Algae Metabolites in Cosmeceutical: An Overview of Current Applications and Challenges

Cosmetics are widely used by people around the world to protect the skin from external stimuli. Consumer preference towards natural cosmetic products has increased as the synthetic cosmetic products caused adverse side effects and resulted in low absorption rate due to the chemicals’ larger molecular size. The cosmetic industry uses the term “cosmeceutical”, referring to a cosmetic product that is claimed to have medicinal or drug-like benefits. Marine algae have gained tremendous attention in cosmeceuticals. They are one of the richest marine resources considered safe and possessed negligible cytotoxicity effects on humans. Marine algae are rich in bioactive substances that have shown to exhibit strong benefits to the skin, particularly in overcoming rashes, pigmentation, aging, and cancer. The current review provides a detailed survey of the literature on cosmeceutical potentials and applications of algae as skin whitening, anti-aging, anticancer, antioxidant, anti-inflammation, and antimicrobial agents. The biological functions of algae and the underlying mechanisms of all these activities are included in this review. In addition, the challenges of using algae in cosmeceutical applications, such as the effectiveness of different extraction methods and processing, quality assurance, and regulations concerning extracts of algae in this sector were also discussed.


Synthetic Versus Natural Ingredients in Cosmetic Industry
Cosmeceuticals are topical cosmetic-pharmaceutical hybrids which refer to a cosmetic product with active ingredients claiming to have medicinal or drug-like benefits to skin health [1,2]. Globally, the cosmeceutical industry is growing each year due to the trend of modern lifestyle. More recently, the cosmeceutical industry is progressively shifting to natural bioactive ingredients because of the ineffectiveness of synthetic cosmetics [3].
Ineffectiveness of synthetic cosmetics includes their side effects and low absorption rate. The low absorption rate of cosmetics could be due to the big size of the molecular compounds. A study by Bos and Marcus [4] asserted that only compounds with the molecular weight lesser than 500 Dalton (Da) could penetrate through the skin. Cyclosporin (MW 1202 Da), a topical immunosuppressant, spores such as aplanspores, which are rich in astaxanthin. Astaxanthin is a carotenoid that protects the cells from photo-oxidation. Algae exposed to UV radiations will produce UV screening compounds such as mycosporine-like amino acids (MAA), which acted as antioxidants and involved in osmotic regulations. Furthermore, algae exposed to high solar radiation and low nitrogen concentration produce more β-carotene, such as Dunaliella [20]. Thus, algae that are naturally exposed to oxidative stress develop defense systems that protect them against reactive oxygen species (ROS) and free radicals. These compounds could be used in cosmetics to protect the cells against the adverse effects of UV radiation. Some of the environmental benefits of algae include fixation of carbon dioxide. Studies have reported that large cultivation of microalgae capable of uptaking carbon from the atmosphere; for instance, Spirulina platensis with carbon fixation rate of 318 mg/L −1 d −1 and Chlorella vulgaris with carbon fixation rate of 251 mg/L −1 d −1 [22,23].
The exploitation of marine algae for the environmental and industrial production of natural products is a fast-growing sector. These natural products are expected to become very competitive in the market due to their higher biological value, improvement in the cultivation process, and lower production cost than synthetic products.

Current Applications of Algae-Derived Metabolites in Cosmeceutical Industrial
The transition from synthetic compounds to natural products such as marine algae have been attracting the attention of many researchers since algae possess a wide range of pharmacological activities with negligible cytotoxicity effects in human cells [24]. Marine algae are used for different purposes in food, pharmaceutical, biofuel, agriculture, and cosmetic industries. Industries, such as Cyanotech, Fuji Chemical Seambiotic, and Mera Pharmaceuticals are producers of microalgae biomass contributing to products in pharmaceuticals, cosmetics, and nutritious feed [25]. Interestingly, phycocyanin (usually found in red algae and cyanobacteria) is accepted as a natural color additive in food and cosmetics by the Food and Drug Administration (FDA) due to its non-toxic, natural, and biodegradable properties. Accordingly, it becomes the major target of the market in the United States [26].
Meanwhile, carotenoid such as astaxanthin plays a crucial role in scavenging free radicals in the human body and it is considered a strong antioxidant; hence, its popularity as a human dietary supplement. Leading cosmeceutical industries, such as Unilever, L'Oreal, Henkel, and Beiersdorf are expected to improve the growth of carotenoid market value in the European market [27]. The market value for carotenoids is expected to reach about $1.53 billion by 2021 [27,28].
Furthermore, red algae Gracilaria account for most of the raw material for the agar extraction. It is reported by the Food and Agriculture Organization (FAO) of the United Nations that more than 80% of the agar were produced from Gracilaria species, which are mainly produced by China and Indonesia [29]. Gracilaria species have been widely used in cosmetics due to their stabilizing, thickening, and gelling characters. Commercially available products from Gracilaria species include hydrogel soap by Sea Laria ® , facial mask by Balinique ® , and hydrating cream by Thalasso ® [29].
A number of algae-based skin products have been marketed, such as Algenist (an anti-aging moisturizer containing microalgae oil and alguronic acid from algae) [30], Helionori ® by Gelyma and Helioguard365 ® (a sunscreen product containing MAAs from red seaweed Porphyra umbilicalis) [31], Protulines ® by Exsymol S.A.M., Monaco (an anti-aging agent from protein-rich extract of Arthrospira), and Dermochlorella by Codif, St. Malo, France (an anti-wrinkling agent from Chlorella vulgaris extract) [32]. Therefore, bioactive compounds derived from algae could be considered a potential cosmeceutical agent for skincare.

