INTRODUCTION
Malaria is classified among the most harmful parasitic diseases that threaten the world population in tropical and subtropical regions (Nasomjai, Arpha, Sodngam, & Brandt, 2014) . It is caused by one of the five Plasmodium species including P. falciparum, P. ovale, P. malariae, P. knowlesi and P. vivax, transmitted by the bites of the mosquitoes female Anopheles (Happi et al., 2015). In 2015, the World Health Organization (WHO) reports that a total of 214 million cases and 438 000 deaths were globally recorded due to malaria (WHO, 2015) . The parasite P. falciparum represents the most virulent species that causes the most severe forms of the disease and the greatest number of deaths (80% worldwide) with children and expectant mothers as the most vulnerable persons leading to high mortality if not taken in charge quickly (Júnior et al., 2012; Ogbole, Segun, Akinleye, & Fasinu, 2018). During the last decades, after the discovery of artemisinin and quinine from the medicinal plants Artemia annua and Cinchona succirubra, respectively, the journey in fighting and controlling malaria has faced several challenges mostly attributed to the resistance of P. falciparum to the administrated potent antimalarial drugs such as chloroquine, mefloquine and artemisinin-based combination therapies (Ma et al., 2015; Nasomjai et al., 2014; Ogbole et al., 2018). This observation of resistance and the significant number of death annually keep continuous the urgent need for new chemotherapeutic compounds to address the current situation of drug resistance (Bathurst & Hentschel, 2006). Other non-neglected resistances were observed by the vector mosquitoes to insecticides (Happi et al., 2015), while several recent chemical investigations have been done to develop new insecticides from bioactive extracts or the natural products obtained from flora and fauna that could help to control larvae, adult mosquitoes and which can be effective, eco-friendly, and biodegradable (Benelli, 2015).
For several centuries, mushrooms have been appreciated for nutritional and medicinal purposes and constitute good sources of bioactive extracts and specialized metabolites (Annang et al., 2018). It is documented that medicinal mushrooms possess more than 100 medicinal functions and among them, Ganoderma is a genus of bracket fungi that is widely used in Chinese herbal medicine for the treatment of several illnesses (Annang et al., 2018). Furthermore, mushrooms are also renowned for their uses in the food industry as dietary foods or in agriculture as pesticides, herbicides and insecticides (Ogbole et al., 2018). Basidiomycetes, especially mushrooms, are a good source of diverse specialized metabolites with a large scale of biological activities including antimalarial properties (Isaka, Srisanoh, Choowong, & Boonpratuang, 2011; Lakornwong et al., 2014). For instance, the extract of Ganoderma lucidum exhibited antimalarial activity (Ma et al., 2014; Oluba, Olushola, Fagbohunka, & Onyeneke, 2012), and the antimalarial properties of Cordyceps species and Bulgaria inquinans have been also reported (Isaka, Tantichareon, Kongsaeree, & Thebtaranonth, 2001). Despite the relevant and interesting data reported on the antimalarial potencies of extracts and compounds of some mushrooms, to the best of our knowledge, very few works have been done on their insecticidal activities while no review article has been published on the phytochemistry and pharmacology of mushrooms concerning their contribution in fighting against malaria as a source of antiplasmodial and insecticidal agents. This review covers the documented works up to 2021.
