Exp Mol Med. 2023 Dec 1. doi: 10.1038/s12276-023-01129-3. Online ahead of print.

ABSTRACT

Exposure to nanomicroplastics (nano-MPs) can induce lung damage. The gut microbiota is a critical modulator of the gut-lung axis. However, the mechanisms underlying these interactions have not been elucidated. This study explored the role of lactate, a key metabolite of the microbiota, in the development of lung damage induced by nano-MPs (LDMP). After 28 days of exposure to nano-MPs (50-100 nm), mice mainly exhibited damage to the lungs and intestinal mucosa and dysbiosis of the gut microbiota. Lactate accumulation was observed in the lungs, intestines and serum and was strongly associated with the imbalance in lactic acid bacteria in the gut. Furthermore, no lactate accumulation was observed in germ-free mice, while the depletion of the gut microbiota using a cocktail of antibiotics produced similar results, suggesting that lactate accumulation in the lungs may have been due to changes in the gut microbiota components. Mechanistically, elevated lactate triggers activation of the HIF1a/PTBP1 pathway, exacerbating nano-MP-induced lung damage through modulation of the epithelial-mesenchymal transition (EMT). Conversely, mice with conditional knockout of Ptbp1 in the lungs (Ptbp1flfl) and PTBP1-knockout (PTBP1-KO) human bronchial epithelial (HBE) cells showed reversal of the effects of lactate through modulation of the HIF1a/PTBP1 signaling pathway. These findings indicate that lactate is a potential target for preventing and treating LDMP.

PMID:38036735 | DOI:10.1038/s12276-023-01129-3

Discov Ment Health. 2023 Nov 30;3(1):27. doi: 10.1007/s44192-023-00050-5.

ABSTRACT

Schizophrenia is a debilitating condition necessitating more efficacious therapies. Previous studies suggested that schizophrenia development is associated with aberrant synaptic pruning by glial cells. We pursued an interdisciplinary approach to understand whether therapeutic reduction in glial cell-specifically astrocytic-phagocytosis might benefit neuropsychiatric patients. We discovered that beta-2 adrenergic receptor (ADRB2) agonists reduced phagocytosis using a high-throughput, phenotypic screen of over 3200 compounds in primary human fetal astrocytes. We used protein interaction pathways analysis to associate ADRB2, to schizophrenia and endocytosis. We demonstrated that patients with a pediatric exposure to salmeterol, an ADRB2 agonist, had reduced in-patient psychiatry visits using a novel observational study in the electronic health record. We used a mouse model of inflammatory neurodegenerative disease and measured changes in proteins associated with endocytosis and vesicle-mediated transport after ADRB2 agonism. These results provide substantial rationale for clinical consideration of ADRB2 agonists as possible therapies for patients with schizophrenia.

PMID:38036718 | DOI:10.1007/s44192-023-00050-5

Nat Commun. 2023 Nov 30;14(1):7878. doi: 10.1038/s41467-023-43936-2.

NO ABSTRACT

PMID:38036530 | DOI:10.1038/s41467-023-43936-2

Nat Commun. 2023 Nov 30;14(1):7912. doi: 10.1038/s41467-023-43724-y.

ABSTRACT

Transcription is regulated by a multitude of activators and repressors, which bind to the RNA polymerase II (Pol II) machinery and modulate its progression. Death-inducer obliterator 3 (DIDO3) and PHD finger protein 3 (PHF3) are paralogue proteins that regulate transcription elongation by docking onto phosphorylated serine-2 in the C-terminal domain (CTD) of Pol II through their SPOC domains. Here, we show that DIDO3 and PHF3 form a complex that bridges the Pol II elongation machinery with chromatin and RNA processing factors and tethers Pol II in a phase-separated microenvironment. Their SPOC domains and C-terminal intrinsically disordered regions are critical for transcription regulation. PHF3 and DIDO exert cooperative and antagonistic effects on the expression of neuronal genes and are both essential for neuronal differentiation. In the absence of PHF3, DIDO3 is upregulated as a compensatory mechanism. In addition to shared gene targets, DIDO specifically regulates genes required for lipid metabolism. Collectively, our work reveals multiple layers of gene expression regulation by the DIDO3 and PHF3 paralogues, which have specific, co-regulatory and redundant functions in transcription.

