PubMed

Commun Biol. 2024 Aug 14;7(1):990. doi: 10.1038/s42003-024-06680-x.ABSTRACTWhile circulating metabolites and immune system have been increasingly linked to hypothyroidism risk, the causality underlying these associations remains largely uninterrogated. We used Mendelian randomization to identified putative causal traits for hypothyroidism via integrating omics data. Briefly, we utilized 1180 plasma metabolites and 731 immune cells traits as exposures to identify putatively causal traits for hypothyroidism in the discovery (40,926 cases) and replication cohorts (14,871 cases). By combining MR results from two large-scale cohorts, we ultimately identified 21 putatively causal traits, including five plasma metabolites and 16 immune cell traits. CD3 on CD28+ CD4+ T cell and 1-(1-enyl-palmitoyl)-2-oleoyl-GPE (p-16:0/18:1) demonstrated the most pronounced positive and negative associations with hypothyroidism risk, respectively. The odds ratio and 95% confidence interval were 1.09 (1.07, 1.12) and 0.81 (0.75, 0.87), respectively. No evidence of horizontal pleiotropy, heterogeneity among instrumental variables or reverse causation were found for these 21 significant associations. Our study elucidates key metabolites and immune cell traits associated with hypothyroidism. These findings provide new insights into the etiology and potential therapeutic targets for hypothyroidism.PMID:39143378 | DOI:10.1038/s42003-024-06680-x

Nat Microbiol. 2024 Aug 14. doi: 10.1038/s41564-024-01746-2. Online ahead of print.ABSTRACTThe bloom and bust patterns of microalgae in aquatic systems contribute massively to global biogeochemical cycles. The decline of algal blooms is mainly caused by nutrient limitation resulting in cell death, the arrest of cell division and the aging of surviving cells. Nutrient intake can re-initiate proliferation, but the processes involved are poorly understood. Here we characterize how the bloom-forming diatom Coscinodiscus radiatus recovers from starvation after nutrient influx. Rejuvenation is mediated by extracellular vesicles that shuttle reactive oxygen species, oxylipins and other harmful metabolites out of the old cells, thereby re-enabling their proliferation. By administering nutrient pulses to aged cells and metabolomic monitoring of the response, we show that regulated pathways are centred around the methionine cycle in C. radiatus. Co-incubation experiments show that bacteria mediate aging processes and trigger vesicle production using chemical signalling. This work opens new perspectives on cellular aging and rejuvenation in complex microbial communities.PMID:39143356 | DOI:10.1038/s41564-024-01746-2

Metabolomics. 2024 Aug 14;20(5):99. doi: 10.1007/s11306-024-02162-7.ABSTRACTBACKGROUND: The incidence of gallstones is high in Qinghai Province. However, the molecular mechanisms underlying the development of gallstones remain unclear.METHODS: In this study, we collected urine samples from 30 patients with gallstones and 30 healthy controls. The urine samples were analysed using multi-omics platforms. Proteomics analysis was conducted using data-independent acquisition, whereas metabolomics analysis was performed using liquid chromatography-mass spectrometry (LC-MS).RESULTS: Among the patients with gallstones, we identified 49 down-regulated and 185 up-regulated differentially expressed proteins as well as 195 up-regulated and 189 down-regulated differentially expressed metabolites. Six pathways were significantly enriched: glycosaminoglycan degradation, arginine and proline metabolism, histidine metabolism, pantothenate and coenzyme A biosynthesis, drug metabolism-other enzymes, and the pentose phosphate pathway. Notably, 10 differentially expressed proteins and metabolites showed excellent predictive performance and were selected as potential biomarkers.CONCLUSION: The findings of our metabolomics and proteomics analyses provide new insights into novel biomarkers for patients with cholelithiasis in high-altitude areas.PMID:39143352 | DOI:10.1007/s11306-024-02162-7

