MUSHROOM SECONDARY METABOLITES: CHEMISTRY AND THERAPEUTIC APPLICATIONS

MUSHROOM SECONDARY METABOLITES: CHEMISTRY AND THERAPEUTIC APPLICATIONS

Darshankumar Prajapati, Ashish Bhatt, Shilpa Gupte and Akshaya Gupte *

Natubhai V. Patel College of Pure and Applied Sciences, Vallabh Vidyanagar, Gujarat, India.

ABSTRACT: Since ancient times, humans have always been captivated by nature and have explored natural products. To combat against novel emerging and reemerging diseases and tremendous side effects imposed by recent therapies, scientists have again taken an interest in natural resources. To date, plants have been the major source of natural bioactive compounds, but recently fungi have got more attention. Amongst fungi, edible and medicinal mushrooms have come out as a rich source of bioactive metabolites. Since long back, they are being consumed heavily because of their outstanding flavour, aroma, nutritional value, and medicinal properties. Both edible, as well as medicinal mushrooms, synthesize bioactive compounds known as secondary metabolites i.e., polysaccharides, steroids, terpenes as well as peptides. Such metabolites possess many medicinal properties like anti-oxidant, anti-tumor, anti-diabetic, anti-cancer, anti-ageing, and also anti-obesity. Furthermore, mushroom secondary metabolites are prioritized over other natural compounds due to their non-toxic nature and low or no side effects. This review mainly covers sources and types of secondary mushroom metabolites and their therapeutic applications.

Keywords:  Mushroom, Bioactive fractions, Secondary metabolites, Therapeutic polysaccharides, Anti-cancer, Anti-oxidant

INTRODUCTION: For more than two centuries, fungi have been identified as a valuable and abundant group of organisms significant to humanity. The kingdom fungi at present is divided into four major phyla: Chytridomycota, Zygomycota, Ascomycota, and Basidiomycota. Ascomycotina (the flask fungi, cup fungi and their allies, including moulds and yeasts), Basidiomycotina (the rusts, smuts, fairy clubs, jelly fungi, stinkhorns, bracket fungi, bird’s-nest fungi, earthstars and puffballs, toadstools and

mushrooms) and their anamorphs (asexual fungi) are considered as representatives of higher fungi divisions, according to evidence of fungal origin, evolution, and phylogeny ¹. Mushrooms are a very large and diversified group of macro-fungi belonging to the class Basidiomycetes and Ascomycetes.

They are a widely distributed food resource on earth and have been consumed because of their nutritional value and medicinal properties for over 2000 years. In addition to their enjoyable flavor and taste, human health has improved by mushrooms due to their nutrients which include digestible proteins, carbohydrates, fiber, vitamins, minerals, and antioxidants ^{2, 3}. The medicinal properties of mushrooms may be because of the presence of various secondary metabolites. Secondary metabolites are bioactive low molecular weight compounds, produced in response to stress but generally not required for the normal growth and reproduction of the fungi.

These compounds, including polysaccharides, lectins, lactones, terpenoids, alkaloids, antibiotics and metal-chelating agents, have been extensively reported for number of therapeutic properties such as anti-oxidant, anti-tumor, immunomodulaotry, anti-cancer, anti-microbial, anti-diabetic, neuro-protective, anti-HIV, hepatoprotective, anti-metastatic and anti-inflammatory activities ^{2, 4-6}.

2. Secondary Metabolites of Mushrooms:

2.1. Polysaccharides: Polysaccharides are the major class of bioactive compounds found in mushrooms and have been reported in most of edible mushrooms. They are long chains of sugar units linked to each other by glycosidic bonds and/or combined with different branches.

They are categorized as homopolyasaccharides, which have uniform monosaccharide units, and hetero-polysaccharides which have more than one type of monosaccharide repeats. Cellulose is homo-poly-saccharides, while pectin is hetero-polysaccharides. Biological and pharmaceutical activities of both homo- and hetero-polysaccharides are closely correlated to their specific structural characteristics ⁷. Several types of bioactive poly-saccharides are available in nature. Lentinan is β-glucan composed of β-(1→3)-D-glucose residues bonded to β-(1→6)-glucopyranoside by glycosidic linkages.

It is derived from Lentinus spp. An average molecular weight of this polysaccharide falls around 500 kDa ^{8, 9}. Ganoderan is extracted from Ganoderma spp., which contains β-(1→3)-D-glucans with β-(1→6)-D-glucopyranosyl branches ¹⁰. Molecular weight was found to remain around 1.2 × 10⁶ Da to 4.4 × 10⁶ Da ^{9, 11}.

