PubMed

World J Microbiol Biotechnol. 2023 Apr 8;39(6):151. doi: 10.1007/s11274-023-03603-6.ABSTRACTPesticide pollution in recent times has emerged as a grave environmental problem contaminating both aquatic and terrestrial ecosystems owing to their widespread use. Bioremediation using gene editing and system biology could be developed as an eco-friendly and proficient tool to remediate pesticide-contaminated sites due to its advantages and greater public acceptance over the physical and chemical methods. However, it is indispensable to understand the different aspects associated with microbial metabolism and their physiology for efficient pesticide remediation. Therefore, this review paper analyses the different gene editing tools and multi-omics methods in microbes to produce relevant evidence regarding genes, proteins and metabolites associated with pesticide remediation and the approaches to contend against pesticide-induced stress. We systematically discussed and analyzed the recent reports (2015-2022) on multi-omics methods for pesticide degradation to elucidate the mechanisms and the recent advances associated with the behaviour of microbes under diverse environmental conditions. This study envisages that CRISPR-Cas, ZFN and TALEN as gene editing tools utilizing Pseudomonas, Escherichia coli and Achromobacter sp. can be employed for remediation of chlorpyrifos, parathion-methyl, carbaryl, triphenyltin and triazophos by creating gRNA for expressing specific genes for the bioremediation. Similarly, systems biology accompanying multi-omics tactics revealed that microbial strains from Paenibacillus, Pseudomonas putida, Burkholderia cenocepacia, Rhodococcus sp. and Pencillium oxalicum are capable of degrading deltamethrin, p-nitrophenol, chlorimuron-ethyl and nicosulfuron. This review lends notable insights into the research gaps and provides potential solutions for pesticide remediation by using different microbe-assisted technologies. The inferences drawn from the current study will help researchers, ecologists, and decision-makers gain comprehensive knowledge of value and application of systems biology and gene editing in bioremediation assessments.PMID:37029313 | DOI:10.1007/s11274-023-03603-6

Oncogene. 2023 Apr 7. doi: 10.1038/s41388-023-02688-5. Online ahead of print.ABSTRACTRecurrence remains a significant clinical barrier to improving breast cancer patient outcomes. The RON receptor is a predictor of metastatic progression and recurrence in breast cancers of all subtypes. RON directed therapies are in development, but preclinical data directly testing the impact of RON inhibition on metastatic progression/recurrence are lacking, and mechanisms to exert this function remain unclear. Herein, we modeled breast cancer recurrence using implantation of RON-overexpressing murine breast cancer cells. Recurrent growth was examined after tumor resection via in vivo imaging and ex vivo culture of circulating tumor cells from whole blood samples from tumor bearing mice. In vitro functional assessment of was performed using mammosphere formation assays. Transcriptomic pathway enrichment identified glycolysis and cholesterol biosynthesis pathways, transcription factor targets, and signaling pathways enriched in RON-overexpressing breast cancer cells. BMS777607, a RON inhibitor, abrogated CTC colony formation tumor cells and tumor recurrence. RON promoted mammosphere formation through upregulated cholesterol production that utilizes glycolysis-derived substrates. In mouse models with RON overexpression, statin-mediated inhibition of cholesterol biosynthesis impeded metastatic progression and recurrence but does not affect the primary tumor. RON upregulates glycolysis and cholesterol biosynthesis gene expression by two pathways: MAPK-dependent c-Myc expression and β-catenin -dependent SREBP2 expression.PMID:37029299 | DOI:10.1038/s41388-023-02688-5

Sci Rep. 2023 Apr 7;13(1):5747. doi: 10.1038/s41598-023-32797-w.ABSTRACTThis study aimed to investigate the metabolite profile and inflammatory state of follicular fluid (FF) in women with stage III-IV ovarian endometriosis (OE) who underwent in vitro fertilization (IVF). A cohort of 20 consecutive patients with OE were recruited and received progestin-primed ovary stimulation (PPOS) protocol (study group), while another 20 OE patients received one-month ultra-long term protocol (control group) for IVF in this prospective, nonrandomized study. FF samples were obtained from dominant follicles during oocyte retrieval, and liquid chromatography-mass spectrometry (LC-MS) was used to investigate the metabolites profile of FF. Results showed that significant increases in the levels of proline, arginine, threonine, and glycine in patients who received PPOS protocol compared to the control group (P < 0.05). A panel of three metabolites (proline, arginine, and threonine) was identified as specific biomarkers of OE patients using PPOS protocol. Additionally, levels of interleukin-1β, regulated on activation, normal T cell expressed and secreted, and tumor necrosis factor-α markedly decreased in women who received PPOS protocol compared to the control group (P < 0.05). In conclusion, PPOS protocol regulates the metabolism of several amino acids in the FF, which may play critical roles in the oocyte development and blastocyst formation, and their specific mechanism should be further elucidated.PMID:37029234 | DOI:10.1038/s41598-023-32797-w