Nature. 2024 Aug 14. doi: 10.1038/s41586-024-07781-7. Online ahead of print.ABSTRACTFasting is associated with a range of health benefits1-6. How fasting signals elicit changes in the proteome to establish metabolic programmes remains poorly understood. Here we show that hepatocytes selectively remodel the translatome while global translation is paradoxically downregulated during fasting7,8. We discover that phosphorylation of eukaryotic translation initiation factor 4E (P-eIF4E) is induced during fasting. We show that P-eIF4E is responsible for controlling the translation of genes involved in lipid catabolism and the production of ketone bodies. Inhibiting P-eIF4E impairs ketogenesis in response to fasting and a ketogenic diet. P-eIF4E regulates those messenger RNAs through a specific translation regulatory element within their 5' untranslated regions (5' UTRs). Our findings reveal a new signalling property of fatty acids, which are elevated during fasting. We found that fatty acids bind and induce AMP-activated protein kinase (AMPK) kinase activity that in turn enhances the phosphorylation of MAP kinase-interacting protein kinase (MNK), the kinase that phosphorylates eIF4E. The AMPK-MNK-eIF4E axis controls ketogenesis, revealing a new lipid-mediated kinase signalling pathway that links ketogenesis to translation control. Certain types of cancer use ketone bodies as an energy source9,10 that may rely on P-eIF4E. Our findings reveal that on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth. Thus, our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer.PMID:39143206 | DOI:10.1038/s41586-024-07781-7

Sci Rep. 2024 Aug 14;14(1):18867. doi: 10.1038/s41598-024-69805-6.ABSTRACTKetamine has recently become an anesthetic drug used in human and veterinary clinical medicine for illicit abuse worldwide, but the detection of illicit abuse and inference of time intervals following ketamine abuse are challenging issues in forensic toxicological investigations. Here, we developed methods to estimate time intervals since ketamine use is based on significant metabolite changes in rat serum over time after a single intraperitoneal injection of ketamine, and global metabolomics was quantified by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Thirty-five rats were treated with saline (control) or ketamine at 3 doses (30, 60, and 90 mg/kg), and the serum was collected at 21 time points (0 h to 29 d). Time-dependent rather than dose-dependent features were observed. Thirty-nine potential biomarkers were identified, including ketamine and its metabolites, lipids, serotonin and other molecules, which were used for building a random forest model to estimate time intervals up to 29 days after ketamine treatment. The accuracy of the model was 85.37% in the cross-validation set and 58.33% in the validation set. This study provides further understanding of the time-dependent changes in metabolites induced by ketamine abuse.PMID:39143187 | DOI:10.1038/s41598-024-69805-6

Sci Rep. 2024 Aug 14;14(1):18879. doi: 10.1038/s41598-024-67588-4.ABSTRACTVitamin D deficiency is increasingly common in systemic lupus erythematosus (SLE) patients and is associated with the disease activity and proteinuria. Recently, alterations in metabolism have been recognized as key regulators of SLE pathogenesis. Our objective was to identify differential metabolites in the serum metabolome of SLE with vitamin D deficiency. In this study, serum samples from 31 SLE patients were collected. Levels of 25(OH)D3 were assayed by ELISA. Patients were divided into two groups according to their vitamin D level (20 ng/ml). Untargeted metabolomics were used to study the metabolite profiles in serum by high-performance liquid chromatography-tandem mass spectrometry. Subsequently, we performed metabolomics profiling analysis to identify 52 significantly altered metabolites in vitamin D deficient SLE patients. The area under the curve (AUC) from ROC analyses was calculated to assess the diagnostic potential of each candidate metabolite biomarker. Lipids accounted for 66.67% of the differential metabolites in the serum, highlighted the disruption of lipid metabolism. The 52 differential metabolites were mapped to 27 metabolic pathways, with fat digestion and absorption, as well as lipid metabolism, emerging as the most significant pathways. The AUC of (S)-Oleuropeic acid and 2-Hydroxylinolenic acid during ROC analysis were 0.867 and 0.833, respectively, indicating their promising diagnostic potential. In conclusion, our results revealed vitamin D deficiency alters SLE metabolome, impacting lipid metabolism, and thrown insights into the pathogenesis and diagnosis of SLE.PMID:39143130 | DOI:10.1038/s41598-024-67588-4