ANTIPLASMODIAL CONSTITUENTS OF MUSHROOMS
It is well reported that mushrooms represent an important source of bioactive secondary metabolites possessing antiplasmodial, antimicrobial, antitumoral, antioxidant or nematocidal potencies (Badalyan, 2004; Morrison et al., 2002; Zang et al., 2013; Zengin et al., 2016). More specifically, Ganoderma is one of the most investigated and used mushroom genus in Chinese herbal medicine (Paterson, 2006) . Previous pharmacological investigations on the identification of antiplasmodial extracts, fractions and compounds from mushrooms led to the report of interesting results that classified some mushroom extracts as promising references in new antimalarial drugs discovery. For instance, the ethyl acetate soluble extract of Ganoderma lucidum revealed antiplasmodial activity with 79% inhibition at 4.9 μg/ml (Adams et al., 2010), while the methanol and dichloromethane soluble extracts of Phellinus linteus showed activity with IC50 values of 3.15 and 3.08 μg/ml, respectively, against P. falciparum K1 (Samchai, Seephonkai, Sangdee, Puntumchai, & Klinhom, 2009). In the same way, the literature survey indicated that the extracts of H. fuscum contain antiplasmodial compounds which support the potencies revealed by these extracts against the strains D6 and W2 of P. falciparum with IC50 values of 6.98 and 8.33 µg/ml, respectively (Ogbole et al., 2018). Moreover, the antiplasmodial screening of the n-hexane extract of the fruiting bodies of Pleurotus ostreatus revealed that the extract inhibited in vitro Plasmodium parasite lactate dehydrogenase with an IC50 of 25.18 μg/ml but remained less active than the standard drug chloroquine diphosphate (IC50 = 0.016 μg/ml) (Afieroho et al., 2019).
Numerous chemical investigations have been conducted on different mushroom species to identify and characterize their antiplasmodial constituents present in their extracts. To date, forty-four compounds have been reported from eighteen species belonging to eleven genera (Table 1).
The great majority of reported specified metabolites are triterpenoids with various changes in their skeleton. The genus Ganoderma includes more than 200 species distributed throughout the world, is one of the most investigated genera among the mushrooms from which numerous (over 200) lanostane-type triterpenoids with a large scale of structural diversity and large scale of biological activities are reported in the literature (Paterson, 2006) . The literature survey shows that twenty-nine compounds with relevant antiplasmodial activity documented have been reported from eight Ganoderma species (Figure 2; Figure 1).
Recently in 2020, Isaka and co-workers reported the isolation of two triterpenoids namely (24E)-3-oxo-7α,15α,26-trihydroxylanosta-8,24-diene (1) and (24E)-7α,26-dihydroxy-3-oxo-lanosta-8,24-diene (2) from Ganoderma casuarinicola with moderate antiplasmodial activity against P. falciparum K1 with IC50 values of 9.2 μg/ml and 9.7 μg/ml, respectively (Isaka et al., 2020). Further triterpenoids with effect detected against the parasite P. falciparum K1 have been reported from the HPLC-based activity profiling and subsequent isolation of the antiplasmodial compounds of G. lucidum by Adams et al. (2010). From this previous work, ganoderic aldehyde TR (3) was the most potent with an IC50 value of 6 μM, while the chemical investigations of Ganoderma colossus led to the isolation of five antiplasmodial triterpenoids with moderate potency against the same strain K1 of P. falciparum. Briefly, the most active among them were ganocolossusin D (4) with an IC50 of 1.4 μg/ml, followed by ganodermalactone V (5), ganodermalactone T (6), ganocolossusin C (7) and ganocolossusin G (8) with IC50 values of 3.6 μg/ml, 5.0 μg/ml, 5.8 μg/ml and 8.2 μg/ml, respectively (Isaka et al., 2020) .
The obtained results chemically demonstrated that the genus Ganoderma is close to the genus Tomophagus based on the similarity of isolated compounds and further supported the taxonomy of Ganoderma colossus as a synonym of Tomophagus colossus (Isaka et al., 2020). Therefore, fifty compounds have been isolated from fruiting bodies Tomophagus sp. After their evaluation against P. falciparum K1, only eight compounds (9‒16) have demonstrated significant or moderate activity. Especially, colossolactone VIII (9), ganodermalactones D, O‒Q (10, 11‒13), tomophagusins B and D (14 and 15) showed activity with IC50 values <10 μM, ranging from 5.1 to 8.1 μM, while 11-oxo-colossolactone E (16) demonstrated potency with IC50 value of 10 μM (Isaka, Chinthanom, Thummarukcharoen, Boonpratuang, & Choowong, 2019).
