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J. Fungi 2021, 7, 51. https://doi.org/10.3390/jof7010051 www.mdpi.com/journal/jof
Review
Taxonomy, Diversity and Cultivation of the
Oudemansielloid/Xeruloid Taxa Hymenopellis, Mucidula,
Oudemansiella, and Xerula with Respect to Their Bioactivities:
A Review
Allen Grace Niego 1,2,3, Olivier Raspé 1,2, Naritsada Thongklang 1,2, Rawiwan Charoensup 4,5, Saisamorn Lumyong 6,7,8,
Marc Stadler 9,* and Kevin D. Hyde 1,10,*
1 Center of Excellence in Fungal Research, Mae Fah Luang University, Chiang Rai 57100, Thailand;
agniego27@gmail.com (A.G.N.); ojmraspe@gmail.com (O.R.); fah_naritsada@hotmail.com (N.T.)
2 School of Science, Mae Fah Luang University, Chiang Rai 57100, Thailand
3 Iloilo Science and Technology University, La Paz, Iloilo 5000, Philippines
4 School of Integrative Medicine, Mae Fah Luang University, Chiang Rai 57100, Thailand;
rawiwan.cha@mfu.ac.th
5 Medicinal Plants Innovation Center, Mae Fah Luang University, Chiang Rai 57100, Thailand
6 Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand;
saisamorn.l@cmu.ac.th
7 Research Center of Microbial Diversity and Sustainable Utilization, Chiang Mai University,
Chiang Mai 50200, Thailand
8 Academy of Science, The Royal Society of Thailand, Bangkok 10300, Thailand
9 Department Microbial Drugs, Helmholtz Centre for Infection Research, and German Centre for Infection
Research (DZIF), Partner Site Hannover-Braunschweig, Inhoffenstrasse 7, 38124 Braunschweig, Germany
10 Institute of Plant Health, Zhongkai University of Agriculture and Engineering,
Guangzhou 510408, China
* Correspondence: marc.stadler@helmholtz-hzi.de (M.S.); kdhyde3@gmail.com (K.D.H.)
Abstract: The oudemansielloid/xeruloid taxa Hymenopellis, Mucidula, Oudemansiella, and Xerula are
genera of Basidiomycota that constitute an important resource of bioactive compounds. Numerous
studies have shown antimicrobial, anti-oxidative, anti-cancer, anti-inflammatory and other bioac-
tivities of their extracts. The bioactive principles can be divided into two major groups: (a) hydro-
philic polysaccharides with relatively high molecular weights and (b) low molecular medium polar
secondary metabolites, such as the antifungal strobilurins. In this review, we summarize the state
of the art on biodiversity, cultivation of the fungi and bioactivities of their secondary metabolites
and discuss future applications. Although the strobilurins are well-documented, with commercial
applications as agrochemical fungicides, there are also other known compounds from this group
that have not yet been well-studied. Polysaccharides, dihydro-citrinone phenol A acid,
scalusamides, and acetylenic lactones such as xerulin, also have potential applications in the
nutraceutical, pharmaceutical and medicinal market and should be further explored. Further stud-
ies are recommended to isolate high quality bioactive compounds and fully understand their modes
of action. Given that only few species of oudemansielloid/xeruloid mushrooms have been explored
for their production of secondary metabolites, these taxa represent unexplored sources of poten-
tially useful and novel bioactive metabolites.
Keywords: Basidiomycota; bioactive compounds; cultivation; diversity; taxonomy
1. Introduction
Basidiomycota, especially mushrooms, have been explored for thousands of years
not only for their nutritional value but also as therapeutic agents [1,2]. Mushrooms are
Citation: Niego, A.G.; Raspé, O.;
Thongklang, N.; Charoensup, R.;
Lumyong, S.; Stadler, M.; Hyde,
K.D. Taxonomy, Diversity and
Cultivation of the
Oudemansielloid/Xeruloid Taxa
Hymenopellis, Mucidula,
Oudemansiella, and Xerula with
Respect to Their Bioactivities:
A review. J. Fungi 2021, 7, 51.
https://doi.org/10.3390/jof7010051
Received: 27 December 2020
Accepted: 9 January 2021
Published: 13 January 2021
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional
claims in published maps and insti-
tutional affiliations.
Copyright: © 2021 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (http://crea-
tivecommons.org/licenses/by/4.0/).
J. Fungi 2021, 7, 51 2 of 24
well-studied for their bioactivities such as anticancer, anti-diabetics, anti-hypertensive,
antimicrobial, anti-inflammatory, anti-oxidant, immunomodulatory and cholesterol-low-
ering properties [2–4]. The discovery of mushroom metabolites pleuromutlin, illudin and
strobilurins lead to the exploration of Basidiomycota as natural product-based candidates
for drugs and agrochemicals [5–7]. On the other hand, medicinal mushrooms have long
been used to treat diseases as traditional folk medicines in Asia [3]. Mushroom metabo-
lites also have great potential to be developed as food supplements and additives for phar-
maceutical and medicinal applications [5]. Producer organisms for commercial products
and development candidates for such applications are mostly derived from genera such
as Agaricus and Ganoderma, but include Oudemansiella [2,5,8,9] Recently, such studies have
been increasingly relying on bioinformatics, genomics and transcriptomics [5,8].
The taxonomy of the oudemansielloid/xeruloid (OX) group, which comprises sapro-
trophic mushrooms that are widespread in all forested areas of the world, is quite complex
and their generic classification has been re-arranged several times over the past decades.
As the work of applied researchers such as chemists did not always keep pace with the
taxonomy, there are a lot of synonyms in the literature that refer to certain species under
different generic names. We here follow the concept derived from the major taxonomic
study by Petersen and Hughes [10]. This work was based on comprehensive morpholog-
ical studies including the reexamination of many types of materials and a concurrent mo-
lecular phylogeny based on rDNA data. The authors erected four new genera (Hymeno-
pellis, Paraxerula, Ponticulomyces, Protoxerula) and reconfiguration of other genera such as
Dactylosporina, Mucidula, Oudemansiella and Xerula. This concept has also been accepted in
recent general overviews on the taxonomy of the Fungi and the Basidiomycota in partic-
ular [11].
Many studies have documented the bioactive compounds produced by these genera,
which are dominated by strobilurins. These compounds, for which some other trivial
names (oudemansins and mucidin) have been used in earlier publications, are all β-meth-
oxy-acrylates with a similar carbon skeleton [8]. These compounds are known to have
antifungal activity which are produced by mushrooms to eliminate competition from
other fungi [12,13]. Oudemansiella canarii also produces oudemansin A with antimicrobial
properties [14]. There are also numerous studies on the polysaccharides from these genera
with focus on health-promoting activities. Due to the increased awareness in the pharma-
ceutical and nutritional values of mushrooms, there is an amplified demand from con-
sumers for other varieties of mushrooms, thus leading to the exploration of wild mush-
rooms for utilization [15]. There are over 30,000 species of Basidiomycota in the world [5],
of which only a small percentage (5%) has been investigated [13].