Commun Biol. 2023 Apr 7;6(1):374. doi: 10.1038/s42003-023-04730-4.ABSTRACTCellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8+Tc, NKT, and epithelial cells. Consequently, we found that a strong dysregulation in immunometabolism was tied to increased cellular exhaustion, attenuated effector function, and impaired memory differentiation. Pharmacological inhibition of mitophagy with mdivi-1 reduced excess glucose metabolism, resulting in enhanced generation of SARS-CoV-2- specific CD8+Tc, increased cytokine secretion, and augmented memory cell proliferation. Taken together, our study provides critical insight regarding the cellular mechanisms underlying the effect of SARS-CoV-2 infection on host immune cell metabolism, and highlights immunometabolism as a promising therapeutic target for COVID-19 treatment.PMID:37029220 | DOI:10.1038/s42003-023-04730-4

Int J Obes (Lond). 2023 Apr 7. doi: 10.1038/s41366-023-01295-4. Online ahead of print.ABSTRACTBACKGROUND/OBJECTIVES: Obesity in pregnancy associates with changes in the glucose-insulin axis. We hypothesized that these changes affect the maternal metabolome already in the first trimester of human pregnancy and, thus, aimed to identify these metabolites.PATIENTS/METHODS: We performed untargeted metabolomics (HPLC-MS/MS) on maternal serum (n = 181, gestational weeks 4+0-11+6). For further analysis, we included only non-smoking women as assessed by serum cotinine levels (ELISA) (n = 111). In addition to body mass index (BMI) and leptin as measures of obesity and adiposity, we metabolically phenotyped women by their fasting glucose, C-peptide and insulin sensitivity (ISHOMA index). To identify metabolites (outcome) associated with BMI, leptin, glucose, C-peptide and/or ISHOMA (exposures), we used a combination of univariable and multivariable regression analyses with multiple confounders and machine learning methods (Partial Least Squares Discriminant Analysis, Random Forest and Support Vector Machine). Additional statistical tests confirmed robustness of results. Furthermore, we performed network analyses (MoDentify package) to identify sets of correlating metabolites that are coordinately regulated by the exposures.RESULTS: We detected 2449 serum features of which 277 were annotated. After stringent analysis, 15 metabolites associated with at least one exposure (BMI, leptin, glucose, C-peptide, ISHOMA). Among these, palmitoleoyl ethanolamine (POEA), an endocannabinoid-like lipid endogenously synthesized from palmitoleic acid, and N-acetyl-L-alanine were consistently associated with C-peptide in all the analyses (95% CI: 0.10-0.34; effect size: 21%; p < 0.001; 95% CI: 0.04-0.10; effect size: 7%; p < 0.001). In network analysis, most features correlating with palmitoleoyl ethanolamide and N-acetyl-L-alanine and associated with C-peptide, were amino acids or dipeptides (n = 9, 35%), followed by lipids (n = 7, 27%).CONCLUSIONS: We conclude that the metabolome of pregnant women with overweight/obesity is already altered early in pregnancy because of associated changes of C-peptide. Changes of palmitoleoyl ethanolamide concentration in pregnant women with obesity-associated hyperinsulinemia may reflect dysfunctional endocannabinoid-like signalling.PMID:37029207 | DOI:10.1038/s41366-023-01295-4