PMID:38036524 | DOI:10.1038/s41467-023-43724-y

Trends Mol Med. 2023 Nov 29:S1471-4914(23)00263-0. doi: 10.1016/j.molmed.2023.11.001. Online ahead of print.

ABSTRACT

Proteolytic processes on cell surfaces and extracellular matrix (ECM) sustain cell behavior and tissue integrity in health and disease. Matrix metalloproteases (MMPs) and a disintegrin and metalloproteases (ADAMs) remodel cell microenvironments through irreversible proteolysis of ECM proteins and cell surface bioactive molecules. Pan-MMP inhibitors in inflammation and cancer clinical trials have encountered challenges due to promiscuous activities of MMPs. Systems biology advances revealed that MMPs initiate multifactorial proteolytic cascades, creating new substrates, activating or suppressing other MMPs, and generating signaling molecules. This review highlights the intricate network that underscores the role of MMPs beyond individual substrate-enzyme activities. Gaining insight into MMP function and tissue specificity is crucial for developing effective drug discovery strategies and novel therapeutics. This requires considering the dynamic cellular processes and consequences of network proteolysis.

PMID:38036391 | DOI:10.1016/j.molmed.2023.11.001

J Invest Dermatol. 2023 Nov 28:S0022-202X(23)03110-X. doi: 10.1016/j.jid.2023.10.029. Online ahead of print.

ABSTRACT

In adult mammals, wound healing predominantly follows a fibrotic pathway, culminating in scar formation. However, cutaneous micro-wounds generated via fractional photothermolysis, a modality that produces a constellation of microthermal zones (MTZs), exhibit a markedly different healing trajectory. Our study delineates the cellular attributes of these MTZs, underscoring a temporally limited, subclinical inflammatory milieu concomitant with rapid re-epithelialization within 24 hours. This wound closure is facilitated by the activation of genes associated with keratinocyte migration and differentiation. In contrast to macrothermal wounds, which predominantly heal through a robust myofibroblast-mediated collagen deposition, MTZs are characterized by absence of wound contraction and feature delayed collagen remodeling, initiating 5-6 weeks post-injury. This distinct wound-healing is characterized by a rapid re-epithelialization process and a muted inflammatory response, which collectively serve to mitigate excessive myofibroblast activation. Furthermore, we identify an initial reparative phase characterized by a heterogeneous extracellular matrix protein composition, which precedes the delayed collagen remodeling. These findings extend our understanding of cutaneous wound healing and may have significant implications for the optimization of therapeutic strategies aimed at mitigating scar formation.

PMID:38036291 | DOI:10.1016/j.jid.2023.10.029

Exp Hematol. 2023 Nov 28:S0301-472X(23)01770-8. doi: 10.1016/j.exphem.2023.11.007. Online ahead of print.

ABSTRACT

CRISPR/Cas gene editing has transformed genetic research and is poised to drive the next generation of gene therapies targeting hematopoietic stem cells (HSCs). However, the installation of the 'desired' edit is most often only achieved in a minor subset of alleles. The array of cellular pathways triggered by gene editing tools produces a broad spectrum of 'undesired' editing outcomes, including short insertions and deletions (indels) and chromosome rearrangements, leading to considerable genetic heterogeneity in gene edited HSC populations. This heterogeneity may undermine the effect of the genetic intervention, since only a subset of cells will carry the intended modification. Also, undesired mutations represent a potential safety concern as gene editing advances toward broader clinical use. Here, we will review the different sources of 'undesired' edits and will discuss strategies for their mitigation and control.

