PubMed

ERJ Open Res. 2023 Mar 20;9(2):00332-2022. doi: 10.1183/23120541.00332-2022. eCollection 2023 Mar.ABSTRACTPURPOSE: Obstructive lung disease is increasingly common among persons with HIV, both smokers and nonsmokers. We used aptamer proteomics to identify proteins and associated pathways in HIV-associated obstructive lung disease.METHODS: Bronchoalveolar lavage fluid (BALF) samples from 26 persons living with HIV with obstructive lung disease were matched to persons living with HIV without obstructive lung disease based on age, smoking status and antiretroviral treatment. 6414 proteins were measured using SomaScan® aptamer-based assay. We used sparse distance-weighted discrimination (sDWD) to test for a difference in protein expression and permutation tests to identify univariate associations between proteins and forced expiratory volume in 1 s % predicted (FEV1 % pred). Significant proteins were entered into a pathway over-representation analysis. We also constructed protein-driven endotypes using K-means clustering and performed over-representation analysis on the proteins that were significantly different between clusters. We compared protein-associated clusters to those obtained from BALF and plasma metabolomics data on the same patient cohort.RESULTS: After filtering, we retained 3872 proteins for further analysis. Based on sDWD, protein expression was able to separate cases and controls. We found 575 proteins that were significantly correlated with FEV1 % pred after multiple comparisons adjustment. We identified two protein-driven endotypes, one of which was associated with poor lung function, and found that insulin and apoptosis pathways were differentially represented. We found similar clusters driven by metabolomics in BALF but not plasma.CONCLUSION: Protein expression differs in persons living with HIV with and without obstructive lung disease. We were not able to identify specific pathways differentially expressed among patients based on FEV1 % pred; however, we identified a unique protein endotype associated with insulin and apoptotic pathways.PMID:36949960 | PMC:PMC10026002 | DOI:10.1183/23120541.00332-2022

Eur J Neurosci. 2023 Mar 22. doi: 10.1111/ejn.15972. Online ahead of print.ABSTRACTA healthy state of life suggests not only a disease-free condition but also normal psychological functioning and behavior. To maintain a healthy life, the duration of light exposure is a crucial factor. Perturbation of the standard light-dark cycle (LD: 12h light-12 h dark in mice) may result in brain, behavioral, and physiological abnormalities. The current study determined the effects of three weeks and five weeks of constant darkness (DD: 00h light-24h dark) on the behavior, hormones, prefrontal cortex (PFC), and metabolome of male and female C57BL/6J mice. We also studied three weeks of restoration in LD following five weeks of DD exposure. The results revealed that three weeks of DD affected male mice more than females, and five weeks of DD had a comparable impact on behavior, hormones, and the PFC of male and female mice. After restoration in LD, the DD-induced changes reverted to time-matched LD conditions in male and female mice. Furthermore, metabolome analysis corroborated male and female mice's behavioral and molecular kinetics. The present study laid the foundation for understanding how DD affects behavior and the PFC as a function of a) time- and b) sex and described the roles of stress and sex hormones, cytokines, neurotrophins, and metabolic pathways.PMID:36949580 | DOI:10.1111/ejn.15972

BMC Bioinformatics. 2023 Mar 22;24(1):106. doi: 10.1186/s12859-023-05149-8.ABSTRACTBACKGROUND: Biochemical reaction prediction tools leverage enzymatic promiscuity rules to generate reaction networks containing novel compounds and reactions. The resulting reaction networks can be used for multiple applications such as designing novel biosynthetic pathways and annotating untargeted metabolomics data. It is vital for these tools to provide a robust, user-friendly method to generate networks for a given application. However, existing tools lack the flexibility to easily generate networks that are tailor-fit for a user's application due to lack of exhaustive reaction rules, restriction to pre-computed networks, and difficulty in using the software due to lack of documentation.RESULTS: Here we present Pickaxe, an open-source, flexible software that provides a user-friendly method to generate novel reaction networks. This software iteratively applies reaction rules to a set of metabolites to generate novel reactions. Users can select rules from the prepackaged JN1224min ruleset, derived from MetaCyc, or define their own custom rules. Additionally, filters are provided which allow for the pruning of a network on-the-fly based on compound and reaction properties. The filters include chemical similarity to target molecules, metabolomics, thermodynamics, and reaction feasibility filters. Example applications are given to highlight the capabilities of Pickaxe: the expansion of common biological databases with novel reactions, the generation of industrially useful chemicals from a yeast metabolome database, and the annotation of untargeted metabolomics peaks from an E. coli dataset.CONCLUSION: Pickaxe predicts novel metabolic reactions and compounds, which can be used for a variety of applications. This software is open-source and available as part of the MINE Database python package ( https://pypi.org/project/minedatabase/ ) or on GitHub ( https://github.com/tyo-nu/MINE-Database ). Documentation and examples can be found on Read the Docs ( https://mine-database.readthedocs.io/en/latest/ ). Through its documentation, pre-packaged features, and customizable nature, Pickaxe allows users to generate novel reaction networks tailored to their application.PMID:36949401 | DOI:10.1186/s12859-023-05149-8

