Ulvan, a Seaweed-Derived Sulfated Polysaccharide: Comparison
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Cancer is one of the most worldwide spread diseases and causes maximum death. Treatment of cancer depends on the host immune system and the type of drugs. The inefficiency of conventional cancer treatments as a result of drug resistance, nontargeted delivery, and chemotherapy-related negative side effects has caused bioactive phytochemicals to come into focus. Ulvan is a polysaccharide derived from various green seaweeds of the

Ulva

species in the family Ulvaceae. It has been demonstrated to have potent anticancer and anti-inflammatory properties through the modulation of antioxidants. It is vital to understand the mechanisms underlying the biotherapeutic activities of Ulvan in cancer and its role in immunomodulation.

  • ulvan
  • anticancer
  • cytotoxicity
  • antioxidant

1. Introduction

Cancer is a major public health concern [1]. Off-target toxicity, drug resistance, and the financial burden of treatment costs pose potential obstacles in clinical oncology despite advancements in diagnosis, prognosis, and conventional therapeutic treatments [2]. In terms of global incidence and annual mortality, cancer has surpassed many other diseases and is now the second leading cause of death worldwide [3]. Global cancer statistics indicate that there were 9.6 million cancer-related deaths and an estimated 18.1 million cancer cases in 2018. Radiation therapy, immunotherapy, chemotherapy, and surgical methods have advanced to the clinical stage; however, despite extraordinary efforts over the past decades to improve conventional therapeutic approaches, some patients still lack treatment options [4,5][4][5]. The use of chemotherapy drugs at doses high enough to eradicate all drug-resistant subpopulations is constrained by side effects, including cardio-, hepato-, and neurotoxicity, along with nephron and life-threatening haematopoietic toxicity [6,7,8,9][6][7][8][9].
Over the past seven decades, natural compounds have been the primary source of innovative medication prospects [10,11][10][11]. Phytochemicals have emerged as prospective anticancer treatments, either alone or in combination with other chemotherapeutic drugs, due to their efficient tumour-targeting ability and low toxicity to normal tissues [10,11,12,13][10][11][12][13]. Phytochemicals act as chemopreventive and synergistic agents, increasing anticancer activity and decreasing chemotherapy-associated toxicity [14]. Pro-oxidative and antioxidative properties of phytochemicals positively regulate the homeostasis of reactive oxygen species (ROS), modifying apoptotic signals to prevent cancer [10,11][10][11]. In general, plant-derived polyphenols dynamically alter apoptotic and autophagic cell death signalling in cancer cells while blocking these signals in healthy organs surrounding the tumour to protect them [10,11][10][11]. Although few novel phytochemicals have been extensively studied in clinical settings, their potential to improve cancer therapy is promising [15].
Marine and freshwater ecosystems are rich in biodiversity and novel bioactive compounds [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Ulvan is a primary polysaccharide found in green seaweeds of the genus Ulva (family Ulvaceae). Ulva is a widely produced natural fiber and is considered an important food source. It also contains additional ingredients for biomass fuel production and therapeutic supplements [32]. Ulvan is a cell wall polysaccharide that makes up 9–36% of the dry-weight biomass of Ulva species and is mainly composed of uronic acids such as glucuronic acid, iduronic acid, sulfated rhamnose, and xylose [33]. Ulva species contain three other cell wall polysaccharides (cellulose, xyloglucan, and glucuronan) that make up to 45% of the dry-weight biomass when combined with ulvan [34]. Similar to ulvan, xyloglucan and glucuronan are soluble polysaccharides; however, they constitute a very small portion of cell wall polysaccharides [35]. Of the four polysaccharides found in the genus Ulva, only ulvan contains both rhamnose and iduronic acid in its cell wall [36]. The two primary repeating disaccharides are type A (A3S) and type B (B3S) ulvanobiuronic acid 3-sulfate [37,38,39][37][38][39]. Ulvan is a common food ingredient, and various studies have investigated its therapeutic potential [40,41][40][41]. Therapeutic applications of ulvan polysaccharides are gaining popularity in seaweed research [42]. The molecular structures of the chief repeating disaccharide units comprising ulvan are shown in Figure 1.
Marinedrugs 21 00300 g001
Figure 1. Structure of major repeating disaccharide units that comprise ulvan. Ulvanobiuronic acid A3s contains glucuronic acid attached to rhamnose 3-sulfate, while similar B3s also contain rhamnose 3-sulfate but have iduronic acid in place of glucuronic acid. Ulvanobioses are composed of rhamnose 3-sulfate attached to xylose. Xylose can contain a sulfate group, as seen in U2s, 3s.
The increased use of artificial chemicals in cancer treatment has resulted in many side effects and risks. Therefore, there is a global tendency to return to natural resources that are therapeutically effective, socially acceptable, and economically accessible to those with a lower socioeconomic status. As a result, Mondal many researchers have focused on finding new anticarcinogenic compounds from algae and plants [43,44,45][43][44][45]. Algal-derived sulfated polysaccharides have been shown to function as free-radical scavengers and antioxidants in the prevention of oxidative damage in living organisms [46,47,48,49,50][46][47][48][49][50].

