PubMed

Int J Biol Macromol. 2023 Apr 15:124436. doi: 10.1016/j.ijbiomac.2023.124436. Online ahead of print.ABSTRACTNAC (NAM, ATAF1/2 and CUC2) transcription factors (TFs) are a class of TFs families unique to plants, which not only play an important role in the growth and developmental stages of plants but also function in response to stress and regulation of secondary metabolite biosynthesis. However, there are few studies on NAC genes in the medicinal plant Isatis indigotica. In this study, 96 IiNAC genes were identified based on the whole-genome data of I. indigotica, distributed in seven chromosomes and three contigs. IiNAC genes were structurally conserved and divided into 15 subgroups. Cis-elements were identified in the promoter region of the IiNAC gene in response to plant growth and development, abiotic stresses and hormones. In addition, transcriptome and metabolome data of I. indigotica leaves under salt stress were analyzed to construct a network of IiNAC gene co-expression and metabolite association. Ten differentially expressed IiNAC genes were co-expressed with 109 TFs, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that most of these genes were associated with plant growth and development and abiotic stress responses. Eleven IiNAC genes were positively associated with 72 metabolites. Eleven IiNAC genes were positively or negatively associated with 47 metabolites through 37 TFs. Commonly associated secondary metabolites include two terpenoids, abscisic acid and bilobalide, two flavonoids, dihydrokaempferol and syringaldehyde, a coumarin, 7-methoxycoumarin, an alkaloid, lupinine, and quinone dihydrotanshinone I. This study provides important data to support the identification of the NAC gene family in I. indigotica and the regulatory functions of IiNAC genes in metabolites under salt stress.PMID:37068542 | DOI:10.1016/j.ijbiomac.2023.124436

J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Mar 30;1222:123686. doi: 10.1016/j.jchromb.2023.123686. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Alzheimer's disease (AD), the most common type of dementia, is hard to recognize early, resulting in delayed treatment and poor outcome. At present, there is neither reliable, non-invasive methods to diagnose it accurately and nor effective drugs to recover it. Discovery and quantification of novel metabolite markers in plasma of AD patients and investigation of the correlation between the markers and AD assessment scores.MATERIALS AND METHODS: Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics with LC-quadrupole- time-of-flight (Q-TOF) was performed in plasma samples of age-matched AD patients and healthy controls. The potential markers were further quantified with targeted multiple reaction monitoring (MRM) approach.RESULTS: Among the candidates, progesterone, and 3-indoleacetic acid (3-IAA) were successfully identified and then validated in 50 plasma samples from 25 AD patients and 25 matched normal controls with MRM approach. As a result, 3-IAA was significantly altered in AD patients and correlated with some AD assessment scores.CONCLUSION: By using untargeted LC-MS metabolomic and LC-MRM approaches to analyze plasma metabolites of AD patients and normal subjects, 3-IAA was discovered and quantified to be significantly altered in AD patients and correlated with several AD assessment scores.PMID:37068461 | DOI:10.1016/j.jchromb.2023.123686

Biomed Pharmacother. 2023 Mar 28;162:114614. doi: 10.1016/j.biopha.2023.114614. Online ahead of print.ABSTRACTThe continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved drugs for inhibitory effects against main protease enzyme (Mpro) substrate-binding pocket of SARS-CoV-2 for non-covalent and covalent binding. Top candidates were screened against infectious SARS-CoV-2 in a cell-based viral replication assay. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. Additionally, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 µM), mebendazole (IC50 19 µM) and entacapone (IC50 9 µM). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential mechanisms. Although atovaquone is Dihydroorotate dehydrogenase (DHODH) inhibitor, we did not observe inhibition of DHODH at the respective SARS-CoV-2 IC50. Metabolomic profiling of atovaquone treated cells showed dysregulation of purine metabolism pathway metabolite, where ecto-5'-nucleotidase (NT5E) was downregulated by atovaquone at concentrations equivalent to its antiviral IC50. Atovaquone and mebendazole are promising candidates with SARS-CoV-2 antiviral activity. While mebendazole does appear to target Mpro, atovaquone may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.PMID:37068330 | DOI:10.1016/j.biopha.2023.114614