J Adv Res. 2024 Aug 12:S2090-1232(24)00359-X. doi: 10.1016/j.jare.2024.08.016. Online ahead of print.ABSTRACTINTRODUCTION: Intracerebral haemorrhage (ICH) is a devastating disease that leads to severe neurological deficits. Microglia are the first line of defence in the brain and play a crucial role in neurological recovery after ICH, whose activities are primarily driven by glucose metabolism. However, little is known regarding the status of glucose metabolism in microglia and its interactions with inflammatory responses after ICH.OBJECTIVES: This study investigated microglial glycolysis and its mechanistic effects on microglial inflammation after ICH.METHODS: We explored the status of glucose metabolism in the ipsilateral region and in fluorescence-activated-cell-sorting-isolated (FACS-isolated) microglia via 2-deoxy-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) analyses and gamma emission, respectively. Energy-related targeted metabolomics, along with 13C-glucose isotope tracing, was utilised to analyse glycolytic products in microglia. Mitochondrial membrane potential and mitochondrial reactive oxygen species (MitoROS) accumulation was assessed by flow cytometry. Behavioural, western blotting, gene regulation, and enzymatic activity analyses were conducted with a focus on microglia.RESULTS: Neurological dysfunction was strongly correlated with decreased FDG-PET signals in the perihaematomal region, where microglial uptake of FDG was reduced. The decreased quantity of glucose-6-phosphate (G-6-P) in microglia was attributed to the downregulation of glucose transporter 1 (GLUT1) and hexokinase 2 (HK2). Enhanced inflammatory responses were driven by HK2 suppression via decreased mitochondrial membrane potential, which could be rescued by MitoROS scavengers. HK inhibitors aggravated neurological injury by suppressing FDG uptake and enhancing microglial inflammation in ICH mice.CONCLUSION: These findings indicate an unexpected metabolic status in pro-inflammatory microglia after ICH, consisting of glycolysis impairment caused by the downregulation of GLUT1 and HK2. Additionally, HK2 suppression promotes inflammatory responses by disrupting mitochondrial function, providing insight into the mechanisms by which inflammation may be facilitated after ICH and indicating that metabolic enzymes as potential targets for ICH treatment.PMID:39142439 | DOI:10.1016/j.jare.2024.08.016

Food Chem. 2024 Jul 30;460(Pt 3):140663. doi: 10.1016/j.foodchem.2024.140663. Online ahead of print.ABSTRACTGestational diabetes mellitus (GDM) is a prevalent metabolic disorder during pregnancy that alters the metabolites in human milk. Integrated Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography-Mass Spectrometry (LC-MS) were employed for comprehensive identification and comparison of metabolites in mature human milk (MHM) from women with and without GDM. A total of 268 differentially expressed metabolites (DEMs) were identified. Among these, linoleic acid, arachidonic acid, 9R-HODE and L-glutamic acid were significantly elevated and 12,13-DHOME was significantly decreased in MHM of women with GDM. These metabolites are significantly enriched in linoleic acid metabolism, fatty acid biosynthesis, galactose metabolism and ABC transporters pathways. Disorders in these metabolic pathways are associated with insulin resistance and poor glucose metabolism indicating these conditions may persist postpartum.PMID:39142199 | DOI:10.1016/j.foodchem.2024.140663

