A REVIEW OF MARINE NATURAL PRODUCTS AS POTENTIAL SOURCE OF ANTIOXIDANTS

Article Highlights
- Marine Natural Products have been the most favorable source of bioactive compounds for drug discovery research.
- Many biologically active chemicals with antioxidant properties can be found in the marine environment.
- A systematic review on potential source of antioxidants linked to marine natural products was carried out.
- Algae, fungi, sponges, mollusks, and sea cucumbers were found to be abundant sources of antioxidants.
- Integrate these discoveries into practical applications for enhancing human health and well-being.

Abstract
Several diseases have been linked to oxidative stress, resulting from an imbalance between the creation of the body’s antioxidant defense mechanisms and reactive oxygen species (ROS). Due to their distinct metabolic makeup and wide range of biological adaptations, marine organisms have attracted interest as possible sources of new antioxidants. This systematic review aims to evaluate the antioxidant potential of marine natural products. To find relevant research published between 2002 and 2022, a thorough search strategy based on the PRISMA standards was used across databases, including PubMed, Google Scholar, Mendeley, and Science Direct. A total of 18 studies were extracted and included in the review. The results consistently showed that marine natural compounds had vigorous antioxidant activity. Algae, fungi, sponges, mollusks, and sea cucumbers were shown to be abundant sources of antioxidants in marine environments. Flavonoids, alkaloids, phenols, tannins, steroids, saponins, glycosides, terpenoids, and carotenoids are only a few types of marine natural products that have been discovered to possess strong antioxidant properties. This systematic review provides compelling evidence for the antioxidant potential of marine natural products. The research validates their potential as sources of novel antioxidants with various bioactive properties. Unlocking the full potential of marine natural products and integrating these discoveries into practical applications for enhancing human health and well-being calls for further research.

INTRODUCTION

It has been established that the ocean, a complex ecosystem, is an excellent chemical and biological diversity source. Compared to non-marine microorganisms and terrestrial plants, marine organisms have been regarded as the most recent source of bioactive natural compounds, including 75% of all living organisms from 36 phyla (Balakrishnan et al., 2014). In recent years, marine natural products (MNPs) are the most promising source of bioactive compounds for drug discovery research (Nie et al., 2020). Bacteria, algae, sponges, and other marine organisms make many subgroups of substances.

These mentioned organisms are extremely promising sources of fascinating compounds that might be applied to food, cosmetics, pharmaceuticals, and other compounds essential to industry.

Despite the enormous potential of MNPs, the marine ecosystem still represents an extensive undeveloped reservoir of biologically active chemicals, which has considerable potential to contribute food components towards producing new functional foods (Mishra et al., 2023). In the world’s seas, between 700,000 and one million different species can be found; however, only a small portion of all MNPs is being examined for their potential bioactivities ((Mohamed et al., 2012) & (, 2021)). Due to the growing need by the food and pharmaceutical industries to produce natural bioactive anti-carcinogenic and anti-aging substances which provide significant health benefits, antioxidant activity has become intensively discussed and the focus of significant research (Balakrishnan et al., 2014). Seaweed and sponges are among the marine organisms with the highest levels of natural antioxidants (Muthiyan et al., 2018). Bioactive substances produced by the said organisms and the bacteria that live on them have been proven to be crucial for illness prevention and health promotion. The complex blend of phytochemicals exhibiting antibacterial, antioxidant, anticancer, and antiviral action is responsible for these positive effects. Sulfated polysaccharides, Phenolic compounds, sand organic acids are responsible for these activities (Balakrishnan et al., 2014).

Thus, to increase the availability and chemical variety of functional marine constituents, more research is needed to completely comprehend the biological activities of MNPs and their potential health advantages (Mohamed et al., 2012). The use of MNPs as a potential source of bioactivity has been discussed in a few recent review publications (Fonseca et al., 2023). However, only a few systematic literature reviews have focused on its potential as a source of antioxidants (El-Shafei et al., 2021). Therefore, this review fills a gap in the existing literature by systematically reviewing the MNPs as a potential source of antioxidants.

