Bioactive Metabolites from Marine Algae as Potent Pharmacophores against Oxidative Stress-Associated Human Diseases: A Comprehensive Review

In addition to cancer and diabetes, inflammatory and ROS-related diseases represent one of the major health problems worldwide. Currently, several synthetic drugs are used to reduce oxidative stress; nevertheless, these approaches often have side effects. Therefore, to overcome these issues, the search for alternative therapies has gained importance in recent times. Natural bioactive compounds have represented, and they still do, an important source of drugs with high therapeutic efficacy. In the “synthetic” era, terrestrial and aquatic photosynthetic organisms have been shown to be an essential source of natural compounds, some of which might play a leading role in pharmaceutical drug development. Marine organisms constitute nearly half of the worldwide biodiversity. In the marine environment, algae, seaweeds, and seagrasses are the first reported sources of marine natural products for discovering novel pharmacophores. The algal bioactive compounds are a potential source of novel antioxidant and anticancer (through modulation of the cell cycle, metastasis, and apoptosis) compounds. Secondary metabolites in marine Algae, such as phenolic acids, flavonoids, and tannins, could have great therapeutic implications against several diseases. In this context, this review focuses on the diversity of functional compounds extracted from algae and their potential beneficial effects in fighting cancer, diabetes, and inflammatory diseases.


Introduction
Epidemiological studies have evidenced the dangerous effects on human health of the ever-increasing intake of junk food, alcohol, and antibiotics. This bad behavior can increase the risk of oxidative stress which, in turn, can lead to accelerated aging and inflammatory diseases, such as cardiovascular and neurodegenerative disease and many types of cancer [1]. According to reports by the WHO, more than 200 types of lethal cancer accounted approximately for 9.6 million deaths per year in 2019 globally [2]. Similarly, diabetes mellitus, a metabolic disorder, has emerged as the third foremost cause of death worldwide (1.6 million deaths per year) with several associated ill-fated diseases, such as heart attack, stroke, kidney failure, high blood pressure, blindness, and lower Figure 1. Potential beneficial effects of algal metabolites on human health. Secondary metabolites in marine algae could provide novel drug candidates for fighting various diseases, e.g., by reducing the α-amylase and α-glucosidase activity in diabetes; by reducing inflammation thanks to their antioxidant capacity; and inhibiting cellular proliferation in tumor cells.

Biological Activities of Marine Algae and Potential Health Benefits via Dietary Supplements
Diet plays an important role in disease prevention as more than 33% of diseases, such Figure 1. Potential beneficial effects of algal metabolites on human health. Secondary metabolites in marine algae could provide novel drug candidates for fighting various diseases, e.g., by reducing the α-amylase and α-glucosidase activity in diabetes; by reducing inflammation thanks to their antioxidant capacity; and inhibiting cellular proliferation in tumor cells.

Biological Activities of Marine Algae and Potential Health Benefits via Dietary Supplements
Diet plays an important role in disease prevention as more than 33% of diseases, such as cancer, diabetes, and inflammation-associated chronic diseases, could be avoided by changing lifestyle and food habits [19,20]. Nutritional supplements from natural sources could also play an important role in preventing diseases. Phytochemicals from marine algae, such as peptides, amino acids, lipids, fatty acids, sterols, polysaccharides, carbohydrates, polyphenols, photosynthetic pigments, vitamins, and minerals, some of which are represented in Figure 2, can act as potent antioxidants and have beneficial effects as anti-diabetic and chemotherapeutic drugs, as detailed below.

Peptides and Amino Acids
Hydrolysis of proteins can lead to bioactive peptides that can present beneficial health aspects and modulate the outcome of the disease. Bioactive phyto-peptides have 3 to 20 amino acid residues and display biological properties such as antioxidant, anti-

Peptides and Amino Acids
Hydrolysis of proteins can lead to bioactive peptides that can present beneficial health aspects and modulate the outcome of the disease. Bioactive phyto-peptides have 3 to 20 amino acid residues and display biological properties such as antioxidant, anticancer, anti-inflammation, and immunomodulation. For example, purified peptides from Chlorella vulgaris can prevent cellular damage and can act as potent anticancer agents [21,22].
The protein content in macro and micro algae comprises all essential amino acids which prevent cellular damage. The red alga Palmaria palmata is rich in Leu, Val, and Met, and their mean levels are similar to ovalbumin. Similarly, Ile and Thr concentrations are comparable to those in legume proteins. The green alga Ulva rigida contains Leu, Phe, and Val as major essential amino acids [23,24].

Lipids and Fatty Acids
The structural complexity of lipids and fatty acids are highly diverse and contribute to their therapeutic efficacy. It has been reported that small amounts of saturated fatty acids can help prevent cardiovascular diseases. Marine algae contain polyunsaturated fatty acids (PUFAs) and significant amounts of monounsaturated fatty acids which are beneficial to human health and could help reduce cardiovascular diseases [25].