Brief Bioinform. 2023 Apr 17:bbad141. doi: 10.1093/bib/bbad141. Online ahead of print.ABSTRACTImaging mass spectrometry (IMS) is one of the powerful tools in spatial metabolomics for obtaining metabolite data and probing the internal microenvironment of organisms. It has dramatically advanced the understanding of the structure of biological tissues and the drug treatment of diseases. However, the complexity of IMS data hinders the further acquisition of biomarkers and the study of certain specific activities of organisms. To this end, we introduce an artificial intelligence tool, SmartGate, to enable automatic peak selection and spatial structure identification in an iterative manner. SmartGate selects discriminative m/z features from the previous iteration by differential analysis and employs a graph attention autoencoder model to perform spatial clustering for tissue segmentation using the selected features. We applied SmartGate to diverse IMS data at multicellular or subcellular spatial resolutions and compared it with four competing methods to demonstrate its effectiveness. SmartGate can significantly improve the accuracy of spatial segmentation and identify biomarker metabolites based on tissue structure-guided differential analysis. For multiple consecutive IMS data, SmartGate can effectively identify structures with spatial heterogeneity by introducing three-dimensional spatial neighbor information.PMID:37068309 | DOI:10.1093/bib/bbad141

Kidney360. 2023 Apr 17. doi: 10.34067/KID.0000000000000129. Online ahead of print.ABSTRACTBACKGROUND: Chronic kidney disease of a nontraditional etiology (CKDnt) is responsible for high mortality in Central America, although its causes remain unclear. Evidence of kidney dysfunction has been observed among youth, suggesting that early kidney damage contributing to CKDnt may initiate in childhood.METHODS: Urine specimens of Nicaraguan adolescents 12-23 years without CKDnt (n=136) were analyzed by proton nuclear magnetic resonance (1H-NMR) spectroscopy for 50 metabolites associated with kidney dysfunction. Urinary metabolite levels were compared by CKiD U25 estimated glomerular filtration rate (eGFR), regional CKDnt prevalence, sex, age, and family history of CKDnt using supervised statistical methods and pathway analysis in MetaboAnalyst. Magnitude of associations and changes over time were assessed through multivariable linear regression.RESULTS: In adjusted analyses, glycine concentrations were higher among youth from high-risk regions (β=0.82, (95% CI: 0.16, 1.85); p=0.01). Pyruvate concentrations were lower among youth with low eGFR (β= -0.36; (95% CI:-0.57, -0.04); p=0.03) and concentrations of other citric acid (TCA) cycle metabolites differed by key risk factors. Over four years, participants with low eGFR experienced greater declines in 1-methylnicotinamide and 2-oxoglutarate and greater increases in citrate and guanidinoacetate concentrations.CONCLUSION: Urinary concentration of glycine, a molecule associated with thermoregulation and kidney function preservation, was higher among youth in high-risk CKDnt regions, suggestive of greater heat exposure or renal stress. Lower pyruvate concentrations were associated with low eGFR, and citric acid cycle metabolites like pyruvate likely relate to mitochondrial respiration rates in the kidneys. Participants with low eGFR experienced longitudinal declines in concentrations of 1-methylnicotinamide, an anti-inflammatory metabolite associated with anti-fibrosis in tubule cells. These findings merit further consideration in research on the origins of CKDnt.PMID:37068179 | DOI:10.34067/KID.0000000000000129

Crit Rev Food Sci Nutr. 2023 Apr 17:1-17. doi: 10.1080/10408398.2023.2199425. Online ahead of print.ABSTRACTFermented foods are important components of the human diet. There is increasing awareness of abundant nutritional and functional properties present in fermented foods that arise from the transformation of substrates by microbial communities. Thus, it is significant to unravel the microbial communities and mechanisms of characteristic flavor formation occurring during fermentation. There has been rapid development of high-throughput and other omics technologies, such as metaproteomics and metabolomics, and as a result, there is growing recognition of the importance of integrating these approaches. The successful applications of multi-omics approaches and bioinformatics analyses have provided a solid foundation for exploring the fermentation process. Compared with single-omics, multi-omics analyses more accurately delineate microbial and molecular features, thus they are more apt to reveal the mechanisms of fermentation. This review introduces fermented foods and an overview of single-omics technologies - including metagenomics, metatranscriptomics, metaproteomics, and metabolomics. We also discuss integrated multi-omics and bioinformatic analyses and their role in recent research progress related to fermented foods, as well as summarize the main potential pathways involved in certain fermented foods. In the future, multilayered analyses of multi-omics data should be conducted to enable better understanding of flavor formation mechanisms in fermented foods.PMID:37068005 | DOI:10.1080/10408398.2023.2199425

