Marine Sulfated Polysaccharides as Promising Antiviral Agents: A Comprehensive Report and Modeling Study Focusing on SARS CoV-2

SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is a novel coronavirus strain that emerged at the end of 2019, causing millions of deaths so far. Despite enormous efforts being made through various drug discovery campaigns, there is still a desperate need for treatments with high efficacy and selectivity. Recently, marine sulfated polysaccharides (MSPs) have earned significant attention and are widely examined against many viral infections. This article attempted to produce a comprehensive report about MSPs from different marine sources alongside their antiviral effects against various viral species covering the last 25 years of research articles. Additionally, these reported MSPs were subjected to molecular docking and dynamic simulation experiments to ascertain potential interactions with both the receptor-binding domain (RBD) of SARS CoV-2’s spike protein (S-protein) and human angiotensin-converting enzyme-2 (ACE2). The possible binding sites on both S-protein’s RBD and ACE2 were determined based on how they bind to heparin, which has been reported to exhibit significant antiviral activity against SARS CoV-2 through binding to RBD, preventing the virus from affecting ACE2. Moreover, our modeling results illustrate that heparin can also bind to and block ACE2, acting as a competitor and protective agent against SARS CoV-2 infection. Nine of the investigated MSPs candidates exhibited promising results, taking into consideration the newly emerged SARS CoV-2 variants, of which five were not previously reported to exert antiviral activity against SARS CoV-2, including sulfated galactofucan (1), sulfated polymannuroguluronate (SPMG) (2), sulfated mannan (3), sulfated heterorhamnan (8), and chondroitin sulfate E (CS-E) (9). These results shed light on the importance of sulfated polysaccharides as potential SARS-CoV-2 inhibitors.     

Emergent Sources of Prebiotics: Seaweeds and Microalgae

In recent years, scientists have become aware that human microbiota, in general, and gut microbiota, in particular, play a major role in human health and diseases, such as obesity and diabetes, among others. A large number of evidence has come to light regarding the beneficial effects, either for the host or the gut microbiota, of some foods and food ingredients or biochemical compounds. Among these, the most promising seem to be polysaccharides (PS) or their derivatives, and they include the dietary fibers. Some of these PS can be found in seaweeds and microalgae, some being soluble fibers, such as alginates, fucoidans, carrageenans and exopolysaccharides, that are not fermented, at least not completely, by colonic microbiota. This review gives an overview of the importance of the dietary fibers, as well as the benefits of prebiotics, to human health. The potential of the PS from marine macro- and microalgae to act as prebiotics is discussed, and the different techniques to obtain oligosaccharides from PS are presented. The mechanisms of the benefits of fiber, in general, and the types and benefits of algal fibers in human health are highlighted. The findings of some recent studies that present the potential effects of prebiotics on animal models of algal biomass and their extracts, as well as oligo- and polysaccharides, are presented. In the future, the possibility of using prebiotics to modulate the microbiome, and, consequently, prevent certain human diseases is foreseen.     

Marine Natural Products: Promising Candidates in the Modulation of Gut-Brain Axis towards Neuroprotection

In recent decades, several neuroprotective agents have been provided in combating neuronal dysfunctions; however, no effective treatment has been found towards the complete eradication of neurodegenerative diseases. From the pathophysiological point of view, growing studies are indicating a bidirectional relationship between gut and brain termed gut-brain axis in the context of health/disease. Revealing the gut-brain axis has survived new hopes in the prevention, management, and treatment of neurodegenerative diseases. Accordingly, introducing novel alternative therapies in regulating the gut-brain axis seems to be an emerging concept to pave the road in fighting neurodegenerative diseases. Growing studies have developed marine-derived natural products as hopeful candidates in a simultaneous targeting of gut-brain dysregulated mediators towards neuroprotection. Of marine natural products, carotenoids (e.g., fucoxanthin, and astaxanthin), phytosterols (e.g., fucosterol), polysaccharides (e.g., fucoidan, chitosan, alginate, and laminarin), macrolactins (e.g., macrolactin A), diterpenes (e.g., lobocrasol, excavatolide B, and crassumol E) and sesquiterpenes (e.g., zonarol) have shown to be promising candidates in modulating gut-brain axis. The aforementioned marine natural products are potential regulators of inflammatory, apoptotic, and oxidative stress mediators towards a bidirectional regulation of the gut-brain axis. The present study aims at describing the gut-brain axis, the importance of gut microbiota in neurological diseases, as well as the modulatory role of marine natural products towards neuroprotection.     

