Unraveling Interspecies Differences in the Phase I Hepatic Metabolism of Alternariol and Alternariol Monomethyl Ether: Closing Data Gaps for a Comprehensive Risk Assessment.

The mycotoxins alternariol (AOH) and alternariol 9--monomethyl ether (AME) are pervasive food contaminants known to exert adverse effects in vitro, yet their toxicokinetics remain inadequately understood. Thus, this study endeavors to elucidate the qualitative and quantitative aspects of the phase I metabolism of AOH and AME. To pursue this goal, reduced nicotinamide adenine dinucleotide phosphate (NADPH)-fortified porcine, rat, and human liver microsomes were incubated for 0-10 min with AOH or AME within a concentration range of 1-100 and 1-50 μM, respectively.

New hemisynthetic derivatives of sphaeropsidin phytotoxins triggering severe endoplasmic reticulum swelling in cancer cells.

Sphaeropsidins are iso-pimarane diterpenes produced by phytopathogenic fungi that display promising anticancer activities. Sphaeropsidin A, in particular, has been shown to counteract regulatory volume increase, a process used by cancer cells to avoid apoptosis. This study reports the hemi-synthesis of new lipophilic derivatives obtained by modifications of the C15,C16-alkene moiety.

Physiologically based kinetic (PBK) modeling as a new approach methodology (NAM) for predicting systemic levels of gut microbial metabolites.

There is a clear need to develop new approach methodologies (NAMs) that combine in vitro and in silico testing to reduce and replace animal use in chemical risk assessment. Physiologically based kinetic (PBK) models are gaining popularity as NAMs in toxico/pharmacokinetics, but their coverage of complex metabolic pathways occurring in the gut are incomplete. Chemical modification of xenobiotics by the gut microbiome plays a critical role in the host response, for example, by prolonging exposure to harmful metabolites, but there is not a comprehensive approach to quantify this impact on human health.

Baricitinib and tofacitinib off-target profile, with a focus on Alzheimer's disease.

Introduction: Janus kinase (JAK) inhibitors were recently identified as promising drug candidates for repurposing in Alzheimer's disease (AD) due to their capacity to suppress inflammation via modulation of JAK/STAT signaling pathways. Besides interaction with primary therapeutic targets, JAK inhibitor drugs frequently interact with unintended, often unknown, biological off-targets, leading to associated effects. Nevertheless, the relevance of JAK inhibitors' off-target interactions in the context of AD remains unclear.

Physiologically-Based Pharmacokinetic Modeling of the Postbiotic Supplement Urolithin A Predicts its Bioavailability Is Orders of Magnitude Lower than Concentrations that Induce Toxicity, but also Neuroprotective Effects.

Scope: A range of health benefits are attributed to consuming urolithin A (UA), such as improved muscle health, anti-aging activity, and neuroprotection, whereas few studies raise possible adverse effects at high doses, including genotoxicity and estrogenic effects. Therefore, understanding UA bioactivity and safety depends on its pharmacokinetics. However, there is no physiologically-based pharmacokinetic (PBPK) model available for UA, thus limiting reliable assessment of effects observed from in vitro experimentation.

Markers for DNA damage are induced in the rat colon by the toxin altertoxin-II, but not a complex extract of cultured .

Mycotoxins produced by spp. act genotoxic in cell-based studies, but data on their toxicity is scarce and urgently required for risk assessment. Thus, male Sprague-Dawley rats received single doses of a complex toxin extract (CE; 50 mg/kg bw), altertoxin II (ATX-II; 0.

Persistence of the antagonistic effects of a natural mixture of Alternaria mycotoxins on the estrogen-like activity of human feces after anaerobic incubation.

Several Alternaria mycotoxins are believed to act as endocrine disruptive chemicals (EDCs), since they are reported to bind estrogen receptors in several experimental models. After ingestion of contaminated food commodities, the mycotoxins reach the intestine, where they come into direct contact with food constituents as well as the gut microbiota. Thus, the aim of the present work was to evaluate the modulatory potential of a complex extract of cultured Alternaria fungi (CE; containing eleven chemically characterized compounds) on the estrogenic signaling cascade of mammalian cells before and after anaerobic incubation with fecal slurries, in order to simulate an in vivo-like condition in the gut.

Natural Dibenzo-α-Pyrones: Friends or Foes?

