Abstract
This study evaluated the biochemical composition and bioactivity of the crude extract of Sargassum dentifolium on the western coast of the Red Sea, Hurghada, Egypt. The biomass contained approximately 25.80% of total carbohydrates, and 8.40% of total protein, while lipids constitute about 2% of the total dry weight which is consistent with the low lipid content typically found in seaweeds. S. dentifolium also produces volatile and non-volatile compounds as part of its metabolic processes. The most abundant volatile compound identified was phytol, which has various industrial and pharmaceutical applications. Saturated fatty acids (SFAs) were the most frequently detected non-volatile compounds, with palmitic acid being the most common. The total phenolic content was 50.6 mg g−1 (5.06%), and the total flavonoid content was 33.9 mg g−1 (3.39%) of the total dry-weight extract. S. dentifolium extract demonstrated significant antioxidant activity, with radical scavenging properties and phenolic content that may contribute to its antioxidant efficacy. It also showed cytotoxic activity against cancer cells, particularly human hepatocellular liver carcinoma (HepG2) and human colon carcinoma (HCT-116) cells, indicating their potential as a source of anti-cancer agents. However, the extract exhibited moderate to weak antiviral activity and limited antimicrobial activity against specific microorganisms. This research could contribute to the development of new functional macroalgae-based food or nutraceutical products with potential health benefits.
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1 Introduction
Marine macroalgae, also known as seaweed, are a diverse group of aquatic photoautotrophs that are found in oceans, seas, and other bodies of saltwater. These algae contain a wide variety of bioactive substances that have important medicinal, industrial, and nutraceutical properties [1]. Some of the most notable active substances found in marine algae include carotenoids, carbohydrates, proteins, lipids, and polyphenolic metabolites. These substances are described to have a range of biological activities. In addition to these active substances, marine algae also contain minerals and vitamins that are essential for human health [2]. Besides the morphological characteristics, phytochemical analysis may contribute to the classification (i.e., species identification and differentiation) of algae based on their chemical profile to develop more precise taxonomic features [3,4,5]. Phytochemical analysis can also reveal the presence of certain compounds, such as pigments, lipids, fatty acids, vitamins, minerals, and sterols that can be used as diagnostic markers for a particular species. In addition, this can be useful in tracking changes in algal populations and understanding the dynamics of aquatic ecosystems [6].
Brown seaweeds (class: Phaeophyceae) are typically the largest (in terms of size) and most complex of all algae and are characterized by the presence of several active substances. Species of the genus Sargassum belong to the class Phaeophyceae, family Sargassaceae, it is typically found in tropical and subtropical waters, where it forms large floating mats or "rafts" that can stretch for miles. Sargassum biomass is an important source of carotenoids (mainly fucoxanthin), polysaccharides (e.g., alginates, laminarins, and fucans), and dietary fibers that have potential medicinal properties including anti-inflammatory, anti-cancer, antibacterial, antiviral, antioxidant and immune-boosting effects [7,8,9,10,11,12,13]. In addition to its medicinal properties, Sargassum biomass has a wide range of industrial applications, including food, beverage, and fertilizers production [14,15,16,17]. It's worth noting that the biochemical composition of Sargassum can vary depending on the species, location, and growth conditions [18,19,20]. Sargassum sp. contains a high amount of carbohydrates, which can be as much as 70% of the dry weight [15, 20, 21]. Unlike carbohydrates, Sargassum sp. contains low to moderate amounts (1–20%) of protein [15, 21,22,23] and relatively lower amounts (less than 1 to 5% of the dry weight) of lipids [24,25,26]. Sargassum sp. is known to contain a variety of phenolic acids. The total phenolic content of Sargassum sp. can vary depending on the species and growth conditions [27], some studies have reported values as high as 20% of the dry weight of the seaweed [28, 29].
Sargassum dentifolium is abundantly distributed along the Western Coast of the Red Sea, Hurghada, Egypt. It is a common species of Sargassum and is known for its ability to form dense mats in shallow waters. Sargassum sp. is an important species in the marine ecosystem as it provides habitat and food for many organisms, including fish, crustaceans, and mollusks [30,31,32]. On the other hand, in recent years, the extensive growth of S. dentifolium and other species of Sargassum along the Hurghada coast has become a growing concern for local communities and the tourism industry due to its negative impacts on beaches and marine activities. Despite its ecological and economic importance, the biochemical content and bioactivity of S. dentifolium have not been adequately investigated, as most previous studies have partially evaluated either limited chemical composition or biological activity of S. dentifolium and other Sargassum species from this region. Matloub and Awad [19] and [28] conducted a comparative study to evaluate the chemical composition of three Sargassum species, S. asperifolium, S. dentifolium, and S. linifolium, focusing on the volatile components and fatty acids. They also evaluated the cytotoxic and antimicrobial properties of the extracts. Salem et al. [33] tested the antibacterial activity of S. dentifolium extracts to understand their potential in therapeutic applications. While Galal et al. [34] assessed the antifungal properties of S. dentifolium extract as a potential source for treating infections caused by the tested plant fungi. Emam et al. [35] took a different approach by assessing the antioxidant potential of S. dentifolium focusing on the species' possible health benefits. Fouda et al. [21] investigated the biochemical and mineral compositions of three Sargassum species (S. aspirofolium, S. latifolium, and S. muticum) to assess their potential significance in animal nutrition. However, some studies, such as the study of El-shafay [36] and Abu Ahmed et al. [37], investigated the qualitative and quantitative chemical composition of other species of Sargassum (excluding S. dentifolium) without considering their biological activity, while other studies investigated the chemical composition and/or biological activity of other species of Sargassum, except for S. dentifolium, from the same area as the current study, e.g., [38,39,40]. Therefore, this study aimed to evaluate the biochemical composition, including total carbohydrates, proteins, and lipids contents; detailed non-volatile and volatile substances; total content, and composition of phenolics, and flavonoids of the crude extract of S. dentifolium that grows abundantly along the western coast of the Red Sea in Hurghada, Egypt, using advanced analytical techniques, additionally, the bioactivity, including antioxidant, cytotoxic, antiviral, and antimicrobial properties of the extract was evaluated through in vitro assays.
