Clinical and scientific studies of CHAGA extract components

Antiviral studies’

Betulic Acid

http://www.biomolther.org/journal/view.html?uid=536&vmd=Full

Betulinic acid, a pentacyclic triterpene isolated from Jujube tree (Zizyphus jujuba Mill), has been known for a wide range of biological and medicinal properties such as antibacterial, antimalarial, anti-inflammatory, antihelmintic, antinociceptive, and anticancer activities. In the study, we investigated the antiviral activity on influenza A/PR/8 virus infected A549 human lung adenocarcinoma epithelial cell line and C57BL/6 mice. Betulinic acid showed the anti-influenza viral activity at a concentration of 50 μM without a significant cytotoxicity in influenza A/PR/8 virus infected A549 cells. Also, betulinic acid significantly attenuated pulmonary pathology including increased necrosis, numbers of inflammatory cells and pulmonary edema induced by influenza A/PR/8 virus infection compared with vehicle- or oseltamivir-treated mice in vivo model. The down-regulation of IFN-γ level, which is critical for innate and adaptive immunity in viral infection, after treating of betulinic acid in mouse lung. Based on the obtained results, it is suggested that betulinic acid can be the potential therapeutic agent for virus infection via anti-inflammatory activity.

https://www.researchgate.net/publication/8081224_Betulinic_acid_derivatives_as_HIV-1_antivirals

Betulinic acid (BA) derivatives are low molecular weight organic compounds synthesized from a plant-derived natural product. Several BA derivatives are potent and highly selective inhibitors of HIV-1. Depending on the specific side-chain modification, these compounds function by inhibiting HIV fusion or, as recently demonstrated, by interfering with a specific step in HIV-1 maturation. BA derivatives have potential as novel HIV-1 therapies, and additional studies of their mechanisms of action are likely to further define the novel targets of these compounds and elucidate the basic biology of HIV-1 fusion and maturation. In this review, recent studies of the novel mechanisms of action of this interesting class of antiviral compounds are discussed.

In vitro antiviral activity of the common birch extract and its main pentacyclic triterpenes (betulin, lupeol and betulinic acid) against Herpes simplex virus type 1 (HSV-1) was also investigated [31]. Both the extract and the triterpenes tested exhibited high levels of antiviral activity against HSV-1. ...

https://aac.asm.org/content/52/1/128

Betulinic acid (BA) derivatives can inhibit human immunodeficiency virus type 1 (HIV-1) entry or maturation depending on side chain modifications. While BA derivatives with antimaturation activity have attracted considerable interest, the anti-HIV-1 profile and molecular mechanism of BA derivatives with anti-HIV-1 entry activity (termed BA entry inhibitors) have not been well defined. In this study, we have found that two BA entry inhibitors, IC9564 and A43D, exhibited a broad spectrum of anti-HIV-1 activity. Both compounds inhibited multiple strains of HIV-1 from clades A, B, and C at submicromolar concentrations. Clade C viruses were more sensitive to the compounds than clade A and B viruses. Interestingly, IC9564 at subinhibitory concentrations could alter the antifusion activities of other entry inhibitors.

https://www.sciencedirect.com/science/article/abs/pii/S0367326X03001230

Antiviral properties of betulin, betulinic and betulonic acids were investigated in cell cultures infected with herpes simplex type I, influenza FPV/Rostock and ECHO 6 viruses. All studied triterpenes were active against herpes simplex virus. Betulin and especially betulinic acid also suppressed ECHO 6 virus reproduction.

https://www.ncbi.nlm.nih.gov/pubmed/12837369

Antiviral properties of betulin, betulinic and betulonic acids were investigated in cell cultures infected with herpes simplex type I, influenza FPV/Rostock and ECHO 6 viruses. All studied triterpenes were active against herpes simplex virus. Betulin and especially betulinic acid also suppressed ECHO 6 virus reproduction.