NPJ Syst Biol Appl. 2023 Apr 7;9(1):11. doi: 10.1038/s41540-023-00274-9.ABSTRACTSaccharomyces cerevisiae is a very well studied organism, yet ∼20% of its proteins remain poorly characterized. Moreover, recent studies seem to indicate that the pace of functional discovery is slow. Previous work has implied that the most probable path forward is via not only automation but fully autonomous systems in which active learning is applied to guide high-throughput experimentation. Development of tools and methods for these types of systems is of paramount importance. In this study we use constrained dynamical flux balance analysis (dFBA) to select ten regulatory deletant strains that are likely to have previously unexplored connections to the diauxic shift. We then analyzed these deletant strains using untargeted metabolomics, generating profiles which were then subsequently investigated to better understand the consequences of the gene deletions in the metabolic reconfiguration of the diauxic shift. We show that metabolic profiles can be utilised to not only gaining insight into cellular transformations such as the diauxic shift, but also on regulatory roles and biological consequences of regulatory gene deletion. We also conclude that untargeted metabolomics is a useful tool for guidance in high-throughput model improvement, and is a fast, sensitive and informative approach appropriate for future large-scale functional analyses of genes. Moreover, it is well-suited for automated approaches due to relative simplicity of processing and the potential to make massively high-throughput.PMID:37029131 | DOI:10.1038/s41540-023-00274-9

J Dairy Sci. 2023 Apr 5:S0022-0302(23)00164-9. doi: 10.3168/jds.2022-22812. Online ahead of print.ABSTRACTSubclinical hyperketonemia (SCHK) is the major metabolic disease observed during the transition period in dairy goats, and is characterized by high plasma levels of nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHB). However, no prior study has comprehensively assessed metabolomic profiles of dairy goats with SCHK. Plasma samples were collected within 1 h after kidding from SCHK goats (BHB concentration >0.8 mM, n = 7) and clinically healthy goats (BHB concentration <0.8 mM, n = 7) with similar body condition score (2.75 ± 0.15, mean ± standard error of the mean) and parity (primiparous). A combination of targeted and untargeted mass spectrometric approaches was employed for analyzing the various changes in the plasma lipidome and metabolome. Statistical analyses were performed using the GraphPad Prism 8.0, SIMCA-P software (version 14.1), and R packages (version 4.1.3). Plasma aminotransferase, nonesterified fatty acids, and BHB concentrations were greater in the SCHK group, but plasma glucose concentrations were lower. A total of 156 metabolites and 466 lipids were identified. The analysis of untargeted metabolomics data by principal component analysis and orthogonal partial least squares discriminant analysis revealed a separation between SCHK and clinically healthy goats. According to the screening criteria (unpaired t-test, P < 0.05), 30 differentially altered metabolites and 115 differentially altered lipids were detected. Pathway enrichment analysis identified citrate cycle, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism, and phenylalanine metabolism as significantly altered pathways. A greater concentration of plasma isocitric acid and cis-aconitic acid levels was observed in SCHK goats. In addition, AA such as lysine and isoleucine were greater, whereas alanine and phenylacetylglycine were lower in SCHK dairy goats. Dairy goats with SCHK also exhibited greater oleic acid, acylcarnitine, and phosphatidylcholine and lower choline and sphingomyelins. Acylcarnitines, oleic acid, and tridecanoic acid displayed positive correlations with several lipid species. Alanine, hippuric acid, and histidinyl-phenylalanine were negatively correlated with several lipids. Overall, altered metabolites in SCHK dairy goats indicated a more severe degree of negative energy balance. Data also indicated an imbalance in the tricarboxylic acid (TCA) cycle, lipid metabolism, and AA metabolism. The findings provide a more comprehensive understanding of the pathogenesis of SCHK in dairy goats.PMID:37028962 | DOI:10.3168/jds.2022-22812