BMC Bioinformatics. 2023 Mar 22;24(1):108. doi: 10.1186/s12859-023-05211-5.ABSTRACTBACKGROUND: Stable Isotope Resolved Metabolomics (SIRM) is a new biological approach that uses stable isotope tracers such as uniformly [Formula: see text]-enriched glucose ([Formula: see text]-Glc) to trace metabolic pathways or networks at the atomic level in complex biological systems. Non-steady-state kinetic modeling based on SIRM data uses sets of simultaneous ordinary differential equations (ODEs) to quantitatively characterize the dynamic behavior of metabolic networks. It has been increasingly used to understand the regulation of normal metabolism and dysregulation in the development of diseases. However, fitting a kinetic model is challenging because there are usually multiple sets of parameter values that fit the data equally well, especially for large-scale kinetic models. In addition, there is a lack of statistically rigorous methods to compare kinetic model parameters between different experimental groups.RESULTS: We propose a new Bayesian statistical framework to enhance parameter estimation and hypothesis testing for non-steady-state kinetic modeling of SIRM data. For estimating kinetic model parameters, we leverage the prior distribution not only to allow incorporation of experts' knowledge but also to provide robust parameter estimation. We also introduce a shrinkage approach for borrowing information across the ensemble of metabolites to stably estimate the variance of an individual isotopomer. In addition, we use a component-wise adaptive Metropolis algorithm with delayed rejection to perform efficient Monte Carlo sampling of the posterior distribution over high-dimensional parameter space. For comparing kinetic model parameters between experimental groups, we propose a new reparameterization method that converts the complex hypothesis testing problem into a more tractable parameter estimation problem. We also propose an inference procedure based on credible interval and credible value. Our method is freely available for academic use at https://github.com/xuzhang0131/MCMCFlux .CONCLUSIONS: Our new Bayesian framework provides robust estimation of kinetic model parameters and enables rigorous comparison of model parameters between experimental groups. Simulation studies and application to a lung cancer study demonstrate that our framework performs well for non-steady-state kinetic modeling of SIRM data.PMID:36949395 | DOI:10.1186/s12859-023-05211-5

Nat Commun. 2023 Mar 22;14(1):1595. doi: 10.1038/s41467-023-37291-5.ABSTRACTThe regulation of the informational flow from the mitochondria to the nucleus (mitonuclear communication) is not fully characterized in the heart. We have determined that mitochondrial ribosomal protein S5 (MRPS5/uS5m) can regulate cardiac function and key pathways to coordinate this process during cardiac stress. We demonstrate that loss of Mrps5 in the developing heart leads to cardiac defects and embryonic lethality while postnatal loss induces cardiac hypertrophy and heart failure. The structure and function of mitochondria is disrupted in Mrps5 mutant cardiomyocytes, impairing mitochondrial protein translation and OXPHOS. We identify Klf15 as a Mrps5 downstream target and demonstrate that exogenous Klf15 is able to rescue the overt defects and re-balance the cardiac metabolome. We further show that Mrps5 represses Klf15 expression through c-myc, together with the metabolite L-phenylalanine. This critical role for Mrps5 in cardiac metabolism and mitonuclear communication highlights its potential as a target for heart failure therapies.PMID:36949106 | DOI:10.1038/s41467-023-37291-5

