The skin is considered the largest organ in the human body with important roles for its homeostasis, such as protection against the harmful environment and dehydration [1]. The skin surface protects against pathogens, pollutants, and UV radiation ^[2][3][2,3]. These external stressors can pose a threat to the skin itself, promoting the formation of reactive oxygen species (ROS) that promote a pro-inflammatory response [4], associated with the pathophysiology of skin diseases, such as eczema, atopic dermatitis, psoriasis, vitiligo, and even skin aging or photoaging ^[5][6][5,6]. However, the pathology of skin diseases is not fully understood, and treatments are sometimes ineffective and inappropriate, with a low impact or with significant side effects [7]. Therefore, novel treatments are being sought out to fight the epidemic of skin inflammatory diseases. Synthetic drugs are not as effective as expected, and consumers are increasingly aware of using natural, organic, and environmentally friendly products. These new market trends and consumer preferences are stimulating the search for natural and sustainable ingredients (e.g., extracts of plants, microbes, or algae) to fight skin diseases ^[8][9][8,9]. The demand for natural molecules with beneficial properties for the skin includes the search for alternatives to synthetic molecules with fewer adverse side effects [10].

Algae (microalgae and macroalgae) are photosynthetic organisms considered natural reservoirs of compounds with bioactive properties, such as polysaccharides, vitamins, pigments, and polyunsaturated fatty acids (PUFA) [11]. These molecules are essential for the development of cosmeceuticals and are potential therapeutic agents with applications in skin diseases, including systemic or topical applications [12]. Algae biomass and algae extracts are already used in the treatment of skin diseases, for example, the use of macroalgae in thalassotherapy [13], or the use of algae oils rich in essential omega-6 and omega-3 PUFA (e.g., docosahexaenoic acid, DHA) in skin products [14]. Interest in algae-based products and natural ingredients has increased in the cosmetic and cosmeceutical industries in recent years [15]. Their main application has been as ingredients with hydrating, emollient, emulsifying, and whitening properties. Their use as anti-inflammatory and antioxidant products is also of great interest, but is less explored, and may be important for the management of skin diseases generally associated with periods of exacerbated inflammatory response and chronic inflammation [16].

2. Algae Lipids with Antioxidant Activity

The antioxidant activity of algae occurring lipids has been studied, but is much less explored compared to well-known natural antioxidants such as pigments and phenolic compounds ^[17][18][67,68] (Table 1).

Studies	Mechanism

Studies	Assay	Identified Lipids	Algae Species	Ref.
Action	Model	Identified Lipids	Algae Species	Ref.
in chemico	Free radical scavenging	ABTS, DPPH, hydroxyl radical, superoxide anion	Polar lipids, neutral lipids, FAME
In chemico	COX-2 inhibition	COX-2 kit assay	Macroalgae:	Bifurcaria bifurcata, Codium tomentosum, Fucus vesiculosus, Gracilaria gracilis Grateloupia turuturu, Palmaria palmata, Porphyra dioica Sargassum muticum, Solieria chordalis, Ulva rigida	Microalgae:	Chlorella vulgaris, Chlorococcum amblystomatis, Nannochloropsis oceanica, Phaeodactylum tricornutum, Scenedesmus intermedius Scenedesmus obliquus, Spirulina	sp.,	Tetraselmis chui	Polar lipids	Macroalgae:	Codium tomentosum, Fucus vesiculosus Gracilaria gracilis, Palmaria palmata, Porphyra dioica, Ulva rigida,	Microalgae:	Chlorella vulgaris, Chlorococcum amblystomatis, Gloeothece sp., Skeletonema	sp.,	[19][20][21][22]	[69,70,82,83]
Tetraselmis sp. mutants	[	19	]	[	32][33][34][35]	[69,92,93,94,95]	in vitro	Detoxify intracellular ROS	Increased the expression of Nrf2 in irradiated HaCat cells Upregulate target antioxidant enzymes Cu/Zn SOD, CAT, and HO-1	Crude ethanolic extract
In vitro	NO inhibition	Macroalga:	Raw 264.7	Carpomitra costata	Polar and non-polar lipids; PC, PG, DGDG, DGTS, MGDG, MGMG, SQDG classes; Free and ethyl esterified DGLA	[23		Macroalgae:	Chondrus crispus, Lobophora sp.Palmaria palmata	, Microalgae:	Chlorella sorokiniana Lobosphaera incisa, Nannochloropsis granulata, Tetraselmis chui,]	[84]
	[	36	]	[	37	][38][39][40][41][42][43]		[96,97,98,99,100,101,102,103]	Free radical scavenging	Superoxide generation on peritoneal leukocytes
	Decrease in PGE2 Downregulation of COX-2	Raw 264.7; White blood cells; Epidermal cells	Sulfoquinovosylacylglycerols	Crude ethanolic extracts; Microalgae:	Porphyridium cruentum	lipid extracts rich in PC; free and ethyl esterified DGLA		[	Macroalgae:	Laminaria ochroleuca	Microalgae:	Chlorella vulgaris, Chloromonas reticulata, Lobosphaera incisa Micractinium	sp.,	Phaeodactylum tricornutum,24]	[86]
	[	41	]	[	44][45][46][47][48]	[101,104,105,106,107,119]		Inhibition of ROS	Photoprotective against UVB in NHDF	Crude ethyl acetate extract	Microalga:	Ettlia	sp. YC001	[
Downregulation of mRNA expression of pro-inflammatory cytokines Downregulation of cytokines levels: TNF-α, IL-6, IL-1α, and IL-1β	THP-1; PBMC; Epidermal cells; HaCaT cells	Crude ethanolic extracts; lipid extracts; lipid extracts rich in MGDG, DGDG and SQDG; Lipid extracts rich in PC; LPC(16:0); oxylipins; ergosterol and 7-dehydroporiferasterol; free and ethyl esterified DGLA	Macroalgae:	Chondrus crispus, Laminaria ochroleuca, Palmaria palmata, Porphyra dioica, Prasiola japonica	Microalgae:	Aurantiochytrium mangrovei, Chlamydomonas debaryana, Chlorella vulgaris, Chloromonas reticulata, Cylindrotheca closterium, Dunaliella tertiolecta, Micratinium	sp.,	Nannochloropsis gaditana, Nitzschia palea, Phaeodactylum tricornutum, Lobosphaera incisa Spirulina maxima, Pavlova lutheri, Tetraselmis suecica,25]	[85]
[	23	]	[	41][44][45][46][47][49][50][51][52][53][57][58]	Enzyme/protein expression	Downregulation of expression of MMPs	Crude ethanolic extract	Microalga:	Arthrospira platensis	[26]	[87]
Enzyme/protein expression	Downregulation of expression of MMPs, IL-6 and TGF-1 in human dermal fibroblast Modulate MAPK in irradiated HaCat cells	Fucosterol	Macroalga:	Sargassum fusiforme	[27][28]	[88,89]