Pharmacological Activities of Sulfated Fucose-Rich Polysaccharides after Oral Administration: Perspectives for the Development of New Carbohydrate-Based Drugs

Marine organisms are a source of active biomolecules with immense therapeutic and nutraceutical potential. Sulfated fucose-rich polysaccharides are present in large quantities in these organisms with important pharmacological effects in several biological systems. These polysaccharides include sulfated fucan (as fucoidan) and fucosylated chondroitin sulfate. The development of these polysaccharides as new drugs involves several important steps, among them, demonstration of the effectiveness of these compounds after oral administration. The oral route is the more practical, comfortable and preferred by patients for long-term treatments. In the past 20 years, reports of various pharmacological effects of these polysaccharides orally administered in several animal experimental models and some trials in humans have sparked the possibility for the development of drugs based on sulfated polysaccharides and/or the use of these marine organisms as functional food. This review focuses on the main pharmacological effects of sulfated fucose-rich polysaccharides, with an emphasis on the antidislipidemic, immunomodulatory, antitumor, hypoglycemic and hemostatic effects.     

The Ameliorative Effect of COST on Diet-Induced Lipid Metabolism Disorders by Regulating Intestinal Microbiota

Background: Chitosan oligosaccharides, with an average molecular weight ≤ 1000 Da (COST), is a natural marine product that has the potential to improve intestinal microflora and resist lipid metabolism disorders. Methods: First, by establishing a mice model of lipid metabolism disorder induced by a high fat and high sugar diet, it is proven that COST can reduce lipid metabolism disorder, which may play a role in regulating intestinal microorganisms. Then, the key role of COST in the treatment of intestinal microorganisms is further confirmed through the method of COST-treated feces and fecal bacteria transplantation. Conclusions: intestinal microbiota plays a key role in COST inhibition of lipid metabolism disorder induced by a high fat and high sugar diet. In particular, COST may play a central regulatory role in microbiota, including Bacteroides, Akkermansia, and Desulfovibrio. Taken together, our work suggests that COST may improve the composition of gut microbes, increase the abundance of beneficial bacteria, improve lipid metabolism disorders, and inhibit the development of metabolic disorders.     

Prebiotics from Marine Macroalgae for Human and Animal Health Applications

The marine environment is an untapped source of bioactive compounds. Specifically, marine macroalgae (seaweeds) are rich in polysaccharides that could potentially be exploited as prebiotic functional ingredients for both human and animal health applications. Prebiotics are non-digestible, selectively fermented compounds that stimulate the growth and/or activity of beneficial gut microbiota which, in turn, confer health benefits on the host. This review will introduce the concept and potential applications of prebiotics, followed by an outline of the chemistry of seaweed polysaccharides. Their potential for use as prebiotics for both humans and animals will be highlighted by reviewing data from both in vitro and in vivo studies conducted to date.     

Comparative Study of Sargassum fusiforme Polysaccharides in Regulating Cecal and Fecal Microbiota of High-Fat Diet-Fed Mice