Cancer Discov. 2023 Apr 17:OF1-OF20. doi: 10.1158/2159-8290.CD-22-0872. Online ahead of print.ABSTRACTCancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence of thymic lymphomas and increased CD8+ T-cell differentiation. Lymphomas derived from dimeric p53 mice show cooperating alterations in the PPAR pathway, further implicating a role for these activities in tumor suppression. Our data reveal novel functions for p53 dimers and support the exploration of PPAR agonists as therapies.SIGNIFICANCE: New mouse models with TP53R342P (monomer) or TP53A347D (dimer) mutations mimic Li-Fraumeni syndrome. Although p53 monomers lack function, p53 dimers conferred noncanonical tumor-suppressive activities. We describe novel activities for p53 dimers facilitated by PPARs and propose these are "basal" p53 activities.PMID:37067911 | DOI:10.1158/2159-8290.CD-22-0872

Neurochem Res. 2023 Apr 17. doi: 10.1007/s11064-023-03937-5. Online ahead of print.ABSTRACTEpilepsy is a chronic brain disease and often occurs suddenly for no reason. Eucommiae folium (EF), an edible herb, can be used in the treatment of various kinds of brain diseases in clinic. From the perspective of safety and efficacy, EF is especially suitable for the treatment of chronic brain diseases. With the help of biolabels, this study was aimed to explore the value and feasibility of EF in the treatment of epilepsy. Proteomics and metabolomics were used to explore the biolabels of EF intervention in brain tissues. Bioinformatics was then applied to topologically analyze its neuroprotective effects and mechanisms and material basis based on biolabels, which were validated in an animal model. The biolabel-led research revealed that EF may exert the therapeutic potential to treat brain diseases through the interaction between multiple compounds and multiple targets, among which its therapeutic potential for epilepsy is particularly prominent. In the pentylenetetrazole-induction model, EF and four active compounds (oleamide, catechol, chlorogenic acid, and kaempferol) protected epileptic hippocampal neurons (Nissl and FJB staining) against mitochondrial dysfunction (MYH6, MYL3, and MYBPC3, etc.) and calcium overload (TNNI3, TNNC1, and TNNT2, etc.) through the hypertrophic cardiomyopathy pathway. This study provides new evidence and insights for the neuroprotective effects of EF, in which four active compounds may be potential drug candidates for the treatment of epilepsy.PMID:37067737 | DOI:10.1007/s11064-023-03937-5

Amino Acids. 2023 Apr 17. doi: 10.1007/s00726-023-03255-8. Online ahead of print.ABSTRACTDiabetes mellitus (DM) is a severe chronic diseases with a global prevalence of 9%, leading to poor health and high health care costs, and is a direct cause of millions of deaths each year. The rising epidemic of diabetes and its complications, such as retinal and peripheral nerve disease, is a huge burden globally. A better understanding of the molecular pathways involved in the development and progression of diabetes and its complications can facilitate individualized prevention and treatment. High diabetes mellitus incidence rate is caused mainly by lack of non-invasive and reliable methods for early diagnosis, such as plasma biomarkers. The incidence of diabetes and its complications in the world still grows so it is crucial to develop a new, faster, high specificity and more sensitive diagnostic technologies. With the advancement of analytical techniques, metabolomics can identify and quantify multiple biomarkers simultaneously in a high-throughput manner, and effective biomarkers can greatly improve the efficiency of diabetes and its complications. By providing information on potential metabolic pathways, metabolomics can further define the mechanisms underlying the progression of diabetes and its complications, help identify potential therapeutic targets, and improve the prevention and management of T2D and its complications. The application of amino acid metabolomics in epidemiological studies has identified new biomarkers of diabetes mellitus (DM) and its complications, such as branched-chain amino acids, phenylalanine and arginine metabolites. This study focused on the analysis of metabolic amino acid profiling as a method for identifying biomarkers for the detection and screening of diabetes and its complications. The results presented are all from recent studies, and in all cases analyzed, there were significant changes in the amino acid profile of patients in the experimental group compared to the control group. This study demonstrates the potential of amino acid profiles as a detection method for diabetes and its complications.PMID:37067568 | DOI:10.1007/s00726-023-03255-8