J Chromatogr A. 2024 Aug 6;1732:465230. doi: 10.1016/j.chroma.2024.465230. Online ahead of print.ABSTRACTUntargeted metabolomics by LCHRMS is a powerful tool to enhance our knowledge of pathophysiological processes. Whereas validation of a bioanalytical method is customary in most analytical chemistry fields, it is rarely performed for untargeted metabolomics. This study aimed to establish and validate an analytical platform for a long-term, clinical metabolomics study. Sample preparation was performed with an automated liquid handler and four analytical methods were developed and evaluated. The validation study spanned three batches with twelve runs using individual serum samples and various quality control samples. Data was acquired with untargeted acquisition and only metabolites identified at level 1 were evaluated. Validation parameters were set to evaluate key performance metrics relevant for the intended application: reproducibility, repeatability, stability, and identification selectivity, emphasizing dataset intrinsic variance. Concordance of semi-quantitative results between methods was evaluated to identify potential bias. Spearman rank correlation coefficients (rs) were calculated from individual serum samples. Of the four methods tested, two were selected for validation. A total of 47 and 55 metabolites (RPLC-ESI+- and HILIC-ESI--HRMS, respectively) met specified validation criteria. Quality assurance involved system suitability testing, sample release, run release, and batch release. The median repeatability and within-run reproducibility as coefficient of variation% for metabolites that passed validation on RPLC-ESI+- and HILIC-ESI--HRMS were 4.5 and 4.6, and 1.5 and 3.8, respectively. Metabolites that passed validation on RPLC-ESI+-HRMS had a median D-ratio of 1.91, and 89 % showed good signal intensity after ten-fold dilution. The corresponding numbers for metabolites with the HILIC-ESI--HRMS method was 1.45 and 45 %, respectively. The rs median ({range}) for metabolites that passed validation on RPLC-ESI+- was 0.93 (N = 9 {0.69-0.98}) and on HILIC-ESI--HRMS was 0.93 (N = 22 {0.55-1.00}). The validated methods proved fit-for-purpose and the laboratory thus demonstrated its capability to produce reliable results for a large-scale, untargeted metabolomics study. This validation not only bolsters the reliability of the assays but also significantly enhances the impact and credibility of the hypotheses generated from the studies. Therefore, this validation study serves as a benchmark in the documentation of untargeted metabolomics, potentially guiding future endeavors in the field.PMID:39142167 | DOI:10.1016/j.chroma.2024.465230

Biochem Biophys Res Commun. 2024 Aug 8;737:150518. doi: 10.1016/j.bbrc.2024.150518. Online ahead of print.ABSTRACTAIMS: Metabolic disease is a multifaceted condition characterized by the disruption of numerous metabolic parameters within the host. Its prevalence has surged significantly in recent years and it has become a prominent non-communicable disease worldwide. The effect of gut microbiota on various beige fat induction is well studied, while the mechanisms behind the link remain unclear. Given that gut microbiota-derived metabolites (meta-metabolites) secreted in the gut serve as a key mode of communication with their host through direct circulation or indirect host physiology modification, understanding the effect of meta-metabolites on adipose tissue is essential.METHODOLOGY: In our previous in-vivo studies, we observed a correlation between gut microbiota and the formation of beige fat. In this study, we further aimed to validate this correlation by treating the adipocyte cell line (3T3-L1) with meta-metabolites collected from the cecum of mice exhibiting beige adipose tissue formation. Additionally, we treated the adipocyte cell line with known beige fat inducers (L-Rhamnose and Ginsenoside) to assess meta-metabolites' efficacy on beige fat formation.KEY FINDINGS: Upon treatment with the meta-metabolites from the antibiotic-treated mice, we observed a significant increase in lipid metabolism and beige-specific gene expression. Analyzing the metabolites in these cells revealed that a set of metabolites potentially govern adipocytes, contributing to a metabolically active state. These effects were at par or even better than those of cells treated with L-Rhamnose or Ginsenoside.SIGNIFICANCE: This research sheds light on the intricate interplay between microbial metabolites and adipose tissue, offering valuable clues for understanding and potentially manipulating these processes for therapeutic purposes.PMID:39142136 | DOI:10.1016/j.bbrc.2024.150518

