Antioxidant compounds from microbial sources: A review

Journal Pre-proofs Review Antioxidant compounds from microbial sources: a review Priyanka Chandra, Rakesh Kumar Sharma, Daljit Singh Arora PII: DOI: Reference:

S0963-9969(19)30735-5 https://doi.org/10.1016/j.foodres.2019.108849 FRIN 108849

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Food Research International

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8 July 2019 18 November 2019 20 November 2019

Please cite this article as: Chandra, P., Kumar Sharma, R., Singh Arora, D., Antioxidant compounds from microbial sources: a review, Food Research International (2019), doi: https://doi.org/10.1016/j.foodres. 2019.108849

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Antioxidant compounds from microbial sources: a review

Priyanka Chandra1, Rakesh Kumar Sharma2* and Daljit Singh Arora3

1 ICAR-Central Soil Salinity Research Institute, Karnal, India 2 Department of Biosciences, Manipal University Jaipur, Jaipur-303007, India 3 Microbial Technology Laboratory, Department of Microbiology, Guru Nanak Dev University, Amritsar-143005, India

*Corresponding author: R. K. Sharma E mail: [email protected] Phone: 0141-3999100 Ext No. 310, 749

Priyanka Chandra; E mail: [email protected] Daljit Singh Arora; E mail: [email protected]

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Abstract Free radicals are one or more unpaired electrons containing reactive molecules, which can damage nucleic acids, proteins, carbohydrates, and lipids, leading to several diseases including early aging, cancer and atherosclerosis. Antioxidants can scavenge these free radicals to prevent cellular damage by ultimately reducing the oxidative stress and thus have a beneficial effect on human health. Epidemiological studies have already revealed that higher intake of antioxidants as food supplements results in reduced risk of many diseases. Exploring natural antioxidants and its role in human health and nutrition is an emerging field. Several biological sources like medicinal plants, vegetables, spices and fruits have been evaluated as sources of potentially safe natural antioxidants. Beside plants, microorganisms are the potential source of novel bioactive compounds to be used in medical, agricultural, and industrial sectors. This review summarizes the potential of different microorganisms including actinomycetes, bacteria, blue green algae, fungi, lichens and mushrooms to be explored as the source of such bioactive compounds. As compared to plants, microbes can be grown under controlled conditions at a faster rate, which make them a potential source of natural bioactive molecules for food and nutraceutical applications.

Keywords: Antioxidants; actinomycetes; bacteria; fungi; lichens; microorganisms

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1. Introduction Today’s life styles with unhealthy dietary habits usually leads to the progression of various physiological threats and maladies including cardiovascular complexities, cancer, immune dysfunction, oxidative stress and early aging. Humankind for centuries depends upon plant biodiversity to cure various diseases. Recent developments in the field of nutrition during the last few decades had scientifically proved their therapeutic potentials. Eternal health, longevity, and cure for several diseases forced man to explore products from different sources including plants, animals, marine life, and microorganisms etc. Natural products are rich source of bioactive molecules and have formed the backbone of modern therapeutics. These bioactive molecules have a range of potential applications, including pharmaceuticals, dietary supplements, biofertilizers and controls for crop pests and diseases (Singh, Rateb, Rodriguez-Couto, De Lourdes Teixeira De Moraes Polizeli, & Li, 2019). Bioactive natural compounds are produced by almost all types of living beings either prokaryotes or eukaryotes including: microorganisms, plants, and animals. Various microorganisms, such as bacteria, fungi and actinomycetes are rich sources of bioactive molecules. However, a vast biodiversity remains untapped that can be exploited for the benefit of humankind (Bérdy, 2005). Aging is always associated with the stresses environment. Among several theories, the free radical theory has received particular attention regarding the aging process (Birch-Machin & Bowman, 2016). Formation and consumption of free radicals (particularly oxygen radicals) in the body are balanced by antioxidant defense systems. Various physio-pathological reasons hinder the antioxidant ability provided by the defense system, which starts accumulating reactive free radicals and may induce lipid peroxidation. This ultimately leads to oxidative stress or damage (Song & Yen, 2002). It is widely accepted that oxidative stress has its role in

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degenerative senescence. Free radicals, i.e. reactive oxygen species (ROS) are involved in the pathogenesis of a number of processes mainly including carcinogenesis, cardiovascular disease, ischemia, Alzheimer’s disease, early aging, arteriosclerosis, liver injury, inflammation, diabetes mellitus, skin damages, and arthritis (Valentão et al., 2002). On the basis of free radical theory of aging, retarding the intrinsic aging process may be achieved by the use of antioxidants or free-radical scavengers. A number of dietary antioxidants have been administered to different organisms in an attempt to increase life expectancy and very promising results have been obtained (Tiwari & Tripathi, 2007). Several synthetic antioxidants such as butylated hydro anisole (BHA), tert-butylated hydroquinone (TBHQ), and butylated hydro toluene (BHT) are generally used as food additives to prevent lipid peroxidation. However, these compounds have very limited applications for food as some toxic and carcinogenic components might be formed during their degradation (Nieva-Echevarría, Manzanos, Goicoechea, & Guillén, 2015). In view of these health concerns, finding safer, effective and economic natural antioxidants are highly desirable. The microbes are of great biotechnological interest in the fermentative processes as they are the efficient producers of secondary metabolites. Microbes produce a diverse group of secondary metabolites, which have an incredible impact on society and exploited frequently for their different pharmaceutical accomplishments (Singh et al., 2019). Plant secondary metabolites and other plant-derived compounds possess well known antioxidant potential, while enormous microbial diversity still need to be explored to develop novel compounds. Microbes have an advantage over plants, as industrial production and downstream processing of bioactive secondary metabolites are relatively easier. 2. Concept of free radicals and antioxidants 4

Free radical could be any atom or molecule (e.g. oxygen, nitrogen) with at least one unpaired electron in the outermost shell, which may exist independently. A free radical is formed when a covalent bond between two entities is destroyed and one electron remains with each newly formed atom. Free radicals are extremely reactive due to the presence of unpaired electron(s). Two types of free radicals; reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generally involved in human physiology (Bhattacharya, 2015). Free radicals present an inconsistency in their biological functions: as they prevent diseases by supporting the immune system, facilitating cell signaling and playing a crucial role in apoptosis. On the other hand, they can damage vital macromolecules in cells and involve in aging process, carcinogenesis and cardiovascular diseases (Birch-Machin & Bowman, 2016). Antioxidants may potentially slow down or prevent the oxidation of other molecules. In oxidation reaction, an electron is transferred from a substance to the oxidizing agent. Thus, oxidation reaction can generate free radicals, which start chain reactions to damage the cells. Antioxidants terminate these chain reactions by eliminating or stabilizing free radicals, and obstruct other oxidation reactions by self-oxidation (Valentão et al., 2002). Antioxidant systems exist in the cells to protect them against ROS. Cellular aqueous compartments like cytosol or extracellular fluids consist of low molecular weight antioxidants e.g. glutathione and ascorbate (vitamin C) along with some antioxidant enzymes namely: superoxide dismutases (SOD), catalases and peroxidases to prevent the oxidative cell damage (Pisoschi & Pop, 2015). Different antioxidant compounds demonstrate different free radicals scavenging activity. O–H group present in phenolic compounds were more active than the N–H group containing compounds due to the lower bond dissociation energies. The antioxidant activity can be positively correlated with the number of active group (OH or NH2). Position of these functional 5

groups also plays an important role as ortho position was more active one, due to its ability to form intramolecular hydrogen bonding, followed by para position and then meta position (Bendary, Francis, Ali, Sarwat, & El Hady, 2013). Figure 1 represents the possible reactions between available hydroxyl and methyl groups in 3’’-Dihydroxyterphenyllin and 3Hydroxyterphenyllin with free radical (ROO.). 3. Antioxidants from natural sources Antioxidants are used in dietary supplements to maintain good health and prevention from deadly diseases. As synthetic antioxidants exhibit carcinogenic and toxic nature, researchers encouraged to look for natural antioxidants, which already have led to the identification of vitamins A, C, and E as antioxidants (Yang et al., 2018). Epidemiological studies have revealed that intake of fresh vegetables, fruits, tea and wines are good source of natural antioxidants and are closely associated with lower risk of heart related diseases (Aguilera, Martin-Cabrejas, & González de Mejia, 2016). This is one of the elementary reasons for the keen interest in natural antioxidants and their potential role in human health and nutrition. Dietary antioxidants include numerous phytochemicals such as vitamin C, vitamin E, α- tocopherol, β-carotene and several phenolic compounds (Faustino et al., 2019). The antioxidant activity of these phytochemicals vary from slight to extremely high depending upon their reactive groups. Vitamin C has higher number of reactive hydroxyl groups as compared to vitamin E or vitamin A, while β-carotene has other functional groups responsible for it. The natural antioxidants from plants and mushrooms have been documented to play significant roles in promotive health along with the treatment of various diseases. Several plants (medicinal plants, spices, vegetables, fruits) and mushrooms have been well documented as a source of potentially safer natural antioxidants. Various compounds have been isolated and a lot of them are phenolic in nature, which are effective 6

hydrogen donors and capable to inactivate lipid peroxidation, inhibit decomposition of hydro peroxides into free radicals as well as chelate metal ions (Shahidi & Ambigaipalan, 2015). Phenolics obtained from natural sources are better source for antioxidants than hazardous synthetic chemicals. Microbial fermentation has the potential for production of such compounds. Several fungal strains produces gallic acid, ferulic acid and ellagic acid under submerged and solid state fermentation conditions (Dey et al., 2016). All these organic acids have two to four reactive hydroxyl groups available, which can be correlated with their antioxidant potential. Some compounds like zeaxanthin and astaxanthin have a long chain structure containing reactive hydroxyl groups. These molecules have also been produced and isolated from various microbial sources and scavenged free radicals, thus demonstrated significant antioxidant effect (Zhang, Liu, Sun, Xue, & Mao, 2018). 4. Antioxidants from microbes Microbial diversity creates a vast pool of novel chemicals, providing a valuable source for innovative biotechnology. There are over 23,000 known microbial secondary metabolites, 42 % of which are solely produced by actinomycetes, while almost similar amount (42 %) is produced by fungi, and remaining 16 % by eubacteria. Microbial metabolites have already become are the significant sources for life saving drugs, mainly including bacterial and fungal infections (amphotericin, erythromycins, penicillins, streptomycin, tetracyclines, and vancomycin), Cancer (bleomycin, doxorubicins, daunorubicin and mitomycin), transplant rejection (cyclosporine and rapamycin) and high cholesterol (lovastatin and mevastatin) (Demain, 2014). Some of these primary and secondary metabolites also possess specific antioxidant potential. 4.1. Actinomycetes