Signal Transduct Target Ther. 2023 Mar 22;8(1):137. doi: 10.1038/s41392-023-01380-0.ABSTRACTTumour cells have exquisite flexibility in reprogramming their metabolism in order to support tumour initiation, progression, metastasis and resistance to therapies. These reprogrammed activities include a complete rewiring of the bioenergetic, biosynthetic and redox status to sustain the increased energetic demand of the cells. Over the last decades, the cancer metabolism field has seen an explosion of new biochemical technologies giving more tools than ever before to navigate this complexity. Within a cell or a tissue, the metabolites constitute the direct signature of the molecular phenotype and thus their profiling has concrete clinical applications in oncology. Metabolomics and fluxomics, are key technological approaches that mainly revolutionized the field enabling researchers to have both a qualitative and mechanistic model of the biochemical activities in cancer. Furthermore, the upgrade from bulk to single-cell analysis technologies provided unprecedented opportunity to investigate cancer biology at cellular resolution allowing an in depth quantitative analysis of complex and heterogenous diseases. More recently, the advent of functional genomic screening allowed the identification of molecular pathways, cellular processes, biomarkers and novel therapeutic targets that in concert with other technologies allow patient stratification and identification of new treatment regimens. This review is intended to be a guide for researchers to cancer metabolism, highlighting current and emerging technologies, emphasizing advantages, disadvantages and applications with the potential of leading the development of innovative anti-cancer therapies.PMID:36949046 | DOI:10.1038/s41392-023-01380-0

Kidney Int. 2023 Apr;103(4):661-663. doi: 10.1016/j.kint.2022.12.025.ABSTRACTGiven their accessibility and relevance to established clinical workflows, blood and urine have been the major focus of investigation in metabolomics studies of human kidney disease. In this issue, Liu et al. describe the application of metabolomics to perfusate from donor kidneys subjected to hypothermic machine perfusion. In addition to providing an elegant model for investigating kidney metabolism, this study highlights the limitations of allograft quality assessment and identifies metabolites of interest in kidney ischemia.PMID:36948766 | DOI:10.1016/j.kint.2022.12.025

J Mol Cell Biol. 2023 Mar 22:mjad019. doi: 10.1093/jmcb/mjad019. Online ahead of print.ABSTRACTYPEL5 is a member of the YPEL gene family that is evolutionarily conserved in the eukaryotic species. To date, the physiological function of YPEL5 has not been yet assessed due to a paucity of genetic animal models. Here, using CRISPR/Cas9-mediated genome editing, we generated a stable ypel5-/- mutant zebrafish line. Disruption of ypel5 expression leads to liver enlargement associated with hepatic cell proliferation. Meanwhile, hepatic metabolism and function are also dysregulated in ypel5-/- mutant as revealed by metabolomic and transcriptomic analysis. Mechanistically, Hnf4a is identified as a crucial downstream mediator and positively regulated by Ypel5. Hnf4a overexpression could largely rescue ypel5 deficiency-induced hepatic defects. Further, PPARα signaling mediates the regulation of Hnf4a by Ypel5 through directly binding to the transcriptional enhancer of Hnf4a gene. Herein, this work demonstrates an essential role for Ypel5 in hepatocyte proliferation and function, and provides the first in vivo evidence for a physiological role of the ypel5 gene in vertebrate.PMID:36948605 | DOI:10.1093/jmcb/mjad019

J Affect Disord. 2023 Mar 20:S0165-0327(23)00408-1. doi: 10.1016/j.jad.2023.03.061. Online ahead of print.ABSTRACTBACKGROUND: Existing research has suggested that depression results in disorders of glucose metabolism in the organism which causing insufficient energy supply. However, the overall changes in glucose metabolism that arise from depression have not been clarified.METHODS: In this study, the depression-like behavior in chronically unpredictable mild stressed rats was investigated, and the fate of glucose was tracked through isotope tracing and mass spectrometry, with a focus on metabolite changes in cecal contents.RESULTS: As indicated by the results, the isotopic results of cecal contents can indicate the metabolic end of the organism. Moreover, the TCA cycle activity was notably reduced, and the gluconeogenesis pathway was abnormally up-regulated in the CUMS-induced rats. The organism expedited other glucose metabolism pathways to make up for the insufficiency of energy. As a result, the activity of the inefficient glycolysis pathway was increased.LIMITATIONS: Existing research has only investigated the metabolism of 13C-glucose, and lipids and proteins have been rarely explored.CONCLUSIONS: The chronic unpredictable mild stress can inhibit the entry of pyruvate into mitochondria in SD rats, such that the activity of TCA is reduced, and insufficient energy supply is caused. The organism is capable of expediting other glucose metabolism rate pathways to make up for the insufficiency of energy, whereas it still cannot compensate for the loss of energy. As a result, CUMS-induced rats exhibited high-rate and low-efficiency glucose metabolism.PMID:36948469 | DOI:10.1016/j.jad.2023.03.061