Talanta. 2024 Aug 10;280:126641. doi: 10.1016/j.talanta.2024.126641. Online ahead of print.ABSTRACTFoodomics employs advanced analytical techniques to provide answers regarding food composition, authenticity control, marker identification and issues related to food quality and safety. Nuclear magnetic resonance (NMR) spectroscopy and chromatography hyphenated to mass spectrometry (MS) are the main analytical platforms used in this field. Nevertheless, they are rarely employed in an integrated manner, and even then, the contribution of each technique remains vague. Table olives (Olea europaea L.) are a food commodity of high economic and nutritional value with an increasing production tendency over the last two decades, which, however, suffers from extensive fraud incidents and quality determination uncertainties. Thus, the current attempt aims towards two axes with the first being the multilevel integration of LC-HRMS and NMR data of the same samples and table olives being the selected matrix. In more detail, UPLC-HRMS/MS-based analysis was compared at different stages within an untargeted metabolomics workflow with an NMR-based study and the complementarity of the two platforms was evaluated. Furthermore, statistical heterospectroscopy (SHY), rarely employed in foodomics, combining the spectroscopic with spectrometric datasets and aiming to increase the confidence level of annotated biomarkers was applied. Amongst these lines, the second parallel axis of this study was the detailed characterization of table olives' metabolome in search for quality markers considering the impact of geographical (from Northern to Southern Greece) and botanical origin (Kalamon, Konservolia, Chalkidikis cultivars), as well as processing parameters (Spanish, Greek). To that end, using deep dereplication tools including statistical methods, with SHY employed for the first time in table olives, different biomarkers, belonging to the classes of phenyl alcohols, phenylpropanoids, flavonoids, secoiridoids and triterpenoids were identified as responsible for the observed classifications. The current binary pipeline, focusing on biomarkers' identification confidence, could be suggested as a meaningful workflow not only in olive-based products, but also in food quality control and foodomics in general.PMID:39142126 | DOI:10.1016/j.talanta.2024.126641

Ecotoxicol Environ Saf. 2024 Aug 13;284:116878. doi: 10.1016/j.ecoenv.2024.116878. Online ahead of print.ABSTRACTBACKGROUND: 2-ethylhexyldiphenyl phosphate (EHDPP) was used widespread in recent years and it was reported to impair reproductive behaviors and decrease fertility in male Japanese medaka. However, whether EHDPP causes spermatogenesis disturbance remains uncertain.OBJECTIVES: We aimed to study the male reproductive toxicity of EHDPP and its related mechanism.METHODS: Human spermatocyte cell line GC-2 was treated with 10 µM, 50 µM or 100 µM EHDPP for 24 h. Male CD-1 mice aged 6 weeks were given 1, 10, or 100 mg/kg/d EHDPP daily for 42 days and then euthanized to detect sperm count and motility. Proliferation, apoptosis, oxidative stress was detected in mice and cell lines. Metabolome and transcriptome were used to detect the related mechanism. Finally, anti-oxidative reagent N-Acetylcysteine was used to detect whether it could reverse the side-effect of EHDPP both in vivo and in vitro.RESULTS: Our results showed that EHDPP inhibited proliferation and induced apoptosis in mice testes and spermatocyte cell line GC-2. Metabolome and transcriptome showed that nucleotide metabolism disturbance and DNA damage was potentially involved in EHDPP-induced reproductive toxicity. Finally, we found that excessive ROS production caused DNA damage and mitochondrial dysfunction; NAC supplement reversed the side effects of EHDPP such as DNA damage, proliferation inhibition, apoptosis and decline in sperm motility.CONCLUSION: ROS-evoked DNA damage and nucleotide metabolism disturbance mediates EHDPP-induced germ cell proliferation inhibition and apoptosis, which finally induced decline of sperm motility.PMID:39142116 | DOI:10.1016/j.ecoenv.2024.116878