Schizophyllan is produced by an edible mushroom called Schizophyllum spp. Just like lentinan, structurally, it also contains a β-(1→3)-glucan with β-glucopyranosyl group linked by β-(1→6) linkage. Molecular weight of schizophyllan is around 450 kDa ⁸. Pleuran is a water-soluble and/or alkali-soluble polysaccharide extracted from Pleurotus spp. It may be either β-(1→3 / 1→6)-D-glucan or α-(1→3)-D-glucan by structure ¹².

Another gel-forming β-(1→3)-D-glucan is Grifolan which is extracted from mushroom known as Grifola spp. Molecular weight falls in range of 770 kDa to 1650 kDa ¹³.

Krestin (polysaccharide-K or PSK) is protein-bound β-glucan which is derived from Trametes spp. It is β-(1→4)-glucan with lateral β-(1→6)-glucopyranoside chains, with molecular weight of around 94 kDa ¹⁴. Another proteoglucan proced by Trametes spp. is PSPC or PSP (polysaccharide protein complex).

The Polyporus polysaccharide (PPS) extracted from mushroom Polyporus spp. consists of (1→3)-β-glucan backbone and (1→6)-β-glucopyranose side chain. Molecular weight remains around 1.6 × 105 Da ¹⁴.

Polysaccharides from Agaricus spp. display various structural varients such as: β-(1→6) / β-(1→3)-glucan, an acidic β-(1→6) / α-(1→4)-glucan and an acidic β-(1→6) / α-(1→3)-glucan and thus range of molecular weight is also very broad starting from 380 kDa to 10,000 kDa ¹³.

Polysaccharide from edible mushrooms Auricularia which are also known as jelly ears fungi was identified to have β-(1→3)-D-glucan linked with two residues of β-(1→6)-D-glucosyl for every three main chain glucose moiety.

Molecular weight was determined as 2.1 × 10³ kDa ¹⁵. Cordyceps extracted polysaccharides α-(1→4)-D-glucan linked with branches of α-(1→6)-D-glucan having molecular weight of about 1180 kDa ¹⁴.

Apart from this, mushrooms like Hericium erinceus, Morchella esculenta, Flammulina velutipes, Inonotus obliquus, Phellinus rimosus, Astraeus hygrometricus, Fomes fomentarius, Hypsizygus marmoreusare also good sources of polysaccharide that have been studied ^{13, 14}.

All these polysaccharides represent therapeutic properties like anti-tumor, immunomodulaotry, anti-microbial, anti-cancer, anti-oxidant, hepato-protective, hypoglycemic, neuroprotective, anti-viral, and anti-inflammatory activities which is advantageous to the human beings.

TABLE 1: SECONDARY METABOLITES OF GANODERMA LUCIDUM (ADAPTED FROM 22, 31)

S. no.	Secondary Metabolites	Examples	Chemical Structures
1	Others	Meroterpenoids (Lingzhiol); Benzofurans (Ganofuran B)
2	C24, C25 lanostanes	Lucidone A, B, C
3	C30 lanostanes	Aldehydes, alcohols, esters, glycosides, lactones, and ketones Ganoderal A; Lucidal; Lucialdehyde A; Lucidadiol; Lucidumol B; etc.
		Ganoderic acid Ganoderic acid A-Z, AM1, B8, C6, Df, Me, Mf, Sz, TR1, DM, LM2, α, β, γ, δ, etc.
4	C27 lanostanes	Lucidenic acid Lucidenic acid A, B, C, D1, D2, E1, E2, F, N, P; 20 Hydroxy lucidenic acid D2,E2,F,N;
		Alcohols, lactones and esters Lucidenic lactone; Lucidenolactone; Methyl lucidenate A, C, F, N, P, Q, D1; Ethyl lucidenate A; Butyl lucidenate A, N, P, Q, D2, E2; Methyl 20(21)-dehydrolucidenate A

2.2 Terpenes: Terpenes are the largest group of anti-inflammatory compounds in mushrooms. They are biologically active compounds that contribute to a vast array of medicinal and health benefits. They are a class of naturally occurring compounds where carbon skeleton are mainly composed of one or more isoprene C5 units. Terpenes are non-polar metabolites comprising of different groups like monoterpenes, diterpenes, triterpenes, and sesquiterpenes. Terpenoids from mushrooms possess numerous bioactive properties like anti-microbial, anti-viral, anti-malarial, anti-fungal, anti-cancer, anti-tumor and anti-oxidant activities ^{16, 17}.

