PubMed

Chemosphere. 2023 Sep 13:140108. doi: 10.1016/j.chemosphere.2023.140108. Online ahead of print.ABSTRACTNanoplastics have been widely studied as environmental pollutants, which can accumulate in the human body through the food chain or direct contact. Research has shown that nanoplastics can affect the immune system and mitochondrial function, but the underlying mechanisms are unclear. Lungs and macrophages have important immune and metabolic functions. This study explored the effects of 100 nm PS-NPs on innate immunity, mitochondrial function, and cellular metabolism-related pathways in lung (BEAS-2B) cells and macrophages (RAW264.7). The results had shown that PS-NPs exposure caused a decrease in mitochondrial membrane potential, intracellular ROS accumulation, and Ca2+ overload, and activated the cGAS-STING signaling pathway related to innate immunity. These changes had been observed at concentrations of PS-NPs as low as 60 μg/mL, which might have been comparable to environmental levels. Non-target metabolomics and Western Blotting results confirmed that PS-NPs regulated prostaglandin B1 and other metabolites to cause cell damage through the cGAS-STING pathway. Supplementation of prostaglandin B1 alleviated the immune activation and metabolic disturbance caused by PS-NPs exposure. This study identified PS-NPs-induced innate immune activation, mitochondrial dysfunction, and metabolic toxicity pathways, providing new insights into the potential for adverse outcomes of NPs in human life.PMID:37714480 | DOI:10.1016/j.chemosphere.2023.140108

Sci Total Environ. 2023 Sep 13:167079. doi: 10.1016/j.scitotenv.2023.167079. Online ahead of print.ABSTRACTIn wild animals, diet and gut microbiota interactions are critical moderators of metabolic functions and are highly contingent on habitat conditions. Challenged by the extreme conditions of high-altitude environments, the strategies implemented by highland animals to adjust their diet and gut microbial composition and modulate their metabolic substrates remain largely unexplored. By employing a typical human commensal species, the Eurasian tree sparrow (Passer montanus, ETS), as a model species, we studied the differences in diet, digestive tract morphology and enzyme activity, gut microbiota, and metabolic energy profiling between highland (the Qinghai-Tibet Plateau, QTP; 3230 m) and lowland (Shijiazhuang, Hebei; 80 m) populations. Our results showed that highland ETSs had enlarged digestive organs and longer small intestinal villi, while no differences in key digestive enzyme activities were observed between the two populations. The 18S rRNA sequencing results revealed that the dietary composition and abundance of highland ETSs were more animal-based and less plant-based than those of the lowland ones. Furthermore, 16S rRNA sequencing results suggested that the intestinal microbial communities were structurally segregated between populations. PICRUSt metagenome predictions further indicated that the expression patterns of microbial genes involved in material and energy metabolism, immune system and infection, and xenobiotic biodegradation were strikingly different between the two populations. Analysis of liver metabolomics revealed significant metabolic differences between highland and lowland ETSs in terms of substrate utilization, as well as distinct sex-specific alterations in glycerophospholipids. Furthermore, the interplay between diet, liver metabolism, and gut microbiota suggests a dietary shift resulting in corresponding changes in gut microbiota and metabolic functions. Our findings indicate that highland ETSs have evolved to optimize digestion and absorption, rely on more protein-rich foods, and possess gut microbiota tailored to their dietary composition, likely adaptive physiological and ecological strategies adopted to cope with extreme highland environments.PMID:37714349 | DOI:10.1016/j.scitotenv.2023.167079

