key: cord-0936294-e4eozkiq
authors: El Sheikha, Aly Farag
title: Nutritional Profile and Health Benefits of Ganoderma lucidum “Lingzhi, Reishi, or Mannentake” as Functional Foods: Current Scenario and Future Perspectives
date: 2022-04-01
journal: Foods
DOI: 10.3390/foods11071030
sha: 8176810d68ae5893a593cf5e24ab9283941f2c74
doc_id: 936294
cord_uid: e4eozkiq

Ganoderma lucidum has a long history of medicinal uses in the Far East countries of more than 2000 years due to its healing properties. Recently, G. lucidum has come under scientific scrutiny to evaluate its content of bioactive components that affect human physiology, and has been exploited for potent components in the pharmacology, nutraceuticals, and cosmetics industries. For instance, evidence is accumulating on the potential of this mushroom species as a promising antiviral medicine for treating many viral diseases, such as dengue virus, enterovirus 71, and recently coronavirus disease of 2019 (COVID-19). Still, more research studies on the biotherapeutic components of G. lucidum are needed to ensure the safety and efficiency of G. lucidum and promote the development of commercial functional foods. This paper provides an extensive overview of the nutraceutical value of Ganoderma lucidum and the development of commercial functional food. Moreover, the geo-origin tracing strategies of this mushroom and its products are discussed, a highly important parameter to ensure product quality and safety. The discussed features will open new avenues and reveal more secrets to widely utilizing this mushroom in many industrial fields; i.e., pharmaceutical and nutritional ones, which will positively reflect the global economy.

"Lingzhi is a miraculous king of herbs"-Chinese people . Historically, the Romans considered mushrooms in general as the food of their gods and only served them for great feasts, while the Greeks and the Vikings believed that eating mushrooms gave them strength and enthusiasm before the war. America's indigenous people have often used mushrooms in age-old rituals (e.g., magical hallucinogens) to cross the body and mental barrier [1] . Considered as one of the main folk medicinal mushrooms, G. lucidum was used for many centuries and reported under several names in China (Lingzhi), Japan (Reishi), and Korea (Mannentake). According to bimillennial beliefs, G. lucidum can promote health and longevity, but it was also considered a combination of spiritual force and a source of immortality [2] [3] [4] . Moreover, the Japanese people have regarded this mushroom as a "10,000-year" mushroom [5] [6] [7] .

G. lucidum are commercially available, including mycelia, spores, and fruit body [6] , and are sold as many different products, including powders, dietary supplements, and herbal tea [6, 13] . Table 1 illustrates some of the commercial cosmetic products produced from G. lucidum mushrooms worldwide. Nowadays, the number of Ganoderma-based products well known commercially is estimated at over 100 brands [32] . The world trade market value of G. lucidum and its derivative products has reached approximately USD 4 billion [33] .

Wide-scale applications of mushrooms including Ganoderma lucidum; i.e., pharmaceuticals, nutraceuticals, and cosmetics. Source: Reprinted from Wu et al. [31] . Licensed under CC BY 4.0. i.e., pharmaceuticals, nutraceuticals, and cosmetics. Source: Reprinted from Wu et al. [31] . Licensed under CC BY 4.0.

During the last decade, the G. lucidum mushroom has attracted multiple research fields, including biochemistry, genetics and molecular biology, agricultural and biological sciences, pharmacology, toxicology, pharmaceutics, and medicine. Figure 3 illustrates the increasing interest in multidisciplinary utilization of G. lucidum based on the number of research articles in the past 10 years. Menard Embellir Night Cream, Japan Eliminating toxins and helping repair skin damage associated with overexposure to UV radiation and free radicals MAVEX Rejuvenating Treatment, Hong Kong Antioxidant action and deep cellular renewal; fight degenerative processes and the negative action of free radicals * Sources: Wu et al. [31] , Taofiq et al. [34] , Hapuarachchi et al. [35] , www.vegamebeljepara.com, www.dazzlinggroup.com, www.dxnmalaysia.com, and www.vegamebeljepara.com (accessed on 16 February 2022) Adapted from Wu et al. [31] . Licensed under CC BY 4.0. Adapted with permission from Taofiq et al. [34] . 2022, Elsevier.

During the last decade, the G. lucidum mushroom has attracted multiple research fields, including biochemistry, genetics and molecular biology, agricultural and biological sciences, pharmacology, toxicology, pharmaceutics, and medicine. Figure 3 illustrates the increasing interest in multidisciplinary utilization of G. lucidum based on the number of research articles in the past 10 years. In the early 1980s, the idiom "functional food" first appeared in Japan. Functional food is a broad term that includes several concepts [36] ; for example, the definition of functional food provided by the Food and Agriculture Organization (FAO) states that "the functional food is the source that provides the human body with the necessary quantities of nutrients, i.e., proteins, carbohydrates, fats, vitamins, minerals, and others to keep it healthy. In addition, functional food can be cooked or prepared using 'artificial intelligence technology' [37] . In addition, the European Food Safety Authority (EFSA) defined functional food as "a food, which beneficially affects one or more target functions in the body, beyond adequate nutritional effects, in a way that is relevant to either an improved state of health and well-being and/or reduction of risk of disease" [38] . As described by the Functional Food Center (FFC) in the United States, functional foods are "real or processed foods that contain known or unknown biologically active compounds that, efficient, in defined and non-toxic quantities, recorded health benefit or provide a scientifically validated using unique biomarkers for the prevention, treatment or control of chronic disease or its symbiotic diseases" [39] . According to the definition of the Institute of Food Technologists (IFT), functional foods are those with ingredients that have health benefits in addition to basic nutrition, which is similar to the definition published by the International Life Sciences Institute (ILSI) [40, 41] .