This paper aims to explore the OX group of mushrooms as sources of bioactive com-
pounds. We highlight the importance of this group by gathering information on the bio-
activities and compounds produced from the earliest records up to the present. Further-
more, we discuss their diversity, distribution, taxonomy and different methods for their
cultivation.
2. Taxonomic Aspects of Oudemansielloid/Xeruloid Genera
Hymenopellis, Mucidula, Oudemansiella and Xerula are Physalacriaceae genera that
share a complicated taxonomical history (Table 1). These species complexes have been
dealt with by different mycologists in order to clarify their classification during the past
140 years and some important papers are mentioned below. Oudemansiella was initially
proposed as Oudemansia in order to accommodate a single species, Agaricus platensis [16].
Spegazzini [17] then changed the name to Oudemansiella. Moser [18] merged the genera
Xerula and Mucidula under Oudemansiella. This arrangement was supported and adopted
by Singer [19–21], but Xerula was regarded as a subgenus only within Oudemansiella.
Clemencon [22] also treated Xerula as one of the five subgenera in Oudemansiella. Dörfelt
[23], however, retained Oudemansiella and Xerula as two independent genera and this was
adopted by other researchers [24–34]. Pegler and Young [35] divided Oudemansiella into 5
J. Fungi 2021, 7, 51 3 of 24
sections under the two subgenera Oudemansiella and Xerula. Other mycologists such as
Rexer and Kost [36,37], Yang and Zang [38], Yang [39] and Mizuta [40] later adopted this
new arrangement.
Yang et al. [41] proposed a taxonomic classification for the genus Oudemansiella s.s.,
which was divided into four sections, i.e., Oudemansiella, Mucidula, Dactylosporina and Rad-
icatae. Section Oudemansiella comprised tropical to south temperate species, e.g., O. platen-
sis, O. australis, O. canarii and O. crassifolia. The distinguishing characteristics of this group
was the ixotrichoderm pileipellis composed of filamentous hyphae often intermixed with
chains of inflated cells. The section Mucidula on the other hand was characterised by an
ixohymeniderm-trichoderm pileipellis composed of more or less clavate terminal cells
and encompassed north temperate and subtropical taxa (e.g., O. mucida, O. venosolamellata
and O. submucida). Sections Oudemansiella and Mucidula shared similar habitats, growing
on exposed rotten wood. Their basidiomata were with or without a (rudimentary) annu-
lus on the stipe. Section Dactylosporina accommodated species from South and Central
America with basidiospores that had finger-like ornamentation. Section Radicatae, repre-
sented by O. radicata and its allies, was the largest section and included the remaining
species of the genus in its restricted sense.
Table 1. History of taxonomic placements of oudemansielloid/xeruloid (OX) genera.
Author Year Arrangement Adopted
Spegazzini
[16] 1880 Initially proposed
Oudemansia
to accommodate a sin-
gle species, Agaricus platensis Speg.
Spegazzini
[17] 1881 Changed the name to Oudemansiella
Patouillard
[42] 1887
Erected
Mucidula
to separate
Agaricus mucidus
from
both Collybia (Fr.) Kummer and Armillaria (Fr.) Kum-
mer based on the presence of velar layers and the vo-
luminous spores
Hoehnel [43]
1910
Emended
Oudemansiella
to include species with velar
layers, a gelatinized pileipellis, and large cystidia
and spores
Boursier [44]
1924
1924
Expanded
Mucidula
to include
Collybia radicata
(Rel-
han: Fr.) Quel. and C. longipes (Bull.) Kummer, em-
phasizing morphological similarities (spores, basidia,
cystidia, hymenioderm)
Maire [45] 1933 Separated
C. longipes
from
Mucidula
and proposed
the new genus Xerula Singer [46,47]
Moser [18] 1955 Merged
Xerula
and
Mucidula
into
Oudemansiella
Singer [19–21]
Clémençon
[22] 1979 Treated
Xerula
as one of the 5 subgenera of
Oudeman-
siella
Dörfelt [23] 1980 Retained Oudemansiella and Xerula as independent
genera
Boekhout & Bas [24], Redhead et al. [25]
, Petersen &
Halling [29], Petersen & Methven [30], Corner [32],
Contu [33], Mueller et al. [34]
, Petersen & Nagasawa
[26], Petersen & Baroni [27], Petersen [28,31]
Pegler &
Young [35] 1987 Divided
Oudemansiella
into five sections under the
subgenera Oudemansiella and Xerula
Rexer & Kost [36,37], Yang & Zang [38], Yang [39],
Mizuta [40]
Yang et al.
[41] 2009 Divided
Oudemansiella
into four sections (
Oudemansi-
ella, Mucidula, Dactylosporina and Radicatae)
Petersen &
Hughes [10] 2010
Introduction of four new genera (
Hymenopellis, Parax-
erula, Ponticulomyces, Protoxerula
) and reconfiguration
of other genera such Dactylosporina, Mucidula,
Oudemansiella and Xerula
accepted until now
J. Fungi 2021, 7, 51 4 of 24
So far the most thorough revision of the OX complex was provided by Petersen and
Hughes [10], and it is still widely accepted today [11,12]. Based on taxonomic and phylo-
genetic analyses, 68 new taxa/or new combinations were proposed. The new arrangement
included introduction of new genera (Hymenopellis, Paraxerula, Ponticulomyces and Pro-
toxerula) and reconfiguration of Dactylosporina, Mucidula, Oudemansiella and Xerula. For
instance, Oudemansiella and Mucidula grow directly on wood without developing pseudo-
rrhizae. Macroscopically, the basidiomata of Oudemansiella differ from those of Mucidula
by lacking a persistent annulus on the stipe and the former genus can only be found in
tropical areas. There are 142 records of names in Index Fungorum [41], with 39 currently
accepted species for Oudemansiella. Mucidula, on the other-hand, was introduced by
Patouillard [42] and 14 records of the genus are presently listed, of which only Mucidula
brunneomarginata and Mucidula mucida are currently accepted [10]. Figure 1 shows some
specimens of Oudemansiella collected from Thailand.
Figure 1. Basidiomata of Oudemansiella collected from the wild in Thailand. (a,b). Oudemansiella spp. (HT19-0047, HT19-
0050). Photos by A.G. Niego.