Beta-D glucan

https://www.betaglucan.org/d-h/

Dectin-1:Immune Cell Receptor – Takano T, Motozono C, et al, “Dectin-1 Intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity,” JBC Papers in Press, Manuscrit M117.800847, Aug 28, 2017. Quote: “Dectin-1 is a well-characterized CLR [c-type lectin receptor] that recognizes B-glucan. …Our bodies are continuously exposed to and infected by various types of pathogens, most of which are recognized by pattern recognition receptors (PRRs)… An…additional member of emerging PRRs is the C-type lectin receptors (CLRs) [including Dectin-1] that sense pathogens or damaged tissues to trigger innate immune responses.” Note: Dectin-1 has been shown to recognize species of several fungal genera, including Candida, Pnemocystis, Coccidioides, Penicillium and others. Recognition of these organisms triggers many protective pathways, such as fungal uptake by phagocytosis and killing via respiratory burst. Activation of dectin-1 also triggers expression of many protecting antifungal cytokines and chemokines.

Dectin-1 Immune Cell Receptor: Batbayar S, Lee DH, Kim HW, “Immunomodulation of Fungal B-Glucan in Host Defense Signaling by Dectin-1,” Biomol Ther (Seoul), (5):433-45, PMID 24009832, Sep 2012. Quote: “Fungal and particulate B-glucans…can be taken up by the M cells of Peyer’s patches, and interact with macrophages or dendritic cells and activate systemic immune responses to overcome the fungal infection. Dectin-1 receptor systems have been incorporated as the PRRs of B-glucans in the innate immune cells of higher animal systems, which function on the front line against fungal infection, and have been exploited in cancer treatments to enhance systemic immune function.”

Dectin-1 Immune Cell Receptor: Drummond RA, Brown GD, “The Role of Dectin-1 in the host defense against fungal infections,” Curr Opin in Microbiol, Vol 14,Issue 4, PP 392-399, PMID 21803640, Aug 2011. Quote: “Dectin-1 is an innate immune pattern recognition receptor (PRR) that, through its ability to bind B-glucans, is involved in the recognition of several pathogenic fungi. Dectin-1 can stimulate a variety of cellular responses …including phagocytosis, cytokine production and the respiratory burst. ….Several advances in our understanding of Dectin-1 immunobiology have been made ….including demonstration of its ability to directly induce the development of adaptive immunity.“

Dectin-1 Immune Cell Receptor: Goodridge H, Reyes C, Becker C, et al, “Activation of the innate immune reeptor Dectin-1 upon formation of a “phagocytic synapse.” , Nature, 472(73(7344): 471-478: PMID 21525931, Apr 28, 2011. Quote: “…In this study we show that despite its ability to bind both soluble and particulate B-glucan polymers, Dectin-1 signaling is only activated by particulate B-glucans. …The “phagocytic synapse” now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular anti-microbial responses only when they are required.”

Dectin-1 Immune Cell Receptor: Reid DM, Gow NA, Brown GD, “Pattern recognition; recent insights from Dectin-1″ , Curr Opin Immunol, (1):30-7, PMID 1922162, Feb 2009. Quote: “The beta-glucan receptor Dectin-1 …can induce …a variety of cellular responses…. Furthermore, a broader appreciation of the cellular responses mediated by this receptor and the effects of interactions with other receptors… have greatly furthered our understanding of innate immunity and how this drives the development of adaptive immunity, particularly Th17 responses. …Recent studies have highlighted the importance of Dectin-1 in anti-fungal immunity, in both mice and humans, and have suggested a possible involvement of this receptor in the control of mycobacterial infections.“ Note: Th17 is a helper T-cell form..

https://pubs.acs.org/doi/full/10.1021/jf102003m

There have been a number of health benefits attributed to the consumption of β-glucans, including immunomodulatory effects (6). Published research has shown that certain β-glucans may enhance the ability of white blood cells to attack tumor cells through a defined mechanism of action (7), reduce the symptoms of respiratory tract infections (8-10), and protect mammals against infectious disease (11). The influence of the source and structure on biological activity was demonstrated in a study that compared the therapeutic efficacy of various sources of β-glucans (12).

https://www.alliedacademies.org/articles/preventive-effect-of-pleuran-glucan-from-pleurotus-ostreatus-in-children-with-recurrent-respiratory-tract-infections--openlabelpro.html

