RESUMEN

Beauvericin, a Fusarium mycotoxin commonly found in feeds, particularly cereals worldwide, exhibits a wide array of biofunction. It exhibits anticancer characteristics in addition to its antiviral, antifungal and antibacterial capabilities against gram-positive and gram-negative microorganisms. The mechanism underlying most of beauvericin's properties lies in its ionophoric activity. By facilitating calcium (Ca2+) flow from the extracellular space as well as its release from intracellular reservoirs, beauvericin increases intracellular free Ca2+. This elevation in Ca2+ levels leads to detrimental effects on mitochondria and oxidative stress, ultimately resulting in apoptosis and cell death. Studies on various cancer cell lines have shown that beauvericin induces apoptosis upon exposure. Moreover, besides its cytotoxic effects, beauvericin also inhibits cancer growth and progression by exerting anti-angiogenic and anti-migratory effects on cancer cells. Additionally, beauvericin possesses immunomodulatory properties, albeit less explored. Recent research indicates its potential to enhance the maturation and activation of dendritic cells (DCs) and T cells, both directly through its interaction with Toll-like receptor 4 (TLR4) and indirectly by increasing intracellular Ca2+ levels. Hence, beauvericin could serve as an adjuvant in chemoimmunotherapy regimens to enhance treatment outcomes. Given these diverse properties, beauvericin emerges as an intriguing candidate for developing effective cancer treatments. This review explores the cellular signaling pathways involved in its anticancer effects.

RESUMEN

Pineapple Fruitlet Core Rot (FCR) is a fungal disease characterized by a multi-pathogen pathosystem. Recently, Fusarium proliferatum, Fusarium oxysporum, and Talaromyces stollii joined the set of FCR pathogens until then exclusively attributed to Fusarium ananatum. The particularity of FCR relies on the presence of healthy and diseased fruitlets within the same infructescence. The mycobiomes associated with these two types of tissues suggested that disease occurrence might be triggered by or linked to an ecological chemical communication-promoting pathogen(s) development within the fungal community. Interactions between the four recently identified pathogens were deciphered by in vitro pairwise co-culture bioassays. Both fungal growth and mycotoxin production patterns were monitored for 10 days. Results evidenced that Talaromyces stollii was the main fungal antagonist of Fusarium species, reducing by 22% the growth of Fusarium proliferatum. A collapse of beauvericin content was observed when FCR pathogens were cross-challenged while fumonisin concentrations were increased by up to 7-fold. Antagonism between Fusarium species and Talaromyces stollii was supported by the diffusion of a red pigmentation and droplets of red exudate at the mycelium surface. This study revealed that secondary metabolites could shape the fungal pathogenic community of a pineapple fruitlet and contribute to virulence promoting FCR establishment.

Asunto(s)

Ananas , Fusarium , Micotoxinas , Enfermedades de las Plantas , Talaromyces , Ananas/microbiología , Fusarium/crecimiento & desarrollo , Fusarium/metabolismo , Fusarium/patogenicidad , Talaromyces/crecimiento & desarrollo , Talaromyces/metabolismo , Enfermedades de las Plantas/microbiología , Micotoxinas/metabolismo , Frutas/microbiología , Técnicas de Cocultivo

RESUMEN

Emerging mycotoxins enniatins (ENNs) and beauvericin (BEA) pose potential health risks to humans through dietary exposure. However, research into their mechanisms of toxicity is limited, with a lack of comprehensive toxicological data. This study investigates from a hepatic lipid metabolism perspective, establishing a more precise and reliable 3D HepaRG hepatocyte spheroid model as an alternative for toxicity assessment. Utilizing physiological indices, histopathological analyses, lipidomics, and molecular docking techniques, it comprehensively elucidates the effects of ENNs and BEA on hepatic lipid homeostasis and their molecular toxicological mechanisms. Our findings indicate that ENNs and BEA impact cellular viability and biochemical functions, significantly altering lipid metabolism pathways, particularly those involving glycerophospholipids and sphingolipids. Molecular docking has demonstrated strong binding affinity of ENNs and BEA with key enzymes in lipid metabolism such as Peroxisome Proliferator-Activated Receptor α (PPARα) and Cytosolic Phospholipase A2 (cPLA2), revealing the mechanistic basis for their hepatotoxic effects and potential to impair liver function and human health. These insights enhance our understanding of the potential hepatotoxicity of such fungal toxins and lay a foundation for the assessment of their health risks.