Terpenes can be categorized as: sesquiterpenes, diterpenes, triterpenes, and meroterpenes. Mono-terpenes generally consist of two isoprene units having molecular formula C₁₀H₁₆. They may be acyclic or possess cyclic rings. Monoterpenes which are having oxygen functionality or missing a methyl group are known as monoterpenoids. The most common example is menthol which is used as a flavour. Linalool is one of the monoterpene derivatives having anti-bacterial activity ¹⁸. Sesquiterpenes are usually composed of three isoprene units, and their general molecular formula is C₁₅H₂₄. They are generally produced by the plant and some fungi. The most common example of sesquiterpenes is geosmin which is produced by actinomycetes ¹⁸. Several fungal sesquiterpenic molecules show effect against Leishmania major, L. infantum, L. donovani, Trypanosoma brucei, T. cruzi, T. gondii, Neospora caninum, Eimeria tenella and Acanthamoeba castellanii, and some other parasites ¹⁷. Lentinus species can yield variety sesquiterpenes. The sesquiterpenes hypnophilin and panepoxydone were isolated from the ethyl acetate extracts of mushroom Lentinus strigosus ^{17, 19}. Some sesquiterpenes like panepoxydone, panepoxydione, and dihydrohypnophilin were isolated from the ethyl acetate extracts of fungus Lentinus conatus. Another mushroom Phallus indusiatus is also known to produce two novel sesquiterpenes. Diterpenes are a class of terpenes consisting four isoprene rings with molecular formula C₂₀H₃₂. They are also produced by some fungi, plant and animals.

Functionalized diterpenes are also called diterpenoids. Retinol and phytol are bioactive diterepenoids which are having anti-inflammatory and anti-bacterial activities ¹⁸. Triterpenes are a class of terpenes that are composed of three terpene units i.e., six isoprene units. Their common molecular formula is C₃₀H₄₈. Triterpenes are also produced by fungi, animals, and plants. Their molecular weight ranges from 400 to 600 kDa. Functionalized triterpenes are also popular as triterpenoids. Chemical structures of triterpenes are based mostly on lanosterol. Triterpenes are a class of naturally occurring biologically active compounds which have a vast range of medicinal applications and health benefits such as cytotoxic, hepatoprotective, hypocholesterolemic, hypo-lipidemic, anti-tumor, anti-cancer, anti-viral, anti-obesity, and neuro-trophic activities ^20-22.

Mushroom species such as Ganoderma, Antrodia and Inonotus have been reported to yield triterpenes ²³. Ganoderic acids produced by Ganoderma spp. is one of the triterpenes composed of four cyclic and two linear isoprene units. Till date, around 140 various kinds of ganoderic acids (GAs) have been successfully isolated from fruiting bodies, mycelia, and cultures of Ganoderma lucidum, and most of them are lanostane type ^{20, 24, 25}. Chemical structures of secondary metabolites extracted from Ganoderma lucidum are recorded in Table 1.

Apart from this, another mushroom named Antrodia cinnamomea is more abundant in bioactive triterpenoids than that of Ganoderma lucidum. Recently, over 40 different types of triterpenoids have been recognized in Antrodia cinnamomea, which are therapeutically potent ²⁶. Many researchers have reported ergostane and lanostane as major components of triterpenoid skeleton in A. cinnamomea. In which, ergostane type occurs mainly as tetracyclic triterpenoids with a 29-carbon skeleton having a  24-exo-methylene-26-oic acid side chain and conjugated double bonds among C-7, C-8, C-9, and C-11, whereas lanostane type triterpenoids generally consist of a eubricane skeleton with 24-exo-methylene-21-oic acid side chain and a double bond system along C-7, C-8, C-9 and C-11 ^27-29. Some tritepenes like ergosterol peroxide, ergosterol, 3β-hydroxy-8,24-dien-21-al, trametenolic acid and inotodiol have also been isolated from Inonotus obliquus, which were identified to possess some medicinal values ^{23, 30}.

2.3 Steroids: All organisms produce steroids as they are an important source of biologically active compounds as they are able to penetrate cell membranes and bind to nuclear and membrane receptors. Structurally steroids are composed of seventeen carbon atoms bonded in four rings arranged in specific molecular configuration. As depicted in Fig. 1, three rings out of four (A, B, and C) are cyclohexane rings, and the fourth (D) is cyclopentane ring. The diversity in steroids is mainly due to the presence of different functional groups attached to this four-ring structure. They are reported to possess anti-tumor, anti-cancer, anti-microbial, anti-inflammatory, and anti-viral properties ¹⁷.

