PubMed

Cell Death Dis. 2023 Jan 11;14(1):14. doi: 10.1038/s41419-022-05529-7.ABSTRACTTP73 is expressed as multiple N- and C-terminal isoforms through two separate promoters or alternative splicing. While N-terminal p73 isoforms have been well studied, very little is known about p73 C-terminal isoforms. Thus, CRISPR was used to delete TP73 Exon13 (E13-KO) to induce p73α to p73β isoform switch. We showed that E13-KO led to decreased cell proliferation and migration and sensitized cells to ferroptosis, which can be reverted by knockdown of TAp73β in E13-KO cells. To understand the biological function of p73β in vivo, we generated a mouse model in that the Trp73 E13 was deleted by CRISPR. We showed that p73α to p73β isoform switch led to increased cellular senescence in mouse embryonic fibroblasts. We also showed that E13-deficient mice exhibited shorter life span and were prone to spontaneous tumors, chronic inflammation and liver steatosis as compared to WT mice. Additionally, we found that the incidence of chronic inflammation and liver steatosis was higher in E13-deficient mice than that in Trp73-deficient mice, suggesting that p73β is a strong inducer of inflammatory response. Mechanistically, we showed that TAp73β was able to induce cysteine dioxygenase 1 (CDO-1), leading to cysteine depletion and subsequently, enhanced ferroptosis and growth suppression. Conversely, knockdown of CDO-1 was able to alleviate the growth suppression and ferroptosis in E13-KO cells. Together, our data suggest that at a physiologically relevant level, TAp73β is a strong inducer of growth suppression but insufficient to compensate for loss of TAp73α in tumor suppression due to aberrant induction of inflammatory response and liver steatosis.PMID:36631448 | DOI:10.1038/s41419-022-05529-7

Physiol Plant. 2023 Jan 11:e13851. doi: 10.1111/ppl.13851. Online ahead of print.ABSTRACTAnthocyanins widely exist in plants and they are important pigments for color of petals and fruits. They are produced through a multi-step pathway controlled by transcription factor complexes. The anthocyanin skeleton modification is the last reaction in the anthocyanin synthesis pathway, which improves the stability of anthocyanins. Acylation modification is an important modification of anthocyanins. However, the identification and function of anthocyanin acyltransferase genes and their expression regulation are rarely reported. In this study, we identified the petunia anthocyanin acyltransferase gene, PhAAT1. PhAAT1 is located in the cytoplasm and PhAAT1 silencing changed flower color and reduced the stability of anthocyanin. Metabolomics analysis showed that PhAAT1 silencing led to the reduction of p-coumaroylated and caffeoylated anthocyanins. In addition, PhAAT1 was positively regulated by the MYB transcription factor, PhAN2, which directly interacts with the promoter of PhAAT1.PMID:36631431 | DOI:10.1111/ppl.13851

Redox Biol. 2023 Jan 2;59:102600. doi: 10.1016/j.redox.2023.102600. Online ahead of print.ABSTRACTCurrent treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high-resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke.PMID:36630820 | DOI:10.1016/j.redox.2023.102600

ACS Chem Biol. 2023 Jan 11. doi: 10.1021/acschembio.2c00587. Online ahead of print.ABSTRACTPhotoreactive fragment-like probes have been applied to discover target proteins that constitute novel cellular vulnerabilities and to identify viable chemical hits for drug discovery. Through forming covalent bonds, functionalized probes can achieve stronger target engagement and require less effort for on-target mechanism validation. However, the design of probe libraries, which directly affects the biological target space that is interrogated, and effective target prioritization remain critical challenges of such a chemical proteomic platform. In this study, we designed and synthesized a diverse panel of 20 fragment-based probes containing natural product-based privileged structural motifs for small-molecule lead discovery. These probes were fully functionalized with orthogonal diazirine and alkyne moieties and used for protein crosslinking in live lung cancer cells, target enrichment via "click chemistry," and subsequent target identification through label-free quantitative liquid chromatography-tandem mass spectrometry analysis. Pair-wise comparison with a blunted negative control probe and stringent prioritization via individual cross-comparisons against the entire panel identified glutathione S-transferase zeta 1 (GSTZ1) as a specific and unique target candidate. DepMap database query, RNA interference-based gene silencing, and proteome-wide tyrosine reactivity profiling suggested that GSTZ1 cooperated with different oncogenic alterations by supporting survival signaling in refractory non-small cell lung cancer cells. This finding may form the basis for developing novel GSTZ1 inhibitors to improve the therapeutic efficacy of oncogene-directed targeted drugs. In summary, we designed a novel fragment-based probe panel and developed a target prioritization scheme with improved stringency, which allows for the identification of unique target candidates, such as GSTZ1 in refractory lung cancer.PMID:36630201 | DOI:10.1021/acschembio.2c00587

