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The Antiviral Activity of Bacterial, Fungal, and Algal Polysaccharides as Bioactive Ingredients: Potential Uses for Enhancing Immune Systems and Preventing Viruses
- 1Interdisciplinary Program in Biotechnology, Graduate School, Chiang Mai University, Chiang Mai, Thailand
- 2Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, Thailand
- 3Cluster of Agro Bio-Circular-Green Industry (Agro-BCG), Chiang Mai University, Chiang Mai, Thailand
- 4College of Maritime Studies and Management, Chiang Mai University, Samut Sakhon, Thailand
- 5Plant Bioactive Compound Laboratory (BAC), Department of Plant and Soil Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand
- 6Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangneung, South Korea
- 7Department of Food Science, College of Agriculture and Life Science, Cornell University, Ithaca, NY, United States
- 8Department of Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine, Faculty of Pharmacy, Universitat de València, Valencia, Spain
Viral infections may cause serious human diseases. For instance, the recent appearance of the novel virus, SARS-CoV-2, causing COVID-19, has spread globally and is a serious public health concern. The consumption of healthy, proper, functional, and nutrient-rich foods has an important role in enhancing an individual's immune system and preventing viral infections. Several polysaccharides from natural sources such as algae, bacteria, and fungi have been considered as generally recognized as safe (GRAS) by the US Food and Drug Administration. They are safe, low-toxicity, biodegradable, and have biological activities. In this review, the bioactive polysaccharides derived from various microorganisms, including bacteria, fungi, and algae were evaluated. Antiviral mechanisms of these polysaccharides were discussed. Finally, the potential use of microbial and algal polysaccharides as an antiviral and immune boosting strategy was addressed. The microbial polysaccharides exhibited several bioactivities, including antioxidant, anti-inflammatory, antimicrobial, antitumor, and immunomodulatory activities. Some microbes are able to produce sulfated polysaccharides, which are well-known to exert a board spectrum of biological activities, especially antiviral properties. Microbial polysaccharide can inhibit various viruses using different mechanisms. Furthermore, these microbial polysaccharides are also able to modulate immune responses to prevent and/or inhibit virus infections. There are many molecular factors influencing their bioactivities, e.g., functional groups, conformations, compositions, and molecular weight. At this stage of development, microbial polysaccharides will be used as adjuvants, nutrient supplements, and for drug delivery to prevent several virus infections, especially SARS-CoV-2 infection.
Viruses are the most numerous living organisms on the earth and can be found in terrestrial and aquatic environments. They are infectious agents containing a genetic material within a protein coat—requiring an appropriate host cell where they can replicate (called infection) often resulting in diseases. Viruses can infect all types of organisms: prokaryotes (archaea and bacteria), eukaryotes (animals, algae, plants, and protozoa), and giant viruses namely virophages (1). Like other viruses, human viruses are able to replicate and mutate. A new virus was discovered in December 2019 and characterized as a pandemic by World Health Organization (WHO) on March 11, 2020 (2). This virus was characterized as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes human infection called coronavirus disease 2019 (COVID-19). The disease has spread worldwide and caused over 200 million cases and 4 million deaths from its start until August 2021 (3).
Coronaviruses (CoV) are enveloped positive-sense single-stranded RNA (+ ssRNA) viruses with crown-like spikes on their spherical surface (4). Coronaviruses belong to the order Nidovirales, the suborder Coronavirineae, and the family Caronaviridae. The family was divided into the subfamilies of Orthocoronavirinae and Letovirinae by the International Committee on Taxonomy of Viruses (ICTV) in 2018 (5). The former sorts into 4 genera, including Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, with α- and β-coronaviruses infect mammalian species, but γ-, and δ-coronaviruses infect avian species causing respiratory and enteric diseases both as acute and persistent infections (6, 7). The human coronavirus first emerged in patients with the common cold in the 1960s. Other human coronaviruses have emerged within the last two decades: SARS-CoV-1 (2003), Middle East respiratory syndrome (MERS-CoV, 2012), as well as SARS-CoV-2 (2019), which is the seventh human-infecting coronavirus identified (7).
SARS-CoV-2 belongs to the β-coronaviruses, which include SARS-CoV-1 and MERS-CoV. These viruses are highly pathogenic and have a high mortality rate (8). The RNA genome of SARS-CoV-2 is 25–32 kb and similar to SARS-CoV-1 (82% similarity) (4). The structural proteins of SARS-CoV-2 are the envelope (E), membrane (M), nucleocapsid (N), and spike (S) proteins (Figure 1). The spike of coronaviruses (S protein) is a glycoprotein associated with the pathogenesis because it is involved in virus adsorption and entry. Thus, the S protein is the virus' important virulence factor (5). The virus uses the S protein for cell binding and membrane fusion. The S protein binds to the angiotensin-converting enzyme 2 (ACE2), a host cell receptor, primed by the transmembrane protease serine protease 2 (TMPRSS2), with the interaction mediating the virus attachment and entry into a host cell (5, 6, 9). The ACE2 receptor is found in a range of human tissues and organs, including the small intestine, lungs, heart, testis, kidneys, blood vessels, muscle, adipose tissues, bladder, epithelia cells of the oral cavity, and the upper esophagus (10–12). Therefore, there are many targets for SARS-CoV-2 infection.
Four antiviral drugs were repurposed for COVID-19, including tocilizumab, remdesivir, favipiravir, and dexamethasone (13). Remdesivir, a drug approved by the US Food and Drug Administration (FDA) for COVID-19, showed a high efficacy as a COVID-19 treatment (14, 15). On the other hand, the WHO Solidarity Trial Consortium announced that remdesivir had little or no effect on hospitalized patients with COVID-19 (16). Various researchers have been evaluating and developing other antiviral agents, as well as vaccines, with high efficacy and low-toxicity (17). As of August 2021, people have been administered different Covid vaccines in many countries, but the pandemic still goes on. Nutrients in foods have an important role in stimulating human immunity and preventing viral infections. Several nutrients including polysaccharides, proteins, and lipids have been reported to have antiviral and immune-enhancing properties. In addition, micronutrients, such as vitamin A, C, D, and E, and few minerals, such as iron, selenium, and zinc have the potential to improve the immune system. Furthermore, natural extracts containing some non-nutrients, such as polyphenols, flavonoids, alkaloids, thiophenes, terpenoids, tannins, and lignins have also shown biological activities (18). For instance, Erodium glaucophyllum extracts containing phenolic compounds such as gallic acid, quercetin 3-O-glucuronide, (+)-gallocatechin, and (+)-catechin exhibited antibacterial and antiviral activities (19). During the COVID-19 pandemic, healthy, nutrient-rich, and functional foods may be more important because their consumption may prevent and modulate the immune system (20). In addition, the development of bioactive ingredients, functional, and nutrient-rich foods that can moderate consumers' overall health will be more interested (21).