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Actinomyctes efficiently produce a variety of bioactive molecules including antioxidants. In a screening program for searching antioxidants from actinomycetes, numerous compounds were isolated (Kawahara et al., 2012). Antioxidants compounds from various microorganisms were summarized in Table 1. Metabolites primarily including benthocyanins A, B, C, and benthophoenin were isolated from Streptomyces prunicolor demonstrated good antioxidant potential when employing rat liver microsomes as a test system. Carazostatin and carbazomycin B isolated form actinomycetes demonstrated better antioxidant activity than synthetic compounds (Kato, Kawasaki, Urata, & Mochizuki, 1993). Both of these compounds have reactive N-H and O-H groups, which might be responsible for their significantly high activity. On the other hand, Streptomyces exfoliates produced Carquinostatin A, which possess N-H and O-H reactive groups and demonstrated brain-protecting activity. It also demonstrated antioxidant activity in rat liver microsomes, which was comparable to vitamin E. In the primarily cultured hippocampal neuron system, it successfully repressed the glutamate toxicity (Shin-Ya et al., 2012).

Streptomyces

sp.

produced

different

antioxidant

isoflavonoids.

4',

7,

8-

trihydroxyisoflavone. Beside their antioxidant activity, these compound have also demonstrated antitumor activity (Komiyama et al., 1989). Extract from Streptomyces LK-3 (JF710608) possessed antioxidant activity, which contains daidzein- 8-C-glucoside (puerarin), (-) gallocatechin gallate, sesamol, cyanidin-3-O-rutinoside and delphinidinas major components (Karthik, Kumar, & Rao, 2013). Terpenoids, naphterpins B and C, and two congeners of naphterpin isolated from Streptomyces sp. possessed antioxidant activity. Available diverse reactive functional groups present in these molecules are the reason for their antioxidant activity. These terpenoids are unsaturated molecules composed of linked isoprene units (Kato et al., 2012). Nitrogen containing metabolites

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like carbazole and phenazinehetero cycles have demonstrated antioxidant activity, which also possess N-H groups. Beside, a few common metabolites such as 5-hydroxymaitol from Streptomyces melanogenes, the napthoquinonic derivatives including naphtherin and 7-demethyl naphtherpin have also been isolated from S. aeriouvifer and S. violaceus, respectively. These metabolites repressed lipid peroxidation in rat liver microsome with IC50 values almost comparable to vitamin E (Komiyama et al., 1989). On the other hand, Stealthins A and B, isolated from S. viridochromogenes, had much stronger activity (upto 30 times) than vitamin E. Stealthins contains O-H, N-H and C=O groups, which might be responsible for its high activity as compared to vitamin E. Carazostatin produced by S. chromofuscus was much efficient than the brain protective agents flunarizine and BHT. Neocarazostatins A to C has been purified from the mycelium of Streptomyces spp. also demonstrated antioxidant activity (Kekuda, Shobha and Onkarappa, 2010). Overall, Carbazole compounds ascertained to be a major class of antioxidant produced by Streptomyces spp. These results point towards the novel antioxidants isolated might be advantageous as a new class of therapeutic agents. Phenazine derivatives constitute another exclusive group of antioxidant produced by Streptomycetes spp. and all the compounds possessed efficient antioxidant activity. Several other compounds including antiostatins A1 to A4 and B1 to B4 isolated from S. cyaneus, while, carbazoquinocins A to F, a series of carbazole containing an o-quinone was extracted from S. violaceus. Two prenylated analogues and benthophoenin have also been extracted from S. exfoliates and S. prunicolor, respectively (Komiyama et al., 1989). Benthocyanins A,B,C produced by S. prunicolor, which hindered lipid peroxidation better than vitamin E (Shin-ya, Furihata, Teshima, Hayakawa, & Seto, 1993). All these molecules possessed at least one additional functional group beside hydroxyl group, which could react with the free radicals. 9

Phenazoviridin produced by Streptomyces sp. and is the first glycosylated phenazine derivative to act as a strong inhibitor of lipid peroxidation. It demonstrated a higher protective activity than indeloxazine against KCN-induced acute hypoxia in mice. Further, nitrogen containing antioxidants including thiazostatins A and B produced by S. tolurosus (Shindo et al., 2012) and benzastatins A to D was produced in the culture broth of S. nitrosporeus, which possessed either a rare p-aminobenzamide unit or a tetrahydroquinolone ring. Benzastatins molecule has one hydroxyl and N-H group, and its derivatives have methoxy group. As a result, it demonstrated a weaker activity against lipid peroxidation in rat liver microsomes as compared to vitamin E, while the activity of benzastatins C and D was similar in preventing glutamate toxicity in neuroblastoma X-retina hybrid cell line N 18-RE-105, which suggested it to be effective against brain ischemia injury. Antioxidant molecule 1,3-Dicarbonyl isolated from Streptomycetes exhibited almost similar activity to that of ascorbic acid by the Rhadon-iron method (Takagi et al., 2005). Actinomycetes have been isolated from diverse habitats also possessed antioxidant activity. Streptomyces lydicus A2 (Lertcanawanichakul, Pondet, & Kwantep, 2015), Streptomyces spp. SRDP-H03 (Rakeshet al., 2016) and BI244 also exhibited antioxidant activity as assayed by DPPH (Kiruthika, Durairaju Nisshanthini, & Angayarkanni, 2013). These fungi were isolated from soil and coastal region, respectively. Streptomyces misionensis isolated from mountain forest soil, showed strong antioxidant capacity on nitric oxide, DPPH and hydrogen peroxide free radicals (Lee et al., 2014). Nocardiopsis alba isolated from the mangrove soil demonstrated the ability to produce antioxidants compounds like (Z)-1-((1-hydroxypenta-2,4-dien-1-yl)oxy) anthracene-9,10-dione (Janardhan, Kumar, Viswanath, Saigopal, & Narasimha, 2014). On the other hand, there are a few reports available on antioxidant potential of marine actinobacteria. A

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Marine isolate Streptomyces sp VITTK3 possessed significantly high DPPH free radical scavenging activity (96%) at 5 mg/mL (Thenmozhi, Sindhura, & Kannabiran, 2010). Similarly, 5-(2, 4-dimethylbenzyl) pyrrolidin-2-one (DMBPO) isolated from marine Streptomyces sp. demonstrated 59.32% DPPH scavenging activity and it also exhibited cytotoxic to cancer cells. It showed fewer chromosomal aberrations as compared to control (Saurav & Kannabiran, 2012). Two phenolic compounds JBIR-94 and JBIR-125 isolated from Streptomyces sp, demonstrated DPPH scavenging activity with an IC50 value of 11.4 M and 35.1 M, respectively (Kawahara et al., 2012). Both of these phenolic compounds possessed reactive hydroxyl and N-H group as a potent free radical scavenger. 4.2. Bacteria Eubacteria involve prokaryotic microbes and almost all of them possess the ability to produce a variety of extracellular metabolites. Bacteria are closely associated with all of the life forms let it be human, animal or plants. Probiotic food contains millions of bacteria, which is an integral part of human diet. The bacteria present in probiotics may colonize gastrointestinal tract and produce exopolysaccharides (EPS), which possess significant antioxidant activity (Rahbar Saadat, Yari Khosroushahi, & Pourghassem Gargari, 2019). Lactic acid bacteria Lactobacillus paracasei subsp. paracasei and Lactobacillus plantarum produced sufficient EPS, which demonstrated significant antioxidant properties (DPPH free radical scavenging activity, chelation of ferrous ions, inhibition of linoleic acid peroxidation, and reducing power) along with the in vitro immunomodulation. Three different probiotic bacteria viz. Lactobacillus casei, Lactobacillus acidophilus and Lactococcus lactis in fermented milk have confirmed their antioxidant potential and cholesterol assimilation activities both, in-vitro and in-vivo. All these strains showed potent DPPH, malonaldialdehyde and H2O2 radical scavenging abilities along with the inhibition of