Cell Mol Life Sci. 2023 Jan 11;80(2):39. doi: 10.1007/s00018-022-04629-z.ABSTRACTNon-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis.PMID:36629912 | DOI:10.1007/s00018-022-04629-z

Anal Chem. 2023 Jan 11. doi: 10.1021/acs.analchem.2c04316. Online ahead of print.ABSTRACTOn-tissue chemical derivatization combined with mass spectrometry imaging (MSI) can effectively visualize low-abundance and poorly ionizable molecules in biological tissues. Owing to the lack of an effective chemical reaction environment on the tissue surface, the development of direct one-step derivatization reactions is challenging. Herein, we present a two-step reaction involving on-tissue chemical oxidation followed by derivatization combined with airflow-assisted desorption electrospray ionization-MSI, enabling the visualization of primary and secondary hydroxyl-containing metabolites (PSHMs) within the tissue sections. This method indirectly achieved on-tissue derivatization by combining two reactions. Hydroxyl was converted to carbonyl using chemical oxidants, and subsequently, carbonyl was derived using Girard's P reagent. Using this methodology, 169 PSHMs, including hydroxy fatty acids (OH-FAs), fatty alcohols (FOHs), and sterol lipids, were detected and imaged in the tissues of rat brain, kidney, and liver. Moreover, we found that the abundant PSHMs, fatty aldehydes, and oxo fatty acids were significantly dysregulated in the liver and kidney tissues of type 2 diabetic rats; in particular, OH-FAs and FOHs were remarkably up-regulated in the diabetic rat liver tissues. The aberrations of these oxidative metabolites provide insights into the understanding of the molecular pathological mechanism of diabetes. This study demonstrates a novel, two-step reaction strategy for on-tissue derivatization with the analysis of previously inaccessible molecules using MSI.PMID:36629515 | DOI:10.1021/acs.analchem.2c04316

FEBS J. 2023 Jan 11. doi: 10.1111/febs.16724. Online ahead of print.ABSTRACTCyclic di-AMP is an essential signaling molecule in Gram-positive bacteria. This second messenger regulates the osmotic pressure of the cell by interacting directly with the regulatory domains, either RCK_C or CBS domains, of several potassium and osmolyte uptake membrane protein systems. Cyclic di-AMP also targets stand-alone CBS domain proteins such as DarB in Bacillus subtilis and CbpB in Listeria monocytogenes. We show here that the CbpB protein of Group B Streptococcus binds c-di-AMP with a very high affinity. Crystal structures of CbpB reveal the determinants of binding specificity and significant conformational changes occurring upon c-di-AMP binding. Deletion of the cbpB gene alters bacterial growth in low potassium conditions most likely due to a decrease in the amount of ppGpp caused by a loss of interaction between CbpB and Rel, the GTP/GDP pyrophosphokinase.PMID:36629470 | DOI:10.1111/febs.16724

