Text/Zhi-bin LIN (professor of the Department of Pharmacology, Peking University School of Basic Medical Sciences)

★This article is reproduced from ganodermanews.com. It is published with the author's authorization.

How does Lingzhi (also called Ganoderma or Reishi mushroom) play its antiviral effects? It is generally accepted that Lingzhi indirectly inhibits viruses from invading the human body and proliferating and damaging in the body by boosting the immune system. Lingzhi can also reduce the inflammation caused by the virus and the damage to vital organs such as lung, heart, liver and kidney through its anti-oxidative and free radical scavenging effects. In addition, there have been research reports since the 1980s that Lingzhi, especially the triterpenoids contained in it, has an inhibitory effect on a variety of viruses.

Professor Zhi-bin LIN has been engaged in the research of Lingzhi pharmacology for half a century and is a pioneer in the research of Lingzhi in China. (Photography/Wu Tingyao)

Coronavirus disease 2019 (COVID-19) is still circulating and has spread globally. Preventing and controlling the epidemic, treating patients and ending the epidemic are the common expectations and responsibilities of the entire society. From various media reports, I am delighted to see that many Ganoderma lucidum manufacturers donate epidemic prevention supplies and Lingzhi products to the epidemic areas and medical teams to Hubei. I hope that Lingzhi can help prevent the novel coronavirus pneumonia and protect doctors and patients.

The culprit of this epidemic is the 2019 novel coronavirus (SARS-CoV-2). Before there were anti-novel coronavirus drugs and vaccines, the most primitive and effective way was to quarantine patients, conduct symptomatic and supportive treatment, enhance immunity, prevent viruses from infecting and damaging vital organs and tissues of the body and ultimately defeat the disease. For susceptible persons, boosting the immune system helps to resist virus attacks.

In addition, the medical field is also trying to find drugs that can fight this new virus from the existing antiviral drugs. There are many rumors on the Internet. Whether they are effective or not has yet to be clinically verified.

Lingzhi enhances the anti-virus ability of the immune system.

Lingzhi (Ganoderma lucidum and Ganoderma sinensis) is a statutory traditional Chinese medicinal material included in the Pharmacopoeia of the People’s Republic of China (Part One), according to which Lingzhi can supplement qi, calm nerves, relieve cough and asthma, and can be used for restlessness, insomnia, palpitation, lung deficiency and cough and panting, consumptive disease and short of breath, and loss of appetite. So far, more than one hundred kinds of Lingzhi drugs have been approved to be marketed for disease prevention and treatment.

Modern pharmacological studies have proved that Lingzhi can enhance immune function, resist fatigue, improve sleep, resist oxidation and scavenge free radicals, and protect the heart, brain, lung, liver and kidney. It has been clinically used in the treatment or adjuvant treatment of chronic bronchitis, recurrent respiratory tract infections, asthma and other diseases.

How does Lingzhi play its antiviral effects? It is generally accepted that Lingzhi indirectly inhibits viruses from invading the human body and proliferating and damaging in the body by boosting the immune system.

Although the virus is very fierce, it will eventually be eliminated in the face of strong immunity. This has been discussed in the article "Lingzhi Enhances Immunity" published in the 58th issue of "GANODERMA" and the article "The Basis for Ganoderma lucidum to Prevent Influenza - When there is sufficient healthy qi inside, pathogenic factors have no way to invade the body" published in the 46th issue of "GANODERMA".

In summary, one is that Lingzhi can enhance the body's non-specific immune functions such as promoting the proliferation, differentiation and function of dendritic cells, enhancing the phagocytic activity of mononuclear macrophages and natural killer cells, and preventing viruses and bacteria from invading the human body. Second, Lingzhi can enhance humoral and cellular immune functions such as promoting the production of Immunoglobulin M (IgM) and Immunoglobulin G (IgG), increasing the proliferation of T lymphocytes and B lymphocytes, and promoting the production of cytokine interleukin-1 (IL-1), Interleukin-2 (IL-2) and interferon gamma (IFN-γ).

Humoral immunity and cellular immunity constitute the body's in-depth defense line against virus and bacterial infections. They can lock specific targets to further defend and eliminate viruses and bacteria invading the body. When the immune function is low due to various reasons, Lingzhi can also improve the immune function.

In addition, Lingzhi can also reduce the inflammation caused by the virus and the viral damage to vital organs such as lung, heart, liver, kidney, and prevent or reduce symptoms through its anti-oxidant and free radical scavenging effects. In the 75th issue of "GANODERMA", it can be used for reference that the significance of anti-oxidant and free radical scavenging effects of Ganoderma lucidum in the prevention and treatment of diseases is specifically discussed in the article titled "Lingzhi - Treating Different Diseases with the Same Method".