J Nutr Biochem. 2023 Mar 20:109320. doi: 10.1016/j.jnutbio.2023.109320. Online ahead of print.ABSTRACTBlack rice displays a series of properties including regulating lipid metabolism and attenuating liver injury. Our study aimed to investigate the effect of Zixiangnuo black rice (ZG), peeled rice (ZPG), rice bran (ZBG) on lipid metabolism, liver inflammation, gut microbiota and metabolite profiles in high-fat/cholesterol (HFCD) diet mice. A total of 5 treatment groups were fed a normal control diet or a HFCD with or without HB supplementation for 10 weeks. The results showed that ZBG significantly improved lipid parameters, liver function and injury and blood glucose indexes related to hyperlipidemia compared with HFCD group. ZBG recovered the disorder of gut microbiota by increasing Bacteroidetes/Firmicutes ratio and Lactobacillus abundance, and decreasing Proteobacteria abundance. ZBG enhanced the levels of 6 short chain fatty acids. Fecal metabolomics analysis showed that the important differential metabolites between ZBG and HFCD group were Deoxycholic acid and Myclobutanil, and metabolic pathways were Arachidonic acid metabolism and ABC transporters. Results suggested that BR or bran were effective dietary candidates to ameliorate hyperlipidemia.PMID:36948432 | DOI:10.1016/j.jnutbio.2023.109320

Neurobiol Dis. 2023 Mar 20:106092. doi: 10.1016/j.nbd.2023.106092. Online ahead of print.ABSTRACTRecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biochemical and biological roles of RecQ helicases are rather well established, however, there is no systematic study comparing the behavioral changes among various RecQ-deficient mice including consequences of exposure to DNA damage. Here, we investigated the effects of ionizing irradiation (IR) on three RecQ-deficient mouse models (RecQ1, WRN and RecQ4). We find abnormal cognitive behavior in RecQ-deficient mice in the absence of IR. Interestingly, RecQ dysfunction impairs social ability and induces depressive-like behavior in mice after a single exposure to IR, suggesting that RecQ proteins play roles in mood and cognition behavior. Further, transcriptomic and metabolomic analyses revealed significant alterations in RecQ-deficient mice, especially after IR exposure. In particular, pathways related to neuronal and microglial functions, DNA damage repair, cell cycle, and reactive oxygen responses were downregulated in the RecQ4 and WRN mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our findings suggest that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing a potential therapeutic target.PMID:36948261 | DOI:10.1016/j.nbd.2023.106092

Phytomedicine. 2023 Mar 13;114:154755. doi: 10.1016/j.phymed.2023.154755. Online ahead of print.ABSTRACTBACKGROUND: Parkinson's disease (PD) is a common, complex, and chronic neurodegenerative disorder involved in multi-system. At present, medicine for PD has many limitations. Buyang Huanwu decoction (BHD), a famous traditional Chinese medicinal (TCM) formulae, is used in the treatment of PD clinically in China. However, the therapeutic mechanism is still unknown.PURPOSE: We aimed to explore the pharmacological mechanism of BHD alleviating PD through an integrated liver metabolome and brain transcriptome analysis.METHODS: The mice with PD were induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral tests and immunohistochemistry were used to evaluate the neuroprotective effects of BHD. The non-targeted metabolomics analysis was conducted to profile differentially accumulated metabolites (DAMs) in the liver using a UHPLC-Q-Exactive MS/MS method. The differentially expressed genes (DEGs) in the brain were investigated by transcriptomic analysis on an Illumina sequencing platform. The correlations of DAMs and DEGs were investigated using an integrated metabolomic and transcriptomic approach.RESULTS: The results of behavioral tests and immunohistochemistry proved the alleviated effects of BHD on PD symptoms. A total of 14 and 36 DAMs were detected in the groups treated with low- (L group) and high-dose (H group) BHD respectively under the positive ion mode. Compared with the PD model group (M group), three enriched pathways including metabolic pathways, ABC transporters, and biosynthesis of amino acids were common in the L and H group. Transcriptomic analysis proved that BHD could regulate the expression of numerous genes, some of which were targeted by Ben-Ldopa such as Creb5, Gm45623, Ccer2, Cd180, Fosl2, Crip3, and Noxred1. Based on the integrated metabolomic and transcriptomic analysis, 7 metabolite-gene pairs were found in four comparisons, including C vs M, M vs P, M vs L, and M vs H, and 6 enriched pathways containing purine metabolism, glycine/serine/threonine metabolism, phenylalanine metabolism, carbon fixation in photosynthetic organisms, thiamine metabolism, and ABC transporters were overlapped.CONCLUSIONS: Though the underlying pharmacological mechanism of BHD is still lacking, we provided evidence that BHD could improve dopaminergic neurons in MPTP-induced PD mice by regulating liver metabolism and brain transcriptome. The correlation between the liver and the brain was preliminarily revealed in this study.PMID:36948142 | DOI:10.1016/j.phymed.2023.154755