Theriogenology. 2024 Aug 8;228:110-120. doi: 10.1016/j.theriogenology.2024.08.007. Online ahead of print.ABSTRACTSuccessful reproductive management of domestic mammals depends primarily upon timely identification of oestrous cycle stages. There is a need to develop an alternative non-invasive, welfare-friendly, accurate and reliable method to identify reproductive cycle stages. This is of particular interest for horse breeders, because horses are high-value farm animals that require careful management and individual monitoring. Saliva sampling is non-invasive, painless and welfare-friendly. Thus, we performed a metabolomic analysis of equine saliva during different reproductive stages to identify changes in the salivary metabolome during anoestrus, the oestrous cycle and early gestation. We compared the saliva and plasma metabolomes to investigate the relationship between the two fluids according to the physiological stage. We collected saliva and plasma samples from six mares during seasonal anoestrus, during the follicular phase 3 days, 2 days and 1 day before ovulation and the day when ovulation was detected, during the luteal phase 6 days after ovulation, and during early gestation 18 days after ovulation and insemination. Metabolome analysis was performed by proton-nuclear magnetic resonance spectroscopy. We identified 58 and 51 metabolites in saliva and plasma, respectively. The levels of four metabolites or groups of metabolites in saliva and five metabolites or groups of metabolites in plasma showed significant modifications during the 4 days until ovulation, ie 3 days prior to and on the day of ovulation. The levels of 11 metabolites or groups of metabolites in saliva and 17 metabolites or groups of metabolites in plasma were significantly different between the seasonal anoestrus and the ovarian cyclicity period. The physiological mechanisms involved in the onset of ovarian cyclicity and in ovulation induced modifications of the metabolome both in plasma and saliva. The metabolites whose salivary levels changed during the reproductive cycle could be potential salivary biomarkers to detect the reproductive stage in a welfare friendly production system. In particular, we propose creatine and alanine as candidate salivary biomarkers of ovulation and of the onset of ovarian cyclicity, respectively. However, extensive validation of their reliability is required. Our study contributes to extend to domestic mammals the use of saliva as a non-invasive alternative diagnostic fluid for reproduction in a welfare-friendly production system.PMID:39141998 | DOI:10.1016/j.theriogenology.2024.08.007

Meat Sci. 2024 Aug 5;217:109624. doi: 10.1016/j.meatsci.2024.109624. Online ahead of print.ABSTRACTThis study examined the impact of dietary guanidino acetic acid (GAA) and rumen-protected methionine (RPM) on beef quality in Simmental bulls. For 140 days, forty-five bulls (453.43 ± 29.05 kg) were randomly divided into control (CON), 0.1% GAA (GAA), and 0.1% GAA + 0.1% RPM (GAM) groups with 15 bulls in each group and containing 3 pen with 5 bulls in each pen. Significant improvements in eye muscle area, pH48h, redness (a*) value, and crude protein (CP) content of longissimus lumborum (LL) muscles were observed in the GAA and GAM groups (P < 0.05). Conversely, the lightness (L*) value, drip loss, cooking loss, and moisture contents decreased (P < 0.05). Additionally, glutathione (GSH) and glutathione peroxidase (GSH-PX) concentrations of LL muscles in GAM were higher (P < 0.05), while malondialdehyde (MDA) content of LL muscles in GAA and GAM groups were lower (P < 0.05). Polyunsaturated fatty acids (PUFA) profiles were enriched in beef from GAM group (P < 0.05). The addition of GAA and RPM affected the expression of genes in LL muscle, such as HMOX1, EIF4E, SCD5, and NOS2, which are related to hypoxia metabolism, protein synthesis, and unsaturated fatty acid synthesis-related signaling pathways. In addition, GAA and RPM also affected the content of a series of metabolites such as L-tyrosine, L-tryptophan, and PC (O-16:0/0:0) involved in amino acid and lipid metabolism-related signaling pathways. In summary, GAA and RPM can improve the beef quality and its nutritional composition. These changes may be related to changes in gene expression and metabolic pathways related to protein metabolism and lipid metabolism in beef.PMID:39141966 | DOI:10.1016/j.meatsci.2024.109624