Comprehensively, functional food can be defined as "a whole ingredient or a part of food that is used as food. It is part of a standard diet and is consumed on a regular basis, in normal quantities. It has proven health benefits that reduce the risk of specific chronic diseases or beneficially affect target functions beyond its basic nutritional functions" [42, 43] .

The use of the term "ingredient" means that functional food is not only conventional food but also could be a part of other food or food ingredients. In addition, the abovementioned definitions of functional foods allow for adaptation to cultural differences, including widely differing "standards" among cultures and countries. Moreover, the use of the term "health benefits" is not restrictive. It refers to physiological, psychological, and biological advantages [43, 44] .

Among the important health effects of foods including the functional ones are those associated with gut health, a major determinant of an individual's overall health. Several diseases are related in this context; e.g., gluten-therapy-resistant celiac, Crohn's disease, ulcerative colitis, and irritable bowel syndrome. These adverse effects are caused by overgrowth and imbalance of intestinal bacteria linked to an individual's food system [45] . The question that comes to mind is, what are the roles of the human gut in the body? These can be summarized as follows [45] :

It converts food to nutrients; • The human gut, via epithelial cell walls, assists in the absorption process of nutrients into the blood; •

The human gut inhibits toxic and strange particles from entering the bloodstream.

Consequently, and directly, any gut malfunction has adverse effects on human health. In this regard, functional foods, including pre-and probiotics, have become increasingly important due to their positive role in human gut health. Historically, mushrooms, including Ganoderma lucidum, were traditionally consumed due to their nutritional and culinary values, and for their medical benefits when used in folk medicine. This historical heritage has recently been translated through molecular research to explore the present bioactive components and unlock mushrooms' nutrition and therapeutic values [46, 47] . Among these health benefits, mushrooms could help prevent diseases; e.g., hypertension, diabetes, hypercholesterolemia, and cancer, as mentioned in many reports. Hence, mushrooms can be considered a curative food [8, 48] . Mushrooms are still untapped sources of bioactive substances such as glycoproteins, polysaccharides, mainly β-glucans, and secondary metabolites; i.e., nucleotide analogs, metal-chelating agents, terpenoids, polyphenols, alkaloids, lactones, and sterols. These biologically active components possess several therapeutic implications, such as antiviral, anticancer, hepatoprotective, immunopotentiating, and hypocholesterolemic agents [47] [48] [49] [50] [51] .

The present paper critically discusses the benefits of G. lucidum, from nutritional value to medicinal impacts, and sheds light on its potential as a source of nutraceuticals and functional food. Moreover, this review provides answers with a critical vision to many questions, such as why the bioactive compounds of G. lucidum need to be further studied in vitro and in vivo, and what secrets are still behind them. Is it important to ensure G. lucidum's quality and safety, as well as the best method to achieve that? With the potential of G. lucidum, will the future carry us to the possibility of commercial widescale use of G. lucidum and its products as new functional foods and medicines?

Despite that Ganoderma lucidum is not edible in its raw state due to its higher content of bitter compounds, its palatability can be increased by turning it into manufactured products such as powders, supplements, and tea [52] . The nutritional value of G. lucidum will be tackled in-depth in the following section.

"Medicines and food have a common origin"-Kaul [53] . For thousands of years, mushrooms have been valued throughout the world as food and medicine [8] . Nevertheless, mushrooms are still largely untapped resources in producing effective pharmaceutical products, nutrients, and cosmetics. Indeed, only approximately 150,224 species have been described [54] out of the estimated 2.2-3.8 million fungal species worldwide [55] . About 3000 species that belong to Macrofungi are safe for human consumption, such as edible mushrooms [56] .

From the nutritionist's point of view, generally, fresh mushrooms contain both soluble and insoluble fibers; the soluble fiber is mainly β-glucanpolysaccharides and chitosans [57] . However, a question comes to mind: does G. lucidum that is grown naturally or wild differ from that grown artificially in its nutritional components? According to the research in this regard, the answer is yes, as it was found that the quantities of crude protein, carbohydrates, and crude fiber were greater in the artificially grown variety [58] . Few studies have revealed the nutritional profile of G. lucidum. Roy and others [59] reported the nutritional value and mineral composition of G. lucidum. Through an analytical view of the nutritional profile of the G. lucidum mushroom (Table 2) , several important conclusions can be reached. [60, 61] ; ** the total energy of 100 g of mushroom samples was calculated according to the equations of Manzi et al. [62] ; *** based on 1.3 kcal/kg body weight/hour for the reference body weight; **** based on 0.8 g/kg body weight/day for the reference body weight; ***** Casselbury [63] ; ****** Duthie et al. [64] . Sources: Roy et al. [59] , Rahman et al. [65] , and http://www.medicinabiomolecular.com. br/biblioteca/pdfs/Biomolecular/mb-0223.pdf. (accessed on 16 February 2022). Adapted from Rahman et al. [65] . Licensed under CC-BY.