Seaweed polysaccharides represent a kind of novel gut microbiota regulator. The advantages and disadvantages of using cecal and fecal microbiota to represent gut microbiota have been discussed, but the regulatory effects of seaweed polysaccharides on cecal and fecal microbiota, which would benefit the study of seaweed polysaccharide-based gut microbiota regulator, have not been compared. Here, the effects of two Sargassum fusiforme polysaccharides prepared by water extraction (SfW) and acid extraction (SfA) on the cecal and fecal microbiota of high-fat diet (HFD) fed mice were investigated by 16S rRNA gene sequencing. The results indicated that 16 weeks of HFD dramatically impaired the homeostasis of both the cecal and fecal microbiota, including the dominant phyla Bacteroidetes and Actinobacteria, and genera Coriobacteriaceae, S24-7, and Ruminococcus, but did not affect the relative abundance of Firmicutes, Clostridiales, Oscillospira, and Ruminococcaceae in cecal microbiota and the Simpson’s index of fecal microbiota. Co-treatments with SfW and SfA exacerbated body weight gain and partially reversed HFD-induced alterations of Clostridiales and Ruminococcaceae. Moreover, the administration of SfW and SfA also altered the abundance of genes encoding monosaccharide-transporting ATPase, α-galactosidase, β-fructofuranosidase, and β-glucosidase with the latter showing more significant potency. Our findings revealed the difference of cecal and fecal microbiota in HFD-fed mice and demonstrated that SfW and SfA could more significantly regulate the cecal microbiota and lay important foundations for the study of seaweed polysaccharide-based gut microbiota regulators.     

Seaweed Components as Potential Modulators of the Gut Microbiota

Macroalgae, or seaweeds, are a rich source of components which may exert beneficial effects on the mammalian gut microbiota through the enhancement of bacterial diversity and abundance. An imbalance of gut bacteria has been linked to the development of disorders such as inflammatory bowel disease, immunodeficiency, hypertension, type-2-diabetes, obesity, and cancer. This review outlines current knowledge from in vitro and in vivo studies concerning the potential therapeutic application of seaweed-derived polysaccharides, polyphenols and peptides to modulate the gut microbiota through diet. Polysaccharides such as fucoidan, laminarin, alginate, ulvan and porphyran are unique to seaweeds. Several studies have shown their potential to act as prebiotics and to positively modulate the gut microbiota. Prebiotics enhance bacterial populations and often their production of short chain fatty acids, which are the energy source for gastrointestinal epithelial cells, provide protection against pathogens, influence immunomodulation, and induce apoptosis of colon cancer cells. The oral bioaccessibility and bioavailability of seaweed components is also discussed, including the advantages and limitations of static and dynamic in vitro gastrointestinal models versus ex vivo and in vivo methods. Seaweed bioactives show potential for use in prevention and, in some instances, treatment of human disease. However, it is also necessary to confirm these potential, therapeutic effects in large-scale clinical trials. Where possible, we have cited information concerning these trials.     

茶叶对IBD肠道微生物菌群影响研究进展

茶叶具备独特的品质特征和保健功效,丰富的内含成分使其具有多种生物活性。近年来,各研究已清楚地表明茶叶具有调节IBD肠道微生物失调,增强机体免疫,调节消化道代谢,显著改善腹泻和结肠损伤等功效。本文就国内外关于茶叶中茶多酚、茶色素、茶多糖、茶皂素等有效成分对IBD肠道微生物菌群多样性影响的实验研究进行综述。     

Perspective on the Use of Sulfated Polysaccharides from Marine Organisms as a Source of New Antithrombotic Drugs

Thromboembolic diseases are increasing worldwide and always require anticoagulant therapy. We still need safer and more secure antithrombotic drugs than those presently available. Sulfated polysaccharides from marine organisms may constitute a new source for the development of such drugs. Investigation of these compounds usually attempts to reproduce the therapeutic effects of heparin. However, we may need to follow different routes, focusing particularly in the following aspects: (1) defining precisely the specific structures required for interaction of these sulfated polysaccharides with proteins of the coagulation system; (2) looking for alternative mechanisms of action, distinct from those of heparin; (3) identifying side effects (mostly pro-coagulant action and hypotension rather than bleeding) and preparing derivatives that retain the desired antithrombotic action but are devoid of side effects; (4) considering that sulfated polysaccharides with low anticoagulant action on in vitro assays may display potent effects on animal models of experimental thrombosis; and finally (5) investigating the antithrombotic effect of these sulfated polysaccharides after oral administration or preparing derivatives that may achieve this effect. If these aspects are successfully addressed, sulfated polysaccharides from marine organisms may conquer the frontier of antithrombotic therapy and open new avenues for treatment or prevention of thromboembolic diseases.     