Since the 1980s, there have been research reports on the antiviral effects of Lingzhi. Most of these studies used virus-infected cell models in vitro, and individual studies also used animal models of virus infection to observe the antiviral effects of Lingzhi.

The column articles published by Professor Zhibin Lin in Issues 46, 58, and 75 of "GANODERMA"

Anti-hepatitis virus

Zhang Zheng et al. (1989) found that Ganoderma applanatum, Ganoderma atrum and Ganoderma capense can inhibit hepatitis B virus DNA polymerase (HBV-DNA polymerase), reduce HBV-DNA replication and inhibit the secretion of hepatitis B surface antigen (HBsAg) by PLC/PRF/5 cells (human liver cancer cells).

The researchers further observed the overall antiviral efficacy of the drug on the duck hepatitis model. The results showed that oral administration of Ganoderma applanatum (50 mg/kg) twice a day for 10 consecutive days can reduce the effects of duck hepatitis B virus DNA polymerase (DDNAP) and duck hepatitis B virus DNA (DDNA) of young ducks infected with duck hepatitis B virus (DHBV), which indicates that Ganoderma applanatum has an inhibitory effect on DHBV in the body [1].

Li YQ et al. (2006) reported that human liver cancer HepG2 cell lines transfected with HBV-DNA can express HBV surface antigen (HbsAg), HBV core antigen (HbcAg) and HBV virus structural proteins, and can stably produce mature hepatitis B viral particles. Ganoderic acid extracted from G. lucidum culture medium dose-dependently (1-8 μg/mL) inhibited the expression and production of HBsAg (20%) and HBcAg (44%), suggesting that ganoderic acid inhibited the replication of HBV in liver cells [2].

Anti-influenza virus

Zhu Yutong (1998) found that gavage or intraperitoneal injection of G. applanatum extract (water decoction or cold infusion) can significantly increase the survival rate and survival time of mice infected with influenza virus FM1 strain, thus having a better protective effect [3].

Mothana RA et al. (2003) found that ganodermadiol, lucidadiol and applanoxidic acid G extracted and purified from European G. pfeifferi showed antiviral activities against influenza A virus and herpes simplex virus type 1 (HSV-1). The ED50 of ganodermadiol to protect MDCK cells (epithelioid cells derived from canine kidney) against influenza A virus infection is 0.22 mmol/L. The ED50 (50% effective dose) that protects Vero cells (African green monkey kidney cells) against HSV-1 infection is 0.068 mmol/L. The ED50 of ganodermadiol and applanoxidic acid G against influenza A virus infection were 0.22 mmol/L and 0.19 mmol/L, respectively [4].

Anti-HIV

Kim et al. (1996) found that the low molecular weight part of G. lucidum fruiting body water extract and the neutral and alkaline part of methanol extract can inhibit the proliferation of human immunodeficiency virus (HIV) [5].

El-Mekkawy et al. (1998) reported that triterpenoids isolated from the methanol extract of G. lucidum fruiting bodies have anti-HIV-1 cytopathic effects and show inhibitory activity on HIV protease but have no inhibitory effect on the activity of HIV-1 reverse transcriptase [6].

Min et al. (1998) found that ganoderic acid B, lucidumol B, ganodermanondiol, ganodermanontriol and ganolucidic acid A extracted from G. lucidum spores have a strong inhibitory effect on HIV-1 protease activity [7].

Sato N et al. (2009) found that new highly oxygenated lanostane-type triterpenoids [ganodenic acid GS-2, 20-hydroxylucidenic acid N, 20(21)-dehydrolucidenic acid N and ganederol F] isolated from the fruiting body of Ganoderma lucidum have an inhibitory effect on HIV-1 protease with the median inhibitory concentration (IC50) as 20-40 μm [8].

Yu Xiongtao et al. (2012) reported that G. lucidum spore water extract has an inhibitory effect on Simian Immunodeficiency Virus (SIV) that infects CEM×174 cells of human T lymphocyte cell line, and its IC50 is 66.62±20.21 mg/L. Its main function is to inhibit SIV from adsorbing to and entering into the cells in the early stage of SIV virus infection, and it can reduce the expression level of SIV capsid protein p27 [9].