PMID:38036097 | DOI:10.1016/j.exphem.2023.11.007

Neuroscience. 2023 Nov 28:S0306-4522(23)00522-5. doi: 10.1016/j.neuroscience.2023.11.028. Online ahead of print.

ABSTRACT

Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, resulting in severe deficits in learning and memory. Alterations in synaptic plasticity have been reported in RTT, however most electrophysiological studies have been performed in male mice only, despite the fact that RTT is primarily found in females. In addition, most studies have focused on excitation, despite the emerging evidence for the important role of inhibition in learning and memory. Here, we performed an electrophysiological characterization in the CA1 region of the hippocampus in both males and females of RTT mouse models with a focus on neurogliaform (NGF) interneurons, given that they are the most abundant dendrite-targeting interneuron subtype in the hippocampus. We found that theta-burst stimulation (TBS) failed to induce long-term potentiation (LTP) in either pyramidal neurons or NGF interneurons in male or female RTT mice, with no apparent changes in short-term plasticity (STP). This failure to induce LTP was accompanied by excitation/inhibition (E/I) imbalances and altered excitability, in a sex- and cell-type specific manner. Specifically, NGF interneurons of male RTT mice displayed increased intrinsic excitability, a depolarized resting membrane potential, and decreased E/I balance, while in female RTT mice, the resting membrane potential was depolarized. Understanding the role of NGF interneurons in RTT animal models is crucial for developing targeted treatments to improve cognition in individuals with this disorder.

PMID:38036056 | DOI:10.1016/j.neuroscience.2023.11.028

Prog Neuropsychopharmacol Biol Psychiatry. 2023 Nov 28:110901. doi: 10.1016/j.pnpbp.2023.110901. Online ahead of print.

ABSTRACT

Epidemiological studies revealed deficits in cognitive learning and memory in smokers who withdrawal from smoking, but the molecular mechanisms underlying it is unclear. Here, we employed the novel object recognition task (NORT) to evaluate cognitive memory and found impaired memory and motor skills after withdrawal from chronic nicotine. Myelin sheath hastens the conduction of signals along axons and thus plays a critical role in learning and memory. We found no effect of nicotine withdrawal on the myelination in both of the Ventral tegmental area (VTA) and Nucleus accumbens (NAc) regions, but unexpectedly, we observed a demyelination phenomenon in the medial prefrontal cortex (mPFC) after withdrawal from chronic nicotine. Moreover, we found a positive correlation between the impaired memory and demyelination, and pharmaceutical rescue of myelination by clemastine specifically improved the impaired recognition memory but not the decreased motor skills caused by withdrawal from chronic nicotine. We further found nicotine directly acts on oligodendrocytes with OPCs potential to decrease their myelination process. Taken together, these results demonstrate demyelination in the mPFC causes impaired recognition memory and reveal a potential of enhancing myelination as a therapeutic strategy to alleviate cognitive memory deficits caused by smoking withdrawal.

PMID:38036034 | DOI:10.1016/j.pnpbp.2023.110901

Math Biosci. 2023 Nov 28:109110. doi: 10.1016/j.mbs.2023.109110. Online ahead of print.

ABSTRACT

Compartmentalised biochemical reactions are a ubiquitous building block of biological systems. The interplay between chemical and compartmental dynamics can drive rich and complex dynamical behaviors that are difficult to analyse mathematically - especially in the presence of stochasticity. We have recently proposed an effective moment equation approach to study the statistical properties of compartmentalised biochemical systems. So far, however, this approach is limited to polynomial rate laws and moreover, it relies on suitable moment closure approximations, which can be difficult to find in practice. In this work we propose a systematic method to derive closed moment dynamics for compartmentalised biochemical systems. We show that for the considered class of systems, the moment equations involve expectations over functions that factorize into two parts, one depending on the molecular content of the compartments and one depending on the compartment number distribution. Our method exploits this structure and approximates each function with suitable polynomial expansions, leading to a closed system of moment equations. We demonstrate the method using three systems inspired by cell populations and organelle networks and study its accuracy across different dynamical regimes.