Polysaccharides are polymeric carbohydrates, defined as composed of more than 10 monomers that are linked by glycosidic linkages. Polysaccharides are grouped into 2 classes: homopolysaccharides (contain one type of monomer) and heteropolysaccharide (contain more than one type of monomer) (22). Polysaccharides from each sources have different branched chains, composition of monosaccharides, molecular weight (MW), and structural conformations (23). Polysaccharides are the most abundant biological macromolecules in nature and can be obtained from every living organisms including animals (24), plants (25), and microorganisms (26). In living cells, polysaccharides are involved in structure, storage, adhesion, and cell recognition (27). Microorganisms including archaea, bacteria, fungi, and microalgae produced diverse polysaccharides with different structures and functions. Moreover, microorganisms synthesize polysaccharides and secrete them to the outside, these are called exopolysaccharides (EPS). Their functions include cell adhesion, migration of bacteria in groundwater, protection from predators and white blood cells, protection from undesired environments (extreme environments), intercellular signal transduction, and molecular recognition (28, 29). Microbial polysaccharides are composed of not only monosaccharides, but also proteins, lipids, metal ions, extracellular DNA (eDNA), and other organic and inorganic compounds (30). Furthermore, polysaccharides derived from microorganisms, especially marine microorganisms may include sulfate groups, and are called sulfated polysaccharides (31). Sulfated polysaccharides are negatively-charged biopolymers found in the cell wall of marine algae (green, brown, and red algae). Sulfate groups are linked to the sugar structure's backbone to stabilize the structure in extreme environments, especially high salinity (32). Sulfated polysaccharides can be founded not only in marine microalgae and macroalgae, but also in marine animals, and marine bacteria (31). Microbial polysaccharides and sulfated polysaccharides show various biological activities such as immunomodulatory, antioxidant, antimicrobial, anticancer, and anti-inflammatory activities (30). In particular, the antiviral activity of microbial polysaccharides has been studied, showing in several cases an inhibitory effect against various animal, human, and plant pathogenic viruses (33–35). Many studies have reported that natural and modified polysaccharides could inhibit various virus infections (36). Some microbial polysaccharides had antiviral activity against various viruses including Herpes simplex, influenza, Newcastle disease (NDV), Varicella zoster (VZV), human immunodeficiency viruses (HIV), and human adenoviruses (37–45). According to their biological activities, the bioactive polysaccharides can be applied as a bioactive ingredients to improve the immune system and reduce the damage caused by viruses (23). Among microbial polysaccharides, EPS produced by lactic acid bacteria (LAB) have been recognized as GRAS, which allows their use in food without the need for regulatory oversight in the USA (46). Although bioactive polysaccharides have been derived from plants, many researchers have investigated the characteristics, compositions, properties, biological activities of novel polysaccharides from various microorganisms (30). There are many advantages to using microbial polysaccharides compared to other polysaccharides. For example, the microbial polysaccharide production can be done using optimized conditions indoors. Microbes grow easily and fast with a high yield of polysaccharides. The recovery process of polysaccharides is simple. Moreover, microbial growth media are simple and non-toxic. If agricultural wastes are used as microbial growth media, the cost of the production is often decreased (32, 47). Microbial polysaccharides are biocompatible and biodegradable, and have no known toxic effects (23). As mentioned above, microbial polysaccharides show antioxidant, anti-inflammatory, antiviral, and immunomodulatory activities; therefore, microbial polysaccharides are attractive as antiviral agents or bioactive ingredients to treat viral infectious diseases, especially COVID-19. This review focuses on microbial polysaccharides with antiviral and immunomodulatory activities and their antiviral mechanisms, and provides the potential approach to use microbial polysaccharides as bioactive ingredients.
Microbial Polysaccharides With Antiviral Activity
Antiviral Polysaccharides From Algae
Algae are eukaryotic photosynthetic organisms, often microorganisms. Some algae are unicellular, but some of them are multicellular organisms lacking of specialized tissues. Both micro- and macroalgae are good sources of biomedical compounds, especially polysaccharides (48). Algal polysaccharides are nontoxic, edible, biocompatible, biodegradable, and easily available; therefore, these biopolymers have been applied in many fields such as the food, pharmaceutical, and biomedical industries (49). Algal polysaccharides have several pharmaceutical properties, including anticancer (50), antioxidant (51), antimicrobial (52), anti-inflammatory (53), and immunomodulatory activities (54). Moreover, several algae, especially marine algae, can produced sulfate polysaccharides, which have different beneficial biological activities (50, 55–58). Different algal polysaccharides possess a variety of structures, composition, and conformations, which influence their properties (55). A summary of algal polysaccharides with antiviral potential are shown in Table 1.
Most of the algal polysaccharides have the ability to decrease viral infections by blocking the attachment of virus particles to host cell surfaces. In this line, three polysaccharides extracted from Sargassum trichophyllum (a brown alga) were characterized as laminaran, alginate and fucoidan, observing that only fucoidan showed an antiviral effect against herpes simplex virus type 2 (HSV-2) (72). The 50% inhibitory concentration (IC50) of the fucoidan was 18 μg·mL−1 when it was added during the viral infection, being lower than adding after the viral infection. Therefore, this polysaccharide might inhibit HSV-2 at the virus adsorption and/or penetration step(s) (72). Sargassum henslowianum produced antiviral fucoidans against both HSV-1 and HSV-2 (84). For instance, the authors observed how two fractions of the fucoidans (SHAP-1 and SHAP-2) could inhibit HSV-1 with IC50 of 0.89 and 0.82 μg·mL−1, respectively. Both SHAP-1 and SHAP-2 showed higher antiviral activity against HSV-2 with IC50 of 0.48 μg·mL−1. These fucoidans interfered with the virions' attachment to host cells (84). Moreover, low MW fucoidan fractions (LF1 and LF2) from Laminaria japonica could inhibit I-type influenza virus, adenovirus and parainfluenza virus I in vitro. The IC50 for LF1 were 0.3, 0.6, and 0.3 mg·mL−1, respectively, whereas The IC50 for LF2 were 0.6, 1.2, and 0.6 mg·mL−1, respectively (66). Fucoidan from Cladosiphon okamuranus also showed higher antiviral activity against NDV with lower cytotoxicity than Ribavirin, an antiviral drug, preventing this polysaccharide the viral infection at early steps by blocking the F protein (85). In addition, Scytosiphon lomentaria, a brown seaweed, also produced fucoidans with antiviral activity, in particular, they had the ability to block HSV-1 and HSV-2 infections (86). Moreover, a fucoidan with high levels of sulfate groups also showed the highest antiviral activity against HSV-1 and HSV-2 (86).
Carrageenans are sulfated linear polysaccharides extracted from some red algae, such as Chondrus, Gigartina, Hypnea, and Eucheuma spp. (49). These polysaccharides showed an antiviral activity against several viruses. For instance, González et al. (87) reported a good inhibitory effect of carrageenan against some enveloped viruses, including HSV-1, HSV-2, Semliki Forest, vaccinia, and swine fever viruses, but they did not find any impact on vesicular stomatitis and measles viruses. Moreover, these authors also showed the antiviral activity of carrageenan against encephalomyocarditis virus (EMCV), a naked virus, but they did not observe significant effects on poliovirus or adenovirus. The carrageenan interfered with the viral protein synthesis. On the other hand, λ-carrageenan and moderately cyclized μ/ℓ-carrageenan extracted from a red seaweed (Gigartina skottsbergii) inhibited the viral attachment of HSV-1 and HSV-2 (88). Various types of carrageenans also have shown antiviral activities against hepatitis A virus (HAV). The 50% effective dose (ED50) for ι-carrageenan, λ-carrageenan, and κ-carrageenan against HAV were >400, >222, and >10 μg·mL−1, respectively (89). λ-Carrageenan from G. skottsbergii showed an inhibitory effect on both bovine herpesvirus type 1 (BoHV-1) and Suid herpesvirus type 1 (SuHV-1). The IC50 of this polysaccharide was 0.52 and 10.4 μg·mL−1, respectively (90).