Anti-Herpes Virus

Eo SK (1999) prepared two water-soluble extracts (GLhw and GLlw) and eight methanol extracts (GLMe-1-8) from the fruiting bodies of G. lucidum. Their antiviral activity was evaluated by the cytopathic effect (CPE) inhibition test and the plaque reduction test. Among them, GLhw, GLMe-1, GLMe-2, GLMe-4, and GLMe-7 show obvious inhibition effects on herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), as well as vesicular stomatitis virus (VSV) Indiana and New Jersey strains. In the plaque reduction assay, GLhw inhibited plaque formation of HSV-2 with EC50 of 590 and 580μg/mL in Vero and HEp-2 cells, and its selectivity indices (SI) were 13.32 and 16.26. GLMe-4 did not exhibit cytotoxicity up to 1000 μg/ml, while it exhibited potent antiviral activity on the VSV New Jersey strain with an SI of more than 5.43 [10].

OH KW et al. (2000) isolated an acidic protein bound polysaccharide (APBP) from carpophores of Ganoderma lucidum. APBP showed potent antiviral activity against HSV-1 and HSV-2 in Vero cells at its EC50 of 300 and 440μg/mL, respectively. APBP had no cytotoxicity on Vero cells at a concentration of 1 x 10(4) μg/ml. APBP has synergistic inhibitory effects on HSV-1 and HSV-2 when combined with the anti-herpes medicine Aciclovir, Ara-A or interferonγ(IFN-γ) respectively [11, 12].

Liu Jing et al. (2005) found that GLP, a polysaccharide isolated from G. lucidum mycelium, can inhibit the infection of Vero cells by HSV-1. The GLP blocked HSV-1 infection at early stages of the infection but cannot inhibit the synthesis of virus and biological macromolecules [13].

Iwatsuki K et al. (2003) found that a variety of triterpenoids extracted and purified from Ganoderma lucidum have inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) in Raji cells (human lymphoma cells) [14].

Zheng DS et al. (2017) found that five triterpenoids extracted from G. lucidum, including ganoderic acid A, ganoderic acid B, and ganoderol B, ganodermanontriol and ganodermanondiol, significantly reduce the viability of nasopharyngeal carcinoma (NPC) 5-8 F cells cultured in vitro, show significant inhibitory effects on both EBV EA and CA activation and inhibit telomerase activity. These results provided evidence for the application of these G. lucidum triterpenoids in the treatment of NPC [15].

Anti-Newcastle Disease Virus

Newcastle disease virus is a kind of avian influenza virus, which has high infectivity and lethality among birds. Shamaki BU et al. (2014) found that Ganoderma lucidum extracts of methanol, n-butanol and ethyl acetate could inhibit neuraminidase activity of Newcastle disease virus [16].

Anti-Dengue Virus

Lim WZ et al. (2019) found that the water extracts of G. lucidum in its antler form inhibited the DENV2 NS2B-NS3 protease activity at 84.6 ± 0.7%, higher than the normal G. lucidum [17] .

Bharadwaj S et al. (2019) employed a virtual screening approach and in vitro tests to predict the potential of functional triterpenoids from Ganoderma lucidum and found that ganodermanontriol extracted from Ganoderma lucidum can inhibit dengue virus (DENV) NS2B -NS3 protease activity [18].

Anti-Enterovirus

Enterovirus 71 (EV71) is the main pathogen of hand, foot and mouth disease, causing fatal neurological and systemic complications in children. However, there are currently no clinically approved antiviral drugs that can be used to prevent and treat this viral infection.

Zhang W et al. (2014) found that the two Ganoderma lucidum triterpenoids (GLTs), including Lanosta-7,9(11),24-trien-3-one,15;26-dihydroxy (GLTA) and Ganoderic acid Y (GLTB), display significant anti-EV71 activities without cytotoxicity.

The results suggested that GLTA and GLTB prevent EV71 infection through interacting with the viral particle to block the adsorption of virus to the cells. In addition, the interactions between EV71 virion and the compounds were predicted by computer molecular docking, which illustrated that GLTA and GLTB may bind to the viral capsid protein at a hydrophobic pocket (F site), and thus may block uncoating of EV71. Moreover, they demonstrated that GLTA and GLTB significantly inhibit the replication of the viral RNA (vRNA) of EV71 replication through blocking EV71 uncoating [19].

Summary and discussion

The above research results indicate that Lingzhi, especially the triterpenoids contained in it, has an inhibitory effect on a variety of viruses. The preliminary analysis shows that its anti-viral infection mechanism involves inhibiting the adsorption and penetration of viruses into cells, inhibiting the activation of virus early antigen, inhibiting the activity of some enzymes required for virus synthesis in cells, blocking viral DNA or RNA replication without cytotoxicity and has a synergistic effect when combined with known antiviral drugs. These results provide evidence for further research on the antiviral effects of Lingzhi triterpenoids.