Sterols are steroid alcohols. Ergosterol with anti-parasitic activity was successfully extracted from mushroom Pleurotus salmoneostramineus ³². The n-hexane extract to Trametes versicolor yielded ergostane named 5α, 8α-epidioxy-22E-ergosta-6, 22-dien-3β-ol ^{17, 33}. It was reported that Pleurotus ostreatus also produced similar ergostane ^{17, 34}. In the course of time, two other sterols, ergosterol and 5α, 8α-epidioxy-(22E, 24R)-ergosta-6, 22-dien-3β-ol were isolated from fruiting bodies of an edible mushroom Agrocybe aegerita. Another mushroom Paxillus panuoides was also reported to yield two ergosteroid compounds: 5α, 8α-epidioxy-(22E, 24R)-ergosta-6, 22-dien-3β-ol and (22E, 24R)-ergosta-4, 6, 8(14), 22-tetraen-3-one. From edible truffle mushroom Tuber indicum four ergostane-type compounds i.e. brassicasterol; (22E,24R)-ergosta-7, 22-dien-3β, 5α, 6β-triol; (22E,24R)-ergosta-4, 6, 8(14), 22-tetraen-3-one and 5α,8α-epidioxy-(22E, 24R)-ergosta-6,22-dien-3β-ol as well as one novel polyhydroxy sterol glycoside named tuberoside i.e. identified as 3-O-β-D-glucopyranosyl-(22E, 24R)-ergosta-7, 22-dien-5α, 6β-diol were obtained. Two novel secoergosterols, tylopiols A and tylopiols B, structurally 3β-hydroxy-8α, 9α-oxido-8, 9-secoergosta-7, 9(11), 22-triene and 3β-hydroxy-8α, 9α-oxido-8, 9-secoergosta-7, 22-diene-12-one respectively were identified from the fresh fruiting bodies of Tylopilus plumbeoviolaceus.

FIG. 1: COMMON STRUCTURE OF STEROIDS (DRAWN USING ACD/CHEMSKETCH FREEWARE)

2.4. Alkaloids: Alkaloids are naturally occurring organic secondary metabolites which mostly contain basic nitrogen moieties. A large variety of organisms, including bacteria, fungi, plants, and animals are able to synthesize alkaloids. From crude extracts, they can be purified either by acid-base extraction or solvent extraction methods, followed by the use of column chromatography techniques. Different alkaloids possess a wide variety of pharmacological activities such as anti-cancer, anti-asthamatic, anti-malarial, cholinomimetic, anti-arrythamic, analgesic, anti-bacterial, vasodilatary and hypoglycemic activities.

Alkaloids like cocaine, caffeine, nicotine, and theobromine have stimulant activities, whereas some alkaloids such as atropine and tubocurarine are toxic too. Tricholoma terreum possesses a rare 10 ring structured alkaloid that has been extracted from its fruiting bodies and is named terreumols ³⁵. Edible mushroom Tricholoma matsutake was reported to synthesize matsutakone with unprecedented polycyclic ring structure ³⁶. From ethyl acetate fractions of the large black fruiting body and valued flavor possessing edible mushroom Phlebopus portentosus, three new pyrrole alkaloids, phlebopines A, B and C, have been isolated. All of these three pyrrole alkaloids were investigated to have neuroprotective activities along with acetylcholine esterase inhibition activities ³⁷. The odoriferous indole and skatole were identified in extracts of genus Tricholoma. A lump of unpleasant coal- or tar-like odor possessing indole-3-carboxaldehyde was found in the volatile extract of Tricholoma sulphureum. The genus Tricholoma of mushrooms produces a number of indole alkaloids containing a methyl group at the C2-position i.e., lascivol. 4-Methoxymethyl-5-methylindole has also been identified in Tricholoma caligatum ^{38, 39}. 6-hydroxyindole-3-carbaldehyde and 6-hydroxy-indole-3-acetamide, have been extracted from Agrocybe cylindracea, with both showing free radical scavenging activity ^{38, 40}. The mushroom Hericium coralloides produces the indole alkaloid corallocin C ^{38, 41}.