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linoleic acid peroxidation activity. Additionally, Lactobacillus casei exhibited maximum Trolox equivalents (48.7 mM) closely followed by Lactobacillus acidophilus (46.3 mM) and Lactococcus lactis (23.4 mM) (Jain, Yadav, & Ravindra Sinha, 2009). Lin and Chang, also reported that both intact and intracellular cell free extracts of intestinal lactic acid bacteria i.e. Bifidobacterium longum and Lactobacillus acidophilus demonstrated strong antioxidant activity by preventing linoleic acid peroxidation (Lin & Chang, 2000). Osuntoki isolated eight Lactobacillus strains from five indigenous Nigerian fermented foods (baba, kunnu,ogi, ugba and wara). Preliminary screening confirmed the antioxidant activity of the whey fraction of skimmed milk fermented for 24 h with the isolates. DPPH free radical scavenging activity for these isolates ranged from 2.8 to 31.5 %. The five selected organisms among them, L. casei, L. brevis, L. plantarum and L. fermentum, L. delbrueckii demonstrated significant increase in DPPH radical scavenging activity and inhibition of lipid peroxidation during 24-hour fermentation period (Osuntoki & Korie, 2010). It was observed that EPS, either cell-bound as produced by Lactobacillus fermentum (Wang et al., 2019) or exogenous from Lactobacillus plantarum (Min et al., 2019) are homogeneous hetero polysaccharide in nature, which contains different sugars e.g. arabinose, rhamnose, xylose, mannose, fructose, galactose, and glucose. Chemical composition and structure of these EPS have shown the presence of different functional groups mainly including reactive hydroxyl, aldehyde and ketone groups. These functional groups may efficiently react with free radicals. Some probiotic bacteria including Bifidobacterium spp. Leuconostoc spp., Lactobacillus spp. Lactococcus spp., Kluyveromyces spp. along with yeast Saccharomyces were evaluated for their antioxidant potential (Virtanen, Pihlanto, Akkanen, & Korhonen, 2007). All the tested strains exhibited radical scavenging activity with the inhibition rate ranging from 3–53%. Among 12

different strains, Leuconostoc and Lactobacillus acidophilus exhibited inhibition rate ranging from 42–53%. Lactobacillus lactis strains, Lactobacillus casei and one kefir strain showed rather low inhibition rate (3–10%). The inhibition rate among Lactobacillus strains varied from 12 to 42%, while among Lactococcus strains, varied from 3% to 22%. The inhibition of lipid peroxidation significantly improved during fermentation with some of the isolated strains. The fermented milk showed an inhibition rate of about 90 % and in whey parts, it ranged from 20 to 24 % as assayed by ABTS. It also indicated that EPS and other metabolites are generally produced during fermentation, which may be the reason for enhanced antioxidant activity beside organic acids. Daily oral dose of Lactobacillus casei (2.8 x 1010 CFU/rat)

upto 8 days

significantly reduced oxidative stress and liver lesions induced by a single intraperitoneal administration of carbon tetrachloride (Liu et al., 2011). Similarly, intracellular metabolites obtained from Lactobacillus casei demonstrated the ability to combat aflatoxin B1 induced oxidative stress in rats (Aguilar-Toalá et al., 2019). Resorstatin, an alkyl resorcinol-type compound, containing two reactive hydroxyl groups was produced by the gram negative bacterium Pseudomonas, which exhibited anti-lipoperoxidative activity almost similar to BHT. Xanthin produced by this bacteria also inhibited the oxidation of linoleic acid, which was synergist to tocopherol (Kato et al., 2012). Bifurcaria bifurcate (marine brown alga) associated epiphytic bacteria were isolated; almost half of this microbial community consists of Vibrio sp. (48.72%). Alteromonas sp. (12.82%) and Shewanella sp. (12.26%) were the other major part of this community, and almost similar content (2.5%) of the other identified bacteria

included:

Serratia sp.,

Citricoccus sp.,

Cellulophaga sp.,

Ruegeria sp.

and

Staphylococcus sp. Solvent extracts (methanol and dichloromethane) of these bacteria demonstrated their potential as excellent sources of natural antioxidant as estimated by DPPH

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radical scavenging activity, oxygen radical absorbance capacity (ORAC), and quantification of total phenolic content (TPC) (Horta et al., 2014). Simlarly, endophytic bacterial community (Pseudomonas hibiscicola, Macrococcus caseolyticus, Enterobacter ludwigii, Bacillus anthracis) isolated from A. vera were also reported to produce bioactive molecules with high DPPH scavenging (75-88%) properties. These antioxidants may help the plants to grow under stress conditions (Akinsanya, Goh, Lim, & Ting, 2015). 4.3. Blue green algae Blue green algae or cyanobacteria are mainly photosynthetic eubacteria. This group of microbes produces a significant amount of carotenoids, namely β-carotene, lycopene and lutein. These carotenoids are efficient in quenching action on ROS, thus, carry intrinsic antioxidant and antiinflammatory properties. Blue green algae also have high phycocynanin like pigment content which can be to 15% of dry weight. C-phycocyanin is a free radical scavenger and has important hepatoprotective effect. Phycocyanin was reported to inhibit inflammation in mouse ears and prevent acetic acid induced colitis in rats. This was accredited to the lower production of leukotriene B4, an inflammatory metabolite of arachidonic acid (Romay et al., 1998). Phycocyanin are water soluble compounds having N-H reactive groups as free radical scavengers. Another carotenoid pigment, astaxanthin has essential metabolic functions such as protection against oxidation and UV radiations, vision, immune response, pigmentation, reproduction and development. The ability of astaxanthin to quench singlet oxygen and scavenge free radicals has been established by a number of in vitro studies, which is about ten times more powerful than other carotenoids and several times than vitamin E (Dose et al., 2016). The ubiquitous microalga, Haematococcus pluvialis contains the highest level of astaxanthin in nature, which may be used

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for different applications (Naguib, 2000). Phenolic compounds quinic acid and catechin produced by Nostoc, Anabaena, and Arthrospira. These phenolic compounds also possess highly reactive hydroxyl groups, which might be responsible for their high antioxidant activity (Blagojević et al., 2018). Phycobili proteins produced by cyanobacteria have been described as potential antioxidant compounds and considered as high-valued natural products for several biotechnological applications. It has different reactive functional groups i.e. N-H, COOH, C-O and O-H to neutralize ROS. Production of phycobiliproteins from cyanobacteria requires well optimized medium and bioprocesss that affects the bacterial growth and phycobili protein accumulation. Extraction and purification of phycobili proteins may lead to enhanced recovery for its further industrial applications (Pagels, Guedes, Amaro, Kijjoa, & Vasconcelos, 2019). 4.4. Lichens Lichens are symbiotic associations between fungi and algae. These organisms produced various unique extracellular secondary metabolites as a result of this association. Several of these molecules were exclusively present in lichens and may be used as potential sources of natural antioxidants (Ranković & Kosanić, 2015). However, not much literature concerning the antioxidative nature of lichens is available. In vitro antioxidant activity of aqueous extracts of C. islandica was first reported by Gülçin (Gülçin, Oktay, Küfrevioǧlu, & Aslan, 2002). The antioxidant activity of this organism was significantly higher than α-tocopherol. Similar results were also reported for the different extracts from lichen Usnea ghattensis (Behera, Verma, Sonone, & Makhija, 2005). Methanolic extracts of Parmelia saxatilis, Platismatia glauca, Ramalina pollinaria, Ramalina polymorpha and Umbilicaria nylanderiana possessed significantly high free radical scavenging activity and preventive role in 15

linoleic acid oxidation (Gulluce et al., 2006). Different extracts (acetone, methanol and aqueous) of the lichens Cetraria islandica, Lecanora atra, Parmelia pertusa, Pseudoevernia furfuraceae and Umbilicaria cylindrical showed a good antioxidant potential as assayed by three different methods including: DPPH scavenging activity, superoxide anion radical scavenging activity and reducing power. The extracts demonstrated DPPH radical scavenging activity ranging from 3295%, while reducing power varied from 0.016 to 0.109. The superoxide anion scavenging activity for different extracts varied from 7 – 84%. High contents of total phenolics (12-76.42 μg of pyrocatechol equivalent) and total flavonoids (1.37-54.77 μg of rutin equivalent) indicated that phenols and flavonoids might be the key antioxidant compounds in these extracts (Kosanić & Rankoví, 2011). Kekuda reported the positive antioxidant activity from the Parmotrema pseudotinctorum and Ramalina hossei extracts (Kekuda et al., 2009). Beside antioxidant potential, Anaptychya ciliaris, Nephroma parile, Ochrolechia tartarea and Parmelia centrifuga also possessed antimicrobial properties (Ranković, Ranković, Kosanić, & Marić, 2010). Lichen species including Stereocaulon alpinum, Ramalina terebrata, Caloplaca sp., Lecanora sp. and Caloplaca regalis isolated from King George Island (Antarctica) also exhibited antioxidant potential (Bhattarai, Paudel, Hong, Lee, & Yim, 2008). This diversity in lichens holds the promising potential for the production of novel bioactive molecules having significant antioxidant activity thus, might be a natural source of antioxidants. Praesorediosic acid, protocetraric acid, usnic acid, α–collatolic acid, β- alectoronic acid, atranorin and chloroatranorin were purified from acetone and methanol extracts of lichens namely: Parmotrema praesorediosum, P. rampoddense, P. tinctorum and P. reticulatum. All these compounds are phenolic in nature having more than one reactive functional group, which mainly includes hydroxyls. Chloroatranorin contains chlorine in addition to O-H and C-O. These

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isolated compounds possessed high antioxidant potential as assayed by DPPH method (Rajan et al., 2016). Solvent extracts of Ramalina roesleri were assayed for DPPH free radical scavenging activity, which ranged from 30 to 88%. A nonpolar solvent extraction of the lichens using hexane revealed the presence of atranorin, protolichesterinic acid, usnic acid, 2-hydroxy-4methoxy-6-propyl benzoic acid, homosekikaic acid, sekikaic acid, benzoic acid, 2,4-dihydroxy6-propyl and 2,4-dihydroxy-3,6-dimethyl benzoate. Among these compounds, sekikaic acid demonstrated maximum DPPH radical scavenging activity followed by homosekikaic acid. Potent antioxidant compounds viz. orcinol, orsellinic acid, methyl orsellinate, methyl haematommate, methyl-orcinolcarboxylate, montagnetol, p-depsides namely atranorin, lecanoric acid, divericatic acid, erythrin, m-depsidesekikiac acid, depsidonelobaric acid, ubiquitous dibenzofuran (þ)-usnic acid and triterpenoid, zeorin were isolated from P. grayana, Cladonia sp., H. obscurata and R. montagnei (Sisodia, Geol, Verma, Rani, & Dureja, 2013). Pleurosticta acetabulum demonstrated DPPH radicals scavenging activity (IC50 151 µg/ml).