Microbiol Spectr. 2023 Apr 17:e0040923. doi: 10.1128/spectrum.00409-23. Online ahead of print.ABSTRACTEndometritis is a common cow disease characterized by inflammation of endometrium, which leads to infertility or low fertility of cows and brings huge economic losses to the dairy industry. Tau interferon (IFN-τ) has many important biological functions, including an anti-inflammatory effect. The present study aimed to survey the effects of IFN-τ administration on gut microflora and body metabolism in mice with endometritis and to explore the potential relationship. The results indicated that IFN-τ obviously alleviated the damage and ultrastructural changes of mouse endometrium induced by Escherichia coli and enhanced tight junction protein's expression level. Through analysis by 16S rRNA gene sequencing, we found that IFN-τ, especially at 12 h, could regulate the composition of gut microbiota associated with Pediococcus, Staphylococcus, and Enterorhabdus in E. coli-induced mouse endometritis. Through histometabonomics, it was found that endometritis was related to 11 different metabolites and 4 potential metabolic pathways. These metabolites and metabolic pathways were major participants in metabolic pathways, cysteine and methionine metabolism, arachidonic acid metabolism, and pyrimidine metabolism. Correlation analysis of gut microbiota with uterine tissue metabolomics showed that changes in metabolic pathways might be affected by gut microbiota, such as Enterorhabdus in mouse endometritis. The above results indicated that the anti-inflammatory mechanism of IFN-τ might be reduction of the abundance of Enterorhabdus in the gut microbiota, affecting the expression level of important metabolites in uterine tissue and thus playing an anti-inflammatory role. IMPORTANCE The change in intestinal flora has been the focus of many disease studies in recent years, but the pathogenetic effect of interferon on endometritis is still unclear. The results of this study showed that IFN-τ alleviated the damage in mouse endometritis induced by E. coli and improved the endometrial tissue barrier. Its functional mechanism may be reduction of the abundance of Enterorhabdus in the intestinal microbiota, affecting the expression level of important metabolites in uterine tissue and thus playing an anti-inflammatory role.PMID:37067455 | DOI:10.1128/spectrum.00409-23

Microbiol Spectr. 2023 Apr 17:e0349522. doi: 10.1128/spectrum.03495-22. Online ahead of print.ABSTRACTRarely has the vast diversity of bacteria on Earth been profiled, particularly on inaccessible plateaus. These uncultured microbes, which are also known as "microbial dark matter," may play crucial roles in maintaining the ecosystem and are linked to human health, regarding pathogenicity and prebioticity. The plateau pika (Ochotona curzoniae) is a small burrowing steppe lagomorph that is endemic to the Qinghai-Tibetan Plateau and is a keystone species in the maintenance of ecological balance. We used a combination of full-length 16S rRNA amplicon sequencing, shotgun metagenomics, and metabolomics to elucidate the species-level community structure and the metabolic potential of the gut microbiota of the plateau pika. Using a full-length 16S rRNA metataxonomic approach, we clustered 618 (166 ± 35 per sample) operational phylogenetic units (OPUs) from 105 plateau pika samples and assigned them to 215 known species, 226 potentially new species, and 177 higher hierarchical taxa. Notably, 39 abundant OPUs (over 60% total relative abundance) are found in over 90% of the samples, thereby representing a "core microbiota." They are all classified as novel microbial lineages, from the class to the species level. Using metagenomic reads, we independently assembled and binned 109 high-quality, species-level genome bins (SGBs). Then, a precise taxonomic assignment was performed to clarify the phylogenetic consistency of the SGBs and the 16S rRNA amplicons. Thus, the majority of the core microbes possess their genomes. SGBs belonging to the genus Treponema, the families Muribaculaceae, Lachnospiraceae, and Oscillospiraceae, and the order Eubacteriales are abundant in the metagenomic samples. In addition, multiple CAZymes are detected in these SGBs, indicating their efficient utilization of plant biomass. As the most widely connected metabolite with the core microbiota, tryptophan may relate to host environmental adaptation. Our investigation allows for a greater comprehension of the composition and functional capacity of the gut microbiota of the plateau pika. IMPORTANCE The great majority of microbial species remain uncultured, severely limiting their taxonomic characterization and biological understanding. The plateau pika (Ochotona curzoniae) is a small burrowing steppe lagomorph that is endemic to the Qinghai-Tibetan Plateau and is considered to be the keystone species in the maintenance of ecological stability. We comprehensively investigated the gut microbiota of the plateau pika via a multiomics endeavor. Combining full-length 16S rRNA metataxonomics, shotgun metagenomics, and metabolomics, we elucidated the species-level taxonomic assignment of the core uncultured intestinal microbiota of the plateau pika and revealed their correlation to host nutritional metabolism and adaptation. Our findings provide insights into the microbial diversity and biological significance of alpine animals.PMID:37067438 | DOI:10.1128/spectrum.03495-22

