Search

Organophosphorothioates (OPT) are pesticides impacting human, animal and environmental health. They enter the environment worldwide, primarily due to their application as insecticides. OPTs are mainly neurotoxic upon bioactivation and inhibition of brain and serum acetylcholinesterase (AChE). Although OPTs are meant to target insects, they are potentially toxic to many other species (including humans), posing risks to non-target organisms and ecosystems. Certain cytochromes P450 (CYP) promote OPTs bioactivation, forming the corresponding oxon metabolites, while others catalyse their detoxification. Understanding the molecular basis of such a bivalent fate may help to clarify the toxicity of OPTs in living organisms, with far-reaching consequences to understand their impact on living organisms and improve risk assessment, to cite but a few. However, although crucial, the underpinning mechanisms still lay unclear. Here, a validated computational pipeline revealed the molecular reasons underlying the differential metabolism of chlorpyrifos in humans by CYP2C19, a primal route of detoxification, and its bioactivation by CYP2B6. The analysis drew the diverse occupancy of the CYP pocket and orientation to the heme group as a convincing evidence-based explanation for the opposite transformation. Moreover, this study explored the impact of CYP2C19 mutational landscape giving a blueprint to unveil the molecular basis of OPTs metabolism and toxicological implications from an inter-individual perspective. Taken together, the outcome described for the first time to the best of our knowledge a structural rationale for the bioactivation/detoxification of OPTs improving the current understanding of their toxicity from a molecular standpoint., 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.)

Some oligopeptides can impart kokumi flavor to foods and beverages, a topic still not addressed in wine. A targeted ultra-high performance liquid-chromatography-mass spectrometry (UHPLC-MS/MS) metabolomics method capable of quantifying both amino acids and oligopeptides in wines was therefore developed and validated, confirming the presence of 50 oligopeptides in wine, most of which had been previously unexplored. In silico screening of the affinity of these oligopeptides to interact with CaSR, the protein necessary to activate kokumi sensations, highlighted 8 dipeptides and 3 tripeptides as putative kokumi compounds. These compounds were ubiquitous in a representative set of Trentodoc classic method sparkling wines, with an average concentration of kokumi oligopeptides of 19.8 mg/L, ranging between 9.1 and 33.3 mg/L. Half of the sparkling wine samples also contained glutamic acid at concentrations equal to or greater than the threshold for the umami taste in wine, namely, 48 mg/L. Sensory tests on the dipeptide Gly-Val confirmed the ability of this novel kokumi compound to significantly modify the perception of complex real wine matrices but not of the simple model one. Preliminary laboratory-scale fermentation tests showed that the oligopeptide profile in wines is linked to the starting grape matrix and that the patterns change by fermenting barley or apple juice with the same yeast.

Free fatty acids receptors, with members among G protein-coupled receptors (GPCRs), are crucial for biological signaling, including the perception of the so called "fatty taste". In recent years, GPR120, a protein belonging to the GPCR family, drew attention as an interesting pharmacological target to cope with obesity, satiety and diabetes. Apart from long chain fatty acids, which are GPR120 natural agonists, other synthetic molecules were identified as agonists expanding the chemical space of GPR120's ligands. In this scenario, we unveiled peptides as possible GPR120 binders toward a better understanding of this multifaceted and relevant target. This study analyzed a virtual library collecting 531 441 low-polar hexapeptides, providing mechanistic insights on the GPR120 activation and further extending the possible chemical space of GPR120 agonists. The computational pipeline started with a narrow filtering of hexapeptides based on their chemical similarity with known GPR120 agonists. The best hits were tested through docking studies, molecular dynamics and umbrella sampling simulations, which pointed to G[I,L]FGGG as a promising GPR120 agonist sequence. The presence of both peptides in food-related proteins was thoroughly assessed, revealing they may occur in mushrooms, food-grade bacteria and rice. Simulations on the counterparts with D-amino acids were also performed. Umbrella sampling simulations described that GdIFGGG may have a better interaction compared to its all-L counterpart (-13 kCal/mol ΔG and -6 kCal/mol ΔG, respectively). Overall, we obtained a predictive model to better understand the underpinning mechanism of GPR120-hexapeptides interaction, hierarchizing novel potential agonist peptides for further analysis and describing promising food sources worth of further dedicated investigations., 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., (© 2024 The Authors.)

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., 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 B.V. All rights reserved.)