Majorly

salazinic, norstictic, protocetraric, evernic acid and atranorin were identified as active compounds of this lichen. These compounds also possessed antimicrobial and anticancer activities along with the antioxidant property (Tomović et al., 2017). These compounds generally have more than one reactive functional group, and their antioxidant potential also depends upon the position of these groups. 4.5. Fungi Fungi have contributed to mankind's wellbeing since the beginning of civilization. The fungal kingdom has a rich biodiversity consists of about 1.5 million species. It includes multicellular molds, mushrooms and unicellular yeasts. Fungi are renowned as both beneficial and harmful in their relationship to humans although they are predominantly beneficial. Fungi are responsible

17

for a major portion of food deterioration; however, the preservative effects, fermentation of foods and beverages are well-known along with the production of organic acids, alcohol, antibiotics, pigments, vitamins, growth regulators, immunomodulating agents, and enzymes (Azizan, Zamani, Stahmann, & Ng, 2016). Diverse groups of fungi may possibly provide a wide range of primary and secondary metabolites such as alkaloids, benzoquinones, flavanoids, organic acids, phenols, steroids, terpenoides, tetralones, xanthones etc. (Bhanja Dey et al., 2016). These metabolites possess numerous biological activities including antioxidant and their function is primarily governed by the molecular structure. This group of microbes is well exploited in medicine industry and considered as potential and constant sources of novel therapeutic agents because of their distinctive features. Natural antioxidants are used to support the endogenous protective system, increasing interest in the antioxidative role of nutraceutical products. Various kinds of edible mushrooms are consumed as an imperative part of human diets around the globe. Mushrooms and filamentous fungi are widely cultivated in Asia, where the medicinal properties of mushrooms are highly valued. Mushrooms are the attractive functional food as they have been used as food and food-flavouring material in soups and sauces for centuries, due to their unique and subtle flavour and ultimately being source for the development nutraceuticals (Gursoy, Sarikurkcu, Cengiz, & Solak, 2009). High protein, carbohydrate and fiber content with low fat is frequently mentioned in the literature to emphasis their nutritional value. The mushrooms have significantly high levels of some vitamins, namely thiamine, riboflavin, ascorbic acid and vitamin D2, as well as some minerals along with the antioxidant activity (Sánchez, 2017). Medicinal value of mushrooms includes antioxidant, antitumor, antibacterial, antiviral and haematological and in immunomodulating properties. Most of the mushroom

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species contain various antioxidant compounds, e.g. alkaloids, organic acids, phenolics, polyketides, steroids and terpenes. Antioxidant potential of different fungi is summarized in Table 2. Antrodia camphorata possessed antioxidant potential along with other biological activities (Song & Yen, 2002). The fruiting body of Inonotus obliquus, a medicinal mushroom called chaga, has been used as a traditional medicine for cancer treatment. This mushroom is also recognized to produce effective antioxidant inonoblins A, B, C and phelligridins D, E, G, which demonstrated high scavenging activity against ABTS and DPPH, and moderate activity against the superoxide radical anion (Lee et al., 2007). Chemical structure of these compounds revealed that the possible mechanisms for free radical scavenging activity might be due to presence of a number hydroxyl groups associated with a phenolic backbone. Seven different species of mushrooms including Cantharellus cibarius, Hypholoma fasciculare, Lepista nuda, Lycoperdon molle, Lycoperdon perlatum, Ramaria botrytis, and Tricholoma acerbum were evaluated for their antioxidant potential. Four different methodologies for antioxidant capacity determination showed that beside synthesizing natural compounds closely associated to nutrition, such as ascorbic acid, carotenoids, phenolics and tocopherols, they demonstrated a broad antioxidant spectrum and antimicrobial property (Barros et al., 2007). Fistulina hepatica, an edible fungus exhibited DPPH and superoxide radical inhibition. Phenolic compounds (caffeic, p-coumaric, ellagic acids, hyperoside and quercetin) and organic acids (oxalic, aconitic, citric, malic, ascorbic and fumaric acids) were the major metabolites produced and responsible for their antioxidant activity (Ribeiro, Valentão, Baptista, Seabra, & Andrade, 2007). Similarly, about 18 Portuguese wild mushrooms showed radical-scavenging capacity, reducing power and inhibition of lipid peroxidation (Heleno, Barros, Sousa, Martins, & Ferreira,

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2010). Mushrooms including Ganoderma lucidum, Phellinus rimosus, Pleurotus florida and Pleurotus pulmonaris reported for their profound antioxidant and antitumor properties (Ajith & Janardhanan, 2007). Yen and Wu, reported the antioxidant and radical scavenging properties of extracts obtained from Ganoderma tsugae (Yen & Wu, 1999). Boletus mushrooms produced water-soluble polysaccharides consists mainly arabinose, xylose, mannose, glucose and galactose and a pyranose ring. Structure-function relationships revealed that the antioxidant activity of these polysaccharides was significantly correlated with their monosaccharide composition, molecular weight and anomeric configuration (Zhang et al., 2018). Numerous mushrooms e. g. button mushroom (Agaricus bisporus), shiitake (Lentinus edodes), straw (Volvariella volvacea), oyster (Pleurotus cystidiosus), winter (Flammulina velutipes), ear (Auricularia sp. and Tremella sp.), tree oyster (P. ostreatus), Agrocybe aegerita (Lo & Cheung, 2005), Dictyophora indusiata, Ganoderma lucidum, Grifola frondosa, Hericium erinaceus, Tricholoma giganteum) (Wachtel-Galor, Tomlinson, & Benzie, 2004), Boletus edulis, Lactarius deterrimus, Suillus collitinus, Xerocomus chrysenteron) (Sarikurkcu, Tepe, & Yamac, 2008) have shown antioxidant and antitumoral activities. Lactarius deterrimus and Boletus edulis demonstrated better antioxidant potential against β-carotene/linoleic acid and DPPH systems among different edible mushrooms collected from Eskisehir, Turkey (Sarikurkcu et al., 2008). The antioxidant potentials of seven Morchella spp. (M. rotunda, M. crassipes, M. esculenta, M. deliciosa, M. elata, M. conica and M. angusticeps) was proved by evaluating these fungi using five different antioxidant assay methods (DPPH and ABTS scavenging effect, β-carotene/linoleic acid, reducing power and chelating effect) (Gursoy et al., 2009). In addition, Elmastas reported that the extracts of Morchella vulgaris and Morchella esculenta scavenged up to 95% of DPPH radicals (Elmastas et al., 2006). These results give an idea that mushrooms are considerable food

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choice for their high nutritional value, as a source of essential fatty acids, minerals, proteins and several biologically active metabolites. On the other hand, filamentous fungi belonging to different phylum are typically not associated with human diet but have also been reported to produce some valuable metabolites having biological activity including antioxidants. The mainstream of the citric acid producers mainly include the fermentation by known strains of Aspergillus niger, which is furthermore a good source of ascorbic acid. Other active and functional medicinal products include lipases, poly and oligosaccharides, dietary fibers, triterpenoids, peptides, proteins, alcohols, phenols, minerals and vitamins along with the food additives like emulsifiers, stabilizers and flavors. Such widespread applications of fungi and their components constantly motivates the scientific community to scrutinize the fungal world for new and better sources of nutrients, nutraceuticals and food additives (Tapal & Tiku, 2019). Chaetomium sp., Cladosporium sp., Torula sp., and Phoma sp. produce several phenolic acid derivatives, which majorly include terpenoids, benzoic acid, rutin as secondary metabolites. Beside antioxidant activity, chlorogenic acid, phenolic acid derivatives and rutin also have a wide range of biological activities such as antibacterial, antiviral, antimutagenic and immunomodulatory (Huang, Cai, Hyde, Corke, & Sun, 2007). Gebhardt reported the antioxidant and anti-inflammatory activity of quercinol isolated from the mycelial biomass of Daedalea quercina (Gebhardt et al., 2007). Various filamentous fungi namely Penicillium spp., Eurotium spp., Aspergillus spp., Mortierella spp., Colletotrichum spp. (Femenía-Ríos, García-Pajón, Hernández-Galán, Macías-Sánchez, & Collado, 2006)., Cladosporium sp., Torula sp., Phoma sp. (Huang et al., 2007) are recognized to produce a number of metabolites possessing antioxidant activity. These fungal metabolites demonstrated stronger free radical scavenging activity as