Reviewing existing clinical efficacies of Lingzhi in preventing and treating viral diseases, we found that Lingzhi can convert the hepatitis B virus markers (HBsAg, HBeAg, anti-HBc) to negative in the prevention and treatment of hepatitis B. But other than that, in the treatment of herpes zoster, condyloma acuminatum and AIDS in combination with antiviral drugs, we have not found evidence that Lingzhi can directly inhibit the virus in patients. The clinical efficacies of Lingzhi on viral diseases may be mainly related to its immunomodulatory effect, its anti-oxidant and free radical scavenging effects and its protective effect on organ or tissue injury. (Thanks to Professor Baoxue Yang for correcting this article.)

References

1. Zhang Zheng, et al. The Experimental Study of 20 Kinds of Chinese Fungi Against HBV.Journal of Beijing Medical University.1989, 21: 455-458.

2. Li YQ, et al. Anti-hepatitis B activities of ganoderic acid from Ganoderma lucidum. Biotechnol Lett, 2006, 28(11): 837-841.

3. Zhu Yutong, et al.Protective Effect of the Extract of Ganoderma applanatum (pers) pat. on Mice Infected with Influenza Virus FM1.Journal of Guangzhou University of Traditional Chinese Medicine.1998, 15(3): 205-207.

4. Mothana RA, et al. Antiviral lanostanoid triterpenes from the fungus Ganoderma pfeifferi. Fitoterapia. 2003, 74(1-2): 177–180.

5. Kim BK. Anti-human Immunodeficiency Virus Activity of Ganoderma lucidum. 1996 International Ganoderma Symposium, Special Lecture, Taipei.

6. El-Mekkawy S, et al. Anti-HIV and anti-HIV-protease substances from Ganoderma lucidum. Phytochemistry. 1998, 49(6): 1651-1657.

7. Min BS, et al. Triterpenes from the spores of Ganoderma lucidum and their inhibitory activity against HIV-1 protease. Chem Pharm Bull (Tokyo). 1998, 46(10): 1607-1612.

8. Sato N, et al. Anti-human immunodeficiency virus-1 protease activity of new lanostane-type triterpenoids from Ganoderma sinense. Chem Pharm Bull (Tokyo). 2009, 57(10): 1076-1080.

9. Yu Xiongtao, et al. Study on Effects of Inhibition of Ganoderma lucidum on Simian Imunodeficiency Virus in vitro. Chinese Journal of Experimental Traditional Medical Formulae.2012, 18(13): 173-177.

10. Eo SK, et al. Antiviral activities of various water and methanol soluble substances isolated from Ganoderma lucidum. J Ethnopharmacol. 1999, 68(1-3): 129-136.

11. Oh KW, et al. Antiherpetic activities of acidic protein bound polysaccharide isolated from Ganoderma lucidum alone and in combinations with acyclovir and vidarabine. J Ethnopharmacol. 2000, 72(1-2): 221-227.

12. Kim YS, et al. Antiherpetic activities of acidic protein bound polysaccharide isolated from Ganoderma lucidum alone and in combinations with interferons. J Ethnopharmacol. 2000, 72(3): 451-458.

13. Liu Jing, et al. Inhibition of Herpes Simplex Virus Infection by a GLP Isolated from Mycelium of Ganoderma Lucidum. Virologica Sinica. 2005, 20(4): 362-365.

14. Iwatsuki K, et al. Lucidenic acids P and Q, methyl lucidenate P, and other triterpenoids from the fungus Ganoderma lucidum and their inhibitory effects on Epstein-Barrvirus activation. J Nat Prod. 2003, 66(12): 1582-1585.

15. Zheng DS, et al. Triterpenoids from Ganoderma lucidum inhibit the activation of EBV antigens as telomerase inhibitors. Exp Ther Med. 2017, 14(4): 3273-3278.

16. Shamaki BU, et al. Methanolic soluble fractions of lingzhi orreishimedicinal mushroom, Ganoderma lucidum (higher Basidiomycetes) extract inhibit neuraminidase activity in Newcastle diseasevirus (LaSota). Int J Med Mushrooms. 2014, 16(6): 579-583.

17. Lim WZ, et al. The identification of active compounds in Ganoderma lucidum var. antler extract inhibiting dengue virus serine protease and its computational studies. J Biomol Struct Dyn. 2019, 24: 1-16.

18. Bharadwaj S, et al. Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease. Sci Rep. 2019, 9(1): 19059.

19. Zhang W, et al. Antiviral effects of two Ganoderma lucidum triterpenoids against enterovirus 71 infection. Biochem Biophys Res Commun. 2014, 449(3): 307-312.

★ The original text of this article was written in Chinese by Professor Zhi-bin LIN and translated into English by Alfred Liu. If there is any discrepancy between the translation (English) and the original (Chinese), the original Chinese shall prevail.