Sci Total Environ. 2023 Sep 13:167071. doi: 10.1016/j.scitotenv.2023.167071. Online ahead of print.ABSTRACTMicro/nanoplastics (M/NPs) and phthalates (PAEs) are emerging pollutants. Polystyrene (PS) MPs and dibutyl phthalate (DBP) are typical MPs and PAEs in the environment. However, how dandelion plants respond to the combined contamination of MPs and PAEs remains unclear. In this study, we evaluated the individual and combined effects of PS NPs (10 mg L-1) and DBP (50 mg L-1) on dandelion (Taraxacum officinale) seedlings. The results showed that compared to control and individual-treated plants, coexposure to PS NPs and DBP significantly affected plant growth, induced oxidative stress, and altered enzymatic and nonenzymatic antioxidant levels of dandelion. Similarly, photosynthetic attributes and chlorophyll fluorescence kinetic parameters were significantly affected by coexposure. Scanning electron microscopy (SEM) results showed that PS particles had accumulated in the root cortex of the dandelion. Metabolic analysis of dandelion showed that single and combined exposures caused the plant's metabolic pathways to be profoundly reprogrammed. As a consequence, the synthesis and energy metabolism of carbohydrates, amino acids, and organic acids were affected because galactose metabolism, the citric acid cycle, and alanine, aspartic acid and glutamic acid metabolism pathways were significantly altered. These results provide a new perspective on the phytotoxicity and environmental risk assessment of MPs and PAEs in individual or coexposures.PMID:37714347 | DOI:10.1016/j.scitotenv.2023.167071

Sci Total Environ. 2023 Sep 13:167016. doi: 10.1016/j.scitotenv.2023.167016. Online ahead of print.ABSTRACTModerate altitude exposure has shown beneficial effects on diabetes incidence but the underlying mechanisms are not understood. Our study aimed to investigate how the human gut microbiome impacted the serum metabolome and associated with glucose homeostasis in healthy Chinese individuals upon moderate-altitude exposure. Faecal microbiome composition was assessed using shotgun metagenomic sequencing. Serum metabolome was acquired by untargeted metabolomics technology, and amino acids (AAs) and propionic acid in serum were quantified by targeted metabolomics technology. The results indicated that the moderate-altitude exposed individuals presented lowered fasting blood glucose (FBG) and propionic acid, increased circulating l-Glutamine but decreased L-Glutamate and L-Valine, which correlated with enriched Bacteroidetes and decreased Proteobacteria. Additionally, the silico causality associations among gut microbiota, serum metabolome and host FBG were analyzed by mediation analysis. It showed that increased Bacteroides ovatus (B. ovatus) and decreased Escherichia coli (E. coli) were identified as the main antagonistic species driving the association between L-Glutamate and FBG in silico causality. Furthermore, the high-fat diet (HFD) fed mice subjected to faecal microbiota transplantation (FMT) were applied to validate the cause-in-fact effects of gut microbiota on the beneficial glucose response. We found that microbiome in the moderate-altitude exposed donor could predict the extent of the FBG response in recipient mice, which showed lowered FBG, L-Glutamate and Firmicutes/Bacteroidetes ratio. Our findings suggest that moderate-altitude exposure targeting gut microbiota and circulating metabolome, may pave novel avenues to counter dysglycemia.PMID:37714338 | DOI:10.1016/j.scitotenv.2023.167016

Int J Biol Macromol. 2023 Sep 13:126861. doi: 10.1016/j.ijbiomac.2023.126861. Online ahead of print.ABSTRACTBioactive polysaccharides known as the biological response modifiers, can directly interact with intestinal epithelium cells (IEC) and regulate key metabolic processes such as lipid metabolism. Here, the coculture of Caco-2/HT29 monolayer (>400 Ω × cm2) and HepG2 cells was developed to mimic the gut-liver interactions. This system was used to investigate the effects of raw and fermented barley β-glucans (RBG and FBG) on lipid metabolism by directly interacting with IEC. Both RBG and FBG significantly and consistently reduced the lipid droplets and triacylglycerol levels in monoculture and coculture of HepG2 overloaded with oleic acid. Notably, FBG significantly and distinctly elevated PPARα (p < 0.05) and PPARα-responsive ACOX-1 (p < 0.01) gene expressions, promoting lipid degradation in cocultured HepG2. Moreover, the metabolomics analyses revealed that FBG had a unique impact on extracellular metabolites, among them, the differential metabolite thiomorpholine 3-carboxylate was significantly and strongly correlated with PPARα (r = -0.68, p < 0.01) and ACOX-1 (r = -0.76, p < 0.01) expression levels. Taken together, our findings suggest that FBG-mediated gut-liver interactions play a key role in its lipid-lowering effects that are superior to those of RBG. These results support the application of Lactiplantibacillus fermentation for improving hypolipidemic outcomes.PMID:37714241 | DOI:10.1016/j.ijbiomac.2023.126861

