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Cavoxin ( 1 ) was isolated as the main phytotoxin produced by Phoma cava Schulzer, a toxigenic fungus isolated from Castanea spp. Its structure was determined by 1D NMR and MS in 1985 along with that of the corresponding chroman-4-one cavoxone ( 2 ), an artifact formed by acid treatment of 1 . Since that time cavoxin was shown to be phytotoxic, antifungal, antifeedant, herbicidal, and antirust with potential application in agriculture and medicine. During a study aimed at improving cavoxin's production by P. cava , single crystals for X-ray diffractometric analysis were obtained. The X-ray crystallography characterization confirmed only in part the structure proposed for cavoxin ( 1 ), revealing a different substitution pattern on the aromatic ring, as depicted in the revised structure 3 .

Lignin, a renewable natural antioxidant and bacteriostat, holds promise as a versatile, cost-effective feed additive. However, traditional industrial lignin faces limitations, including low reactivity, poor uniformity, and unstable properties, necessitating chemical modification. Complex modification methods pose economic and toxicity challenges, so this study adopted a relatively simple alkali-catalyzed phenolization approach, using phenol, catechol, and pyrogallol to modify kraft lignin, and characterized the resulting products using various techniques. Subsequently, their antioxidant, antibacterial, adsorption properties for heavy metal ions and mycotoxins, growth-promoting properties, and antiviral abilities were assessed. The phenolation process led to lignin depolymerization and a notable increase in phenolic hydroxyl content, particularly in pyrogallol-phenolated lignin (Py-L), rising from 3.08 to 4.68 mmol/g. These modified lignins exhibited enhanced antioxidant activity, with over 99 % inhibition against E. coli and S. aureus, and remarkable adsorption capacities for heavy metal ions and mycotoxins. Importantly, Py-L improved the growth performance of mice and reduced influenza mortality. Furthermore, density functional theory calculations elucidated the mechanism behind the enhanced antioxidant properties. This study presents a promising avenue for developing versatile feed additives to address challenges related to animal feed antioxidant supplementation, bacterial control, and growth promotion., Competing Interests: Declaration of competing interest This submission is the authors' original work and has not been submitted or published elsewhere. Further, there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier B.V. All rights reserved.)

C. elegans numr-1/2 ( nu clear-localized m etal- r esponsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts for numr-1p::GFP activation. The most potent activator was chaetocin, a fungal 3,6-epidithiodiketopiperazine (ETP) with promising anticancer activity. Chaetocin activates numr-1/2 strongly in the alimentary canal but is distinct from metal exposure, because it represses canonical cadmium-responsive metallothionine genes. Chaetocin has diverse targets in cancer cells including thioredoxin reductase, histone lysine methyltransferase, and acetyltransferase p300/CBP; further work is needed to identify the mechanism in C. elegans as genetic disruption and RNAi screening of homologues did not induce numr-1/2 in the alimentary canal and chaetocin did not affect markers of integrator dysfunction. We demonstrate that disulfides in chaetocin and chetomin, a dimeric ETP analog, are required to induce numr-1/2. ETP monomer gliotoxin, despite possessing a disulfide linkage, had almost no effect on numr-1/2 , suggesting a dimer requirement. Chetomin inhibits C. elegans growth at low micromolar levels, and loss of numr-1/2 increases sensitivity; C. elegans and Chaetomiaceae fungi inhabit similar environments raising the possibility that numr-1/2 functions as a defense mechanism. There is no direct orthologue of numr-1/2 in humans, but RNaseq suggests that chaetocin affects expression of cellular processes linked to stress response and metal homeostasis in colorectal cancer cells. Our results reveal interactions between metal response gene regulation and ETPs and identify a potential mechanism of resistance to this versatile class of preclinical compounds.

Deoxynivalenol (DON) is one of the frequent Fusarium mycotoxins and poses a serious threat to public health worldwide. DON-induced weight loss is tightly connected with its ability to decrease feed intake by influencing gastrointestinal tract (GIT) motility. Our previous reports indicated that DON interfered with intestinal motility by injuring the contractility of enteric smooth muscle cells (SMC). Here, we further explored the potential mechanisms by employing a complementary method of transcriptomics and proteomics using the porcine enteric smooth muscle cell line (PISMC) as an experimental model. The transcriptomic and proteomic data uncover that the expression of numerous extracellular matrix (ECM) proteins and multiple integrin subunits were downregulated in PISMC under DON exposure, suppressing the ECM-integrin receptor interaction and its mediated signaling. Furthermore, DON treatment could depress actin polymerization, as reflected by the upregulated expression of Rho GTPase-activating proteins and cofilin in PISMC. Meanwhile, the expression levels of downstream contractile apparatus genes were significantly inhibited after challenge with DON. Taken together, the current results suggest that DON inhibits enteric SMC contractility by regulating the ECM-integrin-actin polymerization signaling pathway. Our findings provide novel insights into the potential mechanisms behind the DON toxicological effects in the GIT of humans and animals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Gnomoniopsis smithogilvyi is the major chestnut pathogen, responsible for economic losses and recently described as a 3-nitropropionic acid and diplodiatoxin mycotoxin producer. Bacillus amyloliquefaciens QST 713 (Serenade® ASO), B. amyloliquefaciens CIMO-BCA1, and the fungicide Horizon® (tebuconazole) have been shown to reduce the growth of G. smithogilvyi. However, they enhanced mycotoxin production. Proteomics can clarify the mould's physiology and the impact of antifungal agents on the mould's metabolism. Thus, the aim of this study was to assess the impact of Horizon®, Serenade®, and B. amyloliquefaciens CIMO-BCA1 in the proteome of G. smithogilvyi to unveil their modes of action and decipher why the mould responds by increasing the mycotoxin production. For this, the mycelium close to the inhibition zone provoked by antifungals was macroscopically and microscopically observed. Proteins were extracted and analysed using a Q-Exactive plus Orbitrap., Results: The results did not elucidate specific proteins involved in the mycotoxin biosynthesis, but these agents provoked different kinds of stress on the mould, mainly affecting the cell wall structures and antioxidant response, which points to the mycotoxins overproduction as a defence mechanism. The biocontrol agent CIMO-BCA1 acts similar to tebuconazole. The results revealed different responses on the mould's metabolism when co-cultured with the two B. amyloliquefaciens, showing different modes of action of each bacterium, which opens the possibility of combining both biocontrol strategies., Conclusion: These results unveil different modes of action of the treatments that could help to reduce the use of toxic chemicals to combat plant pathogens worldwide. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Enniatin B1 (ENN B1) is a mycotoxin that can be found in various foods. However, whether ENN B1 is hazardous to the reproductive system is still elusive. Leydig cells are testosterone-generating cells that reside in the interstitial compartment between seminiferous tubules. Dysfunction of Leydig cells could result in male infertility. This study aimed to examine the toxicological effects of ENN B1 against TM3 Leydig cells. ENN B1 significantly inhibited cell viability in a dose-dependent manner. ENN B1 treatment also decreased the expression of functional genes in Leydig cells. Moreover, ENN B1 induced Leydig cells apoptosis and oxidative stress. Mechanistically, ENN B1 leads to the upregulation of Bax and downregulation of Bcl-2 in Leydig cells. In addition, ENN B1 inhibited the Nrf2/HO-1 pathway, which is critical for the induction of oxidative stress. Additionally, ENN B1 treatment repressed the JAK/STAT3 signaling pathway in Leydig cells. Rescue experiments showed that activation of STAT3 resulted in alleviation of ENN B1-induced damage in Leydig cells. Collectively, our study demonstrated that ENN B1 induced Leydig cell dysfunction via multiple mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Four previously undescribed and highly oxygenated α-pyrone-containing mycotoxins designated citreoviridins (E‒H), and an unreported eremophilane-type sesquiterpenoid namely aureoterrolide N, were isolated from the culture broth of Aspergillus aureoterreus. Those isolates were inferred from extensive spectroscopic methods and theoretical computation, where their absolute configurations were unambiguously determined by coupling constants following an empirical rule for the acyclic vicinal diol, theoretical ECD calculation, and NMR computation using the GIAO method and DP4 + analysis. Among them, citreoviridins E‒H are four stereoisomers of a citreoviridin derivative, featuring a methylated α-pyrone, an oxidized polyene linker, and a tetrahydrofuran ring. Cytotoxicity assay of all isolates demonstrated that aureoterrolide N exhibited weak inhibitory effect against human cancer cell line HL-60 with an inhibition rate of 55.2% at 40.0 μM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Discovery of environmentally friendly agents for controlling alien invasive species (AIS) is challenging and in urgent need as their expansion continues to increase. Xanthium italicum is a notorious invasive weed that has caused serious ecological and economic impacts worldwide. For the purpose of exploring the possibility of utilizing herbicidal mycotoxins to control this species, three compounds, a new compound, curvularioxide (1), a new naturally occurring compound, dehydroradicinin (2), and a known compound, radicinin (3), were isolated via activity-guided fractionation from the secondary metabolites of the pathogenic Curvularia inaequalis, which was found to infect X. italicum in natural habitats. All isolated compounds exhibited potent herbicidal activity on receiver species. It is noteworthy to mention that their effects on X. italicum in our bioassays were equivalent to the commercial herbicide glyphosate. Subsequent morphological analysis revealed that application of radicinin (3) severely hindered X. italicum seedlings' hypocotyl and root development. Malondialdehyde content and the activity of catalase and peroxidase of the seedlings were also significantly different from the control, implying the occurrence of induced oxidative stress. Our results suggest that pathogens infecting invasive plants might be valuable resources for developing safer herbicides for controlling weeds. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Fusarium head blight (FHB) is a critical fungal disease causes serious grain yield losses and mycotoxin contaminations. Currently, utilization of chemical fungicides is the main control method which has led to serious resistance. Development of novel synergist is an important strategy to reduce the usage of chemical fungicides and postpone the development of resistance, while natural components are interesting resources. In this study, the synergistic effect of Taxodium 'zhongshansha' essential oil (TZEO) was determined and the best synergistic ratio (SR) of 3.96 in laboratory which was observed when the weight ratio of TZEO and prothioconazole was 1 : 1 with the corresponding EC 50 (half maximal effective concentration) value of Fusarium graminearum was 0.280 mg L -1 . Subsequently, an increase of 6.31% on the control effect to FHB index in field test was observed when compared to the treatment with prothioconazole alone, though there was no significant difference between these treatments. Furthermore, we established an effective method to detect the mycotoxin contaminations in wheat grain with the limits of quantifications (LOQs) value of 5 µg kg -1 (DON, ZEN, 3-DON, and 15-DON) and 1 µg kg -1 (OTA) and the contents were less to the maximum residue limit (MRL) values. It was also shown that the application of 20% TZEO EW led to a 20% reduction in the use of prothioconazole, which was calculated based on the control effect values of 86.41% and 90.20% between the treatments of 30% prothioconazole OD (225 g a.i ha -1 , recommend dosage) and 30% prothioconazole OD (180 g a.i ha -1 ) + 20% TZEO EW (225 mL ha -1 ), significantly. The initial residue of prothioconazole and prothioconazole-desthio was increased in the treatment with TZEO, which may play an important role in the synergistic effect on FHB. Moreover, none of the treatments posed a prothioconazole residue risk in the wheat grain and the environment. In addition, the essential oil has no any negative influence on wheat growth, which was revealed by a study of the chlorophyll content. These results provide an important botanical synergist for use with prothioconazole to control Fusarium head blight, and in-depth study to the synergistic mechanism of this oil is necessary in our future research., (© 2023. The Author(s).)