METHODS

Study design and eligibility criteria

A review of literature conducted using a systematic search was employed using PRISMA guidelines. The following were used as inclusion criteria: (i) the study had to be focused only on primary research, such as experimental studies that looked into marine natural products as a source of antioxidants; (ii) it had to have used marine natural products, such as coral, seaweed, marine sponges, and other marine invertebrates, to look into anti-oxidant activity in humans; and (iii) the main outcome of interest was the antioxidant activity of marine natural products as measured by a recognized assay, e.g., ABTS, DPPH, FRAP, ORAC, etc., (iv) it had to be focused solely on antioxidant assays employing ethanolic and/or methanolic extracts, (v) the study had to be written in English, (vi) it had to be published between 2002 and 2022, and (v) had to be open-access, and peer-reviewed articles published in scientific journals. The study’s inclusion criteria were all met by a total of 18 papers.

Search Strategy

The search engine Science Direct, Google Scholar, PubMed, and Mendeley, were used to obtain the most relevant articles by using the words “marine natural products,” “marine natural resources,” and/or “marine products” combined with “antioxidant,” “antioxidants,” and “antioxidant activity. Only English, open-access peer-reviewed articles with full text were considered, preferably published between 2002 and 2022.

Data Extraction

The search engine Science Direct, Google Scholar, PubMed, and Mendeley, were used to obtain the most relevant articles by using the words “marine natural products,” “marine natural resources,” and/or “marine products” combined with “antioxidant,” “antioxidants,” and “antioxidant activity. Only English, open-access peer-reviewed articles with full text were considered, preferably published between 2002 and 2022.

Study Selection

After removing duplicates from a total of 1244 independently downloaded papers, 1093 published articles remained. 37 articles’ full-text versions were retrieved after their titles and abstracts were screened for further assessment. There are 19 articles with methods that still need to meet the inclusion criteria. In the end, only 18 qualified articles were used in this review, as illustrated in Figure 1.

RESULTS AND DISCUSSION

Studies of MNPs as Antioxidant according to Study Features

The analysis’s results indicate the level of distribution of MNP studies as a potential source of antioxidants in terms of (a) publication year, (b) marine sources, and (c) marine species. Figure 2 below provides information on the frequency distribution of the studies based on the classified feature based on publication year.

Results revealed that out of the 18 qualified studies, only a few published studies focused mainly on the MNPs as a source of antioxidants (2002-2012, 0; 2013, 2; 2014, 2; 2015, 3; 2016, 3; 2017,0; 2018,1; 2019, 1; 2020, 2; 2021, 3; 2022, 1). These indicate that the chemistry of marine sources, in general, has yet to be fully embraced by the field of MNPs, at the expense of its potential as antioxidants based on the inclusion criteria developed for the purpose.

Figure 1.The flow of information for study selection (Adapted from (McKenzie et al., 2021))

The systematic review findings highlight the significant potential of marine natural products as a rich source of antioxidant compounds. As presented in Figure 4, although marine algae are the most studied and considered a rich source of natural antioxidants (Muthiyan et al., 2018), marine fungi have the highest number of species possessing high antioxidant potential.

Marine natural products as a source of antioxidant compounds

The data analysis showed that MNPs have much potential as a source of antioxidant compounds. Almost all the research included in the analysis mentioned MNPs’ antioxidant activity. The abundance of antioxidants in various marine species, such as algae, fungi, sponges, and other invertebrates, is shown in Table 1.