Comparative Study of the Pharmacological Properties of Luteolin and Its 7,3′-Disulfate

The global spread of the metabolic syndrome, oncological and viral diseases forces researchers to pay increased attention to the secondary metabolites of marine hydrobionts, which often have a high therapeutic potential in the treatment of these pathologies and are effective components of functional food. The flavone luteolin (LT), as one of the most widely distributed and studied plant metabolites, is distinguished by a diverse spectrum of biological activity and a pleiotropic nature of the mechanism of action at the molecular, cellular and organismal levels. However, there is still practically no information on the spectrum of biological activity of its sulfated derivatives, which are widely represented in seagrasses of the genus Zostera. In the present work, a comparative study of the pharmacological properties of LT and its 7,3′-disulfate was carried out with a brief analysis of the special role of sulfation in the pharmacological activity of flavonoids.     

Antiparasitic Effects of Sulfated Polysaccharides from Marine Hydrobionts

This review presents materials characterizing sulfated polysaccharides (SPS) of marine hydrobionts (algae and invertebrates) as potential means for the prevention and treatment of protozoa and helminthiasis. The authors have summarized the literature on the pathogenetic targets of protozoa on the host cells and on the antiparasitic potential of polysaccharides from red, brown and green algae as well as certain marine invertebrates. Information about the mechanisms of action of these unique compounds in diseases caused by protozoa has also been summarized. SPS is distinguished by high antiparasitic activity, good solubility and an almost complete absence of toxicity. In the long term, this allows for the consideration of these compounds as effective and attractive candidates on which to base drugs, biologically active food additives and functional food products with antiparasitic activity.     

Fucoidans and Bowel Health

Fucoidans are cell wall polysaccharides found in various species of brown seaweeds. They are fucose-containing sulfated polysaccharides (FCSPs) and comprise 5–20% of the algal dry weight. Fucoidans possess multiple bioactivities, including antioxidant, anticoagulant, antithrombotic, anti-inflammatory, antiviral, anti-lipidemic, anti-metastatic, anti-diabetic and anti-cancer effects. Dietary fucoidans provide small but constant amounts of FCSPs to the intestinal tract, which can reorganize the composition of commensal microbiota altered by FCSPs, and consequently control inflammation symptoms in the intestine. Although the bioactivities of fucoidans have been well described, there is limited evidence to implicate their effect on gut microbiota and bowel health. In this review, we summarize the recent studies that introduce the fundamental characteristics of various kinds of fucoidans and discuss their potential in altering commensal microorganisms and influencing intestinal diseases.     

水稻腺苷5'-磷酰硫酸激酶编码基因的克隆及其酶活分析

硫是植物生长所必需的大量元素之一。植物通过根系吸收土壤中的硫酸盐,经ATP硫酸化酶活化为腺苷5'-磷酰硫酸(adenosine 5'-phosphosulfate,APS)。APS的代谢包括初级代谢和次级代谢,分别是APS还原酶催化APS生成亚硫酸盐;腺苷5'-磷酰硫酸激酶(adenosine 5'-phosphosulfate kinase,APSK)催化APS磷酸化生成3'-磷酸-腺苷5'-磷酰硫酸(3'-phosphoadenosine 5'-phosphosulfate,PAPS),PAPS进一步作为硫酸根供体参与胞内的硫酸化反应。近年来的研究表明,拟南芥APSK在调节硫的初级和次级代谢的过程中具有重要功能,且受氧化胁迫的APSK1在亚基C86和C119间形成二硫键降低其催化活性。水稻的同工酶是否也会受到氧化还原调控尚无相关报道。对APSK序列进行分析,发现水稻APSK1含有与拟南芥APSK1 C86和C69同源的半胱氨酸。本研究对水稻APSK1基因进行了克隆、双突变和酶活分析。OsAPSK1及双突变C36A/C69A经原核表达、纯化,获得了OsAPSK1及双突变蛋白。体外酶活分析表明,在氧化环境中OsAPSK1活性受到抑制,而C36A/C69A双突变蛋白不受氧化环境的影响。推测水稻胞内受到氧化胁迫时会降低OsAPSK1的活性,从而促进还原型谷胱甘肽的合成,提高水稻的抗氧化能力。通过分析PAPS的含量与氧化胁迫之间的相关性及不同OsAPSK亚型的活性调节机制等将有利于进一步阐明APSK在胞内的功能。     