Background: Recurrent respiratory tract infections (RRTIs) are one of the most common problems in pediatric practice. Several natural preparations are used in management of RRTIs, but the scientific for their efficacy is sometimes insufficient. On the other hand, preventive effect of some natural preparation (e.g. β-glucans) was confirmed by relevant clinical studies. Methods: In our prospective open label study we enrolled 194 children suffering from RRTIs. We aimed to analyse the effect of Imunoglukan P4H® syrup containing pleuran (insoluble β-glucan isolated from Pleurotus ostreatus) on general respiratory morbidity comparing previous year with the same season during the study. Results: Supplementation of Imunoglukan P4H® syrup significantly decreased the total number of respiratory tract infections during the treatment and subsequent follow-up period compared to the same period of the previous year (4.18 ± 2.132 vs. 8.71 ± 1.89; p<0.001). In detail, the number of various types of respiratory tract infections (otitis, laryngitis, bronchitis and flu) was also significantly reduced (p<0.01 for all subtypes of infections). Moreover, a reduction in the number of day-off in kindergarten and school was also noticed. The syrup was well tolerated and no serious adverse effects were observed. Conclusion: Our study supports the use of pleuran in the complementary treatment and preventions of RRTIs in children. β-glucans seem to be an effective and safe tool in the management of RRTIs.

https://www.lifeextension.com/magazine/2006/11/report_immunity

Immune-Boosting Power of Beta-Glucan

Activating the communication and microbe-killing capabilities of macrophages is of paramount importance when confronting viral invaders, which may change their molecular “identities” in an effort to evade the body’s natural immune protection system. Numerous substances, including polysaccharides, lymphokines, and peptides, activate the defensive properties of macrophages. A polysaccharide called beta-glucan not only enhances macrophages’ ability to recognize and subdue microbial invaders, but also increases their ability to communicate with other cellular defenders of the immune system. These defenders, the immune “T cells,” subsequently initiate communications among a variety of immune system components, culminating in a cascade of events that amplify the immune response and ultimately overcome microbial invaders.

Korean researchers have demonstrated a direct anti-viral effect of beta-glucan against the influenza virus. Scientists exposed two groups of newborn pigs to the swine flu virus. Capable of infecting humans, it was a type of swine flu that notoriously prompted the US government to attempt the first nationwide flu vaccination program 30 years ago. This dramatic effort was spurred in part by the realization that another strain of swine flu may well have been responsible for the global devastation of the great flu pandemic of 1918, in which millions of people perished.

In this important experiment, one group of piglets received beta-glucan for three days before being infected with swine flu, while the other group received only a placebo for three days before infection with live virus. Objective evidence of swine flu infection in the lungs of piglets that had been infected, but not given beta-glucan, was significantly more severe than in the infected animals that had been pre-treated with beta-glucan.11

Furthermore, pigs that had been pre-treated with beta-glucan had significantly higher concentrations of natural disease-fighting substances, including interferon-gamma, in fluid obtained from the lungs within a week of infection. The researchers concluded that beta-glucan reduced signs of lung disease and the viral replication rate in the test subjects. These findings support the potential application of beta-glucan to prevent or treat influenza virus infection.11

In another experiment, scientists investigated the effects of beta-glucan against another viral challenge. Young piglets were exposed to porcine reproductive and respiratory syndrome virus, and then disease-fighting white blood cells were removed and exposed to varying concentrations of beta-glucan. Beta-glucan increased the production of interferon-gamma in a dose-dependent manner, leading the scientists to conclude that soluble beta-glucan may enhance innate antiviral immunity.12

These experiments demonstrate beta-glucan’s ability to dramatically improve innate immunity, particularly against potentially deadly viral infections.


While beta-glucan is found in several traditional folk remedies (including some Chinese mushrooms) that have been used for centuries to enhance immunity,13-16 these sources provide only limited amounts of the specific beta-glucan now known to provide powerful immune support. An old pharmaceutical preparation, Zymosan, was known to stimulate immunity as far back as the 1940s. Researchers at the Tulane University School of Medicine conducted dozens of studies of this substance, eventually isolating beta-glucan as its active ingredient. After the researchers modified this ingredient for ready ingestion, experimental evidence began to mount showing that beta-glucan is a highly effective immune system stimulator, activating defenses against both bacterial and viral organisms.17-21

Although beta-glucan is one of the most powerful biological response modifiers currently available in supplement form, not all beta-glucan supplements are created equal. As-yet-unpublished research, conducted at the University of Louisville in Kentucky, shows that a specially modified, yeast-derived form of beta-glucan dubbed beta-1,3-D-glucan is orally bioavailable and stimulates production of white blood cells in human bone marrow and spleen. Additionally, this proprietary form of beta-glucan has demonstrated superior ability to activate macrophages, neutrophils, and natural killer cells, effectively boosting immune function to confront threats ranging from radiation poisoning to tumors and infection.