RESUMEN

Triple negative breast cancer (TNBC) presents a significant global health concern due to its aggressive nature, high mortality rate and limited treatment options, highlighting the urgent need for targeted therapies. Beauvericin, a bioactive fungal secondary metabolite, possess significant anticancer potential, although its molecular targets in cancer cells remain unexplored. This study has investigated possible molecular targets of beauvericin and its therapeutic insights in TNBC cells. In silico studies using molecular docking and MD simulation predicted the molecular targets of beauvericin. The identified targets included MRP-1 (ABCC1), HDAC-1, HDAC-2, LCK and SYK with average binding energy of -90.1, -44.3, -72.1, -105 and -60.8 KJ/mol, respectively, implying its multifaceted roles in reversing drug resistance, inhibiting epigenetic modulators and oncogenic tyrosine kinases. Beauvericin has significantly reduced the viability of MDA-MB-231 and MDA-MB-468 cells, with IC50 concentrations of 4.4 and 3.9 µM, while concurrently elevating the intracellular ROS by 9.0 and 7.9 folds, respectively. Subsequent reduction of mitochondrial transmembrane potential in TNBC cells, has confirmed the induction of oxidative stress, leading to apoptotic cell death, as observed by flow cytometric analyses. Beauvericin has also arrested cell cycle at G1-phase and impaired the spheroid formation and clonal expansion abilities of TNBC cells. The viability of spheroids was reduced upon beauvericin treatment, exhibiting IC50 concentrations of 10.3 and 6.2 µM in MDA-MB-468 and MDA-MB-231 cells, respectively. In conclusion, beauvericin has demonstrated promising therapeutic potential against TNBC cells through possible inhibition of MRP-1 (ABCC1), HDAC-1, HDAC-2, LCK and SYK.

Asunto(s)

Antineoplásicos , Proliferación Celular , Supervivencia Celular , Depsipéptidos , Neoplasias de la Mama Triple Negativas , Humanos , Depsipéptidos/farmacología , Depsipéptidos/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Apoptosis/efectos de los fármacos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Estructura Molecular , Relación Dosis-Respuesta a Droga , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/metabolismo , Relación Estructura-Actividad

RESUMEN

Risk assessment (RA) of microbial secondary metabolites (SM) is part of the EU approval process for microbial active substances (AS) used in plant protection products (PPP). As the number of potentially produced microbial SM may be high for a certain microbial strain and existing information on the metabolites often are low, data gaps are frequently identified during the RA. Often, RA cannot conclusively clarify the toxicological relevance of the individual substances. This work presents data and RA conclusions on four metabolites, Beauvericin, 2,3-deepoxy-2,3-didehydro-rhizoxin (DDR), Leucinostatin A and Swainsonin in detail as examples for the challenging process of RA. To overcome the problem of incomplete assessment reports, RA of microbial AS for PPP is in need of new approaches. In view of the Next Generation Risk Assessment (NGRA), the combination of literature data, omic-methods, in vitro and in silico methods combined in adverse outcome pathways (AOPs) can be used for an efficient and targeted identification and assessment of metabolites of concern (MoC).

Asunto(s)

Unión Europea , Medición de Riesgo , Metabolismo Secundario , Depsipéptidos/toxicidad , Depsipéptidos/metabolismo , Humanos