Polyunsaturated Fatty Acids (PUFAs)
Humans are incapable of synthesizing PUFAs that, on the other hand, are abundant in both macro and microalgae. PUFAs in microalgae are mainly composed of omega-3 and omega-6 fatty acids (e.g., EPA and AA) [26]. PUFAs regulate blood clotting and blood pressure and modulate the function of the brain and nervous systems [27]. Moreover, they decrease the risk of several chronic diseases, such as diabetes and cancer. Additionally, they regulate inflammatory responses by producing eicosanoids, well-known inflammation mediators [27]. Omega-3 and omega-6 PUFA from macroalgae are already used as dietary supplements [28]. Red and brown algae have a high level of omega-3 fatty acids (e.g., EPA and GLA) and omega-6 fatty acids (e.g., AA and linoleic acid). Brown algae Laminaria ochroleuca and Undaria pinnatifida are a rich source of octadecatetraenoic acid, an omega-3 PUFA [29]. Green seaweed Ulva pertusa was found to be rich in hexadecatetraenoic (omega-3), oleic (omega-9), and palmitic acids (SFA). The lipid fraction of microalgae C. vulgaris contains oleic, palmitic, and linolenic acids. The green microalga Haematococcus sp. also contains short-chain fatty acids. Long-chain PUFAs are also used as nutritional supplements and food additives [30]. Spirulina sp. is a promising source of GLAs, a precursor of leukotrienes, prostaglandins, and thromboxans that regulate inflammatory, immunological, and cardiovascular disorders. Cyanobacteria and some green algae also contain bioactive fatty acids such as palmitic, oleic, and lauric acids along with DHA [22].

Sterols
Sterols are a class of lipids extensively found in both macro and microalgae. Sterols and some of their derivatives have potential biological, e.g., anti-inflammatory, activity. Sterols from Spirulina triggers the formation of the plasminogen-activating factor in vascular endothelial cells. Fucosterol, ergosterol, and chondrillasterol are found in brown algae and cholesterol has been found in red algae [22,31].

Polysaccharides and Carbohydrates
Polysaccharides are abundant in seaweeds and also found in microalgae. They generally comprise about 4% to 76% of the total dry weight of the alga. Polysaccharides are classified according to their chemical structure, such as sulfuric acid polysaccharides, sulfated xylans, and galactans (generally found in green algae). Moreover, alginic acid, fucoidan, laminarin, and sargassan are found in brown algae [32]. Agar, carrageenans, xylans, and floridean are generally found in red algae. Many algal polysaccharides present bioactivity and could become drug candidates with potential use in several human health disparities [33]. Carrageenans are sulfated galactans and they are extensively used in pharmaceutical and food industries. Soluble fibers such as fucans, alginates, and laminarans are found in brown seaweeds, whereas soluble fibers such as sulfated galactans (agars and carrageenans), xylans, and floridean starch are abundantly found in red seaweeds [34]. Green algae contain xylans, mannans, starch, and ionic sulfate group-containing polysaccharides in combination with uronic acids, rhamnose, xylose, galactose, and arabinose. Many of the polysaccharides can be regarded as dietary fibers and are classified into two groups, i.e., soluble and insoluble fibers [35,36]. Seaweeds contain about 25% to 75% dietary fibers in comparison to their dry weight, a higher percentage compared to that found in fruit and vegetables [37]. The algal dietary fiber consumption has several health benefits as they can be used as antitumor, anticancer, anticoagulant, and antiviral agents. Fucoidans are extensively found in the cell walls of brown macroalgae [38]. Fucoidans have several biological activities and act as antioxidant, antitumor, anti-inflammatory, antidiabetes, antiviral, anticoagulant, and antithrombotic agents. Additionally, they also modulate the human immune system [1]. Furthermore, laminarin is the second main source of glucan, abundantly found in brown algae, and it acts as a facilitator of intestinal metabolism [36].
Carbohydrates, such as glucose and starch, are abundantly found in microalgae [39]. Many biological functions of microalgal species are due to the presence of carbohydrates. Chlorella pyrenoidosa and Chlorella ellipsoidea contain glucose and a wide variety of combinations of galactose, mannose, rhamnose, N-acetylglucosamine, N-acetylgalactosamine, and arabinose that exert immune-modulatory and antiproliferative activity [40]. β-1,3-Glucans extracted from Chlorella have been shown to act as immunomodulators that can reduce blood lipids [41].

Polyphenolic Compounds
Marine algal bioactive compounds are potent antioxidant agents that protect from oxidative damage [42]. The antioxidant activity of bioactive compounds from marine algae is associated with protection against cancer, inflammatory, diabetes, and several ROS-related diseases [43]. Polyphenolic compounds are mainly found in both micro and macroalgae [42]. The phenolic components include hydroxycinnamic acids, phenolic acids, simple phenols, xanthones, coumarins, naphthoquinones, stilbenes, flavonoids, anthraquinones, and lignins [21]. The phlorotannins with potential antioxidant activity belong to polyphenolic compounds that have been screened from several brown algae. Phlorotannins are known for their chemopreventive, antibacterial, antiproliferative, and UV-protective properties [22].