J Ethnopharmacol. 2023 Sep 13:117182. doi: 10.1016/j.jep.2023.117182. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Parkinson's disease (PD) is a rapidly progressing neurological disorder. Currently, Medication for PD has numerous limitations. Baichanting Compound (BCT) is a Chinese herbal prescription, a Combination of Acanthopanax senticosus (Rupr. and Maxim.) Harms, Paeonia lactiflora Pall and Uncaria rhynchophylla (Miq.) Miq. ex Havil, that was developed to treat PD and holds a national patent (ZL, 201110260536.3).AIM OF THE STUDY: To clarify the therapeutic effect of BCT on PD and explore its possible mechanism based on metabolomics and metagenomics.MATERIALS AND METHODS: C57BL/6 mice were used as a control group, and α-syn transgenic C57BL/6 mice were randomly assigned to the PD (without treatment) or BCT (with BCT treatment) group. UPLC-MS was performed to detect dopamine levels in brain tissue, while ELISA was used to determine inflammatory factors such as IL-1β, IL-6, TNF-α, IFN-γ and NO, and oxidative stress indicators such as malondialdehyde, superoxide dismutase and glutathione peroxidase enzyme activity. Fecal metabolomics was used to detect fecal metabolic profiles, screen differential metabolic markers, and predict metabolic pathways by KEGG enrichment analysis. Metagenomics was used to determine the intestinal microbial composition, and KO enrichment analysis was performed to predict the potential function of different gut microbiota. Finally, Spearman correlation analysis was used to find the possible relationships among intestinal flora, metabolic markers, inflammatory factors, oxidative stress and dopamine levels.RESULTS: BCT increased the superoxide dismutase activity of α-Syn transgenic C57BL/6 mice (P < 0.01), decreased the levels of TNF-α, IFN-γ, IL-1β, IL-6, NO and malondialdehyde (P < 0.01, 0.05), and increased the release of dopamine (P < 0.01). Metabolomics results show that BCT could regulate Acetatifactor, Marvinbryantia, Faecalitalea, Anaeromassilibacillus, Anaerobium, Pseudobutyrivibrio and Lachnotalea and Acetatifactor_muris, Marvinbryantia_formatexigens, Lachnotalea_sp_AF33_28, Faecalitalea_sp_Marseille_P3755 and Anaerobium_acetethylicum, Gemmiger_sp_An120 abundance to restore intestinal flora function, and reverse fecal metabolism trend, restoring the content of α-D-glucose, cytidine, L-glutamate, L-glutamine, N-acetyl-L-glutamate, raffinose and uracil. In addition, it regulates arginine biosynthesis, D-glutamine and D-glutamate, pyrimidine, galactose and alanine, aspartate and glutamate metabolic pathways.CONCLUSION: BCT may regulate the composition of the gut microbiota to reverse fecal metabolism in PD mice to protect the substantia nigra and striatum from oxidative stress and inflammatory factors and ultimately play an anti-PD role.PMID:37714224 | DOI:10.1016/j.jep.2023.117182

Medicina (B Aires). 2023 Sep;83 Suppl 4:3-8.ABSTRACTThe advances in the field of inborn errors of metabolism (IEM) are spectacular. New IEM have been described, their pathophysiological bases and implications for the organism are better known. With the advent of new metabolomics, lipidomics and genomics techniques, advances in diagnosis have multiplied and allow new therapeutic options to be explored. A new IEM classification has been established based on the more than 1.450 IEM identified. A new specialty is emerging, which is metabolic medicine. Neonatal screening is becoming universal and allows us today, with tandem mass, to diagnose more than 20 metabolic diseases of the neonatal period, with treatment options. IEM units for adults are being created to follow-up children with IEM who survive the disease and with an increasingly better quality of life, and some IEM that start in adolescence or adulthood are diagnosed. Personalized therapies and clinical practice guidelines appear for any IEM. Finally, new therapeutic options are emerging day to day that allow a longer survival and better quality of life. Conventional gene therapy is already being applied in some IEM. However, gene editing strategies with RNA therapies may allow the correction of the genetic mutation, minimizing the problems associated with conventional compensation gene therapy.PMID:37714115