PMID:38035996 | DOI:10.1016/j.mbs.2023.109110

Front Cell Infect Microbiol. 2023 Nov 14;13:1274573. doi: 10.3389/fcimb.2023.1274573. eCollection 2023.

ABSTRACT

BACKGROUND: Bloodstream infections (BSIs) remain a significant cause of mortality worldwide. Causative pathogens are routinely identified and susceptibility tested but only very rarely investigated for their resistance genes, virulence factors, and clonality. Our aim was to gain insight into the clonality patterns of different species causing BSI and the clinical relevance of distinct virulence genes.

METHODS: For this study, we whole-genome-sequenced over 400 randomly selected important pathogens isolated from blood cultures in our diagnostic department between 2016 and 2021. Genomic data on virulence factors, resistance genes, and clonality were cross-linked with in-vitro data and demographic and clinical information.

RESULTS: The investigation yielded extensive and informative data on the distribution of genes implicated in BSI as well as on the clonality of isolates across various species.

CONCLUSION: Associations between survival outcomes and the presence of specific genes must be interpreted with caution, and conducting replication studies with larger sample sizes for each species appears mandatory. Likewise, a deeper knowledge of virulence and host factors will aid in the interpretation of results and might lead to more targeted therapeutic and preventive measures. Monitoring transmission dynamics more efficiently holds promise to serve as a valuable tool in preventing in particular BSI caused by nosocomial pathogens.

PMID:38035332 | PMC:PMC10682671 | DOI:10.3389/fcimb.2023.1274573

Front Artif Intell. 2023 Nov 16;6:1256352. doi: 10.3389/frai.2023.1256352. eCollection 2023.

ABSTRACT

Graphs are used as a model of complex relationships among data in biological science since the advent of systems biology in the early 2000. In particular, graph data analysis and graph data mining play an important role in biology interaction networks, where recent techniques of artificial intelligence, usually employed in other type of networks (e.g., social, citations, and trademark networks) aim to implement various data mining tasks including classification, clustering, recommendation, anomaly detection, and link prediction. The commitment and efforts of artificial intelligence research in network biology are motivated by the fact that machine learning techniques are often prohibitively computational demanding, low parallelizable, and ultimately inapplicable, since biological network of realistic size is a large system, which is characterised by a high density of interactions and often with a non-linear dynamics and a non-Euclidean latent geometry. Currently, graph embedding emerges as the new learning paradigm that shifts the tasks of building complex models for classification, clustering, and link prediction to learning an informative representation of the graph data in a vector space so that many graph mining and learning tasks can be more easily performed by employing efficient non-iterative traditional models (e.g., a linear support vector machine for the classification task). The great potential of graph embedding is the main reason of the flourishing of studies in this area and, in particular, the artificial intelligence learning techniques. In this mini review, we give a comprehensive summary of the main graph embedding algorithms in light of the recent burgeoning interest in geometric deep learning.

PMID:38035201 | PMC:PMC10687447 | DOI:10.3389/frai.2023.1256352

NAR Cancer. 2023 Nov 28;5(4):zcad056. doi: 10.1093/narcan/zcad056. eCollection 2023 Dec.