• G. lucidum contains a considerable amount of water-soluble proteins (19.5 g/100 g mushroom (w/w)). Moreover, 18 kinds of amino acids have been found in G. lucidum, and the most abundant amino acid was leucine, which possessed strong hypoglycemic and antioxidant activities [66, 67] . • G. lucidum contains 3.5 g of dietary fiber per 100 g of mushroom (d/w). • G. lucidum contains significant amounts of major minerals (e.g., phosphorus, sulfur) and other trace mineral contents; i.e., Cu, Mg, and Fe. • As also mentioned in Table 2 , G. lucidum is a highly rich source of vitamins such as riboflavin, niacin, thiamin, etc. Additionally, Ahmad [68] reported that several vitamins have been found in G. lucidum, such as vitamins B1, B2, B6, β-carotene, C, D, and E. • Based on the nutritional profile of G. lucidum, this mushroom possesses a high nutrient potential that reflects positively on its health benefits.

Through this vision, the G. lucidum mushroom is increasingly becoming one of the natural and untapped medicine resources, which should be of interest to pharmaceutical, nutraceutical, and cosmetics manufacturers and consumers worldwide [69] . Ganoderma lucidum contains myriad biologically active compounds (over 400 compounds), including polysaccharides, triterpenoids, steroids, fatty acids, amino acids, nucleosides, proteins, and alkaloids [70] . Still, how do these bioactive compounds reflect their medical properties?

The following section will discuss the therapeutic impacts of these bioactive compounds.

"Mushroom of immortality & symbol of traditional Chinese medicine"-Chen et al. [71] . The biologically active molecules of G. lucidum rely on their chemical composition, with polysaccharides, peptidoglycans, and triterpenes being the three major bioactive compounds [58, 68, [70] [71] [72] [73] . Additionally, this mushroom contains other constituents with distinct biological functions, such as minerals (e.g., germanium), proteins, lectins, crude fibers, phenols, enzymes, sterols, and long-chain fatty acids [6, [74] [75] [76] [77] . Table 3 shows the major bioactive compounds and their biological effects. Snapshots of these bioactive compounds could be found as follows. 

Proteoglycans, proteins (LZ-8) Antidiabetic Ahmad [68] , Ma et al. [78] Polysaccharide-peptide complex Antioxidant Mehta [83] Phenolic compounds

Phenolic components, phenolic extracts Antioxidant Mehta [83] Saponins Anticancer and antioxidant Lee et al. [84] Sterols; e.g., ergosterol Provitamin D2 Wachtel-Galor et al. [6] Long-chain fatty acids Antitumor Gao et al. [85] 

Polysaccharides, such as ganoderans, represent diverse biological macromolecules with a broad range of biological properties [58] . Additionally, G. lucidum is a source of polysaccharides, glycopeptides, and polysaccharide crude extracts, as indicated by several studies [86] . In addition, these components of G. lucidum mushroom showed strong biological activities, including, for example, antioxidant, anti-tumor, and antibacterial activities due to its content of sugars, glycoproteins, and polysaccharide extracts obtained from the fruiting bodies [81, [87] [88] [89] . Anti-inflammatory, hypoglycemic, antitumorigenic, and immunostimulating activities are among the multiple biological roles of polysaccharides extracted from G. lucidum [90] [91] [92] [93] [94] [95] . Free radical scavenging abilities, reducing power, and chelating on ferrous ions are among the reported antioxidant properties [96, 97] . Ospina et al. [98] reported that the isolated chitosan from G. lucidum has promising and desirable characteristics in specialized sectors such as biomedicine, pharmaceutics, and cosmetics, beyond the food industry. Regarding the peptidoglycans, G. lucidum contains a proteoglucan (GLPG) that has antiviral activity [99] .

Several triterpenes extracted from G. lucidum have been reported (around 100 types of triterpenes), with half of these types being novel and unique to G. lucidum [18] . Ganoderic and lucidenic acids are the major triterpenes produced by G. lucidum, while other triterpenes have been identified; e.g., ganodermic, ganoderiols, and ganoderal acids [58, [100] [101] [102] [103] [104] [105] [106] [107] .

The element germanium has brought some attention to G. lucidum. Germanium is one of the most prevalent elements in wild G. lucidum. With 489 µg/g, germanium occupied the fifth-highest rank among the other detected minerals in terms of concentration [108] . This element possesses significant biological activities; i.e., antimutagenic, antitumor, immunepotentiating, and antioxidant [109] . There is no rigorous proof linking germanium with the specific health benefits of G. lucidum.

Some bioactive proteins purified from G. lucidum have been found to contribute to the medicinal properties of this mushroom; for example:

• LZ-8, an immunosuppressive protein [110] ; • GLP, which possesses both antioxidant and hepatoprotective activities [111, 112] ; • Ganodermin, an antifungal protein [113] .

Many other bioactive compounds have been isolated from G. lucidum, including:

• Enzymes; e.g., a metalloprotease that delays clotting time [6] .