Biochim Biophys Acta Mol Basis Dis. 2023 Sep 13;1870(1):166876. doi: 10.1016/j.bbadis.2023.166876. Online ahead of print.ABSTRACTBACKGROUND: Studies have found that the plasma content of gut-derived 4-hydroxyphenylacetic acid (4-HPA) was significantly increased in septic patients. However, the mechanism of 4-HPA elevation during sepsis and its relationship with sepsis-induced acute kidney injury (SAKI) remain unclear.METHODS: Cecal ligation and puncture (CLP) was performed in C57BL/6 mice to establish the SAKI animal model. Human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide were used to establish the SAKI cell model. The widely targeted metabolomics was applied to analyze the renal metabolite changes after CLP. Proteomics was used to explore potential target proteins regulated by 4-HPA. The blood sample of clinical sepsis patients was collected to examine the 4-HPA content.RESULTS: We found that renal gut-derived 4-HPA levels were significantly increased after CLP. The high permeability of intestinal barrier after sepsis contributed to the dramatic increase of renal 4-HPA. Intriguingly, we demonstrated that exogenous 4-HPA administration could further significantly reduce CLP-induced increases in serum creatinine, urea nitrogen, and cystatin C, inhibit renal pathological damage and apoptosis, and improve the survival of mice. Mechanistically, 4-HPA inhibited necroptosis in renal tubular epithelial cells by upregulating the protein expression of apoptosis repressor with caspase recruitment domain (ARC) and enhancing the interaction between ARC and receptor-interacting protein kinase 1 (RIPK1).CONCLUSIONS: The increase of gut-derived 4-HPA in the kidney after sepsis could play a protective effect in SAKI by upregulating ARC to inhibit necroptosis.PMID:37714058 | DOI:10.1016/j.bbadis.2023.166876

Ecotoxicol Environ Saf. 2023 Sep 13;264:115463. doi: 10.1016/j.ecoenv.2023.115463. Online ahead of print.ABSTRACTPolymer materials have great potential for soil heavy metal contamination remediation, but the metabolic mechanism by which polymer amendments regulate the responses of soil-plant systems to cadmium (Cd) stress is still unclear. To clarify the metabolic mechanism by which a self-developed soluble polymer amendment (PA) remediates Cd contamination in cotton fields, the common and differential metabolites in soil and cotton leaves were analyzed during the critical period of cotton growth (flowering and bolling stage) in a field experiment. The results showed that Cd stress increased Cd concentration in the soil-cotton system, and reduced enzyme activity in soil and cotton leaves. Besides, Cd stress also reduced the abundance of α-linolenic acid in soil and the abundance of 2-Oxoarginine and S-Adenosylmethionine in cotton leaves. These ultimately led to reductions in weight, boll number, yield, and fiber elongation. However, the application of PA to the Cd-contaminated soil significantly reduced the soil exchangeable Cd (Ex-Cd) concentration by 41.43%, and increased the boll number, yield, and fiber strength by 14.17%, 21.04%, and 19.89%, respectively compared with the Cd treatment. The results of metabolomic analysis showed that PA application mainly affected the Nicotinate and nicotinamide metabolism pathway, Lysine degradation pathway, and Arginine and proline metabolism pathway in cotton leaves and soil. Besides, in these metabolic pathways, succinic acid semialdehyde of cotton leaves, saccharopine of soil, and S-Adenosylmethionine of soil and cotton had the most significant response to PA application. Therefore, the application of PA to Cd-contaminated soil can increase soil and cotton leaf enzyme activity and cotton yield (boll number and seed cotton yield) and quality (fiber strength), and maintain soil-plant material balance by regulating the distribution of Cd ions and key metabolites in the soil-cotton system. This study will deepen our understanding of the metabolic mechanism of PA remediating Cd-contaminated cotton fields, and provide a technical reference for the remediation of heavy metal contamination in drip-irrigated cotton fields in arid areas.PMID:37714036 | DOI:10.1016/j.ecoenv.2023.115463