The basidiomes of the other, related genera have pseudorhizae extending below
ground and connected to subterraneous wood or tree roots. Xerula was described by Maire
[45], and currently there are 96 records in Index Fungorum, including the synonyms, of
which only 11 species accepted. This genus differs from Paraxerula by having thick-walled
setae on the pileus [10]. Moreover, basidiomes of Hymenopellis species have a moist to
glutinous pileus, in contrast to Protoxerula, which has a green, sticky pileus and is re-
stricted to Australia. The type species of Hymenopellis is H. radicata described in 1786 under
the name Agaricus radicatus [48]. There are 58 records with 42 species for Hymenopellis in
Index Fungorum. Figure 2 shows some specimens of Xerula and Hymenopellis collected
from Thailand.
J. Fungi 2021, 7, 51 5 of 24
Figure 2. Some basidiomata collected from the wild in Thailand. (a). Xerula sp. (immature basidioma) (b). Xerula sinopudens
(c–e). Hymenopellis sp. Photos by A.G. Niego.
3. Geographical Distribution and Diversity of the Genera
3.1. Hymenopellis
Hymenopellis species are widely distributed in eastern and north America [49] (Figure
3). Although the distribution is well documented in these areas, they can also be found in
other continents. Many species of Hymenopellis were first documented in Asia. For in-
stance, H. amygdaliformis and H. velata were first found in China [10,38], H. aureocystidiata,
H. japonica, H. orientalis and H. vinocontusa in Japan, and H. endochorda in Sri Lanka [10].
Hymenopellis chiangmaiae was first recorded in Thailand but was later synonymized under
H. raphanipes by Petersen and Hughes [10]. Several species of the genus have also been
discovered in Australia. These are H. eradicata, H. gigaspora, H. mundroola, H. superbiens, H.
trichofera and H. variabilis. Other species are distributed almost worldwide, such as H. rad-
icata. This fungus occurs in Europe and North America and can also be found in northern
Africa, in extreme western Asia and Asia minor [10,49,50]. Hymenopellis raphanipes was
first described from India [51] and has also been reported from Australia, China, India,
J. Fungi 2021, 7, 51 6 of 24
Japan and Thailand [10,26,35,38]. Basidiomata of Hymenopellis can grow solitary or gre-
garious on dead or buried hardwoods, and occasionally on exposed, well-decayed wood.
They can appear as growing from the ground because of their long deep tap-root like
pseudorhiza attached to the decayed wood underground [10].
Figure 3. Geographical distribution of OX genera showing their concentration in some continents.
3.2. Mucidula
Mucidula mucida var. mucida, the “porcelain mushroom”, is commonly found and
widespread in Europe including western Russia and typically grows on Fagus [10] (Figure
3). Other varieties, Mucidula mucida var. asiatica and var. venosolamellata, are distributed in
Asia. In Japan, M. mucida var. asiatica has been collected from dead trunks and branches
of several broad-leaved tree species, while M. mucidula var. venosolamellata usually grows
in dead trunks and branches of Fagus crenata [52]. The second species in the genus, Mucid-
ula brunneomarginata, is commonly found on rotting hardwood logs. It was first recorded
in Russia and has also been documented in Japan [10,53].
3.3. Oudemansiella
Oudemansiella is widely distributed throughout tropical and temperate regions (Fig-
ure 3) and its basidiomata grow on rotting wood [10,11]. For instance, Oudemansiella ca-
narii can be found in Asia, Africa and Central America [14,21,43,54]. Oudemansiella platen-
sis var. orinocensis can also be found in tropical and subtropical regions [55]. Many species
of Oudemansiella were first recorded in Asia, as exemplified by O. alphitophylla (as Agaricus
alphitophyllus), O. latilamellata, and O. rhodophylla [40,56], which were all first recorded in
Japan. On the other hand, Oudemansiella bii, O. fanjingshanensis and O. yunnanensis were
first recorded in China. Others, like O. crassifolia and O. submucida were first recorded in
Malaysia, and have also been recorded in Thailand [32,54]. In some cases, it is not possible
to say for sure whether they belong to other genera described here because the descrip-
tions did not rely on the concept by Peterson and Hughes [10]. For instance, O. submicida
is probably better placed in Mucidula as it closely resembles M. mucida. This shows that a
J. Fungi 2021, 7, 51 7 of 24
lot of work remains to be done to harmonize the taxonomy of the OX complex at a global
level. Some species of Oudemansiella such as O. exannulata, O. gloriosa, O. reticulata and O.
turbinispora appear to be endemic to Australia [10,57]. Historically, Europe is the best stud-
ied of all the continents in terms of the number of publications of this genus; however, in
terms of the number of species, Asia seems to be more diverse [10], and Africa, as well as
South and Central America seem to be understudied.
3.4. Xerula
The type species of the genus, Xerula pudens (often treated in the literature under its
synonyms, Xerula or Oudemansiella longipes) has been reported first in Europe (cf. Figure
3). This species is connected to Quercus, thus its distribution could theoretically cover the
whole continent [50,58]. It has also been reported in Thailand [59], but without details on
the morphology, hence this record is highly dubious because Quercus does not actually
occur in that country. The first recorded Asian species are Xerula sinopudens in Japan and
Xerula strigosa in China [26,41]. Other species were documented in different countries,
such as X. australis (Australia), X. fraudulenta (France), X. oronga (D.R. Congo), X. renati
(Switzerland, as Oudemansiella renati) and X. setulosa (Jamaica, as Gymnopus setulosus)
[28,60–63]. The latter species was also documented in Brazil and Belize [27,64]. Generally,
the species are similar to Hymenopellis in being saprobic, and their basidiomata are at-
tached to rotten wood, which is often buried deep beneath leaf litter or soil [10].
4. Cultivation of Important Species with Bioactivities
Generally, mushrooms are cultivated for food because of their good taste and high
nutritional value. In Japan and China, mushrooms are traditionally consumed because of
their medicinal and tonic properties [65]. Mushroom cultivation is an important part of
sustainable agriculture and forestry. Cultivation is necessary to ensure a stable mushroom
source especially for potential sources of bioactive compounds. It can also help small
farming systems by recycling agricultural wastes and returning them to soil as fertilizer
[66]. The most widely known cultivated mushrooms are Agaricus bisporus and Volvariella
volvacea, which represent almost 38% and 16% of total mushroom production in the world
[67]. In any case, the empirical optimization of culture conditions is necessary to assure
that the respective biotechnological production processes is competitive and commer-
cially viable before such products can be introduced into the market.
OX mushrooms are not generally commercially cultivated as food source as the fruiting
bodies are rubbery and do not have good taste. Only in some Asian countries, such as China,
are these mushrooms being commercially cultivating at larger scale, presumably mostly for
medicinal purposes. Aside from Hymenopellis radicata, the cultivation of no other edible mem-
ber of the OX group has been documented in detail (Figure 4). However, several species that
are used as medicinal mushrooms have been successfully grown on different substrates at
laboratory scale with high biological efficiency (Table 2). The later term refers to the percentage
of ratio of fresh mushroom weight vs. the dry weight of the respective substrate [68].
