaccharidesn.d.OH scavenging
O2− scavenging
erythrocyte hemolysis inhibiting
lipid peroxidation
metal chelating activity		[212]
247enzymatically produced from commercially available polysaccharidesn.d.OH scavenging
O2− scavenging
erythrocyte hemolysis inhibiting
lipid peroxidation
metal chelating activity		[212]
248F. vesiculosus
(Ochrophyta, Phaeophyceae, Fucales)		170 kDa/44.10 ± 0.16%OH scavenging: IC50 = 0.157 ± 0.005 mg/mL
O2− scavenging: IC50 = 0.058 ± 0.011 mg/mL
liver microsomal lipid peroxidation: IC50 = 1.250 ± 0.174 mg/mL		[213]
249Cystoseira sedoides
(Ochrophyta, Phaeophyceae, Fucales)		642 kDa/16.3%DPPH scavenging: IC50 = 0.96 ± 0.01 mg/mL[214]
250Cystoseira compressa
(Ochrophyta, Phaeophyceae, Fucales)		545 kDa/16.6%DPPH scavenging: IC50 = 0.84 ± 0.06 mg/mL[214]
251C. crinita
(Ochrophyta, Phaeophyceae, Fucales)		339 kDa/15.7%DPPH scavenging: IC50 = 0.76 ± 0.04 mg/mL[214]
252Padina gymnospora
(Ochrophyta, Phaeophyceae, Dictyotales)		200 kDa/18.40 ± 0.28%OH scavenging
O2− scavenging: IC50 = 0.243 ± 0.014 mg/mL
liver microsomal lipid peroxidation: IC50 = 2.753 ± 0.051 mg/mL		[213]
253P. gymnospora
(Ochrophyta, Phaeophyceae, Dictyotales)		18 kDa/27.57 ± 0.17%OH scavenging: IC50 = 0.353 ± 0.036 mg/mL
O2− scavenging: IC50 = 0.243 ± 0.013 mg/mL
liver microsomal lipid peroxidation: IC50 = 23.887 ± 5.975 mg/mL		[213]
254L. japonica
(Ochrophyta, Phaeophyceae, Laminariales)		742 kDa/16.5%OH scavenging: IC50 = 0.60 mg/mL
O2− scavenging: IC50 = 0.43 mg/mL		[215]
255L. japonica
(Ochrophyta, Phaeophyceae, Laminariales)		175.9 kDa/33.5%OH scavenging: IC50 = 0.85 mg/mL
O2− scavenging: IC50 = 0.53 mg/mL		[215]
256Undaria pinnatifida
(Ochrophyta, Phaeophyceae, Laminariales)		10 kDa/n.d.DPPH scavenging: 8.77 ± 1.24 TE (μg/mL)
OH scavenging: 86.98 ± 1.16%		[216]
257U. pinnatifida
(Ochrophyta, Phaeophyceae, Laminariales)		300 kDa/20.01 ± 0.82%DPPH scavenging: 9.01 ± 1.93 TE (μg/mL)
OH scavenging: 74.32 ± 1.41%		[216]
258F. vesiculosus
(Ochrophyta, Phaeophyceae, Fucales)		n.d./21.1 ± 1.7%ABTS+ scavenging
DPPH scavenging
lipid oxidation
differential pulse voltammetry		[217]
259F. vesiculosus
(Ochrophyta, Phaeophyceae, Fucales)		n.d./21.2 ± 0.8%ABTS+ scavenging
DPPH scavenging
lipid oxidation
differential pulse voltammetry		[217]
260F. vesiculosus
(Ochrophyta, Phaeophyceae, Fucales)		n.d./27.0%DPPH scavenging: IC50 = 0.035 ± 0.002 mg/mL
reducing power: RC0.5AU = 1.48 mg/mL		[218]
261Sargassum binderi
(Ochrophyta, Phaeophyceae, Fucales)		n.d./n.d.DPPH scavenging: IC50 = 2.01 ± 0.29 mg/mL
OH scavenging: 60.95 ± 0.69%
O2− scavenging: 26.78 ± 1.90%