Ecotoxicol Environ Saf. 2023 Sep 13;264:115456. doi: 10.1016/j.ecoenv.2023.115456. Online ahead of print.ABSTRACTExposure to particulate matter (PM) from agricultural environments has been extensively reported to cause respiratory health concerns in both animals and agricultural workers. Furthermore, PM from agricultural environments, containing fungal spores, has emerged as a significant threat to public health and the environment. Despite its potential toxicity, the impact of fungal spores present in PM from agricultural environments on the lung microbiome and metabolic profile is not well understood. To address this gap in knowledge, we developed a mice model of immunodeficiency using cyclophosphamide and subsequently exposed the mice to fungal spores via the trachea. By utilizing metabolomics techniques and 16 S rRNA sequencing, we conducted a comprehensive investigation into the alterations in the lung microbiome and metabolic profile of mice exposed to fungal spores. Our study uncovered significant modifications in both the lung microbiome and metabolic profile post-exposure to fungal spores. Additionally, fungal spore exposure elicited noticeable changes in α and β diversity, with these microorganisms being closely associated with inflammatory factors. Employing non-targeted metabolomics analysis via GC-TOF-MS, a total of 215 metabolites were identified, among which 42 exhibited significant differences. These metabolites are linked to various metabolic pathways, with amino sugar and nucleotide sugar metabolism, as well as galactose metabolism, standing out as the most notable pathways. Cysteine and methionine metabolism, along with glycine, serine and threonine metabolism, emerged as particularly crucial pathways. Moreover, these metabolites demonstrated a strong correlation with inflammatory factors and exhibited significant associations with microbial production. Overall, our findings suggest that disruptions to the microbiome and metabolome may hold substantial relevance in the mechanism underlying fungal spore-induced lung damage in mice.PMID:37714035 | DOI:10.1016/j.ecoenv.2023.115456

Biomed Pharmacother. 2023 Sep 13;167:115487. doi: 10.1016/j.biopha.2023.115487. Online ahead of print.ABSTRACTItaconic acid (IA), a metabolite generated by the tricarboxylic acid (TCA) cycle in eukaryotic immune cells, and its derivative dimethyl itaconate (DI) exert antibacterial functions in intracellular environments. Previous studies suggested that IA and DI only inhibit bacterial growth in carbon-limited environments; however, whether IA and DI maintain antibacterial activity in carbon-enriched environments remains unknown. Here, IA and DI inhibited the bacteria with minimum inhibitory concentrations of 24.02 mM and 39.52 mM, respectively, in a carbon-enriched environment. The reduced bacterial pathogenicity was reflected in cell membrane integrity, motility, biofilm formation, AI-2/luxS, and virulence. Mechanistically, succinate dehydrogenase (SDH) activity and fumaric acid levels decreased in the IA and DI treatments, while isocitrate lyase (ICL) activity was upregulated. Inhibited TCA circulation was also observed through untargeted metabolomics. In addition, energy-related aspartate metabolism and lysine degradation were suppressed. In summary, these results indicated that IA and DI reduced bacterial pathogenicity while exerting antibacterial functions by inhibiting TCA circulation. This study enriches knowledge on the inhibition of bacteria by IA and DI in a carbon-mixed environment, suggesting an alternative method for treating bacterial infections by immune metabolites.PMID:37713987 | DOI:10.1016/j.biopha.2023.115487

EBioMedicine. 2023 Sep 13;96:104798. doi: 10.1016/j.ebiom.2023.104798. Online ahead of print.ABSTRACTBACKGROUND: Asthenozoospermia is the primary cause of male infertility; however, its genetic aetiology remains poorly understood. Adenylate kinase 9 (AK9) is highly expressed in the testes of humans and mice and encodes a type of adenosine kinase that is functionally involved in cellular nucleotide homeostasis and energy metabolism. We aimed to assess whether AK9 is involved in asthenozoospermia.METHODS: One-hundred-and-sixty-five Chinese men with idiopathic asthenozoospermia were recruited. Whole-exome sequencing (WES) and Sanger sequencing were performed for genetic analyses. Papanicolaou staining, Haematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy were used to observe the sperm morphology and structure. Ak9-knockout mice were generated using CRISPR-Cas9. Sperm adenosine was detected by liquid chromatography-mass spectrometry. Targeted sperm metabolomics was performed. Intracytoplasmic sperm injection (ICSI) was used to treat patients.FINDINGS: We identified five patients harbouring bi-allelic AK9 mutations. Spermatozoa from men harbouring bi-allelic AK9 mutations have a decreased ability to sustain nucleotide homeostasis. Moreover, bi-allelic AK9 mutations inhibit glycolysis in sperm. Ak9-knockout male mice also presented similar phenotypes of asthenozoospermia. Interestingly, ICSI was effective in bi-allelic AK9 mutant patients in achieving good pregnancy outcomes.INTERPRETATION: Defects in AK9 induce asthenozoospermia with defects in nucleotide homeostasis and energy metabolism. This sterile phenotype could be rescued by ICSI.FUNDING: The National Natural Science Foundation of China (82071697), Medical Innovation Project of Fujian Province (2020-CXB-051), open project of the NHC Key Laboratory of Male Reproduction and Genetics in Guangzhou (KF202004), Medical Research Foundation of Guangdong Province (A2021269), Guangdong Provincial Reproductive Science Institute Innovation Team grants (C-03), and Outstanding Young Talents Program of Capital Medical University (B2205).PMID:37713809 | DOI:10.1016/j.ebiom.2023.104798

