Immunity x ginseng

Korean ginseng (Panax ginseng) is one of the most prized medicinal plants in the world. As a true icon of Asian culture, its root has been used there for millennia. Ginseng’s medicinal properties are so revered that they played a big part in the border being drawn between China and Korea. The Chinese Emperor believed the people of Korea plundered ginseng from the Manchurian forests and therefore decided to establish a precise border to be able to apply its harvest ban [1]. Even today, much research is being carried out on the therapeutic effects of this “root of a thousand virtues”: metabolic disorders, oncology…, including in the field of immunity [2-5].

Yet in Europe, ginseng is too often considered as a “general tonic”. This largely cultural difference is intensified by the poor quality of ginseng used in Europe compared to premium products from Korea and Japan.

In the best of cases, European laboratories will ensure that the product is not adulterated and that it contains a high level of ginsenosides.

However, as we will see later, not all ginsenosides are equal in terms of their benefits. Ginseng’s main molecules of interest are numerous and can be categorized into 2 groups. There are others but their impact on the immune sphere does not seem crucial.

1. ACTIVE MOLECULES

1.1. Ginsenosides

Ginsenosides are the main active molecules in ginseng. There is a wide variety, but they do not all share the same activity. Most of the ginsenosides found in ginseng are precursors of bioactive ginsenosides. These precursors are poorly assimilated by the body, although the intestinal microbiota converts a small proportion into bioactive form. So the dose of active ginsenosides entering the bloodstream is less than the dose of ginsenosides ingested.

Fortunately, the conversion into active ginsenosides is also possible outside the body. It is achieved via various methods of preparing ginseng, which range from traditional cooking and steaming to the most modern techniques. For example, red ginseng is actually steamed white ginseng. Heat treatment serves to convert ginsenosides into bioactive form – just as the intestinal microbiota does. Black ginseng is cooked nine times to ramp up the level of bioactive ginsenosides.

In Asia, some laboratories have developed sophisticated fermentation methods to boost active ginsenosides level.

Another method is optimizing molecular profiles by modulating growth conditions via vertical farming in a controlled environment. The molecular profile of a plant is defined by the conditions is faces during its existence: temperature, humidity, light, stress, nutrients etc

Ginsenosides are found in the totum (full spectrum molecular profile) but require a significant culture time before being present in significant quantities. That’s why, in general, the longer you cultivate ginseng, the more potent it becomes. For example, most Asian ginseng is cultivated for at least six years.

Ginsenosides are also present in alcoholic extracts, which are conventionally used to concentrate them.

1.2. Ginsan

Recent studies on echinacea suggests much of its immunostimulatory activity derives not from the plant itself but the endophyte organisms colonizing it [1-5]. This preliminary data raises questions about plant function in the absence of these organisms; about the importance of the totum and preparation methods with fresh/dry plants, drying and steaming methods etc.

2. GINSENG & IMMUNITY

2.1. Ginseng & macrophages

The influence of ginseng compounds on macrophages is complex. Scientific publications number in the hundreds and explore a whole series of scenarios ranging from bacterial infection to cancer. However, we can extract three main actions of interest:

2.1.1. Optimization of phagocytosis

Ginseng seems to have the ability to optimize the efficiency of phagocytosis. Ginsenoside Rg3 [6-7] and ginsan [8-9] have been identified as promotors of the phagocytosis process and therefore the effectiveness of active macrophages. Note that this is an ‘optimization’ of active macrophages and not an increase in recruitment or a stimulating effect on the differentiation of macrophages.

2.1.2. A regulating effect on inflammation

Many ginsenosides have been shown to limit the inflammatory response. Ginsenosides Rg5 [10-11], Rk1 [11-12] and Rg3 [13-14] have been identified as active at this level. Data also exist for other ginseng extracts [15-16].

This observation suggests ginseng limits the immune response via fewer macrophages on-site. As we have seen for echinacea, this effect has the advantage of limiting the symptoms linked to excessive inflammation, while “staying the course”.

It will be noted that in the case of ginseng, this positive impact has been reported in vivo, in particular in septisemia models, demonstrating that more ‘efficient”’ but gradually recruited macrophages lead to a better prognosis [17-21].