RESUMEN

BACKGROUND: Fresh ginseng is typically accompanied by soil after harvest, leading to contamination with harmful fungi during storage and distribution. In this study, we investigated the incidence of fungal contamination in fresh ginseng (5-6 years old) purchased from 22 different stores in Geumsan, Korea. RESULTS: The incidence of fungal contamination in the samples was 67.4-111.5%. Fusarium solani was the most abundant species in the head (38.5%) and fine root (19.3%) parts of the ginseng samples, whereas F. oxysporum was the most abundant in the main root (22.0%) part. We isolated Aspergillus, Fusarium and Penicillium spp. (total number of isolates: 395) from the ginseng samples, and 138 isolates were identified using phylogenetic analysis. Polymerase chain reaction-based screening of 65 mycotoxin-producing species revealed that two P. expansum isolates were positive for citrinin and/or patulin, and five F. oxysporum isolates were positive for fumonisin biosynthesis gene. One P. expansum isolate produced 738.0 mg kg-1 patulin, and the other produced 10.4 mg kg-1 citrinin and 12.0 mg kg-1 patulin on potato dextrose agar (PDA) medium. Among the 47 representative F. oxysporum isolates, 43 (91.5%) produced beauvericin (0.1-15.4 mg kg-1) and four of them (8.5%) produced enniatin B and enniatin B1 (0.1-1.8 mg kg-1) as well. However, none of these toxins was detected in fresh ginseng samples. CONCLUSION: Fusarium solani and F. oxysporum were the most abundant species in fresh ginseng samples. Most F. oxysporum (43) and P. expansum (2) strains isolated from fresh ginseng produced beauvericin and enniatins (B and B1), and patulin or citrinin, respectively, on PDA medium. This is the first report of the mycotoxigenic potential of P. expansum and F. oxysporum strains isolated from fresh ginseng. © 2024 Society of Chemical Industry.

Asunto(s)

Contaminación de Alimentos , Hongos , Fusarium , Micotoxinas , Panax , Panax/microbiología , Panax/química , Micotoxinas/metabolismo , Micotoxinas/análisis , Fusarium/aislamiento & purificación , Fusarium/metabolismo , Fusarium/genética , Fusarium/clasificación , República de Corea , Contaminación de Alimentos/análisis , Hongos/aislamiento & purificación , Hongos/genética , Hongos/clasificación , Hongos/metabolismo , Filogenia , Aspergillus/aislamiento & purificación , Aspergillus/metabolismo , Aspergillus/genética , Aspergillus/clasificación , Penicillium/aislamiento & purificación , Penicillium/metabolismo , Penicillium/clasificación , Penicillium/genética , Raíces de Plantas/microbiología

RESUMEN

Poultry farming has developed into one of Algeria's most productive industrial farming because of the growing demand for sources of protein among Algerian society. Laying hen feed consists mainly of cereals, which can be contaminated with molds and subsequently with their secondary metabolites known as mycotoxins. These later can pose a serious danger to the production and quality of eggs in the commercial layer industry. This work focuses on the detection of emerging mycotoxins, mainly enniatins (ENNs) and beauvericin (BEA), in poultry feed and eggs from different locations in Algeria. Two different QuEChERS-based extractions were established to extract ENNs and BEA from chicken feed and eggs. The determination of mycotoxin occurrence was achieved by a UHPLC-MS/MS method using 0.1% (v/v) formic acid in water and MeOH as mobile phase, an ESI interface operating in positive mode, and a triple quadrupole mass spectrometer operating in MRM for the detection. Matrix-matched calibration curves were carried out for both matrices, obtaining good linearity (R2 > 0.99). The method performance was assessed in terms of extraction recovery (from 87 to 107%), matrix effect (from - 47 to - 86%), precision (RSD < 15%), and limits of quantitation (≤ 1.1 µg/kg for feed and ≤ 0.8 µg/kg for eggs). The analysis of 10 chicken feed samples and 35 egg samples composed of a 10-egg pool each showed that ENN B1 was the most common mycotoxin (i.e., found in 9 feed samples) with contamination levels ranging from 3.6 to 41.5 µg/kg, while BEA was detected only in one feed sample (12 µg/kg). However, eggs were not found to be contaminated with any mycotoxin at the detection limit levels. Our findings indicate that the searched mycotoxins are present in traces in feed and absent in eggs. This can be explained by the application of a mycotoxin binder. However, this does not put a stop on the conduction of additional research and ultimately setting regulations to prevent the occurrence of emerging mycotoxins.

