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Lichen-forming fungi produce a vast number of unique natural products with a wide variety of biological activities and human uses. Although lichens have remarkable potential in natural product research and industry, the molecular mechanisms underlying the biosynthesis of lichen metabolites are poorly understood. Here we use genome mining and comparative genomics to assess biosynthetic gene clusters and their putative regulators in the genomes of two lichen-forming fungi, which have substantial commercial value in the perfume industry, Evernia prunastri and Pseudevernia furfuracea. We report a total of 80 biosynthetic gene clusters (polyketide synthases (PKS), non-ribosomal peptide synthetases and terpene synthases) in E. prunastri and 51 in P. furfuracea. We present an in-depth comparison of 11 clusters, which show high homology between the two species. A ketosynthase (KS) phylogeny shows that biosynthetic gene clusters from E. prunastri and P. furfuracea are widespread across the Fungi. The phylogeny includes 15 genomes of lichenized fungi and all fungal PKSs with known functions from the MIBiG database. Phylogenetically closely related KS domains predict not only similar PKS architecture but also similar cluster architecture. Our study highlights the untapped biosynthetic richness of lichen-forming fungi, provides new insights into lichen biosynthetic pathways and facilitates heterologous expression of lichen biosynthetic gene clusters.

In recent years, evidence for the anti-cancer activity of lichen secondary metabolites has been rapidly increasing. In this study, we synthesised analogues of diffractaic acid, a lichen secondary metabolite, and evaluated their ability to suppress colorectal cancer stem potential. Among the 10 compounds after H/CH₃/benzylation of the diffractaic acid structure or modifications in an aromatic hydrophobic domain, TU3 has a more inhibition effect on the stem potential of colorectal cancer compared to other compounds. The compound TU3 targets ALDH1 and suppresses key signalling pathways such as WNT, STAT3, NF-κB, Hedgehog, and AP-1. Inhibition of these signalling pathways by TU3 contribute to attenuate the survival mechanisms of colorectal cancer stem cell and thus inhibit cancer progression.

Questions How do mat thickness, physical structure and allelopathic properties of terricolous mat‐forming lichens affect recruitment of vascular plants in dwarf‐shrub and lichen heath vegetation? Location The mountains of Dovrefjell, central Norway. Methods In autumn, seeds of ten vascular plant species were collected and sown in a common garden experiment with mats of six lichen species and bare soil controls as experimental treatments. We recorded growing season soil temperature and moisture, and seedling recruitment and growth after one year. The effect of lichen secondary compounds on germination was tested in a growth chamber experiment and compared to the lichen–plant interactions detected under field conditions. Results The lichen mats buffered extreme soil temperatures and soil drying in dry weather, with soils below the thickest mats (Cladonia stellaris and C. rangiferina) experiencing the lowest temperature fluctuations. Seedling recruitment and seedling growth in the field and seed germination in the lab were species‐specific. Seedling recruitment rates were overall higher within lichen mats than on bare soil, but the c. 6.5‐cm‐thick mats of C. stellaris reduced recruitment of many species. The lab experiment suggested no overall strong effect of lichen allelopathy on seed germination, and effects on seed germination were only moderately correlated with the lichen–plant interactions observed for seedling recruitment in the field. Conclusions In harsh environments like alpine dwarf‐shrub and lichen heaths, the presence of lichens and the resulting amelioration of the microclimate seem more important for vascular plant recruitment than are allelopathic effects often reported in lab experiments. We might therefore expect most terricolous lichens, depending on the plant species in focus, to facilitate rather than hamper the early stages of plant recruitment into lichen‐dominated arctic‐alpine heath vegetation. Lichens are thought to affect vascular plant recruitment negatively through allelopathy and physical mechanisms but may also have positive effects related to amelioration of microclimate. By combining field and laboratory experiments, we demonstrate predominantly positive effects of lichens on seed germination and seedling growth. Thus, lichens may facilitate rather than hamper vascular plant recruitment.