Radiation’s lethal effects are largely caused by its suppression of immune cell production and activity. In Japan, scientists have shown that the injection of beta-glucan derived from yeast greatly increases the ability of mice to survive whole-body radiation exposure. Additionally, beta-glucan appeared to halt tumor growth in these mice. The scientists attributed the rodents’ increased survival rates to beta-glucan’s ability to sharply boost the production and activity of white blood cells and lymphatic cells. “These results suggest that beta-glucan may be a promising adjunct treatment for cancer patients receiving radiotherapy,” the researchers concluded.22 Other scientists have reported similar results with beta-glucan.23 Since one of the primary causes of serious illness and death in cancer patients is immune suppression caused by radiation treatments, beta-glucan may hold promise for improving outcomes in such patients.

Additionally, beta-glucan may offer some of the best protection—short of a specific vaccine—against biological attack. Canadian scientists have demonstrated that beta- glucan confers protection against deadly anthrax infection. Although testing on humans has not been conducted for obvious reasons, animal tests were highly promising. For example, in mice that received beta-glucan for one week prior to infection with anthrax bacteria, survival increased from 50% to 100%. When beta-glucan was administered only after infection had occurred, survival rates increased from 30% to 90% in the treatment groups. “These results demonstrate the potential for beta-1,3-glucan immune modulators to provide a significant degree of protection against anthrax,” the researchers concluded.24 Similar results against other pathogens have been reported by other researchers.25-27

https://nutritionj.biomedcentral.com/articles/10.1186/1475-2891-13-38

Long before the substance class of β-glucans themselves were identified as immunomodulators, the beneficial effects of β-glucan-containing mushrooms such as Shiitake (Lentinus edodes) in Japan or Lingzhi (Ganoderma lucidum) in China were utilized in the traditional Oriental medicine for the strengthening of the body’s immune system.

The individual glucose subunits are primarily linked either by (1,3)-β, (1,4)-β, or (1,6)-β glycosidic bonds. In most cases, β-glucans exhibit a uniformly constructed backbone of various lengths with side-chains of D-glucose attached by (1,4)-β, or (1,6)-β bindings.

However, not all β-glucans are able to modulate immune functions. These properties mainly depend on the primary chemical structure of the β-glucans. Cellulose for example, a (1,4)-β-linked glucan, does not exhibit immune-modulatory effects. In contrast, β-glucans derived from fungi and yeast, which consist of a (1,3)-β-linked backbone with small numbers of (1,6)-β-linked side chains, are essentially known for their immune-modulating effects [8].

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041399

β-(1→3)-D-glucans with β-(1→6)-glycosidic linked branches produced by mushrooms, yeast and fungi are known to be an immune activation agent, and are used in anti-cancer drugs or health-promoting foods. In this report, we demonstrate that oral administration of Aureobasidium pullulans-cultured fluid (AP-CF) enriched with the β-(1→3),(1→6)-D-glucan exhibits efficacy to protect mice infected with a lethal titer of the A/Puerto Rico/8/34 (PR8; H1N1) strain of influenza virus. The survival rate of the mice significantly increased by AP-CF administration after sublethal infection of PR8 virus. The virus titer in the mouse lung homogenates was significantly decreased by AP-CF administration. No significant difference in the mRNA expression of inflammatory cytokines, and in the population of lymphocytes was observed in the lungs of mice administered with AP-CF. Interestingly, expression level for the mRNA of virus sensors, RIG-I (retinoic acid-inducible gene-I) and MDA5 (melanoma differentiation-associated protein 5) strongly increased at 5 hours after the stimulation of A. pullulans-produced purified β-(1→3),(1→6)-D-glucan (AP-BG) in murine macrophage-derived RAW264.7 cells. Furthermore, the replication of PR8 virus was significantly repressed by pre-treatment of AP-BG. These findings suggest the increased expression of virus sensors is effective for the prevention of influenza by the inhibition of viral replication with the administration of AP-CF.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322159/

Background

The strong immunostimulating potential of β-glucans has been well established in numerous diseases. However, the effects on viral infection were less studied.