UV Radiation and Skin-Related Diseases
Skin is one of the most complex and largest organs that serves as a protective barrier against water losses and environmental stresses, such as ultraviolet radiation (UVR), pathogens, physical agents, and chemicals [33]. The skin comprises three layers-epidermis, dermis, and hypodermis. The presence of keratinocyte cells and melanocyte cells in the epidermis layer plays a vital role in repairing damaged skin and protecting the skin from UV light. The dermis consists of elastin, hyaluronic acid, and collagen which involves tissue repair and stability, whereas hypodermis consists of fats, which involved in body insulation [9]. Several skin-related diseases that have been reported include acne, eczema, dermatitis, hives, psoriasis, and pityriasis rosea which cause rashes [34]. Other skin diseases include pigmentation disorders, such as hypopigmentation due to the absence of melanocytes and hyperpigmentation caused by a metabolic disorder or skin irritation. In addition, one of the biggest concerns is skin cancers (e.g., squamous, basal, and melanoma) with melanoma being the deadliest form in America because of overexposure to UV radiation [35].
In most cases, humans are exposed to UV radiation due to overexposure to sunlight. UV radiation can produce many adverse effects within the cells, including DNA damage, skin pathologies, such as erythema and inflammation, skin aging, and cancer [36]. There are three main components of UV radiation, namely UVA (315-400 nm), UVB (280-315 nm), and UVC (100-280 nm) [37]. UVA can reach the dermis layer of skin, increasing the level of ROS that indirectly induce DNA mutagenesis, which results in skin aging and wrinkling. UVA can act as a carcinogen by shortening telomere in the DNA strand and it has less ability to stimulate melanin production resulting in redness, sun tanning, and freckles. UVB can penetrate the epidermis layer and damage the DNA in skin cells directly and induce skin cancers. UVC is highly bioactive but humans are not exposed to UVC because it is mostly absorbed by the ozone layer. In addition, UV-induced oxidative stress plays a crucial role in causing aging, inflammation, melanogenesis and even cancer which are shown in Figure 1 [9,12,[38][39][40][41].
Mar. Drugs 2019, 17, x FOR PEER REVIEW  4 of 39 include acne, eczema, dermatitis, hives, psoriasis, and pityriasis rosea which cause rashes [34]. Other skin diseases include pigmentation disorders, such as hypopigmentation due to the absence of melanocytes and hyperpigmentation caused by a metabolic disorder or skin irritation. In addition, one of the biggest concerns is skin cancers (e.g., squamous, basal, and melanoma) with melanoma being the deadliest form in America because of overexposure to UV radiation [35]. In most cases, humans are exposed to UV radiation due to overexposure to sunlight. UV radiation can produce many adverse effects within the cells, including DNA damage, skin pathologies, such as erythema and inflammation, skin aging, and cancer [36]. There are three main components of UV radiation, namely UVA (315-400 nm), UVB (280-315 nm), and UVC (100-280 nm) [37]. UVA can reach the dermis layer of skin, increasing the level of ROS that indirectly induce DNA mutagenesis, which results in skin aging and wrinkling. UVA can act as a carcinogen by shortening telomere in the DNA strand and it has less ability to stimulate melanin production resulting in redness, sun tanning, and freckles. UVB can penetrate the epidermis layer and damage the DNA in skin cells directly and induce skin cancers. UVC is highly bioactive but humans are not exposed to UVC because it is mostly absorbed by the ozone layer. In addition, UV-induced oxidative stress plays a crucial role in causing aging, inflammation, melanogenesis and even cancer which are shown in Figure 1 [9,12,[38][39][40][41]. Effect of UV radiation-induced reactive oxygen species (ROS). Accumulation of ROS leads to skin cancer, inflammation, photoaging, wrinkling, and melanogenic through activation of respective signaling pathways.