The red micro algae, Porphyridium spp., produce antiviral polysaccharides against many types of viruses, including HSV-1, HSV-2, and VZV. The algae inhibited viral entry and/or blocked virus replication in host cells (38, 43). In this line, the sulfated polysaccharide SP-2a obtained from a brown alga, Sargassum patens, exhibited strong antiviral property against different strains of HSV-1. The EC50 of SP-2a against the standard, acyclovir (ACV)-sensitive and -resistant strains of HSV-1 were 5.5, 1.5, and 4.1 μg·mL−1, respectively. The SP-2a had a weak virucidal activity against the standard and ACV-sensitive strains of HSV-1, but not the ACV-resistant strain. During virus adsorption, the SP-2a showed ≥80% inhibition of adsorption against all strains of HSV-1 (71). p-KG03 is a sulfated exopolysaccharide with an average MW of 1.87 × 107 Da extracted from a dinoflagellate, Gyrodinium impudicum strain KG03. The p-KG03 could inhibit EMCV in HeLa cells with an EC50 of 26.9 μg·mL−1, and influenza A at the virus adsorption step, but was ineffective against influenza B, HSV-1, HSV-2, human immunodeficiency virus type 1 (HIV-1), HIV-2, Coxsackie B virus type 3 (Cox-B3), and vesicular stomatitis virus (VSV). In addition, the p-KG03 also showed antiviral activity against influenza A virus at the virus adsorption step, but did not inhibit all influenza B virus isolates. The EC50 for p-KG03 against different strains of influenza A virus (H1N1: PR8 and Tw; H3N2: Se) ranged from 0.19 to 0.48 μg·mL−1 (56, 60). Lee et al. (67) reported that Navicula directa, a diatom collected from deep-sea water in Toyama Bay (Japan), produced naviculan (a sulfated polysaccharide). The naviculan is a heteropolysaccharide consisting of fucose, xylose, galactose, mannose, rhamnose, and sulfate with an average MW of ~2.2 × 105 Da. It is a broad-spectrum antiviral against HSV-1, HSV-2, and influenza A virus with IC50 of 14, 7.4, and 170 μg·mL−1, respectively, at the virus adsorption phase. Moreover, it could also interfere with the cell-cell fusion of HIV gp160- and CD4-expressing HeLa cells. Therefore, it might prevent HIV infections.
Antiviral Polysaccharides From Bacteria
Bacteria (including cyanobacteria or blue-green algae) have the ability to synthesize polysaccharides for various purposes such as storage, cell protection, and adhesion. Polysaccharides accumulated in cells are called intracellular polysaccharides (ICP). While those outside of cell are called extracellular polysaccharides or EPS. The latter are secreted by cells or produced extracellularly using cell wall-anchored enzymes (28). Bacterial polysaccharides show biological (bioactive) activities, including anti-inflammatory, anticancer, antimicrobial, antioxidant, and immunomodulatory (91–97). They showed an inhibitory effect against various viruses, both DNA and RNA viruses. The inhibitory effect is usually associated with the viral adsorption and/or replication phases in host cells. For example, Arthrospira platensis (formerly Spirulina platensis) produced calcium spirulan, a sulfated polysaccharide, with antiviral activity against several enveloped viruses. The calcium spirulan composed of rhamnose, ribose, mannose, fructose, galactose, xylose, glucose, glucuronic acid, galacturonic acid, sulfate, and calcium. This polysaccharide showed antiviral activity against HSV-1, human cytomegalovirus (HCMV), measles, mumps, influenza A, and HIV-1 viruses by inhibiting virus penetration (74). Spirulan-like substances extracted from A. platensis showed strong antiviral activity against HCMV, HSV-1, human herpesvirus type 6 (HHV-6), and HIV-1. Their mechanisms depended on the type of virus. For example, in the case of herpesviruses, spirulan-like substances inhibited virus adsorption and/or penetration steps, while HIV-1 was inhibited after viral entry. For HCMV, the inhibition occurred at intracellular steps, especially the viral protein synthesis step (44). EPS from A. platensis also inhibited koi herpesviruses (KHV). Reichert et al. (75) reported that EPS from A. platensis between 18 and 36 μg·mL−1 suppressed KHV in vitro Furthermore, nostoflan, an acidic polysaccharide from Nostoc flagelliforme (a cyanobacterium), showed an interesting antiviral activity against enveloped viruses: HSV-1, HSV-2, HCMV, and influenza A viruses. The virus infections were blocked when nostoflan was added at the same time as viral infections. Therefore, nostoflan blocked the viruses at the virus adsorption stage. The IC50 values of nostoflan for HSV-1, HSV-2, HCMV, and influenza A viruses were 0.37, 2.9, 0.47, and 78 μg·mL−1, respectively (79). In addition, other authors also observed how an EPS derived from Bacillus licheniformis strain T14 can prevent HSV-2 infection at 300 and 400 μg·mL−1 in human peripheral blood mononuclear cells (PBMC) (76). EPS26a from Lactobacillus sp. could completely inhibit human adenovirus type 5 (HAdV-5) formation and release (41).
Bacterial polysaccharides also indirectly inhibited virus infections by modulation of the immune response. For instance, an EPS produced by Lactobacillus delbrueckii OLL1073R-1 activated the Toll-like receptor 3 (TLR3) and the expression of interferon (IFN)-α, IFN-β, MxA, and RNase L in porcine intestinal epithelial (PIE) cells, which was associated with the innate antiviral immune response (77). Mizuno et al. (98) reported that an EPS from Streptococcus thermophilus ST538 can activate TLR3, thus promoting the expression of IFN-β, interleukin 6 (IL-6), and C-X-C motif chemokine 10 (CXCL10). Antiviral bacterial polysaccharides are also shown in Table 1.