For several hundred years, G. lucidum has been used to promote human health as a functional food through traditional treatment strategies. Nowadays, many published studies have established the multiple health benefits of G. lucidum in preventing or fighting multiple gastrointestinal and extraintestinal diseases, from constipation and gastritis, to anorexia, arthritis, asthma, bronchitis, and diabetes [35, 75, 95] . Additional studies have reported on the anticancer [6, 31, 52, 114, 115] , preventing cardiovascular disease, and tumorigenesis [116] [117] [118] [119] , antioxidant [6, 120, 121] , cardioprotective [122] , antidiabetic potency [6, 123, 124] , and antimicrobial activity [6, 35, 125] of this mushroom. Altogether, Figure 4 demonstrates the nutritional and health benefits of G. lucidum, which will be spotlighted individually as follows.

the medicinal properties of this mushroom; for example:

• LZ-8, an immunosuppressive protein [110] ; • GLP, which possesses both antioxidant and hepatoprotective activities [111, 112] ; • Ganodermin, an antifungal protein [113] .

Many other bioactive compounds have been isolated from G. lucidum, including:

• Enzymes; e.g., a metalloprotease that delays clotting time [6] .

For several hundred years, G. lucidum has been used to promote human health as a functional food through traditional treatment strategies. Nowadays, many published studies have established the multiple health benefits of G. lucidum in preventing or fighting multiple gastrointestinal and extraintestinal diseases, from constipation and gastritis, to anorexia, arthritis, asthma, bronchitis, and diabetes [35, 75, 95] . Additional studies have reported on the anticancer [6, 31, 52, 114, 115] , preventing cardiovascular disease, and tumorigenesis [116] [117] [118] [119] , antioxidant [6, 120, 121] , cardioprotective [122] , antidiabetic potency [6, 123, 124] , and antimicrobial activity [6, 35, 125] 

G. lucidum has been reported as a promising source of antimicrobial molecules (mainly polysaccharides) against various viral, bacterial, and fungal pathogens [79, 83, [125] [126] [127] [128] [129] [130] . Table 4 summarizes the antimicrobial activities of the G. lucidum mushroom and its products. 3.1. Antimicrobial Activity G. lucidum has been reported as a promising source of antimicrobial molecules (mainly polysaccharides) against various viral, bacterial, and fungal pathogens [79, 83, [125] [126] [127] [128] [129] [130] . Table 4 summarizes the antimicrobial activities of the G. lucidum mushroom and its products. * NG: data not given.

There have been few scientific studies (particularly on animals) that examined the antiviral effects of G. lucidum (Lingzhi); however, Zhu et al. [149] examined the antiinfluenza effects of a hot water extract of Lingzhi on infected mice through intranasal and oral administration. The authors of this study concluded that short-term oral consumption of Lingzhi hot water extract had a limited effect in fighting influenza. Therefore, the authors recommended further study on the long-term anti-influenza effects that could improve the functional uses of this mushroom against influenza.

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 [150] . However, this viral infection was associated with several clinical diseases, ranging from neurological disorders to hand-foot-mouth disease (HFMD), and is considered a serious threat to children under six years old [151] . Currently, there are no certified prophylactic or therapeutic treatments for EV71 infection [152, 153] . Outbreaks of EV71 infection have been periodically reported worldwide [154] [155] [156] . For instance, China has recently seen increased deaths linked to EV71 infection and HFMD among the young population [131, 138, 157, 158] . As mentioned above, there are no approved drugs for preventing or treating EV71 infection, but currently, 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 [159] . 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 [160, 161] . G. lucidum is widely used as a folk medicine for a variety of ailments [162] . Zhang et al. [79] suggested that Lanosta-7,9(11),24-trien-3-one,15;26-dihydroxy (GLTA), and ganoderic acid Y (GLTB), which are triterpenoid compounds of G. lucidum, 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 (F site), and hence a block uncoating of EV71 ( Figure 5 ). Furthermore, it has been shown that GLTA and GLTB notably prohibited the viral RNA (vRNA) replication of EV71 by blocking EV71 uncoating. Therefore, both GLTA and GLTB may represent two promising curative agents to control and treat EV71 infection. 

The dengue virus (DENV), classified within the Flaviviridae family, is a fatal microbe transmitted to humans through mosquitoes (Aedes albopictus and Aedes aegypti) [163] [164] [165] , causing both hemorrhagic fever [166, 167] , and shock syndrome [168, 169] . A total of five different serotypes of DENV have been reported to induce both dengue fever types while potentially causing fatal infections [170, 171] . Proteome analysis revealed that the translated DENV polyprotein complex comprises three structural and seven nonstructural proteins [171, 172] . 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 NS2B-NS3pro complex of the dengue virus has been recently identified as an ideal target for developing novel anti-DENV drugs [173] [174] [175] . 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, as 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 [176] .