Methods
We provide a comprehensive review of potential cosmeceutical compounds derived from 122 algae species. These compounds were searched by using keywords like 'algae', 'seaweed', 'macroalgae', or 'microalgae' combined with 'cosmetic' or 'cosmeceutical' in three major databases (ScienceDirect, PubMed, and Google Scholar).

Methods
We provide a comprehensive review of potential cosmeceutical compounds derived from 122 algae species. These compounds were searched by using keywords like 'algae', 'seaweed', 'macroalgae', or 'microalgae' combined with 'cosmetic' or 'cosmeceutical' in three major databases (ScienceDirect, PubMed, and Google Scholar).

Marine Algae-Derived Compounds in Cosmeceutical Application
Based on the evidence from previous studies, brown algae contribute the most in cosmeceuticals. Some bioactive compounds from brown algae exhibit multiple cosmeceutical activities, including phlorotannin, which possesses several activities, such as anti-melanogenic, antioxidant, anti-inflammation, and anti-aging [12,[42][43][44]. Likewise, fucoidan, a sulphated polysaccharide isolated from brown algae, contributes to anti-inflammation, anti-melanogenic and anticancer [45][46][47]. Fucoxanthin, a carotenoid isolated from brown, red, green and microalgae exhibit anti-melanogenic, anti-aging and antioxidant activities [48][49][50]. Mycosporine-like amino acids (MAAs), which are commonly found in red and green seaweeds, and microalgae also contribute to antioxidant, anti-inflammation, and anti-aging [51][52][53]. Other examples of bioactive compounds derived from algae, their applications and mode of actions in cosmeceuticals are presented in Table 1. The chemical structures of some prominent bioactive compounds are shown in Figure 4. Fucoxanthin, a carotenoid isolated from brown, red, green and microalgae exhibit anti-melanogenic, anti-aging and antioxidant activities [48][49][50]. Mycosporine-like amino acids (MAAs), which are commonly found in red and green seaweeds, and microalgae also contribute to antioxidant, antiinflammation, and anti-aging [51][52][53]. Other examples of bioactive compounds derived from algae, their applications and mode of actions in cosmeceuticals are presented in Table 1. The chemical structures of some prominent bioactive compounds are shown in Figure 4.

Anti-Aging Activity
Skin aging can occur through intrinsic and extrinsic mechanisms resulting in dryness, fragility, the formation of wrinkles, fine lines, laxity, and enlarged pores. Intrinsic mechanisms are due to genetic and physiological changes, whereas extrinsic mechanisms are caused by exposure to pollution, UVR, and infectious agents [97]. Extrinsic mechanisms result in the alteration of DNA, which leads to skin damage. UVA rays penetrate more deeply into the skin than UVB rays. Nevertheless, both can cause wrinkle formation or skin-related symptoms [33]. On the other hand, the intrinsic mechanisms involve the production of progerin, a lamin A protein that results in the stimulation of cellular senescence in normal human fibroblasts [132].

Photo-Protectivity and Antioxidant Activities
Damage to cellular components can be caused by ROS [97]. ROS is the initiator of oxidative stress, which include hydrogen peroxide, hydroxyl radicals, radical singlet oxygen, and superoxide anion radicals. It is known that UV radiation associated with the generation of ROS leads to the activation of a signaling pathway, such as MMP1-mediated aging, MAPK/AP-1/NF-κB/tumor necrosis factor (TNF-α)/IL-6-mediated inflammation-induced aging, and p53/BAX/cleaved caspase-3/cytochrome c-mediated apoptosis-induced aging [133]. ROS, that is generated by oxidative stress and can trigger apoptotic cell death, plays an essential role in intrinsic aging and extrinsic aging of the human skin, which eventually lead to skin cancer and inflammatory disorder [12,33,134]. Furthermore, lipid peroxidation of ROS causes the skin to lose its youthful appearance. The presence of antioxidant enzymes, such as catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, thioredoxin oxidase, and peroxiredoxin in skin cells protect them from UV-induced ROS and maintain the epidermal homeostasis [135]. Antioxidants protect skin from UV radiation by preventing membrane lipids, DNA, and protein damages caused by UV-induced ROS. Consequently, researchers are focusing on natural antioxidants derived from algae to avoid oxidation.
Notably, zinc oxide (ZnO) and titanium dioxide (TiO 2 ) are the only FDA-approved inorganic physical UV filters for sun protection to block UV radiation from penetrating the epidermis [137]. However, TiO 2 in nano form in sunscreens that provide occlusive skincare can cause blackhead formation and photoallergic contact dermatitis [138]. It has been reported that cosmetics containing chemical sunscreen ingredients cause phototoxic and photoallergic [138]. Natural UV filters such as algae-derived UV filters from Porphyra umbilicalis prevent UV-induced DNA damage and inflammation, and Codium fragile protects against UVB-induced pro-inflammatory and oxidative stress [138,139].