Figure 2.Frequency Distribution of Qualified Studies by Publication Year

Figure 3.Frequency distribution of Marine Sources

Table 1.Marine natural product sources as potential antioxidants

Marine Source	Type	Species	Secondary metabolites	Reference
Marine algae	Red algae	Chlorococcum humicola	Phenols Alkaloids Steroids	(Kavitha & Palani, 2016)
		Avrainvillea erecta	Flavonoids Phenols Tannins	(Chai et al., 2015)
		Chondrophycus ceylanicus Gelidiella acerosa Gracilaria corticata	Alkaloids Saponins Flavonoids Tannins Glycosides	(Lakmal et al., 2014)
		Chondrus crispus	Flavonoids Polyphenols	(Alkhalaf, 2021)
		Gracillaria edulis Centerocerous clavulatum	Lipid soluble total Chlorophylls	(Leelavathi & Prasad, 2014)
		Laurencia synderiae	Total phenolic Flavonoid	(Karimzadeh & Zahmatkesh, 2021)
	Green algae	Chaetomorphacrassa Caulerpa racemosa	Flavonoids Total carotenoids	(Lakmal et al., 2014)
		Spongomorpha indica	Alkaloids Steroids Tannins Flavonoids	(Rajasekaran, 2022)
	Unspecified	Gracillaria crassa Cymodeace serrulata Cymodeace rotundata	Not identified	(Leelavathi & Prasad, 2014)
	Brown algae	Sargassum cassifolium	Alkaloids Saponins Flavonoids Tannins Glycosides	(Lakmal et al., 2014)
Marine fungi	Unspecified	Aspergillus versicolor	Aspermutarubrol/ violaceol-I	(Yang et al., 2020)
	Pavona cactus	Penicillium digitatum Hypocreaceae Sterigmocystis sp.	Butyrolactone Ι Aspernolide E, Phenolic derivative	(Nie et al., 2020)
	Shark gill	Aspergillus flavipes Penicillium polonicum Penicillium chrysogenum Penicilliium corylophilum
Marine Sponge	Unspecified	Zyzzya fuliginosa	Alkaloids	(Utkina, 2013)
		Hyrtios erectus	Not identified
		Aaptos suberitoides
		Fascaplysinopsis reticulata
		Xestospongia sp.
		Acanthella sp.
		Petrosia contignata
Marine Invertebrates	Mollusks	Littorina littorea Galatea paradoxa	Polyphenols	(Borquaye et al., 2016)
	Sea cucumber	Holothuria atra	Flavonoid Terpenoid Phenols Saponin Glycoside	(Murniasih et al., 2015)

Marine Algae

Marine macroalgae, also known as seaweed, is used as food in many countries. As a result, there is much interest in finding bioactive macroalgal metabolites to employ them as active components in developing functional foods, nutraceuticals, and pharmaceuticals (Mohapatra et al., 2013). In this context, searching for natural antioxidants in macroalgae is relevant to ongoing scientific interest and societal needs.

The fresh samples of Chlorococcum humicola in the study of (Kavitha & Palani, 2016); (Lakmal et al., 2014) were obtained from the Rameshwaram seashore in Tamil Nadu. The ethanol extracts showed considerable antioxidant capability in reducing power, DPPH, superoxide, and nitric oxide radical scavenging assays. Therefore, the algae C. humicola can be a substantial source of vital compounds that the pharmaceutical industry can utilize to produce medicines. Based on the GC-MS study’s findings, 14 compounds were present, and their nature varied greatly. The analysis revealed that the 1-propene, 3-(2-cyclopentenyl)-2-methyl-1,1- diphenyl exhibited the most significant peak area (Figure 5). According to the analysis, flavonoids, alkaloids, and steroids are the metabolites responsible for antioxidant activity.

The marine macroalga Avrainvillea erecta (Berkeley) A. Gepp and E.S. Gepp (Family Dichotomosiphonaceae) that was discovered in the South China Sea off the southwest coast of Tinggi Island, Malaysia, was investigated by (Chai et al., 2015). The findings showed that A. erecta’s methanol extract and solvent fractions have the ferric reducing ability as well as scavenging 2,2-diphenyl-1picrylhydrazyl (DPPH), nitrogen oxide (NO), and hydrogen peroxide (H2O2). On the other hand, DPPH scavenging activity is correlated with the total phenolic contents.

Therefore, the antioxidant activity of A. erecta extract revealed in the study is due to flavonoids and other phenolic components. The information showed flavonoids, phenols, and tannins are the main chemical components.