Methods

In our study, we focused on possible effects of a special combined glucan formulation on immunosuppression caused by influenza infection.

Results   We found that a 2-week oral feeding with glucan mixture significantly reduced the effects of influenza infection in total mortality. Our study was focused on phagocytosis, cytokine levels, antibody response and cytotoxicity assay.

Conclusions    Based on our data, we concluded that these effects are caused by stimulation of both cellular and humoral immune reaction resulting in lower viral load.


Caffeic acid

https://www.sciencedirect.com/science/article/pii/S1567576904000190

Caffeic acid phenethyl ester (CAPE), an the active component of propolis, is known to have anticarcinogenic, antiviral and various biological activities; 

https://www.spandidos-publications.com/etm/9/5/1582

Caffeic acid phenethyl ester (CAPE), a naturally occurring compound isolated from propolis extract, has been reported to have a number of biological and pharmacological properties, exerting antioxidant, anti‑inflammatory, anticarcinogenic, antibacterial and immunomodulatory effects. Recent in vivo and in vitro study findings have provided novel insights into the molecular mechanisms involved in the anti‑inflammatory and immunomodulatory activities of this natural compound. CAPE has been reported to have anti‑inflammatory properties involving the inhibition of certain enzyme activities, such as xanthine oxidase, cyclooxygenase and nuclear factor‑κB (NF‑κB) activation. Since inflammation and immune mechanisms play a crucial role in the onset of several inflammatory diseases, the inhibition of NF‑κB represents a rationale for the development of novel and safe anti‑inflammatory agents. The primary goal of the present review is to highlight the anti‑inflammatory and immunomodulatory activities of CAPE, and critically evaluate its potential therapeutic effects.

https://www.sciencedirect.com/science/article/abs/pii/S0378874104002673

The effect of polyphenolic compounds isolated from propolis and propolis itself was investigated on the growth and metastatic potential of a transplantable mammary carcinoma (MCa) of CBA mouse. Metastases in the lung were generated by intravenous injection of tumor cells (2 × 105). A water-soluble derivative of proplis (WSDP), caffeic acid (CA), caffeic acid phenethyl ester (CAPE) and quercetin (QU) were given to mice per os before tumor cells inoculation. Tested compounds significantly decreased the number of tumor nodules in the lung. According to the results obtained the antitumor activity of tested compounds can be related to the immunomodulatory properties of the compounds, their cytotoxicity to tumor cells, and their capacity to induce apoptosis and necrosis. The experimental data support that WSDP, CA, CAPE and QU could be potentially useful in the control of tumor growth in experimental models.

https://www.ncbi.nlm.nih.gov/pubmed/27855523

Many studies have been performed to assess the potential utility of natural products as immunomodulatory agents to enhance host responses and to reduce damage to the human body. To determine whether phenolic compounds (caffeic, ferulic, and p-coumaric acids) have immunomodulatory effects and clarify which types of immune effector cells are stimulated in vitro, we evaluated their effect on splenocyte proliferation and lysosomal enzyme activity. We also investigated the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). In addition, induction of the cellular antioxidant activity in splenocytes, macrophages, and red blood cells was determined by measuring the fluorescence of the DCF product. The study first results indicated that caffeic, ferulic, and p-coumaric acids significantly promote LPS-stimulated splenocyte proliferation, suggesting a potential activation of B cells, and enhanced humoral immune response in hosts treated by the tested natural products. Phenolic acids significantly enhanced the killing activity of isolated NK and CTL cells but had negligible effects on mitogen-induced proliferation of splenic T cells. We showed that caffeic acid enhances lysosomal enzyme activity in murine peritoneal macrophages, suggesting a potential role in activating such cells. Immunomodulatory activity was concomitant with the cellular antioxidant effect in macrophages and splenocytes of caffeic and ferulic acids. We conclude from this study that caffeic, ferulic, and p-coumaric acids exhibited an immunomodulatory effect which could be ascribed, in part, to their cytoprotective effect via their antioxidant capacity. Furthermore, these results suggest that these natural products could be potentially used to modulate immune cell functions in physiological and pathological conditions.