J Hazard Mater. 2024 Aug 5;478:135436. doi: 10.1016/j.jhazmat.2024.135436. Online ahead of print.ABSTRACTPlasmid-mediated conjugative transfer has emerged as a major driver accounting for the dissemination of antibiotic resistance genes (ARGs). In addition to the use of antimicrobial agents, there is growing evidence that non-antibiotic factors also play an important role. Pesticides are widely used to protect crops against vectors of diseases, and are indispensable agents in agricultural production, whereas the impact of pesticide pollution on the transmission of antimicrobial resistance remains poorly understood. Here we reveal that the pesticides at environmentally relevant concentrations, especially cyromazine (Cyr) and kresoxim-methyl (Kre), greatly facilitate the conjugative transfer of antibiotic-resistance plasmids carrying clinically important ARGs. Mechanistic studies indicate that Cyr and Kre treatments trigger reactive oxygen species (ROS) production and SOS response, increase membrane permeability, upregulate bacterial proton motive force (PMF) and promote ATP supply. Further non-targeted metabolomics and biochemical analysis demonstrate that the addition of Cyr and Kre accelerates tricarboxylic acid (TCA) cycle and electron transport chain (ETC), thereby activating bacterial energy metabolism. In the constructed soil model, we prove that two pesticides contribute to the dissemination of resistance plasmids in the soil microbiota. 16S rRNA sequencing analyses indicate that pesticides alter transconjugant microbial communities, and enable more opportunistic pathogens, such as Pseudomonas and Enterobacter, to acquire the multidrug resistance plasmids. Collectively, our work indicates the potential risk in accelerating the spread of antimicrobial resistance owing to pesticide pollution, highlighting the importance of continuous surveillance of pesticide residues in complex environmental settings.PMID:39141944 | DOI:10.1016/j.jhazmat.2024.135436

Sci Transl Med. 2024 Aug 14;16(760):eadl0715. doi: 10.1126/scitranslmed.adl0715. Epub 2024 Aug 14.ABSTRACTExtracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.PMID:39141698 | DOI:10.1126/scitranslmed.adl0715

Elife. 2024 Aug 14;13:RP93260. doi: 10.7554/eLife.93260.ABSTRACTBACKGROUND: Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations.METHODS: We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504).RESULTS: Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p<5 × 10-5). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10-33) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10-9) in White Europeans. However, it was not associated with self-reported exposure (p>0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (-0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (-0.043±0.013 kg, p=0.0011) in the combined cohorts.CONCLUSIONS: This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers.FUNDING: This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.PMID:39141540 | DOI:10.7554/eLife.93260

Chem Biodivers. 2024 Aug 14:e202401259. doi: 10.1002/cbdv.202401259. Online ahead of print.ABSTRACTEfforts are intensifying to identify bioactive microbial metabolites from biocontrol agents to manage plant pathogens in critical crops. This study examined both volatile organic compounds (VOCs) and non-volatile compounds from Metarhizium carneum and Lecanicillium uredinophilum strains for their antimicrobial effects against various phytopathogens and analyzed their exo-metabolomes. M. carneum VOCs inhibited four bacterial and eight fungal species by up to 45.45%, while L. uredinophilum VOCs inhibited five bacterial and eight fungal species by up to 50.91%. Additionally, n-BuOH extracts from both biocontrol agents effectively targeted three fungi and five bacteria. The exo-metabolomes of M. carneum and L. uredinophilum included 125 and 102 spectrometric features, respectively, primarily consisting of polyketides, alkaloids, lipids, organic aromatic compounds, terpenoids, and peptides. Our findings revealed a correlation between the phylogenetic relationships of M. carneum strains, their bioactivity patterns against phytopathogens, and their metabolomic profiles. Notably, some compounds detected in both fungi previously demonstrated biological activity against plant pathogens, enhancing their biocontrol potential. This study not only evidences the antimicrobial properties of diffusible compounds from M. carneum and L. uredinophilum, but also documents the antimicrobial potential of their VOCs for the first time, supporting their use in sustainable agricultural practices, reducing reliance on chemical inputs.PMID:39141524 | DOI:10.1002/cbdv.202401259