J Ethnopharmacol. 2023 Apr 5:116392. doi: 10.1016/j.jep.2023.116392. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Coptis chinensis Franch. (CCF), as an extensively used traditional Chinese medicine, has therapeutic effects on Alzheimer's disease (AD), but its mechanism of action has not yet been elucidated.AIM OF THE STUDY: This study aims to reveal the mechanism of action of CCF via the gut-brain axis, and provide a new strategy for the clinical treatment of AD.MATERIALS AND METHODS: APPswe/PS1ΔE9 mice were used as AD models, and were given CCF extract by intragastric administration. Barnes maze was used to test the therapeutic effect of CCF on the treatment of AD. To reveal the mechanism of action of CCF in the treatment of AD, Vanquish Flex UHPLC-orbitrap fusion lumos mass was chosen to detect endogenous differential metabolite; MetaboAnalyst 5.0 was applied to derive relevant metabolic pathways; similarly, to explore the effects of CCF on the gut-brain axis, Vanquish Flex UPLC-Orbitrap fusion lumos mass was utilized to detect the changes in the content of SCFAs in AD mice after CCF administration; the prototype components and metabolites in CCF were identified by UPLC/ESI/qTOF-MS, then their effects on Bifidobacterium breve were explored.RESULTS: CCF shortened the latency time of AD mice, improved the target quadrant ratio of AD mice, and made the maze roadmap simpler of AD mice; CCF regulated fifteen potential metabolites of AD mice, interestingly, ILA (indole-3-lactic acid) in SCFAs (short-chain fatty acids) was also included; CCF acted on histidine and phenylalanine metabolic pathways of AD mice; CCF increased the contents of acetic acid and ILA in AD mice; magnoflorine, jatrorrhizine, coptisine, groenlandicine, thalifendine, palmatine, berberine, epiberberine, hydroxylated jatrorrhizine, and 3-methoxydemethyleneberberine in CCF were detected in fecal samples of AD mice; magnoflorine, palmatrubine, 13-methylberberine, berberine, coptisine, and palmatine promoted the growth of Bifidobacterium breve.CONCLUSIONS: we have demonstrated that CCF acts on the gut-brain axis by regulating SCFAs to treat AD.PMID:37028611 | DOI:10.1016/j.jep.2023.116392

Food Chem. 2023 Mar 31;419:136043. doi: 10.1016/j.foodchem.2023.136043. Online ahead of print.ABSTRACTScutellaria baicalensis is a functional food that has the potential to treat various diseases. Scutellaria baicalensis can be divided into two types: Ziqin (strip types) and (rotten xylem). Ziqin is used to clear lower energizer large intestine heat syndrome, while Kuqin is used for the treatment of upper energizer lung heat syndrome. At present, the substance basis of the differences between Ziqin and Kuqin is not clear. The changes in metabolite accumulation and protein expression between them were analyzed by the non-targeted metabolomic technique in combination with the label-free proteomics approach. The results showed that the differentially accumulated metabolites and abundant proteins were mainly enriched in the pathways of phenylalanine, tyrosine and tryptophan biosynthesis, phenylpropanoid biosynthesis, flavonoid biosynthesis, flavone and flavonol biosynthesis, isoflavonoid biosynthesis, and anthocyanin biosynthesis. Collectively, these results reveal the changes of Scutellaria baicalensis in different growth years and provide a reference for selecting the appropriate harvest period.PMID:37027979 | DOI:10.1016/j.foodchem.2023.136043

Food Chem. 2023 Mar 29;419:136035. doi: 10.1016/j.foodchem.2023.136035. Online ahead of print.ABSTRACTLepidium latifolium L. is an established phytofood of the Ladakh Himalayas that contains differential content of important glucosinolates (GLS) in specific stages of sprouts. Therefore, in order to harness its nutraceutical potential, a comprehensive mass spectrometry-based stage-specific untargeted metabolomic analysis was performed. A total of 318 metabolites were detected, out of which 229 were significantly (p ≤ 0.05) changed during different stages. The Principal Component Analysis plot clearly differentiated different growth stages into three clusters. The nutritionally important metabolites, including amino acids, sugars, organic acids, and fatty acids, were found significantly (p ≤ 0.05) higher in the first cluster consisting of 1st, 2nd and 3rd week sprouts. The higher energy requirements during the early growth stages were observed with the higher metabolites of glycolysis and the TCA cycle. Further, the trade-off between primary and secondary sulfur-containing metabolites was observed, which may explain the differential GLS content in different growth stages.PMID:37027970 | DOI:10.1016/j.foodchem.2023.136035