https://www.spandidos-publications.com/10.3892/etm.2015.2346

Caffeic acid phenethyl ester (CAPE), a naturally occurring compound isolated from propolis extract, has been reported to have a number of biological and pharmacological properties, exerting antioxidant, anti‑inflammatory, anticarcinogenic, antibacterial and immunomodulatory effects. Recent in vivo and in vitro study findings have provided novel insights into the molecular mechanisms involved in the anti‑inflammatory and immunomodulatory activities of this natural compound. CAPE has been reported to have anti‑inflammatory properties involving the inhibition of certain enzyme activities, such as xanthine oxidase, cyclooxygenase and nuclear factor‑κB (NF‑κB) activation. Since inflammation and immune mechanisms play a crucial role in the onset of several inflammatory diseases, the inhibition of NF‑κB represents a rationale for the development of novel and safe anti‑inflammatory agents. The primary goal of the present review is to highlight the anti‑inflammatory and immunomodulatory activities of CAPE, and critically evaluate its potential therapeutic effects.

https://www.hindawi.com/journals/bmri/2014/145342/

The available studies narrate it as an effective moiety against various pathologies such as infections, oxidative stress, inflammation, cancer, diabetes, neurodegeneration, and anxiety [3, 5–8]. These therapeutic characteristics of CAPE have been summarized in this review article.

https://publons.com/publon/14150261/

Caffeic acid phenethyl ester (CAPE), a naturally occurring compound isolated from propolis extract, has been reported to have a number of biological and pharmacological properties, exerting antioxidant, anti-inflammatory, anticarcinogenic, antibacterial and immunomodulatory effects.

https://en.wikipedia.org/wiki/Caffeic_acid

Caffeic acid is an antioxidant in vitro and also in vivo.[13] Caffeic acid also shows immunomodulatory and anti-inflammatory activity. Caffeic acid outperformed the other antioxidants, reducing aflatoxin production by more than 95 percent. The studies are the first to show that oxidative stress that would otherwise trigger or enhance Aspergillus flavus aflatoxin production can be stymied by caffeic acid. This opens the door to use as a natural fungicide by supplementing trees with antioxidants

https://www.researchgate.net/publication/310585758_Immunomodulatory_and_cellular_anti-oxidant_activities_of_caffeic_ferulic_and_p-coumaric_phenolic_acids_a_structure-activity_relationship_study

The study first results indicated that caffeic, ferulic, and p-coumaric acids significantly promote LPS-stimulated splenocyte proliferation, suggesting a potential activation of B cells, and enhanced humoral immune response in hosts treated by the tested natural products. Phenolic acids significantly enhanced the killing activity of isolated NK and CTL cells but had negligible effects on mitogen-induced proliferation of splenic T cells. We showed that caffeic acid enhances lysosomal enzyme activity in murine peritoneal macrophages, suggesting a potential role in activating such cells. Immunomodulatory activity was concomitant with the cellular antioxidant effect in macrophages and splenocytes of caffeic and ferulic acids. We conclude from this study that caffeic, ferulic, and p-coumaric acids exhibited an immunomodulatory effect which could be ascribed, in part, to their cytoprotective effect via their antioxidant capacity.

https://www.mdpi.com/1422-0067/20/10/2441  diabetes

 Our data demonstrated that inducible nitric oxide synthase/gamma-Glutamyl-cysteine ligase (iNOS/GGCL) and DDAH dysregulation may play a key role in high glucose mediated oxidative stress, whereas HO-1 inducers such as CAPE or its more potent derivatives may be useful in diabetes and other stress-induced pathological conditions. 

https://www.intechopen.com/books/phenolic-compounds-biological-activity/plant-phenolic-compounds-as-immunomodulatory-agents a good one

The discovery of immunomodulatory agents from medicinal plants devoid of toxic side effects, with enhanced bioavailability and that can be used for a long duration, is of great actuality. Research on natural immunomodulators provides a therapeutic solution that addresses a multitude of disorders. Plant phenolic compounds already proved beneficial effects in cardiovascular diseases, diabetes, and cancer, exerting mainly antioxidant and anti-inflammatory effects. The concepts of “immunomodulatory,” “anti-inflammatory,” and “antioxidant” are often strongly related, and a review of phenolic compound action on immune system should be analyzed in a context, revealing their mechanism of action on effector cells and also on the system as a whole.

 
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