J. Fungi 2021, 7, 51 8 of 24
Figure 4. Basidiomata of Hymenopellis raphanipes cultivated in China and in the Mae Fah Luang (MFU) laboratory, Thai-
land. (a). Mature basidiomata, (b). Young basidiomata, (c). Basidomata from bags. Photos from Yu Wei and A.G. Niego.
Table 2. Some cultivable OX species on different substrates and (%) biological efficiency, as effec-
tiveness of mushroom strain growth in the given substrate. Biological efficiency refers to the per-
centage of ratio of fresh mushroom weight over the dry weight of the respective substrate.
Species Substrate Biological Efficiency (%)
References
Hymenopellis radicata
Oak sawdust – Shim et al. [69]
Sawdust 100 Gao [70]
Mucidula mucida
Oak sawdust – Lee et al. [71]
Oudemansiella canarii
Sugar-cane bagasse 55.66 Silveira Ruegger et al. [72]
Eucalyptus sawdust
19.51
Cottonseed hull 113.64
Xu et al. [73] Corncob 105.65
Sawdust 85.49
4.1. Cultivation of Hymenopellis
Kim et al. [74] were able to establish the optimal culture conditions for mycelial
growth of H. radicata at 25 °C and pH 6.0. This species was successfully grown on sawdust,
with biological efficiency of 100% [70]. The addition of 10% rice bran to oak sawdust stim-
ulated mycelial growth since it may contain ingredients favourable for mycelial growth
for H. radicata [69].
Hymenopellis raphanipes is commercially cultivated in China by the local name “Heipi-
jizong” or “Black Termite Mushroom”. It was previous misidentified as H. furfuracea, H.
radicata, Termitomyces fuliginosus or T. badius. Hao et al. [75] correctly identified this mush-
room by using morphologic and phylogenetic (ITS and nrLSU) analyses. The results clar-
ified the phylogenetic position and taxonomy of “Heipijizong” as H. raphanipes. To in-
crease production for large scale cultivation, the use of liquid culture fermentation and
optimization of culture conditions of fermentation technology was studied by Ning et al.
[76].
The best medium for liquid culture fermentation was glucose 20.0 g + sorghum pow-
der 4.0 g + K2HPO4 3.0 g + MgSO4 1.0 g + vitamin B1 2 tablets + distilled water 1000.0 mL,
pH 6.5. The 12% of inoculum was grown in 2 L liquid having an optimum temperature of
J. Fungi 2021, 7, 51 9 of 24
25 °C, stirring speed 90 r/min, culture time 100 h, tank pressure 0.3 MPa and ventilation
volume 0.9 m3/h. By using optimum conditions, the mycelium of the O. raphanipes culti-
vated in the liquid medium had a fast growth rate, filling the bag in 29 days, with an
average yield of 360.0 g per bag. The biological conversion rate reached 78%. Figure 4
shows photographs of some strains taken in China.
4.2. Cultivation of Mucidula
Mucidula mucida can be grown in Potato Dextrose Agar at 25 °C [75]. It can also suc-
cessfully grow in nutrient media for mycelial growth. Musilek et al. [77] grew this species
on glucose-corn-steep media containing 30 or 50 g glucose, 15 g corn-steep (~50 dry
weight), 1.5 g MgSO4.7H2O per liter of water with the pH 5.5. This species was successfully
cultivated in oak sawdust mixed with rice bran (20–30%) in the bottle at 25 °C, incubated
in the dark [71]. The mycelia then colonized the media from the top to bottom. The bottles
were exposed under 12 h of light (350 lux) and dark having a relative humidity of 95% at
17 °C. The primordia were observed after 7 days of incubation. They then developed into
mature fruiting bodies after 7 days [71].
4.3. Cultivation of Oudemansiella
The most common substrate used in the cultivation of Oudemansiella species is saw-
dust. All cultivable species of Oudemansiella can be grown in this substrate [72,73,78,79].
Recently, however, other substrates have been used (Table 2).
Among the species of Oudemansiella, O. canarii is the most commonly cultivated. It
can be grown in different biomass, since this species is able to colonize several kinds of
plant. Silveira Ruegger et al. [72] cultivated O. canarii strain CCB179 in polypropylene
bags in two different substrates (200 g), sugar-cane bagasse and eucalyptus sawdust in-
corporated with wheat bran (50 g). The composts were sterilized at 121 °C for an hour and
were later inoculated with 3 g of spawn. The bags were incubated at 25 °C until the basid-
iomata primordia formed. Mushroom growing in sugar-cane bagasse resulted in higher
biological efficiency (55.66%) as compared with eucalyptus sawdust supplemented with
wheat bran (19.51%). Lignocellulosic wastes such as cottonseed hull and corn-comb can
also be used as substrates in cultivating O. canarii. Xu et al. [73] used these lignocellulosic
wastes as base substrates for the cultivation of O. canarii. The addition of wheat bran and
lime in the substrates provide nitrogen and adjusted the pH of the substrates. 1000 g of
substrate were prepared in each bag with water content adjusted to 65% (w/w). The sub-
strates were then inoculated with spawn at 2% (w/w). The bags were then incubated at 25
°C and 70% relative humidity (RH) in the dark room. Among the substrates cotton-hull
(80%) resulted in highest biological efficiency (113.64) and essential amino acid contents.
The combination of cottonseed hull (80%) supplemented with 8% wheat bran and 2% lime
can give a high yield of basidiomata and should be extended in future use [73].
Oudemansiella submucida has also been domesticated and successfully cultivated. A
wild strain from Hunan Province has been domesticated by Li et al. [79]. The optimal
conditions for primordial growth are 23 °C and 75–95% relative humidity. After 40–50
days following substrate inoculation the primordia appeared. The biological efficiency of
96.1% was obtained from the first flush after 50–55 days.
4.4. Cultivation of Xerula
The artificial cultivation method of Xerula pudens (CN104396561A) was patented by
Houjiang et al. [80] The culture medium was prepared by degumming, degreasing and
curing of saw-dusts from pine and rubber trees. The medium comprised 85 to 92 parts of
any sawdust or sawdust mixtures. Additives such as 5 to 10 parts of broad bean husks
and 3 to 5 parts of bean pulp were incorporated into the medium. The water content was
about 50–70%. The culture medium was placed in plastic bags and sterilized. After cool-
ing, they were inoculated with the mycelial culture under aseptic conditions. The bags
J. Fungi 2021, 7, 51 10 of 24
were covered with vermiculite for fructification. This method is low cost with high yield
of fruiting bodies which could be extensively applied to large-scale cultivation and pro-
duction of X. pudens.