Poult Sci. 2023 Aug 18;102(11):103020. doi: 10.1016/j.psj.2023.103020. Online ahead of print.ABSTRACTLiancheng white duck is a typical local duck breed in Fujian Province famous for its meat traits. To better understand how meat quality varies with breed, the chemical composition of breast meats of Liancheng white ducks (LD) and Cherry Valley ducks (CD) were examined using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS).The correlation between meat quality and the differential metabolites was further analyzed. The results showed that the effects of breed on duck breast meat were significant for pH, color, cooking loss, and shear force. Liancheng white duck breast meat exhibited a higher shear force and pH, and lower cooking loss and lightness (L*24), redness (a*24), and yellowness (b*24) than CD. Metabolomic analysis revealed significant differences between the meat extracts from the 2 duck breeds. A total of 49 and 57 significantly different metabolites were identified in positive and negative ion modes, respectively. These differentially accumulated metabolites (DAMs) could be divided into 28 classes, of which the 4 main categories were carbohydrates, amino acids, fatty acids, and eicosanoids. Liancheng white duck might have better nutritional and medicinal value considering the higher content of (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), and prostaglandinF3α (PGF3α), having anti-inflammatory orantioxidant effects. Carbohydrate concentration negatively correlated with pH24. The 4 metabolites positively correlated with the shear force. These results provide an overall perspective for bridging the gap between variation of duck meat quality and metabolites with respect to breed.PMID:37713801 | DOI:10.1016/j.psj.2023.103020

Int Immunopharmacol. 2023 Sep 13;124(Pt A):110885. doi: 10.1016/j.intimp.2023.110885. Online ahead of print.ABSTRACTRecent studies suggested that altered gut microbiota may be related to the pathogenesis of rheumatoid arthritis (RA), albeit the exact mechanisms are unknown. In this study, we aimed to discover the particular mechanism of RA treatment by microbiota by investigating the effects of ferroptosis on gut microbiota and its metabolites in collagen-induced arthritis (CIA) mice. Mice were divided into five groups: control, CIA, erastin, BzATP, and BzATP + erastin group. We performed 16S rDNA sequencing and metabolomics analysis on mouse feces and found that erastin and BzATP altered the microbiota and metabolites. The findings demonstrated that the microbiota was significantly disturbed at the phylum (Proteobacteria, Firmicutes, and Bacteroidota) and genus level (Lachnospiraceae_NK4A136, Lactobacillus, and Bifidobacterium) in the CIA group, and erastin exacerbated this disturbance. Unexpectedly, BzATP treatment could repair the disruptive effects of erastin. Additionally, there were significant variations in metabolites between each group. Erastin worsened metabolite abnormalities in CIA mice, while BzATP mitigated them, consistent with the microbiota results. These findings provide novel perspectives and insights into the therapy of RA.PMID:37713784 | DOI:10.1016/j.intimp.2023.110885