Fresh marine seaweeds were gathered from sample sites at the Beruwela coral reef in the Southern Province of Sri Lanka for the study by (Lakmal et al., 2014). Among the methanolic extracts of the identified species such as red algae (i.e., Chondrophycus ceylanicus, Gelidiella acerosa, Gracilariacorticata), green algae (i.e., Chaetomorphacrassa, Caulerpa racemosa) and brown algae (i.e., Sargassum cassifolium); C. racemosa showed a significant average radical scavenging activity against DPPH (34.34%), alkyl (85.17%) and hydroxyl (81.16%), respectively. Green seaweed has the highest phenolic content and antioxidant activity of the three macroalgae categories (Mohamed et al., 2012). Alkaloids, saponins, flavonoids, tannins, and glycosides are some of the phytochemicals found in the species (Jayaseelan et al., 2012)

Figure 4.1-Propene, 3(2-cyclopentenyl)-2- methyl-1,1- diphenyl-

Red algae of the Chondrus crispus species from the Red Sea’s coasts near Jeddah City were gathered for Alkhalaf’s (2021) investigation. According to the findings, the methanolic extract made from the red algae species C. crispus had considerable antioxidant activity in the current investigation, and it successfully scavenged ABTS and DPPH free radicals in a dose-dependent manner. The extract’s overall antioxidant capacity was also remarkable. The presence of flavonoids and polyphenols is thought to contribute to the antioxidant properties of several species of red algae, and the potency of this ability is correlated with the concentration of these bioactive chemicals (Zhang et al., 2019). Since flavonoids and phenols were also discovered in C. crispus extract, the antioxidant effects displayed by the extract in the current investigation could be attributed to these bioactive components.

Seaweed samples (Leelavathi & Prasad, 2014) were collected from the Gulf of Mannar. Cymodeace rotundata, Acanthopora spicifera, Ulva lactuca, Ulva reticulate, Turbinaria conoides, Gracillaria edulis, Kappaphycus alvarezii, Gracillaria crassa, Gracillaria foliifera, and Cymodeace serrulata were the specimens identified. Petroleum ether and methanol were used to produce the extracts. By observing the decline in absorbance at 517 nm, the DPPH assays were performed to determine the antioxidant properties of seaweed. The highest overall antioxidant activity was demonstrated by C. rotundata, G. crassa, and C. serrulata in the methanol extract compared to other samples. Red algae samples were collected from the Chabahar coastlines at the coordinates (25° 18′ 53′′N; 60° 37′ 41′′E) in the Oman Sea, Iran, for the study of (Karimzadeh & Zahmatkesh, 2021). The red seaweed Laurencia synderiae was studied, and the results showed that different extracts (methanolic, chloroform, and ethyl acetate) have dose-dependent antioxidant activities. Future medication development is predicted to involve the significant identified compounds that have a strong biological impact on red algae, L. snyderiae. The most prevalent compounds are hexadecanoic acid (19.81%; Figure 6), oleic acid (8.34%; Figure 7), squalene (6.96%; Figure 8); and tetradecanoic acid (6.86%; Figure 9); as well as glycerin (8.62%;Figure 10), xylitol (8.46%; Figure 11 ), and squalene (8.96%; Figure 12). The red algae L. snyderiae has strong bioactive components that it can employ as a natural antioxidant and source of additional resources. Total phenolic and flavonoid concentrations are among its phytochemical components.

Figure 5.Hexadecanoic acid

Figure 6.Oleic acid

Figure 7.Tetradecanoic acid

Figure 8.Glycerine

Figure 9.Xylitol Figure 10 Squalene

Figure 10.Squalene

The green macroalga Spongomorpha indica was gathered from the Visakhapatnam coastal area (Rajasekaran, 2022). The phytochemical tests revealed the presence of potent active constituents such as alkaloids, tannins, steroids, and flavonoids, by which further GCMS analysis was conducted, and seven components were determined. The results of the physicochemical parameters tests were under WHO guidelines. Nonadecanoic acid (Figure 13) had the most significant peak area, around 47.006%, and the most prolonged retention period, 19.050.