2.1.3. A tendency to favor the M2 phenotype

We saw in the first article (read soon HERE), that macrophages can present themselves under two phenotypes: M1, which actively secretes many pro-inflammatory cytokines and phagocytes and M2, which promotes the repair of tissues damaged by infections and trauma. Rg3 has been identified in multiple studies as favoring the M2 phenotype [22-24].

This activity confirms the regulatory potential of a ginseng rich in Rg3 and ginsan on innate immunity. It suggests a double-action on macrophages: limiting any phenomenon of deleterious inflammation on the one hand and promoting the effectiveness of the macrophages on the other.

2.2. Ginseng & dendritic cells

Several studies report a 2-fold influence of ginseng compounds on dendritic cell activity.

2.2.1. Stimulation of dendritic cell activity

Firstly, activation of dendritic cells – immune system stimulating antigens – has been observed with various ginseng molecules, in particular, ginsan [25-26]. Rg3 plays a role as well, although the model is more associated with immunity to cancer cells than to an infection [27]. This activation can have various consequences downstream where Rg3 has been shown to have influence.

2.2.2. Modulation of dendritic cell activity

If ginsan acts as the primary activator of dendritic cells, then bioactive ginsenosides and in particular, Rg3, have been shown to limit the activation of certain types of T lymphocytes by these same dendritic cells [28-29]. In other words, the dendritic cells are activated but perform specific ‘tasks’.vity.

2.3. Ginseng & lymphocytes

So certain ginsenosides limit the activation of certain types of T lymphocytes: Th1 [29], Th2 [30] & Th17 [28] by modulating the activity of dendritic cells. Conversely, they will promote the activity of Treg lymphocytes [31-33]. Tregs are T lymphocytes that act to avoid autoimmune reactions. They prevent cytotoxic T lymphocytes from recognizing antigens specific to the body and do not attack ‘the self’. They are little diplomats of the immune system. One might wonder how Treg stimulation promotes natural defences. In reality, it has been shown that Tregs play a positive role in natural defences. By limiting the action of T lymphocytes, they allow them to focus on important antigens [34].

Beyond the direct effect on immunity, this type of influence suggests that ginsenosides should also limit the production of IgE (Immunoglobulin E) by B lymphocytes in favor of IgA, which is confirmed by the literature [35- 36]. It is interesting to note that this Treg & IgA activation cascade is reminiscent of the health-benefiting interactions between the immune system and the intestinal microbiota.

2.4. Ginseng & natural killer (NK) cells

Ginseng also appears to have an activating effect on NK cells, through some of its constituents [37-40]. This aspect arouses the interest of researchers in an oncological context. The activation of NK cells is obviously interesting in the context of an intracellular infection: viruses, intracellular bacteria etc

2.5. Antiviral activity

Beyond its direct effects on immunity, ginseng exhibits antiviral properties that indirectly strengthen immunostimulatory activity [41-44]. While this is not the most prominent property of ginseng, it remains of great interest.

3. TOMORROW’S TRACKS

3.1. What type of extract?

As we saw in the introduction, two aspects must be considered when selecting an effective ginseng.

The concentration of Rg3 and Rg5:

A ginseng rich in ginsenosides will obviously be more effective than a ginseng containing hardly containing any, but conventional ginsenosides remain little bioavailable and their exhibit limited bioactivity is very limited.

Quality ginseng products will be able to give you define the rate ratio of each ginsenoside. This will allow you to compare the levels of Rg3, Rg5 and Rk1 and therefore identify a really active truly potent ginseng.

The presence of ginsan:

Although they appear secondary in certain areas, ginsan play a significant role in the immune potential of ginseng. These polysaccharides are conventionally more abundant in cooked ginseng (red or black ginseng) but are unfortunately only very slightly soluble in alcohol. The totum is therefore very important in the context of immune health.

Obviously, the ideal is ginseng that is both rich in rare ginsenosides and ginsan. Nevertheless, this type of product is scarce and its elevated price will only be suitable for formulas that aim for excellence. That said, we could also consider that it is better to integrate 100 mg of bioactive ginseng than 500 mg of non-assimilable ginseng.