Anal Chem. 2023 Sep 15. doi: 10.1021/acs.analchem.3c02756. Online ahead of print.ABSTRACTNuclear magnetic resonance (NMR) is a powerful technique with applications ranging from small molecule structure elucidation to metabolomics studies of living organisms. Typically, solution-state NMR requires a homogeneous liquid, and the whole sample is analyzed as a single entity. While adequate for homogeneous samples, such an approach is limited if the composition varies as would be the case in samples that are naturally heterogeneous or layered. In complex samples such as living organisms, magnetic susceptibility distortions lead to broad 1H line shapes, and thus, the additional spectral dispersion afforded by 2D heteronuclear experiments is often required for metabolite discrimination. Here, a novel, slice-selective 2D, 1H-13C heteronuclear single quantum coherence (HSQC) sequence was developed that exclusively employs shaped pulses such that only spins in the desired volume are perturbed. In turn, this permits multiple volumes in the tube to be studied during a single relaxation delay, increasing sensitivity and throughput. The approach is first demonstrated on standards and then used to isolate specific sample/sensor elements from a microcoil array and finally study slices within a living earthworm, allowing metabolite changes to be discerned with feeding. Overall, slice-selective NMR is demonstrated to have significant potential for the study of layered and other inhomogeneous samples of varying complexity. In particular, its ability to select subelements is an important step toward developing microcoil receive-only arrays to study environmental toxicity in tiny eggs, cells, and neonates, whereas localization in larger living species could help better correlate toxin-induced biochemical responses to the physical localities or organs involved.PMID:37713676 | DOI:10.1021/acs.analchem.3c02756

Cell Rep. 2023 Sep 13;42(9):113105. doi: 10.1016/j.celrep.2023.113105. Online ahead of print.ABSTRACTRelationships between the genome, transcriptome, and metabolome underlie all evolved phenotypes. However, it has proved difficult to elucidate these relationships because of the high number of variables measured. A recently developed data analytic method for characterizing the transcriptome can simplify interpretation by grouping genes into independently modulated sets (iModulons). Here, we demonstrate how iModulons reveal deep understanding of the effects of causal mutations and metabolic rewiring. We use adaptive laboratory evolution to generate E. coli strains that tolerate high levels of the redox cycling compound paraquat, which produces reactive oxygen species (ROS). We combine resequencing, iModulons, and metabolic models to elucidate six interacting stress-tolerance mechanisms: (1) modification of transport, (2) activation of ROS stress responses, (3) use of ROS-sensitive iron regulation, (4) motility, (5) broad transcriptional reallocation toward growth, and (6) metabolic rewiring to decrease NADH production. This work thus demonstrates the power of iModulon knowledge mapping for evolution analysis.PMID:37713311 | DOI:10.1016/j.celrep.2023.113105

Anal Chem. 2023 Sep 15. doi: 10.1021/acs.analchem.3c02419. Online ahead of print.ABSTRACTThe identification of xenobiotic biotransformation products is crucial for delineating toxicity and carcinogenicity that might be caused by xenobiotic exposures and for establishing monitoring systems for public health. However, the lack of available reference standards and spectral data leads to the generation of multiple candidate structures during identification and reduces the confidence in identification. Here, a UHPLC-HRMS-based metabolomics strategy integrated with a metabolite structure elucidation approach, namely, FragAssembler, was proposed to reduce the number of false-positive structure candidates. biotransformation product candidates were filtered by mass defect filtering (MDF) and multiple-group comparison. FragAssembler assembled fragment signatures from the MS/MS spectra and generated the modified moieties corresponding to the identified biotransformation products. The feasibility of this approach was demonstrated by the three biotransformation products of di(2-ethylhexyl)phthalate (DEHP). Comprehensive identification was carried out, and 24 and 13 biotransformation products of two xenobiotics, DEHP and 4'-Methoxy-α-pyrrolidinopentiophenone (4-MeO-α-PVP), were annotated, respectively. The number of 4-MeO-α-PVP biotransformation product candidates in the FragAssembler calculation results was approximately 2.1 times lower than that generated by BioTransformer 3.0. Our study indicates that the proposed approach has great potential for efficiently and reliably identifying xenobiotic biotransformation products, which is attributed to the fact that FragAssembler eliminates false-positive reactions and chemical structures and distinguishes modified moieties on isomeric biotransformation products. The FragAssembler software and associated tutorial are freely available at https://cosbi.ee.ncku.edu.tw/FragAssembler/ and the source code can be found at https://github.com/YuanChihChen/FragAssembler.PMID:37713273 | DOI:10.1021/acs.analchem.3c02419