mSphere. 2023 Jan 11:e0045222. doi: 10.1128/msphere.00452-22. Online ahead of print.ABSTRACTIn reproductive-age women, the vaginal microbiome is typically dominated by one or a few Lactobacillus species, including Lactobacillus crispatus, Lactobacillus iners, Lactobacillus paragasseri, Lactobacillus mulieris, and Lactobaccillus crispatus, has been associated with optimal cervicovaginal health; however, much is still unknown about how other lactobacilli metabolically contribute to cervicovaginal health. We hypothesized that metabolites of each Lactobacillus species differ and uniquely contribute to health and homeostasis. To address this hypothesis, we utilized a human three-dimensional (3D) cervical epithelial cell model in conjunction with genomics analyses and untargeted metabolomics to determine the metabolic contributions of less-studied vaginal lactobacilli-L. iners, L. paragasseri, and L. mulieris. Our study validated that vaginal lactobacilli exhibit a close phylogenetic relationship. Genomic findings from publicly available strains and those used in our study indicated that L. iners is metabolically distinct from other species of lactobacilli, likely due to a reduced genome size. Lactobacilli and mock controls were distinguishable based on global metabolic profiles. We identified 95 significantly altered metabolites (P < 0.05) between individual lactobacilli and mock controls. Metabolites related to amino acid metabolism were shared among the lactobacilli. N-Acetylated amino acids with potential antimicrobial properties were significantly elevated in a species-specific manner. L. paragasseri and L. iners shared aromatic, but not carbohydrate-derived, lactic acid metabolites with potential antimicrobial properties that may contribute to homeostasis of the cervicovaginal environment. Additionally, L. iners uniquely altered lipid metabolism, which may be a sign of adaptation to the cervicovaginal niche. Overall, these findings further elucidate the metabolic contributions of three key vaginal Lactobacillus species in gynecological health. IMPORTANCE Lactobacillus species contribute to cervicovaginal health by their production of lactic acid and other antimicrobial compounds. Yet, much is still unknown regarding the metabolic potential of lesser-studied but common vaginal lactobacilli. Here, we used untargeted metabolomics coupled with our 3D cervical epithelial cell model to identify metabolic differences among vaginal Lactobacillus species (Lactobacillus iners, Lactobacillus paragasseri, and Lactobacillus mulieris) and how those differences related to maintaining homeostasis of the cervical epithelium. Human 3D cell models are essential tools for studying host-bacteria interactions and reducing confounding factors inherent in clinical studies. Therefore, these unique models allowed us to decipher the putative lactobacilli mechanisms that contribute to their roles in health or disease. Metabolic analyses revealed distinct profiles of each Lactobacillus species but also shared metabolic contributions associated with antimicrobial activity: amino acid metabolism, N-acetylated amino acids, and aromatic lactic acids. These patterns provided validation of metabolites associated with health in clinical studies and provided novel targets, including immunomodulatory and antimicrobial metabolites, for postbiotic therapies.PMID:36629413 | DOI:10.1128/msphere.00452-22

Food Chem. 2022 Dec 29;410:135360. doi: 10.1016/j.foodchem.2022.135360. Online ahead of print.ABSTRACTThe aim of this paper is to provide a detailed characterisation of grape lipidome. To achieve this objective, it starts by describing a pipeline implemented in R software to allow the semi-automatic annotation of the detected lipid species. It also provides an extensive description of the different properties of each molecule (such as retention time dependencies, mass accuracy, adduct formation and fragmentation patterns), which allowed the annotations to be made more accurately. Most annotated lipids in the grape samples were (lyso)glycerophospholipids and glycerolipids, although a few free fatty acids, hydroxyceramides and sitosterol esters were also observed. The proposed pipeline also allowed the identification of a series of methylated glycerophosphates never previously observed in grapes. The current results highlight the importance of expanding chemical analyses beyond the classical lipid categories.PMID:36628919 | DOI:10.1016/j.foodchem.2022.135360