J Cereb Blood Flow Metab. 2023 Apr 17:271678X231170037. doi: 10.1177/0271678X231170037. Online ahead of print.ABSTRACTCerebral venous thrombosis (CVT) is a special and easily misdiagnosed or undiagnosed subtype of stroke. To identify specific biomarkers with a high predictive ability for the diagnosis of acute CVT, we performed metabolomic analysis in plasma samples from acute CVT patients and healthy controls and confirmed the results in validation cohorts. In the discovery stage, there were 343 differential metabolites, and the caffeine metabolism pathway and the biosynthesis pathway for the branched chain amino acids (BCAAs) valine, leucine, and isoleucine were two significant pathways between the CVT and healthy cohorts. The area under the curve (AUC) for metabolites associated with valine, leucine, and isoleucine biosynthesis was 0.934. In the validation stage, the BCAA concentrations demonstrated an AUC of 0.935 to differentiate patients with acute CVT from the control cohort. In addition, BCAAs combined with D-dimer levels were used to establish a diagnostic model for CVT, and the AUC was 0.951, showing good diagnostic efficacy of separating CVT patients from the control cohort. BCAAs as plasma biomarkers deserve to be further studied and even developed in clinical CVT management.PMID:37066688 | DOI:10.1177/0271678X231170037

bioRxiv. 2023 Apr 6:2023.04.05.535693. doi: 10.1101/2023.04.05.535693. Preprint.ABSTRACTMetabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with sickle cell sickle cell disease (SCD) enrolled in the WALK-PHaSST study. Clinical covariates informed the biological interpretation of metabolomics data, including genotypes (hemoglobin SS, hemoglobin SC), history of recent transfusion (HbA%), response to hydroxyurea treatment (HbF%). We investigated metabolic correlates to the degree of hemolysis, cardiorenal function, as determined by tricuspid regurgitation velocity (TRV), estimated glomerular filtration rate (eGFR), and overall hazard ratio (unadjusted or adjusted by age). Recent transfusion events or hydroxyurea treatment were associated with elevation in plasma free fatty acids and decreases in acyl-carnitines, urate, kynurenine, indoles, carboxylic acids, and glycine- or taurine-conjugated bile acids. High levels of these metabolites, along with low levels of plasma S1P and L-arginine were identified as top markers of hemolysis, cardiorenal function (TRV, eGFR), and overall hazard ratio. We thus uploaded all omics and clinical data on a novel online portal that we used to identify a potential mechanism of dysregulated red cell S1P synthesis and export as a contributor to the more severe clinical manifestations in patients with the SS genotype compared to SC. In conclusion, plasma metabolic signatures - including low S1P, arginine and elevated kynurenine, acyl-carnitines and bile acids - are associated with clinical manifestation and therapeutic efficacy in SCD patients, suggesting new avenues for metabolic interventions in this patient population.PMID:37066337 | PMC:PMC10104066 | DOI:10.1101/2023.04.05.535693