3.2. For which product?

Based on the above data, the potential of ginseng to favorably influence immune function is more than significant and seems suitable for all types of products. However, its global action leans to its use in a preventive context. Some studies also show that while bioavailable ginsenosides can act quickly, the positive impact of ginsan evolves positively week after week [45].

While the data shows ginseng can be effective in prevention, we reiterate the evidence for direct treatment is much more speculative.

3.3. What to associate it with?

3.3.1. For a product in winter

As we have seen, ginseng rich in bioactive ginsenosides has a global impact on natural defences. As part of the development of a ‘winter boost’ formula, we can thus reinforce the two additional pillars: anti-infectious activity and regulation of inflammation. The purely immunomodulating aspect being largely taken into consideration by ginseng itself.

In aromatherapy, we can associate an oil rich in 1,8-cineole for its inflammatory regulating properties and its antiviral activity.

We can also consider adding marjoram oil in capsule form (Origanum majorana) to reinforce the anti-infectious activity.

Finally, fans of more ‘complex’ formulas will consider adding essential turmeric oil (Curcuma longa) rich in aromatic turmerone. This essential oil with properties too often confused with turmeric extract (the essential oil does not contain curcumin), is of great interest in many health spheres. Noted for neuroprotective and anti-inflammatory skin benefits, this essential oil is also immunomodulating [46-49].

Provided that the two ingredients are of premium quality, the duo ginseng + skullcap (Scutellaria baicalensis) represents an almost ideal solution to boost the defences in winter when it comes to herbal medicine. Indeed, the skullcap of Lake Baikal has a very significant antiviral activity [50-55] and inflammation regulatory properties [56-60]. Combined, these two plants address almost all of the relevant aspects of immunity. Only a probiotic could complement this tandem even more.

3.3.3. For a global approach to daily immune health

Science shows ginseng is an excellent global solution for daily immune health. Beyond its immunostimulatory and immunoregulatory properties, a ginseng rich in Rg3, Rg5, and Rk1 is also active in metabolic balance (glycemia, lipid metabolism, and cardiovascular health) or neuroprotection (neuroprotective and nootropic).

These actions can occur alone or in advanced formulas that may include other ingredients active in other spheres, like the intestinal microbiota.

In aromatherapy, we can consider combining it with an oil-rich in geraniol such as the palmarosa (Cymbopogon martinii) or the monard or wild bergamot (Monarda fistulosa) whose beneficial properties on the intestinal microbiota have been highlighted.

Essential oils rich in citral can also be considered in this context [61].

In phytotherapy, a source of chlorogenic acids such as green coffee (Coffea canephora), artichoke (Cynara scolymus), or blueberry leaf (Vaccinium myrtillus), should promote the balance of the microbiota.

Finally, it is worth noting that the positive impact on Tregs and the production of IgA suggests formulations with probiotics could prove to be particularly relevant.

REFERENCES

[1] Kim Seon-min (2017) – “Ginseng and Borderland: Territorial Boundaries and Political Relations Between Qing China and Choson Korea” University of California Press

[2] Shin MS, Song JH, Choi P, Lee JH, Kim SY, Shin KS, Ham J, Kang KS (2018) – “Stimulation of Innate Immune Function by Panax ginseng after Heat Processing.” J Agric Food Chem. 2018 May 9;66(18):4652-4659. doi: 10.1021/acs.jafc.8b00152. Epub 2018 Apr 26.

[3] Liu X, Zhang Z, Liu J, Wang Y, Zhou Q, Wang S, Wang X (2019) – “Ginsenoside Rg3 improves cyclophosphamide-induced immunocompetence in Balb/c mice.” Int Immunopharmacol. 2019 Jul;72:98-111. doi: 10.1016/j.intimp.2019.04.003. Epub 2019 Apr 8.

[4] Lee JS, Hwang HS, Ko EJ, Lee YN, Kwon YM, Kim MC, Kang SM (2014) – “Immunomodulatory activity of red ginseng against influenza A virus infection.” Nutrients. 2014 Jan 27;6(2):517-29. doi: 10.3390/nu6020517.