Table 1
Antiplasmodial compounds from mushrooms.
More interestingly, the artificially cultivated fruiting bodies of Ganoderma weberianum produced two lanostane dimers with strong antiplasmodial activity against P. falciparum K1. Indeed, ganoweberianone A (17) displayed a potency with IC50 value of 0.050 μM while ganoweberianone B (18) showed an IC50 value of 0.46 μM (Isaka et al., 2020).
The chemical investigation of three incompletely identified Ganoderma species allowed the isolation and report of eight compounds that expressed an antiplasmodial activity:
Ganoderic acid AW1 (19) isolated from Ganoderma sp. revealed significant activity against P. falciparum D6 (IC50 of 257.8 nM) and P. falciparum W2 (IC50 of 2000 nM) (Wahba et al., 2019); the lanostane-type triterpenoids (24S)-24-hydroxy-3-oxo-lanosta-7,9(11),25-triene (20), (24S)-7α,24-dihydroxy-3-oxo-lanosta-8,25-diene (21), (24S,25R)-7α,26-dihydroxy-24,25-epoxy-3-oxolanosta-8-ene (22) and 24,25-epoxy-3-oxo-lanosta-7,9(11)-diene (23) isolated from Ganoderma sp. BCC 21329 displayed moderate activity with IC50 values ranging from 3.8 μg/ml to 7.6 μg/ml against P. falciparum K1 (Isaka et al., 2020); the two triterpenoids ganodermalactone F (24) and schisanlactone B (25) obtained from cultured biomass of the macrofungi Ganoderma sp. KM01 showed activity with IC50 values of 10.0 μM (for 24) and 6.0 μM (for 25) against P. falciparum K1 (Lakornwong et al., 2014) .
From the ethyl acetate extract of fruiting bodies of the medicinal mushroom Ganoderma boninense, three nortriterpenes named ganoboninketals A‒C (26-28) containing rearranged 3,4-seco-27-norlanostane skeletons and highly complex polycyclic systems were isolated and showed moderate antiplasmodial activity against P. falciparum 3D7 with IC50 values of 4.0 μM, 7.9 μM and 1.7 μM, respectively (Ma et al., 2014). One year later, the same author reported the same potencies with the IC50 values of 4.04 μM, 7.88 μM and 1.72 μM against P. falciparum 3D7 for ganoboninketals A‒C (26‒28), respectively, isolated from G. boninense Pat (Ma et al., 2015). The compound ganoboninketal C (28) was prepared from methylation of ganoboninketal D isolated from the species Ganoderma orbiforme and was less active against P. falciparum K1 with an IC50 of 3.8 μg/ml equal to 6.8 μM (Isaka et al., 2017). Furthermore, the chemical investigation of G. boninense gave another 3,4-seco-27-norlanostane triterpene ganoboninone F (29) displaying a significant activity with IC50 value of 2.03 μM against P. falciparum 3D7 (Ma et al., 2015).
Astraeusin M (30) from Astraeus asiaticus revealed an activity with IC50 of 3.0 μg/ml against P. falciparum K1 (Isaka et al., 2017).Annang et al. (2018) carried out the bioassay-guided study of two mushrooms Pleurotus ostreatus and Scleroderma areolatum for searching their antiplasmodial constituents against P. falciparum 3D7. Two scalarane sesterterpenes 31 and 32 (Figure 3) isolated from the edible one Pleurotus ostreatus revealed effectiveness with IC50 values of 4.21 μM and 7.63 μM, respectively, while the triterpenes 33 and 34 obtained from S. areolatum showed potency with IC50 values of 1.65 μM and 6.78 μM, correspondingly. Additionnally, no cytotoxicity was observed for the four compounds 31‒34 against HepG2 tumoral human liver cells.