Ecotoxicol Environ Saf. 2023 Jan 9;251:114515. doi: 10.1016/j.ecoenv.2023.114515. Online ahead of print.ABSTRACTRice seedlings were exposed to two CO2 concentrations (400 ± 20 and 800 ± 20 μmol mol-1) and three PbNO3 concentrations (0, 50 and 100 µmol L-1) for 10 days to explore the regulatory mechanisms of elevated CO2 for Pb stress resistance. Electrical conductivity, MDA content, SOD, POD, CAT activities and metabolomics changes were studied. Results showed that: Pb stress damaged cell membrane system, electrical conductivity and MDA content increased 49.34 % and 73.27 %, respectively, and some antioxidant enzymes activities increased. Sugar, polyol, amino acid metabolism and fatty acid β-oxidation were all enhanced to improve osmotic adjustments, maintain cell membrane stability, supply energy, nitrogen assimilates and antioxidant capacity; Under composite treatments, cell membrane damage was reduced, activities of protective enzymes increased compared with only Pb stress, POD activity increased the most (49.14 %) under severe Pb composite treatment. High CO2 caused the enhance of cells antioxidant capacity, TCA cycle intermediate products contents and fatty acid desaturation under mild Pb stress. Many sugars, polyols and amino acids contents were increased as osmotic regulatory substances by high CO2 under severe Pb stress; Secondary metabolites played an important role under Pb stress and composite treatments. The object of this study is to provide a possible molecular mechanism of rice response to Pb stress under high CO2 in the future.PMID:36628876 | DOI:10.1016/j.ecoenv.2023.114515

Anal Chim Acta. 2023 Jan 25;1239:340691. doi: 10.1016/j.aca.2022.340691. Epub 2022 Dec 1.ABSTRACTBile acids (BAs) are a class of vital gut microbiota-host cometabolites, and they play an important role in maintaining gut microbiota-host metabolic homeostasis. Very recently, a new mechanism of BA anabolic metabolism mediated by gut microbiota (BA-amino acid conjugation) has been revealed, which provides a perspective for the research on BA metabolism and gut metabolome. In this study, we established a polarity-switching multiple reaction monitoring mass spectrometry-based screening method to mine amino acid-conjugated bile acids (AA-BAs) derived from host-gut microbiota co-metabolism. In addition, a retention time-based annotation strategy was further proposed to identify the AA-BA isomers and epimers. Using the developed methods, we successfully screened 118 AA-BA conjugates from mouse and human feces, 28 of them were confirmed by standards, and 62 putatively identified based on their predicted retention times. Moreover, we observed that the levels of most AA-BAs were significantly downregulated in the feces of chronic sleep deprivation mice, suggesting that the AA-BA metabolism was closely related to the physiological state of the host.PMID:36628759 | DOI:10.1016/j.aca.2022.340691

Anal Chim Acta. 2023 Jan 25;1239:340650. doi: 10.1016/j.aca.2022.340650. Epub 2022 Nov 21.ABSTRACTThe application of dried blood spots (DBS) has gradually increased in different fields because of its several advantages. The hematocrit (Hct) effect is one major analytical challenge that may affect the quantification accuracy of DBS samples and should be investigated when developing a novel DBS method. However, previous studies usually overlooked the Hct-related distribution bias when evaluating the Hct effect. This study aimed to propose an effective DBS preparation protocol for the comprehensive evaluation of the Hct effect. We selected voriconazole and posaconazole as the demonstration drugs. Fifteen microliters of the blood samples were spotted on DBS cards followed by whole spot extraction. An LC-MS/MS method was first developed to quantify voriconazole and posaconazole in DBS samples. The quantitation accuracy for both azole drugs was within 93.5%-111.7%, except for the accuracies of posaconazole at the LLOQ, which were less than 119%. The intra- and interday precision were below 11%. The validated LC-MS/MS method was used to develop the DBS preparation protocol for evaluating the Hct effect. Three critical parameters that may affect the observed Hct effect were investigated. The results showed that using the solid-state of the target analytes, spiking the target analytes before preparing different Hct levels, and allowing enough equilibrium time after spiking target analytes can provide a more holistic Hct effect evaluation. The validity of the proposed new protocol was verified by conversion factors obtained from 71 paired DBS and plasma samples. Conversion factors calculated by clinical samples were consistent with the Hct effect evaluated by manually prepared DBS samples. This new DBS preparation protocol eliminated the common pitfalls in studying the Hct effect and offered a comprehensive strategy to assess the Hct effect for further DBS studies.PMID:36628747 | DOI:10.1016/j.aca.2022.340650