[5] Nguyen NH, Nguyen CT (2019) – “Pharmacological effects of ginseng on infectious diseases.” Inflammopharmacology. 2019 Oct;27(5):871-883. doi: 10.1007/s10787-019-00630-4. Epub 2019 Aug 12.

[6] Xin C, Kim J, Quan H, Yin M, Jeong S, Choi JI, Jang EA, Lee CH, Kim DH, Bae HB (2019) – “Ginsenoside Rg3 promotes Fc gamma receptor-mediated phagocytosis of bacteria by macrophages via an extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent mechanism.” Int Immunopharmacol. 2019 Dec;77:105945. doi: 10.1016/j.intimp.2019.105945. Epub 2019 Oct 20.

[7] Liu X, Zhang Z, Liu J, Wang Y, Zhou Q, Wang S, Wang X (2019) – “Ginsenoside Rg3 improves cyclophosphamide-induced immunocompetence in Balb/c mice.” Int Immunopharmacol. 2019 Jul;72:98-111. doi: 10.1016/j.intimp.2019.04.003. Epub 2019 Apr 8.

[8] Shin JY, Song JY, Yun YS, Yang HO, Rhee DK, Pyo S (2002) – “Immunostimulating effects of acidic polysaccharides extract of Panax ginseng on macrophage function.” Immunopharmacol Immunotoxicol. 2002 Aug;24(3):469-82.

[9] Seo JY, Choi JW, Lee JY, Park YS, Park YI (2018) – “Enzyme Hydrolysates of Ginseng Marc Polysaccharides Promote the Phagocytic Activity of Macrophages Via Activation of TLR2 and Mer Tyrosine Kinase.” J Microbiol Biotechnol. 2018 Jun 28;28(6):860-873. doi: 10.4014/jmb.1801.01003.

[10] Kim TW, Joh EH, Kim B, Kim DH (2012) – “Ginsenoside Rg5 ameliorates lung inflammation in mice by inhibiting the binding of LPS to toll-like receptor-4 on macrophages.” Int Immunopharmacol. 2012 Jan;12(1):110-6. doi: 10.1016/j.intimp.2011.10.023. Epub 2011 Nov 19.

[11] Ahn S, Siddiqi MH, Aceituno VC, Simu SY, Zhang J, Jimenez Perez ZE, Kim YJ, Yang DC (2016) – “Ginsenoside Rg5:Rk1 attenuates TNF-α/IFN-γ-induced production of thymus- and activation-regulated chemokine (TARC/CCL17) and LPS-induced NO production via downregulation of NF-κB/p38 MAPK/STAT1 signaling in human keratinocytes and macrophages.” In Vitro Cell Dev Biol Anim. 2016 Mar;52(3):287-295. doi: 10.1007/s11626-015-9983-y. Epub 2015 Dec 29.

[12] Yu Q, Zeng KW, Ma XL, Jiang Y, Tu PF, Wang XM (2017) – “Ginsenoside Rk1 suppresses pro-inflammatory responses in lipopolysaccharide-stimulated RAW264.7 cells by inhibiting the Jak2/Stat3 pathway.” Chin J Nat Med. 2017 Oct;15(10):751-757. doi: 10.1016/S1875-5364(17)30106-1.

[13] Shi Y, Wang H, Zheng M, Xu W, Yang Y, Shi F (2020) – “Ginsenoside Rg3 suppresses the NLRP3 inflammasome activation through inhibition of its assembly.” FASEB J. 2020 Jan;34(1):208-221. doi: 10.1096/fj.201901537R. Epub 2019 Nov 20.

[14] Lee JW, Choi YR, Mok HJ, Seong HA, Lee DY, Kim GS, Yoon JH, Kim KP, Kim HD (2017) – “Characterization of the changes in eicosanoid profiles of activated macrophages treated with 20(S)-ginsenoside Rg3.” J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Oct 15;1065-1066:14-19. doi: 10.1016/j.jchromb.2017.09.002. Epub 2017 Sep 5.

[15] Lee YY, Saba E, Irfan M, Kim M, Chan JY, Jeon BS, Choi SK, Rhee MH (2019) – “The anti-inflammatory and anti-nociceptive effects of Korean black ginseng.” Phytomedicine. 2019 Feb 15;54:169-181. doi: 10.1016/j.phymed.2018.09.186. Epub 2018 Sep 18.