December 2019 marked in Wuhan (Hobby Province, China) the beginning of a mysterious pneumonia outbreak [177] . A month later, the infectious agent was revealed to be a new kind of coronavirus named SARS-CoV-2 (formerly 2019-nCOV) [178] . The World Health Organization (WHO) declared the pneumonia outbreak that appeared in Wuhan a major public health crisis on 11 February 2020 and gave it the official name of Coronavirus Disease-2019 (COVID-19) [179] . Multiple symptoms were reported in the COVID-19 patients, including cough, lung damage, fever, fatigue, muscle pain, diarrhea, myalgia, and respiratory symptoms [180, 181] . As of 27 April 2021, 147,539,302 cases of SARS-CoV-2 infected pneumonia and 3,116,444 deaths had been reported in China and 223 other countries, areas, or territories, of which 103,503 cases were found in China [182] . Natural products are among the most important sources for modern medication industry technology, if not the most important, due to their advantages such as abundant clinical use, and their unique diversity of chemical structures and biological activities [183, 184] . In this context, traditional Chinese medicine (TCM) is one of the gold mines rich in untapped natural resources [185, 186] 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 

The dengue virus (DENV), classified within the Flaviviridae family, is a fatal microbe transmitted to humans through mosquitoes (Aedes albopictus and Aedes aegypti) [163] [164] [165] , causing both hemorrhagic fever [166, 167] , and shock syndrome [168, 169] . A total of five different serotypes of DENV have been reported to induce both dengue fever types while potentially causing fatal infections [170, 171] . Proteome analysis revealed that the translated DENV polyprotein complex comprises three structural and seven nonstructural proteins [171, 172] . 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 NS2B-NS3pro complex of the dengue virus has been recently identified as an ideal target for developing novel anti-DENV drugs [173] [174] [175] . 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, as 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 [176] .

December 2019 marked in Wuhan (Hobby Province, China) the beginning of a mysterious pneumonia outbreak [177] . A month later, the infectious agent was revealed to be a new kind of coronavirus named SARS-CoV-2 (formerly 2019-nCOV) [178] . The World Health Organization (WHO) declared the pneumonia outbreak that appeared in Wuhan a major public health crisis on 11 February 2020 and gave it the official name of Coronavirus Disease-2019 (COVID-19) [179] . Multiple symptoms were reported in the COVID-19 patients, including cough, lung damage, fever, fatigue, muscle pain, diarrhea, myalgia, and respiratory symptoms [180, 181] . As of 27 April 2021, 147,539,302 cases of SARS-CoV-2 infected pneumonia and 3,116,444 deaths had been reported in China and 223 other countries, areas, or territories, of which 103,503 cases were found in China [182] . Natural products are among the most important sources for modern medication industry technology, if not the most important, due to their advantages such as abundant clinical use, and their unique diversity of chemical structures and biological activities [183, 184] . In this context, traditional Chinese medicine (TCM) is one of the gold mines rich in untapped natural resources [185, 186] 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 [187] . For instance, the helicase domain is being investigated as a possible drug target. Yu et al. [188] reported that 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, being 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), Sinomenium acutum (IC50:198.6 µg/mL), and Kang Du Bu Fei Tang (IC50:471.3 µg/mL) [189] . Therefore, G. lucidum could serve as a novel and promising source of bioactive natural compounds with anticoronavirus activity [187] .

Multiple research studies reported a close relationship between the richness of G. lucidum in "phenolic compounds, triterpenes, polysaccharides, polysaccharide peptide" and its antioxidant biological activity [83, 97, [190] [191] [192] . Clinical nutritionists have demonstrated that consuming antioxidant-rich plant-based foods may protect from cancer and many other chronic diseases [193, 194] ; however, this causality is still not proven yet for the antioxidants of G. lucidum [195] . Hence, one of the research priorities for the G. lucidum mushroom is to conduct more studies to close the gap in the interplay between antioxidants and the host immune system [191] .

The long-term presence of free radicals and reactive oxygen species (ROS) accelerates aging and numerous age-associated illnesses [13] . Therefore, studies on scavenging free radicals and ROS are particularly important in antiaging research. G. lucidum polysaccharides (GLPs) can inhibit ROS production in fibroblasts following UVB treatment [196] .

Cancer is still one of the most fatal diseases worldwide and poses a major clinical challenge despite the notable boom in early diagnostic techniques and evolution in its treatment techniques [197] . Hundreds of plant species have been investigated as sources for new therapeutics (chemopreventive or chemotherapeutic) [198] . In this regard, mushrooms; e.g., Ganoderma species, are rich sources of many biologically active components, including antitumoral agents [199, 200] . 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 [6, 31, 52, 114, 115, [201] [202] [203] . In addition, the antitumor activity exhibited by G. lucidum is achieved via induction of programmed cell death, as reported by many studies [81, 204, 205] . Moreover, the isolated compounds from G. lucidum have been previously described as modulators of autophagy in numerous human tumor cell lines [206] [207] [208] [209] . 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 mechanism that involved cellular autophagy [209] . Still, it is unknown if the extract is an inducer of autophagy or an autophagic flux inhibitor. More recently, Reis et al. [210] demonstrated that a methanolic extract of G. lucidum caused autophagy induction, rather than reducing the autophagic flux in AGS cells.

G. lucidum has been proved to possess compounds responsible for hypoglycemic effects, such as polysaccharides, proteoglycans, proteins, and triterpenoids [6, 78, 123, 124] . For instance, Wang et al. [211] reported that consuming a G. lucidum spore powder (GLSP) induced a decrease in blood glucose levels by promoting glycogen synthesis and preventing gluconeogenesis.