Zearalenone (ZEA) is a prevalent mycotoxin functions as an endocrine disrupter to the reproductive systems of farm animals, especially in pigs. To evaluate the effect and the underlying molecular changes that occurred when the porcine germline stem cells were exposed to ZEA, prospermatogonia (ProSGs) were enriched and treated with a gradient concentration (0-10 μM) of ZEA for 2-8 days. Our results showed that the ZEA treatment inhibited the proliferation of ProSGs in a dose-dependent manner with a critical concentration at 1 μM. Transcriptome analysis revealed that the differentially expressed genes mainly concentrated on the molecular function of positive regulation of response to stimulus, and the most enriching pathway is cytokine-cytokine receptor interaction. ZEA exposure decreased a buck of cytokine/chemokine expression involved in the inflammatory response and stem cells maintenance/self-renewal, moreover, some energy expenditure and anti-apoptosis genes were also down-regulated, while the up-regulated genes were mainly connected with the innate immunity. These data demonstrate that ZEA induces multiply cellular damage and may eventually do harm to the health and fertility of animals., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Organic acids and essential oils are commonly used in the poultry industry as antimicrobials and for their beneficial effects on gut health, growth performance, and meat quality. A common postharvest storage fungal colonist, Aspergillus flavus , contaminates corn, the primary component of poultry feed, with the highly detrimental mycotoxin, aflatoxin. Aflatoxin adversely affects poultry feed intake, feed conversion efficiency, weight gain, egg production, fertility, hatchability, and poultry meat yield. Both organic acids and essential oils have been reported to inhibit the growth of A. flavus. Thus, we evaluated if the inhibitory synergy between combined essential oils (cinnamon, lemongrass, and oregano) and organic acids (acetic, butyric, and propionic) prevents A. flavus growth. The study confirmed that these compounds inhibit the growth of A. flavus and that synergistic interactions do occur between some of them. Overall, cinnamon oil was shown to have the highest synergy with all the organic acids tested, requiring 1000 µL/L air of cinnamon oil and 888 mg/kg of butyric acid to fully suppress A. flavus growth on corn kernels. With the strong synergism demonstrated, combining certain essential oils and organic acids offers a potentially effective natural method for controlling postharvest aflatoxin contamination in poultry feed.