Photosynthetic Pigments
Macroalgae contain chlorophylls and carotenoids as major photosynthetic pigments. Carotenoids are well known for their antioxidant properties and dietary carotenoids have high nutritional and therapeutic value [44]. Carotenoids are well known for their chemopreventive effect against several cancer subtypes. Microalgae are also the main source of antioxidants such as β-carotene and astaxanthin. β-Carotene is a natural colorant that has been conventionally used as food and drinks colorants and can act as dietary food supplements or additives with a high antioxidant capacity [45].

Vitamins and Minerals
Vitamins are micronutrients essential for human body growth and development. Seaweeds and microalgae are known to be a good source of vitamin B1, B2, and B12. Vitamin B12 (cobalamin) is extensively found in higher concentrations in green and red algae compared to brown algae [46]. Vitamin B12 is generally found in red macroalgae such as Palmaria longat and Porphyra tenera. The highest vitamin B12 content was found in red seaweed Porphyra sp. and green algae, such as Enteromorpha sp. and Spirulina. Cobalamin deficiency can cause health diseases, such as neuropsychiatric disorders and megaloblastic anaemia. Vitamin C (ascorbic acid) is present in all red, brown, and green seaweeds. Vitamin C has several health benefits, such as radical scavenging activity, antiaging, and im-mune stimulant activity. Vitamin E is a mixture of tocopherols. α Tocopherol occurs in green, red, and brown seaweeds. Phaeophyceae also contain βand γ-tocopherols and displayed outstanding antioxidant activity. Vitamins C and E were also found in Laminaria digitata and U. pinnatifida [22].
Seaweeds and macroalgae are rich in minerals, trace elements, and maintain inorganic atoms in seawater. Minerals and trace elements are required for the human diet [47]. Phaeophyceae, such as U. pinnatifida and Sargassum, and rhodophyta, such as Chondrus crispus and Gracilariopsis, are considered dietary supplement that meet the recommended daily intake of some of the major minerals, such as Na, K, Ca, and Mg, as well as trace minerals, such as Fe, Zn, Mn, and Cu. In addition, seaweeds are also important sources of Ca as they reduce Ca deficiency risk in pregnant women and adolescents and they inhibit preadolescent aging [48].

Marine Bioactive Metabolites and Their Therapeutic Efficacy
The marine ecosystem is a source of novel natural secondary metabolites with promising biomedical applications [49]. The impact of marine algae in the area of traditional medicine is huge and they have been used as Yunani hakim in many countries, such as China and Egypt. Marine algae produce diverse secondary metabolites and might be the most promising sources of proteins, vitamins, omega-3, carotenoids, phenolic acids, and flavonoids, as well as other natural antioxidants [50]. These marine bioactive compounds act as free radical scavengers and prevent oxyradical formation thus reducing oxidative stress and, as such, they have great importance in the prevention of cancer, diabetes, early aging, and several other inflammatory diseases ( Figure 3). aging, and immune stimulant activity. Vitamin E is a mixture of tocopherols. α-Tocopherol occurs in green, red, and brown seaweeds. Phaeophyceae also contain β-and γ-tocopherols and displayed outstanding antioxidant activity. Vitamins C and E were also found in Laminaria digitata and U. pinnatifida [22]. Seaweeds and macroalgae are rich in minerals, trace elements, and maintain inorganic atoms in seawater. Minerals and trace elements are required for the human diet [47]. Phaeophyceae, such as U. pinnatifida and Sargassum, and rhodophyta, such as Chondrus crispus and Gracilariopsis, are considered dietary supplement that meet the recommended daily intake of some of the major minerals, such as Na, K, Ca, and Mg, as well as trace minerals, such as Fe, Zn, Mn, and Cu. In addition, seaweeds are also important sources of Ca as they reduce Ca deficiency risk in pregnant women and adolescents and they inhibit preadolescent aging [48].

Marine Bioactive Metabolites and Their Therapeutic Efficacy
The marine ecosystem is a source of novel natural secondary metabolites with promising biomedical applications [49]. The impact of marine algae in the area of traditional medicine is huge and they have been used as Yunani hakim in many countries, such as China and Egypt. Marine algae produce diverse secondary metabolites and might be the most promising sources of proteins, vitamins, omega-3, carotenoids, phenolic acids, and flavonoids, as well as other natural antioxidants [50]. These marine bioactive compounds act as free radical scavengers and prevent oxyradical formation thus reducing oxidative stress and, as such, they have great importance in the prevention of cancer, diabetes, early aging, and several other inflammatory diseases ( Figure 3).  Marine bioactive compounds, such as algal photosynthetic pigments, phycobiliproteins, carotenoids, polyphenols, terpenes, phlorotannins, and polysaccharides, have shown promising therapeutic activity in both in vitro and in vivo models [25,29,38,51].