Asunto(s)

Alimentación Animal , Pollos , Huevos , Contaminación de Alimentos , Micotoxinas , Espectrometría de Masas en Tándem , Animales , Alimentación Animal/análisis , Argelia , Micotoxinas/análisis , Espectrometría de Masas en Tándem/métodos , Huevos/análisis , Cromatografía Líquida de Alta Presión/métodos , Contaminación de Alimentos/análisis , Depsipéptidos/análisis

RESUMEN

There is still considerable controversy about the relative risk of mycotoxin exposure associated with the consumption of organic and conventional cereals. Using validated protocols, we carried out a systematic literature review and meta-analyses of data on the incidence and concentrations of mycotoxins produced by Fusarium, Claviceps, Penicillium, and Aspergillus species in organic and conventional cereal grains/products. The standard weighted meta-analysis of concentration data detected a significant effect of production system (organic vs. conventional) only for the Fusarium mycotoxins deoxynivalenol, with concentrations ∼50% higher in conventional than organic cereal grains/products (p < 0.0001). Weighted meta-analyses of incidence data and unweighted meta-analyses of concentration data also detected small, but significant effects of production system on the incidence and/or concentrations of T-2/HT-2 toxins, zearalenone, enniatin, beauvericin, ochratoxin A (OTA), and aflatoxins. Multilevel meta-analyses identified climatic conditions, cereal species, study type, and analytical methods used as important confounding factors for the effects of production system. Overall, results from this study suggest that (i) Fusarium mycotoxin contamination decreased between the 1990s and 2020, (ii) contamination levels are similar in organic and conventional cereals used for human consumption, and (iii) maintaining OTA concentrations below the maximum contamination levels (3.0 µg/kg) set by the EU remains a major challenge.

Asunto(s)

Grano Comestible , Contaminación de Alimentos , Micotoxinas , Grano Comestible/química , Grano Comestible/microbiología , Micotoxinas/análisis , Contaminación de Alimentos/análisis , Fusarium/química , Alimentos Orgánicos/análisis , Alimentos Orgánicos/microbiología

RESUMEN

Drug discovery was initially attributed to coincidence or experimental research. Historically, the traditional approaches were complex, lengthy, and expensive, entailing costly random screening of synthesized compounds or natural products coupled with in vivo validation largely depending on the availability of appropriate animal models. Currently, in silico modeling has become a vital tool for drug discovery and repurposing. Molecular docking and dynamic simulations are being used to find the best match between a ligand and a molecule, an approach that could help predict the biomolecular interactions between the drug and the target host. Beauvericin (BEA) is an emerging mycotoxin produced by the entomopathogenic fungus Beauveria bassiana, being originally studied for its potential use as a pesticide. BEA is now considered a molecule of interest for its possible use in diverse biotechnological applications in the pharmaceutical industry and medicine. In this manuscript, we provide an overview of the repurposing of BEA as a potential therapeutic agent for multiple diseases. Furthermore, considerable emphasis is given to the fundamental role of in silico techniques to (i) further investigate the activity spectrum of BEA, a secondary metabolite, and (ii) elucidate its mode of action.

RESUMEN

Multidrug resistance in bacteria is a major challenge worldwide, increasing both mortality by infections and costs for the health systems. Therefore, it is of utmost importance to find new drugs against resistant bacteria. Beauvericin (BEA) is a mycotoxin produced by entomopathogenic and other fungi of the genus Fusarium. Our work determines the effect of BEA combined with antibiotics, which has not been previously explored. The combination analysis included different antibiotics against non-methicillin-resistant Staphylococcus aureus (NT-MRSA), methicillin-resistant Staphylococcus aureus (MRSA), and Salmonella typhimurium. BEA showed a synergy effect with oxacillin with a fractional inhibitory concentration index (FICI) = 0.373 and an additive effect in combination with lincomycin (FICI = 0.507) against MRSA. In contrast, it was an antagonist when combined with ciprofloxacin against S. typhimurium. We propose BEA as a molecule with the potential for the development of new therapies in combination with current antibiotics against multidrug-resistant bacteria.