5. Bioactivities and Mode of Action
Basidiomycota have long been recognized as sources of interesting secondary metab-
olites; however, because of the slow mycelial growth and diverse nutritional requirements
they were often been neglected as a source of important bioactive compounds [5,81]. Re-
cently, due to the progress in -Omics technology, such as improved fermentation technol-
ogies and the development of sophisticated chemical analysis methods for secondary me-
tabolites, the chances of developing new products from Basidiomycota have increased
considerably [8,82–84].
Aside from low molecular metabolites, they contain beta-glucans and other oligo-
mers that constitute the active ingredients of medicinal mushrooms [3,4,85–87]. The Phy-
salacriaceae are known to produce manifold antibiotics from mycelial cultures [8,88], but
can also produce polysaccharides with anticancer, antihypertensive, anti-inflammatory
and hemagglutination activities [89–92]. Many studies have documented the bioactivities
of these mushrooms; however, most were inconclusive since they did not go further in
identifying the active principles using chromatography and spectral techniques, such as
mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Table 3 lists
some metabolites isolated from OX genera and their bioactivities.
The challenge of finding antimicrobial agents has become evident due to the increas-
ing resistance of pathogenic microorganisms to present-day drugs [2]. The exploration of
bioactive compounds especially from natural sources such as plants, bacteria and fungi is
needed to develop less toxic and more potent antibiotics [93]. Recently, mushrooms have
been subjected to screening for bioactive compounds and many studies have revealed
their antimicrobial activities [2,94]. The Agaricales were explored for their antimicrobial
capacity. The antimicrobial properties of mushrooms have potential in the defense against
several diseases [95]. Oudemansiella canarii has been well studied for its significant antimi-
crobial activities against Candida albicans, C. glabrata, C. krusei, C. tropicalis and C. sphaer-
ospermum [13,14,96]. The extract of Mucidula mucida (as O. mucida) was shown to have an-
tibacterial activity against the Gram positive bacterial pathogen, Staphylococcus aureus
[95], but this cannot be explained by the presence of strobilurins, which are selective anti-
fungal agents. Therefore, oudemansielloid species could turn out to be a source of novel
potent compounds with antimicrobial properties, once they have been studied more thor-
oughly.
Some compounds from OX taxa are already well studied. The strobilurins, first re-
ported by Anke et al. [97] from fermentations of Strobilurus tenacellus, were later also iso-
lated from numerous other Basidiomycota. The species H. radicata (as O. radicata and M.
mucida (as O. mucida) were also able to produce this compound and its derivatives (stro-
bilurins A (4), B (5) and X (6) [14,98–100] (Figure 5). The trivial names of these natural
fungicides are based on the order of their discovery (Table 3, Figure 5). They are potent
inhibitors of respiration owing to their ability to inhibit electron transfer between mito-
chondrial cytochrome b and cytochrome c1 through binding at the ubiquinol-oxidation
centre [101,102]. This development opened the door to new synthetic fungicides. The syn-
thetic analogues based on Quantitative Structural Activity Relationships (QSAR) of the
structures of the natural strobilurins are more effective and stable [103].
J. Fungi 2021, 7, 51 11 of 24
Table 3. Secondary metabolites produced by some species of the OX complex with their bioactivities.
Species Bioactive Compounds Biological Activities References
Mucidula mucida
Mucidin/strobilurin A/mucidermin Antifungal Musilek et al. [77], Anke et al.
[98], Subik et al. [104]
Strobilurins Antifungal Iqbal et al. [99],
Anke et al. [98]
Oudemansins
Cytotoxic Ying et al. [105]
Antifungal Vondracek [106], Anke et al.
[100]
Strobilurin X, 4’-methoxymucidin
Anke et al. [107]
Hymenopellis radicata
Oudemansin X Anke et al. [107]
Umezawa et al. [90], Tsantrizos
et al.[90,107]
Strobilurins Antifungal
Oudemansins Antihypertensive
Oudenone Hemagglutinating activity Liu et al. [92]
Lectin Antifungal Anke et al. [100,104,108]
Mucidin Antioxidative, anti-inflamma-
tory, lung-protective effects Gao et al. [91]
SMPS, MPS (mycelia polysaccharides) Antioxidant; antifungal Wang et al. [9], Zou [109]
, Liu et
al. [110]
Polysaccharides Antifungal Rosa et al. [14,96]
Oudemansiella canarii Oudemansin A Antifungal, inhibitor of eu-
caryotic respiration Anke et al. [108]
Oudemansiella melanotricha
Oudemansin B, strobilurin C Inhibitor of cholesterol bio-
synthesis Kuhnt & Anke [111]
Xerulin, di-hydro-xerulin, xerulinic
acid Antifungal Weber et al. [112]
Hydroxy-strobilurin D Antifungal, inhibitor of eu-
caryotic respiration Anke et al. [108]
Xerula longipes
Oudemansin B, strobilurin C Antifungal Sivanandhan et al. [88]
Xerula pudens
Strobilurin C Antifungal Sivanandhan et al. [88]
Sadorn et al. [113] Oudemansin B Antimalarial, antifungal, cy-
totoxic
Xerula sp. BCC56836
Oudemansins Antibacterial
Sadorn et al. [113]
Strobilurin derivatives Antibacterial, antifungal
Scalusamides A Enzyme-inhibitory activity;
antifouling activity
Phenol A acids Enzyme-inhibitory activity
Dihydro-citrinone Antibacterial
Xerulins Antibacterial
Xerucitrinic acid A Antimicrobial, insecticidal
2-(5-Heptenyl)-6,7,8,8a-tetrahydro-3-
methyl-4H-pyrrolo [2,1-b][1,3]oxazin-4-
one (17)
Oudemansins and strobilurins have been reported from a variety of Basidiomycota,
which are widely distributed all over the world in tropical and temperate climates, but
the most frequently reported producers are the genera of the Physalacriaceae treated here
and the related genera Strobilurus and Mycena [114]. Mycelial cultures of M. mucida pro-
duce oudemansin A, which is closely related to strobilurin A [104], and these compounds
show high antifungal activity at very low concentrations [77,115]. Oudemansin also in-
hibited the growth of Ehrlich ascites carcinoma in rats, but at rather weak concentrations
[105]. Rosa et al. [14] later found the compound in O. canarii. An extract of cultures of the
latter species showed antifungal effects but inhibited the growth of UACC-62 cells by 47%
and the enzyme trypanothione reductase (TryR), thus indicating anti-tumor activity. Hy-
menopellis radicata is also known to produce oudemansins [14,100]. Mucidin and stro-
bilurin A were found to be identical [84,102]. Mucidin was discovered in the 1960s from
J. Fungi 2021, 7, 51 12 of 24
the submerged culture of M. mucida as an antifungal agent and its structure was described
and established in 1979 [98]. Šubík et al. [104] noted that mucidin could inhibit the growth
and germination of the conidia of Aspergillus niger. It also completely prevented the
growth of yeasts in glycerol and ethanol and inhibited the growth of wild-type yeasts
including anaerobes. Mucidin repressed the oxidation of glucose and ethanol under aer-
obic condition; however, in an anaerobic environment, the metabolism of glucose was not
affected. In the presence of glucose, mucidin was able to reduce cytochrome b and com-
pletely oxidized cytochrome a and c by inhibiting mitochondrial electron transport, thus
contributing to its antifungal activity. Specifically, it inhibits electron-transfer reactions in
the cytochrome bc1 complex of the mitochondrial respiratory chain [102].