Ginekol Pol. 2023 Sep 15. doi: 10.5603/gpl.96864. Online ahead of print.ABSTRACTPolycystic ovary syndrome (PCOS) is a multifactorial disorder with unknown etiology. The purpose of this systematic review is to analyze the available clinical trials on elemental supplementation in terms of improving biochemical parameters in women with PCOS. Electronic databases were searched from their inception until February 2023. Randomized controlled trials (RCTs) of PCOS during therapy with elemental supplementation alone or in combination with other elements were analyzed. Recommendations regarding supplementation with elements are not clear. There are many factors to consider, with the primary factor being the type of element and the possibility of supplementation and a balanced diet. Another aspect to consider is the presence of comorbidities, which may increase the demand for and absorption of elements. A final factor to be considered is the determination of the body's need for specific elements. Some elements may require supplementation (e.g., magnesium, selenium, iodine, calcium), while others (e.g., iron, copper, potassium, zinc, manganese, chromium) are in sufficient amounts in a proper diet, and some should be limited (e.g., sodium, phosphorus). It is necessary to determine the optimal dose of each element in order to improve the biochemical parameters of PCOS as much as possible, while at the same time avoiding the negative effects of excessive consumption.PMID:37713235 | DOI:10.5603/gpl.96864

Appl Microbiol Biotechnol. 2023 Sep 15. doi: 10.1007/s00253-023-12763-2. Online ahead of print.ABSTRACTCrotonis Fructus (CF), a poisonous traditional laxative, has been used to treat constipation, edema, ascites, and inflammation for more than 2000 years. However, CF possesses toxicity and its toxic mechanism is still unclear. Thus, this research explored the deleterious impacts and underlying mechanisms of CF by evaluating alterations in gut microbiota composition and metabolites. High-throughput sequencing was employed on the 16S rDNA gene to explore the intestinal flora. The untargeted metabolomics method was utilized for evaluating serum metabolomics analysis. The results showed that CF could induce obvious hepatic and gastrointestinal damage by histopathologic morphology of the liver, stomach, duodenum, and colon. According to 16S rDNA sequencing, CF can cause gut microbiota disturbance in rats, and the abundance of opportunistic pathogens such as Clostridia_UCG_014_unclassified increased significantly, while the levels of beneficial bacterial Lactobacillus remarkably declined after CF treatment. Additionally, metabolomics analysis demonstrated that CF may induce toxicity by disrupting the glycerophospholipid metabolism pathway and metabolites such as phosphatidylcholine and phosphatidylethanolamine. Moreover, a correlation study revealed the link between intestinal flora, serum metabolites, and toxicity-related biochemical markers. The results provide a new idea for the research and clinical application of toxic traditional medicine. KEY POINTS: • Crotonis Fructus could affect the gut flora and serum metabolic disruption in SD rats. • Crotonis Fructus could promote the proliferation of harmful bacteria and inhibit beneficial bacteria. • Glycerophospholipid metabolism was disturbed by Crotonis Fructus.PMID:37713114 | DOI:10.1007/s00253-023-12763-2

Gigascience. 2022 Dec 28;12:giad065. doi: 10.1093/gigascience/giad065.ABSTRACTIn human health research, metabolic signatures extracted from metabolomics data have a strong added value for stratifying patients and identifying biomarkers. Nevertheless, one of the main challenges is to interpret and relate these lists of discriminant metabolites to pathological mechanisms. This task requires experts to combine their knowledge with information extracted from databases and the scientific literature. However, we show that most compounds (>99%) in the PubChem database lack annotated literature. This dearth of available information can have a direct impact on the interpretation of metabolic signatures, which is often restricted to a subset of significant metabolites. To suggest potential pathological phenotypes related to overlooked metabolites that lack annotated literature, we extend the "guilt-by-association" principle to literature information by using a Bayesian framework. The underlying assumption is that the literature associated with the metabolic neighbors of a compound can provide valuable insights, or an a priori, into its biomedical context. The metabolic neighborhood of a compound can be defined from a metabolic network and correspond to metabolites to which it is connected through biochemical reactions. With the proposed approach, we suggest more than 35,000 associations between 1,047 overlooked metabolites and 3,288 diseases (or disease families). All these newly inferred associations are freely available on the FORUM ftp server (see information at https://github.com/eMetaboHUB/Forum-LiteraturePropagation).PMID:37712592 | DOI:10.1093/gigascience/giad065