2. Seaweeds: Potentially the Most Important Source of Bioactive Compounds

Lifestyle and dietary changes can prevent more than 33% of diseases such as cancer, diabetes, and chronic diseases linked with inflammation [51,52][51][52]. Nutritional supplements derived from natural sources may play important roles in disease prevention. Peptides, polysaccharides, amino acids, sterols, fatty acids, lipids, carbohydrates, polyphenols, vitamins, photosynthetic pigments, and minerals, found in marine algae, can act as potent antioxidants, and have antidiabetic and chemotherapeutic benefits in a variety of diseases [51,52][51][52].

2.1. Seaweeds as a Chief Source of Polysaccharides and Carbohydrates

Polysaccharides are abundant in seaweeds [53]. They make up about 4–76% of the total dry weight of the algae. Sulfuric acid polysaccharides, sulfated xylans, and galactans are examples of polysaccharides that are classified based on their chemical structures and are generally found in green algae. Brown algae also contain alginic acid, laminarin, fucoidan, and sargassan [54]. Red algae commonly contain agar, carrageenan, xylan, and floridean [55]. Due to the bioactive nature of these algal polysaccharides, they can be used as therapeutic candidates to address a wide range of human health issues [55]. For example, sulfated galactans such as carrageenans are widely used in the pharmaceutical and food industries. Brown seaweeds contain soluble fibers such as fucans, alginates, and laminarans, while red seaweeds contain soluble fibers such as sulfated galactans (carrageenans and agars), floridean starch, and xylans [56]. In addition to uronic acids, galactose, xylose, rhamnose, and arabinose, green algae also contain polysaccharides containing mannans, starches, xylans, and ionic sulfate groups. Numerous polysaccharides are classified as dietary fibers and are divided into two categories: insoluble and soluble [57,58][57][58]. In contrast to their dry weight, seaweeds contain 25–75% dietary fiber, which is a higher percentage than that found in vegetables and fruits [59]. Algal dietary fibers have various health benefits, including antitumor, anticancer, anticoagulant, and antiviral properties [60]. Brown macroalgae contain numerous fucoidans in their cell walls [42,61][42][61]. Fucoidans have a wide range of biological effects, including antioxidant, anticancer, anti-inflammatory, antidiabetic, antiviral, antithrombotic, and anticoagulant properties [62,63,64,65][62][63][64][65]. They also influence the human immune system [62,63,64,65][62][63][64][65]. Furthermore, laminarin, which is abundant in brown algae and acts as an inhibitor of intestinal metabolism, is the second most abundant source of glucan [58].