reducing power: 0.60 ± 0.08 mg GAE/100 g		[219]
262hydrolyzed from commercially available polysaccharides5–30 kDa/n.d.LPS-induced ROS generation in RAW 264.7 macrophages[220]
263not specifiedn.d./n.d.HO-1, SOD1, Nrf2 and Keap1 expression in human keratinocytes[221]
264U. pinnatifida
(Ochrophyta, Phaeophyceae, Laminariales)		n.d./n.d.DPPH scavenging
metal chelating activity
NO scavenging
OH scavenging
reducing power
arthritis-induced physical changes in rats		[222]
265Eucheuma spinosa
(Rhodophyta, Florideophyceae, Gigartinales)		n.d./27.60 ± 0.12%OH scavenging: IC50 = 0.281 ± 0.072 mg/mL
O2− scavenging: IC50 = 0.332 ± 0.080 mg/mL
liver microsomal lipid peroxidation: IC50 = 0.830 ± 0.063 mg/mL		[213]
266Eucheuma cottonii
(Rhodophyta, Florideophyceae, Gigartinales)		n.d./17.90 ± 0.05%OH scavenging: IC50 = 0.335 ± 0.016 mg/mL
O2− scavenging: IC50 = 0.112 ± 0.003 mg/mL
liver microsomal lipid peroxidation: IC50 = 0.323 ± 0.011 mg/mL		[213]
267Gigartina acicularis, Gigartina pisillata
(Rhodophyta, Florideophyceae, Gigartinales)		n.d./33.38 ± 0.06%OH scavenging: IC50 = 0.357 ± 0.120 mg/mL
O2− scavenging: IC50 = 0.046 ± 0.001 mg/mL
liver microsomal lipid peroxidation: IC50 = 2.697 ± 0.267 mg/mL		[213]
268Porphyra haitanensis
(Rhodophyta, Bangiophyceae, Bangiales)		n.d./17.7%OH scavenging: IC50 = 6.55 mg/mL
O2− scavenging: ~60% at 2.5 μg/mL
reducing power: 0.42 at 6.17 mg/mL		[223]
269Ulva pertusa
(Chlorophyta, Ulvophyceae, Ulvales)		n.d./19.5%OH scavenging
O2− scavenging: IC50 = 20.0 μg/mL
metal chelating assay
reducing power		[224]
270U. pertusa
(Chlorophyta, Ulvophyceae, Ulvales)		151.7 kDa/n.d.Fe2+ chelation
OH scavenging: IC50 > 1 mg/mL
O2− scavenging: IC50 = 22.1 μg/mL
reducing power		[225]
271U. pertusa
(Chlorophyta, Ulvophyceae, Ulvales)		n.d./n.d.Fe2+ chelation: 10% to 20% at 0.31–1.88 mg/mL
OH scavenging: 3.3–37% at 0.25–1.52 mg/mL
O2− scavenging: IC50 = 9.17 μg/mL
reducing power		[226]
AChE: acetylcholinesterase; BChE: butyrylcholinesterase; DPPH: 1,1-diphenyl-2-picrylhydrazyl free radical; GAE: gallic acid equivalents; GSH: glutathione; HO-1: heme oxygenase-1; LPS: lipopolysaccharide; MMP: matrix metalloproteinase; MPO: myeloperoxidase; n.d.: not determined; NO: nitric oxide; Nrf2: nuclear factor erythroid 2-related factor 2; OH: hydroxyl; O2−: superoxide anion; RC0.5AU: reducing capacity at 0.5 absorbance unit; ROS: reactive oxygen species; SOD: superoxide dismutase; TE: trolox equivalents.
Table
Table 7. Miscellaneous compounds from macroalgae with antioxidant activity.
Table 7. Miscellaneous compounds from macroalgae with antioxidant activity.
