The Antiviral Potential of Reishi Ganoderma Lucidum Lingzhi

1. Ganoderma lucidum against Enterovirus 71 (EV71)

Since 1969, “the same year in which the infection of human enterovirus 71 (EV71) infection was identified for the first time”, the infection mechanism has not been fully understood. However, this viral infection was associated with several clinical diseases, ranging from neurological disorders to hand–foot–mouth disease (HFMD), and is considered a severe threat to children under six years old.

Currently, there are no certified prophylactic treatments for EV71 infection. Outbreaks of EV71 infection have been periodically reported worldwide. For instance, China has recently seen increased deaths linked to EV71 infection and HFMD among the young population. As mentioned above, there are no approved drugs for preventing or treating EV71 infection. Still, antiviral drugs with a broad spectrum (e.g., acyclovir, ganciclovir, and ribavirin) are used to partially relieve infection symptoms, although they have high cytotoxic side effects.

Therefore, investigation of novel and efficient medicines is urgently needed to control this severe viral infection. The adoption of natural medicinal compounds and Chinese herbal medicines has been observed across Asian countries for centuries and recently in Western medicine. G. lucidum is widely used as a folk medicine for various ailments. The triterpenoid compounds of G.lucidum, Lanosta-7,9(11),24-trien-3-one,15;26-dihydroxy (GLTA), and ganoderic acid Y (GLTB) could prevent EV71 infection by interfering with the viral particle and limiting the viral adsorption to the host cells.

Additionally, the interaction dynamics of GTLA and GLTA with the EV71 virion, predicted by molecular docking, showed potent molecular binding to the viral capsid protein at a hydrophobic pocket and hence a block uncoating EV71. Furthermore, it has been shown that GLTA and GLTB notably prohibited the viral RNA (vRNA) replication of EV71 by blocking EV71 uncoating. Therefore, GLTA and GLTB may represent two promising curative agents to control and treat EV71 infection.

2. Ganoderma lucidum against Dengue Virus (DENV)

The dengue virus (DENV), classified within the Flaviviridae family, is a fatal microbe transmitted to humans through mosquitoes (Aedes albopictus and Aedes aegypti), causing both hemorrhagic fever and shock syndrome. A total of five different serotypes of DENV have been reported to induce both dengue fever types while potentially causing fatal infections.

Proteome analysis revealed that the translated DENV polyprotein complex comprises three structural and seven nonstructural proteins. Of particular interest, the cofactor NS2B is required to fully activate the viral NS3 protease (NS3pro) domain that encodes a serine protease (S7 family). The dengue virus’s NS2B–NS3 pro complex has been recently identified as an ideal target for developing novel anti-DENV drugs.

As one of the bioactive compounds extracted from G. lucidum, triterpenoids have been proposed and tested as antiviral agents against different viral pathogens, e.g., the human immunodeficiency virus. Ganodermanontriol, a potent bioactive triterpenoid, was suggested to inhibit the DENV NS3pro protein based on in vitro studies. Thus, ganodermanontriol could act as a drug against DENV infection.

3. Ganoderma lucidum against the 2019 Novel Coronavirus (SARS-CoV-2)

December 2019 marked the beginning of a mysterious pneumonia outbreak in Wuhan (Hubei Province, China). A month later, the infectious agent was revealed to be a new kind of coronavirus named SARS-CoV-2. The World Health Organization (WHO) declared the pneumonia outbreak in Wuhan a major public health crisis on 11 February 2020 and gave it Coronavirus Disease-2019 (COVID-19). Multiple symptoms were reported in the COVID-19 patients, including cough, lung damage, fever, fatigue, muscle pain, diarrhea, myalgia, and respiratory symptoms.

Natural products are among the most important sources for modern medication industry technology, if not the most important, due to their advantages, abundant clinical use, and unique diversity of chemical structures and biological activities. Traditional Chinese medicine (TCM) is one of the gold mines rich in untapped natural resources that can be employed to treat many diseases that represent a challenge for humankind, including COVID-19. The previous studies on SARS-CoV and its homology with SARS-CoV-2 may provide avenues to natural compounds that inhibit SARS-CoV-2.

For instance, the helicase domain is being investigated as a possible drug target. Yu et al. Scutellarein and myricetin potently prevented nsP13, a SARS-CoV helicase protein, in vitro by altering its ATPase activity. The RNA-dependent RNA polymerase is another potential target for developing antiviral compounds, an essential enzyme for RNA synthesis. Indeed, dose-dependent inhibition of this SARS-CoV enzyme was reported for the extracts of G. lucidum (IC50:41.9 µg/mL), Coriolus Versicolor (IC50:108.4 µg/mL), and Sinomenium acutum (IC50:198.6 µg/mL). Therefore, G. lucidum could serve as a novel and promising source of bioactive natural compounds with anticoronavirus activity.

4. Antioxidant and Antiaging Activity

Multiple research studies reported a close relationship between the richness of G. lucidum in “phenolic compounds, triterpenes, polysaccharides, polysaccharide peptides” and its antioxidant biological activity. Clinical nutritionists have demonstrated that consuming antioxidant-rich plant-based foods may protect from cancer and many other chronic diseases.

The long-term presence of free radicals and reactive oxygen species (ROS) accelerates aging and numerous age-associated illnesses. Therefore, scavenging free radicals and ROS studies are particularly important in antiaging research. G. lucidum polysaccharides (GLPs) can inhibit ROS production in fibroblasts following UVB treatment.

5. Anticancer Activity

Cancer is still one of the fatal diseases worldwide and poses a major clinical challenge despite the notable boom in early diagnostic techniques and evolution in its treatment techniques. Hundreds of plant species have been investigated as sources for new therapeutics (chemopreventive or chemotherapeutic). In this regard, mushrooms, e.g., Ganoderma species, are rich sources of many biologically active components, including antitumoral agents. For example, polysaccharides and triterpenes are two major groups of compounds extracted from G. lucidum that were reported to possess chemopreventive and/or tumoricidal activities.