MMP Inhibition and Prevention of Collagen Degradation
The stimulation of mitogen-activated protein kinase by ROS causes phosphorylation of transcription factor activator protein 1, which results in the upregulation of MMP and eventually degrades skin collagen and leads to skin aging [97]. MMP is produced by keratinocytes, macrophages, fibroblasts, neutrophils, and mast cells. MMPs' functional groups include interstitial collagenases that involve the degradation of Type I, Type II, and Type III collagen, gelatinases that involve the degradation of Type IV and Type V collagen, and stromelysin that degrades proteoglycan, laminin, and fibronectin [136]. UV-induced skin damage can be caused by the gelatinases, MMP-2 and MMP-9 as well. Collagen plays an essential role in maintaining the structural integrity and stability of tissues. The loss of structural protein like Type 1 collagen can result in the formation of wrinkles. Wrinkles are typically induced by intrinsic and extrinsic aging due to the upregulation of MMP-1 and elastase, which result in the breakdown of collagen and elastin [33]. Therefore, compounds with MMP, hyaluronidase and elastase inhibitory activities, and with collagen synthesis could be used in cosmetic products to prevent wrinkling on the skin.
Several studies have been conducted to determine the bioactive compounds in algae that can act as an anti-aging agent. Algae extracts from Meristotheca dakarensis and Jania rubens that produce glycosaminoglycans, Type I and Type III collagen synthesis, and keratin have been marketed [75]. A study on anti-aging by using Pyropia yezoensis (peptide PYP1-5) showed its ability to stimulate collagen synthesis, elastin synthesis, and suppress the expression of MMP-1 protein as well as enhance TGF-β1 protein, which involved in collagen synthesis [106]. Studies have found that the methanol extract of Macrocystis pyrifera contained hyaluronic acid and enhanced the production of syndecan-4, a protein component of the extracellular matrix and useful in anti-aging product [75]. Other examples include Fucus vesiculosus [8], Hizikia fusiformis [18], Sargassum muticum [85], Chlorella vulgaris [117], Haematococcus pluvialis [121], and Undaria pinnatifida [50], which showed that phytochemicals in marine algae are potential anti-photoaging agents in cosmetics.
According to a study by Joe et al. [43], Ecklonia stolonifera had a higher inhibitory effect on nuclear factor-kappa B (NF-κβ) and activator protein-1 (AP-1), which are the transcription factors involved in activating MMP-1 transcription, as compared to other seaweeds. The experiment was carried out by using reporter gene assay with reporter plasmids that contained NF-κB or AP-1. During the study, dieckol and eckol (phlorotannin) were extracted from Ecklonia stolonifera and tested on human dermal fibroblast. The results showed that these compounds inhibited the expression of MMP-1 by interfering with the expression of NF-κB and AP-1. These compounds are also involved in collagen synthesis, ROS inhibition, and cytokine blockade, whereby the findings provided evidence that phlorotannin can reduce the expression of MMP-1 and prevent skin aging.
A study by Kim et al. [83] reported that sargachromanol E derived from Sargassum horneri has been tested on UVA-irradiated dermal fibroblast, whereby it provides protection against UVA-induced collagen degradation by inhibiting MMP expression. It was found that the MMP expression was inhibited by tissue inhibitor of matrix metalloproteinase (TIMP)-1 and TIMP-2, which were treated with sargachromanol E. They demonstrated higher effect as compared to treatment with retinoic acid. It is reported that this compound has no risk of cytotoxicity as LPS-stimulated RAW 264.7 macrophages were still viable even when treated with a high concentration of the compound. Sargachromanol E can inhibit the formation of ROS and lipid peroxidation, and all these provide evidence that this compound is effective in preventing skin aging and could be a potential cosmetic agent.

