1,721,028 research outputs found
In silico approach to evaluate molecular interaction between mycotoxins and the estrogen receptors ligand binding domain: A case study on zearalenone and its metabolites.
No full textAn association of virtual screening, docking and a good rescoring procedure is a well known technique to discover and design new lead compounds in medicinal chemistry. We have demonstrated that the study on the interactions of unsuspected molecules with estrogen receptors, using the same technique applied in medicinal chemistry could be a valuable choice to discover new hypothetical xenoestrogens. The same approach can be applied to a wide set of chemicals found in food and seed. We propose this approach using as a case study on the zearalenone family to food safety. Zearalenone and its reductive metabolites are a well known set of mycotoxins able to bind estrogen receptors (ERs) thereby interfering with the endogenous estrogenic response. Their endocrine disrupting behavior is tightly related to their capability to competitively bind the ligand binding pocket (LBP) and to stabilize at least one of the functionally active conformational assets of the ligand binding domain (LBD). Although proposing an interacting model alongside for three-dimensional complexes is not yet solved, this kind of computational aided analysis is a potentially intriguing tool to predict the binding event and to evaluate the xenoestrogenic role of any kind of chemicals and derivatives
Virtual display of targets: A new level to rise the current understanding of ochratoxin A toxicity from a molecular standpoint
No full text: Ochratoxin A (OTA) is a mycotoxin spread worldwide contaminating several food and feed commodities and rising concerns for humans and animals. OTA toxicity has been thoroughly assessed over the last 60 years revealing a variety of adverse effects, including nephrotoxicity, hepatotoxicity and possible carcinogenicity. However, the underpinning mechanisms of action have yet to be completely displayed and understood. In this framework, we applied a virtual pipeline based on molecular docking, dynamics and umbrella simulations to display new OTA potential targets. The results collected consistently identified OGFOD1, a key player in protein translation, as possibly inhibited by OTA and its 2'R diastereomer. This is consistent with the current knowledge of OTA's molecular toxicology and may fill some gaps from a mechanistic standpoint. This could pave the way for further dedicated analysis focusing their attention on the OTA-OGFOD1 interaction, expanding the current understanding of OTA toxicity at a molecular level
Molecular modelling approach to evaluate poisoning of topoisomerase I by alternariol derivatives
No full textAlternaria species are widespread microfungi the secondary metabolites of which may accumulate in crops and enter into food production chain. Among them, the "emerging mycotoxin" alternariol and alternariol-methyl ether arouse concern due to evidences of toxicity. In particular, the disruption of topoisomerases leads to genotoxic outcomes. Metabolic modifications may drastically reduce toxic potency by enhancing clearance and/or by preventing interaction with the pharmacological targets. However, the metabolic activation may occur as well. For this reason, understanding the role of metabolised forms is paramount for the in-depth comprehension of adverse effects on living organisms, thus providing a more informed scenario for risk assessment. Regardless that a wealth of alternariol metabolites and derivatives has been identified, most have not been tested with respect to topoisomerases. Consequently, their effects in living organism are not yet well understood. Unfortunately, experimental analysis is challenging and time-consuming. With the aim of analysing a wide array of alternariol metabolites and derivatives, we presented an effective framework based on a straightforward in silico procedure. Interestingly, several metabolites were predicted to be poisons, strongly suggesting the need for further experimental trials and their inclusion in future risk assessment studie
A mechanistic investigation on kokumi-active γ-Glutamyl tripeptides – A computational study to understand molecular basis of their activity and to identify novel potential kokumi-tasting sequences
Full text linkA mechanistic toxicology study to grasp the mechanics of zearalenone estrogenicity: spotlighting aromatase and the effects of its genetic variability
Full text link: Zearalenone is a mycoestrogen produced by Fusarium fungi contaminating cereals and in grain-based products threatening human and animal health due to its endocrine disrupting effects. Germane to the mechanisms of action, zearalenone may activate the estrogen receptors and inhibit the estrogens-producing enzyme aromatase (CYP19A1). Both show single nucleotide variants (SNVs) among humans associated with a diverse susceptibility of being activated or inhibited. These variations might modify the endocrine disrupting action of zearalenone, requiring dedicated studies to improve its toxicological understanding. This work focused on human aromatase investigating via 3D molecular modelling whether some of the variants reported so far (n=434) may affect the inhibitory potential of zearalenone. It has been also calculated the inhibition capability of α-zearalenol, the most prominent and estrogenically potent phase I metabolite of zearalenone, toward those aromatase variants with an expected diverse sensitivity of being inhibited by ZEN. The study: i) described SNVs likely associated with a different susceptibility to zearalenone and α-zearalenol inhibition - like T310S that is likely more susceptible to inhibition, or D309G and S478F that are possibly inactive variants; ii) proofed the possible existence of inter-individual susceptibility to zearalenone; iii) prioritized aromatase variants for future investigations toward a better comprehension of ZEN xenoestrogenicity at an individual level
On the masked mycotoxin zearalenone-14-glucoside. Does the mask truly hide?