[16] Adam GO, Kim GB, Lee SJ, Lee H, Kang HS, Kim SJ (2019) – “Red Ginseng Reduces Inflammatory Response via Suppression MAPK/P38 Signaling and p65 Nuclear Proteins Translocation in Rats and Raw 264.7 Macrophage.” Am J Chin Med. 2019;47(7):1589-1609. doi: 10.1142/S0192415X19500812. Epub 2019 Oct 23.

[17] Choi SY, Park JS, Shon CH, Lee CY, Ryu JM, Son DJ, Hwang BY, Yoo HS, Cho YC, Lee J, Kim JW, Roh YS (2019) – “Fermented Korean Red Ginseng Extract Enriched in Rd and Rg3 Protects against Non-Alcoholic Fatty Liver Disease through Regulation of mTORC1.” Nutrients. 2019 Dec 4;11(12). pii: E2963. doi: 10.3390/nu11122963.

[18] Saba E, Jeong D, Irfan M, Lee YY, Park SJ, Park CK, Rhee MH (2018) – “Anti-Inflammatory Activity of Rg3-Enriched Korean Red Ginseng Extract in Murine Model of Sepsis.” Evid Based Complement Alternat Med. 2018 Oct 11;2018:6874692. doi: 10.1155/2018/6874692. eCollection 2018.

[19] Kim JE, Lee W, Yang S, Cho SH, Baek MC, Song GY, Bae JS (2019) – “Suppressive effects of rare ginsenosides, Rk1 and Rg5, on HMGB1-mediated septic responses.” Food Chem Toxicol. 2019 Feb;124:45-53. doi: 10.1016/j.fct.2018.11.057. Epub 2018 Nov 26.

[20] Ahn JY, Song JY, Yun YS, Jeong G, Choi IS (2006) – « Protection of Staphylococcus aureus-infected septic mice by suppression of early acute inflammation and enhanced antimicrobial activity by ginsan.” FEMS Immunol Med Microbiol. 2006 Mar;46(2):187-97.

[21] Ahn JY, Choi IS, Shim JY, Yun EK, Yun YS, Jeong G, Song JY (2006) – “The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll-like receptor-mediated inflammatory signals.” Eur J Immunol. 2006 Jan;36(1):37-45.

[22] Guo M, Xiao J, Sheng X, Zhang X, Tie Y, Wang L, Zhao L, Ji X (2018) – “Ginsenoside Rg3 Mitigates Atherosclerosis Progression in Diabetic apoE-/- Mice by Skewing Macrophages to the M2 Phenotype.” Front Pharmacol. 2018 May 9;9:464. doi: 10.3389/fphar.2018.00464. eCollection 2018.

[23] Kang S, Park SJ, Lee AY, Huang J, Chung HY, Im DS (2018) – “Ginsenoside Rg3 promotes inflammation resolution through M2 macrophage polarization.” J Ginseng Res. 2018 Jan;42(1):68-74. doi: 10.1016/j.jgr.2016.12.012. Epub 2017 Jan 1.

[24] Im DS (2020) – “Pro-Resolving Effect of Ginsenosides as an Anti-Inflammatory Mechanism of Panax ginseng.” Biomolecules. 2020 Mar 13;10(3). pii: E444. doi: 10.3390/biom10030444.

[25] Kim MH, Byon YY, Ko EJ, Song JY, Yun YS, Shin T, Joo HG (2009) – “Immunomodulatory activity of ginsan, a polysaccharide of panax ginseng, on dendritic cells.” Korean J Physiol Pharmacol. 2009 Jun;13(3):169-73. doi: 10.4196/kjpp.2009.13.3.169. Epub 2009 Jun 30.

[26] Na HS, Lim YJ, Yun YS, Kweon MN, Lee HC (2010) – “Ginsan enhances humoral antibody response to orally delivered antigen.” Immune Netw. 2010 Feb;10(1):5-14. doi: 10.4110/in.2010.10.1.5. Epub 2010 Feb 28.