2.5 Peptides and Proteins: A short chain of amino acids bonded together via peptide bonds is known as a peptide. Many peptides join together to form a polypeptide, and when such polypeptides fold into a typical confirmation, they yield a macromolecule called protein. Several biologically active peptides and proteins are synthesized by mushrooms. Such proteins or peptides may or may not possess catalytic activity. For example, lectins do not have enzymatic activity. Some of the important bioactive proteins are laccases, ribosome-inactivating proteins (RIPS), and fungal immunomodulatory proteins (FIPS). Lectins are glycoproteins or non-immune proteins which specifically bind to carbohydrates of the fungal cell wall and have cell agglutination abilities. Enzymes that inactivate ribosomes by removing adenosine from rRNA are recognized as RIPS. FIPS are novel bioactive proteins that target immune cells. Laccases are phenol oxidases which are generally employed for degradation of lignocellulosic biomass; also possess bioactive properties ²³. These peptides and proteins possess several bioactive properties like anti-microbial, anti-inflammatory, anti-mitogenic, anti-tumor as well as immunomodulatory activities. Pleurostrin, a 7 kDa anti-fungal peptide, was extracted from Pleurotus ostreatus ⁴². An anti-inflammatory peptide, cordymin with 10,906 kDa molecular weight was obtained from mushroom Cordyceps sinensis and Cordyceps militaris ^{43, 44}. Xylose-specific lectins having molecular weight of about 28.8 kDa showing anti-mitogenic and anti-tumor activities was extracted from fruiting bodies of Xylaria hypoxylon ⁴⁵. Laccases isolated from Pleurotus eryngii and Pleurotus ostreatus display antiviral properties ^{46, 47}. Various FIPS have been successfully isolated from different mushrooms such as Fip-fve from F. velutipes, Fip-vvo from Volvariella volvacea and Fip-gts from Ganoderma tsugae ^48-50.

It was reported that Fip-fve had been successfully applied for tumor immunotherapy ^{51, 52}. Marmorin, a 9 kDa RIP with anti-tumor properties, was isolated from Hypsizigus marmoreus ⁵³.

3. Therapeutic Applications of Mushroom Secondary Metabolites: Traditionally, mushrooms were unknowingly being consumed, which provided nutrition as well as many health benefits.

These benefits were the results of their secondary metabolites, which are nowadays well known for bioactive properties. A few of those bioactivities are summarized in Fig. 2.

FIG. 2: VARIOUS BIOACTIVE PROPERTIES OF MUSHROOM SECONDARY METABOLITES

3.1. Anti-tumor and Anti-cancer Activities: Cancer is one of the leading causes of the death around the globe. Surgery and chemotherapy are usually the remedy for its treatment. Chemotherapy is the widely used treatment of cancer which has mostly relied on cytotoxic drugs, which act by inhibiting tumor cell proliferation and in turn, cause cell death. But major disadvantage of chemo-therapy is its harsh side effects on the human body. Thus it became compulsory to discover novel chemotherapeutic and chemopreventive agents. Luckily, mushrooms have got those bioactive secondary metabolites which have anti-tumor and anti-cancerous properties. Tumors formed in cancer are due to unrestricted growth of cells. Generally, tumors are classified as: benign and malignant tumors. Former one is less harmful as it grows and stays at a single place inside the body, but the later one is more dangerous as it can travel inside the body along with the body fluids. Anti-tumor compounds are those which can restrict the growth of tumor cells. Many biologically active secondary metabolites with anti-tumor activities have been investigated from mushrooms. The growth of several types of tumors like Sarcoma ³⁷, Sarcoma 180 solid tumor, Ehrlich solid tumor, Lewis lung carcinoma and Yoshida sarcoma were inhibited by polysaccharides produced by mushrooms ^{54, 55}. For the very first time in 1960s, anti-tumor activity of mushroom polysaccharide lentinan was reported ⁵⁶. Cordyceps militaris polysaccharide has shown promising in vitro anti-tumor activity against HeLa and HepG-2 cells and significantly inhibited the growth of K562 and HT-29 cells ²¹. Pluerotus ostreatus extracted polysaccharides are compounds of β-glucan family.

They have ability to boost cellular immunity because of anti-tumorogenic properties. They exerted anti-tumor activities against HeLa cells ^{23, 57}. Triterpenoids extracted from Ganoderma lucidum inhibited the growth of hepatoma cells was inhibited by suppressing protein kinase C and activating nitrogen-activated protein kinases ^{31, 58}. A triterpenoid Ganoderic acid T isolated from Ganoderma lucidum leads to apoptosis and prevent growth of lung tumor cell via an intrinsic pathway and by causing mitochondrial dysfunction ^{58, 59}.