Asunto(s)

Antibacterianos , Depsipéptidos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Salmonella typhimurium , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/farmacología , Salmonella typhimurium/efectos de los fármacos , Depsipéptidos/farmacología , Sinergismo Farmacológico , Farmacorresistencia Bacteriana Múltiple

RESUMEN

Beauvericin (BEA) is a newly identified mycotoxin produced by various Fusarium species, and its contamination in food and animal feed is widespread globally. This mycotoxin demonstrates cytotoxic effects by inducing oxidative stress in multiple models. Furthermore, evidence indicates that BEA possesses diverse toxic activities, making it a promising candidate for toxicological research. Recent studies have highlighted the ability of BEA to traverse the blood-brain barrier, suggesting its potential neurotoxicity. However, limited information is available regarding the neurotoxic effects of BEA on human astrocytes. Therefore, this study aimed to assess the neurotoxic effects of BEA on the Gibco® Human Astrocyte (GHA) cell line and elucidate the underlying mechanisms. Additionally, the study aimed to investigate the protective effects of the antioxidant N-acetylcysteine (NAC) against BEA-induced toxicity. The data show that exposure to BEA within the 2.5-15 µM concentration range resulted in concentration-dependent cytotoxicity. BEA-treated cells exhibited significantly increased levels of reactive oxygen species (ROS), while intracellular glutathione (GSH) content was significantly reduced. Western blot analysis of cells treated with BEA revealed altered protein levels of Bax, cleaved caspase-9, and caspase-3, along with an increased Bax/Bcl-2 ratio, indicating the induction of apoptosis. Additionally, BEA exposure triggered antioxidant responses, as evidenced by increased protein expression of Nrf2, HO-1, and NQO1. Significantly, pretreatment with NAC partially attenuated the significant toxic effects of BEA. In conclusion, our findings suggest that BEA-induced cytotoxicity in GHA cells involves oxidative stress-associated apoptosis. Furthermore, NAC demonstrates potential as a protective agent against BEA-induced oxidative damage.

Asunto(s)

Acetilcisteína , Apoptosis , Astrocitos , Depsipéptidos , Estrés Oxidativo , Especies Reactivas de Oxígeno , Humanos , Acetilcisteína/farmacología , Astrocitos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Depsipéptidos/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Antioxidantes/farmacología

RESUMEN

Beauvericin is an emerging Fusariotoxin naturally occurring in cereal grains throughout the world whereas glyphosate (N-phosphonomethyl-glycine) is a non-selective systemic herbicide used worldwide. The purpose of this study is to evaluate a newly developed ovarian cell culture system (that includes both granulosa and theca cells) as an in vitro model for toxicological studies. Specifically, the effects of beauvericin and glyphosate in formulation with Roundup on ovarian cell numbers and steroid production were evaluated. Ovaries collected from cattle without luteal structures were sliced into 30-70 pieces each, and granulosa and theca cells were collected. Harvested cells were cultured for 48 h in 10% fetal bovine serum-containing medium followed by 48 h in serum-free medium containing testosterone (500 ng/mL; as an estrogen precursor) with the following eight treatments: (1) controls, (2) FSH (30 ng/mL) alone, (3) FSH plus insulin-like growth factor-1 (IGF1; 30 ng/mL), (4) FSH plus IGF1 plus beauvericin (3 µM), (5) FSH plus IGF1 plus glyphosate in Roundup (10 µg/mL), (6) FSH plus IGF1 plus fibroblast growth factor 9 (FGF9, 30 ng/mL), (7) a negative control without added testosterone, and (8) IGF1 plus LH (30 ng/mL) with basal medium without added testosterone. In the presence of FSH, IGF1 significantly increased cell numbers, estradiol and progesterone production by severalfold. Glyphosate in Roundup formulation significantly inhibited IGF1-induced cell numbers and estradiol and progesterone production by 89-94%. Beauvericin inhibited IGF1-induced cell numbers and estradiol and progesterone by 50-97% production. LH plus IGF1 significantly increased androstenedione secretion compared with controls without added testosterone indicating the presence of theca cells. In conclusion, the present study demonstrates that toxicological effects of beauvericin and glyphosate in Roundup formulation are observed in a newly developed ovarian cell model system and further confirms that both glyphosate and beauvericin may have the potential to impair reproductive function in cattle.