Natural dibenzo-α-pyrones (DAPs) can be viewed from two opposite angles. From one angle, the gastrointestinal metabolites urolithins are regarded as beneficial, while from the other, the emerging mycotoxin alternariol and related fungal metabolites are evaluated critically with regards to potential hazardous effects. Thus, the important question is: can the structural characteristics of DAP subgroups be held responsible for distinct bioactivity patterns? If not, certain toxicological and/or pharmacological aspects of natural DAPs might yet await elucidation.

A target fishing study to spot possible biological targets of fusaric acid: Inhibition of protein kinase-A and insights on the underpinning mechanisms.

Fusaric acid is a secondary metabolite produced by various Fusarium fungi, present with relatively high incidence in Fusarium-contaminated foods. It was already described as phytotoxic and cytotoxic. However, the understanding of its molecular mechanisms is still fragmentary and further data are needed to ensure an informed assessment of the risk related to its presence in food.

Alternaria toxins-Still emerging?

Alternaria molds are known to cause the contamination of food with their secondary metabolites, a chemically very heterogeneous group of compounds. Yet, after decades of research on the occurrence and the toxicity of Alternaria toxins in academia, no regulation has been implemented yet, thus leaving these potential food contaminants in the status of so-called "emerging mycotoxins". However, research on this topic has been far from static, leading to the European Food Safety Authority repeatedly calling for more data on the occurrence and toxicity of genotoxic metabolites such as alternariol (AOH) and its monomethyl ether (AME).

Systemically Achievable Doses of Beer Flavonoids Induce Estrogenicity in Human Endometrial Cells and Cause Synergistic Effects With Selected Pesticides.

Some prenylated polyphenols originating from hops, which are thus natural constituents of beer, have been discussed critically for their agonistic potential toward estrogen receptors. So far, little attention has been attributed to the fact that humans are typically not exposed to isolated compounds, but to mixtures which for example might comprise in addition to hop flavonoids further xenoestrogens, e.g.

In vitro interactions of Alternaria mycotoxins, an emerging class of food contaminants, with the gut microbiota: a bidirectional relationship.

The human gut microbiota plays an important role in the maintenance of human health. Factors able to modify its composition might predispose the host to the development of pathologies. Among the various xenobiotics introduced through the diet, Alternaria mycotoxins are speculated to represent a threat for human health.

Microfiltration results in the loss of analytes and affects the in vitro genotoxicity of a complex mixture of Alternaria toxins.

Alternaria molds produce a variety of chemically diverse secondary metabolites with potentially adverse effects on human health. However, data on occurrence in food and human exposure is inconsistent for some of these mycotoxins. Membrane filtration is a frequent step in many sample preparation procedures for LC-MS-based methods analyzing food contaminants.

Toxins Synergistically Activate the Aryl Hydrocarbon Receptor Pathway In Vitro.

molds simultaneously produce a large variety of mycotoxins, of which several were previously reported to induce enzymes of phase I metabolism through aryl hydrocarbon receptor activation. Thus, we investigated the potential of naturally occurring toxin mixtures to induce Cytochrome P450 (CYP) 1A1/1A2/1B1 activity. Two variants of an extract from cultured as well as the toxins alternariol (AOH), alternariol monomethyl ether (AME), altertoxin I (ATX-I), and altertoxin II (ATX-II), were tested singularly and in binary mixtures applying the 7-ethoxy-resorufin--deethylase (EROD) assay in MCF-7 breast cancer cells.

Gut microbiota and undigested food constituents modify toxin composition and suppress the genotoxicity of a naturally occurring mixture of Alternaria toxins in vitro.

Molds of the genus Alternaria produce several mycotoxins, some of which may pose a threat for health due to their genotoxicity. Due to the lack of adequate toxicological and occurrence data, they are currently not regulated. Interactions between mycotoxins, gut microbiota and food constituents might occur after food ingestion, modifying the bioavailability and, therefore, overall toxicity of mycotoxins.

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study.

Emerging mycotoxins produced by Alternaria spp. were previously reported to exert cytotoxic, genotoxic, but also estrogenic effects in human cells. The involved mechanisms are very complex and not fully elucidated yet.

The Aza-Analogous Benzo[]phenanthridine P8-D6 Acts as a Dual Topoisomerase I and II Poison, thus Exhibiting Potent Genotoxic Properties.