A water-soluble polysaccharide (ORWP) from Hymenopellis radicata also inhibited the
growth mould P. digitatum by disrupting the hyphal membrane, leading to leakage of in-
tracellular materials, and impaired cellular metabolism [116]. There are other promising
compounds identified with antimicrobial activities which do not belong to the group of
strobilurins. One is scalusamide A, an antifungal agent and its derivatives (B,C) isolated
from Xerula sp. BCC56836 [113].
Figure 5. Chemical structures of bioactive compounds isolated from OX genera with antimicro-
bial/antifungal activities.
Many studies have been conducted on the anti-oxidant and anti-cancer properties of
other oudemansielloid species, which cannot be explained by the presence of strobilurins.
As early as 1987, Mucidula mucida extracts demonstrated inhibitory effect on sarcoma 180
and Erhrlich carcinoma of mice [105]. Oudemansiella canarii has moderate anticancer and
anti-oxidant properties [96,117]. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scav-
enging, total antioxidant activity and 2,2-azinobis (3-ethyl benzothiaoline-6-sulfonic acid)
(ABTS) assays were used to determine anti-oxidation properties of the methanolic extracts
J. Fungi 2021, 7, 51 13 of 24
of O. canarii [117]. HPLC analysis was also used to record and analyse phenolic finger-
prints. Acharya et al. [117] were able to quantify the DPPH radical scavenging activity
using EC50 at 0.912 µg/mL. The total antioxidant activity was 15.33 µg ascorbic acid equiv-
alent/mg of extract. ABTS revealed 12.91 µm TE/mg of extract antioxidant activity.
Oudemansiella canarii can therefore be a novel source of antioxidants with functional food
and supplement applications. An ethyl acetate extract from O. canarii was active against
enzyme TryR from Trypanosoma cruzi, three human cancer cell lines (MCF-7- breast, TK-
10- renal and UACC-62-melanoma) and phytopathogenic fungus Cladosporium sphaer-
ospermum [96]. However, in its activity against three cancer cell lines, it was noted that it
exhibited a degree of selectivity against UACC-62, 2–3 times more active as compared
with MCF-7 and TK-10. As an important note, the extract was inactive in lymphocyte pro-
liferation assays, thus indicating that this compound has a low level of toxicity to normal
human cells. It is therefore likely to be safe when used and developed in pharmaceutical
applications [96].
Polysaccharides isolated from the oudemansielloid genera showed anti-oxidative
properties [9,91,116,118]. Polysaccharides such as water-soluble polysaccharides (ORWP)
and alkali-soluble polysaccharides (ORAP) from Hymenopellis radicata were tested for in
vitro antioxidant and in vivo hepatoprotective activities [9,116]. The polysaccharides dis-
played anti-oxidative activity against CCl4-induced liver injury of mice, thus demonstrat-
ing the hepato-protective effect of these compounds [9]. Mycelia polysaccharides (MPS)
and mycelia selenium polysaccharides (MSPS) (Figure 6) isolated from H. radicata also
have antioxidative and lung-protective effects [92,118]. The MSPS derived from the fun-
gus was able to relieve lung injury and prevent oxidative stress from lipopolysaccharide-
induced lung injured mice, thus they can possibly be developed into functional foods and
natural drugs in preventing lung injury [91]. These polysaccharides showed potential for
relieving liver injury by monitoring the serum levels of hypersensitive C-reactive proteins,
complement 3, and serum enzyme activities (aspartate aminotransferase, alanine ami-
notransferase, and alkaline phosphatase). They also enhanced antioxidant enzyme abili-
ties (superoxide dismutase, glutathione peroxidase, catalase, and total antioxidant capac-
ity). Lipid peroxidation (lipid peroxidation and malondialdehyde) also decreased. The
polysaccharides were mainly composed of mannose, glucose and galactose as monosac-
charide components [116].
The enzymatic- and acid- hydrolysed mycelia polysaccharides (En-MPS and Ac-
MPS) from Hymenopellis radicata on lipopolysaccharide-induced acute lung injury (ALI)
mice was tested for their antioxidative and pulmonary protective effects [118]. En-MPS
has more antioxidative effect than Ac-MPS. Selenium polysaccharides were also produced
by H. radicata. The hydrolysates (enzymatic-SPS) and acidic-SPS) were acquired by enzy-
molysis and acidolysis. The in vivo mice experiments showed that the enzymatic-SPS dis-
played higher antioxidant and protective effects against the lipo-poly-ssachardide-toxici-
ties than selenium polysaccharides and acidic-SPS by increasing the antioxidant activities
and reducing lipid peroxidation. Enzymatic-SPS also helps improve the inflammatory re-
sponse which could aid in improving kidney and lung functions. This shows that the pol-
ysaccharides by H. radicata might be apt for functional foods. They can also be developed
as natural drugs in preventing the endo-toxemia and its complications [118]. Figure 6
shows the chemical structures of polysaccharides and salinised polysaccharides.
J. Fungi 2021, 7, 51 14 of 24
Figure 6. Chemical structures of polysaccharides isolated from OX genera with anti-oxidative
properties.