Background: Toxigenic fungi (Aspergillus and Fusarium) and their metabolites represent the major cause of corn and corn-based products contamination and consequently lead to severe economic and health issues., Aim: Our current study aimed to investigate the efficacy of using L. macroides Bac6 as a biological control agent against the toxigenic fungi; A. flavus f10 and F. proliferatum f30 and their mycotoxins., Results: The results illustrated that A. flavus f10 produced the aflatoxins AFB 1 and AFG 2 with concentrations of 21.239 and 13.593 ppb, respectively. While F. proliferatum f30 produced fumonisin B 1 (9600 ppb). Furthermore, L. macroides showed a high potential for inhibition of toxigenic fungal growth using a dual culture method. F. proliferatum f30 and A. flavus f10 were found to be inhibited by a percentage of 80 and 62.5%, respectively. The results were confirmed using the scanning electron microscope. The antagonistic bacteria, L. macroides, showed chitinase productivity and activity of 26.45 U/L and 0.12 U/mL/min, respectively, which illustrates its potential application as a biocontrol agent. The GC-MS analysis revealed an abundance of Pyrrolo[1,2-a] pyrazine-1,4-dione, Hexahydro in the bacterial supernatant that exhibited antifungal characteristics. L. macroides had a significant reduction of AFB 1 and AFG 2 produced by A. flavus f10, recording 99.25% and 99% inhibition, respectively. It also showed strong inhibition of fumonisin B 1 (90% inhibition) produced by F. proliferatum f30., Conclusion: Thus, the current study is a prospective study evaluating for the first time the potential impact of L. macroides Bac6 against the toxigenic fungi and their toxins., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Fusarium head blight caused by Fusarium asiaticum is an important cereal crop disease, and the trichothecene mycotoxins produced by F. asiaticum can contaminate wheat grain, which is very harmful to humans and animals. To effectively control FHB in large areas, the application of fungicides is the major strategy; however, the application of different types of fungicides has varying influences on the accumulation of trichothecene mycotoxins in F. asiaticum. In this study, phenamacril inhibited trichothecene mycotoxin accumulation in F. asiaticum; however, carbendazim (N-1H-benzimidazol-2-yl-carbamic acid, methyl ester) induced trichothecene mycotoxin accumulation. Additionally, phenamacril led to a lower level of reactive oxygen species (ROS) by inducing gene expression of the catalase and superoxide dismutase (SOD) pathways in F. asiaticum, whereas carbendazim stimulated ROS accumulation by inhibiting gene expression of the catalase and SOD pathways. Based on these results, we conclude that phenamacril and carbendazim regulate trichothecene mycotoxin synthesis by affecting ROS levels in F. asiaticum., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Black soldier fly (BSF), Hermetia illucens (L.) (Diptera: Stratiomyidae), is predominantly reared on organic wastes and other unused complementary substrates. However, BSF may have a buildup of undesired substances in their body. The contamination of undesired substance, e.g., heavy metals, mycotoxins, and pesticides, in BSF mainly occurred during the feeding process in the larval stage. Yet, the pattern of accumulated contaminants in the bodies of BSF larvae (BSFL) is varied distinctively depending on the diets as well as the contaminant types and concentrations. Heavy metals, including cadmium, copper, arsenic, and lead, were reported to have accumulated in BSFL. In most cases, the cadmium, arsenic, and lead concentration in BSFL exceeded the recommended standard for heavy metals occurring in feed and food. Following the results concerning the accumulation of the undesired substance in BSFL's body, they did not affect the biological parameters of BSFL, unless the amounts of heavy metals in their diets are highly exceeding their thresholds. Meanwhile, a study on the fate of pesticides and mycotoxins in BSFL indicates that no bioaccumulation was detected for any of the target substances. In addition, dioxins, PCBs, PAHs, and pharmaceuticals did not accumulate in BSFL in the few existing studies. However, future studies are needed to assess the long-term effects of the aforementioned undesired substances on the demographic traits of BSF and to develop appropriate waste management technology. Since the end products of BSFL that are contaminated pose a threat to both human and animal health, their nutrition and production process must be well managed to create end products with a low contamination level to achieve a closed food cycle of BSF as animal feed., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Rabies is a highly fatal disease, and it is vital to find effective ways to manage and control infection. There is a need for new effective antiviral drugs that are particularly effective treatments for rabies. Deoxynivalenol (DON) is known mainly for its toxicity, but at the molecular level, it can inhibit RNA and DNA replication, and there is increasing evidence that different doses of DON have a positive effect on inhibiting virus replication. Based on this, we evaluated the effect of DON on inhibiting the rabies virus in vitro. The inhibitory effect of DON on rabies virus activity was dose- and time-dependent, and 0.25 μg/mL of DON could inhibit 99% of rabies virus activity within 24 h. Furthermore, DON could inhibit the adsorption, entry, replication, and release of rabies virus but could not inactivate the virus. The inhibitory effect of DON on rabies virus may be achieved by promoting apoptosis. Our study provides a new perspective for the study of anti-rabies virus and expands the direction of action of mycotoxins.

The toxins produced by Aspergillus flavus can significantly inhibit the use of maize. As a result of climate change, toxin production is a problem not only in tropical and subtropical areas but in an increasing number of European countries, including Hungary. The effect of meteorological factors and irrigation on mould colonization and aflatoxin B1 (AFB1) mycotoxin production by A. flavus were investigated in natural conditions, as well as the inoculation with a toxigenic isolate in a complex field experiment for three years. As a result of irrigation, the occurrence of fungi increased, and toxin production decreased. The mould count of fungi and toxin accumulation showed differences during the examined growing seasons. The highest AFB1 content was found in 2021. The main environmental factors in predicting mould count were temperature (T avg , T max ≥ 30 °C, T max ≥ 32 °C, T max ≥ 35 °C) and atmospheric drought (RH min ≤ 40%). Toxin production was determined by extremely high daily maximum temperatures (T max ≥ 35 °C). At natural contamination, the effect of T max ≥ 35 °C on AFB1 was maximal (r = 0.560-0.569) in the R4 stage. In the case of artificial inoculation, correlations with environmental factors were stronger (r = 0.665-0.834) during the R2-R6 stages.

The study aimed to investigate toxicity and the mechanism of toxicity of two Fusarium mycotoxins, deoxynivalenol (DON) and zearalenone (ZEA). DON and ZEA were applied to HepG2 cells as single compounds and in combination at low environmentally relevant concentrations. HepG2 cells were exposed to DON (0.5, 1, and 2 µM), ZEA (5, 10, and 20 µM) or their combinations (1 µM DON + 5 µM ZEA, 1 µM DON + 10 µM ZEA and 1 µM DON + 20 µM ZEA) for 24 h and cell viability, DNA damage, cell cycle and proliferation were assessed. Both mycotoxins reduced cell viability, however, combined treatment with DON and ZEA resulted in higher reduction of cell viability. DON (1 µM) induced primary DNA damage, while DON (1 µM) in combination with higher ZEA concentrations showed antagonistic effects compared to DON alone at 1 µM. DON arrested HepG2 cells in G2 phase and significantly inhibited cell proliferation, while ZEA had no significant effect on cell cycle. The combined treatment with DON and ZEA arrested cells in G2 phase to a higher extend compared to treatment with single mycotoxins. Potentiating effect observed after DON and ZEA co-exposure at environmentally relevant concentrations indicates that in risk assessment and setting governments' regulations, mixtures of mycotoxins should be considered.

Fungal pathogens cause significant human morbidity and mortality globally, where there is a propensity to infect vulnerable people such as the immunocompromised ones. There is increasing evidence of resistance to antifungal drugs, which has significant implications for cutaneous, invasive and bloodstream infections. The World Health Organization (WHO) published a priority list of fungal pathogens in October 2022, thus, highlighting that a crisis point has been reached where there is a pressing need to address the solutions. This review provides a timely insight into the challenges and implications on the topic of antifungal drug resistance along with discussing the effectiveness of established disease mitigation modalities and approaches. There is also a need to elucidate the cellular and molecular mechanisms of fungal resistance to inform effective solutions. The established fungal decontamination approaches are effective for medical device processing and sterilization, but the presence of pathogenic fungi in recalcitrant biofilms can lead to challenges, particularly during cleaning. Future design ideas for implantable and reusable medical devices should consider antifungal materials and appropriates for disinfection, and where it is relevant, sterilization. Preventing the growth of mycotoxin-producing fungi on foods through the use of appropriate end-to-end processes is advisable, as mycotoxins are recalcitrant and challenging to eliminate once they have formed.

Most of the toxic effects of fumonisins can be related to sphingolipid alteration, but there is little sphingolipidomic data in animals fed fumonisins in organs other than the liver. This study aimed to measure fumonisin B1 (FB1) in kidney, lung, and brain and determine its effects on sphingolipids. Thirty chickens divided into three groups received a diet containing 20.8 mg FB1+FB2/kg for 0, 4, or 9 days. FB1 increased in kidney from 1.7 to 5.6 nmol/kg and in lung from 0.5 to 1 nmol/kg at 4 and 9 days, respectively. No FB1 was detected in brain. In kidney, sphinganine increased, C14-C16 ceramides decreased, whereas C18-C26 ceramides increased. Most of the changes in dihydroceramides, dihydrodeoxyceramides, deoxyceramides sphingomyelins, dihydrosphingomyelins, and hexosylceramides paralleled those on ceramides. In lung, sphinganine was unaffected by fumonisins, whereas sphinganine-1-phosphate increased. Other major changes corresponded to decreases in glycosylceramides. In brain, sphinganine was unchanged, whereas deoxysphinganine, sphingosine, C14-C20 ceramides, and C14-C20 sphingomyelins increased. These results revealed that alterations in sphingolipids in kidney were close to those measured in liver and could correspond to inhibition of ceramide synthase 5 activity. In contrast, effects of fumonisins in lung and brain cannot be explained by inhibition of ceramide synthase., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alteration of sphingolipid synthesis is a key event in fumonisins toxicity, but only limited data have been reported regarding the effects of fumonisins on the sphingolipidome. Recent studies in chickens found that the changes in sphingolipids in liver, kidney, lung, and brain differed greatly. This study aimed to determine the effects of fumonisins on sphingolipids in heart, gizzard, and breast muscle in chickens fed 20.8 mg FB1 + FB2/kg for 9 days. A significant increase in the sphinganine:sphingosine ratio due to an increase in sphinganine was observed in heart and gizzard. Dihydroceramides and ceramides increased in the hearts of chickens fed fumonisins, but decreased in the gizzard. The dihydrosphingomyelin, sphingomyelin, and glycosylceramide concentrations paralleled those of ceramides, although the effects were less pronounced. In the heart, sphingolipids with fatty acid chain lengths of 20 to 26 carbons were more affected than those with 14-16 carbons; this difference was not observed in the gizzard. Partial least squares-discriminant analysis on sphingolipids in the heart allowed chickens to be divided into two distinct groups according to their diet. The same was the case for the gizzard. Pearson coefficients of correlation among all the sphingolipids assayed revealed strong positive correlations in the hearts of chickens fed fumonisins compared to chickens fed a control diet, as well as compared to gizzard, irrespective of the diet fed. By contrast, no effect of fumonisins was observed on sphingolipids in breast muscle.