The chemical modifications of astraodorol isolated as a major compound from the edible mushroom Astraeus odoratus led to the preparation of ten derivatives that were evaluated for their antiplasmodial activity. The seven triterpenes 35‒41 exhibited strong antimalarial activity against P. falciparum K1 with IC50 values of 4.85, 4.48, 4.16, 4.46, 3.45, 3.23, and 3.41 μg/ml, respectively (Nasomjai et al., 2014) .
The aromatic sesquiterpenoids hitoyopodin A (42) (Figure 4 ) obtained from Coprinopsis cinerea showed potency with IC50 values of 6.7 μM against P. falciparum 3D7 (Otaka et al., 2018). The total synthesis of compound 42 was achieved and the synthetic compound was slightly more potent (IC50 of 6.2 μM) than the natural one (IC50 of 6.7 μM) against P. falciparum 3D7. Aurisins A (43) and K (44) (Figure 4) are dimeric sesquiterpenoids isolated from Anthracophyllum sp. BCC18695 (Intaraudom et al., 2013) and Neonothopanus nambi (Kanokmedhakul et al., 2012) were evaluated for their antiplasmodial potencies against P. falciparum K1. The results showed that aurisin A (43) from Anthracophyllum sp. BCC18695 exhibited moderate activity with IC50 of 1.43 μM (Intaraudom et al., 2013), while the activity was more significant for the one isolated from N. nambi with an IC50 of 0.80 μM (Kanokmedhakul et al., 2012). Aurisin K (44) displayed similar strong potency from both sources with IC50 of 0.69 μM (from Anthracophyllum sp. BCC18695) and 0.61 μM (from N. nambi), respectively (Intaraudom et al., 2013; Kanokmedhakul et al., 2012). A third dimeric sesquiterpenoid aurisin G (45) has been reported from Anthracophyllum sp. BCC18695 and exhibited a strong activity with IC50 value of 0.27 μM against P. falciparum K1 (Intaraudom et al., 2013).
From the cultures Stereum ostrea BCC 22955, the dimeric sesquiterpene sterostrein A (46) was isolated and exhibited antimalarial activity with IC50 of 2.3 μg/ml against P. falciparum K1 (Isaka et al., 2011). Among the compounds isolated from Gloeostereum incarnatum BCC41461 and tested for their antiplasmodial activity against P. falciparum K1, only chondrosterin B (47), incarnatins A and B (48 and 49) (Figure 5) demonstrated a moderate activity with IC50 values of 3.10 μM, 9.80 μM and 3.93 μM, respectively (Bunbamrung et al., 2017). The culture and chemical examination of Xerula sp. BCC56836 led to the isolation of (−)-oudemansin X (50) that showed significant activity with IC50 of 1.19 μM against P. falciparum K1, while (−)-oudemansin A (51) was found moderately active with IC50 value of 9.23 μM (Sadorn et al., 2016).
CYTOTOXICITY OF ANTIPLASMODIAL COMPOUNDS FROM MUSHROOMS
Along with the evaluation of their antiplasmodial potency, several reported metabolites from mushrooms have been tested for their cytotoxicity against cancerous and noncancerous cell lines (Table 2). Briefly, numerous specialized metabolites demonstrating a strong or moderate antiplasmodial activity were found inactive in cytotoxicity assay even at the highest concentration of 50 μM.
The isolated compounds from Gloeostereum incarnatum BCC41461 were assessed for cytotoxicity against MCF-7, KB, NCI-H187 and vero cells. Compound 47 demonstrated strong activity against cancerous cells (IC50 values of 0.63 μg/ml for NCI-H187, 2.05 μg/ml for KB and 4.98 μg/ml for MCF-7) and noncancerous cell vero (IC50 of 0.65 μg/ml) (Bunbamrung et al., 2017), but was reported in 2012 by Li and co-workers to be inactive against three cancer cell lines (human cancer cell A549, human nasopharyngeal carcinoma cell CNE2, and human colon cancer cell LoVo) with an IC50 value > 200 μM (Li et al., 2012). Moderate cytotoxicity was detected for compound 49 against the four same cell lines with IC50 values ranging from 18.86 μg/ml (for vero) to 29.76 μg/ml (for MCF-7), while compound 48 was inactive (IC50 > 50 μg/ml) against all the four cell lines (Bunbamrung et al., 2017).