Anal Chim Acta. 2023 Jan 25;1239:340739. doi: 10.1016/j.aca.2022.340739. Epub 2022 Dec 25.ABSTRACTThe research on antibiotics occurrence in the aquatic environment has become a hot topic in the last years due to their potential negative effects, associated to possible bacterial antibiotic-resistance, after continuous exposure to these compounds. Most of antibiotic residues are not completely removed in the wastewater treatment plants (WWTPs) and end up in the aquatic environment through treated wastewater (WW). The development of reliable analytical methodologies for the determination of antibiotics in influent (IWW) and effluent wastewater (EWW) is needed with different purposes, among others: monitoring their occurrence in the aquatic environment, performing environmental risk assessment, estimating removal efficiencies of WWTPs, or estimating the consumption of these compounds. In this paper, we perform an in-depth investigation on analytical key issues that pose difficulties in the determination of antibiotics in complex matrices, such as WW, and we identify challenges to be properly addressed for successful analysis. The analytical technique selected was liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), as it is the most powerful and widely applied at present for antibiotic residues determination. The mass spectrometric behavior of 18 selected antibiotics, the chromatographic performance, ion ratio variations associated to the sample matrix when using different precursor ions or protomers, and the macrolides adsorption to glass vial, were some of the issues studied in this work. On the basis of the detailed study performed, an analytical LC-MS/MS method based on sample direct injection has been developed for quantification of 18 antibiotics in IWW and EWW, allowing their determination at low ng L-1 levels.PMID:36628733 | DOI:10.1016/j.aca.2022.340739

G3 (Bethesda). 2023 Jan 11:jkad005. doi: 10.1093/g3journal/jkad005. Online ahead of print.ABSTRACTEnzymes of one-carbon metabolism play pivotal roles in proliferating cells. They are involved in the metabolism of amino acids, nucleotides, and lipids and the supply of all cellular methylations. However, there is limited information about how these enzymes are regulated during cell division and how cell cycle kinetics are affected in several loss-of-function mutants of one-carbon metabolism. Here, we report that the levels of the S. cerevisiae enzymes Ade17p and Cho2p, involved in the de novo synthesis of purines and phosphatidylcholine, respectively, are cell cycle-regulated. Cells lacking Ade17p, Cho2p, or Shm2p (an enzyme that supplies one-carbon units from serine) have distinct alterations in size homeostasis and cell cycle kinetics. Loss of Ade17p leads to a specific delay at START, when cells commit to a new round of cell division, while loss of Shm2p has broader effects, reducing growth rate. Furthermore, the inability to synthesize phosphatidylcholine de novo in cho2Δ cells delays START and reduces the coherence of nuclear elongation late in the cell cycle. Loss of Cho2p also leads to profound metabolite changes. Besides the expected changes in the lipidome, cho2Δ cells have reduced levels of amino acids, resembling cells shifted to poorer media. These results reveal the different ways that one-carbon metabolism allocates resources to affect cell proliferation at multiple cell cycle transitions.PMID:36627750 | DOI:10.1093/g3journal/jkad005

BMC Med. 2023 Jan 11;21(1):17. doi: 10.1186/s12916-022-02685-7.ABSTRACTBACKGROUND: Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming.METHODS: Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings.RESULTS: Forty-seven CpGs were associated with rapid weight growth at suggestive p-value <1e-05 and, among them, three CpGs (cg14459032, cg25953130 annotated to ARID5B, and cg00049440 annotated to KLF9) passed the genome-wide significance level (p-value <1.25e-07). Sixteen differentially methylated regions (DMRs) were identified as associated with rapid weight growth at false discovery rate (FDR)-adjusted/Siddak p-values < 0.01. Gestational age acceleration was associated with decreasing risk of rapid weight growth (p-value = 9.75e-04). Identified DNA methylation signals slightly increased the prediction of rapid weight growth in addition to conventional risk factors. Among the identified signals, three CpGs partially mediated the effect of gestational age on rapid weight growth. Both CpGs (N=3) and DMRs (N=3) were associated with differential expression of transcripts (N=10 and 7, respectively), including long non-coding RNAs. An AURKC DMR was associated with childhood overweight. We observed enrichment of CpGs previously reported associated with birthweight.CONCLUSIONS: Our findings provide evidence of the association between cord blood DNA methylation and rapid weight growth and suggest links with prenatal exposures and association with childhood obesity providing opportunities for early prevention.PMID:36627699 | DOI:10.1186/s12916-022-02685-7