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compared to synthetic antioxidants and phytochemicals (Ishikawa, Morimoto, & Hamasaki, 1984). Phenolic glycoside isolated from Mycelia sterilia demonstrated higher antioxidant potential as compared to BHA (Moon et al., 2006). Phenolic and hydroxyl groups present in phenolic glycoside play key role towards their free radical scavenging activity. Similarly, tetrahydroxylated compound isolated as a peracteylated derivative from the culture broth of Colletotrichum gloesosporioides also demonstrated comparable antioxidant activity to BHT, caffeic acid and protocatecheic acid (Femenía-Ríos et al., 2006). Fungus Pestalotiopsis microspora produced 1, 3-dihydroisofuran, pestacin and isopestacin, which exhibited antifungal and antioxidant activity even more than 10 times as compared to vitamin E. Isopestacin believed to possess its antioxidant activity based on its structural similarity to the flavonoids. Electron spin resonance spectroscopy measurements confirmed these believe and the compound was able to scavenge superoxide and hydroxyl free radicals in solution. Pestacin was documented as naturally occurring racemic mixture with potent antioxidant activity. Harper proposed the mechanisms involved in antioxidant activity of pestacin arose primarily mediated by the cleavage of an unusually reactive COH bond and secondly though OOH abstraction (Harper et al., 2003). Graphislactone produced by Cephalosporium sp. and Microsphaeropsis olivacea demonstrated significant antioxidant effect (Gunatilaka, 2006). Aspergillus candidus produced 3, 3’’Dihydroxyterphenyllin, 3-hydroxyterphenyllin and candidusin B, and both of these compounds exhibited antioxidant activity. As observed, the presence of a number of phenolic hydroxyl groups was responsible for their activity. 3, 3’’-dihydroxyterphenyllin showed considerably higher activity than BHA and α tocopherol, while 3-hydroxyterphenyllin demonstrated a significant scavenging effects on DPPH radicals. These effects were almost similar to the activity

22

of BHA and α tocopherol. All of these three compounds were neither cytotoxic nor genotoxic as tested against human intestine 407 cells and also did not show any mutagenic behavior on Salmonella typhimurium TA98 and TA100 (Yen & Chang, 2016; Yen, Chang, Sheu, & Chiang, 2001). A phenolic compound flavoglaucin isolated from mycelium of Eurotium chevalieriis an excellent antioxidant and synergist for tocopherol. It was reported to stabilize many edible oils and fats, as the addition of flavoglaucin (0.05 %) helped in retaining the original stabilities of vegetable oil even after harsh thermal treatment at 180oC. Flavoglaucin also could not induce the mutagenicity in Salmonella typhimurium TA 100 and TA 98(Ishikawa et al., 1984). Lignans are phenolic alcohols having reactive hydroxyl group. Trametes hirsute produced the lignans, which exhibit potent antioxidant, anticancer, and radio protective properties (Puri et al., 2006). Aromatic polyketide isolated from Aspergillus versicolor and its various activities pertaining to antioxidant potential i.e. radical scavenging activity, reducing power, and inhibitory activity to lipid oxidation were compared with the standard antioxidants such as BHA, BHT, TBHQ, and ascorbic acid. Polyketide showed antioxidant activity almost similar to BHA, while significantly higher than BHT (Lee et al., 2010). Polyketide contains carbonyl and methylene groups along with the hydroxyl and N-H, which are the key factors for their mechanisms as radical scavenging activity. About 120 fungal isolates from soil of different zones of Punjab, India were screened for their antioxidant potential using dot blot assay. Out of 120 fungal isolates, 51 demonstrated positive antioxidant activity and these were further assayed quantitatively (Chandra & Arora, 2017). Antioxidant activity of some soil fungi viz. Aspergillus fumigatus, Aspergillus terreus, Aspergillus wentii, Penicillium citrinum, Penicillium expansum and Penicillium granulatum was

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also reported and optimization of their antioxidant potential was also carried out (Arora & Chandra, 2011; Chandra & Arora, 2012). Wood degrading fungi Phanerochaete chrysosporium, Daedalea flavida, Ceriporiopsis subvermispora, Phlebia brevispora, Phlebia fascicularia, Phlebia floridensis and Phlebia radiata have also demonstrated antioxidant activity (Sharma, Chandra, & Arora, 2010). Beside biosynthesis of antioxidants, the wood degrading fungi could depolymerize the lignin polymer present in agricultural biomass to produce different phenolic compounds, which ultimately enhanced the antioxidant potential of degraded straw for its possible use as animal feed (Arora, Sharma, & Chandra, 2011). Carotenes pigments are used as coloring agent and strong antioxidants in food. Microbes accumulate several types of carotenoids in response to different environmental stresses. Some pigment producers, e.g. Rhodotorula sp., have been taxonomically classified based on qualitative and quantitative evaluations of their carotenoids biosynthesis (Bhosale, 2004). Carotenoid production has been described in some fungal classes: zygomycetes (Phycomyces blakesleeanus), ascomycetes (Neurospora crassa and Gibberella fujikuroi), and basidiomycetes Xanthophyllomyces dendrorhous) (Hoffmeister & Keller, 2007). Kojic acid, a secondary metabolite produced by Aspergillus and Penicillium. This molecule hinders tyrosinase activity and is used as a food additive, a skin-whitening agent for the treatment of melasma, antioxidant, antitumour agent and radio-protective agent. In vitro antiproliferation and cytotoxic properties of kojic acid derivatives have also been described (Kono et al., 2012). Rhizopus and Aspergillus spp. have been grown in fruit and agro residues (solid state fermentation) targeting to enhance the concentration of free phenol compounds with antioxidant activity, since these compounds are frequently found in conjugate forms having a sugar or lipidic moiety (Correia, McCue, Magalhães, Macêdo, & Shetty, 2004).

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Sclerotiorin, a chlorine containing pigment produced by Penicillium sclerotiorum and Penicillium frequentans acted as a potent reversible, uncompetitive inhibitor against soybean lipoxygenase-1 (LOX-1). This inhibitor also exhibited an antioxidant potential by scavenging free radicals along with the inhibition of non enzymatic lipid peroxidation. The finding suggested that sclerotiorin might be inhibiting the LOX either by interacting with the enzyme-substrate complex or by quenching the free radical intermediates formed during the enzyme reactions. Sclerotiorin demonstrated a comparable activity with that of the other known natural and synthetic lipoxygenase inhibitors (Chidananda & Sattur, 2007). Sclerotiorin belongs to the azaphillone class of compounds containing a typical isochromane ring (Tabata et al., 2012). Azaphilones pigments are secondary metabolites of fungal origin having a diverse structure. It contains highly oxygenated bicyclic quaternary rings responsible fornumerous biological activities. Free radical scavenging property of sclerotiorin has also been documented along with some of the xanthones produced by lichen mycobiont Pyrenula japonica (Takenaka, Tanahashi, Nagakura, Itoh, & Hamada, 2004). Melanins pigments are usually produced by a variety of microbes. These high molecular weight compounds are formed by oxidative polymerization of phenolic or indolic compounds. Several fungal species have already been reported to produce this compound. Aspergillus nidulans produced a pigment identical to melanin, which was found on cell walls or sometimes exists as extracellular polymers. HOCl and H2O2scavenging property of melanin was evaluated by inhibition of the oxidation of 5-thio-2-nitrobenzoic acid (TNB) with varying concentrations. The results confirmed scavenging properties of this pigment against HOCl oxidant, which was almost similar to that of synthetic melanin. Thus, it was recommended that the melanin from A. nidulans is might be a potential and promising material for the cosmetic industry in different formulations

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to protect the skin against probable oxidative damage (Goncalves & Pombeiro-Sponchiado, 2005). Phenolic antioxidants are efficiently produced by several Penicillium species. Homogentisic acid, 3-methoxytoluhydroquinone and a novel phenolic metabolite was successfully isolated from the culture broth of P. janthinellum. The antioxidant activity of these compounds was established by peroxide value of linoleic acid. Similarly, curvulic acid has also been isolated from a Penicillium strain (Nakakita, Yomosa, Hirota, & Sakai, 1984) and a phealenone nucleus containing metabolite atrovenetin was produced by P. paraherquei (Ishikawa, Morimoto, & Iseki, 1991). The later compound was proved to be a potent antioxidant and a strong tocopherol synergist to be used as a food additive. Similar chemical properties were also demonstrated by other related metabolite i.e. aurantionone isolated from P. aurantivirens. 2,3- dihydroxybenzoic acid effectively produced by P. roquefortii is commercially used for manufacturing Roquefort cheese, which exhibited antioxidant activity almost similar to that of BHA (Mapari et al., 2005). A halotolerant fungus Penicillium citrinum produced citrinin dimers having distinguishable antioxidant potential (Lu et al., 2008). Phyllosticta sp. culture filtrate extracted with ethanol, possessed phenolic and flavanoid content, which showed excellent activity of against ABTS and DPPH radicals (Srinivasan, Jagadish, Shenbahgaaraman, & Muthumary, 2010). Ten species of filamentous fungi (Grifola frondosa, Lentinula edodes, Monascus purpureus, Pleurotus salmoneo-stramineus, Pleurotus eryngii, Pleurotus ostreatus Pleurotus citrinopileatus and Trametes versicolor) grown under submerged culture conditions were evaluated for antioxidant capacity. The antioxidant potential was demonstrated in terms of radical scavenging, β–carotene/linoleic acid bleaching, reduction of metal ions and chelating capabilities against ferrous ions (Smith, Doyle, & Murphy, 2015).