2.2. Ulva and Its Food Value

Seaweed is increasingly being considered as a source of nutraceuticals and functional foods, where it can perform a variety of roles ranging from simple nutrition to sophisticated physiological mechanisms because it contains high levels of polysaccharides and natural fibers. In tThis context, the e green seaweed Ulva lactuca has been widely used as a food and nutraceutical agent [66]. Ulva spp. are often rich in bioactive compounds known for their health-promoting properties and are traditionally used as a source of functional or nutraceutical foods. These products are sometimes consumed as whole foods or as dietary supplements. Seaweeds are assumed to contain several physiologically active compounds that can be employed as therapeutic agents in dietary supplements [67]. Ulva spp., such as U. linza, have evolved into supplements that can be used to treat a variety of ailments and as food and biomedical preservatives [68]. Numerous studies have established that U. compressa, U. rigida, and U. intestinalis can be employed as healing agents in antioxidant, anticancer, anti-inflammatory, antidiabetic, and antibacterial medicines [48,62,69,70,71,72][48][62][69][70][71][72].

3. Ulvan Has the Foremost Powerful Antioxidant Activity

In 2019 and 2020, several Ulva sp. sources were discovered to have antioxidant effects, including U. rigida, U. australis, U. lactuca, and U. ohnoi [73,74,75][73][74][75]. The antioxidant ability of ulvan was assessed using various in vitro methods, including DPPH (2,2-diphenyl-1-picrylhydrazyl), superoxide, hydroxyl, ferric reducing antioxidant power (FRAP), and lipid peroxidation inhibition experiments. Compared to other commonly used methods, such as reducing power and superoxide anion radical scavenging activity, the DPPH assay is the fastest approach for measuring antioxidant capabilities [74,76,77,78,79][74][76][77][78][79]. The antioxidant properties of ulvan from Ulva sp. have been associated with sulfate concentration and molecular weight [76,80,81,82][76][80][81][82]. Seaweeds such as U. lactuca can provide antioxidants. This alga exhibits antiradical properties by decreasing lipid peroxidation and enhancing antioxidant enzyme activity [83]. The degree of substitution of sulfate groups along the polymeric backbone is correlated with antioxidant activity [83]. Several studies have been conducted to compare methodologies and establish which method is more sensitive. As a method for tracking changes in peroxide generation, ORAC (Oxygen Radical Absorbance Capacity), FRAP, and β-carotene linoleic acid bleaching can be used [84,85][84][85]. The antioxidant effectiveness of ulvan has been compared with that of other substances such as BHA (Butylated hydroxyanisole), BHT (Butylated hydroxytoluene), and tocopherol. Although peroxide inhibition with ulvan (54.9%) was lower than that with BHA (73.20%) and BHT (69.40%), the differences were not statistically significant [77]. Ulvan exhibits antioxidative potential, as shown by a comparison of the numerous methodologies described above, according to an antioxidant testing study. To assess the antioxidant capabilities of ulvan, animal products, such as erythrocytes, and 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH) tests have also been used [86,87][86][87]. Ulvan inhibits lipid peroxidation and lowers ROS formation by AAPH, as measured by thiobarbituric acid reactive substances (TBARS) in erythrocytes [86]. Sulfate and low-molecular-weight polysaccharides are used for antioxidant action [88,89,90][88][89][90]. The latter inhibits choline stresses and may be neuroprotective [38]. Malondialdehyde levels are reduced, whereas glutathione peroxidase (GSH), catalase (CAT), superoxide dismutase (SOD), telomerase, and other antioxidants are increased by oligosaccharide components [91,92][91][92]. Ulvan’s IC50 for radical activity is 623.58 µg/mL, whereas its IC50 for scavenging superoxide anions is 785.48 µg/mL. Pigments (chlorophyll and carotenoids), essential oils, and low-molecular-weight polysaccharides are the antioxidants found in U. lactuca [82]. The antioxidant properties of ulvan are also affected by the extraction process. Methanol extracts cause greater inhibition than water extracts, with a higher percent inhibition [93]. Furthermore, compared to acid extraction, enzymatic extraction results in a larger percentage of inhibition [94]. In addition to in vitro antioxidant studies, animals can be exposed to radicals such as thiacloprid and then treated with an extract [39,95][39][95]. Ulvan decreased oxidative stress in hypercholesterolemic mice by boosting the activity of antioxidant enzymes (110% for CAT, 77% for GPx, and 23% for SOD) and the levels of nonenzymatic antioxidants (GSH-stressed mice were treated with ulvan, which prevented abnormal lipid metabolism, controlled hepatic antioxidant defence mechanisms, and decreased lipid peroxidation) [96,97][96][97].