Anti-Inflammatory Activity
Inflammation is a non-specific response by our body to detect harmful stimuli that could damage the tissue or cause specific diseases. Mechanical injuries, chemical, biological, and physical agents as well as immunological disorders, can induce skin inflammation. Neutrophilic infiltration can damage chromatin and result in DNA mutations or promote intercellular transduction pathway, leading to inflammation. Inflammation is categorized into acute and chronic, whereby acute phase involves the fluid accumulation and an increase in blood flow, leukocyte, and vascular permeability, and chronic phase is associated with the initiation of the immune response [13].
The exposure of skin to UV radiation stimulates inflammatory responses, such as microvascular structural changes, vasodilation, transendothelial migration of leukocyte, and the escape of plasma protein [15]. UV radiation could trigger inflammation by inducing chemical reactions on the skin. The generation of high ROS during skin inflammation is to remove and destroy invading microorganism and to degrade damaged tissues [133]. The patterns of inflammation might vary based on exposure to a specific wavelength of light. UVB radiation is characterized as sunburn-induced erythema in the skin. UVB radiation induces inflammatory responses through mediators, such as nitric oxide, inducible NO synthase, prostaglandin E2, cyclooxygenase-2, tumor necrosis factor-α, and other cytokines, such as interleukin 1 and interleukin 6. These molecules produced in keratinocytes are regulated by NF-κB. NF-κB, which is associated with skin diseases, such as psoriasis, vulgaris, and allergic dermatitis that cause skin dryness, irritation, itching, swelling, redness, and rashes on the affected area [140] as well as induced MMP-1 expression, leading to aging. NF-κB is vital as it regulates telomerase gene expression, inflammation, cellular proliferation, angiogenic, anti-apoptotic, and it is responsible for cellular longevity [133]. Studies reported that Ecklonia kurome and Ecklonia cava extracts have anti-inflammatory effects by inhibiting nitric oxide production [42,61]. Furthermore, Spirulina platensis and Dunaliella salina inhibit nitric oxide synthesis [120,130] and Porphyridium sp. inhibits pro-inflammatory modulator [103]. Other examples of algae that have anti-inflammatory activities include Eisenia bicyclis [42], Ecklonia stolonifera [63], Ishige okamurae [73], Codium fragile [110], Chlamydomonas hedleyi [52], Chlorella vulgaris [118], Ulva lactuca [75], and Undaria pinnatifida [92].

Anti-Melanogenic Activity
Exposure of skin cells to UV radiation results in the production of melanin by melanocytes, as a measure to protect the cells. Melanin is the matured form of melanosome, which moves to keratinocyte and degrades to induce skin tanning and melanization [9,46]. The use of tyrosinase inhibitors is one way to achieve skin hypopigmentation [12,141] as tyrosinase is a key enzyme for the synthesis of melanin, which determines the skin and hair color [136]. Tyrosinase catalyses involve two stages; hydroxylation of L-tyrosine to 3,4-dihydroxy-L-phenylalanine (DOPA) and oxidation 3,4-dihydroxy-L-phenylalanine (DOPA) into dopaquinone [142].
UV radiation excites endogenous chromophores that stimulate ROS and induce DNA damage. DNA damage causes the stabilization of p53, which increases the expression of proopiomelanocortin (POMC). POMC produces an α-melanocyte-stimulating hormone (α-MSH) that acts on the melanocortin 1 receptor (MC1R) of basal melanocytes. Polymorphic variants of MC1R produce the red hair/fair skin phenotype, which results in the inability to tan. Consequently, there is an increase of cAMP and the transcription of microphthalmia-associated transcription factor (MITF). This initiates the transcription of pigmentation genes which synthesizes and transports melanin [140].
Notably, hydroquinone is a skin whitening agent that has been banned from cosmetics due to mutagenicity and its adverse side effects, such as cataract, pigmented colloid milia, exogenous ochronosis, sclera, and nail pigmentation [3,143]. However, naturally occurring hydroquinone, such as arbutin, a hydroquinone glycoside, and aloesin, a C-glycosylated chromone, have been used in the cosmetic industry as a skin whitening agent because of their strong inhibition of tyrosinase enzyme, which is responsible for pigmentation and no side effects were reported [143].
Studies have shown that marine algae possess tyrosinase inhibitor activities, especially brown seaweed that is rich in phloroglucinol, which can chelate copper in this enzyme [12]. Apart from that, phlorotannin (7-phloroeckol) from Ecklonia cava and zeaxanthin from Nannochloropsis oculata have skin whitening activities by inhibiting tyrosinase [44,124]. Another bioactive compound, fucoxanthin from Laminaria japonica, has been treated on UVB-irradiated guinea pigs and melanogenesis in UVB irradiated mice. It was reported that this compound had reduced the tyrosinase activity. Topical treatment of fucoxanthin on mice has down-regulated the mRNA expression of endothelin receptor A, p75 neurotrophin receptor, melanocortin 1 receptor (MC1R), and prostaglandin E receptor 1, resulting in the suppression of cyclooxygenase (COX)-2 expression, which interferes with prostaglandin in the epidermis [48]. The study reported that fucoxanthin suppressed the tyrosinase mRNA expression. However, the suppression was not significant. Interestingly, they found that fucoxanthin suppressed tyrosinase-related protein 1 (TRP1) instead of tyrosinase. They also demonstrated that the pigmentation in the guinea pigs was suppressed by a daily consummation of fucoxanthin of about 0.001% through their diet [39,48]. Furthermore, the oral treatment of fucoxanthin can inhibit transcription for melanogenesis by repressing mRNA expression of COX-2, p75NTR, EP1, and MC1R [39]. The findings showed that fucoxanthin has anti-pigmentary effect by suppressing prostaglandin E2 synthesis and melanogenic stimulant receptors [39,48].