Field experiments were conducted to investigate the efficacy of fungicide treatments in combination with genetic resistance against Fusarium head blight (FHB) and its associated mycotoxins under persistently wet pre- and postanthesis conditions in plots inoculated with Fusarium graminearum -colonized corn spawn. Treatments consisted of a single application of prothioconazole + tebuconazole at early anthesis (PA), or at 3 (P3), 6 (P6), or 9 (P9) days after early anthesis, or PA followed by a single application of metconazole at 3 (PA+C3), 6 (PA+C6), or 9 (PA+C9) days after early anthesis. PA and P3 were the most efficacious of the single-application treatments in terms of mean percentage control of FHB index (IND), deoxynivalenol (DON), zearalenone (ZEA), and mean increase in grain yield and test weight (TW) relative to the nontreated susceptible check (S_CK). The double-application treatments (PA+C3, PA+C6, and PA+C9) were the most effective of all tested fungicide programs. However, relative to S_CK, the highest overall mean percentage reduction in IND, DON, and ZEA and increase in grain yield and TW were observed when the double-application fungicide programs were integrated with genetic resistance. The estimated net cash income (NCI) of the integrated management (IM) programs was consistently higher than the NCI of other tested programs across different grain prices and fungicide application costs. Thus, the benefits of the two-treatment IM programs under highly favorable conditions for FHB development were enough to offset the cost of two applications, making these programs profitable.

The emerging Fusarium mycotoxins enniatins (ENNs) have been the focus of new research because of their well-documented existence in various cereal and grain products. Research findings indicate that reproductive disorders may be caused by exposure to Fusarium mycotoxins, but little work has evaluated ENNs on reproductive function. Therefore, to determine the effects of ENNA on the proliferation and steroidogenesis of granulosa cells (GC), experiments were conducted using bovine GC cultures. In vitro, ENNA (1−5 μM) inhibited (p < 0.05) hormone-induced GC progesterone and estradiol production. The inhibitory effect of ENNA on estradiol production was more pronounced in small- than large-follicle GC. In large-follicle GC, 0.3 μM ENNA had no effect (p > 0.10) whereas 1 and 3 μM ENNA inhibited GC proliferation. In small-follicle GC, ENNA (1−5 μM) dramatically decreased (p < 0.05) GC proliferation. Using cell number data, the IC50 of ENNA was estimated at 2 μM for both follicle sizes. We conclude that ENNA can directly inhibit ovarian function in cattle, decreasing the proliferation and steroid production of GC.

Nanochitin whisker (NC) is an advanced nanobiomaterial with novel physicochemical and biological properties. Fusarium pseudograminearum (Fpg) is an important pathogenic fungus causing wheat crown rot disease. This study explored the mode of action of NC against Fpg as a target microorganism. The effects of different treatments and concentrations of NC on the fungal growth and conidial germination were investigated by in vitro bioassay. The impacts of NC on cell structure integrity, membrane permeability, pathogenesis related key enzymes activity, and the mycotoxin production were examined by electron microscopy, fluorescence spectroscopy, IR spectroscopy, conductometry, and spectrophotometry, respectively. The results showed that NC significantly reduced hyphal growth, and the spore germination rate of Fpg declined by 33.0 % and 23.2 % when Fpg was treated with 30 and 300 μg/mL of NC, respectively. NC vigorously influenced structural stability of cell wall by destroying dextran structure, and strongly stimulated ergosterol production altering membrane integrity of the fungus. It reduced the activities of enzymes related to energy-supply like nicotinamide adenine dinucleotide oxidase and succinate dehydrogenase remarkably. The production of fungal mycotoxin deoxynivalenol was also decreased by NC. These findings provide an important basis for fully understanding the mechanism of nanobiomaterial in plant fungal disease control., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The egress of Candida hyphae from macrophages facilitates immune evasion, but it also alerts macrophages to infection and triggers inflammation. To better define the mechanisms, here we develop an imaging assay to directly and dynamically quantify hyphal escape and correlate it to macrophage responses. The assay reveals that Candida escapes by using two pore-forming proteins to permeabilize macrophage membranes: the fungal toxin candidalysin and Nlrp3 inflammasome-activated Gasdermin D. Candidalysin plays a major role in escape, with Nlrp3 and Gasdermin D-dependent and -independent contributions. The inactivation of Nlrp3 does not reduce hyphal escape, and we identify ETosis via macrophage extracellular trap formation as an additional pathway facilitating hyphal escape. Suppressing hyphal escape does not reduce fungal loads, but it does reduce inflammatory activation. Our findings explain how Candida escapes from macrophages by using three strategies: permeabilizing macrophage membranes via candidalysin and engaging two host cell death pathways, Gasdermin D-mediated pyroptosis and ETosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fungal contamination of animal feed can severely affect the health of farm animals, and result in considerable economic losses. Certain filamentous fungi or molds produce toxic secondary metabolites known as mycotoxins, of which aflatoxins (AFTs) are considered the most critical dietary risk factor for both humans and animals. AFTs are ubiquitous in the environment, soil, and food crops, and aflatoxin B 1 (AFB 1 ) has been identified by the World Health Organization (WHO) as one of the most potent natural group 1A carcinogen. We reviewed the literature on the toxic effects of AFB 1 in humans and animals along with its toxicokinetic properties. The damage induced by AFB 1 in cells and tissues is mainly achieved through cell cycle arrest and inhibition of cell proliferation, and the induction of apoptosis, oxidative stress, endoplasmic reticulum (ER) stress and autophagy. In addition, numerous coding genes and non-coding RNAs have been identified that regulate AFB 1 toxicity. This review is a summary of the current research on the complexity of AFB 1 toxicity, and provides insights into the molecular mechanisms as well as the phenotypic characteristics., Competing Interests: The authors declare there are no competing interests., (©2022 Li et al.)

Secondary metabolites/toxins produced by Purpeocillium lilacinum (Hypocreales; Phiocordycipitaceae), a well-known insect pathogen, can be used for the management of different insect pests. We report the lethal and sublethal effects of cyclosporin C (a toxin produced by P. lilacinum ) against a major vegetable pest, Plutella xylostella , at specific organismal (feeding rate, larval growth, adult emergence, fecundity, and adult longevity) and sub-organismal levels (changes in antioxidant and neurophysiological enzyme activities). The toxicity of cyclosporin C against different larval instars of P. xylostella increased with increasing concentrations of the toxin and the maximum percent mortality rates for different P. xylostella larval instars at different times were observed for the 300 µg/mL cyclosporin C treatment, with an average mortality rate of 100% for all larval instars. The median lethal concentrations (LC 50 ) of cyclosporin C against the first, second, third, and fourth larval instars of P. xylostella 72 h post-treatment were 78.05, 60.42, 50.83, and 83.05 μg/mL, respectively. Different concentrations of cyclosporin C caused a reduction in the average leaf consumption and average larval weight. Different life history parameters, such as the pupation rate (%), adult emergence (%), female fecundity, and female longevity were also inhibited when different concentrations of cyclosporin C were applied topically. The cyclosporin C concentrations inhibited the activities of different detoxifying (glutathione S-transferase, carboxylesterase, and acetylcholinesterase) and antioxidant enzyme (superoxide dismutase, catalase, and peroxidase) activities of P. xylostella when compared to the control. These findings can serve as baseline information for the development of cyclosporin C as an insect control agent, although further work on mass production, formulation, and field application is still required.