Marine Bioactive Metabolites and Modulation of In Vitro Antioxidant Activity
Reactive oxygen species (ROS) comprise a group of oxygenic ions that are highly reactive and pose a serious threat to biological components, ultimately leading to serious disorders such as cancer, diabetes mellitus, neurodegenerative and inflammatory diseases [52]. The oxygen-containing radicals comprise of peroxyl ( , and nitric oxide (NO • ) radical, as well as non-radical oxidizing agents such as singlet oxygen ( 1 O 2 ), hydrogen peroxide (H 2 O 2 ), hypochlorous acid (HOCl), and organic hydroperoxides (ROOH) [52][53][54][55]. Cells can detoxify ROS as they are furnished with antioxidant defense mechanisms to maintain cellular equilibrium. Antioxidants fight against ROS and exert a positive effect on human health by protecting macromolecules such as proteins, DNA, and membrane lipids [56]. The use of synthetic antioxidants used as food additives, such as butylated hydroxyanisole, butylated hydroxytoluene, tertiary-butylhydroquinone, and propyl gallate, might represent a threat because of their side effects [57]. Hence, the development of novel antioxidants from natural sources like marine flora can represent a promising approach. Marine algae could neutralize ROS because of their antioxidant compounds, such as phycobilins, phycocyanin, carotenoids, astaxanthin, polyphenols, and vitamins, which can act against cancer, diabetes, inflammation, aging, and immune responses. The antioxidant capacity of various marine algae, such as green, red, and brown algae species, has been already extensively reported in the literature.

Intricate Role of Algal Bioactive Metabolites as Anticancer Agents
Free radicals and ROS generally promote cancer initiation. Synthetic chemopreventive drugs often present several adverse side-effects to the tumor vicinity and bodily organs because of poor specificity and generalized biodistribution [65]. Several marine algal bioactive compounds have been designated as potent chemopreventives due to inhibition of cellular proliferation, modulation of the cell cycle, and induction of apoptosis [66,67].

Inhibition of Cell Proliferation
Several studies have reported that marine algal bioactive compounds have antiproliferative and inhibitory activity against several cancer subtypes in in vitro as well as in vivo [68]. Sulfated polysaccharides purified from brown seaweeds exhibited an antiproliferative effect on human leukemia and lymphoma cell lines [38]. They have also been reported to inhibit proliferation of breast (MCF-7) and cervical (HeLa) cancer cells [38]. Sulfated polysaccharides extracted from the brown seaweed Sargassum vulgare displayed inhibition of cell proliferation in HeLa and B16 cells without cytotoxicity in normal rabbit aortic endothelial cells [69]. Furthermore, sulfated polysaccharides from red seaweed Amansia multifidi inhibited the cellular viability of HeLa cells. The polysaccharides isolated from Gracilariopsis lemaneiformis, consisting of 3,6-anhydro-L-galactose and D-galactose and a linear structure of repeated disaccharide agarobiose units, hindered the viability of B16, A549, and MKN-28 cell lines [70]. Similarly, low-molecular-weight sulfated polysaccharides from green seaweed Gayralia oxysperma inhibited the cell viability of U87MG glioblastoma cells even at microgram-level concentrations (10, 100, and 1000 µg/mL) without any evident cytotoxicity [71]. Fucoidans isolated from Undaria pinnatifida also showed inhibition of cellular viability in SK-MEL-28, T-47, RPMI-7951, T47D, and DLD-1 cancer cell lines at microgram concentrations. Moreover, fucoidans isolated from the sporophyll of U. pinnatifida demonstrated to be able to inhibit cell growth in HeLa, A549, PC-3, and HepG2 cell lines, although at higher concentrations (treatment with 0.8 mg/mL for 24 h) [72]. Furthermore, in prostate cell lines (DU-145), fucoidans treatment marked a 90% reduction in cell viability [73]. Similarly, Fucus vesiculosus derived fucoidans were reported to reduce cell viability of human colorectal carcinoma (HCT116) cell line by 60% [74]. Fucoidan from Ecklonia cava have been also reported to inhibit proliferation of MDA-MB-231 cells. Moreover, the administration of fucoidan (20 mg/kg for 28 days) in a DU-145 cell-induced xenograft rat model has reduced the tumor growth by 50% [73]. Carrageenans from Kappaphycus alvarezii reduced the growth of liver, colon, breast, and osteosarcoma cell lines [75]. Similarly, treatment of phlorotannins (a type of polyphenol) isolated from E. cava has marked a reduction in cell viability in MDA-MB-231 and MCF-7 cells by 55% and 64%, respectively [76]. Similarly, phlorotannin-rich extracts from Ascophyllum nodosum reduced the cell viability of HT-29 colon cancer cells [77].