Potential Anti-HPV and Related Cancer Agents from Marine Resources: An Overview

Recently, the studies on the prevention and treatment of human papillomavirus (HPV) which is closely related to the cervical cancer and other genital diseases are attracting more and more attention all over the world. Marine-derived polysaccharides and other bioactive compounds have been shown to possess a variety of anti-HPV and related cancer activities. This paper will review the recent progress in research on the potential anti-HPV and related cancer agents from marine resources. In particular, it will provide an update on the anti-HPV actions of heparinoid polysaccharides and bioactive compounds present in marine organisms, as well as the therapeutic vaccines relating to marine organisms. In addition, the possible mechanisms of anti-HPV actions of marine bioactive compounds and their potential for therapeutic application will also be summarized in detail.     

Fucanomics and galactanomics: marine distribution, medicinal impact, conceptions, and challenges

Glycomics turned out to be a very extensive project where its subdivision is consequently emerging. This is seen by the growing number of terminologies used to define subprojects concerning particular classes of bioactive carbohydrates. Sulfated fucans (SFs) and sulfated galactans (SGs) are relatively new classes of sulfated polysaccharides (SPs) that occur mostly in marine organisms, and exhibit a broad range of medicinal effects. Their structures are taxonomically dependent, and their therapeutic actions include benefits in inflammation, coagulation, thrombosis, angiogenesis, cancer, oxidation, and infections. Some red algae, marine angiosperm and invertebrates express SPs of unique structures composed of regular repeating oligomeric units of well-defined sulfation patterns. This fine pattern of structural regularity is quite rare among any naturally occurring long SPs, and enables accurate structure-biofunction correlations. Seeing that, fucanomics and galactanomics may comprise distinguished glycomics subprojects. We hereby discuss the relevance that justifies the international recognition of these subprojects in the current glycomics age associated with the beneficial outcomes that these glycans may offer in drug development.     

Influence of Fucoidans on Hemostatic System

Three structurally different fucoidans from the brown seaweeds Saccharina latissima (SL), Fucus vesiculosus (FV), and Cladosiphon okamuranus (CO), two chemically modified fucoidans with a higher degree of sulfation (SL-S, CO-S), and a synthetic totally sulfated octasaccharide (OS), related to fucoidans, were assessed on anticoagulant and antithrombotic activities in different in vitro experiments. The effects were shown to depend on the structural features of the compounds tested. Native fucoidan SL with a degree of sulfation (DS) of 1.3 was found to be the most active sample, fucoidan FV (DS 0.9) demonstrated moderate activity, while the polysaccharide CO (DS 0.4) was inactive in all performed experiments, even at high concentrations. Additional introduction of sulfate groups into fucoidan SL slightly decreased the anticoagulant effect of SL-S, while sulfation of CO, giving rise to the preparation CO-S, increased the activity dramatically. The high level of anticoagulant activity of polysaccharides SL, SL-S, and CO-S was explained by their ability to form ternary complexes with ATIII-Xa and ATIII-IIa, as well as to bind directly to thrombin. Synthetic per-O-sulfated octasaccharide OS showed moderate anticoagulant effect, determined mainly by the interaction of OS with the factor Xa in the presence of ATIII. Comparable tendencies were observed in the antithrombotic properties of the compounds tested.     