The benzo[]phenanthridine P8-D6 was recently found to suppress the catalytic activity of both human topoisomerase (Topo) I and II. Concomitantly, potent cytotoxic activity was observed in different human tumor cell lines, raising questions about the underlying mechanisms in vitro. In the present study, we addressed the question of whether P8-D6 acts as a so-called Topo poison, stabilizing the covalent Topo-DNA intermediate, thus inducing fatal DNA strand breaks in proliferating cells.

Combinatory estrogenic effects of bisphenol A in mixtures with alternariol and zearalenone in human endometrial cells.

Humans are typically exposed to mixtures of substances, whereby their bioactivity can be significantly altered by co-occurring compounds. Thus, over the last years, research on combinatory effects has gained increasing attention. In particular, several xenoestrogens have been recently reported to interact synergistically, among them alternariol (AOH) and zearalenone (ZEN), two toxins produced by molds which contaminate crops or food commodities.

Co-Occurrence and Combinatory Effects of Mycotoxins and other Xenobiotics of Food Origin: Current Scenario and Future Perspectives.

Mycotoxins are low-molecular weight compounds produced by diverse genera of molds that may contaminate food and feed threatening the health of humans and animals. Recent findings underline the importance of studying the combined occurrence of multiple mycotoxins and the relevance of assessing the toxicity their simultaneous exposure may cause in living organisms. In this context, for the first time, this work has critically reviewed the most relevant data concerning the occurrence and toxicity of mycotoxins produced by spp.

Bioavailability, metabolism, and excretion of a complex Alternaria culture extract versus altertoxin II: a comparative study in rats.

Despite the frequent infection of agricultural crops by Alternaria spp., their toxic secondary metabolites and potential food contaminants lack comprehensive metabolic characterization. In this study, we investigated their bioavailability, metabolism, and excretion in vivo.

Naturally occurring mixtures of Alternaria toxins: anti-estrogenic and genotoxic effects in vitro.

Alternaria molds can produce a variety of different mycotoxins, often resulting in food contamination with chemical mixtures, posing a challenge for risk assessment. Some of these metabolites possess estrogenic properties, an effect whose toxicological relevance is questioned in the light of the strong genotoxic and cytotoxic properties of co-occurring toxins. Thus, we tested a complex extract from A.

A Generic Liquid Chromatography-Tandem Mass Spectrometry Exposome Method for the Determination of Xenoestrogens in Biological Matrices.

We are constantly exposed to a variety of environmental contaminants and hormones, including those mimicking endogenous estrogens. These highly heterogeneous molecules are collectively referred to as xenoestrogens and hold the potential to affect and alter the delicate hormonal balance of the human body. To monitor exposure and investigate potential health implications, comprehensive analytical methods covering all major xenoestrogen classes are needed but not available to date.

Impact of Oxidative Metabolism on the Cytotoxic and Genotoxic Potential of Genistein in Human Colon Cancer Cells.

Scope: Genistein (GEN) is known to be genotoxic via targeting topoisomerase-II (TOPII). Oxidative metabolism of GEN is shown to generate hydroxylated metabolites with catecholic structures. The present study focuses on the impact of oxidative metabolism of GEN, exemplified for 3'-hydroxygenistein (3'-OH-GEN) and 6-hydroxygenistein (6-OH-GEN), on topoisomerase interference and the resulting genotoxic potential in HT-29 human colon carcinoma cells.

First insights into Alternaria multi-toxin in vivo metabolism.

Alternaria mycotoxins frequently contaminate agricultural crops and may impact animal and human health. However, data on mammalian metabolism and potential biomarkers of exposure for human biomonitoring (HBM) are scarce. Here, we report the preliminary investigation with respect to metabolism and excretion of Alternaria toxins in Sprague Dawley rats.

The Hop Polyphenols Xanthohumol and 8-Prenyl-Naringenin Antagonize the Estrogenic Effects of Mycotoxins in Human Endometrial Cancer Cells.

The toxin zearalenone (ZEN) and its reductive metabolite α-zearalenol (α-ZEL) are well-documented endocrine disruptors that are frequently found to contaminate cereal products, including beer. But also hop is known to represent a source for endocrine active compounds, containing amongst others xanthohumol (XAN), which might be converted to the potent phytoestrogen 8-prenylnaringenin (8-PN). In the present study, we investigated the interaction of these xenoestrogens in mixtures which might occur in beer.