Zearalenone (ZEN) 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, ZEN 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 ZEN, requiring dedicated studies to improve its toxicological understanding. This work focused on human aromatase investigating via 3D molecular modelling whether some of the SNVs reported so far (n = 434) may affect the inhibitory potential of ZEN. It has been also calculated the inhibition capability of α-zearalenol, the most prominent and estrogenically potent phase I metabolite of ZEN, 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 ZEN 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 ZEN; iii) prioritized aromatase variants for future investigations toward a better comprehension of ZEN xenoestrogenicity at an individual level., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The bitter taste perception evolved in human and animals to rapidly perceive and avoid potential toxic compounds. This is mediated by taste receptors type 2 (TAS2R), expressed in various tissues, which recently proved to be involved in roles beyond the bitter perception itself. With this study, the interaction between food-related toxic compounds and TAS2R46 has been investigated via computational approaches, starting with a virtual screening and moving to molecular docking and dynamics simulations. The virtual screening analysis identified trichothecolone and the trichothecenes class it belongs to, which includes mycotoxins widespread in several commodities raising food safety concerns, as possible TAS2R46 binders. Molecular docking and dynamics simulations were performed to further explore the trichotecenes-TAS2R46 interaction. The results indicated that deoxynivalenol and its 15-acetylated derivative could activate TAS2R46. Eventually, this study provided initial evidence supporting the involvement of TAS2R46 in the underpinning mechanisms of deoxynivalenol action highlighting the need of digging into the involvement of TAS2R46 and TAS2Rs in the adverse effects of deoxynivalenol and congeners., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Stigma is defined by the World Health Organization (WHO) as "a mark of shame, disgrace or disapproval that results in an individual being rejected, discriminated against and excluded from participating in a number of different areas of society". Extensive literature searches have documented stigma in the context of health. Among the physical health conditions that are associated with stigma, chronic pain deserves particular attention. Stigma experienced by individuals with chronic pain affects their entire life. Literature identifies multiple dimensions or types of stigma, including public stigma, structural stigma and internalized stigma. Recent literature supports the biopsychosocial model of pain, according to which biological, psychological and sociocultural variables interact in a dynamic manner to shape an individual's response to chronic pain. Chronic pain affects a higher proportion of women than men around the world. There is an inadequate education of health care professionals regarding pain assessment and their insecurity to manage patients with chronic pain. A first-line intervention strategy could be to promote pain education and to expand knowledge and assessment of chronic pain, as recently highlighted for headache disorders, paradigmatically for resistant or refractory migraine, whose diagnosis, without an adequate education to understand the possible fluctuations of the disease, may have profound psychological implications with the idea of insolvability and contribute to stigmatizing the patient., (© 2022. The Author(s).)

Bioactive peptides may exert beneficial activities in living organisms such as the regulation of glucose metabolism through the inhibition of alpha amylases. Algae and cyanobacteria are gaining a growing interest for their health-promoting properties, and possible effects on glucose metabolism have been described, although the underlying mechanisms need clarification. This study proposes a computer-driven workflow for a proteome-wide mining of alpha amylase inhibitory peptides from the proteome of Chlorella vulgaris , Auxenochlorella protothecoides and Aphanizomenon flos-aquae . Overall, this work presents an innovative and versatile approach to support the identification of bioactive peptides in annotated proteomes. The study: (i) highlighted the presence of alpha amylase inhibitory peptides within the proteomes under investigation (including ELS, which is among the most potent inhibitory tripeptides identified so far); (ii) mechanistically investigated the possible mechanisms of action; and (iii) prioritized further dedicated investigation on the proteome of C. vulgaris and A. flos-aquae , and on CSSL and PGG sequences.

Background: The reported efficacy of memantine in the treatment of patients with cluster headache (CH) suggests that NMDA receptors are involved in mechanisms of nociceptive sensitization within the trigeminal system associated with CH. NMDA receptors are activated or inhibited by neuroactive compounds generated by tryptophan metabolism through the kynurenine pathway. In the accompanying manuscript, we have found that serum levels of all kynurenine metabolites are altered in patients with chronic migraine. Here, we have extended the study to patients affected by episodic or chronic CH as compared to healthy controls., Method: We assessed serum levels of kynurenine (KYN), kynurenic Acid (KYNA), anthranilic acid (ANA), 3-hydroxy-anthranilic acid (3-HANA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), quinolinic acid (QUINA), tryptophan (Trp) and 5-hydroxyindolacetic acid (5-HIAA) by means of a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method in 21 patients affected by CH (15 with episodic and 6 with chronic CH), and 35 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded., Results: LC/MS-MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-36 %), KYNA (-34 %), 3-HK (-51 %), 3-HANA (-54 %), XA (-25 %), 5-HIAA (-39 %) and QUINA (-43 %) in the serum of the overall population of patients affected by CH, as compared to healthy controls. Serum levels of Trp and ANA were instead significantly increased in CH patients (+18 % and +54 %, respectively). There was no difference in levels of any metabolite between patients affected by episodic and chronic CH, with the exception of KYN levels, which were higher in patients with chronic CH., Conclusion: The reduced levels of KYNA (an NMDA receptor antagonist) support the hypothesis that NMDA receptors are overactive in CH. A similar reduction in KYNA levels was shown in the accompanying manuscript in patients affected by chronic migraine. The reduced levels of XA, a putative analgesic compound, may contribute to explain the severity of pain attacks in CH. These data, associated with the data reported in the accompanying manuscript, supports a role for the kynurenine pathway in the pathophysiology of chronic headache disorders.