2 Materials and methods
2.1 Solvents and reagents
Methanol used for extraction and methanol solutions preparations was acquired from Merck (Darmstadt, Germany). Dimethyl sulfoxide (DMSO) was purchased from Sigma (St. Louis, MO, USA). Folin-Ciocalteu reagent, 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical, and tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT) was from Sigma (St. Louis, MO, USA). All other chemicals used were of analytical reagent grade.
2.2 S. dentifolium collection and identification
The thallus of S. dentifolium (Fig. 1) was collected from the Red Sea coast of Egypt, Hurghada City (27° 17′ 02.5" N, 33° 46′ 21.0" E), at a very shallow area at depths of 0.5–1 m below the lowest level of the tide (chart datum). A one-time sampling strategy was applied across the collection area. The biomass was kept in an ice box and transported to the laboratory, then separated from other attached and intertwined species. Healthy portions of S. dentifolium were preserved in formalin for documentation. Ten fresh branches of S. dentifolium were collected from ten independent plants and subjected to morphological measurements, with each branch being measured ten times for accuracy to the nearest millimeter. The measured characteristics included the range (minimum to maximum) of the length, width, and thickness of the vegetative and reproductive structures. Species identification was adopted according to the authentic taxonomic references [41,42,43,44]. Furthermore, species taxonomy and distribution literature collections were primarily according to AlgaeBase [45].
A typical healthy branch, showing the morphological features of S. dentifolium. A phylloid (leaf-like blade), B stalked vesicle (air bladder), and C reproductive receptacle
2.3 S. dentifolium crude extract preparation
The collected biomass was washed with running tap water followed by double-distilled water (DDW) to remove the epiphytes, salt minerals, and debris on the surface. The biomass was dried at a shady open-air place. The dried materials were milled into fine powder by using an electric blender. The Soxhlet extraction method was conducted by using 25 g of dried seaweed powder and 200 mL of 70% methanol (prepared from methanol with a purity of 99%) at 70 °C for 12 h. Methanol, a polar solvent capable of dissolving both polar and nonpolar compounds, has been recommended as one of the most efficient solvents for the extraction of the complex mixture of compounds present in Sargassum biomass [27, 34, 46,47,48]. The extraction process continued cyclically, with the condensed solvent re-dissolving the compounds in the extraction chamber. The evaporation–condensation cycle was repeated until the color of the seaweed biomass turned from deep brown to pale brown. After the extraction was completed, the resulting solution was concentrated under reduced pressure at 40 °C using a rotary evaporator (Buchi, Switzerland). The evaporation process was continued to concentrate the extract to approximately 1 mL. Evaporation was continued for an extended period by gently heating the concentrated extract (~ 1 mL) using a vacuum oven to further remove any residual solvent. Finally, the concentrated extract was collected and stored in the refrigerator at 4 °C.
2.4 Determination of total carbohydrates, proteins, and lipids
The total carbohydrate content of S. dentifolium biomass was estimated according to the method of Umbreit et al. [49]. Total proteins were assayed according to the methods of Lowry et al. [50]. Total lipids were estimated according to the method of James [51].
2.5 Determination of volatile and non-volatile constituents
To determine the volatile and non-volatile constituents in S. dentifolium crude extract, gas chromatography-mass spectrometry (GC–MS) analysis was accomplished using a GC instrument (Agilent 7890A) equipped with an HP-5MS column (30 m × 250 μm × 0.25 μm film thickness) and coupled with an MS detector (Agilent 5975C). The initial oven temperature was programmed to be held at 90 °C for 1 min then risen to 300 °C for 30 min at a rate of 8 °C min−1. Helium was used as a carrier gas at a flow rate of 1.5 ml min−1. The injection volume of each sample was 1μL in the splitless mode where the injector temperature was 290 °C. The mass spectrum was operated at 70 eV, and mass ranged from 60–600 amu.
2.6 Determination of phenolics and flavonoids
2.6.1 Quantitation of total phenolic and flavonoid content
The total content of phenolics and flavonoids in Sargassum has been recommended to determine in extracts prepared with methanol [52, 53]. The total phenolic content was determined using the Folin-Ciocalteu reagent following the Ainsworth and Gillespie [54] method. The total flavonoid content was estimated using the aluminum chloride colorimetric method [55].