The most commonly administrated drugs to reduce inflammation in the body are
presently nonsteroidal anti-inflammatory drugs (NSAIDs). The negative effects of long-
term use of these drugs, especially their significant side effects on the gastrointestinal
tract, are well-known [119–121]. Therefore, much effort has been devoted to the search for
novel compounds as alternative anti-inflammatory agents that would be natural and safe,
without the harmful side effects of NSAIDs [122]. Mushrooms have been explored for
their favourable therapeutic and health-promoting benefits, particularly in relation to dis-
eases associated with inflammation [2]. Compounds with highly diversified chemical
structures and anti-inflammatory activities have been isolated and purified from different
types of mushrooms. Mushrooms, such as those from the oudemansielloid genera, are
rich in anti-inflammatory components, such as polysaccharides, phenolic and indolic
compounds [123]. The antioxidant activity of extracts is mostly coupled with anti-inflam-
matory effects. The enzymatic-mycelia polysaccharides and acid-hydrolysed mycelia pol-
ysaccharides from Hymenopellis radicata, for example, have anti-inflammatory effect aside
from the antioxidative and pulmonary protective activities of the mycelial selenium-en-
riched polysaccharides and mycelial polysaccharides from other studies [92,116,118]. The
anti-inflammatory and reno-protective effects of selenized mycelial polysaccharides from
the same species have also been reported [124]. Further studies should be conducted to
identify and elucidate the bioactive compounds from OX genera responsible for its anti-
inflammatory properties.
Edible mushrooms have the ability to stimulate the immune system by exerting ef-
fects on cellular activities, producing secondary metabolites that boost the immune sys-
tem, modulate humoral and cellular immunity, and potentiate antimutagenic and anti-
tumorigenic activity, as well as rejuvenating the immune system destroyed by radiation
and chemotherapy in cancer treatment, usually linked to β-glucans [125,126]. Specifically,
β-glucan, a water-soluble polysaccharide, activates immune cells and proteins and mac-
rophages, T cells, natural killer cells, and cytokines that attack tumor cells [127,128]. This
potential of mushrooms, therefore, qualifies them as candidates for immunomodulation
and immunotherapy in cancer and other disease treatments [128]. In addition, lectins from
mushrooms have many biological activities, such as antiproliferative, antitumor, im-
munomodulatory, and HIV-1 reverse transcriptase inhibiting activities [3,129].
Sadorn et al. [113] identified 12 (Figure 7) different compounds from a Xerula sp.
(strain BCC56836) in Thailand. These were mostly known compounds, such as
oudemansins, derivative of strobilurin, scalusamides A–C, phenol A acid and di-hydro-
J. Fungi 2021, 7, 51 15 of 24
citrinone. The strain also produced compounds such 2-(5-heptenyl)-6,7,8,8a-tetrahydro-3-
methyl-4H-pyrrolo [2 ,1-b][1,3]oxazin-4-one with insecticidal activity. Some oudemansins
known for their antifungal activity also exhibit antimalarial activity against Plasmodium
falciparum (IC50 1.19–13.7 µM) and antifungal activity against Alternaria brassicicola and
Colletotrichum capsici with MIC values ranging from 12.5−50 µg/mL. Aside from antifungal
and antibacterial activities of 2-(E-hept-5-en-1-yl)-3-methyl-6,7,8,8a-tetrahydro-4H-pyr-
rolo[2,1-b][1,3]oxazin-4-one, the compound also has insecticidal activity against the four-
instar Oncopeltus fasciatus (milkweed bug) and anti-phyto-pathogenicity against Fusarium
culmorum, Colletotrichum coccodes, Alternaria tenuis, and Penicillium italicum. The com-
pounds phenol A acid and di-hydro-citrinone have enzyme-inhibitory activity against ca-
thepsin B with IC50 values of 20.4 ± 1.9 and 28.5 ± 1.7 µM, respectively. Most of the com-
pounds isolated have low cytotoxicity in both the both cancerous and non-cancerous cells.
Xerulins (27) with their derivatives, di-hydro-xerulin (28) and xerulinic acid (29) (Fig-
ure 8) were isolated from Oudemansiella melanotricha. These compounds act as inhibitors
of cholesterol biosynthesis. They strongly inhibit the incorporation of 14C acetate into cho-
lesterol in HeLa cells [112]. Xerulin and di-hydro-xerulin inhibited the biosynthesis of cho-
lesterol in HeLa S3 cells (ID50 = 1 µg/mL) without being cytotoxic [111,130]. Xerulinic acid,
however, also inhibited biosynthesis but was found to be cytotoxic [111].
Oudenone from cultures of Hymenopellis radicata is an inhibitor of tyrosine hydrolase,
an enzyme responsible for catalysing the conversion of the amino acid L-tyrosine to L-3,4-
dihydroxyphenylalanine, thus it could have potential as antihypertensive agent
[89,90,107].
Ingestible polysaccharides are the main components of mushrooms that play a prebi-
otic role by modulating the composition of gut microbiota [110]. Liu et al. [110] showed
that polysaccharides from Hymenopellis radicata (as Oudemansiella radicata) were utilized
by gut microbes to produce short-chain fatty acids during anaerobic fermentation of indi-
gestible polysaccharides, therefore regulating the composition of gut microbiota. Hence
the polysaccharides found in this mushroom cold be developed into a functional food that
promotes intestinal health and prevents diseases.
J. Fungi 2021, 7, 51 16 of 24
Figure 7. Chemical structures of compounds identified from Xerula sp. BCC56836 with antifungal
and insecticidal properties.
Figure 8. Chemical structures of other compounds act as inhibitors of cholesterol biosynthesis iso-
lated from Oudemansiella melanotricha.
6. Biosynthesis of Strobilurins and Total Synthesis of Xerulins
The bio-synthethic gene cluster for strobilurin was first identified from Strobilurus
sp.; however, its detailed molecular biosynthesis remains cryptic. Nofiani et al. [84] re-
ported the biosynthesis of strobilurin using Aspergillus oryzae by identifying the biosyn-
thesis gene cluster, which encodes the highly reducing polyketide synthase. The synthesis
is via a novel route initiated with benzoyl CoA molecules rather than the usual acetyl unit
(Figure 9). The compound is formed by the degradation of phenylalanine via cinnamate
[99]. As the core polyketide chain is formed, it undergoes a complex rearrangement to
make the β-meth-oxy-acrylate toxophore. The antifungal activity of strobilurins is brought
J. Fungi 2021, 7, 51 17 of 24
about by the β-methoxy-acrylate toxophore preventing the synthesis of adenosine triphos-
phate by targeting the Qo site of complex III of the mitochondrial electron transport chain
[131].
The synthesis of dihydroxerulin was first described by Siegel and Brückner [132]. It
began with stereoselective preparations of phosphorus ylide 1 and lactone aldehyde 2 and
ended with a Wittig reaction between these entities. The process resulted in the formation
of up to 30% of the trans Z isomer 3, along with up to 25% of a mixture of at least two
stereoisomers. The same researchers synthesized xerulin via a convergent route and were
able to get the pure form of the compound [132]. The total synthesis of xerulin by Negishi
et al. [133] was accomplished from commercially available (E)-1-bromopropene, acety-
lene, and propynoic acid with 30% overall yield and >96% stereoselectivity.
Figure 9. Biosynthesis of strobilurin A [85].