How does G. lucidum have cardioprotective impacts? Many studies have answered this question. Firstly, Sudheesh et al. [122] reported the presence of α-tocopherol in G. lucidum that protected the mitochondria, reducing cardiac toxicity and mitochondrial dysfunction. Additionally, Gao et al. [212] referred to the positive effects of ganopoly (G. lucidum polysaccharide extract) on coronary heart disease (CHD) patients. The same authors showed that a polysaccharide extract of G. lucidum induced decreased blood pressure and serum cholesterol levels.

The GLPs and Ganoderma triterpenoids (GTs) can act on the immune system and effectively exhibit hepatoprotective effects and treat liver damage. The hepatoprotective effects of G. lucidum have been widely studied [213] . GLPs can protect hepatocyte injury by inhibiting lipid peroxidation, elevating antioxidant enzyme activity, and suppressing apoptosis and immune-inflammatory response [214] . GTs offered significant cytoprotection against the oxidative damage induced by tertbutyl hydrogen peroxide (t-BHP) in hepatocellular carcinoma cells by decreasing the level of malondialdehyde and increasing the contents of glutathione and superoxide dismutase (SOD) [215] . 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 [216] . In addition, a G. lucidum mycelium-fermented liquid (GLFL) was reported to possess hepatoprotective properties in rats [217] .

Inflammation is a normal physiological response to an infection or injury and is part of host defense and tissue healing [218] . GLPs can prevent inflammation, maintain intestinal homeostasis, and regulate the intestinal immunological barrier functions in mice [219] . The anti-inflammatory effect of GLPs plays an important role in the care of sensitive skin [213] .

Prebiotics are defined as "a substrate that is selectively utilized by host microorganisms conferring a health benefit" [220, 221] . 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 [222] . 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 [223] . For instance, mushrooms are a rich source of prebiotics that may play a pivotal role in treating pneumonia and atherosclerosis, as well as in their antitumor activity [224] . In the same context, a study conducted on mice (C57BL/6) confirmed that the Mexican G. lucidum is a rich source of prebiotics that reduced blood cholesterol [225] . The same study attributed the ability of Mexican 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 [225] . 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 ( Figure 6 ). Thus, GLPP can be considered a potential functional food component for treating hyperlipidemia and gut microbiota dysbiosis [226] . 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 ( Figure 6 ). Thus, GLPP can be considered a potential functional food component for treating hyperlipidemia and gut microbiota dysbiosis [226] . Furthermore, to date, no extensive studies have examined the biological activities and functions of GLFL on the regulation of the gut microbiota and cardiovascular diseases (CVDs) [227] .

Concerning this, it has been demonstrated that the gut microbiota could play an important role in host health through their influence on cardiovascular risk factors [228, 229] . As was mentioned previously, the products associated with G. lucidum have positive effects on the gut microbiota, and thus these products can regulate the risk factors for cardiovascular disease in the intestine. Chang et al. [230] reported an altered gut microbiota composition in an obese mouse model treated with a water extract of G. lucidum mycelium. In addition, GLFL was shown to reduce plasma low-density lipoprotein (LDL-c) cholesterol, triglycerides, and total cholesterol, and increase high-density lipoprotein (HDL-c) cholesterol in mice [231] . Additionally, Wu et al. [227] reported that when GLFL was fed to humans, it profoundly altered the gut microbiota. In the post-feeding group, there was an evident difference in β diversity as compared to the case of the pre-feeding group; this suggested that GLFL had altered the composition of the gut microbiota. Furthermore, the same authors reported that GLFL could protect humans by stimulating the Figure 6 . Regulatory mechanism of GLPP on hyperlipidaemia, hypercholesterolemia, and gut microbiota dysbiosis in rats fed on HFD. GLPP: Ganoderma lucidum polysaccharide peptide; HFD: high-fat diet; TG: triglyceride; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; FFA: free fatty acids; SCFA: short-chain fatty acids; OSTα: organic solute transporter alpha; CYP7A1: cholesterol 7α-hydroxylase; SREBP-1C: sterol regulatory element-binding protein-1C; PPARα: peroxisome proliferator-activated receptor alpha; HMG-Coa: 3-hydroxy-3-methylglutaryl coenzyme A; BSEP: bile salt export pump; MRP3: multidrug-resistance-associated protein 3; OATP2: organic-aniontransporting polypeptides 2. Source: Reprinted with permission from Lv et al. [226] . 2022, Elsevier. Furthermore, to date, no extensive studies have examined the biological activities and functions of GLFL on the regulation of the gut microbiota and cardiovascular diseases (CVDs) [227] .

Concerning this, it has been demonstrated that the gut microbiota could play an important role in host health through their influence on cardiovascular risk factors [228, 229] . As was mentioned previously, the products associated with G. lucidum have positive effects on the gut microbiota, and thus these products can regulate the risk factors for cardiovascular disease in the intestine. Chang et al. [230] reported an altered gut microbiota composition in an obese mouse model treated with a water extract of G. lucidum mycelium. In addition, GLFL was shown to reduce plasma low-density lipoprotein (LDL-c) cholesterol, triglycerides, and total cholesterol, and increase high-density lipoprotein (HDL-c) cholesterol in mice [231] . Additionally, Wu et al. [227] reported that when GLFL was fed to humans, it profoundly altered the gut microbiota. In the post-feeding group, there was an evident difference in β diversity as compared to the case of the pre-feeding group; this suggested that GLFL had altered the composition of the gut microbiota. 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)).