In addition, the antitumor activity exhibited by G. lucidum is achieved via induction of programmed cell death, as reported by many studies. Moreover, the isolated compounds from G. lucidum have been previously described as modulators of autophagy in numerous human tumor cell lines. In the same context, a methanolic extract (extraction at room temperature) of G. lucidum fruiting bodies prevented the growth of a human gastric tumor cell line via a cellular autophagy mechanism.

6. Antidiabetic Activity

G.lucidum has been proven to possess compounds responsible for hypoglycemic effects, such as polysaccharides, proteoglycans, proteins, and triterpenoids. For instance, consuming a G. lucidum spore powder (GLSP) decreases blood glucose levels by promoting glycogen synthesis and preventing gluconeogenesis.

7. Cardioprotective Effects

How does G. lucidum have cardioprotective impacts? Many studies have answered this question. Firstly, the presence of α-tocopherol in G. lucidum protected the mitochondria, reducing cardiac toxicity and mitochondrial dysfunction. Additionally, the positive effects of ganopoly (G. lucidum polysaccharide extract) were shown on coronary heart disease (CHD) patients. Polysaccharide extract of G. lucidum decreased blood pressure and serum cholesterol levels.

8. Hepatoprotection

The GLPs and Ganoderma triterpenoids (GTs) can act on the immune system, effectively exhibit hepatoprotective effects, and treat liver damage. The hepatoprotective effects of G. lucidum have been widely studied. GLPs can protect hepatocyte injury by inhibiting lipid peroxidation, elevating antioxidant enzyme activity, and suppressing apoptosis and immune-inflammatory response. GTs offered significant cytoprotection against the oxidative damage induced by tertbutyl hydrogen peroxide (t-BHP) in hepatocellular carcinoma cells by decreasing malondialdehyde and increasing the contents of glutathione and superoxide dismutase (SOD). Analysis of histopathology and serum enzymes in mice revealed an important hepatoprotective function of an ethanol extract of G. lucidum (GLE). It was therefore assumed that GLE could improve alcohol-induced liver injury. In addition, a G. lucidum mycelium-fermented liquid (GLFL) was reported to possess hepatoprotective properties in rats.

9. Anti-Inflammatory Effects

Inflammation is a normal physiological response to an infection or injury and is part of host defense and tissue healing. GLPs can prevent inflammation, maintain intestinal homeostasis, and regulate intestinal immunological barrier functions in mice. The anti-inflammatory effect of GLPs plays an important role in sensitive skin care.

10. Prebiotic Potential

Prebiotics are “a substrate that is selectively utilized by host microorganisms conferring a health benefit.” Mushrooms are considered untapped sources of prebiotics, such as fibers, oligosaccharides (major constituents of mushrooms), and polyphenols, which can boost the growth and metabolic activity of beneficial members of the gut microbiota. For example, nondigestible polysaccharides can prevent pathogen proliferation by improving the growth of probiotics in the gut.

During the last decade, the interplay between prebiotics and human gut microbiota and its implications in mitigating many diseases, e.g., cancer, diabetes, and obesity, gained much focus and has emerged as one of the principal trending axes of food science and technology. Scientific evidence has accumulated on the critical role of gut microbiota dysbiosis in exacerbating inflammation in host tissues, from the intestinal environment to the brain.

Likewise, critical data has established the gut microbiota’s regulatory role in energy metabolism, which may cause disturbances in the metabolism processes. For instance, mushrooms are a rich source of prebiotics that may play a pivotal role in treating pneumonia and atherosclerosis and their antitumor activity. In the same context, a study conducted on mice (C57BL/6) confirmed that G. lucidum is a rich prebiotic source that reduces blood cholesterol. The same study attributed the ability of G. lucidum to lower the blood cholesterol level to the significant decrease in the lipid-generating gene expression (Hmgcr, Fasn, Srebp1c, Acaca), and Abcg5, Abcg8 as genes responsible for reverse cholesterol transport, simultaneous with an increase in Ldlr gene expression in the liver.

Another study showed the possibility that G. lucidum polysaccharide peptides (GLPP) may have a role in alleviating the disturbance in the metabolism of fats through the ability of these compounds to alter the composition of the gut microbiota, which in turn has a positive effect on controlling and reducing the disruption of fat metabolism, regulating genes involved in intestinal integrity, bile acid homeostasis, and extrauterine fat deposition. Thus, GLPP can be a potential functional food component for treating hyperlipidemia and gut microbiota dysbiosis.

It has been demonstrated that gut microbiota could play an important role in host health through their influence on cardiovascular risk factors. As was mentioned previously, the products associated with G. lucidum have positive effects on the gut microbiota. Thus these products can regulate the risk factors for cardiovascular disease in the intestine. An altered gut microbiota composition was shown in an obese mouse model treated with a water extract of G. lucidum mycelium.

In addition, GLFL was shown to reduce low-density plasma lipoprotein (LDL-c) cholesterol, triglycerides, and total cholesterol and increase high-density lipoprotein (HDL-c) cholesterol in mice. Additionally, When GLFL was fed to humans, it profoundly altered the gut microbiota. There was an evident difference in β diversity in the post-feeding group compared to the pre-feeding group; this suggested that GLFL had changed the gut microbiota composition. Furthermore, the same authors reported that GLFL could protect humans by stimulating the growth of probiotics (i.e., genus Lactobacillus (p < 0.05)) while inhibiting the growth of pathogens (i.e., genus Aggregatibacter and Campylobacter (p < 0.05)).