Figure 11.Nonadecanoic acid

In the DPPH assay model, S. indica demonstrated a considerable dose-dependent reduction in the case of the DPPH radical. All the data demonstrated the highest levels of antioxidant activity, with superoxide scavenging activity displaying the most significant outcomes. Based on the findings, it was established that S. indica had powerful active ingredients with potent antioxidant activity.

Seaweeds were gathered from the station in Rameshwaram on the southern Indian coast of Olaikuda (N.Lat. 09°18.300’ and E. Long. 079°20.096’) for the study by (Elangovan et al., 2019) The methanolic extracts of all the test species, including green algae Enteromorpha intestinalis and red algae Gracillaria edulis, exhibit high antioxidant activity (DPPH). The stated activity results from the high concentration of total chlorophylls that are lipid soluble, particularly Chl-a and related compounds, as well as the high concentration of total carotenoids.

Marine Fungi

In the study by (Muthiyan et al., 2018), marine fungus strains were obtained from biological samples taken in the intertidal zone of Dalian, China (Utkina, 2013), from shark gill tissues captured in the East China Sea, and from various corals in the Zhanjiang Sea region of China. The methanolic extracts of Aspergillus flavipes, Hypocreaceae, Sterigmocystis sp., Penicillium digitatum, Penicillium polonicum, Penicillium chrysogenum, and Penicillium corylophilum were some of the strain samples that showed DPPH free radical scavenging activity (scavenging ratios > 30% at 200 g/ml). Thus, found to exhibit antioxidant activity. The said antioxidants were assigned as Aspernolide E (Figure 14), butyrolactone I (Figure 15), a phenolic derivative, and possibly unidentified compounds.

Figure 12.Aspernolide E

Figure 13.Butyrolactone Ι

The Aspergillus versicolor SH0105 fungus strain (Yang et al., 2020) was isolated from a deep- sea sediment sample from the Mariana Trench at a depth of 5455 m. The bioactive assay revealed that A. versicolor demonstrated a substantial reduction of Fe3+ and significant DPPH radical scavenging activity, which were more potent than ascorbic acid. This suggests discovering chemical entities with antioxidant activities from the marine medicinal microbial resources. Aspermutarubrol/ violaceol-I (Figure 16) was identified as the chemical responsible for the antioxidant activity.

Figure 14.Aspermutarubrol/violaceol-I

Marine sponge

Many sedentary marine organisms, such as sponges, have acquired the capacity to create a variety of toxic substances to defend themselves against predators or to compete with other marine species (Paul et al., 2006). Sponges are receiving the most interest from the pharmaceutical industry because they produce the most bioactive secondary metabolites among all marine organisms. Alkaloids, steroids, terpenes, peptides, macrolides, and polyketides are only a few marine sponges’ structurally diverse natural compounds (Dias et al., 2012).

The marine sponge Zyzzya fuliginosa (order Poecilosclerida) is a rich source of alkaloids with a pyrrolo[4,3,2-de]quinoline structure (Utkina, 2013). The antioxidant properties of zyzzyanones A to D (1-4) and makaluvamines C, E, G, H, and L (Figure 16) were tested, which were isolated from the ethanolic extracts of the Australian marine sponge Z. fuliginosa. According to research on their effectiveness as radical scavengers, zyzzyanones and makaluvamines have moderate antioxidant activity, indicated by a phenolic function in the molecules.

Figure 15.Structures of tested zyzzyanones and makaluvamines (Utkina 2013)

The marine sponge Hyrtios erectus was procured from the North Bay of the South Andaman Sea for the study of (Muthiyan et al., 2018). According to the findings, the methanolic extract of H. erectus exhibited antioxidant activity against DPPH free radicals, superoxide anions, and hydroxyl radicals. With 50 µg/mL sponge extract, more than 50% inhibition (half inhibitory concentration) was observed. However, there is a need for further functional characterization of the bioactive compounds to determine the compound responsible for the activities.