bioRxiv. 2023 Apr 9:2023.04.08.535933. doi: 10.1101/2023.04.08.535933. Preprint.ABSTRACTCancer cells frequently undergo metabolic reprogramming as a mechanism of resistance against chemotherapeutic drugs. Metabolomic profiling provides a direct readout of metabolic changes and can thus be used to identify these tumor escape mechanisms. Here, we introduce piTracer, a computational tool that uses multi-scale molecular networks to identify potential combination therapies from pre- and post-treatment metabolomics data. We first demonstrate piTracer’s core ability to reconstruct cellular cascades by inspecting well-characterized molecular pathways and previously studied associations between genetic variants and metabolite levels. We then apply a new gene ranking algorithm on differential metabolomic profiles from human breast cancer cells after glutaminase inhibition. Four of the automatically identified gene targets were experimentally tested by simultaneous inhibition of the respective targets and glutaminase. Of these combination treatments, two were be confirmed to induce synthetic lethality in the cell line. In summary, piTracer integrates the molecular monitoring of escape mechanisms into comprehensive pathway networks to accelerate drug target identification. The tool is open source and can be accessed at https://github.com/krumsieklab/pitracer .PMID:37066188 | PMC:PMC10104160 | DOI:10.1101/2023.04.08.535933

Front Chem. 2023 Mar 29;11:1128671. doi: 10.3389/fchem.2023.1128671. eCollection 2023.ABSTRACTBackground: Herb pair of Astragali Radix (AR) and Spreading Hedyotis Herb (SH) has been frequently prescribed in clinical for the treatment of lung cancer owing to its favorable efficacy. Yet, the mechanism under the therapeutic effects remained unveiled, which has limited its clinical applications, and new drug development for lung cancer. Methods: The bioactive ingredients of AR and SH were retrieved from the Traditional Chinese Medicine System Pharmacology Database, with the targets of obtained components predicted by Swiss Target Prediction. Genes related to lung adenocarcinoma (LUAD) were acquired from GeneCards, OMIM and CTD databases, with the hub genes of LUAD screened by CTD database. The intersected targets of LUAD and AR-SH were obtained by Venn, with David Database employed to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Survival analysis of the hub genes of LUAD was carried out using TCGA-LUAD dataset. Molecular docking of core proteins and active ingredients was performed by Auto-Dock Vina software, followed by molecular dynamics simulations of protein-ligand complexes with well-docked conformations. Results: 29 active ingredients were screened out with 422 corresponding targets predicted. It is revealed that AR-SH can act on various targets such as EGFR, MAPK1, and KARS by ursolic acid (UA), Astragaloside IV(ASIV), and Isomucronulatol 7,2'-di-O-glucoside (IDOG) to alleviate the symptoms of LUAD. Biological processes involved are protein phosphorylation, negative regulation of apoptotic process, and pathways involved are endocrine resistance, EGFR tyrosine kinase inhibitor resistance, PI3K-Akt, and HIF-1 pathway. Molecular docking analysis indicated that the binding energy of most of the screened active ingredients to proteins encoded by core genes was less than -5.6 kcal/mol, with some active ingredients showing even lower binding energy to EGFR than Gefitinib. Three ligand-receptor complexes including EGFR-UA, MAPK1-ASIV, and KRAS-IDOG were found to bind relatively stable by molecular dynamics simulation, which was consistent with the results of molecule docking. Conclusion: We suggested that the herb pair of AR-SH can act on targets like EGFR, MAPK1 and KRAS by UA, ASIV and IDOG, to play a vital role in the treatment and the enhancement of prognosis of LUAD.PMID:37065830 | PMC:PMC10090857 | DOI:10.3389/fchem.2023.1128671