Fungal toxins can have various adverse health effects, including carcinogenic, teratogenic or hepatotoxic impacts. In addition, fungal alteration has also a negative impact on agricultural plant production. The use of chemical fungicides to control mycotoxin contamination is increasingly controversial and regulated. More environmentally friendly methods are therefore being explored. Essential oils, as compounds extracted from plants, are liquids whose specific aromatic compounds give each essential oil its own unique characteristics. Due to their rich chemical composition, essential oils (EOs) have many interesting properties, including antifungal activities. The objective of the present study was to analyze volatile chemical composition of EOs (Cymbopogon schoenanthus, Cymbopogon nardus and Eucalyptus camaldulensis) by GC/MS and to investigate their effects on the growth, sporulation and mycotoxin production of Aspergillus flavus, Aspergillus carbonarius and Fusarium verticillioides (aflatoxin B1, ochratoxin A and fumonisin B1, respectively). In addition, EOs influence on aflatoxin B1 (AFB1) and fumonisin B1 (FB1) biosynthesis pathways was explored using real-time qRT-PCR. The results obtained in vitro, by direct contact with the EOs and by diffusion of their volatile compounds, showed that the essential oils had inhibitory effects on the growth and the production of mycotoxins of the 3 fungal strains and modified the expression of some toxin synthesis genes. We conclude that the recorded effects were dependent on the combined effects of the EOs type, the fungal strains and the doses studied., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Zearalenone (ZEN), a common non-steroidal estrogenic mycotoxin of the Fusarium genus, is one of the most frequent and powerful contaminant of grains and cereal products representing a serious threat for people and livestock health. In fact, ZEN causes cytotoxicity and genotoxicity in a variety of cell types at least in part through binding to estrogen receptors (ERs). The main pathways through which ZEN induces such effects remain, however, elusive. In particular, how the mycotoxin causes DNA damage, dysregulates DNA repair mechanisms, changes epigenome of targeted cells and, not least, affects chromatin conformation and non-coding RNA (ncRNA), is unclear. In the present paper, following extensive review of the literature about such ZEN effects and our own experience in studying the effects of this compound on reproductive processes, we propose that increased production of reactive oxygen species (ROS) and consequently oxidative stress (OS) are central in ZEN genotoxicity. Besides to shed light on the action mechanisms of the mycotoxin, this notion might help to develop effective strategies to counteract its deleterious biological effects., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The objectives of this research were to obtain the extracts of lemon balm ( Melissa officinalis ) using supercritical CO 2 (SC-CO 2 ) and methanol as co-solvent and evaluate the antifungal activity of those extracts against two selected strains of Fusarium species ( Fusarium culmorum and Fusarium proliferatum ). The extraction conditions were set at 40 and 60 °C and 250 bar. The obtained extracts were characterized in terms of antifungal activity on potato dextrose agar media (PDA). The results showed that the extraction parameters had different effects on mycelium growth and mycotoxins biosynthesis reduction. All studied lemon balm extracts (1, 2.5, 5, 7.5, and 10%) inhibited the growth of F. proliferatum and F. culmorum mycelia compared to the control. The lemon balm extracts significantly reduced ergosterol content and synthesized mycotoxins in both tested strains. These findings support the antifungal activity of lemon balm extracts against F. proliferatum and F. culmorum . However, more research on other Fusarium species is needed, as well as in vivo applications, before considering lemon balm extracts as a natural alternative to synthetic fungicides.

Conjugated bile acids are synthesized in liver and subsequently secreted into the intestinal lumen from which they are actively reabsorbed and transported back to liver. The efficient enterohepatic circulation of conjugated bile acids is important to maintain homeostasis. The mycotoxin deoxynivalenol (DON) is a fungal secondary metabolite that contaminates cereal food. Upon human exposure, it can cause intestinal dysfunction. We explored the effects of DON exposure on the intestinal absorption of conjugated bile acids and the expression of bile acid transporters using an in vitro model based on Caco-2 cell layers grown in transwells. Our study shows that the transport rate of taurocholic acid (TCA) is decreased after 48-h pre-exposure of the Caco-2 cells to 2 µM DON, which is a realistic intestinal DON concentration. Exposure to DON downregulates expression of the genes coding for the apical sodium-dependent bile acid transporter (ASBT), the ileal bile acid-binding protein (IBABP) and the organic solute transporter α (OSTα), and it counteracts the agonist activity of Farnesoid X receptor (FXR) agonist GW4064 on these genes. In addition, the transport of ten taurine or glycine-conjugated bile acids in a physiological relevant mixture by the intestinal Caco-2 cell layers was decreased after pre-exposure of the cells to DON, pointing at a potential for DON-mediated accumulation of the conjugated bile acids at the intestinal luminal side. Together the results reveal that DON inhibits intestinal bile acid reabsorption by reducing the expression of bile acid transporters thereby affecting bile acid intestinal kinetics, leading to bile acid malabsorption in the intestine. Our study provides new insights into the hazards of DON exposure., (© 2022. The Author(s).)

Humans are chronically exposed to the mycotoxins deoxynivalenol (DON) and fumonisin B1 (FB1), as indicated by their widespread presence in foods and occasional exposure in the workplace. This exposure is confirmed by human biomonitoring (HBM) studies on (metabolites of) these mycotoxins in human matrices. We evaluated the exposure-health relationship of the mycotoxins in humans by reviewing the available literature. Since human studies did not allow the identification of unequivocal chronic health effects upon exposure to DON and FB1, the adverse outcome pathway (AOP) framework was used to structure additional mechanistic evidence from in vitro and animal studies on the identified adverse effects. In addition to a preliminary AOP for DON resulting in the adverse outcome (AO) 'reduced body weight gain', we developed a more elaborated AOP for FB1, from the molecular initiating event (MIE) 'inhibition of ceramide synthases' leading to the AO 'neural tube defects'. The mechanistic evidence from AOPs can be used to support the limited evidence from human studies, to focus FB1- and DON-related research in humans to identify related early biomarkers of effect. In order to establish additional human exposure-health relationships in the future, recommendations are given to maximize the information that can be obtained from HBM.