Asunto(s)

Depsipéptidos , Glicina , Glifosato , Herbicidas , Animales , Femenino , Bovinos , Glicina/análogos & derivados , Glicina/toxicidad , Depsipéptidos/toxicidad , Herbicidas/toxicidad , Ovario/efectos de los fármacos , Ovario/metabolismo , Progesterona/metabolismo , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Células Tecales/efectos de los fármacos , Células Tecales/metabolismo , Estradiol/metabolismo , Estradiol/análogos & derivados , Recuento de Células , Células Cultivadas , Factor I del Crecimiento Similar a la Insulina/metabolismo , Testosterona/análogos & derivados

RESUMEN

In current study, Fusarium mycotoxin, beauvericin (BEA), has endocrine disrupting potential through suppressing the exogenous androgen receptor (AR)-mediated transcriptional activation. BEA was classified as an AR antagonist, with IC30 and IC50 values indicating that it suppressed AR dimerization in the cytosol. BEA suppress the translocation of cytosolic activated ARs to the nucleus via exogenous androgens. Furthermore, we investigated the impact of environmental conditions for BEA production on rice cereal using response surface methodology. The environmental factors affecting the production of BEA, namely temperature, initial moisture content, and growth time were optimized at 20.28 °C, 42.79 % (w/w), and 17.31 days, respectively. To the best of our knowledge, this is the first report showing that BEA has endocrine disrupting potential through suppressing translocation of cytosolic ARs to nucleus, and temperature, initial moisture content, and growth time are important influencing environmental factors for its biosynthesis in Fusarium strains on cereal.

Asunto(s)

Depsipéptidos , Fusarium , Micotoxinas , Oryza , Receptores Androgénicos , Humanos , Depsipéptidos/toxicidad , Grano Comestible/química , Fusarium/metabolismo , Micotoxinas/toxicidad , Oryza/química , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Disruptores Endocrinos/química , Disruptores Endocrinos/toxicidad

RESUMEN

Myxotoxins can contaminate algal-based products and arrive to the food chain to consumers producing chronic toxicity effects. Here, we studied phytotoxicity of mycotoxins, beauvericin (BEA) and ennaitin B (ENN B) in four phytoplankton strains: Acutodesmus sp., Chlamydomonas reinhardtii, Haematococcus pluvialis, and Monoraphidium griffithii, which are all green algae. It was tested the capacity of clearing the media of BEA and ENN B at different concentrations by comparing nominal and measured quantifications. Results revealed that Acutodesmus sp. and C. reinhardtii tended to flow up and down growth rate without reaching values below 50% or 60%, respectively. On the other hand, for H. pluvialis and M. griffith, IC50 values were reached. Regarding the clearance of media, in individual treatment a decrease of the quantified mycotoxin between nominal and measured values was observed; while in binary treatment, differences among both values were higher and more noted for BEA than for ENN B.

Asunto(s)

Chlorophyta , Depsipéptidos , Micotoxinas , Micotoxinas/toxicidad , Ecosistema

RESUMEN

Beauvericin (BEA) is a cyclic depsipeptide secondary metabolite of Fusarium species. It causes chemical hazards in food products and exists in an environment containing soil and various food types. On the other hand, the purified BEA has various biological activities and is regarded as a potential candidate for pharmaceutical research. This study was performed to assess the anti-proliferation activity of BEA against human breast cancer cells by regulating the estrogen receptor-alpha (ERα)/p38 pathway. TA and BA assays verified that BEA is a completed ER antagonist. Additionally, BEA suppressed cell proliferation in the anti-proliferation assay involving ER-positive human breast cancer cells co-treated with BPA and BEA. In respect to an anti-proliferation activity, the BPA-induced phosphorylation of p38 protein was inhibited in the presence of BEA. These results suggested that BEA exerts inhibitory potentials on endocrine disrupting effect and possibly acts as a natural therapeutic material for human estrogen hormonal health.