Cell Cycle Arrest and Inhibition of Angiogenesis
Inhibition of cell cycle hinders cancer cell proliferation for the subsequent exhibition of anticancer activity. Sulfated polysaccharides from G. oxysperma arrested the cell cycle [71]. Fucoidan from Fucus vesiculosus arrested the cell cycle at the G1 phase in HCT116 human colorectal carcinoma and HT-29 colon cancer cells [74]. Fucoxanthin arrested the cell cycle via downregulation of cyclin D1, D2, CDK4 and upregulation of p15INK4B and p27Kip1 expression [90]. Fucoxanthin from Laminaria japonica arrested the sub-G1 phase of the cell cycle in WiDr cancer cells [91]. Moreover, in LNCap prostate cancer cells, fucoxanthin arrested the G1 phase of the cell cycle via MAPK/ JNK and GDD45A pathways [92]. Pheophorbide a, from G. elliptica arrested the cell cycle in the G0/G1 phase in glioblastoma cells [93]. Aqueous extract of G. tenuistipitata induced G2/M arrest in the H1299 cell line [64]. Angiogenesis plays a key role in tumor growth and metastasis. Polysaccharides isolated from S. vulgare exhibited angiogenesis inhibitory activity. Fucoidans isolated from U. pinnatifida significantly reduced the expression of the angiogenesis factors VEGF-A and VEGF-162 [94]. Sulfated polysaccharides from brown seaweed Sargassum vulgare displayed antiangiogenic activity in HeLa and B16 cells without damage to the tumor vicinity [69]. Furthermore, dieckol decreased the expression of angiogenic markers such as PCNA, VEGF, COX-2, MMP-2, and MMP-9 to inhibit metastasis [95].

Induction of Apoptosis
Apoptosis (or programmed cell death, PCD) is the main goal of anticancer drugs. Several reports have demonstrated the role of algal bioactive compounds and polysaccharides as potent anticancer agents by modulating apoptosis, as schematized in Figure 4. Sulfated polysaccharides from Phaeophyceae act as novel chemopreventive drugs owing to their free-radical scavenging activity [1]. Sulfated polysaccharides induced apoptosis in human leukemic monocyte lymphoma cell line (U-937) [1]. Polysaccharides from Capsosiphon fulvescens induced apoptosis in gastric cancer cells via modulation of PI3K/Akt pathway [96]. Polysaccharides from U. lactuca increased the activity of antioxidant enzymes in a DMBA-induced breast cancer model via diminished lipid peroxidation as well as GSH-Px activity to restrain apoptosis [97]. Polysaccharides from red seaweed Champia feldmannii demonstrated in vivo antitumor effects in mice transplanted with sarcoma 180 tumors via modulation of apoptosis [98]. The polysaccharides isolated from sea lettuce U. lactuca displayed in vitro and in vivo anticancer activity in breast cancer via modulation of apoptosis. It also displayed a chemopreventive effect in DMBA-induced breast cancer in rat post-administration for 10 weeks and prevented breast-histological alterations and carcinogenic wounds. Additionally, it also amplified the p53 expression and inhibited the Bcl-2 expression to induce apoptosis in breast cancer cells [97].