EBioMedicine. 2023 Apr 5;91:104533. doi: 10.1016/j.ebiom.2023.104533. Online ahead of print.ABSTRACTBACKGROUND: Probiotics have been increasingly proposed for enhancing immune checkpoint blockade (ICB) treatments against cancer. However, its causal relationship with immunotherapeutic efficacy remains unclear, which promoted us to explore if and how probiotic Lacticaseibacillus rhamnosus Probio-M9 manipulates gut microbiome for expected outcomes.METHODS: We evaluated the effects of Probio-M9 on the anti-PD-1 treatment against colorectal cancer in mice via a multi-omics approach. We defined the mechanisms of Probio-M9-mediated antitumor immunity by comprehensive analyses of metagenome and metabolites of commensal gut microbes as well as the immunologic factors and serum metabolome of the host.FINDINGS: The results indicated that Probio-M9 intervention strengthened the anti-PD-1-based tumor inhibition. Both prophylactic and therapeutic administration of Probio-M9 showed conspicuous performance in controlling tumor growth with ICB treatment. The supplement of Probio-M9 modulated enhanced immunotherapy response through promoting beneficial microbes (e.g., Lactobacillus and Bifidobacterium animalis), producing beneficial metabolites including butyric acids in the gut, and accumulating blood-derived α-ketoglutaric acid, N-acetyl-l-glutamic acid and pyridoxine in particular, which promoted the infiltration and activation of cytotoxic T lymphocytes (CTLs) and suppressing the function of regulatory T cells (Tregs) in the tumor microenvironment (TME). Subsequently, we found that enhanced immunotherapeutic response was transmissible by transplanting either post-probiotic-treatment gut microbes or intestinal metabolites to new tumor-bearing mice.INTERPRETATION: This study offered valuable insight into the causal role of Probio-M9 in correcting the defects in gut microbiota that compromised anti-PD-1 therapeutic efficacy, which can be used as an alternative synergetic agent with ICB for clinical cancer treatment.FUNDING: This research was supported by Research Fund for the National Key R&D Program of China (2022YFD2100702), Inner Mongolia Science and Technology Major Projects (2021ZD0014), and China Agriculture Research System of MOF and MARA.PMID:37027929 | DOI:10.1016/j.ebiom.2023.104533

J Hazard Mater. 2023 Apr 3;452:131358. doi: 10.1016/j.jhazmat.2023.131358. Online ahead of print.ABSTRACTHuman activities have led to elevated levels of selenium (Se) in the environment, which poses a threat to ecosystems and human health. Stenotrophomonas sp. EGS12 (EGS12) has been identified as a potential candidate for the bioremediation of repair selenium-contaminated environment because of its ability to efficiently reduce Se(IV) to form selenium nanospheres (SeNPs). To better understand the molecular mechanism of EGS12 in response to Se(IV) stress, a combination of transmission electron microscopy (TEM), genome sequencing techniques, metabolomics and transcriptomics were employed. The results indicated that under 2 mM Se(IV) stress, 132 differential metabolites (DEMs) were identified, and they were significantly enriched in metabolic pathways such as glutathione metabolism and amino acid metabolism. Under the Se(IV) stress of 2 mM, 662 differential genes (DEGs) involved in heavy metal transport, stress response, and toxin synthesis were identified in EGS12. These findings suggest that EGS12 may respond to Se(IV) stress by engaging various mechanisms such as forming biofilms, repairing damaged cell walls/cell membranes, reducing Se(IV) translocation into cells, increasing Se(IV) efflux, multiplying Se(IV) reduction pathways and expelling SeNPs through cell lysis and vesicular transport. The study also discusses the potential of EGS12 to repair Se contamination alone and co-repair with Se-tolerant plants (e.g. Cardamine enshiensis). Our work provides new insights into microbial tolerance to heavy metals and offers valuable information for bio-remediation techniques on Se(IV) contamination.PMID:37027916 | DOI:10.1016/j.jhazmat.2023.131358

Sci Adv. 2023 Apr 7;9(14):eadd4791. doi: 10.1126/sciadv.add4791. Epub 2023 Apr 7.ABSTRACTCells maintain a constant dialog between the extracellular matrix and their plasma membrane to fine tune signal transduction processes. We found that the receptor kinase FERONIA (FER), which is a proposed cell wall sensor, modulates phosphatidylserine plasma membrane accumulation and nano-organization, a key regulator of Rho GTPase signaling in Arabidopsis. We demonstrate that FER is required for both Rho-of-Plant 6 (ROP6) nano-partitioning at the membrane and downstream production of reactive oxygen species upon hyperosmotic stimulus. Genetic and pharmacological rescue experiments indicate that phosphatidylserine is required for a subset of, but not all, FER functions. Furthermore, application of FER ligand shows that its signaling controls both phosphatidylserine membrane localization and nanodomains formation, which, in turn, tunes ROP6 signaling. Together, we propose that a cell wall-sensing pathway controls via the regulation of membrane phospholipid content, the nano-organization of the plasma membrane, which is an essential cell acclimation to environmental perturbations.PMID:37027473 | DOI:10.1126/sciadv.add4791