Among various types of cancer, colorectal cancer is the second most leading cause of death occurring due to cancer. A biologically active low molecular weight α-glucan extracted from mycelia of an edible mushroom Pleurotus ostreatus displayed anti-apoptotic activity ⁴. Bioactive fractions of Cerrena unicolor and Pycnoporus sanguineus in habited the growth of colon cancer cells ⁶⁰. The medicinal mushroom Sarcodona spratus produced sterol 9, 11-dehydroergosterol peroxide 9(11)-DHEP which was reported to suppress the growth of human colon adenocarcinoma HT-29 cells ⁴.

Breast cancer occurs due to the proliferation of cell growth and DNA damage caused by the presence of estrogen in the breast of postmenopausal women. Triterpenes of Ganoderma lucidum, the medicinal mushroom, suppress the growth of MDA-MB breast cancer cell lines by inhibiting cell proliferation ⁶². Researchers have reported the inhibition of the transcription factors AF-1 and NF-κB which in turn downregulate the expression of Cdk4 and suppress the uPA secretion ⁴.

Leukemia, the cancer of the blood, occurs at high rates of about 3-5% with 4-5% of mortality rate. Ganoderma tsugae extracts strobfly inhibited growth of human chronic myeloid leukemia cells ^{4, 61}. The triterpenes obtained from mycelia of Ganoderma lucidum arrest cell cycle of HT-29 human leukemia cancer cell lines between G2-M phases ^{4, 63}.

Factors such as cigarette smoking, tobacco chewing, deficiency of niacin and iron are responsible for oral cancer. Increased intake of vitamins A and C reduces the risk of oral cancer. In patients with oral leucoplakia, the incidence of oral malignancy can be reduced by retinoids. Polysaccharides obtained from mushroom Lentinus edodes (LEP) increased serum, and oral mucosa IL-1b and TNF-α levels healed oral ulcers effectively in rats ^{4, 64}.

An uncommon gastric cancer may occur because of risk factors like environmental, genetic, and infection. Inflammation of gastric mucosa is caused due to bacterial infection from Helicobacter pylori. Endogenous nitrosamines, smoked meat, high-salt, high-carbohydrate, and high-fat diet are also accountable for the occurrence for gastric cancer. The consumption of high dietary fiber, fruits, and dairy products reduces the risk of gastric cancer ^{4, 65}. The methanolic extracts of Ganoderma lucidum enhance autophagy and formation of autophagosomes in the treatment of a gastric adenocarcinoma cell line (AGS) ^{4, 66}.

Pleurotus pulmonarious extracted polysaccharide-protein complex inhibits the proliferation of hepatocellular carcinoma by suppressing PI3K / AKT signaling pathway and overexpressing the constitutively active form Myr-AKT in liver cancer cells ^{4, 67}. It was reported that the cell cycle of HuH-7 hepatocarcinoma cells was arrested due to the treatment of triterpenes ^{20, 6}8.

3.2. Anti-oxidant Activities: Antioxidants assist in guarding the cellular components from oxidative damage, thereby reducing the risk of mutation and carcinogenesis. They are also important in the protection of the immune cells, allowing them to sustain immune surveillance and response. Oxidative stress is known to be one of the risk factors for the cause of cancer. Free radicals and reactive oxygen species (ROS) are by-products of metabolic processes. ROS and free radicals damage cells and tissues that may lead to age-associated diseases.

An anti-oxidative enzyme such as superoxide dismutase, catalase, and peroxidase has potential to repair the damage caused due to oxidative stress up to some extent. Polysaccharide extracted from Pleurotus eryngii by ultrasonic extraction method showed best DPPH and superoxide radical scavenging activities ⁶⁹. Polysaccharides of Amanita strobiliformis displayed hydroxyl radical scavenging activities ⁷⁰. Some researchers have reported that the triterpenes of Ganoderma lucidum have ability to decrease oxidative damage directly by scavenging free radicals ⁷¹. Triterpenes isolated from Ganoderma lucidum displayed anti-oxidant activity in mice that may be because of elevated activity of anti-oxidant enzymes. It was also observed that total terpenes could prevent radiation-induced DNA damage in mice under in-vivo conditions ^{20, 72}. Furthermore, when total triterpenes were administrated in Swiss albino mice under in vivo conditions, they were found to be very much efficient in decreasing the levels of protein oxidation and lipid peroxidation. Total triterpenes have also successfully repaired the DNA strand breaks and restored the activities of antioxidant enzymes as well as glutathione level in both liver and brain of irradiated mice ^{20, 73}. A lanostane triterpene glycoside, fomitoside-K, extracted from the fruiting bodies of Fomitopsis nigra induce apoptosis of human oral squamous cell carcinomas via the ROS-dependent mitochondrial apoptosis pathway ^{58, 74, 75}.