Proc Natl Acad Sci U S A. 2024 Aug 20;121(34):e2321686121. doi: 10.1073/pnas.2321686121. Epub 2024 Aug 14.ABSTRACTTo broadly measure the spectrum of cellular self-antigens for natural killer T cells (NKT), we developed a sensitive lipidomics system to analyze lipids trapped between CD1d and NKT T cell receptors (TCRs). We captured diverse antigen complexes formed in cells from natural endogenous lipids, with or without inducing endoplasmic reticulum (ER) stress. After separating protein complexes with no, low, or high CD1d-TCR interaction, we eluted lipids to establish the spectrum of self-lipids that facilitate this interaction. Although this unbiased approach identified fifteen molecules, they clustered into only two related groups: previously known phospholipid antigens and unexpected neutral lipid antigens. Mass spectrometry studies identified the neutral lipids as ceramides, deoxyceramides, and diacylglycerols, which can be considered headless lipids because they lack polar headgroups that usually form the TCR epitope. The crystal structure of the TCR-ceramide-CD1d complex showed how the missing headgroup allowed the TCR to predominantly contact CD1d, supporting a model of CD1d autoreactivity. Ceramide and related headless antigens mediated physiological TCR binding affinity, weak NKT cell responses, and tetramer binding to polyclonal human and mouse NKT cells. Ceramide and sphingomyelin are oppositely regulated components of the "sphingomyelin cycle" that are altered during apoptosis, transformation, and ER stress. Thus, the unique molecular link of ceramide to NKT cell response, along with the recent identification of sphingomyelin blockers of NKT cell activation, provide two mutually reinforcing links for NKT cell response to sterile cellular stress conditions.PMID:39141352 | DOI:10.1073/pnas.2321686121

Invest Ophthalmol Vis Sci. 2024 Aug 1;65(10):24. doi: 10.1167/iovs.65.10.24.ABSTRACTPURPOSE: The purpose of this study was to investigate the molecular mechanisms underlying anti-vascular endothelial growth factor (anti-VEGF) efficacy and response variability in neovascular age-related macular degeneration (nAMD) using longitudinal proteomic and metabolomic analysis alongside three-dimensional lesion measurements.METHODS: In this prospective study, 54 treatment-naive patients with nAMD underwent "3+ pro re nata" (3+PRN) anti-VEGF regimens followed for at least 12 weeks. Aqueous humors were collected pre- and post-treatment for proteomic and metabolomic analysis. Three-dimensional optical coherence tomography (OCT) and OCT angiography assessed different types of nAMD lesion volumes and areas.RESULTS: There were 1350 proteins and 1268 metabolites that were identified in aqueous humors, with 301 proteins and 353 metabolites significantly altered during anti-VEGF treatment, enriched in pathways of angiogenesis, energy metabolism, signal transduction, and neurofunctional regulation. Sixty-seven changes of (Δ) molecules significantly correlated with at least one type of ΔnAMD lesion. Notably, proteins FGA, TALDO1, and ASPH significantly decreased during treatment, with their reductions correlating with greater lesion regression in at least two lesion types. Conversely, despite that YIPF3 also showed significant downregulation, its decrease was associated with poorer regression in total nAMD lesion and subretinal hyper-reflective material.CONCLUSIONS: This study identifies FGA, TALDO1, and ASPH as potential key molecules in the efficacy of anti-VEGF therapy, whereas YIPF3 may be a key factor in poor response. The integration of longitudinal three-dimensional lesion analysis with multi-omics provides valuable insights into the mechanisms and response variability of anti-VEGF treatment in nAMD.PMID:39140961 | DOI:10.1167/iovs.65.10.24