Curr Opin Chem Biol. 2023 Mar 20;74:102287. doi: 10.1016/j.cbpa.2023.102287. Online ahead of print.ABSTRACTHow has metabolomics helped our understanding of infectious diseases? With the threat of antimicrobial resistance to human health around the world, metabolomics has emerged as a powerful tool to comprehensively characterize metabolic pathways to identify new drug targets. However, its output is constrained to known metabolites and their metabolic pathways. Recent advances in instrumentation, methodologies, and computational mass spectrometry have accelerated the use of metabolomics to understand pathogen-host metabolic interactions. This short review discusses a selection of recent publications using metabolomics in infectious/bacterial diseases. These studies unravel the links between metabolic adaptations to environments and host metabolic responses. Moreover, they highlight the importance of enzyme function and metabolite characterization in identifying new drug targets and biomarkers, as well as precision medicine in monitoring therapeutics and diagnosing diseases.PMID:36948086 | DOI:10.1016/j.cbpa.2023.102287

Phenomics. 2022 Jun 15;3(1):1-21. doi: 10.1007/s43657-022-00061-2. eCollection 2023 Feb.ABSTRACTSoil salinity is among the abiotic stressors that threaten agriculture the most, and purslane (Portulaca oleracea L.) is a dicot species adapted to inland salt desert and saline habitats that hyper accumulates salt and has high phytoremediation potential. Many researchers consider purslane a suitable model species to study the mechanisms of plant tolerance to drought and salt stresses. Here, a robust salinity stress protocol was developed and used to characterize the morphophysiological responses of young purslane plants to salinity stress; then, leaf tissue underwent characterization by distinct omics platforms to gain further insights into its response to very high salinity stress. The salinity stress protocol did generate different levels of stress by gradients of electrical conductivity at field capacity and water potential in the saturation extract of the substrate, and the morphological parameters indicated three distinct stress levels. As expected from a halophyte species, these plants remained alive under very high levels of salinity stress, showing salt crystal-like structures constituted mainly by Na+, Cl-, and K+ on and around closed stomata. A comprehensive and large-scale metabolome and transcriptome single and integrated analyses were then employed using leaf samples. The multi-omics integration (MOI) system analysis led to a data-set of 51 metabolic pathways with at least one enzyme and one metabolite differentially expressed due to salinity stress. These data sets (of genes and metabolites) are valuable for future studies aimed to deepen our knowledge on the mechanisms behind the high tolerance of this species to salinity stress. In conclusion, besides showing that this species applies salt exclusion already in young plants to support very high levels of salinity stress, the initial analysis of metabolites and transcripts data sets already give some insights into other salt tolerance mechanisms used by this species to support high levels of salinity stress.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43657-022-00061-2.PMID:36947413 | PMC:PMC9883379 | DOI:10.1007/s43657-022-00061-2