Most research on G. lucidum and its products has reported positive clinical outcomes and potential therapeutic uses, while the innocuity and potential toxic effects in humans have been poorly investigated. For instance, G. lucidum extracts could cause toxicity in vitro [35] . Moreover, G. lucidum spore-powder treatment caused hepatotoxic effects, as reported by Wanmuang et al. [232] Although no adverse effects of consumption of G. lucidum on lactation were proven, it is not advised for pregnant or lactating women [233] .

Thus far, many questions have arisen regarding why and how to expand and maximize the utilization of G. lucidum and its derivatives, and what to do about the new applications and innovative techniques used in this regard. These points will be discussed via three axes as follows.

Several publications have reported that G. lucidum may have diverse beneficial therapeutical characteristics via its myriad bioactive compounds, such as triterpenes, polysaccharides, and proteins; hence, G. lucidum and its products are still common as commercial products. Therefore, the efficacy and safety of the consumption of G. lucidum are still considered knowledge gaps that are poorly investigated. During the past three decades, in vitro/in vivo studies reported by Western researchers have shown biomedical benefits for G. lucidum, which helped promote this mushroom in the Western world. However, there still is an urgent need to fully understand the related biomechanisms, and thus unlock their biotherapeutic application. The isolation, purification, and identification of active compounds of G. lucidum should be carried out to decipher the bioactivity of these compounds within its nutraceutical and pharmaceutical products. This aspect is a big challenge when implementing the commercial standardization strategies of G. lucidum products [6, 35] .

More research is needed to re-examine and study the bioactive ingredients extracted from G. lucidum, and this will be beneficial for clinical applications due to the discrepancy in the research results for G. lucidum or its derivative products (e.g., GLFL, GLPP, and WEGL). For example, Wu et al. [231] reported that a GLFL was unsafe because it increased the number of opportunistic pathogens; e.g., Acinetobacter, and decreased probiotics; e.g., Lactococcus. These results were in contrast to what was obtained when they were applied to mice [226] .

Continued genetic studies of G. lucidum will elucidate the biosynthesis of the therapeutically active compounds produced by this mushroom; e.g., the unique triterpenoid antitumor ganoderic acids (GAs). The clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR-CAS9) technology has positively identified active curative components in G. lucidum by constructing functional genes of GA biosynthesis in this mushroom, thus serving as a vital platform for metabolic engineering in G. lucidum. Therefore, the CRISPR-CAS9 technique can be a cornerstone in all biotechnological applications of G. lucidum, such as molecular breeding. Therefore, a complete understanding of the G. lucidum genome will pave the way for its future roles in medical and industrial applications [71, 115, 234] .

Large-scale studies on G. lucidum mushrooms will be conducted with standard scientific methods in the near future.

Nowadays, several Ganoderma lucidum-based products are available in nutraceutical form. Some of them are marketed as dietary supplements and are widely consumed in many countries such as the United States, where they are combined with many other ingredients; e.g., coffee and tea. Because there is no proper toolkit, the consistency of the quality of dietary supplements derived from G. lucidum is rarely evaluated. Additionally, G. lucidum could be considered a source of food preservatives [5, 187, 235] .

To validate G. lucidum's nutraceutical usage, more research on this mushroom is needed.

Research conducted by Loyd and others [14] showed that manufactured G. lucidumbased products (e.g., dietary supplements), which are marketed as derived from G. lucidum, contain not only G. lucidum but also multiple Ganoderma species, are unfortunately sold for medicinal uses. Of course, not all Ganoderma species produce the same therapeutic compounds, the same quality, or the same quantities. This raises questions about the traceability and authenticity of mushroom species, and how important this is in the industry. Therefore, this question should be addressed in subsequent research focusing on G. lucidum and its products.

As mentioned by Qi et al. [236] , the geographical-origin traceability of mushrooms and their products is critical to assure their quality and safety. Indeed, the nutritional and therapeutic properties of each mushroom species vary depending on the geo-origins [237] [238] [239] [240] . Lu et al. [237] proved this fact through their research on samples of G. lucidum collected from different geographic regions, in which they found that the content of each G. lucidum sample of ganoderic acids A and B, polysaccharides, and triterpenoids varied according to their geographical origin (including the differences in cultivation and environmental conditions). Hence, the geo-origin traceability of G. lucidum will reinforce the value of this mushroom globally at all levels, whether industrial or economic.

Then, what is the best method that can be used for species and geo-traceability targets? El Sheikha and Hu [8] proposed the DNA barcoding approach as a new "cutting edge" technology to significantly enhance food traceability in general and in mushrooms, especially from the field to the table.

Recently, research on G. lucidum and its products has achieved substantial progress and has become a focus of the attention of the scientific community in many fields. Many studies from different viewpoints elucidated the biological characteristics, chemical composition and active components, pharmacological effects and related mechanisms, and clinical applications based on G. lucidum. Furthermore, at the industrial level, G. lucidum has made some progress.

In the future, new chemical compositions and active components (as a promising functional food), cellular and molecular mechanisms of biological activities (e.g., prebiotic effects), rapid and confirmatory methods to identify effective ingredients, fermentation and cultivation techniques, double-blind large-scale clinical trials, and quality control monitoring of product will be the aims of G. lucidum research (see Figure 7 ). Foods 2022, 11, x FOR PEER REVIEW 20 of 30 Infographic 1. Ganoderma lucidum: current scenario and future perspectives.