2.6.2 Composition of phenolics and flavonoids
The detailed composition of phenolics and flavonoids was accomplished using High-performance liquid chromatography (HPLC) analysis. The analyses were carried out using an Agilent 1260 series. The separation was carried out using Eclipse C18 column (4.6 mm × 250 mm i.d., 5 μm). The mobile phase consisted of water (A) and 0.05% trifluoroacetic acid in acetonitrile (B) at a flow rate of 0.9 ml min−1. The mobile phase was programmed consecutively in a linear gradient as follows: 0 min (82% A); 0–5 min (80% A); 5–8 min (60% A); 8–12 min (60% A); 12–15 min (82% A); 15–16 min (82% A) and 16–20 (82%A). The multi-wavelength detector was monitored at 280 nm. The injection volume was 5μL for each of the sample solutions, and the column temperature was maintained at 40 °C.
2.7 Antioxidant activity (free radical-scavenging assay)
The antioxidant activity of S. dentifolium extract was evaluated by free radical-scavenging activity assay based on the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. Freshly prepared (0.004% w/v) methanol solution of DPPH radical was prepared and stored at 10 °C in the dark. A methanol solution of the tested extract of S. dentifolium was prepared (final concentration 1280 μg mL−1). Two-fold serial dilutions of 2.5, 5, 10, 20, 40, 80, 160, 320, 640, and 1280 μg mL−1 were prepared from the extract-methanol solution. For the reactions, 40 μL of each aliquot of the extract-methanol solution was added to 3 mL of DPPH-methanol solution. Absorbance measurements were recorded immediately with a UV–visible spectrophotometer (model: Milton Roy, Spectronic 1201). The decrease in absorbance at 515 nm was determined continuously, with data being recorded at 1-min intervals until the absorbance stabilized (after 16 min). The absorbance of the DPPH radical without antioxidant (control) and ascorbic acid, as a reference compound, were also measured. All the determinations were performed in three replicates and averaged. The percentage inhibition of the DPPH radical was calculated according to the formula (1).
where, Abscontrol is the absorbance of the control solution (at time = 0 min) and Abssample is the absorbance (at time = 16 min) of DPPH solution + sample or ascorbic acid [56]. The effective concentrations of antioxidants necessary to obtain half-maximal (EC50) radical-scavenging activity were estimated using the web-based tool: "Quest Graph™ EC50 Calculator" [57,58,59]. A sigmoidal function (a special case of the logistic regression model) was applied to calculate the EC50 values from the sigmoidal curves of radical-scavenging activity percentage versus antioxidants concentrations (i.e., algal extract and ascorbic acid; μg mL−1). The antioxidant activity of the S. dentifolium extract, expressed as EC50 (μg mL−1), was compared with the activity of ascorbic acid as a standard antioxidant.
2.8 Cytotoxicity
2.8.1 Mammalian cell line
HepG2 cells (human hepatocellular liver carcinoma), HCT-116 cells (human colon carcinoma) were obtained from VACSERA Tissue Culture Unit, Cairo, Egypt. Vero cells (derived from the kidney of African green monkey) were obtained from the American Type Culture Collection (ATCC), Manassas, VA, USA. The cells were propagated in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 1% L-glutamine, HEPES buffer, and 50 μg mL−1 gentamycin. All cells were maintained at 37 °C in a humidified atmosphere with 5% CO2 and were sub-cultured two times a week [60].
2.8.2 Evaluation of cytotoxicity
The cell lines in the cytotoxicity assay were seeded in 96-well plates at a cell concentration of 2 × 105 cells ml−1 in 100 μL of the growth medium. Fresh medium containing different concentrations of the tested sample was added after 24 h of seeding. Serial two-fold dilutions of the tested compound (started from 3000 to 2 μg mL−1) were added to confluent cell monolayers dispensed into 96-well, flat-bottomed microtiter plates (Falcon, Jersey, NJ, USA) using a multichannel pipette. The microtiter plates were incubated at 37 °C in a humidified incubator with 5% CO2 for a period of 48 h. Three wells were used for each concentration of the tested sample. Vinblastine sulfate (VS) at a concentration of 2.5 mg ml−1 was utilized as the standard positive control. The negative control cells were incubated without test samples and with or without dimethyl sulfoxide (DMSO) [61]. The small percentage of DMSO present in the wells (maximal 0.1%) was not found to affect cell viability [62]. After the end of the incubation period, the viable cell yield was determined by the tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT) colorimetric method according to Mosmann [63], the optical density was measured at 590 nm with the microplate reader (SunRise, TECAN, Inc, USA) to determine the number of viable cells. The percentage of viability was calculated as:
where ODtreated is the mean optical density of wells treated with the tested sample and ODcontrol is the mean optical density of untreated cells. The relation between surviving cells and tested compound concentration is plotted to get the survival curve of cell lines after treatment with the specified compound. The 50% cytotoxic concentration (CC50), the concentration required to cause toxic effects in 50% of intact cells, was estimated from graphic plots of the dose–response curve for each concentration using Graphpad™ Prism™ software (San Diego, CA. USA). S. dentifolium extract was considered to have strong cytotoxicity at CC50 < 20 µg mL−1, moderate at CC50 = 20–50 µg mL−1, or weak at CC50 > 50 µg mL−1.