[27] Son KJ, Choi KR, Lee SJ, Lee H (2016) – “Immunogenic Cell Death Induced by Ginsenoside Rg3: Significance in Dendritic Cell-based Anti-tumor Immunotherapy.” Immune Netw. 2016 Feb;16(1):75-84. doi: 10.4110/in.2016.16.1.75. Epub 2016 Feb 25.

[28] Park YJ, Cho M, Choi G, Na H, Chung Y (2020) – “A Critical Regulation of Th17 Cell Responses and Autoimmune Neuro-Inflammation by Ginsenoside Rg3.” Biomolecules. 2020 Jan 10;10(1). pii: E122. doi: 10.3390/biom10010122.

[29] Cho M, Choi G, Shim I, Chung Y (2019) – “Enhanced Rg3 negatively regulates Th1 cell responses.” J Ginseng Res. 2019 Jan;43(1):49-57. doi: 10.1016/j.jgr.2017.08.003. Epub 2017 Aug 16.

[30] Jung JH, Kang TK, Oh JH, Jeong JU, Ko KP, Kim ST (2020) – “The Effect of Korean Red Ginseng on Symptoms and Inflammation in Patients With Allergic Rhinitis.” Ear Nose Throat J. 2020 Feb 19:145561320907172. doi: 10.1177/0145561320907172.

[31] Shin KK, Yi YS, Kim JK, Kim H, Hossain MA, Kim JH, Cho JY (2020) – “Korean Red Ginseng Plays An Anti-Aging Role by Modulating Expression of Aging-Related Genes and Immune Cell Subsets.” Molecules. 2020 Mar 25;25(7). pii: E1492. doi: 10.3390/molecules25071492.

[32] Jhun J, Lee J, Byun JK, Kim EK, Woo JW, Lee JH, Kwok SK, Ju JH, Park KS, Kim HY, Park SH, Cho ML (2014) – “Red ginseng extract ameliorates autoimmune arthritis via regulation of STAT3 pathway, Th17/Treg balance, and osteoclastogenesis in mice and human.” Mediators Inflamm. 2014;2014:351856. doi: 10.1155/2014/351856. Epub 2014 Jul 23.

[33] Heo SB, Lim SW, Jhun JY, Cho ML, Chung BH, Yang CW (2016) – “Immunological benefits by ginseng through reciprocal regulation of Th17 and Treg cells during cyclosporine-induced immunosuppression.” J Ginseng Res. 2016 Jan;40(1):18-27. doi: 10.1016/j.jgr.2015.04.005. Epub 2015 Apr 30.Treg

[34] Pace L, Tempez A, Arnold-Schrauf C, Lemaitre F, Bousso P, Fetler L, Sparwasser T, Amigorena S (2012) – « Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory.” Science. 2012 Oct 26;338(6106):532-6. doi: 10.1126/science.1227049.

[35] Kim HI, Kim JK, Kim JY, Han MJ, Kim DH (2019) – “Fermented red ginseng and ginsenoside Rd alleviate ovalbumin-induced allergic rhinitis in mice by suppressing IgE, interleukin-4, and interleukin-5 expression.” J Ginseng Res. 2019 Oct;43(4):635-644. doi: 10.1016/j.jgr.2019.02.006. Epub 2019 Mar 7.

[36] Park HY, Lee SH, Lee KS, Yoon HK, Yoo YC, Lee J, Choi JE, Kim PH, Park SR (2015) – “Ginsenoside Rg1 and 20(S)-Rg3 Induce IgA Production by Mouse B Cells.” Immune Netw. 2015 Dec;15(6):331-6. doi: 10.4110/in.2015.15.6.331. Epub 2015 Dec 24.

[37] Zhang B, Zhou WJ, Gu CJ, Wu K, Yang HL, Mei J, Yu JJ, Hou XF, Sun JS, Xu FY, Li DJ, Jin LP, Li MQ (2018) – “The ginsenoside PPD exerts anti-endometriosis effects by suppressing estrogen receptor-mediated inhibition of endometrial stromal cell autophagy and NK cell cytotoxicity.” Cell Death Dis. 2018 May 1;9(5):574. doi: 10.1038/s41419-018-0581-2.

[38] Lu P, Su W, Miao ZH, Niu HR, Liu J, Hua QL (2008) – “Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer.” Chin J Integr Med. 2008 Mar;14(1):33-6. doi: 10.1007/s11655-007-9002.