Cell Biosci. 2023 Jan 11;13(1):6. doi: 10.1186/s13578-023-00956-1.ABSTRACTOBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare acquired immune-mediated neuropathy. Although microbial infection is potentially a contributing factor, a causative link between CIDP and microbial infection remains unclear. There is also no definitive biomarker for CIDP diagnostics and therapies. The present study aimed to characterize the serum metabolic profile and gut microbiome structure in CIDP.METHODS: Targeted metabolomics profiling of serum, using liquid chromatography-mass spectrometry, and metagenomics sequencing of stool samples from a cohort of CIDP and non-CIDP subjects were performed to evaluate serum metabolic profiles and gut microbiome structure in CIDP subjects relative to healthy controls.RESULTS: Metabolome data revealed that the bile acids profile was perturbed in CIDP with bile acids and arachidonic acid enriched significantly in CIDP versus non-CIDP controls. Metagenome data revealed that opportunistic pathogens, such as Klebsiella pneumonia and Megamonas funiformis, and genes involved in bacterial infection were notably more abundant in CIDP subjects, while gut microbes related to biotransformation of secondary bile acids were abnormal in CIDP versus non-CIDP subjects. Correlation analysis revealed that changes in secondary bile acids were associated with altered gut microbes, including Bacteroides ovatus, Bacteroides caccae, and Ruminococcus gnavus.CONCLUSION: Bile acids and arachidonic acid metabolism were disturbed in CIDP subjects and might be affected by the dysbiosis of gut microbial flora. These findings suggest that the combination of bile acids and arachidonic acid could be used as a CIDP biomarker and that modulation of gut microbiota might impact the clinical course of CIDP.PMID:36627678 | DOI:10.1186/s13578-023-00956-1

Sci Rep. 2023 Jan 10;13(1):493. doi: 10.1038/s41598-022-27131-9.ABSTRACTFaecal or biopsy samples are frequently used to analyse the gut microbiota, but issues remain with the provision and collection of such samples. Rectal swabs are widely-utilised in clinical practice and previous data demonstrate their potential role in microbiota analyses; however, studies to date have been heterogenous, and there are a particular lack of data concerning the utility of swabs for the analysis of the microbiota's functionality and metabolome. We compared paired stool and rectal swab samples from healthy individuals to investigate whether rectal swabs are a reliable proxy for faecal sampling. There were no significant differences in key alpha and beta diversity measures between swab and faecal samples, and inter-subject variability was preserved. Additionally, no significant differences were demonstrated in abundance of major annotated phyla. Inferred gut functionality using Tax4Fun2 showed excellent correlation between the two sampling techniques (Pearson's coefficient r = 0.9217, P < 0.0001). Proton nuclear magnetic resonance (1H NMR) spectroscopy enabled the detection of 20 metabolites, with overall excellent correlation identified between rectal swab and faecal samples for levels all metabolites collectively, although more variable degrees of association between swab and stool for levels of individual metabolites. These data support the utility of rectal swabs in both compositional and functional analyses of the gut microbiota.PMID:36627399 | DOI:10.1038/s41598-022-27131-9