2.9 Antiviral activity
2.9.1 Virus propagation
The cytopathogenic viruses were propagated and assayed in confluent Vero cells [64]. Infectious viruses were enumerated by determining the 50% tissue culture infectious dose (TCID50) with eight wells per dilution and 20 µL of inoculum per well using the Spearman-Karber method [65].
2.9.2 Evaluation of antiviral activity
The antiviral activity of S. dentifolium extract was evaluated using a cytopathic effect inhibition assay. This assay was chosen due to its ability to demonstrate specific inhibition of a biological function—the cytopathic effect in susceptible mammalian cells as measured by the MTT method [63]. Previous studies by Hu and Hsiung [66] and Al-Salahi et al. [67] have utilized this assay. The methodology involved seeding monolayers of Vero cells in a 96-well microtiter plate. After incubating the cells at 37 °C for 24 h, the plates were washed with Dulbecco's Modified Eagle Medium (DMEM), and subsequently, the cells were infected with 104 doses of the viruses. The cultures were then treated with varying concentrations of the tested extract (six wells per concentration) in a fresh maintenance medium and incubated for 48 h. Infection controls, and untreated Vero cell control, were prepared in the absence of extract. Antiviral activity was assessed by calculating the protection offered by the extract to the cells against the cytopathic effect in comparison to a control. The experiment was performed in independent triplicate with four sub-replicates per treatment. The positive control (i.e., a reference drug) used in this assay system was Amantadine. The viral inhibition rate (VIR) was calculated as follows:
where A, B, and C indicate the absorbance of the tested extract with virus-infected cells, the absorbance of the virus control, and the absorbance of the cell control, respectively [67].
2.10 Evaluation of antimicrobial activity
The antimicrobial activity of S. dentifolium extract was estimated using the diffusion agar technique (well diameter: 6.0 mm; 100 µl of the tested extract in each well). The algal extract was filtered through a 0.2-μm filter to remove contaminating bacteria and fungi before conducting the antibiotic assay. A slow suction was applied to facilitate the filtration process. Six pathogenic species were tested including two Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis, two Gram-negative bacteria Escherichia coli, and Proteus vulgaris, and two fungal species, Aspergillus fumigatus, and Candida albicans. The extract was tested at a concentration of 10 mg mL−1 in three replicates against each pathogenic species. The positive control for bacteria was Gentamycin (4 μg mL−1), and for fungi was Ketoconazole (100 μg mL−1). The diameter of the inhibition zone (i.e., the microbial cell-free zone) was measured in mm with a vernier caliper and the mean diameter values were calculated from the three replicates. Microbial isolates were obtained from the Regional Center for Mycology & Biotechnology, Al-Azhar University, Cairo, Egypt.
2.11 Statistical data analyses
One-way analysis of variance (ANOVA), followed by the Holm-Sidak method for all pairwise multiple comparisons, and one sample t-test were applied to determine the significance between different treatments. All significances were tested at α = 0.05. All replicated treatments were applied independently with a sample size of n = 3, and results are represented as the mean ± Standard Deviation (SD). All statistical procedures and analyses were done using SigmaPlot version 15, from Systat Software, Inc., San Jose, California, USA.
3 Results and discussion
3.1 S. dentifolium thallus description
Thallus (Fig. 1) erect, to 75 cm high, leathery, light to dark brown, and morphologically distinguished into a sub-quadrangular short main axis (2–4 cm long) that is attached to the substratum by a discoid holdfast; the main axis produces flattened primary branches, with a slightly dense appearance; primary branches give rise to alternate lateral branchlets. The phylloids (leaf-like blades) are often arranged in an alternate pattern and have a lanceolate to linear-lanceolate shape; 1–3.5 cm in length and 0.2–0.9 cm in width; the phylloids have irregular sharp serrated margins with symmetrical cuneate base; cryptostomata (dark-brown sterile pits) distinct, scattered randomly or often arranged in longitudinal rows on the blades; the midrib is distinct at the phylloids base and gradually disappearing towards the apex. Vesicles (air bladders) subspherical to elliptical, numerous in size 0.3–1.2 cm long and 0.3–0.9 cm in diameter, stalked, often rounded, or more rarely mucronate at the apices. Reproductive receptacles are arranged in the form of a raceme, 0.4–0.9 cm long, with a warty surface and short dark spines in the upper part, often dichotomous, androgynous, and developed in the axils between the phylloid and the vesicle.