[39] Shin KK, Yi YS, Kim JK, Kim H, Hossain MA, Kim JH, Cho JY (2020) – “Korean Red Ginseng Plays An Anti-Aging Role by Modulating Expression of Aging-Related Genes and Immune Cell Subsets.” Molecules. 2020 Mar 25;25(7). pii: E1492. doi: 10.3390/molecules25071492.

[40] Sun Y, Guo M, Feng Y, Zheng H, Lei P, Ma X, Han X, Guan H, Hou D (2016) – “Effect of ginseng polysaccharides on NK cell cytotoxicity in immunosuppressed mice.” Exp Ther Med. 2016 Dec;12(6):3773-3777. doi: 10.3892/etm.2016.3840. Epub 2016 Oct 26.

[41] Wright S, Altman E (2020) – “Inhibition of Herpes Simplex Viruses, Types 1 and 2, by Ginsenoside 20(S)-Rg3.” J Microbiol Biotechnol. 2020 Jan 28;30(1):101-108. doi: 10.4014/jmb.1908.08047.

[42] Yang H, Oh KH, Kim HJ, Cho YH, Yoo YC (2018) – “Ginsenoside-Rb2 and 20(S)-Ginsenoside-Rg3 from Korean Red Ginseng Prevent Rotavirus Infection in Newborn Mice.” J Microbiol Biotechnol. 2018 Mar 28;28(3):391-396. doi: 10.4014/jmb.1801.01006.

[43] Kim SJ, Jang JY, Kim EJ, Cho EK, Ahn DG, Kim C, Park HS, Jeong SW, Lee SH, Kim SG, Kim YS, Kim HS, Kim BS, Lee J, Siddiqui A (2017) – “Ginsenoside Rg3 restores hepatitis C virus-induced aberrant mitochondrial dynamics and inhibits virus propagation.” Hepatology. 2017 Sep;66(3):758-771. doi: 10.1002/hep.29177. Epub 2017 Aug 1.

[44] Kang LJ, Choi YJ, Lee SG (2013) – “Stimulation of TRAF6/TAK1 degradation and inhibition of JNK/AP-1 signalling by ginsenoside Rg3 attenuates hepatitis B virus replication.” Int J Biochem Cell Biol. 2013 Nov;45(11):2612-21. doi: 10.1016/j.biocel.2013.08.016. Epub 2013 Sep 1.

[45] Cho YJ, Son HJ, Kim KS (2014) – “A 14-week randomized, placebo-controlled, double-blind clinical trial to evaluate the efficacy and safety of ginseng polysaccharide (Y-75).” J Transl Med. 2014 Oct 9;12:283. doi: 10.1186/s12967-014-0283-1.

[46] Yonggang T, Yiming M, Heying Z, Cheng S, Qiushi W, Xianghong Y, Wei Z, Huawei Z, Shan F (2012) – “Maturation and upregulation of functions of murine dendritic cells (DCs) under the influence of purified aromatic-turmerone (AR).” Hum Vaccin Immunother. 2012 Oct;8(10):1416-24. doi: 10.4161/hv.21526. Epub 2012 Oct 1.

[47] Kim D, Suh Y, Lee H, Lee Y (2013) – “Immune activation and antitumor response of ar-turmerone on P388D1 lymphoblast cell implanted tumors.” Int J Mol Med. 2013 Feb;31(2):386-92. doi: 10.3892/ijmm.2012.1196. Epub 2012 Nov 29.

[48] Li YL, Du ZY, Li PH, Yan L, Zhou W, Tang YD, Liu GR, Fang YX, Zhang K, Dong CZ, Chen HX (2018) – “Aromatic-turmerone ameliorates imiquimod-induced psoriasis-like inflammation of BALB/c mice.” Int Immunopharmacol. 2018 Nov;64:319-325. doi: 10.1016/j.intimp.2018.09.015. Epub 2018 Sep 19.

[49] Yue GG, Chan BC, Hon PM, Lee MY, Fung KP, Leung PC, Lau CB (2010) – “Evaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longa.” Food Chem Toxicol. 2010 Aug-Sep;48(8-9):2011-20. doi: 10.1016/j.fct.2010.04.039. Epub 2010 May 9.