Anticancer Activity
Skin cancer is categorized into basal cell carcinoma, melanoma, and squamous cell carcinoma. Melanoma is the most common skin cancer, which is derived from melanocytes. Melanoma appears in brown, black, pink, or red shades and induces itchiness as well as bleeding. One of the common factors that lead to skin cancer is prolonged exposure to UV radiation [16]. UV radiation can trigger DNA mutations, such as converting cytosine to thymine that results in the formation of dimers. These mutations affect the functions of oncogene (bcl-2) and tumor suppressor gene (p53), an important housekeeping gene, and causes the cell cycle to be out of control; thus, transformed keratinocyte and melanocyte. This expression leads to the development of precursor lesions such as actinic keratosis, and the progression of this expression eventually results in squamous cell carcinoma, basal cell carcinoma, or melanoma by the accumulation of additional genetical alterations [144]. UV radiation can also alter signal transduction that affects mutation indirectly; for instance, by reducing the time taken for DNA repair or reducing the level of the enzyme that protects the cells from UV damage [144]. Accordingly, UV radiation is one of the common factors that cause skin cancer. The use of sunscreen, which could decrease the exposure to UV radiation is an effective method to prevent skin cancer. Previous studies reported that Ascophyllum nodosum [54], Fucus evanesens [45], Stoechospermum marginatum [89], Porphyra yezoensis [51], Haematococcus pluvialis [122], and Skeletonema marinoi [129] have anticancer activities, such as inhibiting cell proliferation, inducing apoptosis, preventing ROS production, reducing the expression of MMP, or by activating caspase.
A study by Hwang et al. [40] investigated the effect of dietary feeding and topical application of polyphenol extracted from brown algae on UVB radiation-induced skin carcinogenesis in SKH-1 mice. The results demonstrated that dietary feeding (0.1%) and topical application (3 mg) of polyphenol significantly reduced tumor multiplicity by 45% and 60%, respectively. Therefore, it was concluded that topical application of polyphenol gave a better impact on inhibiting skin cancer compared to dietary feeding. Interestingly, increasing the concentration of polyphenol in the topical application decreased its ability to reduce tumor multiplicity. The result showed that both dietary feeding and topical treatment of brown algal polyphenols, phlorotannin suppressed cyclooxygenase-2 (COX-2) expression and cell proliferation, which implies that polyphenol acts as an anticancer agent [12]. The study reported that UV radiation induces COX-2 expression and elevates the level of prostaglandin E2 (PGE2) [40]. PGE2 binds to G-protein receptors, such as EP1, EP2, and EP4, involves in tumor cell proliferation, inhibits apoptosis, facilitates immunosuppression and tumor invasions as well as stimulates the inflammatory response, which eventually induces skin cancer [145].

Antimicrobial Activity
Microbiological purity of cosmetics is one of the main problems faced by the cosmetic industry. Microbiological impurities increase the risk of infection to users and cause physicochemical changes in the cosmetic properties such as odor change, effectiveness, color and phase separation in solutions. In order to solve this issue, chemical compounds were added as preservatives to inhibit microorganism contamination and to maintain the physicochemical stability of the cosmetic products. However, the presence of synthetic preservatives (parabens, benzyl alcohol, and tetrasodium ethylenediaminetetraacetic acid) causes allergies to users; hence, natural preservatives are in demand to replace synthetic preservatives [146,147].
Some preservatives were considered toxic; therefore, the application and selection are strictly regulated by law and regulations in many countries [148]. Algae extracts are the promising preservative agents that can be used in cosmetics to prevent microbial, environmental, and personal contamination. In particular, the phenolic compound that improves the shelf-life of cosmetic products by inhibiting the growth of microorganisms [149]. In addition, antibacterial compounds derived from macroalgae can fight acne and chronic wounds. Kamei et al. [150] suggested that Sargafuran derived from Sargassum macrocarpum that showed antibacterial activity against Propionibacterium acnes might be useful as a lead compound for developing new skincare cosmetics to prevent acne.
The bioactive compound from algae such as phlorotannin contributes to antibacterial activity by inhibiting oxidative phosphorylation and binding to bacterial proteins, such as enzyme and cell membrane, which lead to cell lysis [128]. Algal polysaccharides that contain glycoprotein-receptor on their surface bind with the bacterial cell wall, cytoplasmic membrane, and DNA which increase the permeability of the cytoplasmic membrane and cause protein leakage. In addition, fatty acids derived from algae act as electron transport chain and oxidative phosphorylation inhibitors in the bacterial cell membrane. Subsequently, they interfere with the adenosine triphosphate energy transfer and inhibit enzymes such as bacterial enoyl-acyl carrier protein reductase that is necessary for the synthesis of fatty acids within the bacterial cell. This eventually causes cell lysis.