Marine sponge species were gathered in Pecaron Situbondo, East Java, Indonesia, for the study of Abdillah et al. (2013). Results showed that only Aaptos suberitoides exhibited vigorous antioxidant activity in an assay using the DPPH method, as evidenced by an IC50 value of less than 30 mg/mL. In contrast, Fascaplysinopsis reticulata, Acanthella sp, Petrosia contignata, and Xestospongia exigua displayed moderate antioxidant activity, with an IC50 value of less than 100 mg/mL. The IC50 value for Callyspongia sp. and Xestospongia sp. was more significant than 100 mg/ml. The research has shown the high potential of Xestospongia sp, F. reticulata, Callyspongia sp, Petrosia contignata, and Aaptos suberitoides for developing bioactive chemical isolation as antioxidant agents.

Marine Invertebrates

Aquatic species’ capacity for adaptation and survival in various habitats relies on their physical and chemical adaptations (Thakur et al., 2005). Bryozoans, mollusks, andothermarineinvertebrates all have soft bodies and sedentary lifestyles, making a chemical defense system necessary for survival. When introduced into their aqueous habitat, these compounds are rapidly diluted. The compounds must be very potent to be effective (Karimzadeh & Zahmatkesh, 2021). Numerous researchers have investigated these environments in quest of biologically active molecules due to the high potency of chemicals used in aquatic defense systems and the requirement that they be water-soluble.

Molluscs

The two mollusks, Littorina littorea, and Galatea paradoxa, used in the study by (Borquaye et al., 2016), were gathered from Labadi Beach in Accra and Sogakope on the Volta River. According to the IC50 values from the antioxidant experiments, methanol extracts are more effective at scavenging DPPH radicals than ethyl acetate extracts. Compared to the standard ascorbic acid medication, the methanolic extracts of G. paradoxa and L. littorea demonstrated outstanding DPPH radical scavenging ability, indicating they may be a good source of antioxidant chemicals. Polyphenols are one family of secondary metabolites with proven antioxidant action. Both G. paradoxa and L. littorea methanol extracts may have significant concentrations of these chemical compounds.

Sea cucumbers

Sea cucumber extracts from Holothuria scabra, Holothuria atra, Holothuria leucospilota, and Holothuria excellens were gathered from Jor Bay in East Lombok, Indonesia, for the study by (Murniasih et al., 2015). Among the extracts, H. leucospilota and H. atra have strong antioxidant properties, particularly for DPPH method-based radical scavenging activity. The phytochemicals flavonoid, terpenoid, phenols, saponins, and glycoside were the constituents of H. leucospilota and H. atra. According to the results of the GC-MS study, 3-chloro-4-hydroxybenzoic acid (Figure 16) was found to be one of H. atra’s active antioxidant components. This phenolic substance is crucial for its antioxidant effects.

Figure 16.3-chloro-4-hydroxybenzoic acid

A wide variety of marine natural compounds with antioxidant activity were shown in the identified investigations. The polyphenols group, which includes flavonoids, alkaloids, phenols, and tannins, was the most frequently mentioned class of chemicals with antioxidant activity. Saponins, glycosides, terpenoids, and carotenoids are a few more types of chemicals that have been found to possess antioxidant activity.

CONCLUSIONS

According to the systematic review’s findings, there is growing evidence that many bio-logically active chemicals with antioxidant properties can be found in the marine environment (Mehbub et al., 2014). Flavonoids, alkaloids, phenols, tannins, steroids, saponins, glycosides, terpenoids, and carotenoids, are just a few of the structurally diverse natural compounds that MNPs are a highly rich source. According to several screening studies, marine-derived methanolic and ethanolic extracts exhibit potent antioxidant activity.

This review provides compelling evidence for the antioxidant potential of marine natural products. The research validates their potential as sources of novel antioxidants with a range of bioactive properties identified from MNPs and positions them as potential therapeutic options in the future. Thus, it is recommended that the identification and functional characterization of the bioactive molecules necessary for the activities are needed. Unlocking the full potential of marine natural products and integrating these discoveries into practical applications for enhancing human

health and well-being calls for further research.

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