Pediatr Res. 2023 Jan 10. doi: 10.1038/s41390-022-02449-2. Online ahead of print.ABSTRACTBACKGROUND: The metabolomics profiles of maternal plasma during pregnancy and cord plasma at birth might influence fetal growth and birth anthropometry. The objective was to examine how maternal plasma and umbilical cord plasma metabolites are associated with newborn anthropometric measures, a known predictor of future health outcomes.METHODS: Pregnant women between 24 and 28 weeks of gestation were recruited as part of a prospective cohort study. Blood samples from 413 women at enrollment and 787 infant cord blood samples were analyzed using the Biocrates AbsoluteIDQ® p180 kit. Multivariable linear regression models were used to examine associations of cord and maternal metabolites with infant anthropometry at birth.RESULTS: In cord blood samples from this rural cohort from New Hampshire of largely white residents, 13 metabolites showed negative associations, and 10 metabolites showed positive associations with birth weight Z-score. Acylcarnitine C5 showed negative association, and 4 lysophosphatidylcholines showed positive associations with birth length Z-score. Maternal blood metabolites did not significantly correlate with birth weight and length Z-scores.CONCLUSIONS: Consistent findings were observed for several acylcarnitines that play a role in utilization of energy sources, and a lysophosphatidylcholine that is part of oxidative stress and inflammatory response pathways in cord plasma samples.IMPACT: The metabolomics profiles of maternal plasma during pregnancy and cord plasma at birth may influence fetal growth and birth anthropometry. This study examines the independent effects of maternal gestational and infant cord blood metabolomes across different classes of metabolites on birth anthropometry. Acylcarnitine species were negatively associated and glycerophospholipids species were positively associated with weight and length Z-scores at birth in the cord plasma samples, but not in the maternal plasma samples. This study identifies lipid metabolites in infants that possibly may affect early growth.PMID:36627359 | DOI:10.1038/s41390-022-02449-2

Gut. 2023 Jan 10:gutjnl-2022-328406. doi: 10.1136/gutjnl-2022-328406. Online ahead of print.ABSTRACTOBJECTIVE: Gestational diabetes mellitus (GDM) is a condition in which women without diabetes are diagnosed with glucose intolerance during pregnancy, typically in the second or third trimester. Early diagnosis, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing incidence and associated short-term and long-term morbidities.DESIGN: We comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy, before GDM diagnosis. We then built a model that can predict GDM onset weeks before it is typically diagnosed. Further, we demonstrated the role of the microbiome in disease using faecal microbiota transplant (FMT) of first trimester samples from pregnant women across three unique cohorts.RESULTS: We found elevated levels of proinflammatory cytokines in women who later developed GDM, decreased faecal short-chain fatty acids and altered microbiome. We next confirmed that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin resistance more than 10 weeks prior to GDM diagnosis using FMT experiments. Following these observations, we used a machine learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers with high accuracy.CONCLUSION: GDM onset can be identified in the first trimester of pregnancy, earlier than currently accepted. Furthermore, the gut microbiome appears to play a role in inflammation-induced GDM pathogenesis, with interleukin-6 as a potential contributor to pathogenesis. Potential GDM markers, including microbiota, can serve as targets for early diagnostics and therapeutic intervention leading to prevention.PMID:36627187 | DOI:10.1136/gutjnl-2022-328406

Environ Pollut. 2023 Jan 7:121049. doi: 10.1016/j.envpol.2023.121049. Online ahead of print.ABSTRACTEnvironmental sources of chromium (Cr) such as solid waste, battery chemicals, automotive exhaust emissions, mineral mining, fertilizers, and pesticides, have detrimental effects on plants. An excessive amount of Cr exposure can lead to toxic accumulations in human, animal, and plant tissues. In plants, diverse signaling molecules like hydrogen sulfide (H2S) and nitric oxide (NO) play multiple roles during Cr stress. Consequently, the molecular mechanisms of Cr toxicity in plants, such as metal binding, modifying enzyme activity, and damaging cells are examined by several studies. The reactive oxygen species (ROS) that are formed when Cr reacts with lipids, membranes, DNA, proteins, and carbohydrates are all responsible for damage caused by Cr. ROS regulate plant growth, programmed cell death (PCD), cell cycle, pathogen defense, systemic communication, abiotic stress responses, and growth. Plants accumulate Cr mostly through the root system, with very little movement to the shoots. The characterization of stress-inducible proteins and metabolites involved in Cr tolerance and cross-talk messengers has been made possible due to recent advances in metabolomics, transcriptomics, and proteomics. In this review article, we discussed Cr absorption, translocation, subcellular distribution in plants, and cross-talk between secondary messengers as a mechanism for Cr toxicity and tolerance. To mitigate this problem, soil-plant systems need to be monitored for the biogeochemical behavior of Cr and the identification of secondary messengers in plants.PMID:36627046 | DOI:10.1016/j.envpol.2023.121049