Induction of Apoptosis
Apoptosis (or programmed cell death, PCD) is the main goal of anticancer Several reports have demonstrated the role of algal bioactive compounds and polys rides as potent anticancer agents by modulating apoptosis, as schematized in Fig  Sulfated polysaccharides from Phaeophyceae act as novel chemopreventive drugs ow their free-radical scavenging activity [1]. Sulfated polysaccharides induced apopt human leukemic monocyte lymphoma cell line (U-937) [1]. Polysaccharides from siphon fulvescens induced apoptosis in gastric cancer cells via modulation of PI3 pathway [96]. Polysaccharides from U. lactuca increased the activity of antioxida zymes in a DMBA-induced breast cancer model via diminished lipid peroxidation a as GSH-Px activity to restrain apoptosis [97]. Polysaccharides from red seaweed C feldmannii demonstrated in vivo antitumor effects in mice transplanted with sarcom tumors via modulation of apoptosis [98]. The polysaccharides isolated from sea lett lactuca displayed in vitro and in vivo anticancer activity in breast cancer via modu of apoptosis. It also displayed a chemopreventive effect in DMBA-induced breast in rat post-administration for 10 weeks and prevented breast-histological alteratio carcinogenic wounds. Additionally, it also amplified the p53 expression and inhibi Bcl-2 expression to induce apoptosis in breast cancer cells [97].  Apoptosis modulation by algal metabolites in cancer prevention. Polysaccharides, sulfated polysaccharides, iodine, dieckol, fucoxanthine, fucoidan, and polyphenols downregulate the expression of anti-apoptotic protein Bcl-xl, Bcl-2. Similarly, they enhance the Bax expression to aid apoptosis. Fucoidan supports the intrinsic apoptosis via regulating the cytosolic release of cytochrome C. Fucoxanthine and fucoidan induces the expression of caspase 9 and caspase 3 to induce apoptotic cell death. Moreover, fucoidan, fucoxanthine, heterofucans, dieckol, iodine, and carrageenans induce apoptosis through modulation of caspase 3 activity via death receptor-mediated apoptotic cell death in several cancer cell lines. In addition to this, they also regulate caspase 8 activity inducing extrinsic apoptosis in different cancer cells.
Fucoidans isolated from the sporophyll of U. pinnatifida displayed apoptosis in DU-145 cell-induced xenograft rat model via inhibition of the JAK3/STAT pathway. In addition, fucoidan (IC 50 530 ± 3.32 mg/mL) also reduced the viability of B16 melanoma cells via activating apoptosis [99]. Fucoidan from Fucus vesiculosus induced p53-independent apoptosis in HCT116 human colorectal carcinoma cell line [74]. Fucoidan from L. japonica induced apoptosis via activation of caspase-3, poly(ADP-ribose) polymerase (PARP), and DNA degradation in HT-29 cell line [100]. Moreover, fucoidan from E. cava induced apoptosis in MDA-MB-231 and MCF-7 cells via induction of p53 and activation of Bax, caspases 3 and 9, and PARP with inhibition of Bcl-2 [76]. Furthermore, fucoidan from Cladosiphon okamuranus displayed induction of apoptosis in MCF-7 cells via activation of caspase-3 and DNA fragmentation [101]. F. vesiculosus extracts enhanced mitochondria membrane permeability thus inducing apoptosis via cytoplasmic release of cytochrome C and the Smac/DIABLO pathway in human colon cancer cells [102]. Similarly, fucoidan from F. vesiculosus treatment induced apoptosis in HT-29 colon cancer cells via decreasing the expression of Bcl-xL, Bcl-2 and upregulation of Bax, pro-caspases 3, 7, and 9. An upregulation of Rb and E2 factor proteins and Fas-regulated extrinsic apoptosis was also evident post fucoidan treatment in HT-29 colon cancer cells [103].
Fucoxanthin from Laminaria japonica induced apoptosis via DNA fragmentation in human colon adenocarcinoma WiDr cells [91]. Fucoxanthin from Ishige okamurae exhibited anticancer activity in melanoma B16F10 cells both in vitro (B16F10 cell line) and in vivo (Balb/c mice implanted with B16F10 cells) via induction of apoptosis. Moreover, fucoxanthin induced apoptosis via caspases activation and reduction of BclxL and IAP expression [90]. Laminarin from Laminaria digitata induced apoptosis in human colon cancer (HT-29) cells and activated ErbB2 phosphorylation. Moreover, it also inhibited cell proliferation and induced apoptosis in prostate cancer (PC-3) cells and increased the expression of P27kip1 and PTEN [104]. Dieckol from E. cava daily administration (40 mg/kg for 15 weeks) decreased cancer cell proliferation in albino rats via induction of apoptosis [95]. The guaiane sesquiterpene derivative guai-2-en-10-ol from green seaweed Ulva fasciata induced apoptosis in MDA-MB-231 breast cancer cell line via direct interaction with the kinase site of EGFR [82]. The halogenated monoterpene, mertensene from red alga Pterocladiella capillacea induced apoptosis in HT-29 and LS174 via modulation of ERK1/2, Akt, and NF B pathways [78]. Ethanolic and methanolic solvent extracts of Gracilaria tenuistipitata displayed apoptosis in Ca9-22 oral cancer cells via DNA damage. Furthermore, methanol extract of Plocamium telfairiae induced caspase-dependent apoptosis in HT-29 colon cancer cells [88]. Iodine and polyphenols from L. japonica induced apoptosis via inhibiting SOD activity [105]. The red alga Porphyra yezoensis can induce cancer cell death via apoptosis in a dose-dependent manner in in vitro cancer cell lines without exhibiting cytotoxicity towards the normal cells. Moreover, Carrageenans, heterofucans, dieckol, and iodine can induce cancer cell death via apoptosis in a dose-dependent manner in in vitro cancer cell lines without exhibiting cytotoxicity towards the normal cells. Furthermore, L. japonica water extracts induced apoptosis in several human breast cancer cell lines. Moreover, Eucheuma cottonii extract displayed the upregulation of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) in cancer-induced rats [89]. Methanolic extracts of Fucus serratus and F. vesiculosus exhibited protection of DNA damage induced by H 2 O 2 in Caco-2 cells [106]. Furthermore, Pelvetia canaliculata inhibited H 2 O 2 -induced superoxide dismutase depletion in Caco-2 cells [106]. C. japonica ethanol extracts inhibited H 2 O 2 -induced apoptosis via activating cellular antioxidant enzymes [63]. G. tenuistipitata aqueous extract enhanced the recovery of these cells from H 2 O 2 -induced DNA damage in the H1299 cell line [59]. Apoptosis modulation by algal metabolites in different cancerous cell lines with molecular pathways are summarized in Table 1.