Plant Foods Hum Nutr. 2023 Mar 22. doi: 10.1007/s11130-023-01055-9. Online ahead of print.ABSTRACTAntioxidative and antiaging abilities of probiotic fermented ginseng (PG) were evaluated in Caenorhabditis elegans (C. elegans). Lifespan and effect on heat stress and acute oxidative stress in C. elegans were significantly enhanced by PG. Antioxidative enzymes such as T-SOD, GSH-PX, CAT were significantly up-regulated, and MDA, ROS and apoptosis levels were significantly down-regulated. At the same time, PG exerted antioxidant and anti-aging activities by reducing the expression of DAF-2 mRNA and increasing the expression of SKN-1 and SOD-3 mRNA in C. elegans. In addition, the mechanism of antioxidative and antiaging activities of PG was explored through gut microbiota sequencing and untargeted metabolomics. The results of gut microbiota indicated that PG could significantly improve the composition and structure of microbes in the gut of C. elegans, and the relative abundance of beneficial bacteria was up-regulated. Untargeted metabolomic results elucidated that PG modulated antioxidant and antiaging activities through neuroactive ligand-receptor interaction, Citrate cycle (TCA cycle), pyruvate metabolism, ascorbate and aldarate metabolism and D-Arginine and D-ornithine metabolism of C. elegans. These results indicated that PG had excellent antioxidant and anti-aging activities, providing research value for the development of functional foods and improvement of aging-related diseases.PMID:36947370 | DOI:10.1007/s11130-023-01055-9

Microb Ecol. 2023 Mar 22. doi: 10.1007/s00248-023-02200-2. Online ahead of print.ABSTRACTFungal pigments are characterized by a diverse set of chemical backbones, some of which present photosensitizer-like structures. From the genus Cortinarius, for example, several biologically active photosensitizers have been identified leading to the hypothesis that photoactivity might be a more general phenomenon in the kingdom Fungi. This paper aims at testing the hypothesis. Forty-eight fruiting body-forming species producing pigments from all four major biosynthetic pathways (i.e., shikimate-chorismate, acetate-malonate, mevalonate, and nitrogen heterocycles) were selected and submitted to a workflow combining in vitro chemical and biological experiments with state-of-the-art metabolomics. Fungal extracts were profiled by high-resolution mass spectrometry and subsequently explored by spectral organization through feature-based molecular networking (FBMN), including advanced metabolite dereplication techniques. Additionally, the photochemical properties (i.e., light-dependent production of singlet oxygen), the phenolic content, and the (photo)cytotoxic activity of the extracts were studied. Different levels of photoactivity were found in species from all four metabolic groups, indicating that light-dependent effects are common among fungal pigments. In particular, extracts containing pigments from the acetate-malonate pathway, e.g., extracts from Bulgaria inquinans, Daldinia concentrica, and Cortinarius spp., were not only efficient producers of singlet oxygen but also exhibited photocytotoxicity against three different cancer cell lines. This study explores the distribution of photobiological traits in fruiting body forming fungi and highlights new sources for phototherapeutics.PMID:36947169 | DOI:10.1007/s00248-023-02200-2

J Agric Food Chem. 2023 Mar 22. doi: 10.1021/acs.jafc.3c00050. Online ahead of print.ABSTRACTHerbaspirillum sp. ZXN111 and its mutants (Δacc, Δtyrb, and Δacc-tyrb), which show PGP activity on Zijuan, were tested for tea plants' colonization characteristics and the strain-dependent response of tea metabolites. The results showed that strain ZXN111 could widely colonize in different tea cultivars of Zijuan, Yunkang-10, Longjin 43, and Shuchazao, but with significant colonization preference to Zijuan, which might be ascribed to anthocyanins' chemotaxis. After 9 weeks of co-cultivation, l-theanine and theobromine in Zijuan leaves that were inoculated with wild-type ZXN111 were decreased, while theobromine, caffeine, and l-theanine that were inoculated with mutant Δacc were increased; especially l-theanine increased much significantly. Metabolomics analysis showed that tea metabolite profiling of inoculant groups was clearly separated from the control; therein, the flavanols were downregulated in ZXN111 and Δacc groups, but the l-theanine of the Δacc group was significantly upregulated compared to control and ZXN111 groups. These results indicated that strain ZXN111, especially of mutant Δacc, improved Zijuan tea flavor.PMID:36946772 | DOI:10.1021/acs.jafc.3c00050