Antiviral Polysaccharides From Fungi
Fungi are unicellular-to-multicellular eukaryotic microorganisms. They can produce a plethora of biologically active compounds, especially secondary metabolites. Similar to algae and bacteria, fungal polysaccharides (primary metabolites) also showed antiviral activity. Fungal polysaccharides can be derived from culture broth, mycelial culture and/or fruiting bodies (99). Fungal polysaccharides, such as glucan, chitin, mannan, PSK or lentinan, showed antiviral potential against animal, human, and plant viruses (100–103). Fungal polysaccharides with antiviral activity are summarized in Table 1. For example, BAS-F, a polysaccharide from Fomes fomentarius, at 2 μg·mL−1 can prevent tobacco mosaic virus (TMV) infection on the leaf surfaces (34). Porodaedalea pini (formerly known as Phellinus pini) produced two antiviral polysaccharides (EP-AV1 and EP-AV2) against HSV-1 and coxsackie virus B3 (CVB3) in Vero and HeLa cells, respectively. The EP-AV2 with a lower MW (~100 kDa) showed more potent antiviral activity than EP-AV1 (~1,010 kDa) against CVB3. It was observed how EP-AV1 and EP-AV2 polysaccharides inhibited the plaque formation caused by CVB3 in HeLa cells by 32 and 84% at 1 mg·mL−1, respectively. These polysaccharides specifically inhibited HSV-1 more than CVB3 as indicated by their EC50 values. The EC50 values of EP-AV1 and EP-AV2 for HSV-1 were 0.20 and 0.21 μg·mL−1, respectively, whereas CVB3 were 1 and 0.576 mg·mL−1, respectively (81). Furthermore, a polysaccharide extracted from the mycelium and fruiting body of Lentides edodes was able to inhibit poliovirus type 1 (PV-1) and bovine herpes virus type 1 (BoHV-1) with IC50 values of 0.19 and 0.1 mg·mL−1, respectively (101). In another study, Grifola frondosa mycelia were evaluated as a source of antiviral polysaccharides, observing that it had the antiviral polysaccharide, GFP1. This polysaccharide was a heteropolysaccharide containing glucose and fucose with a MW of ~40.5 kDa. Zhao et al. (82) reported that GFP1 blocked enterovirus 71 (EV71) infection at the virus replication phase. The GFP1 suppressed the viral protein expression and viral RNA genome synthesis. Fungal polysaccharides also showed important antiviral properties against animal viruses. For example, a polysaccharide from L. edodes, called lentinan comprised of glucose, mannose, and galactose with MW of ~3.79 × 105 Da showed antiviral activity against infectious hematopoietic necrosis virus (IHNV) infecting rainbow trout (Oncorhynchus mykiss) and several species of salmon. The LNT-I acted both direct inactivation and inhibition of viral replication with 62.3, and 82.4% inhibition, respectively (83). Inonotus obliquus, chaga mushroom, also produced broad-spectrum antiviral polysaccharides against feline viruses. The polysaccharides suppressed infections of feline calicivirus (FCV), feline herpesvirus 1 (FHV-1), feline panleukopenia (FPV), feline coronavirus (FCoV), and feline influenza (FIV, H3N2, and H5N6) viruses. These polysaccharides had low toxicity and blocked virus entry by affecting the virions and/or the receptor(s) on host cell surfaces (35).
Therefore, polysaccharides from different species show various biological activities with different levels of action. Sulfated polysaccharides derived from marine microalgae and seaweeds showed many different bioactive properties and were effective against viruses at low concentrations, compared to other polysaccharides. In addition, bacteria and fungi are easily grow on simple media or agricultural wastes. The production can be done using controllable conditions and they produce high amounts of polysaccharides. Therefore, it would also benificial if the bioactivities and physicochemical properties of bacterial and fungal polysaccharides could be modified. The molecular modification of polysaccharides is an alternative approach to modulate their properties.
Antiviral Mechanisms of Microbial Polysaccharides
In viral replication, there are 6 major steps during the infection: (1) virus attachment, (2) penetration, (3) uncoating, (4) genome replication and protein synthesis, (5) viral assembly, and (6) release of new virions (104). Different microbial polysaccharides have different antiviral mechanisms depending on virus types. The polysaccharides mostly prevented the initial steps of the virus life cycle. They interacted with virus particles and/or receptors on host cells to interfere with virus adsorption and invasion. However, some microbial polysaccharides could inhibit viral replication and protein translation. While others showed immune-enhancing activity, especially antiviral immune responses, which prevent virus infections and reduce disease severity (31, 105).
Inactivating Virus Particles Directly
Microbial polysaccharides, especially sulfated polysaccharides, have a negative charge that can interact directly with the viral surfaces. The virucidal activity of microbial polysaccharides is caused by theses interactions (106). The complexes interfere with the viral infection process, reducing viral proliferation in host cells (Figure 2). For example, polysaccharides extracted from Auricularia auricular, a basidiomycete mushroom, can inhibit NDV in CEF cells. During the process of adding polysaccharides and virus simultaneously, the virus inhibitory rates were higher than pre- and post-addition of the polysaccharides. These polysaccharides might be combined with virus particles to block virus attachment to host cells (42). Inonotus obliquus polysaccharides also directly blocked feline virus virions (FCV, FHV-1, FPV, feline coronavirus FCoV, and FIV). These polysaccharides were mixed with the viruses for 1 h before adding to the cell lines, decreasing significantly the viral infectivity compared to untreated viruses (35).
Inhibiting Virus Adsorption and Penetration
Viruses bind to a host cell surface using electrostatic interactions. Some microbial polysaccharides mimic virus particles. Microbial polysaccharides, especially sulfated polysaccharides, are strongly anionic and bind to the positively charged host cell receptors blocking virus attachment, which prevents virus infection (Figure 3) (7). Additionally, some microbial polysaccharides are able to prevent the allosteric process of viral protein formation and/or virus internalization and uncoating steps (106).
Many microbial polysaccharides act at this step. For example, a polysaccharide SP-2a from S. patens showed ≥80% inhibition against all strains of HSV-1 when added during virus adsorption (71). Fucoidans from a brown alga, Padina tetrastromatica showed the highest percentage (>70%) inhibition against HSV-1 during the virus adsorption period (37). Human influenza virus H1-364 was blocked by sulfated polysaccharides from Gracilaria lemaneiformis, a red alga, at virus adsorption and replication on host cells. The sulfated polysaccharides inhibited against the virus at ≥60% during virus adsorption and replication, while these polysaccharides were not effective at the virus release step. The polysaccharides at 62.5 μg·mL−1 showed 83.5 and 83.0% inhibition against human influenza virus H1-364 at the virus adsorption and replication steps, respectively (59).
Inhibiting Viral Genome Replication and Protein Synthesis
Microbial polysaccharides, especially the low MW polysaccharides, show antiviral effects on infected host cells. They interfere directly with enzymes associated with the viral replication and inhibit other intracellular targets (107) as presented in Figure 4. Carrageenans are sulfated polysaccharide that are available from most of red seaweeds. These polysaccharides show a broad-spectrum antiviral activity. González et al. (87) reported that carrageenan inhibited HSV-1 at viral protein synthesis. When carrageenan was added 1 h after HSV-1 infection, viral proteins were not detected, whereas when carrageenan was added immediately, viral proteins were detected. Furthermore, polysaccharide GFP1 from G. frondosa, which was composed of glucose and fucose with a MW of 40.5 kDa, acted on viral replication and protein synthesis against EV71. The GFP1 was effective in inhibiting EV71 when it was added before or shortly after the viral inoculation. The viral RNA synthesis and VP1 protein were suppressed in a dose-dependent manner (82).
Figure 4. The inhibition mechanism by interfering with viral genome replication and protein synthesis.
Modulating Host Antiviral Immune Responses
During virus infection in animals, the body induces the immune responses to defend against viral infection. The responses regulate immune cells such as natural killer (NK) cells and macrophages, and increase the production of cytokines, i.e., the type I interferon system (IFN-α/β system) (36). The microbial polysaccharides interact with cell receptors on the macrophage and NK cell, and then activate the cells using the nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathways. These proteins are inducible factors, which increases the gene expression of various cytokines, chemokines, enzymes, and other proteins involving both innate and adaptive immunity (27). The IFN secreted from activated immune cells triggers activation of other immune cells including NK cells, macrophages, and T-cell lymphocytes, which have important roles in the host immune system and antiviral responses. Meanwhile, microbial polysaccharides can activate NK cells that non-specifically kill virus-infected cells by secreting perforins and granzymes (Figure 5).
Figure 5. The modulation of the antiviral immune response by activation of macrophage and NK cell using the NF-κB and MAPK signaling pathways.