3.2 Properties and yield of S. dentifolium methanolic extract
The methanolic extract of S. dentifolium was a yellowish-brown, semi-solid material with a faint, disagreeable odor. It was soluble in petroleum ether (boiling point 40–60 °C), ether, chloroform, benzene, and methyl and ethyl alcohol. The extract yield of S. dentifolium was typically 2.5%. This means that for every 100 g of S. dentifolium biomass, 2.5 g of active compounds were extracted. Extract yield may vary depending on a variety of factors including algae species, extraction method, and extraction conditions [68, 69]. Darfiah and Latama [69] reported that the methanolic extract yield Sargassum sp. was 2.4%. The importance of the extract yield in large-scale utilization is a critical factor in determining the cost-effectiveness and efficacy of bioactive substances that can be obtained from a given amount of algal biomass.
3.3 Total carbohydrates, proteins, and lipids contents
Seaweeds are primarily composed of carbohydrates, proteins, and lipids, which represent their main biochemical constituents. S. dentifolium, like all autotrophic organisms, produces carbohydrates through the process of photosynthesis as an energy source needed to complete the metabolic processes, as well as being stored as a reserve of energy in the form of various chemical compounds. The results (Fig. 2) revealed that S. dentifolium contains a moderate amount of 25.80% of the total carbohydrates content of its total dry weight. Fouda et al. [21] compared the total carbohydrate content of three Sargassum species, S. latifolium, S. aspirofolium, and S. muticum, from the Red Sea at Hurghada Coast, where they reported that the total carbohydrates contents were 41.42, 39.25, and 24.79%, respectively. However, certain species of Sargassum exhibited lower quantities of carbohydrates. Robledo and Freile Pelegrín [70], for example, reported that Sargassum filipendula contains 3.73% carbohydrates of its dry weight. Proteins are complex molecules composed of long chains of amino acids, and they play important roles in the structure and function of cells including enzymes, structural components, and transport and defense molecules. Brown algae have relatively low protein contents (~ 24% of the dry weight), unlike green and red algae, which have higher protein levels [17, 71, 72]. The results of the total protein content in S. dentifolium showed that the percentage of protein was 8.40% of dry weight. Wong and Chikeung Cheung [73] reported a significant wide difference in protein content among three Sargassum species, ranging from 7.81–48.0%. However, most of the other studies recorded relatively low protein contents, ranging from 3–16% of dry weight, e.g., [21, 26, 74,75,76]. Emam et al. [35] studied the protein content of S. dentifolium collected from the same site as this study and reported that the protein content was lower (0.882% fresh weight) compared to our result (8.40% dry weight), indicating that the protein content may vary depending on the season and biomass state (i.e., fresh, or dry). Lipids constitute about 1–5% of the dry weight of seaweed and include different groups of fatty acids, sterols, and dyes necessary to store energy, membrane structure, and the regulation of physiological processes. The present study revealed that the lipid content of S. dentifolium was 2% of the dry weight (Fig. 2). Previous studies have revealed that seaweeds contain relatively low amounts of lipids of less than 5% of dry weight [24,25,26, 77] which makes them beneficial for human health as a food source due to their low energy density. El-shafay [36] stated that the lipid content in Sargassum vulgare and Sargassum fusiforme, collected from Hurghada, along the Red Sea coastal, Egypt, was very low, 0.0403 and 0.0204% of total dry matter, respectively.
Total contents (%) of carbohydrates, proteins, lipids, phenolics, and flavonoids in S. dentifolium extract (left), with detailed quantities (right) of phenolic acids (solid) and flavonoids (dashed)
3.4 Volatile and non-volatile constituents
As a part of its metabolic process, brown seaweeds produce volatile compounds as a defense mechanism against predators and pathogens, as well as chemical communication [78,79,80]. Results of GC/MS analysis of the volatile and non-volatile components in S. dentifolium revealed the presence of 20 peaks, 14 peaks were identified and represented 91.31% of the total constituents (Table 1, and Fig. 3). The most abundant compounds of the total extract were, phytol (volatile; RT: 49.5; Relative %: 50), methyl butyric acid (volatile; RT: 10.5; Relative %: 9.55), palmitic acid (non-volatile; RT: 46.5; Relative %: 6.0) and stearic acid, (non-volatile; RT: 50.6; Relative %: 5.30). Phytol is sesquiterpene alcohol, that is produced by the breakdown of chlorophyll and other organic compounds in seaweeds. Phytol is a hydrophobic compound and is commonly used as a flavoring agent, fragrance, and in various cosmetics, as well as in the production of lubricants, polymers, and polyethylene. Pharmaceutically, phytol is used as an anti-inflammatory [81,82,83], anti-cancer [83,84,85], antioxidant [83, 86, 87], antiviral [88, 89], and antimicrobial [83, 90, 91] agent. Saturated fatty acids (SFAs) were the most frequently detected chemical groups in S. dentifolium extract, accounting for 6 compounds (40%) out of the total of 15 identified compounds with a total relative ratio of 25.45% (Table 1), including one short chain fatty acid (methyl butyric acid), two medium chain FAs (suberic acid and caproic acid), and three long chain FAs (palmitic acid, stearic acid, and margaric acid). Palmitic acid has been reported as the most frequent saturated fatty acid in seaweeds [25, 28, 92,93,94]. Algae produce SFAs to maintain membrane integrity and increase their energy storage capacity in response to environmental stress conditions [95]. Matloub and Awad [19] investigated the volatile fractions of S. Asperifolium, S. dentifolium, and S. linifolium and identified a variety of compounds, including terpenes, phenolic compounds, free fatty acids, and esters. Palmitic acid was the major fatty acid in all three Sargassum species studied. On the contrary, in a study conducted by Shanab [96], palmitic acid was not detected in the dichloromethane extract of S. dentifolium. The saturated fatty acids (SFAs) detected in the current study, along with other identified volatile and non-volatile constituents, such as carboxylic acids, a diterpene, allyl chain-substituted phenols, an aromatic amine, and an alpha-amino acid, have a variety of pharmaceutical applications, as shown in Table 1.