CompoundIsolation SourceAssay/ActivityReference
272G. furcata
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 = 290.5 ± 1.5 μM
ONOO− scavenging: IC50 = 8.45 ± 0.46 μM
AChE inhibition: IC50 = 94.4 ± 1.7 μM
BChE inhibition: IC50 = 242.0 ± 4.8 μM		[75]
273G. furcata
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 > 274.4
ONOO− scavenging: IC50 = 218.7 ± 1.5 μM
AChE inhibition: IC50 = 31.2 ± 1.0 μM
BChE inhibition: IC50 = 526.7 ± 6.1 μM		[75]
274G. furcata
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 > 195.0 μΜ
ONOO− scavenging: IC50 = 28.5 ± 0.0 μM
AChE inhibition: IC50 = 33.9 ± 0.9 μM
BChE inhibition: IC50 > 390.0 μM		[75]
275Cystoseira sp.
(Ochrophyta, Phaeophyceae, Fucales)
guglone-induced oxidative stress and intracellular ROS measurement in Caenorhabditis elegans[141,232]
276G. furcata
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 > 179.6 μΜ
ONOO− scavenging: IC50 = 58.3 ± 0.3 μM
AChE inhibition: IC50 = 44.9 ± 1.4 μM
BChE inhibition: IC50 = 57.1 ± 2.7 μM		[75]
277G. furcata
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 > 165.3 μΜ
ONOO− scavenging: IC50 = 52.4 ± 0.2 μM
AChE inhibition: IC50 = 38.1 ± 1.4 μM
BChE inhibition: IC50 = 21.7 ± 1.1 μM		[75]
278L. undulata
(Rhodophyta, Florideophyceae, Ceramiales)		alkyl scavenging: IC50 = 45.0 ± 1.6 µM
DPPH scavenging: IC50 = 27.1 ± 1.1 µM
OH scavenging: IC50 = 22.8 ± 0.8 µM
O2− scavenging: IC50 = 33.5 ± 1.3 µM
gene expression of enzymes GSH and SOD
intracellular ROS levels (DCFH–DA) in RAW264.7 cells
membrane protein oxidation
MPO activity		[233]
279G. furcata
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 > 220.9 μΜ
ONOO− scavenging: IC50 = 206.6 ± 1.0 μM
AChE inhibition: IC50 = 13.6 ± 0.5 μM
BChE inhibition: IC50 = 420.1 ± 7.8 μM		[75]
280Kappaphycus alvarezii
(Rhodophyta, Florideophyceae, Gigartinales)		ABTS+ scavenging: IC50 = 3.63 ± 0.55 mM
DPPH scavenging: IC50 = 3.53 ± 0.05 mM		[234]
281K. alvarezii
(Rhodophyta, Florideophyceae, Gigartinales)		ABTS+ scavenging: IC50 = 1.96 ± 0.51 mM
DPPH scavenging: IC50 = 1.75 ± 0.20 mM 		[234]
282Jania rubens
(Rhodophyta, Florideophyceae, Corallinales)		ABTS+ scavenging: IC50 = 1.48 mM
DPPH scavenging: IC50 = 0.80 mM		[235]
283S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 2.89 ± 0.04 mM
DPPH scavenging: IC50 = 2.44 ± 0.11 mM
Fe2+ chelation: IC50 = 3.64 ± 0.08 mM		[236]
284S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 3.76 ± 0.08 mM
DPPH scavenging: IC50 = 3.26 ± 0.04 mM
Fe2+ chelation: IC50 = 4.65 ± 0.08 mM		[236]
285K. alvarezii
(Rhodophyta, Florideophyceae, Gigartinales)		ABTS+ scavenging: IC50 = 0.67 ± 0.25 mM
DPPH scavenging: IC50 = 0.61 ± 0.06 mM		[234]
286Gracilaria opuntia
(Rhodophyta, Florideophyceae, Gracilariales		ABTS+ scavenging: IC50 = 0.50 mM
DPPH scavenging: IC50 = 0.41 mM		[237]
287C. trinodis
(Ochrophyta, Phaeophyceae, Fucales)
most probably as a contamination from Laurencia sp.