Ganoderma lucidum (Lingzhi, Reishi, or Mannentake) is a promising source of prebiotics due to its abundance of several bioactive compounds that have nutritional and medicinal effects and are present in all parts of the fungus (fruit bodies, mycelium, and spores). Therefore, since ancient times, G. lucidum has been used traditionally in Chinese medicine to treat chronic diseases. In addition, Chinese tradition refers to G. lucidum as "the lucky fungus" for its power to alleviate conditions such as arthritis, insomnia, and chest tightness.

There has been an increased interest in G. lucidum as a dietary supplement containing Reishi, which is a widespread therapeutic agent worldwide. As for Western countries, the bioactive substances extracted from G. lucidum have been used in alternative medicine to support traditional medicine in treating severe diseases, including diabetes, hepatitis, and cancer. Nevertheless, continuing this trend requires more clinical trials, typically to 

Ganoderma lucidum (Lingzhi, Reishi, or Mannentake) is a promising source of prebiotics due to its abundance of several bioactive compounds that have nutritional and medicinal effects and are present in all parts of the fungus (fruit bodies, mycelium, and spores). Therefore, since ancient times, G. lucidum has been used traditionally in Chinese medicine to treat chronic diseases. In addition, Chinese tradition refers to G. lucidum as "the lucky fungus" for its power to alleviate conditions such as arthritis, insomnia, and chest tightness.

There has been an increased interest in G. lucidum as a dietary supplement containing Reishi, which is a widespread therapeutic agent worldwide. As for Western countries, the bioactive substances extracted from G. lucidum have been used in alternative medicine to support traditional medicine in treating severe diseases, including diabetes, hepatitis, and cancer. Nevertheless, continuing this trend requires more clinical trials, typically to confirm efficacy and safety. Soon, more studies will be conducted on this mushroom on a larger scale in terms of medicinal applications or the food industry. The geographical origin is considered one of the critical factors that greatly impact both the safety and quality of mushrooms. Therefore, the determination of geographical origin has become an essential requirement to provide consumers with safe and high-quality mushrooms, including G. lucidum. Although there are many challenges facing the production of nutraceuticals and functional foods from G. lucidum on a large scale, especially in light of the limited clinical trials in humans, there is a potential for innovation, development, and expansion of applications (e.g., in food and pharmaceutical applications) due to G. lucidum's promising nutritional and health characteristics. 

The author declares no conflict of interest.

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Advances in research on the active constituents and physiological effects of Ganoderma lucidum

Anti-inflammatory and hepatoprotective effects of Ganoderma lucidum polysaccharides on carbon tetrachloride-induced hepatocyte damage in common carp

Hepatoprotective effect of ganoderma triterpenoids against oxidative damage induced by tert-butyl hydroperoxide in human hepatic HepG2 cells

Hepatoprotective activity of Ganoderma lucidum triterpenoids in alcohol-induced liver injury in mice, an iTRAQ-based proteomic analysis

Hepatoprotective effect of extracellular polymer produced by submerged culture of Ganoderma lucidum WK-003

Suppression of Th17 cell response in the alleviation of dextran sulfate sodium-induced colitis by Ganoderma lucidum polysaccharides

Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics

The importance of prebiotics in functional foods and clinical practice

Mushroom polysaccharides as a potential prebiotics

The role of the gut microbiota in energy metabolism and metabolic disease

A critical review on health promoting benefits of edible mushrooms through gut microbiota

Hypocholesterolemic properties and prebiotic effects of Mexican Ganoderma lucidum in C57BL/6 Mice

Polysaccharide peptides from Ganoderma lucidum ameliorate lipid metabolic disorders and gut microbiota dysbiosis in high-fat diet-fed rats

Evaluation of the efficacy and safety of Ganoderma lucidum mycelium-fermented liquid on gut microbiota and its impact on cardiovascular risk factors in human

The impact of the gut microbiota on human health: An integrative view

World Health Organization (WHO)

Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota

Hypolipidemic effect of exo-and endo-biopolymers produced from submerged mycelial culture of Ganoderma lucidum in rats

Fatal fulminant hepatitis associated with Ganoderma lucidum (Lingzhi) mushroom powder

An evidence-based systematic review of stevia by the Natural Standard Research Collaboration

CRISPR-Cas9 assisted functional gene editing in the mushroom Ganoderma lucidum

Evaluation on quality consistency of Ganoderma lucidum dietary supplements collected in the United States

Feature fusion of ICP-AES, UV-Vis and FTMIR for origin traceability of Boletus edulis mushrooms in combination with chemometrics

Quality difference study of six varieties of Ganoderma lucidum with different origins

Polyporus squamosus (Huds.) Fr from different origins: Chemical characterization, screening of the bioactive properties and specific antimicrobial effects against Pseudomonas aeruginosa

A comparative overview of antioxidative properties and phenolic profiles of different fungal origins: Fruiting bodies and submerged cultures of Coprinus comatus and Coprinellus truncorum

Traceability of Boletaceae mushrooms using data fusion of UV-visible and FTIR combined with chemometrics methods