Front Chem. 2023 Mar 31;11:1142287. doi: 10.3389/fchem.2023.1142287. eCollection 2023.ABSTRACTNatural products derived from herbal medicine are a fruitful source of lead compounds because of their structural diversity and potent bioactivities. However, despite the success of active compounds derived from herbal medicine in drug discovery, some approaches cannot effectively elucidate the overall effect and action mechanism due to their multi-component complexity. Fortunately, mass spectrometry-based metabolomics has been recognized as an effective strategy for revealing the effect and discovering active components, detailed molecular mechanisms, and multiple targets of natural products. Rapid identification of lead compounds and isolation of active components from natural products would facilitate new drug development. In this context, mass spectrometry-based metabolomics has established an integrated pharmacology framework for the discovery of bioactivity-correlated constituents, target identification, and the action mechanism of herbal medicine and natural products. High-throughput functional metabolomics techniques could be used to identify natural product structure, biological activity, efficacy mechanisms, and their mode of action on biological processes, assisting bioactive lead discovery, quality control, and accelerating discovery of novel drugs. These techniques are increasingly being developed in the era of big data and use scientific language to clarify the detailed action mechanism of herbal medicine. In this paper, the analytical characteristics and application fields of several commonly used mass spectrometers are introduced, and the application of mass spectrometry in the metabolomics of traditional Chinese medicines in recent years and its active components as well as mechanism of action are also discussed.PMID:37065828 | PMC:PMC10102349 | DOI:10.3389/fchem.2023.1142287

Front Mol Biosci. 2023 Mar 29;10:1166182. doi: 10.3389/fmolb.2023.1166182. eCollection 2023.ABSTRACTAims: Interocular comparison of the metabolomic signature of aqueous humor (AH) was performed. The aim of the study was to quantitatively evaluate the symmetry in concentrations of various metabolites belonging to different categories. Methods: The study included AH samples from 23 patients, 74.17 ± 11.52 years old, undergoing simultaneous bilateral cataract surgery at the Ophthalmology Department of the Medical University of Bialystok, Poland. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics and lipidomics analyses of AH samples were performed using the AbsoluteIDQ® p180 kit. Out of 188 metabolites available in the kit, 67 were measured in the majority (>70%) of the samples: 21/21 amino acids, 10/22 biogenic amines, 9/40 acylcarnitines, 0/14 lysophosphatidylcholines, 21/76 phosphatidylcholines, 5/15 sphingolipids, and 1/1sum of hexoses. Results: The comparison of both eyes revealed that the concentrations of metabolites did not differ significantly (p < 0.05) except for taurine (p = 0.037). There was moderate-to-strong positive interocular correlation (r > 0.5) between most metabolites regarding concentration. This was confirmed by the high intraclass correlation coefficient (ICC) values of different levels, which varied for the different metabolites. However, there were exceptions. Correlations were not significant for 2 acylcarnitines (tiglylcarnitine and decadienylcarnitine) and 3 glycerophospholipids (PC aa C32:3, PC aa C40:2, and PC aa C40:5). Conclusion: With a few exceptions, a single eye was found to be representative of the fellow eye in terms of the concentration of most of the analyzed metabolites. The degree of intraindividual variability in the AH of fellow eyes differs for particular metabolites/metabolite categories.PMID:37065449 | PMC:PMC10090416 | DOI:10.3389/fmolb.2023.1166182

Front Microbiol. 2023 Mar 31;14:1137643. doi: 10.3389/fmicb.2023.1137643. eCollection 2023.ABSTRACTTemperature is one of the main factors affecting aflatoxin (AF) biosynthesis in Aspergillus flavus. Previous studies showed that AF biosynthesis is elevated in A. flavus at temperatures between 28°C-30°C, while it is inhibited at temperatures above 30°C. However, little is known about the metabolic mechanism underlying temperature-regulated AF biosynthesis. In this study, we integrated metabolomic and lipidomic analyses to investigate the endogenous metabolism of A. flavus across 6 days of mycelia growth at 28°C (optimal AF production) and 37°C (no AF production). Results showed that both metabolite and lipid profiles were significantly altered at different temperatures. In particular, metabolites involved in carbohydrate and amino acid metabolism were up-regulated at 37°C on the second day but down-regulated from days three to six. Moreover, lipidomics and targeted fatty acids analyses of mycelia samples revealed a distinct pattern of lipid species and free fatty acids desaturation. High degrees of polyunsaturation of most lipid species at 28°C were positively correlated with AF production. These results provide new insights into the underlying metabolic changes in A. flavus under temperature stress.PMID:37065116 | PMC:PMC10102665 | DOI:10.3389/fmicb.2023.1137643