Several polysaccharides can enhance the antiviral immune responses, thus reducing the number of virus particles and the severity of diseases. For example, an EPS extracted from S. thermophilus ST538 was able to induce the expression of IFN-β, IL-6, and CXCL10 in response to TLR3 stimulation. These immune factors are associated with antiviral immune responses, which induce the recruitment and activation of immune cells to struggle pathogens (98). Moreover, L. delbrueckii OLL1073R-1 produced immunomodulatory EPS. These EPS activated TLR3 and induced the expression of IFN-α, IFN-β, MxA, and RNase L. The latter two factors are known as antiviral factors (77). Polysaccharides also showed immune-enhancing activity. Ren et al. (83) reported that LNT-I from L. edodes mycelia could modulate the immune response by up-regulating the expression of IFN-1 and IFN-γ to prevent IHNV infection. In addition, an acidic polysaccharide (APS) from Cordyceps militaris enhanced TNF-α, IFN-γ, and nitric oxide (NO) production, and induced the expression of several cytokines: IL-1β, IL-6, IL-10, and TNF-α. These cytokines have the potential to prevent influenza A virus infection (39). Cao et al. (64) also reported a polysaccharide from L. japonica which could increase IFN-α secretion in a dose-dependent manner. The IFN-α level was 144 pg·mL−1 when cells were treated with 1000 μg·mL−1 of polysaccharide.
Factors Influencing the Antiviral Activity
Polysaccharides derived from different sources showed several unique characteristics, properties, and bioactivities at different levels. Table 2 shows various microbial polysaccharides and/or polysaccharide fractions with different characteristics. Their MW, compositions, functional groups, and structural conformations including type of linkage and degree of branching associate with their biological properties, especially antiviral and immunomodulatory activities. Moreover, extraction and purification methods affect the compositions of polysaccharides; therefore, these factors also influence biological activities of the polysaccharides (110).
Table 2. Some microbial polysaccharides from various sources with different characteristics and bioactivities.
Sulfate Content
Several studies have reported that sulfated polysaccharides could exhibit several biological activities (antiviral, anticancer, antioxidant, and immunomodulatory activities), so the sulfate contents could be an important factor affecting antiviral and other bioactivities. Sulfation has been used for enhancing various biological activities of polysaccharides (111, 112). For example, a marine Pseudomonas sp. WAK-1 produces extracellular glycosaminoglycan (A1) and sulfated polysaccharide (A2) with antiviral activity. Matsuda et al. (80) modified the polysaccharides by over-sulfation using a dicyclohexyl-carbodiimide-mediated reaction. The over-sulfated polysaccharides were called A1S and A2S, respectively. These 4 compounds showed antiviral activity against influenza A virus with EC50 values of >100, >100, 11.0, and 2.9 μg·mL−1, respectively. From the results, over-sulfated polysaccharides (A1S and A2S) showed higher antiviral activity against influenza A virus than the natural polysaccharides (A1 and A2). Moreover, a xylogalactofucan (sulfated polysaccharide) from a brown alga Sphacelaria indica also exhibited antiviral activity against HSV-1. The sulfate contents of the polysaccharide affected the antiviral property. The sulfate content of the purified polysaccharide was 4% (w/w). Bandyopadhyay et al. (113) chemically modified the xylogalactofucan produced derivatives with up to 7% (w/w). The IC50 values of natural and artificially over-sulfated polysaccharides were 1.3 and 1.5 μg·mL−1, respectively, while a desulfated derivative of the polysaccharide had no effect on HSV-1. Furthermore, Ponce et al. (86) also reported that the level of sulfated esters in sulfated galactofucans extracted from a brown alga Scytosiphon lomentaria was an important factor influencing the antiviral activity. The whole extract (A) of S. lomentaria was fractionated to yield fractions A0, A5, A10, A20, A30, and A40, with different components, MW, and monosaccharide composition. A0 was soluble and the fraction A5 was an uronofucoidan. A10–A40 were galactofucans and showed antiviral activity against HSV-1 and HSV-2 with IC50 values in the range 0.76–10.0 μg·mL−1. Among the 4 galactofucan fractions, A30 (pure galactofucan) contained the highest sulfate content (29.5% SO3Na) and the lowest uronate content (1.8%). A30 showed the strongest antiviral activity against HSV-1 and HSV-2 with IC50 values of 0.76 and 1.3 μg·mL−1, respectively. Therefore, the low content of uronic acids and the high content of sulfate was associated with the antiviral activity of these polysaccharides. In conclusion, sulfate content is an important factor influencing biological activities. Adding sulfate groups into polysaccharide structures led to enhance bioactivities, whereas desulfation decreased their bioactivities.
Molecular Weight
The MW of polysaccharides also influenced their biological properties. Polysaccharides with low MW could easily pass through target cells to act inside the cells. Moreover, the low MW polysaccharides might bind better to cell receptors to inactivate or activate the target cells (114). Some polysaccharides with lower MW showed high biological activities, but some polysaccharides with higher MW were better. For example, Surayot et al. (26) reported the effect of MW of an EPS from Weisella confusa on immunomodulatory activity. The EPS with low MW (≤70 × 103 Da) could stimulate RAW264.7 cells to induce NO and production of various cytokines such as TNF-α, IL-1β, IL-6, and IL-10, but the native EPS (MW of ~506 × 106 Da) had no immunomodulatory activity. In addition, Ponce et al. (86) reported that the galactofucan fraction A30 had the lowest MW (~8.5 kDa) and the low MW might be another factor influencing the antiherpes activity against HSV-1 and HSV-2. On the contrary, high molecular weight carrageenans from different rea algae (Chondrus armatus, Kappaphycus alvarezii, and Tichocarpus crinitus) had effective antiviral activity (115). The different carrageenans with molecular weight of 250, 390, and 400 kDa, respectively show antiviral activity with 88, 85, and 77%, respectively. While low molecular weight (LMW) derivatives (1.2–3.5 kDa) were obtained from different depolymerization methods. The LMW derivatives showed low antiviral properties (28–54%) compared to the native polysaccharides. Therefore, the antiviral activity of these polysaccharides depended on their molecular weight (115).
Enhancement of Bioactivities
To enhance the biological activities, natural microbial polysaccharides need molecular modification of their structure, size, and functional groups to optimize activity (114). The MW can be reduced using external energy and/or specific enzymes to break glucoside chains. Using ultrasonic disruption and microwave exposure to reduce the MW are "physical modification," whereas the enzymatic degradation is "biological modification" (114). For instance, Surayot et al. (26) hydrolyzed an EPS from W. confusa TISTR 1498 using HCl and heating in hot water or in a microwave oven. The low MW products could induce production of cytokines from RAW264.7 macrophage cells. Bioactivities were also enhanced by changing the functional substituents of polysaccharides, which is "chemical modification," such as alkylation, sulfation, sulfonation, phosphorylation, carboxymethylation, and selenization (114).
The Potential Uses of Microbial Polysaccharides to Prevent Viral Diseases
Microbial polysaccharides showed various bioactivities, while almost always having any significant side-effects, yet are biodegradable, biocompatible, and cost-effective. Microbial and algal polysaccharides may be applied as drug resistance solutions. These polysaccharides can combine with other antiviral drugs for preventing drug-resistance strains (110). In addition to the prevention of viral infections, these polysaccharides also prevent recurrence of latent viruses. For example, calcium spirulan (Ca-SP) derived from Spirulina platensis was developed as microalgal cream, which effectively prevented the recurrence of HSV-1 (116). Therefore, the bioactive polysaccharides may be used to prevent viral diseases and reduce the risks of diseases, especially COVID-19.