ABSTRACT

Gene regulatory networks (GRNs) are often deregulated in tumor cells, resulting in altered transcriptional programs that facilitate tumor growth. These altered networks may make tumor cells vulnerable to the inhibition of specific regulatory proteins. Consequently, the reconstruction of GRNs in tumors is often proposed as a means to identify therapeutic targets. While there are examples of individual targets identified using GRNs, the extent to which GRNs can be used to predict sensitivity to targeted intervention in general remains unknown. Here we use the results of genome-wide CRISPR screens to systematically assess the ability of GRNs to predict sensitivity to gene inhibition in cancer cell lines. Using GRNs derived from multiple sources, including GRNs reconstructed from tumor transcriptomes and from curated databases, we infer regulatory gene activity in cancer cell lines from ten cancer types. We then ask, in each cancer type, if the inferred regulatory activity of each gene is predictive of sensitivity to CRISPR perturbation of that gene. We observe slight variation in the correlation between gene regulatory activity and gene sensitivity depending on the source of the GRN and the activity estimation method used. However, we find that there is consistently a stronger relationship between mRNA abundance and gene sensitivity than there is between regulatory gene activity and gene sensitivity. This is true both when gene sensitivity is treated as a binary and a quantitative property. Overall, our results suggest that gene sensitivity is better predicted by measured expression than by GRN-inferred activity.

PMID:38035131 | PMC:PMC10683780 | DOI:10.1093/narcan/zcad056

iScience. 2023 Nov 1;26(12):108377. doi: 10.1016/j.isci.2023.108377. eCollection 2023 Dec 15.

ABSTRACT

Tumor suppressor p53 plays a pivotal role in suppressing cancer, so various drugs has been suggested to upregulate its function. However, drug resistance is still the biggest hurdle to be overcome. To address this, we developed a deep learning model called AnoDAN (anomalous gene detection using generative adversarial networks and graph neural networks for overcoming drug resistance) that unravels the hidden resistance mechanisms and identifies a combinatorial target to overcome the resistance. Our findings reveal that the TGF-β signaling pathway, alongside the p53 signaling pathway, mediates the resistance, with THBS1 serving as a core regulatory target in both pathways. Experimental validation in lung cancer cells confirms the effects of THBS1 on responsiveness to a p53 reactivator. We further discovered the positive feedback loop between THBS1 and the TGF-β pathway as the main source of resistance. This study enhances our understanding of p53 regulation and offers insights into overcoming drug resistance.

PMID:38034356 | PMC:PMC10682260 | DOI:10.1016/j.isci.2023.108377

Front Bioeng Biotechnol. 2023 Nov 14;11:1258753. doi: 10.3389/fbioe.2023.1258753. eCollection 2023.

ABSTRACT

Many preclinical studies have shown that birth-associated tissues, cells and their secreted factors, otherwise known as perinatal derivatives (PnD), possess various biological properties that make them suitable therapeutic candidates for the treatment of numerous pathological conditions. Nevertheless, in the field of PnD research, there is a lack of critical evaluation of the PnD standardization process: from preparation to in vitro testing, an issue that may ultimately delay clinical translation. In this paper, we present the PnD e-questionnaire developed to assess the current state of the art of methods used in the published literature for the procurement, isolation, culturing preservation and characterization of PnD in vitro. Furthermore, we also propose a consensus for the scientific community on the minimal criteria that should be reported to facilitate standardization, reproducibility and transparency of data in PnD research. Lastly, based on the data from the PnD e-questionnaire, we recommend to provide adequate information on the characterization of the PnD. The PnD e-questionnaire is now freely available to the scientific community in order to guide researchers on the minimal criteria that should be clearly reported in their manuscripts. This review is a collaborative effort from the COST SPRINT action (CA17116), which aims to guide future research to facilitate the translation of basic research findings on PnD into clinical practice.

PMID:38033821 | PMC:PMC10682948 | DOI:10.3389/fbioe.2023.1258753

Front Microbiol. 2023 Nov 14;14:1258975. doi: 10.3389/fmicb.2023.1258975. eCollection 2023.

ABSTRACT

INTRODUCTION: Both spill over and spill back of SARS-CoV-2 virus have been reported on mink farms in Europe and the United States. Zoonosis is a public health concern as dangerous mutated forms of the virus could be introduced into the human population through spillback.