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Antioxidant activity of ethyl acetate extract from Aspergillus terreus was assayed by different in vitro procedures i.e. DPPH, H2O2 radical scavenging, and β-caroten-linoleate model assay. Terreic acid and terremutin were purified from the extract, which were the responsible compounds for its antioxidant activity (Dewi, Tachibana, Itoh, & Ilyas, 2012). The antioxidant ability of two filamentous fungi Acremonium charticola and Rhizopus oryzae isolated from the Indonesian fermented dried cassava (gathot) was assessed by ABTS method. Both the fungi exhibited antioxidant potentials as demonstrated by their capabilities to scavenge ABTS radicals. A. charticola had a higher antioxidant capacity than R. oryzae (Sugiharto, Yudiarti, & Isroli, 2016). Neoechinulin A isolated from the fungus Aspergillus repens possessed only N-H, while no hydroxyl group, which also exhibited a strong antioxidant potential (Yagi and Doi, 1999). Beside such aromatic compounds, a peptide purified from A. oryzae and was also able to prevent the oxidation of fish oil. The phenalenedione produced by Paecilomyces carneus, with a backbone structure related to aurantionone, showed

antioxidant activity in

addition to

immunomodultory properties (Shibata et al., 1989). Endophytic fungus Achaetomium sp., isolated from Euphorbia hirta demonstrated antioxidant and hepatoprotective potentials (Anitha and Mythili, 2017). Ethyl acetate extract of endophytic fungus Penicillium sp. isolated from medicinal plant Centella asiatica demonstrated antioxidant ability and also exhibited a promising cytotoxic activity against HeLa, A431 and human breast cancer (MCF7) cell lines (Devi, Prabakaran, & Wahab, 2012). Among twenty one different endophytic fungi Aspergillus peyronelii, Aspergillus niger and Chaetomium sp., showed a promising antioxidant activity (Yadav, Yadav, & Yadav, 2014). Antioxidant potential of these fungi endorses their symbiotic relationship with the plants, which might help the plants to combat environmental factors induced oxidative stress.

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Yeasts are commonly used organisms in the fermentation process. Production of antioxidant molecules during the fermentation may enhance the availability of these therapeutic compounds. Among several strains, Kluyveromyces marxianus, Pichia kudriavzevii, Yarrowia lipolytica, Candida utilis showed their antioxidant producing potential (Rai, Pandey, & Sahoo, 2019). Engineered yeast strain S. cerevisiae has been efficiently produced astaxanthin and resveratrol like strong antioxidants (Li et al., 2015; Zhou, Ye, Xie, Lv, & Yu, 2015). Glucan andα-D mannan fractions obtained from yeast cell wall consists of significantly high number of hydroxyl groups showed a high erducing power, metal chelating and hydroxyl radical scavenging activities. Bioactive protein hydrolysate obtained from S. cerevisiae cell wall increased the viability of probiotic bacteria and contributed to enhanced antioxidant activity (Al-Manhel & Niamah, 2017). 5. Applications Antioxidants are widely used in food industry for various reasons mainly including prevention from oxidation, neutralization of free radicals, preserving the food, enhancing its flavor, aroma or color. Natural bioactive phenolic compounds e.g. quercetin-3-rutinoside, hesperidin, isoquercetin, caffeic acid, and 5,7-dihydroxyflavone have demonstrated antihypertensive and antidiabetic properties along with antioxidant activity, which may directly be used as nutraceuticals having their medical importance. Recently, a formulated ice cream was proposed containing such bioactive compounds, which also demonstrated improved storage stability for commercial applications (Gremski et al., 2019). Lipid oxidation and deterioration due to microbial growth is a typical problem in meat industry during meat processing, storage and distribution. Increasing health-consciousness of consumers and their preference for natural additives have encouraged to the research to look for natural 28

alternatives instead of synthetic antioxidants. Essential oils with high antioxidant activity are used in food processing and meat industry. Active packaging involves antioxidant to delay the lipid oxidation as an emerging technology to extend the products’ shelf life. It mainly involves the development of active film and the use of biopolymers as a substitute for synthetic polymers (Domínguez et al., 2018). Similarly, chitosan based active films were developed using berry pomace extract as an active agent. Involvement of pH indicator in these smart films may lead to a visible and significant colour changes for determination of food spoilage in real foodstuff. Thus the concept of eco-friendly smart films with high antioxidant activity seems to be a safer and cost effective for packaging industry (Kurek et al., 2018). The anthocyanin, present in the extract my change its colour during chemical reactions and develops a specific colour to detect the spoilage. Beside food supplements, animal feed industry is also exploiting these molecules to control lipid rancidity and increase feed stability and storage time. It was suggested to replace the harmful synthetic antioxidant like ethoxyquin from animal feed industry with efficient and economic natural antioxidants (Aklakur, 2018). In cosmetic industry, the use of natural products is always encouraged to reduce the risk of side effect or allergy. Microbial ability to produce kojic acid like compounds has got its importance for the industrial production of such molecules to be used in cosmetic industry. Natural phenolics having high antioxidant properties have already been used for cosmetic applications (Kusumawati & Indrayanto, 2013). Amendment of antioxidants producing microbes are suggested for organic farming. Overall soil properties along with the plant growth, photosynthesis and grain yield in different cereals including wheat, barley, oat, maize and sorghum were significantly improved by the naturally occurring actinomycetes. Phenolics, sugars vitamins, amino acids and organic acids contents in the grains were improved by the microbial treatment, which highlights the significance of 29

antioxidant producing microbes as an alternative to agrochemicals (Hozzein et al., 2019). Plant probiotic bacteria, Bacillus amylolequefaciens and Paraburkholderia fungorum significantly increased strawberry fruit yield up to 48%. These fruits had significantly higher contents of phenolics, carotenoids, flavonoids and anthocyanins, which ultimately enhanced the total antioxidant activity in fruits as compared to untreated control (Rahman et al., 2018). Natural phenolics demonstrated almost similar antioxidant activity as compared to the commercial antioxidant BHT. Advanced application of antioxidants enabled the researches to develop an industrial technology for manufacturing oxidation-resistant edible flaxseed oil (Shadyro, Sosnovskaya, & Edimecheva, 2017). Natural phenolic extracts also exhibited improved oxidation stability of biodiesel and biolubricants (Chandrasekaran et al., 2016), which further highlights the application of antioxidants in the emerging field of biolubricants. Recently, the antioxidants are also being explored for their possible application as countermeasures in chemical warfare. Neutralizing or minimizing the adverse consequences arising due to the exposures of ‘chemical warfare agents’ and ‘toxic industrial chemicals’ using antioxidants seems to be a promising approach to develop medical countermeasures (McElroy & Day, 2016). Instead of direct use of antioxidant molecules some advanced processing like microencapsulation of natural antioxidants was also suggested (Aguiar, Estevinho, & Santos, 2016). Thus, antioxidants based on their capability to slow down the autoxidation process of other compounds or neutralize free radicals may be explored for further applications. 6. Conclusion The review explores the potential of microbes to produce antioxidant compounds and further highlights their significance as novel sources of natural bioactive molecules for their application in different sectors. It endorses its future prospect for the commercial production of 30

natural and safer antioxidants from different microbes. These microbes may provide easier fermentation set up and faster production of natural antioxidants as compared to higher plants. The compound produced by different microbes seems to be potent antioxidant as well as better than some of the synthetic antioxidants, moreover they are proved to be non-mutagenic and non-cytotoxic. Further, in vivo investigations can be more useful for their wide use in medical and pharmaceutical field. Downstream processing strategies must be developed to enable the purification of these compounds easily. As microbes possess different compounds with antioxidant potential, these bioactive molecules may be served as valuable drugs directly or after modifying chemically. It may also be used as a template to design synthetic molecules responsible for various bioactivities. As processing of food may reduce the bioactivity of these molecules, some thermostable compounds may help in this regard. Microbial compounds produced by different organisms suggested them to be a possible natural source of antioxidants for incorporation into food products as a supplement to prevent many free radical mediated diseases thus providing a good health to the consumers. References Abdullah, N., Ismail, S. M., Aminudin, N., Shuib, A. S., & Lau, B. F. (2012). Evaluation of selected culinary-medicinal mushrooms for antioxidant and ACE inhibitory activities. Evidence-Based Complementary and Alternative Medicine, 2012. https://doi.org/10.1155/2012/464238 Aguiar, J., Estevinho, B. N., & Santos, L. (2016). Microencapsulation of natural antioxidants for food application – The specific case of coffee antioxidants – A review. Trends in Food Science and Technology, Vol. 58, pp. 21–39. https://doi.org/10.1016/j.tifs.2016.10.012

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Figure caption Figure 1Possible mechanism to scavenge free radical (ROO.) through reactive hydroxyl and methyl groups in 3’’-Dihydroxyterphenyllin and 3-Hydroxyterphenyllin

55

Table 1 Antioxidants compounds purified from microbial sources S.

Compounds Structure of Compounds

No.

Source

Activity

Reference

Aspergillus

Inhibition of lipid

(Yen et al.,

candidus

peroxidation

2001)

Aspergillus

Inhibition of lipid

(Yen et al.,

candidus

peroxidation

2001)

Aspergillus

Inhibition of linoleic acid

(Yagi & Doi,

repens

oxidation

1999)

Purified 3’’Dihydroxyterphen

1.

yllin and 3Hydroxyterphenyll in

2.