Results of GC/MS analysis of volatile and non-volatile constituents in S. dentifolium extract
3.5 Total phenolic and flavonoid content; and compounds
Seaweeds produce phenolic compounds for a variety of biological regulations, including growth and development, defense against herbivores and pathogens, and protection against UV radiation and oxidative stress [97, 98]. Results of the colorimetric assays revealed that the methanolic extract of S. dentifolium exhibited a total phenolic content of 50.6 mg g−1 (5.06%) and total flavonoids of 33.9 mg g−1 (3.39%) of total dry weight (Fig. 2).
The amount of phenols in seaweeds is affected by spatiotemporal changes in environmental factors [12, 97, 124], consequently, the estimated quantity of total phenols in S. dentifolium has varied among different studies, with values ranging from 0.82 mg g−1 of fresh weight [35] and 12.35 [27] to 620.13 mg g−1 [53] of dry weight. The HPLC analysis of the detailed composition showed the presence of 6 phenolics and 2 flavonoids (Table 2 and Fig. 4). Three phenolic compounds belong to hydroxybenzoic acids, gallic acid (77.25 µg g−1), syringic acid (28.44 µg g−1), and methyl gallate (5.85 µg g−1); two compounds belong to hydroxycinnamic acids, caffeic acid (23.83 µg g−1) and coumaric acid (4.06 µg g−1); and one belongs to hydrolyzable tannins, ellagic acid (15.57 µg g−1) have been identified. As for the two flavonoids, naringenin (52.77 µg g−1) which belongs to the group of hydroxy flavanones, and rutin (33.55 µg g−1) which belongs to the hydroxy flavonols were determined.
HPLC profile of phenolic acids and flavonoids of S. dentifolium extract
Gallic acid and naringenin were prominent in S. dentifolium extract. Several studies have reported the detection of gallic acid and naringenin, in varying concentrations, in Sargassum sp. extracts [38, 125,126,127]. Gallic acid is a trihydroxy benzoic acid with the molecular formula C6H2(OH)3COOH, each OH group represents a hydroxyl (-OH) functional group, and the COOH group represents a carboxylic acid (-COOH) functional group. The C6H2 portion of the molecule is a benzene ring with three hydroxyl groups attached at different positions (Fig. 5-A). The structure of gallic acid makes it a versatile chemical with many useful pharmacological and biological applications, for instance, it has strong antioxidant activity due to the presence of three hydroxyl groups on the benzene ring which can scavenge free radicals and protect cells from oxidative damage [128, 129]. Gallic acid has also been shown to have anti-inflammatory, anti-cancer, antiviral, and antimicrobial activity [130,131,132,133,134,135]. Naringenin is a hydroxy flavanone, a type of flavonoid with the molecular formula C15H12O5. The structure consists of two aromatic rings and a three-carbon chain that links the two aromatic rings together, with three hydroxyl (-OH) groups attached at different positions (Fig. 5-B). In addition to naringenin being used as an important starting material for the synthesis of certain flavonoids [136], it has also been demonstrated to possess a wide range of potential health benefits due to its anti-inflammatory, antioxidant, anti-cancer, antiviral, and antimicrobial properties [137,138,139,140,141,142]. However, the identified phenolics and flavonoids have a variety of bioactivities as shown in Table 2.
Chemical structure of major phenolic and flavonoid compounds, (A) gallic acid and (B) naringenin, identified in S. dentifolium extract
3.6 Antioxidant activity
Antioxidant properties refer to the ability of a material to prevent or inhibit oxidative damage due to the imbalance in the regulation of biological functions caused by free radicals. Free radicals are highly reactive molecules that can damage cells and tissues, leading to various health problems, including aging, cancer, and heart disease. The stable free radical DPPH is commonly used to assess the antioxidant capacity of natural compounds due to its simplicity and precision. The S. dentifolium extract exhibited radical scavenging activity between 1.23% to 85.04% at concentrations ranging from 2.5 to 1280 μg ml−1. In comparison, ascorbic acid, a standard antioxidant, demonstrated higher activity, ranging from 34.57% to 98.91% at the same concentrations range (Fig. 6). The results indicate that the radical scavenging activity of S. dentifolium extract increased with increasing concentration, reaching a maximum of 85.04%. This is consistent with the findings of Shanab [96], who reported that the highest free radical scavenging activity (86%) was observed in the highest concentration of the dichloromethane extract of S. dentifolium. The antiradical efficacy (EC50) value represents the concentration of the extract required to scavenge 50% of free radicals in the DPPH test. Lower EC50 values indicate higher antioxidant activity, which means that a lower concentration of the compound is needed to effectively neutralize free radicals [181]. In the current study, a reported EC50 value of 298 µg mL−1 indicates moderate antioxidant activity. However, when this value is compared to the EC50 value for ascorbic acid, a known potent antioxidant, of 7.7 µg mL−1, it indicates that it has much stronger antioxidant activity compared to the extract.