Dietary flaxseed oil regulate lipid metabolism associated with modulation of gut microbiota in high-fat-diet fed mice

Accumulating data suggest that consuming dietary flaxseed oil(FSO)was a potential strategy for treating diet-induced lipid metabolism disorder(LMD).Effects of FSO on high-fat-diet(HFD)induced LMD and gut microbiota were studied in C57/BL6J mice.Results showed that FSO remarkably suppressed body weight gain induced by HFD and also attenuated LMD by decreasing levels of total cholesterol(TC),total triglyceride(TG),lowdensity lipoprotein cholesterol(LDL-C),non-esterified fatty acid(NEFA)and fasting bloodglucose(FBG)in serum.FSO treatment modulated mRNA expression level of genes associated with glucose and lipid metabolism.It regulated gut microbiome at different taxonomic levels by increasing proportions of beneficial Alistipes,Anaeroplasma,Bifidobacterium and inhibiting the growth of insulin resistance or obesity-associated bacteria such as Adlercreutzia,Dorea and Sporosarcina,compared with HFD group.Spearman's correlation analysis suggested that modulation of gut microbiota by FSO were closely related with LMD parameters.These findings might help us to better understand FSO impact on human health.     

Sulfated Polysaccharide Extracted from the Green Algae Codium bernabei: Physicochemical Characterization and Antioxidant,Anticoagulant and Antitumor Activity

Codium bernabei is a green alga that grows on Chilean coasts. The composition of its structural polysaccharides is still unknown. Hence, the aim of this work is to isolate and characterize the hot water extracted polysaccharide fractions. For this purpose, the water extracts were further precipitated in alcohol (TPs) and acid media (APs), respectively. Both fractions were characterized using different physicochemical techniques such as GC-MS, GPC, FTIR, TGA, and SEM. It is confirmed that the extracted fractions are mainly made of sulfated galactan unit, with a degree of sulfation of 19.3% (TPs) and 17.4% (ATs) and a protein content of 3.5% in APs and 15.6% in TPs. Other neutral sugars such as xylose, glucose, galactose, fucose, mannose, and arabinose were found in a molar ratio (0.05:0.6:1.0:0.02:0.14:0.11) for TPs and (0.05:0.31:1.0:0.03:0.1:0.13) for ATs. The molecular weight of the polysaccharide samples was lower than 20 kDa. Both polysaccharides were thermally stable (Tonset > 190 °C) and showed antioxidant activity according to the ABTS^•+ and DPPH tests, where TPs fractions had higher scavenging activity (35%) compared to the APs fractions. The PT and APTTS assays were used to measure the anticoagulant activity of the polysaccharide fractions. In general, the PT activity of the TPs and APs was not different from normal plasma values. The exception was the TPs treatment at 1000 µg mL⁻¹ concentration. The APTTS test revealed that clotting time for both polysaccharides was prolonged regarding normal values at 1000 µg mL⁻¹. Finally, the antitumor test in colorectal carcinoma (HTC-116) cell line, breast cancer (MCF-7) and human leukemia (HL-60) cell lines showed the cytotoxic effect of TPs and APs. Those results suggest the potential biotechnological application of sulfate galactan polysaccharides isolated from a Chilean marine resource.     

The Antiviral Activities and Mechanisms of Marine Polysaccharides: An Overview

Recently, the studies on the antiviral activities of marine natural products, especially marine polysaccharides, are attracting more and more attention all over the world. Marine-derived polysaccharides and their lower molecular weight oligosaccharide derivatives have been shown to possess a variety of antiviral activities. This paper will review the recent progress in research on the antiviral activities and the mechanisms of these polysaccharides obtained from marine organisms. In particular, it will provide an update on the antiviral actions of the sulfated polysaccharides derived from marine algae including carrageenans, alginates, and fucans, relating to their structure features and the structure–activity relationships. In addition, the recent findings on the different mechanisms of antiviral actions of marine polysaccharides and their potential for therapeutic application will also be summarized in detail.