3.3. Anti-microbial Activities: Antibiotic resistance is one of the major obstacles in curing infections now days. Besides, strains are also getting more pathogenic as well as virulent due to some environmental factors and mutation. Thus researchers are now developing more interest in discovering novel compounds with anti-microbial properties such as anti-bacterial, anti-fungal, and anti-viral properties ¹. Secondary metabolites produced by mushrooms possess strong anti-microbial properties.

Coprinol, a cuparane-type terpenoid which has been isolated from mushroom Coprinus spp. showed remarkable anti-bacterial activity against multi-drug-resistant Gram-positive bacteria ^{58, 76}. Most of the polypore fungi exhibit strong anti-microbial activities ^{1, 77}. Clitopilus passeckerianus mushroom synthesizes a tricyclic diterpenoid, pleuromutilin, which was later identified as retapamulin antibiotic ^{58, 78, 79}.

Terpenoids nambione A-D and 1-epi-nambinone B yielded by a bioluminescent mushroom Neonothopanus nambi were reported to exhibit antitubercular activity ^{16, 58}. Antimycobacterial activity was also observed in lanostane type triterpenoids ganorbiformins A-G extracted from Ganoderma orbiforme ^{58, 80}.

Extracts of Ganoderma lucidum showed better anti-bacterial against Staphylococcus aureus and Bacillus cereus than ampicillin and streptomycin antibiotics ^{22, 81}. Some fungi such Candida albicans, Aspergillus spp., Cryptococcus neoformans, Pneumocystis carinii, Fusarium oxysporum, Botrytis cinera and few others are associated with life-threatening diseases. But for treatment of such diseases, only a few numbers of agents with anti-fungal activities are available.

An anti-fungal protein ganodermin with 15 kDa of molecular weight inhibited the growth of Fusarium oxysporum, Botrytis cinera, and Physalospora piricola ^{22, 47}. Ganoderma lucidum extract also showed activity against Trichoderma viride fungus with higher activities than that of standards, bifonazole and ketoconazole ^{22, 81}.

Viruses are found to be very disastrous for the last two decades, as very few anti-viral agents exist. Therefore it is now mandatory to discover new natural anti-viral agents. Researchers have studied and reported that there are some mushrooms that synthesize secondary metabolites with anti-viral properties. The triterpenoids like lucidiadol, applanoxidic, and ganodermadiol from Ganoderma pfeifferi and other species of Ganoderma mushrooms depicted activity against type A influenza virus under laboratory conditions. Alongside, ganodermadiol also displays anti-viral properties against type 1 herpes simplex virus ⁵⁸.

Apart from Ganoderma, other mushrooms like Trametes versicolor, Trametes gibbosa, Datronia mollis, Ischnoderma benzoinum, Lenzites betulina, Laricifomes officinalis have been recognized to generate anti-viral compounds ^{58, 82, 83}. HIV-I (human immunodeficiency virus type 1) is causative agent of AIDS (acquired immune-deficiency syndrome), the deadliest viral disease. Colossolactones extracted from Ganoderma colossum mushroom are the lanostane type triterpenes. Varients like colossolactone V and colossolactone G were identified to be effective against HIV-I ^{58, 84}. Ganoderma sinensis extracted triterpenes i.e. ganoderic acid GS-2, and gaoderiol F, 20-hydroxylucidenic acid N and 20(21)-dehydrolucideinc acid N are found to have anti-HIV protease activity ^{58, 85}.

Neuro-protective Activities: Neurodegenerative Diseases are those which result in nerve cells degeneration and/or death, which either cause ataxias or cause dementias. Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease are the most common neurodegenerative diseases.

Treatments available today can’t completely cure but can somehow hinder their progression ^{22, 86}. Thus lack of treatment forces researchers to come out with novel compounds. Polysaccharide derived from Ganoderma lucidum altered the expression of MCP-1 as well as Clq and displayed neuro-protective properties in LPS and amyloid β-induced BV2 microglia cells ^{22, 87}.