METHODS: The purpose of our study was to determine the SARS-CoV-2 entry mechanism using the mink lung epithelial cell line (Mv1Lu) and to block entry with drug inhibitors.

RESULTS: Mv1Lu cells were susceptible to SARS-CoV-2 viral pseudoparticle infection, validating them as a suitable disease model for COVID-19. Inhibitors of TMPRSS2 and of endocytosis, two pathways of viral entry, were tested to identify those that blocked infection. TMPRSS2 inhibitors had minimal impact, which can be explained by the apparent lack of activity of this enzyme in the mink and its localization within the cell, not on the cell surface.

DISCUSSION: Dyngo4a, a small molecule endocytosis inhibitor, significantly reduced infection, supporting the conclusion that the entry of the SARS-CoV-2 virus into Mv1Lu cells occurs primarily through endocytosis. The small molecule inhibitors that were effective in this study could potentially be used therapeutically to prevent SARS-CoV-2 infection in mink populations. This study will facilitate the development of therapeutics to prevent zoonotic transmission of SARS-CoV-2 variants to other animals, including humans.

PMID:38033586 | PMC:PMC10682793 | DOI:10.3389/fmicb.2023.1258975

Oxf Med Case Reports. 2023 Nov 28;2023(11):omad121. doi: 10.1093/omcr/omad121. eCollection 2023 Nov.

ABSTRACT

Encephalitis occasionally occurs due to the central nervous system (CNS) infection by Varicella-zoster virus (VZV). The coincidence of herpes Encephalitis-brain infection and brucellosis occurs rarely. In this case, a 56-year-old woman was described with low consciousness, seizures, fever, and mood disorders. The brain CT revealed no pathological lesions, but MR showed non-specific plaques in the periventricular white matter. VZV was detected in molecular tests for the panel of viral Encephalitis in cerebrospinal fluid (CSF). The blood culture and the Wright test revealed the presence of Brucella spp. The antiviral treatment of choice was Acyclovir, Levetiracetam to control seizures, and Ampicillin/Sulbactam as prophylaxis antibiotics. Coinfections common poor prognoses makes it crucial to administer antiviral medications immediately. Many clinical challenges require a multidisciplinary team, including involvement of the CNS, resistance to viral strains, reactivation of diseases, and drug toxicity. The early detection of Encephalitis and treatment can promptly prevent exacerbation and complications.

PMID:38033406 | PMC:PMC10686003 | DOI:10.1093/omcr/omad121

Bioinform Biol Insights. 2023 Nov 27;17:11779322231214445. doi: 10.1177/11779322231214445. eCollection 2023.

ABSTRACT

Having a previous history of sexually transmitted diseases (STDs) such as gonorrhea and chlamydia increases the chance of developing prostate cancer, the second most frequent malignant cancer among men. However, the molecular functions that cause the development of prostate cancer in persons with gonorrhea and chlamydia are yet unknown. In this study, we studied RNA-seq gene expression profiles using computational biology methods to find out potential biomarkers that could help us in understanding the patho-biological mechanisms of gonorrhea, chlamydia, and prostate cancer. Using statistical methods on the Gene Expression Omnibus (GEO) data sets, it was found that a total of 22 distinct differentially expressed genes were shared among these 3 diseases of which 14 were up-regulated (PGRMC1, TSC22D1, SH3BGRL, NNT, CTSC, FRMD3, CCR2, FAM210B, VCL, PTGS1, SLFN11, SLC40A1, PROS1, and DSE) and the remaining 8 genes were down-regulated (PRNP, HINT3, MARCKSL1, TMED10, SH3KBP1, ENSA, DERL1, and KMT2B). Investigation on these 22 unique dysregulated genes using Gene Ontology, BioCarta, KEGG, and Reactome revealed multiple altered molecular pathways, including regulation of amyloid precursor protein catabolic process, ferroptosis, effects on gene expression of Homo sapiens PPAR pathway, and innate immune system R-HSA-168249. Four significant hub proteins namely VCL, SH3KBP1, PRNP, and PGRMC1 were revealed by protein-protein interaction network analysis. By analyzing gene-transcription factors and gene-miRNAs interactions, significant transcription factors (POU2F2, POU2F1, GATA6, and HIVEP1) and posttranscriptional regulator microRNAs (hsa-miR-7-5p) were also identified. Three potential therapeutic compounds namely INCB3284, CCX915, and MLN-1202 were found to interact with up-regulated protein C-C chemokine receptor type 2 (CCR2) in protein-drug interaction analysis. The proposed biomarkers and therapeutic potential molecules could be investigated for potential pharmacological targets and activity in the fight against in patients with gonorrhea, chlamydia, and prostate cancer.