Antioxidant activity measured by the percentage of DPPH radical scavenging activity of S. dentifolium extract
The radical-scavenging properties of seaweeds biomass have been reported to be associated with its phenolic and flavonoid content [35, 38], this is because phenolic and flavonoid compounds can donate hydrogen atoms to free radicals, thus neutralizing them and protect cells from damage [12, 182,183,184,185,186]. The moderate antioxidant activity observed in S. dentifolium may be attributed to the type and quantity of phenolic compounds and flavonoids present in the extract, as shown in Table 2, however, More comprehensive studies and evaluations using other antioxidant assays such as Cupric Ion Reducing Antioxidant Capacity (CUPRAC), Ferric Reducing Antioxidant Power (FRAP), and the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) radical cation-based assays, are needed to fully understand the antioxidant potential of the extract.
3.7 Cytotoxic activities
Cytotoxic activity of the methanol extract of S. dentifolium has been evaluated against HepG2 (human hepatocellular liver carcinoma), HCT-116 (human colon carcinoma), and Vero (derived from the kidney of African green monkey) cells using viability assay. S. dentifolium extract showed a strong cytotoxic effect against HepG2 (CC50 = 16.3 ± 0.96 µg mL−1) and HCT-116 (CC50 = 15.1 ± 0.63 µg mL−1), indicating its potential as a source of anti-cancer agents, while it showed a weak cytotoxic effect against Vero cells (CC50 = 78.34 ± 3.42 µg mL−1), suggesting that it may have a selective cytotoxicity towards cancer cells rather than normal cells, which is a desirable characteristic in potential anti-cancer agents [187,188,189]. The CC50 values for HepG2 and HCT-116 cells are similar (p-value ≥ 0.05), indicating that the extract's cytotoxic effect is not cell-type specific and could potentially be effective against other cancer cell types as well. However, the results indicate that the S. dentifolium extract had significantly higher CC50 values, i.e., lower cytotoxicity (p-value < 0.05) compared to the standard positive control, Vinblastine sulfate (Fig. 7). Matloub and Awad [28] found that the methanolic crude extract of S. dentifolium had significant cytotoxic activity against the HepG2 cell line. However, previous studies have shown that other Sargassum species collected from the Egyptian Red Sea and Mediterranean coasts had low to no cytotoxic activity against HepG2 or HCT-116 cells. For example, Abu-Khudir et al. [46] found that Sargassum linearifolium extract had a weak cytotoxic effect against HepG2 cells, while Hassan et al. [190] found that Sargassum arnaudianum extract had no cytotoxic activity against HepG2 cells. Mofeed et al. [39] also found that S. filipendula extract had less cytotoxicity on HCT-116 cells. Several studies attributed the cytotoxic activity of seaweeds extracts to the presence of a variety of active compounds, which are mainly polysaccharides, terpenes, phenolic, and flavonoid compounds [39, 191,192,193,194,195,196,197], which were mostly identified in the S. dentifolium extract in this study (Fig. 1, Table 1 and 2).
Cytotoxicity CC50 (µg mL.−1) of S. dentifolium extract and standard VS against HepG2, HCT-116, and Vero cells. Capital letters represent the pairwise comparison between cell lines within the cytotoxicity of S. dentifolium extract only. Asterisks represent pairwise comparisons between the cytotoxicity of S. dentifolium extract and standard VS within each cell line. Error bars represent standard deviation (SD)
3.8 Antiviral activity
The antiviral activity, represented by the viral inhibition rate (VIR) of S. dentifolium extract was tested against HAV-10 (hepatitis A virus), HSV-1 (herpes simplex virus 1; usually causes oral herpes), and HSV-2 (herpes simplex virus 2; typically causes genital herpes). The results shown in Table 3 revealed that the extract has a moderate VIR of 34.1% against HAV-10 with a Maximal Non-Cytotoxic Concentration (MNCC) of 20 µg mL−1 of the extract, while amantadine, a reference drug, has an excellent antiviral effect of 83.24% at MNCC of 100 µg mL−1. The extract showed a weak VIR of 18.43% and 5.79% against HSV-1 and HSV-2, respectively, at a low MNCC of 20 µg mL−1. S. dentifolium extract showed a low MNCC (20 µg mL−1) for the three tested viruses, which suggests that it may be more toxic to healthy host cells at higher concentrations. This is a concern, as a higher MNCC is desirable in antiviral drugs to ensure the safety of the host cells [198, 199].