Anti-Inflammatory Activity of Marine Algal Bioactive Metabolites
Inflammation is a molecular marker of carcinogenesis. Marine natural products are well-known anti-inflammatory agents due to their potent antioxidant activity. Several anti-inflammatory compounds with potential pharmacological applications have been isolated from marine algal sources. Macroalgae contain several polysaccharides, such as fucoidan, fucans, alginates, laminarin, agar, and carrageenans, which are used as prebiotic compounds and that can have potential application as anti-inflammatory agents. Marinederived carotenoids and astaxanthin exhibit potent anti-inflammatory activity [108,109].
The anti-inflammatory activity of marine algae is due to the presence of PUFAs (e.g., omega-3) that potentiate inhibition of inflammation [27]. Several studies have demonstrated that omega-3 to 6 fatty acids reduce inflammation when taken as dietary supplements [27]. The polysaccharide extracted from Turbinaria ornate, Delesseria sanguinea exhibited anti-inflammatory potential in several in vitro systems. Sulfated polysaccharide fraction from Gracilaria caudate, a galactan from Gelidium crinale, a mucin-binding agglutinin from Hypnea cervicornis, lectin from Pterocladiella capillacea, and sulfated galactofucan from Lobophora variegata also exhibited anti-inflammatory potency [110]. Oral administration of marine polysaccharide in an in vivo mouse model reduced the initiation of inflammation [111].
The alga Spirulina had demonstrated anti-inflammatory effects when assessed using a non-alcoholic steatohepatitis model [112]. C-phycocyanin from Spirulina platensis blocked inflammation via inhibiting the expressions of nitric oxide synthase, cyclooxygenase-2, and production of pro-inflammatory cytokines [113,114]. Methanolic extracts of Ulva lactuca and U. conglobate have shown anti-inflammatory effects in murine hippocampal HT22 cell line [115]. Lycopene from Chlorella marina demonstrated anti-inflammatory effects in an arthritic rat model [116]. Phytosterols from Dunaliella tertiolecta, aqueous and methanolic extracts of Caulerpa mexicana and lectin from Caulerpa cupressoides exhibited antiinflammatory activities in several in vitro models [117]. Ethanolic extract of Ecklonia cava inhibited LPS-induced inflammation in human endothelial cells [118]. Furthermore, Ishige okamurae showed anti-inflammatory effects in a few in vitro models [119]. The astaxanthin isolated from Haematococcus pluvialis reduced gastric inflammation in Helicobacter pyloriinfected mice via decreasing bacterial density [120]. Moreover, astaxanthin reduced the production of pro-inflammatory mediators and cytokines such as nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), and suppresses T lymphocyte activation in asthma patients [120]. Fucans from Sargassum vulgare, Lobophora variegata, and Spatoglossum schroederi also displayed anti-inflammatory effects [121]. Furthermore, Alginic acid from Sargassum wightii exhibited anti-inflammatory effects in vivo in a rat model [121].

Significance of Marine Algal Bioactive Metabolites as Anti-Diabetes Drugs
Diabetes mellitus is a chronic metabolic disorder which is characterized by high blood glucose levels that lead to renal dysfunction, cardiovascular diseases, and retinal damage [1]. Dietary management is a novel target for treating diabetes via maintaining the correct concentrations of both blood glucose and blood lipids [130]. Commercially available antidiabetic drugs exert several diseases-associated adverse side effects during treatments [131]. In this context, the identification of natural antidiabetic drugs with enhanced drug efficacy and lesser adverse effects has gained the attention of researchers in recent times. Marine algae-derived bioactive compounds exhibited antidiabetic properties furnished by regulation of various signaling pathways, such as inhibitory effect on enzymes such as α-amylase, α-glucosidase, aldose reductase, dipeptidyl peptidase-4, and protein tyrosine phosphatase 1B (PTP 1B) enzyme [132]. Enzymes like α-amylase and α-glucosidase play a significant role in the digestion of carbohydrates, leading to a delay in glucose absorption in blood and also to a reduction of glucose levels in blood plasma. Subsequently, these compounds may be exploited as potential functional food ingredients for preventing or diminishing insulin resistance and diabetes [132].
Marine algal compounds modulated the GLUT-4 and AMPK signaling pathways and triggered glucose tolerance [1]. Recent investigations displayed that fucoidan act as prebiotics and regulate the intercellular metabolism and blood sugar level [1]. Fucoidan isolated from S. fusiforme controlled the blood glucose level, recovered liver function, and inhibited oxidative stress in STZ-induced diabetic rats [133]. Fucoidan from Ecklonia maxima acted as a potent α-glucosidase inhibitor with a very low IC 50 value (0.27-0.31 mg/mL) and regulated type II diabetes [134]. Fucoidan from Fucus vesiculosus displayed a robust α-glucosidase inhibitor in diabetes treatment [135]. Furthermore, low molecular weight fucoidan (LMWF) from S. hemiphyllum in combination with fucoxanthin displayed antidiabetic properties in type II diabetes rat model (db/db). The oral administration of LMWF in combination with fucoxanthin decreased blood glucose and fasting blood sugar levels [135]. The synergistic drug effect was more effective in the in vivo model via reduction of urinal sugar level as compared to the LMWF treatment alone. LMWF enhanced the hepatic glycogen concentration and antioxidant enzymes which were assisted by lipid metabolism. The lipid metabolism displayed the regulation of glucose transporter (GLUT), insulin receptor substrate (IRS-1), peroxisome proliferator-activated receptor-gamma (PPARγ), and uncoupling protein (UCP)-1 level with the treatment of LMWF in combination with fucoxanthin [135]. Fucoidan from Cucumaria frondosa amplified the expression of insulin receptor substrate 1, Glut-4, and PI3K/Akt, glucose transporter protein in insulin-resistant rats [1]. Fucoidan from Saccarina japonica abridged blood sugar level too [1,136].