Cancer Res. 2023 Mar 22:OF1-OF19. doi: 10.1158/0008-5472.CAN-22-1826. Online ahead of print.ABSTRACTClinical management of melanomas with NRAS mutations is challenging. Targeting MAPK signaling is only beneficial to a small subset of patients due to resistance that arises through genetic, transcriptional, and metabolic adaptation. Identification of targetable vulnerabilities in NRAS-mutated melanoma could help improve patient treatment. Here, we used multiomics analyses to reveal that NRAS-mutated melanoma cells adopt a mesenchymal phenotype with a quiescent metabolic program to resist cellular stress induced by MEK inhibition. The metabolic alterations elevated baseline reactive oxygen species (ROS) levels, leading these cells to become highly sensitive to ROS induction. In vivo xenograft experiments and single-cell RNA sequencing demonstrated that intratumor heterogeneity necessitates the combination of a ROS inducer and a MEK inhibitor to inhibit both tumor growth and metastasis. Ex vivo pharmacoscopy of 62 human metastatic melanomas confirmed that MEK inhibitor-resistant tumors significantly benefited from the combination therapy. Finally, oxidative stress response and translational suppression corresponded with ROS-inducer sensitivity in 486 cancer cell lines, independent of cancer type. These findings link transcriptional plasticity to a metabolic phenotype that can be inhibited by ROS inducers in melanoma and other cancers.SIGNIFICANCE: Metabolic reprogramming in drug-resistant NRAS-mutated melanoma cells confers sensitivity to ROS induction, which suppresses tumor growth and metastasis in combination with MAPK pathway inhibitors.PMID:36946761 | DOI:10.1158/0008-5472.CAN-22-1826

Mol Nutr Food Res. 2023 Mar 22:e2200633. doi: 10.1002/mnfr.202200633. Online ahead of print.ABSTRACTSCOPE: Holothuria leucospilota polysaccharides (HLP) are bioactive polysaccharides with immunomodulatory effects. This study aimed to investigate the impact of HLP on dextran sodium sulfate (DSS)-induced colitis in rats and further investigate the complex interactions between changes in intestinal microbiota, co-metabolites, and intestinal inflammation under HLP intervention.METHODS AND RESULTS: The ulcerative colitis (UC) model of Sprague Dawley (SD) rats was established by a normal diet with 3%DSS. The effects of HLP on UC were studied by gavage of different doses of HLP for two weeks. The results showed that HLP alleviated the inflammation of UC and reduced histological damage and secretion of TNF-α, IL-6, IL-1β, and IL-10. After HLP treatment, the intestinal flora of UC rats was regulated, and the flora diversity was restored. Fecal metabolomics analysis revealed the modulatory effects of HLP on amino acid metabolism, antimicrobial peptide anabolism and energy metabolism in rats with colitis. Correlation analysis of microbial and intestinal metabolites revealed the potential mechanism of HLP affecting colitis.CONCLUSION: HLP repaired the intestinal compartment's metabolic disorder by regulating intestinal flora's structure and alleviating colonic mucosal injury and inflammation in colitis rats. This article is protected by copyright. All rights reserved.PMID:36946468 | DOI:10.1002/mnfr.202200633

Food Funct. 2023 Mar 22. doi: 10.1039/d2fo03030f. Online ahead of print.ABSTRACTThe herb Astragali Radix is a food-medicine herb. A major component of Astragali Radix, astragaloside IV (AS-IV), has neuroprotective effects in IS, but its mechanisms are not well understood. Our research used a transient middle cerebral artery occlusion (MCAO) rat model for longitudinal multi-omics analyses of the side of the brain affected by ischemia. Based on transcriptomic and proteomic analysis, we found that 396 differential expression targets were up-regulated and 114 differential expression targets were down-regulated. A total of 117 differential metabolites were identified based on metabonomics. Finally, we found 8 hub genes corresponding to the compound-reaction-enzyme-gene network using the Metscape plug-in for Cytoscape 3.7.1. We found that the related key metabolites were 3,4-dihydroxy-L-phenylalanine, 2-aminomuconate semialdehyde, (R)-3-hydroxybutanoate, etc., and the affected pathways were tyrosine metabolism, tryptophan metabolism, butanoate metabolism, purine metabolism, etc. We further validated these targets using 4D-PRM proteomics and found that seven targets were significantly different, including Aprt, Atic, Gaa, Galk1, Glb1, Me2, and Hexa. We aimed to uncover the mechanism of AS-IV in the treatment of ischemic brain injury through a comprehensive strategy combining transcriptomics, proteomics, and metabolomics.PMID:36946308 | DOI:10.1039/d2fo03030f