[50] Li R, Wang L (2019) – “Baicalin inhibits influenza virus A replication via activation of type I IFN signaling by reducing miR 146a.” Mol Med Rep. 2019 Dec;20(6):5041-5049. doi: 10.3892/mmr.2019.10743. Epub 2019 Oct 15.

[51] Oo A, Teoh BT, Sam SS, Bakar SA, Zandi K (2019) – “Baicalein and baicalin as Zika virus inhibitors.” Arch Virol. 2019 Feb;164(2):585-593. doi: 10.1007/s00705-018-4083-4. Epub 2018 Nov 3.

[52] Qian K, Kong ZR, Zhang J, Cheng XW, Wu ZY, Gu CX, Shao HX, Qin AJ. (2018) – “Baicalin is an inhibitor of subgroup J avian leukosis virus infection.” Virus Res. 2018 Mar 15;248:63-70. doi: 10.1016/j.virusres.2018.02.017. Epub 2018 Feb 23.

[53] Li X, Liu Y, Wu T, Jin Y, Cheng J, Wan C, Qian W, Xing F, Shi W (2015) – “The Antiviral Effect of Baicalin on Enterovirus 71 In Vitro.” Viruses. 2015 Aug 19;7(8):4756-71. doi: 10.3390/v7082841.

[54] Ding Y, Dou J, Teng Z, Yu J, Wang T, Lu N, Wang H, Zhou C (2014) – “Antiviral activity of baicalin against influenza A (H1N1/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase.” Arch Virol. 2014 Dec;159(12):3269-78. doi: 10.1007/s00705-014-2192-2. Epub 2014 Jul 31.

[55] Chen F, Chan KH, Jiang Y, Kao RY, Lu HT, Fan KW, Cheng VC, Tsui WH, Hung IF, Lee TS, Guan Y, Peiris JS, Yuen KY (2004) – “In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds.” J Clin Virol. 2004 Sep;31(1):69-75.

[56] Meng X, Hu L, Li W (2019) – “Baicalin ameliorates lipopolysaccharide-induced acute lung injury in mice by suppressing oxidative stress and inflammation via the activation of the Nrf2-mediated HO-1 signaling pathway.” Naunyn Schmiedebergs Arch Pharmacol. 2019 Jul 4. doi: 10.1007/s00210-019-01680-9.

[57] Zhi HJ, Zhu HY, Zhang YY, Lu Y, Li H, Chen DF (2019) – “In vivo effect of quantified flavonoids-enriched extract of Scutellaria baicalensis root on acute lung injury induced by influenza A virus.” Phytomedicine. 2019 Apr;57:105-116. doi: 10.1016/j.phymed.2018.12.009. Epub 2018 Dec 10.

[58] Peng LY, Yuan M, Song K, Yu JL, Li JH, Huang JN, Yi PF, Fu BD, Shen HQ (2019) – “Baicalin alleviated APEC-induced acute lung injury in chicken by inhibiting NF-κB pathway activation.” Int Immunopharmacol. 2019 Jul;72:467-472. doi: 10.1016/j.intimp.2019.04.046. Epub 2019 Apr 28.

[59] Deng J, Wang DX, Liang AL, Tang J, Xiang DK (2017) – “Effects of baicalin on alveolar fluid clearance and α-ENaC expression in rats with LPS-induced acute lung injury.” Can J Physiol Pharmacol. 2017 Feb;95(2):122-128. doi: 10.1139/cjpp-2016-0212. Epub 2016 Aug 31.

[60] Shi H, Ren K, Lv B, Zhang W, Zhao Y, Tan RX, Li E (2016) – “Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice.” Sci Rep. 2016 Oct 21;6:35851. doi: 10.1038/srep35851.

[61] Wang L, Zhang Y, Fan G, Ren JN, Zhang LL, Pan SY (2019) – “Effects of orange essential oil on intestinal microflora in mice.” J Sci Food Agric. 2019 Jun;99(8):4019-4028. doi: 10.1002/jsfa.9629. Epub 2019 Mar 12.