Table 2
Cytotoxicity activity (IC50) of some antiplasmodial agents from mushrooms.
In the same way, the cytotoxicity of aurisins A (43), G (45) and K (44) against the four previous cell lines were conducted and led to the observation that the three compounds were inactive against the MCF-7 cell lines, while the three compounds were less active against the noncancerous cell line vero with IC50 values above 30.52 μM, but displayed relevant activity against the KB cell line with potency recorded in term of IC50 values ranging from 1.64 μM to 2.50 μM. However, aurisins A (43) and G (45) isolated from Anthracophyllum sp. BCC18695 displayed strong activity against NCI-H187 with IC50 values of 0.86 μM and 0.52 μM, respectively (Intaraudom et al., 2013). However, compounds 43 and 44 obtained from N. nambi displayed good cytotoxicity against NCI-H187 cell lines with IC50 values of 1.55 μM and 1.45 μM, respectively (Kanokmedhakul et al., 2012).
Furthermore, aurisin A (43) showed cytotoxicity against BC1 cell lines (IC50 of 3.72 μM) and aurisins K (44) against KB cell lines (IC50 of 6.87 μM). Both compounds were not active against MCF-7 cell lines while compound 43 exerted strong cytotoxicity against cholangiocarcinoma cell lines KKU-100, KKU-139, KKU-156 and KKU-213 with IC50 values of 2.77 μM, 1.83 μM, 1.57 μM and 1.75 μM, respectively. At the same time, compound 44 gave a moderate activity against the cell lines KKU-139, KKU-156 and KKU-213 with IC50 values of 28.61, 7.63, and 20.90 μM, respectively (Kanokmedhakul et al., 2012).
Among the derivatives obtained from chemical modifications of lanostane-type triterpene astraodorol, compounds 37‒39 possessed moderate cytotoxicity with IC50 values of 23.36, 34.28, and 9.84 μg/ml, respectively, against NCI-H187. Additionally, compound 39 was also active against KB cell line with IC50 of 16.94 μg/ml and displayed activity against MCF-7 cell line with IC50 value of 49.60 μg/ml (Nasomjai et al., 2014).
The compounds (−)-oudemansins A (51) and X (50) demonstrated low cytotoxicity against both cancerous (KB, MCF-7, NCI-H187) and non-cancerous (vero) cells (Sadorn et al., 2016) . Compounds 20‒23 showed weak cytotoxicity to vero cells (African green monkey kidney fibroblasts) with IC50 values ranging from 17 μg/ml to 34 μg/ml (Isaka et al., 2020). The cytotoxicity of compounds 1 and 2 was evaluated against vero cells and led to the observation of significant cytotoxicity with IC50 values of 13.1 and 12.0 μg/ml, respectively (Isaka et al., 2020). The triterpenoids ganoweberianones A (17) and B (18), presented important cytotoxicity against vero cell lines with IC50 values of 0.21 and 10 μM, respectively (Isaka et al., 2020), while ganodermalactone V (5) showed a potency of IC50 equal to 8.5 μg/ml (Isaka et al., 2020).
In cytotoxicity assay, ganoboninketals A (26) and C (28) demonstrated IC50 values of 47.6 μM and 35.8 μM, respectively, against the A549 cell line while ganoboninketal B (27) also showed weak potency (IC50 = 65.5 μM) against HeLa cell line (Ma et al., 2014).