Full text linkIn the matter of foodborne mycotoxins, beside a number of regulated compounds, regulations are totally missing for phase-II plant metabolites - the toxicological knowledge of which is still in its infancy. Currently, zearalenone-14-glucoside is in the pipeline and its toxicological role is under a glowing scientific debate. In our work it clearly showed high toxicological concerns as it is prone to conversion to well-known toxic compounds (i.e. zearalenone and both zearalenol isomers) when exposed to breast cancer cells culture. The need of future risk assessment studies has been pointed out accordingly
Hazard identification of cis/trans-zearalenone through the looking-glass
No full textAmong the food-related health issues, the presence of contaminants has a prominent role, due to the wide range of exogenous compounds that can occur in food commodities and to their large differences in structure and biological activity. A comprehensive assessment of the related risk is thus actually demanding in terms of time and facilities involved. In this context, the use of computational strategies can be an effective choice for supporting the hazard identification procedure at the early stage. In this work, we focused on the food contaminant zearalenone by comparing the trans and cis isomers, respectively the well-known mycoestrogen and its still largely understudied isomer. We estimated the possible effects exerted by human metabolism on the xenoestrogenicity of cis-ZEN by using a validated in silico strategy based on docking simulations and rescoring procedures. Similarly, the exploitation of the most promising enzymatic detoxifying routes designed for trans-ZEN - which relies on the enzyme lactono hydrolase from Clonostachys rosea - has been assessed for the cis-isomer as well. Our results showed that both isomers can act as functional analogues with respect to xenoestrogenic activity, and several cis-ZEN metabolites with high biological potential have been identified. On the contrary, in spite of the high degree of structural analogy, the cis isomer showed a pattern of interaction with the degrading enzyme in stark contrast with that observed for trans-ZEN. For these reasons, the outcomes presented herein strongly support the inclusion of cis-ZEN in further studies of occurrence, metabolism and bioactivity assessment, and suggest the need for a dedicated handling for the cis isomer in risk assessment studies
Assessing the hydrolytic fate of the masked mycotoxin zearalenone-14-glucoside–A warning light for the need to look at the “maskedome”
Full text linkMasked mycotoxins are plant metabolites of mycotoxins that contaminate food and feed. They pose
health concern as the shortage of toxicological data forces the lack of regulation worldwide. The present
work investigated the toxicological relevance of the masked mycotoxin zearalenone-14-glucoside.
In vitro, it shows a lower toxicity in respect to the parent compound. However, the major risks related to
the consumption of masked mycotoxins depend on the possibility to undergo hydrolysis. Therefore, the
hydrolysis and further transformation of zearalenone-14-glucoside in bovine blood and blood components
(i.e. plasma, serum and serum albumin) were monitored using LC/MS-MS analysis to gain insights
on the possible systemic fate. Hydrolysis was observed in all matrices, and both cell-dependent and
eindependent contributions were pointed out. Moreover, further metabolism was observed in the whole
blood as zearalenol isomers were found. Serum albumin was identified among the active components,
and the protein-ligand interaction was investigated via computational analysis. The blood has been
pointed out as possible district of reversion and further activation of zearalenone-14-glucoside, and a
similar fate cannot be excluded for other masked mycotoxins. Therefore, the systemic hydrolysis should
be evaluated beside the absorption, bioavailability and bioaccessibility to deeply understand the toxicity
of masked mycotoxins
Ergot alkaloids: From witchcraft till in silico analysis. Multi-receptor analysis of ergotamine metabolites
No full textAbstractThe term Ergot is referred to the sclerotium of ascomycetes – a protective kernel produced during resting stage of some fungi – which replaces seeds of susceptible cereals and plants intended for human and animal diet. It contains various composition of tryptophan-derived toxins defined ergot alkaloids. Since sclerotia can be harvested and milled together with cereals, they represent a source of food and feed contamination after breakage and spreading of mycotoxins into the various milling fractions. The effects of ergot alkaloids, including those adverse for human health, have been known since the Middle Ages. Nevertheless, as recently stated by the European Food Safety Authority, further information is needed on metabolism and target receptors-binding of common alkaloids in food. Unfortunately, the experimental investigation is challenging due to the high costs in terms of time and money. This study was thus aimed at assessing whether the in silico modeling can be an effective tool to investigate the interaction between multiple serotonin receptors and a wide set of ergotamine metabolites, including experimentally detected molecules and predicted derivatives. Validated models provided precious insights about the effects exerted by metabolic modifications on the receptor–ligand interaction. Such structural information may be useful to support the design of further experimental analysis
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