Cell Rep. 2023 Apr 6;42(4):112335. doi: 10.1016/j.celrep.2023.112335. Online ahead of print.ABSTRACTNeurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.PMID:37027294 | DOI:10.1016/j.celrep.2023.112335

Metabolomics. 2023 Apr 7;19(4):38. doi: 10.1007/s11306-023-01985-0.ABSTRACTINTRODUCTION: Despite their ban, Anabolic Androgenic Steroids (AAS) are considered as the most important threat for equine doping purposes. In the context of controlling such practices in horse racing, metabolomics has emerged as a promising alternative strategy to study the effect of a substance on metabolism and to discover new relevant biomarkers of effect. Based on the monitoring of 4 metabolomics derived candidate biomarkers in urine, a prediction model to screen for testosterone esters abuse was previously developed. The present work focuses on assessing the robustness of the associated method and define its scope of application.MATERIALS AND METHODS: Several hundred urine samples were selected from 14 different horses of ethically approved administration studies involving various doping agents' (AAS, SARMS, β-agonists, SAID, NSAID) (328 urine samples). In addition, 553 urine samples from untreated horses of doping control population were included in the study. Samples were characterized with the previously described LC-HRMS/MS method, with the objective of assessing both its biological and analytical robustness.RESULTS: The study concluded that the measurement of the 4 biomarkers involved in the model was fit for purpose. Further, the classification model confirmed its effectiveness in screening for testosterone esters use; and it demonstrated its ability to screen for the misuse of other anabolic agents, allowing the development of a global screening tool dedicated to this class of substances. Finally, the results were compared to a direct screening method targeting anabolic agents demonstrating complementary performances of traditional and omics approaches in the screening of anabolic agents in horses.PMID:37027080 | DOI:10.1007/s11306-023-01985-0

Mol Cancer Res. 2023 Apr 7:MCR-22-0909. doi: 10.1158/1541-7786.MCR-22-0909. Online ahead of print.ABSTRACTCancer is one of the leading causes of human death. As metabolomics techniques become more and more widely used in cancer research, metabolites are increasingly recognized as crucial factors in both cancer diagnosis and treatment. In this study, we developed MACdb (https://ngdc.cncb.ac.cn/macdb), a curated knowledgebase to recruit the metabolic associations between metabolites and cancers. Unlike conventional data-driven resources, MACdb integrates cancer-metabolic knowledge from extensive publications, providing high quality metabolite associations and tools to support multiple research purposes. In the current implementation, MACdb has integrated 40,710 cancer-metabolite associations, covering 267 traits from 17 categories of cancers with high incidence or mortality, based entirely on manual curation from 1,127 studies reported in 462 publications (screened from 5,153 research papers). MACdb offers intuitive browsing functions to explore associations at multi-dimensions (metabolite, trait, study, and publication), and constructs knowledge graph to provide overall landscape among cancer, trait, and metabolite. Furthermore, NameToCid (map metabolite name to PubChem Cid) and Enrichment tools are developed to help users enrich the association of metabolites with various cancer types and traits. Implications: MACdb paves an informative and practical way to evaluate cancer-metabolite associations and has a great potential to help researchers identify key predictive metabolic markers in cancers.PMID:37027007 | DOI:10.1158/1541-7786.MCR-22-0909