3.

Candidusin B

Neoechinulin A

56

hydrogen

Aspergillus 4.

Terreic Acid terreus

peroxide radical-scavenging activity and lipid

(Dewi et al., 2012)

peroxidation inhibitory activity hydrogen

Aspergillus 5.

Terremutin terreus

peroxide radical-scavenging activity and lipid

(Dewi et al., 2012)

peroxidation inhibitory activity

57

Aspergillus 6.

Versicolone A

ABTS scavenging activity

(Li et al., 2018)

ABTS scavenging activity

(Li et al., 2018)

ABTS scavenging activity

(Li et al., 2018)

Versicolor

Aspergillus 7.

Phomapyrone C Versicolor

Aspergillus 8.

Kojic acid Versicolor

58

4,6-dihydroxy-59.

Cephalosporium

DPPH radical-scavenging

(Huang et al.,

sp.

activity

2012)

methyl-1,3-

Cephalosporium

DPPH radical-scavenging

(Huang et al.,

dihydro-

sp.

activity

2012)

Cephalosporium

DPPH radical-scavenging

(Huang et al.,

sp.

activity

2012)

methoxy-7methylphthalide

4,5,6-trihydroxy-7-

10.

isobenzofuran 4,6-dihydroxy-5methoxy-711.

methyl-1,3dihydroisobenzofu ran

59

(Hormazabal, SchmedaHirschmann, Microsphaeropsi 12.

Active towards the tyrosine Astudillo,

Graphislactone solivacea

kinase Rodríguez, & Theoduloz, 2005)

(Z)-1-((1Hydroxypenta-2,413.

Nocardiopsis

DPPH radical-scavenging

(Janardhan et

alba

activity

al., 2014)

Dien-1Yl)Oxy)Anthracen e-9,10-Dione

60

2-Acetonyl-2,4,9,Trihydroxy-6Methoxy-7-

Paecilomyces

Methyl-1 H-

carneus

14.

(Shibata et al., Immunoactive substance 1989)

Phenalene-1,3(2 H)- Dione

15.

Penicilliumpara

Stabilization of vegetable

(Ishikawa et al.,

herquei

oils

1991)

Atrovenetin

Inhibition of oxidation Pestalotiopsismi 16.

Pestacin crospora

(Harper et al., of α-Keto-γ-

2003)

methiolbutyric acid

61

Inhibition of oxidation Isopestacin

Pestalotiopsismi

17. crospora

(Harper et al., of α-Keto-γ-

2003)

methiolbutyric acid

18.

19.

Streptomyces

Suppression of lipid

(Takagi et al.,

nitrosporeus

peroxidation

2005)

Streptomyces

Suppression of lipid

(Takagi et al.,

nitrosporeus

peroxidation

2005)

Benthocyanins A,

Streptomyces

Inhibition of lipid

(Shin-ya et al.,

B and C,

prunicolor

peroxidation

1993)

Benzastatins A

Benzastatins C

20.

62

21.

Streptomyces

Inhibition of lipid

(Shin-ya et al.,

prunicolor

peroxidation

1993)

Benthophoenin

(Kato, Shindo, Inhibition of lipid 22.

Phenazoviridin

Yamagishi, et

Streptomyces sp peroxidation

al., 2012)

5-(2, 4-

(Saurav & DPPH radical scavenging

23.

Dimethylbenzyl)

Kannabiran,

Streptomyces sp activity

Pyrrolidin-2-One

24.

2012)

Streptomyces

Inhibitory effect against

(Shindo et al.,

tolurosus

erythrocyte hemolysis

2012)

Thiazostatins A

63

Table 2 Summary of mushrooms /filamentous fungi demonstrated antioxidant activity S. No. 1.

Fungi

Type of Extract

Assay method and maximum activity

References

Achaetomium sp.

Ethyl acetate

DPPH free radical scavenging assay (87.34 (Anitha & Mythili, 2017) %)

2.

Acremonium charticola

Methanolic

ABTS free radical scavenging assay (93.11 (Sugiharto et al., 2016) %)

3.

Agaricus bisporus

Methanolic

Thiobarbituric Acid Reactive Substances (Reis, Martins, Barros, & (TBARS) assay (EC50 3.64 mg/ml) and DPPH Ferreira, 2012) free radical assay (EC50 39 mg/ml)

4.

Agrocybea egerita

Ethyl acetate

ABTS free radical assay (51.2 %) and (Lo & Cheung, 2005) inhibition of lipid peroxidation of rat brain homogenate (96.1 %)

5.

Antrodia camphorata

Aqueous

DPPH free radical assay (63 %)

(Song & Yen, 2002)

6.

Aspergillus candidus

Broth filtrate

DPPH radicals (96.0%)

(Yen et al., 2001)

7.

Aspergillus fumigatus

Broth filtrate

DPPH assay (89.8%)

(Arora & Chandra, 2011)

64

8.

Aspergillus niger

Ethyl acetate

DPPH free radical scavenging (40 %), (Yadav et al., 2014) hydrogen peroxide scavenging (30 %)

9.

Aspergillus peyronelii

Ethyl acetate

DPPH free radical scavenging (70 %), (Yadav et al., 2014) hydrogen peroxide scavenging (65 %)

10.

Aspergillus terreus

Broth filtrate

DPPH assay (88.1 %), Nitric oxide ion (NO) (Arora & Chandra, 2010) scavenging activity (70.2 %)

11.

Aspergillus versicolor

Purified

compound ABTS free radical scavenging activity (EC50

(versicolones)

8.0 μM)

(Li et al., 2018)

12.

Aspergillus wentii

Broth filtrate

DPPH assay (70.4 %)

(Arora & Chandra, 2011)

13.

Auriculariaauricular

Purified

ABTS free radical scavenging activity (30 %)

(Zhang et al., 2011)

polysaccharide 14.

Boletus edulis

Methanolic

β-carotene/linoleic acid (73.12 %), DPPH free (Sarikurkcu et al., 2008) radical scavenging (94.66 %)

15.

Cantharellus cibarius

Methanolic

DPPH (EC50 19.65 mg/ml), Inhibition of β- (Barros et al., 2008) Carotene Bleaching assay (EC50 8.40 mg/ml).

16.

Cephalosporium sp.

Purified compound

DPPH fee radical (EC50 22 μM)

(Huang et al., 2012)

17.

Ceriporiopsis

Aqueous

DPPH assay (65.4 %)

(Arora et al., 2011)

65

subvermispora 18.

Cerrena unicolor

Low molecular sub- Chemiluminescence Assay (70 %), ABTS (Jaszek et al., 2013) fraction of secondary scavenging (60 %) and DPPH free radical metabolites

scavenging activity (32 %)

19.

Chaetomium sp.,

Methanolic

ABTS assay (150 µM trolox/100 ml)

(Huang et al., 2007)

20.

Cladosporium

Methanolic

ABTS assay (9.5 µM trolox/100 ml)

(Huang et al., 2007)

21.

Clitocybe alexandri

Methanolic

DPPH free radical scavenging assay (20 %)

(Heleno et al., 2010)

22.

Colletotrichum

Purified compound

DPPH (EC50 0.14 mol/L)

(Femenía-Ríos

gloesosporioides

et

al.,

2006)

23.

Cortinarius glaucopus

Methanolic

DPPH free radical scavenging assay (50 %)

(Heleno et al., 2010)

24.

Daedalea flavida

Aqueous

DPPH assay (74.3 %)

(Sharma,

Chandra,

&

Arora, 2010) 25.

Daedalea quercina

Purified compound

Xanthine oxidase (XO) assay (IC50 21 µmol (Gebhardt et al., 2007) /L)

26.

Dictyophora indusiata

Hot water

DPPH free radical scavenging (97 %)

(Oyetayo, Dong, & Yao, 2009)

27.

Fistulina hepatica

Methanolic

DPPH free radical (80 %)

(Heleno et al., 2010)

66

28.

Flammulina velutipes

Aqueous

DPPH free radical assay (67.37 %)

(Shah, Ukaegbu, Hamid, & Alara, 2018)

29.

Ganoderma lucidum

Methanolic

DPPH free radical scavenging (64 %), Lipid (Mau, peroxidation (2.30 %)

30.

Ganoderma tsugae

Methanolic

Lin,

&

Chen,

2002)

DPPH free radical, ferrous ion scavenging (Mau et al., 2002) assay, (74.4 %) Lipid peroxidation (6.41 %)

31.

Grifola frondosa

Hot water

DPPH free radical scavenging (IC50 5.28 (Abdullah, mg/mL),

β-carotene

bleaching

Ismail,

assay Aminudin, Shuib, & Lau,

(IC50 7.94 mg/mL)

2012)

32.

Hericium erinaceus

Methanolic

DPPH free radical scavenging assay (70 %)

(Mau et al., 2002)

33.

Hydnum repandum

Methanolic

DPPH free radical scavenging assay (30 %)

(Heleno et al., 2010)

34.

Hygrophoropsis

Methanolic

DPPH free radical scavenging assay (50 %)

(Heleno et al., 2010)

(Heleno et al., 2010)

aurantiaca 35.

Hypholoma capnoides

Methanolic

DPPH free radical scavenging assay (80 %)

36.

Hypholoma fasciculare

Methanolic

DPPH free radical assay (EC50 1.3 mg/ml), (Barros et al., 2008) Inhibition of β-Carotene Bleaching assay (EC50 0.86 mg/ml).