Challenges of Algae in Cosmeceuticals
A study conducted by Klaschka [151] reported that there were 1358 natural substances listed in the International Nomenclature of Cosmetic Ingredients (INCI), of which, 369 were considered hazardous substances (i.e., 257 to the skin, 182 to the aquatic environment, and 53 with carcinogenic property). Evidently, none of the products is 100% safe to be used in cosmetic products. However, consumers have changed their preference and more inclined towards natural products, as it is less harmful compared to chemicals-based cosmetics. A diverse range of bioactive metabolites derived from marine algae has been given much importance in cosmetic products due to their multidirectional effects on the skin [9,12,136]. Algae are considered safe as they have negligible cytotoxicity effects when tested on human cell lines [24] and can be bioprocessed using eco-friendly novel extraction techniques [152]. They contain many bioactive compounds and fatty acids that are useful not only in the cosmetic sector, but also in biofuel production, wastewater treatment, CO 2 sequestration, and oxygen release into the atmosphere, which eventually reduce the greenhouse effect [8]. In addition, algae are used in the food and pharmaceutical industry to develop food supplements for preventing neurodegenerative diseases [153]. By-products produced by these industries could also be a promising source of compounds with biological properties that are favorable for skin applications [149]. By doing these, algae could be an efficacious and cost-effective alternative to synthetic products. However, there are some challenges in using algae as a cosmeceutical ingredient, such as (i) biomass culturing techniques, (ii) metabolites extraction methods, and (iii) Quality assurance and regulations.

Biomass Culturing Techniques
Large scale algae cultivation requires optimum conditions, such as light intensity, pH control, free of contamination, nutrients availability, the presence of CO 2 , salinity, inorganic carbon, temperature, and nutrients [8,154]. In addition, the type of bioreactor used for algae cultivation is designed based on the type of algae and the purpose of culture. Algae are usually harvested from natural habitats (e.g., Nostoc sp. in Asia) or by cultivation under certain conditions [152]. Land cultivation near the sea is typically open cultivation such as tanks or ponds. Culturing algae in an open system is inexpensive, but it can be contaminated easily. Algae can be cultured by using seawater instead of freshwater, which enhances the production of lipids and other nutrients while reduces cost [154]. Nevertheless, this could be a challenge as well since open cultivation requires extensive use of seawater and the cost for the construction, operation and maintenance of the ponds or tanks is substantial. Open cultivation can cause interferences between algae cultures and the biotic and abiotic environments resulting in low quality of algae produced [155]. Closed cultivation of algae involves stirred tank reactors and closed bubble column photobioreactors for cultivating algal tissue [156]. Thus far, this method has not been able to produce large scale production. However, a study by Sebök et al. [157] designed a ring-shaped cultivation vessel that is better than cultivation tanks, as it can decrease the cost by reducing the usage of cultivation medium and eliminate the interference of the environment. Nevertheless, they reported that the algae initial growth rate is low until the optimal growth condition is determined.

Biometabolites Extraction Methods
Biometabolites extraction methods can be categorized into conventional and novel techniques. Conventional methods comprise saponification, maceration, soxhlet extraction, classical solvent extraction; whereas novel extraction methods include enzyme-assisted extraction (EAE), microwave-assisted extraction (MAE), supercritical fluid extraction (SFE), and ultrasound-assisted extraction (UAE) [152]. The novel techniques application is preferred as it offers several advantages including low extraction time, minimum usage of solvents, higher extraction yields, and quality.

Enzyme-Assisted Extraction (EAE)
EAE is a safe and eco-friendly approach for extracting algae metabolites. EAE uses enzymes (e.g., peptidase, glucosidase, and carbohydrase) to disrupt the cell wall of algae to release the intracellular bioactive metabolites. This method can also remove the barriers of water solubility and insolubility of bioactive compounds, preserve the original efficacy of bioactive compounds and provide high catalytic efficiency [152,158]. Previous studies had proven that EAE is applicable for recovering different bio-compounds using selected enzymes, for instance, using alginase lyase enzyme to extract fucoxanthin from Undaria pinnatifida, and carbohydrases and proteases to extract antioxidants from Sargassum horneri [158,159]. The limitation of this method could be the cost of enzymes, lack of substrate-specific enzymes, and difficulty in maintaining bioreactor conditions [158]. Hyphenated extraction technologies can be adopted to overcome these limitations [160].

Microwave-Assisted Extraction (MAE)
MAE can be operated in open and closed vessels. Open vessels are safer, effective, and able to process larger samples. MAE is environmentally friendly and economical because of the reduction of extraction time and minimization of the solvent consumption. Studies have reported that MAE has successfully extracted polyphenols from Enteromorpha prolifera [161] and polysaccharides from Fucus vesiculosus [162]. However, high power, temperature, and pressure tend to degrade and reduce the yield of the phenolic compounds. Low pressure exhibits less destruction on the structure of algae, resulting in a lower yield of polysaccharides released from the cells. In addition, an increase in time can increase the yield, but at the same time, excessive time can cause degradation of polysaccharide. MAE is a preferred method for extracting ulvan and rhamnan sulfate as the use of toxic solvents can be eliminated [163].