Plant Cell Physiol. 2023 Mar 17:pcad017. doi: 10.1093/pcp/pcad017. Online ahead of print.ABSTRACTAcetylation is one of the most common chemical modifications found on a variety of molecules ranging from metabolites to proteins. Although numerous chloroplast proteins have been shown to be acetylated, the role of acetylation in the regulation of chloroplast functions has remained mainly enigmatic. The chloroplast acetylation machinery in Arabidopsis thaliana consists of eight General control non-repressible 5 (GCN5)-related N-acetyltransferase (GNAT)-family enzymes that catalyze both N-terminal and lysine acetylation of proteins. Additionally, two plastid GNATs have also been reported to be involved in the biosynthesis of melatonin. Here, we have characterized six plastid GNATs (GNAT1, GNAT2, GNAT4, GNAT6, GNAT7 and GNAT10) using a reverse genetics approach with an emphasis on the metabolomes and photosynthesis of the knock-out plants. Our results reveal the impact of GNAT enzymes on the accumulation of chloroplast-related compounds, such as oxylipins and ascorbate, and the GNAT enzymes also affect the accumulation of amino acids and their derivatives. Specifically, the amount of acetylated arginine and proline was significantly decreased in the gnat2 and gnat7 mutants, respectively, as compared to the wild-type Col-0 plants. Additionally, our results show that the loss of the GNAT enzymes results in increased accumulation of Rubisco and Rubisco activase (RCA) at the thylakoids. Nevertheless, the reallocation of Rubisco and RCA did not have consequent effects on carbon assimilation under the studied conditions. Taken together, our results show that chloroplast GNATs affect diverse aspects of plant metabolism and pave way for future research into the role of protein acetylation.PMID:37026998 | DOI:10.1093/pcp/pcad017

Hepatol Commun. 2023 Apr 4;7(4):e0072. doi: 10.1097/HC9.0000000000000072. eCollection 2023 Apr 1.ABSTRACTTo explore the potential mechanisms underlying the effects of a probiotic in cirrhotic patients, we analyzed the blood metabolome using proton nuclear magnetic resonance (1H-NMR) spectroscopy in 32 patients with cirrhosis and cognitive dysfunction or falls. Patients were randomized to receive a multistrain probiotic or placebo for 12 weeks. Among the 54 metabolites identified, the only significant changes in the probiotic group were an increase in glutamine, a decrease in glutamate, and an increase in the glutamine/glutamate ratio. In the placebo group, glutamate increased and the glutamine/glutamate ratio decreased. Our results suggest the multistrain probiotic could influence glutamine/glutamate metabolism, increasing the capacity of ammonia detoxification.PMID:37026745 | DOI:10.1097/HC9.0000000000000072

J Agric Food Chem. 2023 Apr 7. doi: 10.1021/acs.jafc.3c00531. Online ahead of print.ABSTRACTFinding herbicides with new and multiple modes of action is a solution to stop the increase in resistant weed species. Harmaline, a natural alkaloid with proven phytotoxic potential, was tested on Arabidopsis adult plants by watering and spraying; watering resulted as the more effective treatment. Harmaline altered several photosynthetic parameters, reducing the efficiency of the light- (ΦII) and dark-adapted (Fv/Fm) PSII, suggesting physical damages in photosystem II, although dissipation of the energy in excess under the form of heat was not compromised as demonstrated by the significant increase in ΦNPQ. Metabolomic alterations, such as osmoprotectant accumulation and reduction in sugars' content, also indicate a reduction of photosynthetic efficiency and suggest early senescence and water status alteration induced by harmaline. Data suggest that harmaline might be considered a new phytotoxic molecule interesting for further studies.PMID:37026701 | DOI:10.1021/acs.jafc.3c00531

Cancer Discov. 2023 Apr 7:OF1-OF25. doi: 10.1158/2159-8290.CD-22-1220. Online ahead of print.ABSTRACTGenomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting the demise of cells with unrepairable DNA lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig-naling can also favor tumor progression and resistance to therapy. Indeed, DDR signaling in cancer cells has been consistently linked to the inhibition of tumor-targeting immune responses. Here, we discuss the complex interactions between the DDR and inflammation in the context of oncogenesis, tumor progression, and response to therapy.SIGNIFICANCE: Accumulating preclinical and clinical evidence indicates that DDR is intimately connected to the emission of immunomodulatory signals by normal and malignant cells, as part of a cell-extrinsic program to preserve organismal homeostasis. DDR-driven inflammation, however, can have diametrically opposed effects on tumor-targeting immunity. Understanding the links between the DDR and inflammation in normal and malignant cells may unlock novel immunotherapeutic paradigms to treat cancer.PMID:37026695 | DOI:10.1158/2159-8290.CD-22-1220