SARS-CoV-2 has an S-protein on its envelope and the protein has an important role with binding to a host cell receptor (ACE2) (8). Heparin, heparan sulfates, and other sulfated polysaccharides can bind tightly to the S-protein in vitro (117). The binding inhibits viral infection. Other microbial polysaccharides showed immunomodulatory properties that stimulated the immune system to prevent SARS-CoV-2 infection. Several microbes can produce sulfated polysaccharides. Beneficial sulfated polysaccharides might be produced from natural microbial polysaccharides (114). Type I IFN, including IFN-α, -β, -ε, -κ, -ω, -δ, -ζ, and -τ, are essential cytokines for antiviral immune responses. Type I IFN can induce antiviral responses within infected and neighboring cells that block the spread of virus particles. They activate both innate and adaptive immune responses that promote NK cell functions and antibody production (118, 119). Hadjadj et al. (120) reported that most severe COVID-19 patients had a low type I IFN response (No IFN-β and low IFN-α production and activity). Many microbial and algal polysaccharides induced type I IFN production in vivo. Thus, these polysaccharides might be applied to modulate the immune system in both patients and healthy people. In severe COVID-19 cases, aggressive inflammatory responses were found and the inflammation caused tissue damage in many organs (121). Some microbial polysaccharides showed anti-inflammatory activity. These polysaccharides inhibited the production of pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-8 (122–124).
ACE2 receptors are expressed by several tissues and organs as described above, especially the respiratory and gastrointestinal tracts. Microbial polysaccharides with antiviral activity can be used as a nasal spray, metered dose inhaler, or delivered orally to prevent the binding of SARS-CoV-2 (117). Several natural polysaccharides have been designed as nanomaterials for drug delivery systems, such as antiviral agent. These nanomaterials may be not only used to treat the virus, but also to modulate the immune responses (7).
Algal, bacterial, and fungal polysaccharides and sulfated polysaccharides showed pharmaceutical properties due to their biological activities as mentioned above. These polysaccharides could be used as bioactive supplements in foods and could enrich nutritional quality. Indeed, some of these polysaccharides have been granted as GRAS status by the US FDA, so they can consume to enhance immune response and reduce the severity of viral diseases, especially COVID-19 (117). Some microbial polysaccharides have prebiotic properties, which enhance the proliferation of beneficial intestinal microflora, especially Bifidobacterium spp. (125). In addition, some algal polysaccharides (alginate and laminaran) could be fermented by gut microbiota and promoted the growth of Bacteroides, Bifidobacterium, and Lactobacillus species (126). When microbial polysaccharides were consumed, they could enhance the host's immune response and modulate the microbial community (microflora). The microbes degrade the polysaccharides into short-chain fatty acids (SCFA) such as acetic, propionic, and butyric acids. SCFA show benefit for the maintenance intestinal cells and modulating of the immune system (27). Microbial polysaccharides have the potential to be bioactive ingredients that can be added into foods or food products to enhance the nutritional quality of foods by modulating consumers' immune response. Therefore, the biological activities of foods supplemented with these polysaccharides should be investigated. The intake of foods with bioactive polysaccharides in patients and healthy people to prevent viruses and/or reduce the adverse symptoms needs further study.
Microorganisms produce various types of polysaccharides with unique characteristics and can be produced on a large scale with controllable conditions. Several microbial/algal polysaccharides show bioactivities, especially antiviral and immunomodulatory activities. They have strong antiviral effects by interfering with the life cycle of viruses and/or modulating host immune responses, which may benefit patients infected with COVID-19. Polysaccharides and sulfated polysaccharides from different microorganism and algae species have different characteristics and levels of bioactivities. Their constituents, structural conformations, MW, and functional groups significantly influence their bioactivities. To enhance their activities, physical, chemical, or biological modifications might be beneficial. The microbial polysaccharides have potential uses as adjuvants for antiviral vaccines and micro- and/or nano-particles for drug delivery systems. Some sulfated polysaccharides obtained from microbes and algae have been approved as GRAS, which may be used as bioactive ingredients adding in food products to prevent viruses. Many microbial polysaccharides are safe, biocompatible, biodegradable, and easily available. Therefore, the intake of proper dosage of the right polysaccharides may modulate physiological functions to prevent viral diseases and decrease their damage. They may be an alternative therapy to treat COVID-19 patients. In the future, the development of polysaccharides as functional food products should be explored. For foods supplemented with bioactive polysaccharides, more pharmaceutical investigations and clinical evidence are required to analyze their antiviral and immune-enhancing effects. The mechanisms that occur in the food products against viral infections should also be further investigated.
Author Contributions
PS, TC, CT, and SY contributed to conception and supervised the project. WC, NL, KJ, and SS contributed in doing literature searches and wrote the manuscript draft. YP, PR, SW, JR, FB, and PS equally revised and approved the manuscript. All authors have read and approved the final draft manuscript.
The authors gratefully acknowledge the financial support from the National Research Council of Thailand (NRCT) through the Royal Golden Jubilee Ph.D. Program, Thailand (grant no. PHD/0185/2560) to WC and PS. Additionally, this work was also partially financially supported along with in-kind support by the Biotechnology Program of the Graduate School of Chiang Mai University; the Cluster of Agro Bio-Circular-Green Industry (Agro BCG) Faculty of Agro-Industry; and Chiang Mai University.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
ACE2, Angiotensin-converting enzyme 2; ACV, Acyclovir; APS, Acidic polysaccharide; BoHV-1, Bovine herpesvirus type 1; BoHV-1, Bovine herpes virus type 1; CoV, Coronaviruses; COVID-19, Coronavirus disease 2019; Cox-B3, Coxsackie B virus type 3; CVB3, Coxsackie virus B3; CXCL10, C-X-C motif chemokine 10; ED50, 50% effective dose; EMCV, Encephalomyocarditis virus; EPS, Exopolysaccharides; EV71, Enterovirus 71; FCoV, Feline coronavirus; FCV, Feline calicivirus; FDA, US Food and Drug Administration; FHV-1, Feline herpesvirus 1; FIV, Feline influenza; FPV, Feline panleukopenia; HAdV-5, Human adenovirus type 5; HAV, Hepatitis A virus; HCMV, Human cytomegalovirus; HHV-6, Human herpesvirus type 6; HIV, Human immunodeficiency virus; HSV, Herpes simplex virus; IC50, 50% inhibitory concentration; ICP, Intracellular polysaccharides; ICTV, International Committee on Taxonomy of Viruses; IFN, Interferon; IHNV, Hematopoietic necrosis virus; IL, Interleukin; KHV, Koi herpesviruses; LAB, Lactic acid bacteria; MAPK, Mitogen-activated protein kinase; MERS-CoV, Middle East respiratory syndrome; MW, Molecular weight; NDV, Newcastle disease virus; NF-κB, Nuclear factor kappa B; NK, Natural killer cells; NO, Nitric oxide; PBMC, Peripheral blood mononuclear cells; PV-1, Poliovirus type 1; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; SCFA, Short-chain fatty acids; SuHV-1, Suid herpesvirus type 1; TLR3, Toll-like receptor 3; TMPRSS2, Transmembrane protease serine protease 2; TMV, Tobacco mosaic virus; VSV, Vesicular stomatitis virus; VZV, Varicella zoster virus; WHO, World Health Organization.