(Rhodophyta, Florideophyceae, Ceramiales)		ABTS+ scavenging: 26.01 ± 0.01%[135]
288K. alvarezii
(Rhodophyta, Florideophyceae, Gigartinales)		ABTS+ scavenging: IC50 = 1.30 ± 0.48 mM
DPPH scavenging: IC50 = 0.97 ± 0.07 mM		[238]
289K. alvarezii
(Rhodophyta, Florideophyceae, Gigartinales)		ABTS+ scavenging: IC50 = 2.28 mM
DPPH scavenging: IC50 = 2.02 mM		[235]
290K. alvarezii
(Rhodophyta, Florideophyceae, Gigartinales)		ABTS+ scavenging: IC50 = 1.42 mM
DPPH scavenging: IC50 = 2.50 mM		[235]
291Spatoglossum variabile
(Ochrophyta, Phaeophyceae, Dictyotales)		O2− scavenging: IC50 = 22.2 μM[239]
292S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 1.28 ± 0.00 mM
DPPH scavenging: IC50 = 1.05 ± 0.03 mM		[240]
293Hypnea musciformis
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 = 231.2 ± 2.0 μM
Fe2+ chelation: IC50 = 667.9 ± 0.8 μM
lipid peroxidation (TBARS): 1.34 ± 0.01 MDAEQ/kg at 0.1 μg/mL		[241]
294S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 1.81 ± 0.03 mM
DPPH scavenging: IC50 = 1.2 ± 0.05 mM
Fe2+ chelation: IC50 = 2.28 ± 0.03 mM 		[236]
295T. conoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 2.00 mM
DPPH scavenging: IC50 = 1.71 mM		[242]
296T. conoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 1.39 mM
DPPH scavenging: IC50 = 1.29 mM		[242]
297H. musciformis
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 = 25.0 ± 0.5 μM
Fe2+ chelation: IC50 = 350.7 ± 0.5 μM
lipid peroxidation (TBARS): 0.88 ± 0.01 MDAEQ/kg at 0.1 μg/mL		[241]
298H. musciformis
(Rhodophyta, Florideophyceae, Gigartinales)		DPPH scavenging: IC50 = 322.4 ± 1.1 μM
Fe2+ chelation: IC50 = 5115.3 ± 2.1 μM
lipid peroxidation (TBARS): 0.76 ± 0.01 MDAEQ/kg at 0.1 μg/mL		[241]
299S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 0.81 ± 0.04 mM
DPPH scavenging: IC50 = 0.64 ± 0.02 mM
Fe2+ chelation: IC50 = 1.42 ± 0.02 mM		[236]
300S. wightii
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 0.79 ± 0.03 mM
DPPH scavenging: IC50 = 0.67 ± 0.03 mM		[240]
301T. conoides
(Ochrophyta, Phaeophyceae, Fucales)		ABTS+ scavenging: IC50 = 2.18 mM
DPPH scavenging: IC50 = 1.95 mM		[242]
ABTS+: 2,2’-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid) diammonium salt; AChE: acetylcholinesterase; BChE: butyrylcholinesterase; DPPH: 1,1-diphenyl-2-picrylhydrazyl free radical; IC50: half maximal inhibitory concentration; MDAEQ/kg: malondialdehyde equivalent compounds formed per kg sample; ONOO−: peroxynitrite; O2−: superoxide anion; TBARS: thiobarbituric acid reactive substances.
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Tziveleka, L.-A.; Tammam, M.A.; Tzakou, O.; Roussis, V.; Ioannou, E. Metabolites with Antioxidant Activity from Marine Macroalgae. Antioxidants 2021, 10, 1431. https://doi.org/10.3390/antiox10091431

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Tziveleka L-A, Tammam MA, Tzakou O, Roussis V, Ioannou E. Metabolites with Antioxidant Activity from Marine Macroalgae. Antioxidants. 2021; 10(9):1431. https://doi.org/10.3390/antiox10091431

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Tziveleka, Leto-Aikaterini, Mohamed A. Tammam, Olga Tzakou, Vassilios Roussis, and Efstathia Ioannou. 2021. "Metabolites with Antioxidant Activity from Marine Macroalgae" Antioxidants 10, no. 9: 1431. https://doi.org/10.3390/antiox10091431

APA Style

Tziveleka, L. -A., Tammam, M. A., Tzakou, O., Roussis, V., & Ioannou, E. (2021). Metabolites with Antioxidant Activity from Marine Macroalgae. Antioxidants, 10(9), 1431. https://doi.org/10.3390/antiox10091431

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