PMID:38033384 | PMC:PMC10683397 | DOI:10.1177/11779322231214445

PLoS One. 2023 Nov 30;18(11):e0292030. doi: 10.1371/journal.pone.0292030. eCollection 2023.

ABSTRACT

The liver is the primary site for the metabolism and detoxification of many compounds, including pharmaceuticals. Consequently, it is also the primary location for many adverse reactions. As the liver is not readily accessible for sampling in humans; rodent or cell line models are often used to evaluate potential toxic effects of a novel compound or candidate drug. However, relating the results of animal and in vitro studies to relevant clinical outcomes for the human in vivo situation still proves challenging. In this study, we incorporate principles of transfer learning within a deep artificial neural network allowing us to leverage the relative abundance of rat in vitro and in vivo exposure data from the Open TG-GATEs data set to train a model to predict the expected pattern of human in vivo gene expression following an exposure given measured human in vitro gene expression. We show that domain adaptation has been successfully achieved, with the rat and human in vitro data no longer being separable in the common latent space generated by the network. The network produces physiologically plausible predictions of human in vivo gene expression pattern following an exposure to a previously unseen compound. Moreover, we show the integration of the human in vitro data in the training of the domain adaptation network significantly improves the temporal accuracy of the predicted rat in vivo gene expression pattern following an exposure to a previously unseen compound. In this way, we demonstrate the improvements in prediction accuracy that can be achieved by combining data from distinct domains.

PMID:38032940 | DOI:10.1371/journal.pone.0292030

J Agric Food Chem. 2023 Nov 30. doi: 10.1021/acs.jafc.3c05252. Online ahead of print.

ABSTRACT

Roasted coffee contains atractyligenin-2-O-β-d-glucoside and 3'-O-β-d-glucosyl-2'-O-isovaleryl-2-O-β-d-glucosylatractyligenin, which are ingested with the brew. Known metabolites are atractyligenin, atractyligenin-19-O-β-d-glucuronide (M1), 2β-hydroxy-15-oxoatractylan-4α-carboxy-19-O-β-d-glucuronide (M2), and 2β-hydroxy-15-oxoatractylan-4α-carboxylic acid-2-O-β-d-glucuronide (M3), but the appearance and pharmacokinetic properties are unknown. Therefore, first time-resolved quantitative data of atractyligenin glycosides and their metabolites in plasma samples from a pilot human intervention study (n = 10) were acquired. None of the compounds were found in the control samples and before coffee consumption (t = 0 h). After coffee, neither of the atractyligenin glycosides appeared in the plasma, but the aglycone atractyligenin and the conjugated metabolite M1 reached an estimated cmax of 41.9 ± 12.5 and 25.1 ± 4.9 nM, respectively, after 1 h. M2 and M3 were not quantifiable until their concentration enormously increased ≥4 h after coffee consumption, reaching an estimated cmax of 2.5 ± 1.9 and 55.0 ± 57.7 nM at t = 10 h. The data suggest that metabolites of atractyligenin could be exploited to indicate coffee consumption.

PMID:38032344 | DOI:10.1021/acs.jafc.3c05252