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Keywords: sulfated polysaccharides, immunomodulation, SARS-CoV-2, COVID-19, antiviral activity
Citation: Chaisuwan W, Phimolsiripol Y, Chaiyaso T, Techapun C, Leksawasdi N, Jantanasakulwong K, Rachtanapun P, Wangtueai S, Sommano SR, You S, Regenstein JM, Barba FJ and Seesuriyachan P (2021) The Antiviral Activity of Bacterial, Fungal, and Algal Polysaccharides as Bioactive Ingredients: Potential Uses for Enhancing Immune Systems and Preventing Viruses. Front. Nutr. 8:772033. doi: 10.3389/fnut.2021.772033
Received: 07 September 2021; Accepted: 15 October 2021;
Published: 05 November 2021.
Edited by:
Ding-Tao Wu, Chengdu University, ChinaReviewed by:
Kit Leong Cheong, Shantou University, ChinaBin Du, Hebei Normal University of Science and Technology, China
Copyright © 2021 Chaisuwan, Phimolsiripol, Chaiyaso, Techapun, Leksawasdi, Jantanasakulwong, Rachtanapun, Wangtueai, Sommano, You, Regenstein, Barba and Seesuriyachan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Phisit Seesuriyachan, firstname.lastname@example.com


text:
Retro-Blue The Bird Regular Fit Shorts - GOTS Certified Organic Cotton and Linen
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The Bird Short is a summer staple comfortable, modern and endlessly wearable. Be it adventuring or relaxing you will find yourself reaching for these again and again. In our playful Retro- Blue Supersoft organic linen and GOTS certified cotton these minimal modern chino shorts are designed to finish just on the knee giving you the option to roll them or leave them to suit your style. Modelled by Dilijohn, 5ft9 wearing a 32" waist these are a true to size fit.
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UK shipping is free on orders over £50. And £3.95 for orders below £50. International Shipping is calculated at Checkout.
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The Vaccine Hustle
Older adults around the country are struggling to get a vaccine appointment thanks to limited supply, overwhelmed phone lines, dysfunctional websites. Today, CNN checks in with seniors on the search and tries to figure out why this is happening.
To learn more about how CNN protects listener privacy, visit cnn.com/privacy


text:
Using Pre-Fire High Point Cloud Density LiDAR Data to Predict Fire Severity in Central Portugal
Área de conocimiento
Título de la revista
Remote Sensing
Número de la revista
Datos de la obra
Fernández-Guisuraga, and Fernandes, P. M. (2023). Using Pre-Fire High Point Cloud Density LiDAR Data to Predict Fire Severity in Central Portugal. Remote Sensing (Basel, Switzerland), 15(3), 768. https://doi.org/10.3390/rs15030768
[EN], The wall-to-wall prediction of fuel structural characteristics conducive to high fire severity is essential to provide integrated insights for implementing pre-fire management strategies designed to mitigate the most harmful ecological effects of fire in fire-prone plant communities. Here, we evaluate the potential of high point cloud density LiDAR data from the Portuguese áGiLTerFoRus project to characterize pre-fire surface and canopy fuel structure and predict wildfire severity. The study area corresponds to a pilot LiDAR flight area of around 21,000 ha in central Portugal intersected by a mixed-severity wildfire that occurred one month after the LiDAR survey. Fire severity was assessed through the differenced Normalized Burn Ratio (dNBR) index computed from pre- and post-fire Sentinel-2A Level 2A scenes. In addition to continuous data, fire severity was also categorized (low or high) using appropriate dNBR thresholds for the plant communities in the study area. We computed several metrics related to the pre-fire distribution of surface and canopy fuels strata with a point cloud mean density of 10.9 m−2. The Random Forest (RF) algorithm was used to evaluate the capacity of the set of pre-fire LiDAR metrics to predict continuous and categorized fire severity. The accuracy of RF regression and classification model for continuous and categorized fire severity data, respectively, was remarkably high (pseudo-R2 = 0.57 and overall accuracy = 81%) considering that we only focused on variables related to fuel structure and loading. The pre-fire fuel metrics with the highest contribution to RF models were proxies for horizontal fuel continuity (fractional cover metric) and the distribution of fuel loads and canopy openness up to a 10 m height (density metrics), indicating increased fire severity with higher surface fuel load and higher horizontal and vertical fuel continuity. Results evidence that the technical specifications of LiDAR acquisitions framed within the áGiLTerFoRus project enable accurate fire severity predictions through point cloud data with high density.
Palabras clave
Peer review
ID proyecto
- Portuguese Foundation for Science and Technology/UIDB/04033/2020
- Untitled [3530]
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Decorate for the Holidays with these lovely, fragrant wax ornaments. These wax ornaments are made with high quality soy and bees wax as well as premium fragrance and essential oil blends. They can be used to scent artificial Christmas trees or as an air freshener for closets, bathrooms or other small spaces. Scent lasts up to 6 months if stored properly before using. Each rectangular ornament is approximately 2"x 1/4" x 3". Ornament comes in zip tight packaging with decorative label & instructions These make great Holiday gifts for friends, teachers and family.
This listing is for ONE ornament only.
Scents Include:
*Apples & Oak
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*Chestnut & Clove
*Cranberry Woods
*Autumn Magic-Top notes of lemon and Apple, followed by middle notes of cinnamon, anise & ginger on base notes of vanilla, mahogany woods & musk.
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*Fireside-warm spicy scent with a touch of herbals over woodsy notes.
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**These ornaments are made of wax and may melt in warm temperatures. If using as a car freshener, use only in cold winter months. Only use on trees with LED lights. Do not use with incandescent lights. These are highly scented with a higher volume of fragrance oils and are not to be used as a wax melt. Do not put near a heat source or open flame. It is very important to store in the original pouch or use proper packaging such as a zip lock bag in a cool, dry place. Do not lay ornament on wooden surfaces as the oils in the wax may cause damage. For this reason, we do not recommend using in drawers. Ornament is meant to be hung in upright position. Failure to follow instructions can result in damage to ornament and other items.**
Jan 21, 2024
The ornaments smelled wonderful and looked great
Nov 10, 2023
Arrived quickly smells amazing and is cute!
Oct 23, 2023
The Fireside wax sachet just arrived today. The scent is very pleasant, and the presentation is great. Fast shipping. I'm looking forward to placing it in my home.
Dec 11, 2022
Yum! This smells amazing and is so pretty. I hang it in our small bathroom and the scent carries. Will purchase other scents


text:
Issues of member democracy and governance have gatecrashed the front pages over the past week as plans by leading European football clubs to form a breakaway Super League were scuppered by an outcry from angry fans.
The controversial scheme, which also drew attacks from politicians, football associations, players and the press, involved two co-operatively owned clubs, FC Barcelona and Real Madrid, alongside AC Milan, Arsenal FC, Atlético de Madrid, Chelsea FC, FC Internazionale Milano, Juventus FC, Liverpool FC, Manchester City, Manchester United, and Tottenham Hotspur.
Two German clubs – Bayern Munich and Borussia Dortmund – which are more than 50% fan owned, were invited to join but refused.