Background Despite the application of various tools for the control of vectors of Plasmodium falciparum , malaria remains the major killer disease in sub-Saharan Africa accounting for up to 90% of deaths due to the disease. Due to limitations of the useage of chemical insecticides such as resistance, negative impact on the environment and to nontarget organisms, the World Health Organization (WHO) requires that affected countries find alternative vector control tools. This study evaluated the effectiveness of ( +)-usnic acid (UA) as an insecticide through oral administration to male and female Anopheles gambiae as an alternative or additional active ingredient to be used in toxic sugar bait. Methods ( +)-usnic acid was diluted using acetone at 5, 10, and 15 mg/ml concentrations in three replicates. A 5 ml mixture of 2% food dye and 10% sugar using chlorine-free water mixed with the dilutions of the ( +)-usnic acid and negative control was made containing 2% food dye and 10% sugar solution. The preparations were soaked on a ball of cotton wool and placed over the net of a cup. 5 male and 5 non-blood-fed female newly hatched starved An. gambiae Kisumu strain were introduced together into a cup and monitored for knockdown and mortalities after 4, 24 48, and 72 h. The data were analysed using a multiple linear regression model using the lm function, a base R function and a posthoc test were conducted on the significant main effects and interaction terms using the emmeans function from the emmeans R package. All analyses were performed in RStudio using base R (version 4.3.3). Results There was high mortality of both male and female An. gambiae after ingestion of the toxic sugar bait. 15 mg/ml usnic acid caused the highest mortality (50%) within the first 4 h compared to 5 and 10 mg/ml ( +)-UA. There was a decline in the mortality rate with increased exposure time from 24 to 72 h, however, there was a significant difference in mortality at 5, 10 and 15 mg/ml. Acute toxicity was associated with ingestion of 15 mg/ml after 24 h. 72 h post-mortality was lower in all concentrations than in the control. High mortality was observed among females over the first 4 h (60%) compared to males (40%) due to higher feeding rate of the toxic agent. The proportion of dead males and females was equal after 24 h while after 48 h, the proportion of dead males was high.There was a significantly lower mortality rate after 72 h for both males and females (0 to 13.3%). Compared to all the treatments, high mortality of males was observed. Conclusions The results of this study indicate that ( +)-UA when administered as oral sugar bait to An. gambiae has insecticidal properties and is a suitable ingredient to be used as a toxic agent in the novel attractive toxic sugar bait for the control of malaria vectors. ( +)-UA may be an alternative active ingredient as toxic bait in the effort to reduce and eliminate the transmission of Plasmodium falciparum in Africa.

Lichens are a source of secondary metabolites with significant pharmacological potential. Data regarding their possible application in glioblastoma (GBM) treatment are, however, scarce. The study aimed at analyzing the mechanism of action of six lichen secondary metabolites: atranorin, caperatic acid, physodic acid, squamatic acid, salazinic acid, and lecanoric acid using two- and three-dimensional GBM cell line models. The parallel artificial membrane permeation assay was used to predict the blood-brain barrier penetration ability of the tested compounds. Their cytotoxicity was analyzed using the MTT test on A-172, T98G, and U-138 MG cells. Flow cytometry was applied to the analysis of oxidative stress, cell cycle distribution, and apoptosis, whereas qPCR and microarrays detected the induced transcriptomic changes. Our data confirm the ability of lichen secondary metabolites to cross the blood-brain barrier and exert cytotoxicity against GBM cells. Moreover, the compounds generated oxidative stress, interfered with the cell cycle, and induced apoptosis in T98G cells. They also inhibited the Wnt/β-catenin pathway, and this effect was even stronger in case of a co-treatment with temozolomide. Transcriptomic changes in cancer related genes induced by caperatic acid and temozolomide were the most pronounced. Lichen secondary metabolites, caperatic acid in particular, should be further analyzed as potential anti-GBM agents.

Cerebral ischemia/reperfusion causes complex pathological mechanisms that lead to brain tissue damage. Usnic acid is a lichen secondary metabolite that has many different biological properties including anti-inflammatory and anti-oxidant activities. Therefore, the objective of the current study was to investigate the neuroprotective effects of usnic acid on apoptotic cell death, neuroinflammation, anti-oxidant enzyme activities, and oxidative stress levels after transient cerebral ischemia/reperfusion. Forty-two male Wistar rats were randomly assigned to three groups (sham, ischemia/reperfusion, and ischemia/reperfusion+usnic acid). Ischemia was induced by 20 min occlusion of common carotid arteries. Injection of usnic acid (25 mg/kg, intraperitoneally) and saline was done at the beginning of reperfusion time. Morris water maze was applied to assess spatial memory. The protein expression amount was measured using immunohistochemical and immunofluorescence staining. Spectrophotometric assay was performed to determine the levels of anti-oxidant enzymes. Usnic acid significantly reduced caspase-3, glial fibrillary acidic protein- positive and ionized calcium-binding adaptor molecule 1-positive cells ( 0.001) and enhanced spatial memory disorders ( 0.05) due to brain ischemia. In addition, treatment with usnic acid improves effects in the antioxidant system following cerebral ischemia ( 0.05). Our findings indicate that usnic acid has neuroprotective properties, which possibly is applicable as a promising candidate for cerebral injuries caused by ischemia.