Brain Commun. 2023 Mar 29;5(2):fcad099. doi: 10.1093/braincomms/fcad099. eCollection 2023.ABSTRACTAmbroxol is a well-known mucolytic expectorant, which has gained much attention in amyotrophic lateral sclerosis, Parkinson's and Gaucher's disease. A specific focus has been placed on ambroxol's glucocerebrosidase-stimulating activity, on grounds that the point mutation of the gba1 gene, which codes for this enzyme, is a risk factor for developing Parkinson's disease. However, ambroxol has been attributed other characteristics, such as the potent inhibition of sodium channels, modification of calcium homeostasis, anti-inflammatory effects and modifications of oxygen radical scavengers. We hypothesized that ambroxol could have a direct impact on neuronal rescue if administered directly after ischaemic stroke induction. We longitudinally evaluated 53 rats using magnetic resonance imaging to examine stroke volume, oedema, white matter integrity, resting state functional MRI and behaviour for 1 month after ischemic stroke onset. For closer mechanistic insights, we evaluated tissue metabolomics of different brain regions in a subgroup of animals using ex vivo nuclear magnetic resonance spectroscopy. Ambroxol-treated animals presented reduced stroke volumes, reduced cytotoxic oedema, reduced white matter degeneration, reduced necrosis, improved behavioural outcomes and complex changes in functional brain connectivity. Nuclear magnetic resonance spectroscopy tissue metabolomic data at 24 h post-stroke proposes several metabolites that are capable of minimizing post-ischaemic damage and that presented prominent shifts during ambroxol treatment in comparison to controls. Taking everything together, we propose that ambroxol catalyzes recovery in energy metabolism, cellular homeostasis, membrane repair mechanisms and redox balance. One week of ambroxol administration following stroke onset reduced ischaemic stroke severity and improved functional outcome in the subacute phase followed by reduced necrosis in the chronic stroke phase.PMID:37065090 | PMC:PMC10090797 | DOI:10.1093/braincomms/fcad099

Front Physiol. 2023 Mar 31;14:1155324. doi: 10.3389/fphys.2023.1155324. eCollection 2023.ABSTRACTLittle attention has been paid to the biological role of arginine and its dietary supplementation in broilers under heat stress (HS) conditions. Therefore, the main aim of this study was to assess the response of broilers to arginine supplementation and cyclic HS, with a focus on liver, pectoral muscle, and blood metabolic profiles and the cecal microbiota. Day-old male Ross 308 broilers (n = 240) were placed in 2 rooms with 12 pens each for a 44-day trial. Pens were assigned to one of two groups (6 pens/group/room): the control group (CON) was given a basal diet in mash form and the treated group (ARG) was fed CON diet supplemented with crystalline L-arginine. The total arginine:lysine ratio of CON diet ranged between 1.02 and 1.07, while that of ARG diet was 1.20. One room was constantly kept at thermoneutral (TN) conditions, while the birds in the other room were kept at TN conditions until D34 and subjected to cyclic HS from D35 onwards (∼34°C; 9:00 A.M.-6:00 P.M.). Blood, liver, Pectoralis major muscle, and cecal content were taken from 2 birds per pen (12 birds/group/room) for metabolomics and microbiota analysis. Growth performance data were also collected on a pen basis. Arginine supplementation failed to reduce the adverse effects of HS on growth performance. Supplemented birds showed increased levels of arginine and creatine in plasma, liver, and P. major and methionine in liver, and reduced levels of glutamine in plasma, liver, and P. major. HS altered bioenergetic processes (increased levels of AMP and reduced levels of fumarate, succinate, and UDP), protein metabolism (increased protein breakdown to supply the liver with amino acids for energy production), and promoted the accumulation of antioxidant and protective molecules (histidine-containing dipeptides, beta-alanine, and choline), especially in P. major. Arginine supplementation may have partially counterbalanced the effects of HS on energy homeostasis by increasing creatine levels and attenuating the increase in AMP levels, particularly in P. major. It also significantly reduced cecal observed diversity, while HS increased alpha diversity indices and affected beta diversity. Results of taxonomic analysis at the phylum and family level are also provided.PMID:37064901 | PMC:PMC10102354 | DOI:10.3389/fphys.2023.1155324