Most of the teams involved have pulled out but managers of the supporter-owned Spanish teams are still in favour of the idea. Today, Real Madrid president Florentino Perez said the plan was still "on standby" – while supporters of the club staged a protest against the Super League at the club's Bernabeu stadium.
Meanwhile, Barcelona supporters' organisation Seguiment FCB responded to the plan by calling for a fan vote, in a statement which added: "We believe that obtaining the maximum consensus before the possible registration to a football Super League is not only a duty given the deep democratic roots of our club but an obligation and a sign of respect towards all the fans across Europe, given the non-existent decision-making power that, unfortunately, the fans of 10 out of the 11 other founding clubs have (in theory)."
Barcelona president Joan Laporta said today that the Super League is a "necessity", adding: "It should be an attractive competition, based on sporting merits … We are open to an open dialogue with UEFA. I think there will be an understanding."
But he also maintains that the club's members will have the final say.
SD Europe, which campaigns to increase supporter involvement in the running of football clubs, was among those speaking out against the Super League.
It welcomed the news that the plan had been scrapped but warned: "There are no real winners here. The problems besetting the game – unequal financial distribution, lack of consultation with fans and players, inadequate governance, lack of solidarity – remain the same and they remain unresolved."
Noting that many stakeholders in the game had thanked supporters for mobilising, it added: "All too often, the views of fans, along with those of players, go unheard. We are not at the table when decisions affecting the future of the game, such as the reform of the UEFA club competitions, are discussed and agreed.
"Supporters everywhere are tired of hearing the phrases 'football without fans is nothing' and 'fans are not customers'. We need the football governing bodies to recognise that life has to be breathed into empty phrases like these."
It said there is a need for "structured involvement of supporters in the governance of football clubs, national associations and leagues". And it argued that the Super League debacle pointed to a need for "far-reaching measures to ensure financial and social solidarity through appropriate redistribution of revenue".
It added: "The involvement of fans in decision-making has been supported by a range of stakeholders in recent discussions with SD Europe, including UEFA, the European Leagues, FIFPro, club executives, fan representatives, MEPs and the European Commission.
"We call upon the governing bodies and clubs to enter into a discussion with the national and local supporter organisations about how the views of the game's most important stakeholders – the players and the fans – can flow into recommendations and ultimately policies designed to shape the future of football."
In the UK, the affair has left Boris Johnson's Conservative government considering mechanisms for fan control, including the possibility of adopting the 50-plus-1 rule from Germany that gives fans the majority of voting rights. Tory MPs condemning the Super League include some of those supportive of co-operative ideas such as Jesse Norman, who branded it "a shambles of an idea, bad for fans, bad for competition, rotten for other clubs, rotten for the game".
"Our fan-led review will still happen and I remain convinced of the need for reform," said sports minister Oliver Dowden. "We must make sure this never happens again."
This marks a Tory move onto Co-op Party turf, prompting a response from the Party's general secretary Joe Fortune.
"We in the Co-operative Party and movement have been campaigning for fan ownership in football for over 20 years," he wrote on the Party's website. "I'm glad that the backlash against the European Super League has seen some new converts to the cause – but some of those conversions are more believable than others."
He added: "When it's time for action, this government has never been willing to truly take on the vested interests in football … Instead of genuine support for fan-owned football, the spectre of introducing a 50+1 fan ownership model like that used in Germany is being wielded by Boris Johnson as a threat, rather than a real solution to longstanding issues in the game.
"This latest scandal has finally pushed the Government to begin their promised fan-led review. But we've had reviews before and they haven't been acted on."
Mr Fortune cited the work of the Labour and Co-operative Parties in helping the effort in 20078 to set up fan ownership body Supporters Direct (which merged with the Football Supporters Federation in 2018), and their campaigns for resources to help supporters start fan ownership trusts and take over clubs.
"We developed and campaigned for the community shares model," he added, "which is often used in supporter trusts, and we have argued for strengthened community asset legislation to more easily stop ground sales."
He said the fan backlash against the Super League offers a "moment to push for real change".
"Over the past decade, both the government and the FA have failed to take action as greed paralysed the sport we all love," he said. "It's that inaction that allowed the owners of the Big Six to believe they'd get away with an idea as audacious as the Super League. But together, fans can prove them wrong."
Meanwhile, Andy Burnham – Labour Co-op mayor for Greater Manchester who was involved in the foundation of Supporters Direct – joined his Liverpool counterpart Steve Rotherham to launch a five-point plan, Reclaim the Game, to prevent a repeat of the Super League incident. Along with regulatory reform this includes adopting Germany's '50 plus one' rule, which would see season tickets holder balloted on any major changes to their club, and adopting the same model for ownership, giving fans at least 51% of a club's shares. This would be done by making it law for supporters trusts to given the first option to buy any shares that become available.


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Color Apricot
Apricot - Wikipedia
An apricot (US: / ˈ æ p r ɪ k ɒ t / (), UK: / ˈ eɪ p r ɪ k ɒ t / ()) is a fruit, or the tree that bears the fruit, of several species in the genus Prunus.. Usually, an apricot is from the species P. armeniaca, but the fruits of the other species in Prunus sect. Armeniaca are also called apricots.
Symbolism Of Color: Using Color For Meaning
Color also represents feelings, people, countries, cultures, and color symbolism. In the western world, the color red is seen frequently of symbolizing anger or aggression. Some car insurance companies charge more for red cars because some of the owners of red cars are more aggressive or take more risks.
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Mary Kay ® Gel Semi-Matte Lipstick is the first full-coverage lipstick by Mary Kay to utilize gel microsphere technology for rich, stay-true color that lasts for hours – without leaving lips looking or feeling dry. With color this pure, you can saturate lips, delivering a gorgeous level of color clarity. And with beautiful shades to choose from, it's a breeze to update your look to match ...
Champagne (color) - Simple English Wikipedia, The Free ...
The color champagne is a name given for various very pale tints of yellowish-orange that are close to beige.The color's name came from the average color of the drink champagne.. The first written use of champagne as a color name in English was in 1915.
Mahogany (color) - Wikipedia
Mahogany is a reddish-brown color. It is approximately the color of the wood mahogany. However, the wood itself, like most woods, is not uniformly the same color and is not recognized as a color by most. The first recorded use of mahogany as a color name in English was in 1737.
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Shop Hourglass's brightening Vanish™ Airbrush Concealer at Sephora. This full-coverage, weightless, and waterproof concealer blurs for up to 16 hours.
Alligator Copyright C By KIZCLUB.COM. All Rights Reserved.
anchor add Copyright c by KIZCLUB.COM. All rights reserved. 9 + 7. Title: A-color Created Date: 6/3/2014 1:31:33 PM
AIC - International Colour Association - Home
1.Your organization is either a national or regional color associations. 2. Your organization should be open to anyone in your country or region, and should cover all aspects of color. 3. ... Powered by Wild Apricot Membership Software ...
ColorStay™ Makeup For Combination/Oily Skin SPF 15 - Revlon
Available in 43 shades for every skin tone and type, Colorstay's makeup foundation provides flawless longlasting coverage for dry, oily and normal skin.
13 Spring 2022 Hair Color Trends Experts Predict Will Be Huge
Feb 15, 2022 · Apricot Ginger. For a brighter version of the warm reds that took over fall, Gillen is seeing variations of this peachy apricot hue. ... This color is …
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