67

37.

Inonotus obliquus

Methanolic

ABTS radical (IC50 0.65 µM) and DPPH free (Lee et al., 2007) radical (IC50 1.57 µM)

38.

Laccariaam ethystina

Methanolic

DPPH free radical scavenging assay (60 %)

(Heleno et al., 2010)

39.

Laccaria laccata

Methanolic

DPPH free radical scavenging assay (40 %)

(Heleno et al., 2010)

40.

Lactarius aurantiacus

Methanolic

DPPH free radical scavenging assay (30 %)

(Heleno et al., 2010)

41.

Lactarius deterrimus

Methanolic

β-carotene/linoleic acid (14.85 %), DPPH (Sarikurkcu et al., 2008) free radical scavenging (27.73 %)

42.

Lactarius salmonicolor

Methanolic

DPPH free radical scavenging assay (70 %)

(Heleno et al., 2010)

43.

Lentinus edodes

Methanolic

Thiobarbituric Acid Reactive Substances (Reis et al., 2012) (TBARS) assay (EC50 1.66 mg/ml) and DPPH free radical assay (EC50 7.82 mg/ml)

44.

Lepista inversa,

Methanolic

DPPH free radical scavenging assay (80 %)

(Heleno et al., 2010)

45.

Lepista nuda

Methanolic

DPPH free radical assay (EC50 4.41 mg/ml), (Barros et al., 2007) Inhibition of β-Carotene Bleaching assay (EC50 4.21 mg/ml).

46.

Lepista sordida,

Methanolic

DPPH free radical scavenging assay (80 %)

(Heleno et al., 2010)

47.

Lycoperdon molle

Methanolic

DPPH free radical assay (EC50 3.32 mg/ml), (Barros et al., 2007)

68

Inhibition of β-Carotene Bleaching assay (EC50 1.92 mg/ml) 48.

Lycoperdon perlatum

Methanolic

DPPH free radical assay (EC50 3.95 mg/ml), (Barros et al., 2007) Inhibition of β-Carotene Bleaching assay (EC50 2.49 mg/ml)

49.

Morchella angusticeps

Methanolic

β-carotene/linoleic acid (67 %), DPPH (5.23 (Gursoy et al., 2009) %) and ABTS scavenging effect (51 %)

50.

Morchella conica

Methanolic

β-carotene/linoleic acid (82 %), DPPH (13.91 (Gursoy et al., 2009) %) and ABTS scavenging effect (48 %)

51.

Morchella crassipes

Methanolic

β-carotene/linoleic acid (77 %), DPPH (10.7 (Gursoy et al., 2009) %) and ABTS scavenging effect (49 %)

52.

Morchella deliciosa

Methanolic

β-carotene/linoleic acid (86%), DPPH (3.7 %) (Gursoy et al., 2009) and ABTS scavenging effect (44 %)

53.

Morchella elata

Methanolic

β-carotene/linoleic acid (63 %), DPPH (4.6 (Gursoy et al., 2009) %) and ABTS scavenging effect (48 %)

54.

Morchella esculenta

Methanolic

β-carotene/linoleic acid (86 %), DPPH (10.7 (Gursoy et al., 2009) %) and ABTS scavenging effect (52 %)

55.

Morchella rotunda

Methanolic

β-carotene/linoleic acid (85.7 %), DPPH (8.24 (Gursoy et al., 2009)

69

%) and ABTS scavenging effect ( 50%) 56.

Morchella vulgaris

Ethanolic

DPPH free radical scavenging (94 %), (Elmastas et al., 2006) hydrogen peroxide scavenging (84 %)

57.

Mycelia sterilia

Pure compound

Superoxide and ABTS free radical scavenging (Moon et al., 2006) assay (EC50 1.9-2.4 µM)

58.

Mycena rosea,

Methanolic

DPPH free radical scavenging assay (70 %)

(Heleno et al., 2010)

59.

Penicillium citrinum

Aqueous

DPPH assay (80 %)

(Arora & Chandra, 2011)

60.

Penicillium expansum

Aqueous

DPPH assay (84 %)

(Chandra & Arora, 2017)

61.

Penicillium frequentans

Purified

radical scavenging activity EC50 of 0.12 μM

2007)

DPPH assay (74.8 %)

(Arora & Chandra, 2011)

Penicillium granulatum

Aqueous

63.

Pestalotiopsis microspora,

Purified

Phanerochaete

Lipid peroxidation (IC50 4.2 μM), DPPH free (Chidananda & Sattur,

(sclerotiorin) 62.

64.

compound

compound Oxyradical

scavenging

capacity

(TOSC) (Harper et al., 2003)

(pestacin)

assay (IC50 1.7 mM)

Aqueous

DPPH assay (72.5 %)

Aqueous

Hydroxyl radical scavenging (IC50 68 µg/ml), (Ajith & Janardhanan,

(Sharma et al., 2010)

chrysosporium 65.

Phellinus rimosus

Lipid peroxidation inhibiting (IC50

160 70

µg/ml)

2007)

66.

Phlebia brevispora

Aqueous

DPPH assay (72.8 %)

(Arora et al., 2011)

67.

Phlebia fascicularia

Aqueous

DPPH assay (66.13 %)

(Arora et al., 2011)

68.

Phlebia floridensis

Aqueous

DPPH assay (72.1 %)

(Arora et al., 2011)

69.

Phlebia radiate

Aqueous

DPPH assay (65.2 %)

(Arora et al., 2011)

70.

Phoma

Methanolic

ABTS assay (46.78 µmol trolox/100 ml)

(Huang et al., 2007)

71.

Phyllosticta sp.

Ethanolic

ABTS (EC50 580 µg/ml) and DPPH free (Srinivasan et al., 2010) radical scavenging activity (EC50 2030 µg/ml)

72.

Pleurotus cystidiosus

Methanolic

DPPH free radical assay (85 %), H2O2 (Babu, Pandey, & Rao, scavenging effect (45 %)

73.

Pleurotus eryngii

Methanolic

2014)

Thiobarbituric Acid Reactive Substances (Reis et al., 2012) (TBARS) assay (EC50 21 mg/ml) and DPPH free radical assay (EC50 25 mg/ml)

74.

Pleurotus florida

Aqueous

Hydroxyl

radical

scavenging

(IC50

530 (Ajith & Janardhanan,

µg/ml), Lipid peroxidation inhibiting (IC50 2007) 496 µg/ml) 75.

Pleurotus ostreatus

Methanolic

Thiobarbituric Acid Reactive Substances (Reis et al., 2012)

71

(TBARS) assay (EC50 2.5 mg/ml) and DPPH free radical assay (EC50 58 mg/ml) 76.

Pleurotus pulmonaris

Aqueous

Hydroxyl

radical

scavenging

(IC50

476 (Ajith & Janardhanan,

µg/ml), Lipid peroxidation inhibiting (IC50 2007) 960 µg/ml) 77.

Ramaria botrytis

Methanolic

DPPH free radical assay (EC50 0.66 mg/ml), (Barros et al., 2007) Inhibition of β-Carotene Bleaching assay (EC50 0.67 mg/ml)

78.

Rhizopus oryzae

Methanolic

ABTS free radical scavenging assay (14.20 (Sugiharto et al., 2016) %)

79.

Russula delica,

Methanolic

DPPH free radical scavenging assay (40 %)

(Heleno et al., 2010)

80.

Russula vesca

Methanolic

DPPH free radical scavenging assay (70 %)

(Heleno et al., 2010)

81.

Suillus collinitus

Methanolic

DPPH free radical scavenging assay (88.27 (Heleno %), β-carotene/linoleic acid (79.94 %)

et

al.,

2010)(Sarikurkcu et al., 2008)

82.

Suillus mediterraneensis

Methanolic

DPPH free radical scavenging assay (80 %)

(Heleno et al., 2010)

83.

Torula sp.,

Methanolic

ABTS assay (30 µmol trolox/100 ml)

(Huang et al., 2007)

72

84.

Trametes gibbosa

Ethanolic

ABTS (EC50 31.43 mg/ml)

(Knežević et al., 2018)

85.

Trametes hirsuta

Ethanolic

ABTS (EC50 27.5 mg/ml)

(Knežević et al., 2018)

86.

Tricholoma acerbum

Methanolic

DPPH free radical assay (EC50 3.60 mg/ml), (Barros et al., 2007) Inhibition of β-Carotene Bleaching assay (EC50 5.89 mg/ml)

87.

Tricholoma giganteum

Methanolic

DPPH free radical scavenging (47.4 %)

(Mau et al., 2002)

88.

Tricholoma sulphureum

Methanolic

DPPH free radical scavenging assay (85 %)

(Heleno et al., 2010)

89.

Xerocomus chrysenteron

Methanolic

β-carotene/linoleic acid (74.99 %), DPPH free (Sarikurkcu et al., 2008) radical scavenging (81.61 %)

EC:

Efficient

concentration,

IC:

Inhibitory

concentration

73

Food

Fungi (Yeast & Mold)

Bacteria

Nutraceutical Industrial Production

Antioxidants

Microbes Actenomycetes

Lichens Blue Green Algae

Pharmaceutical

Agriculture

Highlights



Microorganisms are rich source of bioactive compounds and antioxidants.



Several phenolic compounds are naturally produced as potential antioxidants.



Actinomycetes, bacteria, blue green algae, fungi and lichens are emerging sources.



Natural compounds frommicrobes are safe alternative for industrial applications.

74