Algal Metabolites as Prebiotics for Human Health with Special References to Fucoidan
Algal metabolite consumption, such as polysaccharides, sulfated polysaccharides, fucoidans, chlorophylls, phycobilins, fucoxanthins, carotenoids, polyphenols, and omega-3 fatty acids, decreases blood pressure and sugar level, and it can have antiviral, antiinflammatory, anticancer, and neuroprotective effects, as well as act as immune boost-up. The immunomodulatory potential of prebiotics modulates immune fitness via several metabolic processes and interactions with the gut microbiota in humans [165]. The gut microbiota produces short-chain fatty acids (SCFA) such as propionate, acetate and butyrate by breaking down prebiotics and modulating the immune response [165]. Intravenous use of acetate amplified the activity of NK cells in cancer patients. In addition, it activated G protein-coupled receptors (GPR41 and GPR43) in rats, thus triggering mitogen-activated protein kinase (MAPK) signaling and modulating the transcription factors activity [166]. Acetate also increased the production of IL-10 in rats and prevented the inhibitory activity of butyrate on IL-2 production [167]. Daily administration of fucoidans from A. nodosum increased in Lactobacillus and Ruminococcus in the intestine of mice [168].
Fucoidan possesses a wide range of immune-modulation effects by stimulating activation of natural killer (NK) cells, dendritic cells (DCs), and T cells and increasing anti-tumor and anti-viral responses [169]. Fucoidan enhanced immune modulation via activation of macrophage facilitated by membrane receptors, such as TLR4, cluster of differentiation 14 (CD14), competent receptor-3 (CR-3), and scavenging receptor (SR). This led to signal transduction via MAPK and activation of transcription factors, and it also induced cytokines production, which regulates activation of NK cells and T lymphocytes [170]. In this regard, treatment of C57BL/6 rats with fucoidan extracted from Fucus vesiculosus upregulated pro-inflammatory cytokines (IL-6, IL-12, and TNF-α) in serum and spleenocytes after 3 h of administration [171]. Furthermore, fucoidan from L. cichorioides, L. Japonica, and F. evanescens served as TLR ligands and their interaction with TLR-2 and TLR-4 receptors in vitro activated NF-jB. Furthermore, it also controlled the expression of the defense mechanisms of intrinsic immunity, such as secretion of chemokines, cytokines, and manifestation of MHC class I and II particles [1]. These are essential for the defense against foreign attackers and for activating adaptive immune systems. A clinical trial based on the diet supplementation of 1 g/day of fucoidan from Undaria pinnatifida on adult male and female volunteers for 24 weeks showed modulation of the immunity to seasonal influenza vaccine by antibody production [172]. Based on these reports, there are several evidences that fucoidan acts as a potent prebiotic and that it is able to modulate immunity. This is achieved by interacting with intestinal cells of the gut microbiota and direct motivation of immune cells through TLRs.

Conclusions and Future Perspectives
Natural extracts have been used since ancient times for treating various illnesses. Products from natural products have also provided a large number of pharmaceuticals, or their prototypes, in recent times. Among the many natural sources, marine algae can still play a pivotal role in human health and disease because of the need for novel drug candidates. Their extracts are already well-known in traditional medicine and more recent studies investigated the many beneficial effects of their secondary metabolites, such as reduction of oxidative stress and modulation of apoptosis, and the main findings of these researches are summarized in this review. The exploitation of these results might lead to the development of novel algal dietary supplements and pharmaceuticals for preventing and treating chronic malfunctions and other age-associated chronic diseases. For example, sulfated fucoidans have been shown to be potential candidates as new pharmaceuticals in fighting cancer and diabetes. However, despite the extensive use of algae-derived compounds and extracts in the food industry, there are still no FDA-approved anticancer, antioxidant, anti-inflammatory, and antidiabetic drugs. Technology transfer from the preclinical results to the clinical application of secondary metabolites extracted from marine algae is still in its infancy and not fully exploited and more clinical studies are needed to really evaluate the pharmaceutical efficacy algal compounds.
In conclusion, marine algae offer a great variety of bioactive molecules with potential health benefits. Several types of marine algae are already consumed as food additives and nutritional supplements, potentially exerting their beneficial effects through diet. There is, however, an impelling necessity of considering the algal bioactive compounds in new drug discovery programs and to investigate their biological effects in deeper detail in order to find new pharmaceuticals with preventive and therapeutic efficacy.