Background and Objective: Beauvericin (BEA), a cyclic hexadepsipeptide mycotoxin, is a potent inhibitor of the acyl-CoA: cholesterol acyltransferase enzyme 1 (ACAT1), involved in multiple tumor-correlated pathways. However, the binding mechanisms between BEA and ACAT1 were not elucidated., Methods: BEA was purified from a mangrove entophytic Fusarium sp. KL11. Single-crystal X-ray diffraction was used to determine the structure of BEA. Wound healing assays of BEA against KB cell line and MDA-MB-231 cell line were evaluated. Inhibitory potency of BEA against ACAT1 was determined by ELISA assays. Molecular docking was carried out to illuminate the bonding mechanism between BEA and ACAT1., Results: The structure of BEA was confirmed by X-ray diffraction, indicating a monoclinic crystal system with P21 space group (α = 90°, β = 92.2216(9)°, γ= 90°). BEA displayed migration-inhibitory activities against KB cells and MDA-MB-231 cells In Vitro. ELISA assays revealed that the protein expression level of ACAT1 in KB cells was significantly decreased after BEA treatment (P ＜0.05). Molecular docking demonstrated that BEA formed hydrogen bond with His425 and pi-pi staking with Tyr429 in ACAT1., Conclusion: BEA sufficiently inhibited the proliferation and migration of KB cells and MDA-MB-231 cells by downregulating ACAT1 expression. In addition, BEA potentially possessed a strong binding affinity with ACAT1. BEA may serve as a potential lead compound for the development of a new ACAT1-targeted anticancer drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ageritin is the prototype of a new ribotoxin-like protein family, which has been recently identified also in basidiomycetes. The protein exhibits specific RNase activity through the cleavage of a single phosphodiester bond located at sarcin/ricin loop of the large rRNA, thus inhibiting protein biosynthesis at early stages. Conversely to other ribotoxins, its activity requires the presence of divalent cations. In the present study, we report the activity of Ageritin on both prokaryotic and eukaryotic cells showing that the protein has a prominent effect on cancer cells viability and no effects on eukaryotic and bacterial cells. In order to rationalize these findings, the ability of the protein to interact with various liposomes mimicking normal, cancer and bacterial cell membranes was explored. The collected results indicate that Ageritin can interact with DPPC/DPPS/Chol vesicles, used as a model of cancer cell membranes, and with DPPC/DPPG vesicles, used as a model of bacterial cell membranes, suggesting a selective interaction with anionic lipids. However, a different perturbation of the two model membranes, mediated by cholesterol redistribution, was observed and this might be at the basis of Ageritin selective toxicity towards cancer cells., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

New and potent agents that evade multidrug resistance (MDR) and inhibit epigenetic modifications are of great interest in cancer drug development. Here, we describe that a moniliformin derivative (IUPAC name: 3-(naphthalen-2-ylsulfanyl)-4-{[(2Z)-1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene]methyl}cyclobut-3-ene-1,2-dione; code: MCC1381) bypasses P-gp-mediated MDR. Using transcriptomics, we identified a large number of genes significantly regulated in response to MCC1381, which affected the cell cycle and disturbed cellular death and survival. The potential targets of MCC1381 might be histone deacetylases (HDACs) as predicted by SwissTargetPrediction. In silico studies confirmed that MCC1381 presented comparable affinity with HDAC1, 2, 3, 6, 8 and 11. Besides, the inhibition activity of HDACs was dose-dependently inhibited by MCC1381. Particularly, a strong binding affinity was observed between MCC1381 and HDAC6 by microscale thermophoresis analysis. MCC1381 decreased the expression of HDAC6, inversely correlated with the increase of acetylated HDAC6 substrates, acetylation p53 and α-tubulin. Furthermore, MCC1381 arrested the cell cycle at the G 2 /M phase, induced the generation of reactive oxygen species and collapse of the mitochondrial membrane potential. MCC1381 exhibited in vivo anti-cancer activity in xenografted zebrafish. Collectively, MCC1381 extended cytotoxicity towards P-gp-resistant leukemia cancer cells and may act as a pan-HDACs inhibitor, indicating that MCC1381 is a novel candidate for cancer therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The high cytotoxicity of the secondary metabolites of mycotoxins is capable of killing microbes and tumour cells alike, similarly to the genotoxic effect characteristic of Janus-faced molecules. The "double-edged sword" effect of several cytotoxins is known, and these agents have, therefore, been utilized only reluctantly against fungal infections. In this review, consideration was given to (a) toxins that could be used against plant and human pathogens, (b) animal models that measure the effect of antifungal agents, (c) known antifungal agents that have been described and efficiently prevent the growth of fungal cells, and (d) the chemical interactions that are characteristic of antifungal agents. The utilization of apoptotic effects against tumour growth by agents that, at the same time, induce mutations may raise ethical issues. Nevertheless, it deserves consideration despite the mutagenic impact of Janus-faced molecules for those patients who suffer from plant pathogenic fungal infections and are older than their fertility age, in the same way that the short-term cytotoxicity of cancer treatment is favoured over the long-term mutagenic effect.

Deoxynivalenol (DON), a frequent mycotoxin worldwide, impairs human and animal health. The response of microRNAs, small non-coding RNAs, to DON has been scarcely investigated, but holds remarkable potential for biomarker applications. Hence, we aimed to investigate DON-induced changes in the microRNA expression in porcine liver, jejunum and serum by combining targeted and untargeted analyses. Piglets received uncontaminated feed or feed containing 900 µg/kg and 2500 µg/kg DON for four weeks, followed by a wash-out period. In tissue, only slight changes in microRNA expression were detected, with ssc-miR-10b being downregulated in liver of DON-exposed piglets. In serum, several microRNAs were differentially expressed upon DON exposure, four of which were validated by qPCR (ssc-miR-16, ssc-miR-128, ssc-miR-451, ssc-miR-205). The serum microRNA response to DON increased over time and declined after removal of contaminated diets. Receiver operating curve analyses for individual microRNAs were significant, and a combination of the four microRNAs increased the predictive capacity for DON exposure. Predicted microRNA target genes showed enrichment of several pathways including PIK3-AKT, Wnt/β-catenin, and adherens junctions. This study gives, for the first time, a comprehensive view of the porcine microRNA response to DON, providing a basis for future research on microRNAs as biomarkers for mycotoxins.

Alternaria toxins are considered as emerging mycotoxins, however their toxicity has not been fully evaluated in humans. Alternariol (AOH), the most prevalent Alternaria mycotoxin, was previously reported to be genotoxic and to affect hormonal balance in cells; however, its direct molecular mechanism is not known. The imbalance in androgen/estrogen ratio as well as chronic inflammation are postulated as factors in prostate diseases. The environmental agents affecting the hormonal balance might participate in prostate carcinogenesis. Thus, this study evaluated the effect of two doses of AOH on prostate epithelial cells. We observed that AOH in a dose of 10 µM induces oxidative stress, DNA damage and cell cycle arrest and that this effect is partially mediated by estrogen receptor β (ERβ) whereas the lower tested dose of AOH (0.1 µM) induces only oxidative stress in cells. The modulation of nuclear erythroid-related factor 2 (Nrf2) was observed in response to the higher dose of AOH. The use of selective estrogen receptor β (ERβ) inhibitor PHTPP revealed that AOH-induced oxidative stress in both tested doses is partially dependent on activation of ERβ, but lack of its activation did not protect cells against AOH-induced ROS production or DNA-damaging effect in case of higher dose of AOH (10 µM). Taken together, this is the first study reporting that AOH might affect basic processes in normal prostate epithelial cells associated with benign and malignant changes in prostate tissue.

Trichothecenes are a family of major secondary metabolites produced by some common filamentous fungi, including plant pathogenic and entomopathogenic fungi. It may be considered difficult to conduct a comparison between the toxicities of trichothecenes with consideration of different conditions and cell lines. In the current study, we developed an in vitro assay based on a commercially available system to estimate the translation inhibition, that is, the main toxicity, of trichothecenes. The assay was applied to estimate the inhibition of protein synthesis by trichothecenes. Initially, we examined the assay using trichothecene dissolved in water followed by an assessment of trichothecene solutions dissolved in acetonitrile. The obtained data showed that the assay tolerated the small amount of acetonitrile. The assay examined in this study has the advantages of a short operation time (one day), ease of use, and data stability, as it is a non-cell-based assay whose components are commercially available. It is expected that this assay will contribute to the evaluation of the toxicity of a vast number of trichothecenes.