In lichens, each symbiotic partner cooperates for the survival of the symbiotic association. The protection of the susceptible photosynthetic apparatus is essential for both participants. The mycobiont and photobiont contribute to the protection against the damaging effect of excess light by various mechanisms. The present study investigated the effect of seasonality and microhabitat exposure on photoprotection and photoacclimation in the photo- and the mycobiont of six lichen species with different thallus morphology in inland dune system in the Kiskunság region (Hungary) with shaded, more humid and exposed, drier dune sides. High-Performance Liquid Chromatography, spectrophotometry, chlorophyll a fluorescence kinetic technique were used, and micrometeorological data were collected. The four years data series revealed that the north-east-facing side was characterized by higher relative humidity and lower light intensities compared to the south-west-facing drier and more exposed sides. The south-west facing side was exposed to direct illumination 3–4 hours longer in winter and 1–2 hours shorter in summer than the north-east facing side of the dune, influencing the metabolism of sun and shade populations of various species. Because rapid desiccation caused short active periods of lichens during bright and drier seasons and on exposed microhabitats, the rapid, non-regulated non-photochemical quenching mechanisms in the photobiont had a significant role in protecting the photosynthetic system in the hydrated state. In dehydrated conditions, thalli were mainly defended by the solar screening metabolites produced by the mycobiont and curling during desiccation (also caused by the mycobiont). Furthermore, the efficacy of light use (higher chlorophyll and carotenoid concentration) increased because of short hydrated periods. Still, a lower level of received irradiation was appropriate for photosynthesis in dry seasons and on sun exposed habitats. In humid seasons and microhabitats, more extended active periods lead to increased photosynthesis and production of solar radiation protectant fungal metabolites, allowing a lower level of photoprotection in the form of regulated non-photochemical quenching by the photobiont. Interspecific differences were more pronounced than the intraspecific ones among seasons and microhabitat types.

Cystic Fibrosis is a genetic disease and it affects the respiratory and digestive systems. Pseudomonas aeruginosa infections in Cystic Fibrosis are presented as the main cause for high mortality and morbidity rates. Pseudomonas aeruginosa populations can regulate their virulence gene expressions via the bacterial communication system: quorum sensing. Inhibition of quorum sensing by employing quorum sensing inhibitors can leave the bacteria vulnerable. Therefore, determining natural sources to obtain potential quorum sensing inhibitors is essential. Lichens have ethnobotanical value for their medicinal properties and it is possible that their secondary metabolites have quorum sensing inhibitor properties. This study aims to investigate an alternative treatment approach by utilizing lichen secondary metabolite evernic acid to reduce the expressions of Pseudomonas aeruginosa virulence factors by inhibiting quorum sensing. For this purpose, fluorescent monitor strains were utilized for quorum sensing inhibitor screens and quantitative reverse-transcriptase PCR analyses were conducted for comparison. Results indicate that evernic acid is capable of inhibiting Pseudomonas aeruginosa quorum sensing systems.

Lichen secondary metabolites are natural products of high medicinal and industrial value, which are produced by the fungal symbiont (mycobiont) of lichens in response to environmental changes. It has been shown that the cultured mycobiont is capable of secondary metabolite production, specifically polyketides, and polyketide production is affected by the presence or absence of the algal or cyanobacterial symbiont (photobiont). Identification of polyketide synthases encoding genes is, in turn, key for understanding the regulation of secondary metabolite synthesis. Using a previously established method of resynthesis for Cladonia rangiferina as well as the sequenced and assembled genome of that species, we compared transcriptomes of C. rangiferina cultured alone and resynthesized with the photobiont (Asterochloris glomerata) to reveal transcriptionally active genes in secondary metabolic gene clusters, as well some of the neighbouring genes, induced by the presence of the photobiont and events of lichenization. The results identify potential candidates for PKS genes in C. rangiferina, identify potential neighbouring genes in the PKS cluster, and offer insights into further research. The study provides preliminary insights into the activity of several identified biosynthetic gene clusters (BGC) as well as interactions of genes within those clusters.

Melanin is the main pigment of human skin, playing the primary role of protection from ultraviolet radiation. Alteration of the melanin production may lead to hyperpigmentation diseases, with both aesthetic and health consequences. Thus, suppressors of melanogenesis are considered useful tools for medical and cosmetic treatments. A great interest is focused on natural sources, aimed at finding safe and quantitatively available depigmenting substances. Lichens are thought to be possible sources of this kind of compounds, as the occurrence of many phenolic molecules suggests possible effects on phenolase enzymes involved in melanin synthesis, like tyrosinase. In this work, we used four lichen species, Cetraria islandica Ach., Flavoparmelia caperata Hale, Letharia vulpina (L.) Hue, and Parmotrema perlatum (Hudson) M. Choisy, to obtain extracts in solvents of increasing polarity, viz. chloroform, chloroform-methanol, methanol, and water. Cell-free, tyrosinase inhibition experiments showed highest inhibition for L. vulpina methanol extract, followed by C. islandica chloroform-methanol one. Comparable results for depigmenting activities were observed by means of in vitro and in vivo systems, such as MeWo melanoma cells and zebrafish larvae. Our study provides first evidence of depigmenting effects of lichen extracts, from tyrosinase inhibition to cell and in vivo models, suggesting that L. vulpina and C. islandica extracts deserve to be further studied for developing skin-whitening products.