The pathophysiology of inflammatory skin diseases is associated with unregulated elevated levels of ROS and the activity of enzymes and proteins involved in the regulation of oxidative stress ^[29][30]. In cells, mitochondria metabolize oxygen, producing ROS. During the oxidative phosphorylation in mitochondria, oxygen is converted to O₂^•−, which can be transformed in H₂O₂ by superoxide dismutase, and then to water by glutathione peroxidase (GPX) or peroxiredoxin III (PRX III) radical ^[30][90]. Under normal conditions, the mitochondria ROS production is balanced by the production of a variety of antioxidants. However, oxidative stress occurs when there is an imbalance between ROS and antioxidants production. An imbalance in ROS production leads to redox signaling from cellular organelles, causing mitochondrial damage and dysfunction in several conditions ^[31][91]. However, the application of algae lipids to prevent mitochondrial dysfunction and modulate the oxidative status is little understood and requires in-depth study to understand the mechanisms underlying this potential antioxidant role. The use of crude extracts from algae may reduce ROS levels induced by UVB and impair the expression of MMPs and thymine dimers formation due to UVB exposure in skin cells ^[26][87]. These studies were performed using complex crude extracts rich in lipids and not with isolated lipids or fractions. This hinders the understanding of the mechanisms of action of algal lipids as antioxidants, and more work is needed to determine the potential protective role of algal lipids in skin diseases. A better understanding of this antioxidant action is needed, for example, there is a lack of knowledge about the impact of specific lipid classes or lipid molecules in the enzymes and proteins involved in the regulation of oxidative stress, such as metalloproteinases, HO-1, catalase, or superoxide dismutase.

3. Algae Lipids with Anti-Inflammatory Activity

The lipids of macro- and microalgae have been studied for their anti-inflammatory and immunomodulatory activity. Most of the studies tested crude lipid extracts or fractions of lipid classes of algae and were mainly performed in chemico and in vitro (Table 2). They mainly measured the impact of lipids on the levels of inflammatory effector molecules such as prostaglandins and nitric oxide (NO), cytokines such as TNF-α, IL-6, and IL-1β, and on the activation of inflammatory signaling pathways (NF-κB) or cyclooxygenase-2 (COX-2) activity. Few studies have evaluated in vivo models measuring the effect of lipids on skin cells, such as epidermal cells.

[

84

,

101

,

104

[

54

,105

]

,106

[

,107,111,112,113,114,115

55][56][48

,110

]

,116,118,119,121,122]

Inhibition of pro-inflammatory signaling pathways mediated by TLR and NF-κB

THP-1

Lipid extracts rich in MGDG, DGDG, and SQDG

Macroalgae:

Chondrus crispus, Palmaria palmata, Porphyra dioica

Microalgae:

Pavlova lutheri

[49]

[110]

In vivo

Attenuation of ear oedema

PLA2 kit assay; Mice with ear oedema; DNFB-induced in naive C57BL/6 mice

MMHDA; Lipid extracts rich in PC; MGDG, DGDG, and SQDG fractions

Macroalgae:

Ishige okamurae

,

Laminaria ochroleuca

Microalgae: ETS-05 cyanobacterium.