Lanostane triterpenes are promising inhibitors of acetylcholine esterase and may be regarded as better drug candidates. The triterpenoids from Ganoderma spp. such as methyl ganoderate A acetamide and n-butyl ganoderate H were reported to elicit specific acetlycholinesterase inhibitory activity. Other triterpenes like ganodermanondiol, lucidadiol were also recognized to show moderate antiacetylcholinesterase activity. Labdane diterpenes obtained from fruiting bodies of Antrodia camphorate restricted apoptosis of serum deprivation-induced PC12 cells in-vitro ^{29, 58, 88}.

Other Activities: The bioactive secondary metabolites from mushrooms have been recognized to have anti-parasitic activities. Six lanostane triterpenes from Ganoderma lucidum have been identified to possess in-vitro antiplasmodial activity ^{58, 89}. Aurisin A and aurisin K from poisonous mushroom Neonothopanus nimbi were found to be effective against Plasmodium falciparum and Mycobacterium tuberculosis ^{58, 90}. Apart from these, several mushroom secondary metabolites have been studied for their anti-parasitic activities.

One of the major health problems today is obesity, which in turn can result in various diseases such as diabetes, atherosclerosis, and hyperlipidemia. Pleurotus sajor-caju extracted β-glucan reduced obesity in obese mice consuming high-fat diet ^{4, 91}. Administration of Pleurotus florida extracts restrained weight gain in high-cholesterol diet rats, minimized fat deposition and total cholesterol level, triglycerides as well as LDL ^{4, 92}. Like this, several metabolites display anti-obesity activities.

Today, millions of people are suffering from diabetes worldwide. Diabetes is a metabolic disorder resulting due to insulin imbalances which in turn raises blood glucose levels. Polysaccharides extracted from the medicinal mushroom Phellinus badius displayed hypoglycemic activity in streptozotocin-induced diabetic mice ^{4, 93}. Compounds such as polysaccharides, triterpenoids, proteins and glycoproteins from Ganoderma lucidum acquire hypoglycemic properties ^{22, 94}.

A high ratio of total cholesterol to HDL cholesterol is a sign of cardiovascular diseases. Cardio-vascular diseases may result in a heart attack or stroke. When atherosclerosis-susceptible mice were orally administrated with 30% dried Pleurotus florida mushroom, total cholesterol level was reduced in comparison to the control mice ^{4, 95}. Angiotensin II, the potent vasopressor octapeptide, is responsible for hypertensive effects. An edible mushroom Pleurotus cornucopiae extracted ᴅ-glucopyranose mannitol inhibited angiotensin I-converting enzyme (ACE) which is responsible for conversion of angiotensin I to angiotensin II. Thus it shows hypotensive effects ^{4, 96}.

Moreover, mushroom secondary metabolites are also reported to possess anti-asthamatic, anti-mutagenic, anti-ageing as well as anti-mutagenic properties4.

CONCLUSION: Mushrooms are abundant sources of a vast variety of natural products with numerous therapeutic applications. Mushroom bioactive secondary metabolites can aid resources as well as modern therapeutics. Recently, mushrooms have emerged with lot of biologically active constituents such as polysaccharides, alkaloids, terpenes, etc. The administration of extracts containing such mushroom metabolites can help the patients to recover and people to protect them from various diseases. Though mushroom cultivation is a challenging task, mycelia can also serve as a promising source for such compounds. We hope that this review may help scientists for conducting research in edible and medicinal mushrooms.

FUTURE PROSPECTS: Unlike today’s available drugs, mushrooms and their bioactive metabolites have very limited or no side effects as they are natural compounds.

Thus they serve as a promising resource to pharmaceutical industries for drug designing with minimum toxicity. Mushrooms can be used as nutraceuticals in order to protect people from life-threatening diseases. Besides, on larger scales, genomic, proteomic as well as metabolomic studies should be carried out for significant development and advanced bioprocessing platform for industrial production of mushroom secondary metabolites.

ACKNOWLEDGEMENT: The author feels grateful to acknowledge UGC for granting National Fellowship for OBCs (NFOBC).

CONFLICTS OF INTEREST: The authors have no conflicts of interest in the present review.

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    Prajapati D, Bhatt A, Gupte S and Gupte A: Mushroom secondary metabolites: chemistry and therapeutic applications. Int J Pharm Sci & Res 2021; 12(11): 5677-89. doi: 10.13040/IJPSR.0975-8232.12(11).5677-89.

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