Supercritical Fluid Extraction (SFE)
SFE uses carbon dioxide as a solvent because of its nontoxicity and low cost. Supercritical carbon dioxide (SC-CO 2 ) extraction is applicable for extracting non-polar compounds, such as fatty acids, phenolic, phytosterols, triglycerides, tocopherols, and carotenoids [163]. According to past studies, this method isolated mostly phenolic compounds and carotenoid from Cladophora glomerata, Ulva flexuosa, Chara fragilis, and Gracilaria mammillaris [164]. Ethanol has been used as co-solvent to increase the extraction efficiency of phenolic compounds and carotenoids compared to the use of SC-CO 2 alone [163,165].

Ultrasound-Assisted Extraction (UAE)
UAE is usually used to extract phenolic compounds. The efficiency of UAE is influenced by temperature, time, and the power of an ultrasonic bath. Higher temperature facilitates in increasing the yield, and optimum extraction time is also required to prevent the degradation of phenolic compounds. UAE with acid as a solvent can extract laminarin from algae. One of the challenges faced by the UAE is cell disruption for the release of biomolecules [163]. The combination of two extraction techniques, such as maceration and ultrasonication, resulted in the highest yield and efficiency of extracting phycobiliproteins from Gelidium pusillum [166].

Quality Assurance and Regulations
Quality control and standardization of cosmetic products are crucial to ensure the safety, efficacy, and quality of products and its raw material. Some algae are high-value cosmetic raw materials, and it is essential to evaluate the presence of heavy metal like arsenic, mercury, lead and cadmium, pesticides, such as organochlorine, allergens, toxins, and other chemical contaminations in the algae samples. The level of contaminations must be low, as set by the World Health Organization and US Food and Drug Administration, for instance, lead and arsenic 10 ppm, mercury 1 ppm, and cadmium 0.3 ppm [152]. One of the precautions to be considered in developing cosmetic products is that certain drugs have side effects of phototoxicity. This is due to the presence of phototoxin or photoallergen, which is activated following skin contact and light exposure, known as phytophoto contact dermatitis. Many of these compounds are generators of singlet oxygen and other ROS [167]. Photoallergen such as chlorophyll can be categorized into four types, namely chlorophyll a in algae and cyanobacteria; chlorophyll b in green algae; chlorophyll c in brown algae, diatoms, dinoflagellates; and chlorophyll d in red algae [168]. Consumers are unaware that natural-based cosmetic products are made up of a complex mixture of natural raw materials and chemical compounds, which might develop potential adverse human health effects. Cyanotoxins, a metabolite derived from algae, has been reported to have toxic effects on the immune and brain cell; however, it could be used in agriculture as pesticides [169,170]. Bioaccumulation of algal toxins, such as aplysiatoxin, debromoaplysiatoxin, lingbyatoxin, and lipopolysaharide endotoxin, can also affect animal health [171]. Thus, a clinical study has to be carried out to determine the safety and efficacy of these compounds on human [151].

Conclusions and Future Studies
Cosmeceutical industries are exploring new compounds derived from natural products due to consumers' demand, as synthetic cosmetic products are evidently causing adverse side effects on human. The current review focused on the importance of algae-derived compounds in cosmeceutical (e.g., antioxidant, anti-melanogenic, anticancer, anti-aging, antimicrobial, and anti-inflammation), scientific evidence of their commercial value, and their challenges and limitations. The current findings revealed that brown algae contributed the most in cosmeceuticals, followed by red algae, microalgae, and green algae. Furthermore, most of the algae possess antioxidant activities due to their ability to live in stress conditions. Interestingly, a diverse range of bioactive compounds, such as pigments, polysaccharides, phenol, lipids, and proteins have been isolated from algae for the cosmeceutical industry. In conclusion, bioactive compounds derived from algae possess antioxidant, anti-inflammation, anti-pigmentation, anti-aging, and anticancer activities; thus, they can be used as active ingredients in cosmetic formulations. Apart from that, natural compounds from algae are effective to be used in cosmeceuticals as they are less harmful to the skin compared to synthetic compounds. However, the exact mechanisms of these compounds in performing the biological functions have not been fully explored. Therefore, further studies are essential to understand the cell-signaling pathway and the exact mechanisms of the compounds. In order to improve the quality of cosmetic products, more clinical trials have to be carried out to determine skin absorption, irritation, genetic and phototoxicity, and allergens contents.