[48][59][60]

[119,123,127]

Neutrophil gathering in the wound region

Wounded zebrafish model

Glycolipids rich in γ-linolenic acid

Microlagae:

Spirulina platensis

[61]

[124]

Inhibition of pro-inflammatory cytokines production: TNF-α, IL-6, IL-8, IFN- γ, IL-1β, IL-17

db/db and CD1 mice model of diabetes mellitus; TNBS-induced colitis rats; BALB/c mice skin; TPA-induced hyperplasia murine model

Crude ethanolic extract; omega-3 fatty acids; oxylipins; MGDG cream

Macroalgae:

Sargassum cristaefolium

Microalgae:

Chlamydomonas debaryana, Isochrysis galbana

[62][63][64][65]

[125,126,128,129]

Downregulation of iNOS and COX-2, and decrease in NO and PGE2 production

TNBS-induced colitis rat; BALB/c mice skin; TPA-induced hyperplasia murine model

Crude ethanolic extract; oxylipins; MGDG cream

Macroalgae:

Sargassum cristaefolium

Microalgae:

Chlamydomonas debaryana, Isochrysis galbana

[63][64][65]

[126,128,129]

It was demonstrated that methoxylated fatty acids (MMHDA) isolated from macroalga Ishige okamurae ^[60][127] and MGDG, DGDG, and SQDG fractions from microalga ETS-05 cyanobacterium ^[59][123] presented anti-inflammatory activity by reducing ear oedema (swelling) in a mouse model. The anti-inflammatory action of MMHDA has been associated with the inhibition of phospholipase A2 (PLA2), the enzyme responsible for the hydrolysis of the sn-2 position of membrane glycerophospholipids to liberate arachidonic acid (AA). The reduction in neutrophils was observed in the wound region of a zebrafish model when glycolipids rich in γ-linolenic acid from the microalga Spirulina platensis were used ^[61][124]. Extracts with omega-3 FA isolated from microalgae promoted the reduction of CD4+ T cells production of the pro-inflammatory mediators IFN-γ, TNF-α, and IL-4 and increased the secretion of IL-17A, IL-14, and TGF-β in a db/db and CD1 mouse model of diabetes Mellitus ^[62][125]. Downregulation of TNF-α was also observed, as well as decreased expression of iNOS and COX-2, when 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rats were supplemented with oxylipins extracted from Chlamydomonas debaryana ^[63][126].

In model studies on skin diseases, the protective effect of the ethanolic extract of Sargassum cristaefolium against ultraviolet-irradiated skin keratinocytes and BALB/c mice skin has been demonstrated ^[64][128]. The inhibition of ROS production and suppression of the apoptotic process in irradiated cells, such as the decrease of caspases, downregulation of COX-2, IL-1β, IL-8, IL-6, TNF-α, and INF-γ, and down-modulation of NF-κB signaling, were some of the reported mechanisms of action. L. ochroleuca lipid extract have been shown to reduce ear oedema, in a murine model of skin inflammation induced by the chemical sensitizer 2,4-dinitro-fluorobenzene applied to the ear of naive C57BL/6 mice ^[48][119]. A cream containing MGDG extracted from the microalga Isochrysis galbana has been reported to have beneficial effects in the treatment of a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced hyperplasia murine model ^[65][129]. Pre-treatment of these mice with this MGDG cream reduced skin oedema and epidermal thickness. In addition, the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-17 produced in epidermal tissue were downregulated and the expression of COX-2 was inhibited. The results of this study were very promising as they involved a model of skin disease and isolated algal lipids and showed a strong anti-inflammatory effect as well as an improved skin condition. Such results highlight algal lipids as promising pharmacological strategies for the therapy of inflammatory skin pathologies. Algal lipids have shown anti-inflammatory potential as modulators of signaling pathways and mediators, known as the main hallmarks of inflammation, such as COX-2 and iNOS, but also the modulation of the production of cytokines (TNF-α, IL-6, IL-1β, and IFN-γ), as described in Figure 1. Indeed, as mentioned in Section 2, inflammatory skin diseases are characterized by systemic inflammation ^[66][130] with the infiltration of immune cells, such as neutrophils. Algal lipids such as glycolipids rich in γ-linolenic acid from the microalga S. platensis have been reported to reduce neutrophil infiltration in a wound region model of zebrafish ^[61][124]. Neutrophils are the main producers of ROS capable of activating transcription factors, such as NF-κB, responsible for the regulation of genes involved in inflammation ^[67][43]. Interestingly, the use of extracts in immune and skin cell lines reduced this pro-inflammatory pathway ^[49][50][59][110,111,123]