INSECTICIDAL PROPERTIES OF MUSHROOM EXTRACTS
The challenge in the management of malaria is both at the curative level in fighting against P. falciparum as well as at the prevention level in mosquito control programs. In addition to the previous presented chemical and pharmacological works on the search for antiplasmodial extracts and compounds from mushrooms, few investigations have been done on the evaluation of their insecticidal activity. The works done bySivanandhan, Ganesan, Paulraj, and Ignacimuthu (2018) aimed to evaluate the mosquitocidal activity of 6 mushroom species including Clitocybe rivulosa, Calocybe indica, Lentinus squarrosulus, Laetiporus sulphureus, Marasmius sullivantii and Marasmiellus candidus on eggs and larvae of Culex quinquefasciatus and Anopheles stephensi.
Their results reported that the Laetiporus sulphureus methanol extract was the most active against mosquitoes with 96% larvicidal activity against A. stephensi (LC50 of 155.862 ppm and LC90 of 424.128 ppm) and 76% larvicidal activity against C. quinquefasciatus (LC50 of 227.225 ppm and LC90 of 1011.663 ppm). Furthermore, after 120 hours of treatment, at 500 ppm, that L. sulphureus methanol extract displayed significant ovicidal activity against A. stephensi eggs (100% activity) and C. quinquefasciatus eggs (91% activity).
Additionally, more recent investigations of the methanol extract of Psathyrella candolleana against C. quinquefasciatus and Anopheles stephensi showed good larvicidal activity with LC50 and LC90 values of 166.713 and 259.17 ppm, respectively, against the third instar larvae of C. quinquefasciatus after 24 hours of treatment, as well as 88% ovicidal activity against C. quinquefasciatus eggs at 500 ppm concentration 120 h after treatment (Sivanandhan, Ganesan, David, Paulraj, & Ignacimuthu, 2019).
These two works on the insecticidal activity of some mushroom extracts showed that the methanol extract of L. sulphureus is a good natural source for controlling mosquitoes like A. stephensi and C. quinquefasciatus while the methanol extract of P. candolleana could be used in the development of new eco-friendly insecticides to control C. quinquefasciatus. Therefore, mushrooms require more attention because they represent a non-negligible and unexplored source of bioactive extracts and compounds for the development of new insecticides to control the mosquitoes like A. stephensi which is the major vector of the malaria parasite P. falciparum.
CONCLUSION AND FUTURE PROSPECTS
The present review summarizes the previously-reported investigations on the chemistry and biological evaluations of compounds isolated from mushrooms for their antiplasmodial, cytotoxicity and insecticidal activities up to 2021. A total of forty-four distinct compounds including twenty-four lanostane-type triterpenoids as a major class of isolated compounds mostly from the genus Ganoderma, have been reported with significant antiplasmodial efficiency against two major strains K1 and 3D7 of P. falciparum. Among the tested compounds, some of them displayed very significant effectiveness against chloroquine-resistant strain P. falciparum K1, this includes ganoweberianones A (17) and B (18), ganoderic acid AW1 (19), as well as aurisins A (43), K (44) and G (45). These compounds more specifically, represent promising data that deserve further investigations for new antiplasmodial drug discovery. Furthermore, the reported works on the insecticidal activities of some mushrooms extracts showed that some methanol extracts of mushroom species could contain significant insecticidal agents. However, several investigations as ADMET, chemical modifications of active compounds to increase their activity and decrease their toxicity, some pharmacokinetics or clinical trials could be done in the continuity. Since very few studies have been done on the search for antiplasmodial and insecticidal constituents from mushrooms, we expect that this review will be a significant summary to motivate and empower further investigations in this field to obtain new additional potent leads from mushrooms against P. falciparum and the mosquitoes Anopheles.
Author contributions
Research concept and design: Gervais Mouthé Happi, Jean Duplex Wansi; Collection and/or assembly of data: Livine Zemo Meikeu, Klev Gaïtan Sikam, Liliane Clotilde Dzouemo, Gervais Mouthé Happi ; Data analysis and interpretation: Gervais Mouthé Happi, Jean Duplex Wansi; Writing the article: Livine Zemo Meikeu, Gervais Mouthé Happi, Klev Gaïtan Sikam, Liliane Clotilde Dzouemo; Critical revision and Final approval of the article: Jean Duplex Wansi.