4. Immunomodulating Activity of Ulvan

Humans use the immune system as a defence against invading agents. The modulation of the immune system is critical for disease management in humans. The importance of the immune system stems from the need to eliminate and control pathogenic and nonpathogenic microbes that can disrupt the body’s ability to maintain homeostasis [136][98]. For example, seaweed can be used to boost the immune system. Ulva sp. has immunomodulatory properties, and ulvan is its active constituent. Over the last five years, various Ulva species, most notably Ulva intestinalis, have been studied for their potential as immunomodulators. U. intestinalis, for instance, possesses both biochemical and immunomodulatory properties including in J774A macrophage cells where it increases the production of nitric oxide (NO) and of proinflammatory cytokines such as tumour necrosis factor (TNF-α) and interleukin-1β (IL-1β) [130][99]. Other studies support the in vitro findings that ulvan from U. ohnoi has immunomodulatory properties. To quantify ulvan’s in vitro immunomodulatory effect, the ability of the ulvan fraction to moderate inflammation produced by LPS-stimulated murine macrophages RAW264.7 was measured at the molecular level. All ulvan fractions showed no toxicity to RAW 264.7 cells at doses less than 100 g/mL for more than 48 h. The higher molecular weight ulvan fractions of interleukin-10 and prostaglandin E2 have anti-inflammatory properties at 100 g/mL [77]. Water-soluble sulfated polysaccharides were extracted from U. intestinalis and fractionated using a DEAE Sepharose rapid flow column to determine their molecular characteristics and macrophage cell-stimulating activity [137][100]. U. ohnoi’s immunomodulatory effects on Senegalese soles have also been studied in the fields of nutraceuticals and aquaculture (Solea senegalensis).) [134][101]. Furthermore, ulvan extracted from U. ohnoi to obtain fractions of various molecular weights (7, 9, 13, 21, and 209 kDa) demonstrated immunomodulatory activity [77]. Ulvan extracted from U. ohnoi displayed multiple immune system signalling pathways that were activated in different tissues as a result of intraperiotnean injection of ulvan into Senegalese sole juveniles, according to gene expression profiles [134][101]. Furthermore, ulvan modulates immune system pathways after challenge, and Phdp is a potential candidate nutraceutical and/or vaccine adjuvant for aquaculture [134][101]. In S. senegalensis macrophages, ulvan has a stimulatory effect that is enhanced when delivered via nanoparticles. Ulvan nanoparticles have the potential to act as macrophage activators and an immune stimulant in marine fish feed [138][102]. Dietary ulvan supplementation from U. clathrata increases the immune response in Nile tilapia [139][103]. The ulvan diet provides numerous health benefits against F. columnare by increasing antioxidant capacity, improving growth rate, innate–adaptive defence mechanisms, and modulating immune-antioxidant-related gene expression. Ulvan influences the innate–adaptive defence mechanism and expression of antioxidant genes in fish [140][104]. Supplementation with green macroalgae (Ulva intestinalis) increases the expression of immune-related genes such as lysozyme (Lyz) and interleukin 1 beta (IL-1β). Gutweed treatment significantly increased the expression of antioxidant-related genes (SOD and CAT) and growth hormone (GH) and insulin-like growth factor-I (IGF-1). Furthermore, dietary U. intestinalis improved immunity, and the same effects were observed on antioxidant and growth-related gene expression in zebrafish [141][105]. The Molecular weight of ulvan influences the inflammatory response of murine macrophages in vitro [142][106].

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