Introduction: Fusarium graminearum is a most destructive fungal pathogen that causes Fusarium head blight (FHB) disease in cereal crops, resulting in severe yield loss and mycotoxin contamination in food and feed. Silver nanoparticles (AgNPs) are extensively applied in multiple fields due to their strong antimicrobial activity and are considered alternatives to fungicides. However, the antifungal mechanisms and the effects of AgNPs on mycotoxin production have not been well characterized., Objectives: This study aimed to investigate the antifungal activity and mechanisms of AgNPs against both fungicide-resistant and fungicide-sensitive F. graminearum strains, determine their effects on mycotoxin deoxynivalenol (DON) production, and evaluate the potential of AgNPs for FHB management in the field., Methods: Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and fluorescence microscopy were used to examine the fungal morphological changes caused by AgNPs. In addition, RNA-Seq, qRT-PCR, and western blotting were conducted to detect gene transcription and DON levels., Results: AgNPs with a diameter of 2 nm exhibited effective antifungal activity against both fungicide-sensitive and fungicide-resistant strains of F. graminearum . Further studies showed that AgNP application could impair the development, cell structure, cellular energy utilization, and metabolism pathways of this fungus. RNA-Seq analysis and sensitivity determination revealed that AgNP treatment significantly induced the expression of azole-related ATP-binding cassette (ABC) transporters without compromising the control efficacy of azoles in F. graminearum . AgNP treatment stimulated the generation of reactive oxygen species (ROS), subsequently induced transcription of DON biosynthesis genes, toxisome formation, and mycotoxin production., Conclusion: This study revealed the underlying mechanisms of AgNPs against F. graminearum , determined their effects on DON production, and evaluated the potential of AgNPs for controlling fungicide-resistant F. graminearum strains. Together, our findings suggest that combinations of AgNPs with DON-reducing fungicides could be used for the management of FHB in the future., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)

The molecular target of mycotoxins is not fully understood. Extensive data derived from cell and animal experimental studies demonstrate that long non-coding RNAs (lncRNAs) play crucial roles in mycotoxin-induced toxicities. Mycotoxins stimulate the upregulation/downregulation of lncRNA expression, which further promote apoptosis, is related to the mTOR/FoxO signaling pathway, and contributes to tumor cell growth, death, and liver and chondrocyte damage. Moreover, lncRNA can establish interactions with NF-κB and cause immune evasion. These preliminary data suggest that lncRNAs are involved in potential upstream regulatory events and further regulate downstream apoptosis, oxidative stress, and anti-apoptotic events that affect cell death and survival. Therefore, we hypothesize that lncRNAs are potential targets of mycotoxins. Investigation of the expression of the potential target lncRNAs by mycotoxin-mediated stimulation, and exploration of the upstream and downstream relationship between lncRNA and the key proteins involved in mycotoxin toxicity, should be performed. This Hypothesis provides clues for further understanding of the molecular mechanisms of mycotoxins., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Corynespora cassiicola, a fungal plant pathogen with a large host range, causes important damages in rubber tree (Hevea brasiliensis), in Asia and Africa. A small secreted protein named cassiicolin was previously identified as a necrotrophic effector required for the virulence of C. cassiicola in specific rubber tree clones. The objective of this study was to decipher the cassiicolin-mediated molecular mechanisms involved in this compatible interaction. We comparatively analyzed the RNA-Seq transcriptomic profiles of leaves treated or not with the purified cassiicolin Cas1, in two rubber clones: PB260 (susceptible) and RRIM600 (tolerant). The reads were mapped against a synthetic transcriptome composed of all available transcriptomic references from the two clones. Genes differentially expressed in response to cassiicolin Cas1 were identified, in each clone, at two different time-points. After de novo annotation of the synthetic transcriptome, we analyzed GO enrichment of the differentially expressed genes in order to elucidate the main functional pathways impacted by cassiicolin. Cassiicolin induced qualitatively similar transcriptional modifications in both the susceptible and the tolerant clones, with a strong negative impact on photosynthesis, and the activation of defense responses via redox signaling, production of pathogenesis-related protein, or activation of the secondary metabolism. In the tolerant clone, transcriptional reprogramming occurred earlier but remained moderate. By contrast, the susceptible clone displayed a late but huge transcriptional burst, characterized by massive induction of phosphorylation events and all the features of a hypersensitive response. These results confirm that cassiicolin Cas1 is a necrotrophic effector triggering a hypersensitive response in susceptible rubber clones, in agreement with the necrotrophic-effector-triggered susceptibility model., Competing Interests: We have received funding from commercial sources (Cirad, Michelin, Socfin and SIPH) for this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

A novel killer toxin produced by yeast Metschnikowia pulcherrima was purified and added into ready to cook meatballs to enhance their microbial safety and extension of their shelf life. The agent was added into ready to cook meatballs at two different concentrations (1%-K1 and 2%-K2). The results of those two groups were compared to the control group (K0) lacking the killer toxin. Physical, chemical and microbiological analyses were carried out in meat dough and all analyses were repeated at two day intervals during 10 day-storage at +4 °C. Addition of inhibitor compound in meat dough decreased the numbers of total aerobic mesophillic bacteria, yeast and molds and lactic acid bacteria. Staphylococci/Micrococci, coliform bacteria and total psychrotrophic bacterial counts of the samples were determined as well. Results showed that all indicators of microbial deterioration were found to be higher in K1 group than K2 group, revealing that there was an inverse correlation between the concentration of killer toxin and the number of microorganisms causing spoilage. In addition to 1 log decrease in the number of microorganisms in toxin added groups, the high TBARS values of the control group also showed the effectiveness of the toxin. Toxic effect analysis results showed that the killer toxin had no toxic effect on L929 mouse fibroblast cells after 24h exposure., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The research on bioactive secondary metabolites from Aspergillus fumigatus afforded six compounds, which were identified by mass spectrometer (MS) and nuclear magnetic resonance (NMR) spectroscopic analysis as cyclopyazonic acid (1), trypacidin A (2), asterric acid (3), methyl asterrate (4), demethylcitreoviranol (5), as well as (5-hydroxy-2-oxo-2H-pyran-4-yl) methyl acetate (6). Cyclopyazonic acid (1) was found to have potent antibacterial effects, especially against Bacillus licheniformis with minimal inhibitory concentration (MIC) value of 3.7μg/mL. Its antibacterial effects were possibly related to the olefinic acid group in the structure. Phenyl ether derivatives 3 and 4, and trypacidin A (2) also exhibited antimicrobial effects. In addition, compound 6 showed significant antioxidant effects with half maximal effective concentration (EC 50 ) value of 10.2μM in the ABTS (2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid) assay, which was better than the positive control.

Deoxynivalenol (DON) is the most prevalent mycotoxin in swine feedstuffs. The intestinal epithelial cells represent the first target for the DON. Here, we studied the effects of DON and mycotoxin adsorbent agents on mitogen-activated protein kinase (MAPK) signaling pathways and inflammation-associated gene expression in porcine intestinal epithelial cells (IPEC-J2). Results showed that phosphorylation of MAPK signaling pathways (p38, ERK, and JNK) was increased after treatment of DON or lipopolysaccharide (LPS) in IPEC-J2 cells. The phosphorylation of p38, ERK, and JNK was not further enhanced after co-treatment with DON and LPS. The inos and cox-2 mRNA expression were significantly induced at 6 h after treatment of DON. DON treatment significantly increased the claudin 3 and occludin mRNA expression at 12 h. DON in combination with LPS treatment did not further increase the inflammation and tight junction-associated gene expression. The DON-induced phosphorylation of MAPK signaling pathways was impaired by mycotoxin adsorbent agent (nanoscale silicate platelets and the mixture of montmorillonites and yeast cell walls) treatment, thereby decreasing inflammation and tight junction-associated gene expression. Taken together, these findings demonstrate that DON triggers the inflammation in IPEC-J2 cells by phosphorylation of MAPK signaling pathways and LPS does not further augment the DON-induced inflammatory responses. Mycotoxin adsorbent agents can attenuate DON-induced inflammatory responses in IPEC-J2 cells through modulation of the phosphorylation of p38, ERK, and JNK.