7. Market and Commercialization
Among the many compounds isolated from the OX genera, only strobilurins have
made it to the commercial market, but the natural products were too unstable in the field
experiments and it was considered a great challenge to achieve the biotechnological pro-
duction of the natural compounds in ton scale as generally required for agrochemical fun-
gicides. The discovery of the strobilurins, however, allowed the opportunity to develop
synthetic fungicides by mimetic synthesis because the natural core structure was rela-
tively simple [5]. The first synthetic fungicide arising from mimetic synthesis using stro-
bilurins as a template was published in 1996 [134]. Natural strobilurins were named con-
secutively according to the order of discovery such as strobilurin A, B, and C. Applying
Quantitative Structural Activity Relationship on the structures of the natural strobilurins,
numerous companies were able to produce synthetic analogues, which are more effective
in combating target organisms [103]. Nofiani et al. [84] stated that there are eight synthetic
strobilurins on the market worldwide, some of which are already registered for agro-
chemical use. The key compounds are azoxystrobin (30), di-moxystrobin (31), fluoxastro-
bin (32), kresoxim-methyl (33), pyraclostrobin (34), picoxystrobin (35) and tri-floxystrobin
(36) [135] (Figure 10). The estimated worth of these synthetic compounds is $3.4 billion in
2015, making up to 25% of the fungicide market and 6.7% of the total crop protection mar-
ket [84]. Currently, China is able to produce 4 strobilurin fungicides namely azoxystrobin,
pyraclostrobin, tri-floxystrobin and kresoxim-methyl (Figure 10). Some synthetic strobilurins
as fungicides with brand names, used against pumpkin diseases in Mississippi, were also
listed [136]. Many of these synthetic fungicides have been developed from azoxystrobin.
Azoxystrobin is a broad-spectrum fungicide with activity against several diseases on many
edible crops and ornamental plants such as rice blast, rusts, downy mildew, powdery mildew,
J. Fungi 2021, 7, 51 18 of 24
late blight, apple scab, and Septoria [137]. Amaro et al. [138] also showed that applying pyra-
clostrobin can enhance productivity and increase the antioxidative system, thereby reducing
stress in Japanese cucumber (Cucumis sativus).
In general, these properties have made the strobilurins one of the most commercially suc-
cessful natural product based class of agrochemicals and products from all the major agro-
companies, which have distributed them for decades. However, the pathogenic fungi and oo-
mycetes have increasingly developed resistance against the beta-methoxy-acrylates, and
therefore it is advisable to use them in combination with other antifungal agents [5]. It is urgent
to develop new antifungal pesticides in the near future based on different compound classes
and with different modes of action, and fungi appear to be a very promising source for these.
Therefore, the quest for antifungal metabolites from hitherto untapped sources should be in-
tensified.
Other compounds from OX genera, though thoroughly studied in terms of bioactiv-
ities, have not yet been introduced to the market. Further research is needed in order to
introduce these compounds for pharmaceutical, nutraceutical and medicinal applications.
Figure 10. Chemical structures of synthetic strobilurins on the market.
J. Fungi 2021, 7, 51 19 of 24
8. Future Perspectives
Mushrooms have been shown to have profound health-promoting benefits and are
commonly use in cosmetics [2,139]. The medical efficacy of bioactive compounds ex-
tracted from mushrooms is well-known. With advancements in chemical technology, it is
now possible to isolate and identify relevant compounds such as polysaccharides, glyco-
proteins, and other bioactive compounds [140].
Oudemansiella, Xerula, Mucidula and Hymenopellis, among other genera of mushrooms
produce important bioactive compounds, confirming their efficacy as antimicrobial, anti-
oxidants and anti-inflammatory agents. The compounds isolated were mostly dominated
by strobilurins; however, studies also identified xerulins, scalusamides, phenol A acid, di-
hydro-citrinone and polysaccharides with bioactivities and have not been fully exploited.
These promising compounds may have a bright future in pharmaceutical, nutraceutical
and medicinal application. These future applications, however, face challenges. Studies
on the cultivation of the OX genera are few as cultivation is generally developed only
edible species. The OX complex are only cultivated in Asian countries. Therefore, thor-
ough studies on the optimum cultivation methods of important species with bioactivities
are necessary for stable bioactive sources to supply future demands. Mushrooms grown
in greenhouses do not comply with current Good Manufacturing Practice (cGMP) require-
ments. Mushrooms should be grown in submerged cultures in a sterile environment to
produce high quality bioactive compounds for pharmaceutical and medical applications.
Another challenge is that the content of bioactive ingredients varies widely depending on
the procedure, harvest, extraction time, and other environmental factors. Therefore, es-
tablishing a stable protocol considering important physical parameters is necessary. Fur-
thermore, bioactivities of mushrooms are usually demonstrated using crude extracts, with
a mixture of solvents and other metabolites.
Some compounds, especially strobilurins, have already been identified with struc-
ture elucidation but many are strongly cytotoxic. However, it is possible that other inter-
esting compounds may be isolated from OX taxa in the future. Polysaccharides, for in-
stance, are non-toxic and should be further explored for their bioactivities. The possible
side effects of these compounds are an important concern and must be studied in order to
upgrade for pharmaceutical applications. It is also essential to establish and validate
standard testing protocols to guarantee the quality of the bioactive compounds isolated
for pharmaceutical applications, thus further studies are necessary.
Author Contributions: Conceptualization, A.G.N., O.R., K.D.H., and M.S.; chemical structures
preparation, R.C., and M.S.; investigation, K.D.H., A.G.N., M.S. and O.R.; visualization, N.T., R.C.
and S.L.; resources, N.T., S.L. and R.C.; data curation, A.G.N., O.R. and M.S.; writing—original draft
preparation, A.G.N., O.R. and N.T.; writing—review and editing, K.D.H., M.S. and O.R. All authors
have read and agreed to the published version of the manuscript.
Funding: This review is supported by the Thailand Research Fund grant “Domestication and bio-
active evaluation of Thai Hymenopellis, Oudemansiella, Xerula and Volvariella species (Basidiomy-
cetes)” (Grant No. DBG6180033) and Thailand Science Research and Innovation grant “Macrofungi
diversity research from the Lancang-Mekong Watershed and surrounding areas (Grant No.
DBG6280009).
Acknowledgments: We would like to acknowledge Jaidee Wuttichai and Wanpen Kanthathong for
assisting in the preparation of chemical structures of bioactive compounds used in the figures. We
also would like to thank Nuwanthika Wijesinghe and Achala Rathnayaka for helping in mapping
the OX species. K.D.H. thanks Chiang Mai University for the award of Visiting Professor.
Conflicts of Interest: The authors declare no conflict of interest.
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