Asunto(s)

Compuestos de Bencidrilo , Neoplasias de la Mama , Depsipéptidos , Fusarium , Fenoles , Humanos , Femenino , Receptor alfa de Estrógeno/metabolismo , Fusarium/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Depsipéptidos/farmacología , Depsipéptidos/metabolismo , Proliferación Celular , Línea Celular , Línea Celular Tumoral

RESUMEN

Mycotoxins, produced by fungi, frequently occur at different stages in the food supply chain between pre- and postharvest. Globally produced cereal crops are known to be highly susceptible to contamination, thus constituting a major public health concern. Among the encountered mycotoxigenic fungi in cereals, Fusarium spp. are the most frequent and produce both regulated (i.e., T-2 toxin, deoxynivalenol -DON-, zearalenone -ZEA-) and emerging (i.e., enniatins -ENNs-, beauvericin -BEA-) mycotoxins. In this study, we investigated the in vitro cytotoxic effects of regulated and emerging fusariotoxins on HepaRG cells in 2D and 3D models using undifferentiated and differentiated cells. We also studied the impact of ENN B1 and ENN B exposure on gene expression of HepaRG spheroids. Gene expression profiling pinpointed the differentially expressed genes (DEGs) and overall similar pathways were involved in responses to mycotoxin exposure. Complement cascades, metabolism, steroid hormones, bile secretion, and cholesterol pathways were all negatively impacted by both ENNs. For cholesterol biosynthesis, 23/27 genes were significantly down-regulated and could be correlated to a 30% reduction in cholesterol levels. Our results show the impact of ENNs on the cholesterol biosynthesis pathway for the first time. This finding suggests a potential negative effect on human health due to the essential role this pathway plays.

Asunto(s)

Antineoplásicos , Depsipéptidos , Micotoxinas , Humanos , Micotoxinas/toxicidad , Perfilación de la Expresión Génica , Transcriptoma , Colesterol

RESUMEN

In this work, a complete study of the distribution of emerging mycotoxins in the human body has been carried out. Specifically, the presence of enniatins (A, A1, B, B1) and beauvericin has been monitored in brain, lung, kidney, fat, liver, and heart samples. A unique methodology based on solid-liquid extraction (SLE) followed by dispersive liquid-liquid microextraction (DLLME) was proposed for the six different matrices. Mycotoxin isolation was performed by adding ultrapure water, acetonitrile, and sodium chloride to the tissue sample for SLE, while the DLLME step was performed using chloroform as extraction solvent. Subsequently, the analysis was carried out by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). The proposed method allowed limits of quantification (LOQs) to be obtained in a range of 0.001-0.150 ng g-1, depending on the tissue and mycotoxin. The precision was investigated intraday and interday, not exceeding of 9.8% of relative standard deviation. In addition, trueness studies achieved 75 to 115% at a mycotoxin concentration of 25 ng g-1 and from 82 to 118% at 5 ng g-1. The application of this methodology to 26 forensic autopsies demonstrated the bioaccumulation of emerging mycotoxins in the human body since all mycotoxins were detected in tissues. Enniatin B (ENNB) showed a high occurrence, being detected in 100% of liver (7 ± 13 ng g-1) and fat samples (0.2 ± 0.8 ng g-1). The lung had a high incidence of all emerging mycotoxins at low concentrations, while ENNB, ENNB1, and ENNA1 were not quantifiable in heart samples. Co-occurrence of mycotoxins was also investigated, and statistical tests were applied to evaluate the distribution of these mycotoxins in the human body.