Different species of Sargassum have been shown to have different antiviral activities against a variety of viruses, including HIV and herpes simplex viruses (HSV-1 and HSV-2). The results of Zaid et al. [40] reported that Sargassum latifolium, collected from the same site as the current study, had good antiviral activity against HAV-10, HSV-1, and HSV-2, while Hudson et al. [200] showed that among the extracts of 13 seaweeds, Sargassum sagamianum extract had a significant broad-spectrum antiviral activity against all tested viruses including HSV-1 in contrast to other extracts that were only active against specific viruses. Further spatiotemporal research, in vitro and in vivo experiments, as well as the identification of the active compounds, are needed to fully understand, assess, and validate the potential therapeutic application of S. dentifolium extracts as an antiviral agent.
3.9 Antimicrobial activity
The antimicrobial activity results reported in Table 4 showed that the methanolic extract of S. dentifolium biomass did not exhibit antibacterial activity against Gram-positive bacteria, S. aureus, and B. subtilis, as well as against Gram-negative bacterium E. coli. The extract did not show antifungal activity against A. fumigatus. However, the extract showed antibacterial activity against the Gram-negative bacterium P. vulgaris and antifungal activity against C. albicans, with a 15 and 9-mm zone of inhibition, respectively. These results are in contrast to those reported by Shanab [96], who found that S. dentifolium dichloromethane and ethanol (70%) extracts showed antimicrobial activity against B. subtilis, E. coli, Staphylococcus albus, Streptococcus fuels, and C. albicans (inhibition zone in a range of 10-12 mm), but not against Aspergillus flavus. Salem et al. [33] reported that some pathogenic bacteria were the most resistant to methanolic and ethyl acetate extracts of S. dentifolium biomass collected from the same location as the current study. They also concluded that the antibacterial activity of S. dentifolium depended on the solvent used in the extraction process. Matloub and Awad [28], on the other hand, found that antimicrobial activities against bacteria and fungi depend on the quality and quantity of the biochemical compounds present in the fractions isolated from S. dentifolium extract. In this study, the limited antimicrobial activity of the S. dentifolium extract was probably not due to antimicrobial resistance, as indicated by the comparison of the extract results with those of the positive controls. This suggests that the limited antimicrobial activity of the extract may be due to the absence or insufficient levels of bioactive compounds with specific targets or mechanisms of action. These compounds are necessary to disrupt bacterial cell walls or interfere with other cellular biological processes, which would make the extract effective against a wide range of pathogens. However, many factors could contribute to the extract's limited antimicrobial activity, including differences in the extraction method, the target specificity of the compounds, the strain of the microorganism, the testing method, and the potential synergistic or antagonistic effects of the bioactive compounds [38, 46, 48, 93, 201, 202].
4 Conclusion
The discovery of biologically active compounds in seaweeds highlights their potential for the development of new therapies and health-promoting products. This study profiled the biochemical composition and evaluated the bioactivity of the methanolic extract of S. dentifolium biomass, revealing that it contains varying amounts of carbohydrates, protein, lipids, non-volatile and volatile substances, phenols, and flavonoids, which give the biomass potential antioxidant, cytotoxic, antiviral, and antimicrobial properties. Further research is likely to unveil more discoveries regarding the utility value of S. dentifolium biomass across various applications. This research could contribute to the development of new functional macroalgae-based food or nutraceutical products with potential health benefits. Additionally, it could provide insight into the variability of the biochemical composition of Sargassum species from different regions and how this variability affects the bioactivity of their compounds. In conclusion, this study provides a basis for further research on the biochemical composition and bioactivity of S. dentifolium biomass, and future studies should focus on identifying the specific bioactive compounds and their mechanisms of action, as well as evaluating the safety, efficacy, and sustainability of extracting and using these compounds from S. dentifolium biomass. With further research, S. dentifolium biomass could be utilized on a large scale to develop new functional foods, nutraceuticals, and/or pharmaceuticals with potential health benefits.
Data availability
The data used to support the findings of this study are available from the corresponding author upon request.
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Conceptualization: Muhamed A. Helal, Ahmed D. El-Gamal, Atef A. Elhela, and Ehab F. El-Belely.; Methodology and Resources: Muhamed A. Helal, Ahmed D. El-Gamal, Atef A. Elhela, and Ehab F. El-Belely.; Validation and Visualization: Muhamed A. Helal, Ahmed D. El-Gamal, Atef A. Elhela, and Ehab F. El-Belely.; Formal Analysis: Muhamed A. Helal, Ahmed D. El-Gamal, Atef A. Elhela, and Ehab F. El-Belely.; Writing Original Draft Preparation: Muhamed A. Helal, Ahmed D. El-Gamal, Atef A. Elhela, and Ehab F. El-Belely.; Writing Review and Editing: Muhamed A. Helal, Ahmed D. El-Gamal, Atef A. Elhela, and Ehab F. El-Belely.; Supervision: Ahmed D. El-Gamal, Atef A. Elhela, and Ehab F. El-Belely. All authors have read and agreed to the published version of the manuscript.
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Helal, M.A., El-Gamal, A.D., Elhela, A.A. et al. Biochemical composition and bioactivity of the crude extract of Sargassum dentifolium (Turner) C. Agardh, of Western Coast of the Red Sea, Hurghada, Egypt. Biomass Conv. Bioref. (2023). https://doi.org/10.1007/s13399-023-04721-9
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DOI: https://doi.org/10.1007/s13399-023-04721-9