Ageritin is a specific ribonuclease, extracted from the edible mushroom Cyclocybe aegerita (synonym Agrocybe aegerita ), which cleaves a single phosphodiester bond located within the universally conserved alpha-sarcin loop (SRL) of 23-28S rRNAs. This cleavage leads to the inhibition of protein biosynthesis, followed by cellular death through apoptosis. The structural and enzymatic properties show that Ageritin is the prototype of a novel specific ribonucleases family named 'ribotoxin-like proteins', recently found in fruiting bodies of other edible basidiomycetes mushrooms (e.g., Ostreatin from Pleurotus ostreatus , Edulitins from Boletus edulis , and Gambositin from Calocybe gambosa ). Although the putative role of this toxin, present in high amount in fruiting body (>2.5 mg per 100 g) of C. aegerita, is unknown, its antifungal and insecticidal actions strongly support a role in defense mechanisms. Thus, in this review, we focus on structural, biological, antipathogenic, and enzymatic characteristics of this ribotoxin-like protein. We also highlight its biological relevance and potential biotechnological applications in agriculture as a bio-pesticide and in biomedicine as a therapeutic and diagnostic agent.

Cordyceps fumosorosea , an insect pathogenic fungus, produces different toxins/secondary metabolites which can act as pest control agents. This study reports the extraction and characterization of crude mycelial extracts of C. fumosorosea isolate SP502 along with their bio-efficacy against Bemisia tabaci and Aphis craccivora . Fourier transform infrared spectroscopy, liquid chromatography, mass spectrometery and nuclear magnetic resonance analysis of C. fumosorosea isolate SP502 extracts showed the presence of five major compounds-Trichodermin, 5-Methylmellein, Brevianamide F, Enniatin and Beauvericin-which all may potentially be involved in insecticidal activity. The HPLC analysis of C. fumosorosea mycelial extracts and Beauvericin standard showed similar chromatographic peaks, with the content of Beauvericin in the crude toxin being calculated as 0.66 mg/ml. The median lethal concentrations of C. fumosorosea mycelial extracts towards first, second, third and fourth instar nymphs of A. craccivora were 46.35, 54.55, 68.94, and 81.92 µg/mL, respectively. The median lethal concentrations of C. fumosorosea mycelial extracts towards first, second, third and fourth instar nymphs of B. tabaci were 62.67, 72.84, 77.40, and 94.40 µg/mL, respectively. Our results demonstrate that bioactive compounds produced by C. fumosorosea isolate SP502 have insecticidal properties and could, therefore, be developed into biopesticides for the management of B. tabaci and A. craccivora .

The presence of cyclic depsipeptide mycotoxins in foods and feedstuffs could potentially cause endocrine disrupting effects on humans and wildlife by their inhibition of active steroidogenesis. Therefore, we attempted to assess the human estrogen receptor (ER) and androgen receptor (AR) agonistic/antagonistic effects of representative cyclic depsipeptide mycotoxins, enniatin A1 (ENN A1), and enniatin B1 (ENN B1), by OECD Performand Based Test Guideline (PBTG) No.455, VM7Luc ER transcriptional activation (TA) assay and OECD TG No. 458, 22Rv1/MMTV&#95;GR-KO AR TA assay. No tested cyclic depsipeptide mycotoxins were found to be ER and AR agonists in VM7Luc ER TA and 22Rv1/MMTV&#95;GR-KO AR TA assays. On the other hand, ENN A1, and ENN B1 exhibited the ER and AR antagonistic effects with IC 30 and IC 50 values in both TA assays. These two cyclic depsipeptide mycotoxins, which were determined as ER and AR antagonists by two in vitro assays, bound to ERα, and AR. Then ENN A1, and ENN B1 inhibited the dimerization of ERα, and AR. These results, for the first time indicated that ENN A1, and ENN B1 could have potential endocrine disrupting effects mediated by interaction of ERα and AR using international standard testing methods to determine the potential endocrine disrupting chemical., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Beauvericin (BEA) is a member of the enniatin family of mycotoxins which has received increasing interest because of frequent occurrence in food and feed. By its ionophoric properties, BEA is able to alter membrane ion permeability uncoupling oxidative phosphorylation. It was also shown to alter oocyte mitochondrial function. In this study, the effects of BEA at 0.5, 1, ,3 and 5 μmol/L on expression of genes coding for key proteins of the mitochondrial chain in ovine oocytes and cumulus cells were evaluated at different time points of in vitro maturation (IVM), germinal vesicle (GV; t = 0), metaphase I (MI; t = 7 h), and metaphase II (MII; t = 24 h). The expression of nuclear (TFAM, NDUFA12, UQCRH, COX4, ATP5O) and mitochondrial (ND1, COX1, COX2, ATP6, ATP8) genes coding for proteins of Complexes I, III, IV, and V was analyzed by qRT-PCR. After BEA exposure, perturbed expression of all genes was observed in cumulus cells and in oocytes at the MI stage (7 h IVM). Expression of ND1, UQCRH, COX4 and ATP5O was downregulated in cumulus cells and upregulated in oocytes starting from 0.5 μmol/L BEA. Expression of TFAM, NDUFA12, COX1, COX2, ATP6, and ATP8 was upregulated starting from 1 μmol/L in cumulus cells and from 3 μmol/L in oocytes. Cumulus cells and oocytes displayed different gene expression patterns upon BEA exposure. The downregulation in cumulus cells of four genes coding for proteins of mitochondrial complexes could represent a major toxic event induced by BEA on the cumulus-oocyte complex which may result in mitochondrial functional alteration.

Nine new xanthone-type and anthraquinone-type mycotoxins including austocystins J-N (1-5), 7-chloro versicolorin A (6), 3'-hydroxy-8-O-methyl versicolorin B (7), 8-O-methyl versiconol (8) and 2',3'-dihydroxy versiconol (9), together with 17 known analogues (10-26) were isolated from an extract of the deep-sea-derived fungus Aspergillus puniceus SCSIO z021. Their structures were elucidated by detailed analysis of spectroscopic data, and their absolute configurations were further determined by quantum chemical calculations of ECD spectra or comparison of the experimental ECD spectra. Eleven hydrogenated austocystins were synthesized from 1-2, 10-15 and 17 by catalytic hydrogenation for bioactivities evaluation. Totally, 18 of the all 37 compounds showed strong toxicity against brine shrimps or Vero cell, and the toxicity of 8-O-methyldemethylsterigmatocystin (18) (LC 50  = 0.020 µM) against brine shrimps was higher than those of three positive controls. In addition, 22 of the isolated compounds also exhibited significant inhibitory activity against seven different protein tyrosine phosphatases (PTPs), among them austocystin H (15) and methyl-averantin (24) were the most potent inhibitors with IC 50 values of 0.20-3.0 µM. Their structure-bioactivity relationship was also discussed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Patulin (PAT) is a mycotoxin produced by various fungal species that commonly contaminate apples and other fruit products. PAT is associated with glutathione (GSH) depletion and oxidative stress. Cytoprotective and antioxidant (AO) enzymes limit toxic outcomes and confer resistance to oxidative stress by influencing the expression of cytoprotective genes. The induction of these genes is tightly regulated by transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2), a potential target of microRNA (miR)-144. This study aims to determine a possible role for miR-144 in NRF2 pathway activation following PAT exposure in human embryonic kidney (HEK293) cells. HEK293 cells were exposed to varying PAT concentrations (0, 0.2, 0.5, 1 μmol/L; 24 h). Protein expression of Keap1, NRF2, and phosphorylated (p) NRF2 (ser40) was quantified using western blotting. Gene expression of NRF2, SOD2, CAT, GPx, NQO1, GSTA1, HMOX, and miR-144 were evaluated by qPCR. PAT significantly decreased miR-144 (p = 0.0249) and concomitantly increased NRF2 protein expression, stability, and activation as evidenced by increased pNRF2 (p = 0.0216) expression and decreased total NRF2 (p = 0.0237). This was consistent with qPCR data which showed increased transcript levels of NRF2 (p = 0.0378) as well as the target genes CAT (p = 0.0273), NQO1 (p = 0.0156), HMOX (p = 0.0249), and GSTA1 (p = 0.0237). No changes were observed in Keap1 expression (p = 0.6444). This study implicates microRNAs in a mechanistic role in PAT-induced toxicity. PAT decreased miR-144 expression leading to NRF2 pathway activation and elevated AO gene expression.