Asunto(s)

Microextracción en Fase Líquida , Micotoxinas , Humanos , Cromatografía Líquida con Espectrometría de Masas , Espectrometría de Masas en Tándem/métodos , Micotoxinas/análisis , Cromatografía Líquida de Alta Presión

RESUMEN

Beauvericin (BEA), a naturally occurring cyclic peptide with good pharmacological activity, has been widely explored in anticancer research. Although BEA is toxic, studies have demonstrated its antioxidant activity. However, to date, the antioxidant mechanisms of BEA remain unclear. Herein, we conducted a comprehensive and detailed study of the antioxidant mechanism of BEA using an untargeted metabolomics approach, subsequently validating the results. BEA concentrations of 0.5 and 1 µM significantly inhibited H2O2-induced oxidative stress (OS), decreased reactive oxygen species levels in PC-12 cells, and restored the mitochondrial membrane potential. Untargeted metabolomics indicated that BEA was primarily involved in lipid-related metabolism, suggesting its role in resisting OS in PC-12 cells by participating in lipid metabolism. BEA combated OS damage by increasing phosphatidylcholine, phosphatidylethanolamine, and sphingolipid levels. In the current study, BEA upregulated proteins related to the PI3K/AKT/mTOR pathway, thereby promoting cell survival. These findings support the antioxidant activity of BEA at low concentrations, warranting further research into its pharmacological effects.

Asunto(s)

Antioxidantes , Apoptosis , Depsipéptidos , Metabolismo de los Lípidos , Antioxidantes/farmacología , Supervivencia Celular , Depsipéptidos/farmacología , Peróxido de Hidrógeno/toxicidad , Metabolismo de los Lípidos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TOR , Células PC12/efectos de los fármacos , Células PC12/metabolismo , Animales , Ratas

RESUMEN

Introduction: The enniatins A, A1, B and B1 (ENNs) and beauvericin (BEA) are structurally related compounds produced by Fusarium species. They occur as contaminants in cereals, such as wheat, barley and maize. They are called "emerging mycotoxins", because they have been reported in feed and food and their toxic effects are not fully known. Data on their levels in food (especially in milk) are limited. The study aimed to evaluate the occurrence of ENNs and BEA in milk. Material and Methods: A total of 103 bovine milk samples (76 of raw milk and 27 of UHT milk) were collected from different parts of Poland and analysed using liquid chromatography-tandem mass spectrometry. Results: Among the 76 raw milk samples, 31 (41%) and 15 (20%) samples were contaminated with ENN B and with BEA, respectively. No contamination with other enniatins was found. The highest concentration of BEA was found in raw milk and was 6.17 µg kg-1. Out of the 27 samples of UHT milk, 16 (59%) were contaminated with ENN B at concentrations ranging from 0.157 µg kg-1 to 0.587 µg kg-1 (limit of quantification (LOQ) 0.098 µg kg-1). Beauvericin was detected in 9 UHT milk samples (33%) at concentrations ranging from 0.101 µg kg-1 to 1.934 µg kg-1 (LOQ 0.095 µg kg-1). Conclusion: This study demonstrated constant but low milk contamination in Poland with ENN B and BEA. The analysis of milk samples revealed that the emerging mycotoxins ENN B and BEA were measured in trace amounts. It does not suggest any immediate risk to milk consumers; however, it is unknown whether long-term exposure to low levels of toxins may be harmful.

RESUMEN

Osteosarcoma (OS) patients, particularly those with distant metastasis, experience rapid progression and derive poor survival benefits from traditional therapies. Currently, effective drugs for treating patients with metastatic OS remain scarce. Here, we found that the cyclic hexadepsipeptide beauvericin (BEA) functioned as a new selective TGFBR2 inhibitor with potent antiproliferative and antimetastatic activities against OS cells. Functionally, BEA inhibited TGF-ß signaling-mediated proliferation, invasiveness, mesenchymal phenotype, and extracellular matrix remodeling of OS cells, and suppressed tumor growth and reduced pulmonary metastasis in vivo. Mechanistic investigation revealed that BEA selectively and directly bound to Asn 332 of TGFBR2 and inhibited its kinase activity, thereby suppressing the aggressive progression of OS cells. Together, our study identifies an innovative and natural selective TGFBR2 inhibitor with effective antineoplastic activity against metastatic OS and demonstrates that targeting TGFBR2 could be a potential therapeutic strategy for metastatic OS.

Asunto(s)

Neoplasias Óseas , Osteosarcoma , Humanos , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Línea Celular Tumoral , Proliferación Celular/genética , Osteosarcoma/metabolismo , Neoplasias Óseas/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica