PubMed

Sci Rep. 2023 Nov 21;13(1):20325. doi: 10.1038/s41598-023-47800-7.ABSTRACTPrimary glomerulonephritis diseases (PGDs) are known as the top causes of chronic kidney disease worldwide. Renal biopsy, an invasive method, is the main approach to diagnose PGDs. Studying the metabolome profiles of kidney diseases is an inclusive approach to identify the disease's underlying pathways and discover novel non-invasive biomarkers. So far, different experiments have explored the metabolome profiles in different PGDs, but the inconsistencies might hinder their clinical translations. The main goal of this meta-analysis study was to achieve consensus panels of dysregulated metabolites in PGD sub-types. The PGDs-related metabolome profiles from urine samples in humans were selected in a comprehensive search. Amanida package in R software was utilized for performing the meta-analysis. Through sub-type analyses, the consensus list of metabolites in each category was obtained. To identify the most affected pathways, functional enrichment analysis was performed. Also, a gene-metabolite network was constructed to identify the key metabolites and their connected proteins. After a vigorous search, among the 11 selected studies (15 metabolite profiles), 270 dysregulated metabolites were recognized in urine of 1154 PGDs and control samples. Through sub-type analyses by Amanida package, the consensus list of metabolites in each category was obtained. Top dysregulated metabolites (vote score of ≥ 4 or ≤ - 4) in PGDs urines were selected as main panel of meta-metabolites including glucose, leucine, choline, betaine, dimethylamine, fumaric acid, citric acid, 3-hydroxyisovaleric acid, pyruvic acid, isobutyric acid, and hippuric acid. The enrichment analyses results revealed the involvement of different biological pathways such as the TCA cycle and amino acid metabolisms in the pathogenesis of PGDs. The constructed metabolite-gene interaction network revealed the high centralities of several metabolites, including pyruvic acid, leucine, and choline. The identified metabolite panels could shed a light on the underlying pathological pathways and be considered as non-invasive biomarkers for the diagnosis of PGD sub-types.PMID:37990116 | DOI:10.1038/s41598-023-47800-7

Sci Rep. 2023 Nov 21;13(1):20365. doi: 10.1038/s41598-023-47657-w.ABSTRACTAbscisic acid (ABA) has been shown to mitigate the deleterious effects of abiotic stresses and to regulate plant growth and development. Salinity is one of the important abiotic stresses affecting plant cell metabolism and physiology, which causes serious damages to crops. In this study, we investigated the protective role of exogenous ABA on leaves in response to salinity stress using rice seedlings (two leaf-one heart) subjected to three treatments: ZCK (control), ZS (50 mM NaCl), and ZSA (5 mg L-1 ABA + 50 mM NaCl). We carried out transcriptomic and metabolomic analyses to identify the molecular mechanisms by which ABA protects plants against salt stress. Results showed that 1159 differentially expressed genes (DEGs) (916 up-regulated, 243 down-regulated) and 63 differentially accumulated metabolites (DAMs) (42 up-regulated, 21 down-regulated) were identified between the ZS and ZSA treatments, respectively. In addition, ABA pretreatment regulated the expression pattern of genes responsible for oxidation redox, starch and sucrose metabolism, and phenylpropanoid biosynthesis. The combined transcriptomic and metabolomic analysis revealed that 16 DEGs and 2 DAMs were involved in Flavonoid biosynthesis and 8 DEGs and 2 DAMs were involved alpha-Linolenic acid metabolism which are responsible for salinity stress tolerance through induced by exogenous ABA. Overall, ABA could enhance rice leaves growth and development mainly by regulating flavonoid biosynthesis and linoleic acid metabolism pathway.PMID:37990109 | DOI:10.1038/s41598-023-47657-w

Nat Commun. 2023 Nov 21;14(1):6763. doi: 10.1038/s41467-023-42424-x.ABSTRACTCholine is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.PMID:37990006 | DOI:10.1038/s41467-023-42424-x

NPJ Aging. 2023 Nov 21;9(1):28. doi: 10.1038/s41514-023-00124-2.ABSTRACTGlaucoma is a leading cause of blindness worldwide in older people. Profiling the aqueous humor, including the metabolites it contains, is useful to understand physiological and pathological conditions in the eye. In the current study, we used mass spectrometry (MS) to characterize the aqueous humor metabolomic profile and biological features of patients with glaucoma. Aqueous humor samples were collected during trabeculectomy surgery or cataract surgery and analyzed with global metabolomics. We included 40 patients with glaucoma (32 with POAG, 8 with NTG) and 37 control subjects in a discovery study. VIP analysis revealed five metabolites that were elevated and three metabolites that were reduced in the glaucoma patients. The identified metabolomic profile had an area under the receiver operating characteristic curve of 0.953. Among eight selected metabolites, the glutathione level was significantly decreased in association with visual field defects. Moreover, in a validation study to confirm the reproducibility of our findings, the glutathione level was reduced in NTG and POAG patients compared with a cataract control group. Our findings demonstrate that aqueous humor profiling can help to diagnose glaucoma and that various aqueous humor metabolites are correlated with clinical parameters in glaucoma patients. In addition, glutathione is clearly reduced in the aqueous humor of glaucoma patients with both IOP-dependent and IOP-independent disease subtypes. These findings indicate that antioxidant agents in the aqueous humor reflect glaucomatous optic nerve damage and that excessive oxidative stress may be involved in the pathogenesis of glaucoma.PMID:37990002 | DOI:10.1038/s41514-023-00124-2

Metabolomics. 2023 Nov 21;19(12):96. doi: 10.1007/s11306-023-02061-3.ABSTRACTINTRODUCTION: Plastics used in everyday materials accumulate as waste in the environment and degrade over time. The impacts of the resulting particulate micro- and nanoplastics on human health remain largely unknown. In pregnant mice, we recently demonstrated that exposure to nanoplastics throughout gestation and during lactation resulted in changes in brain structure detected on MRI. One possible explanation for this abnormal postnatal brain development is altered fetal brain metabolism.OBJECTIVES: To determine the effect of maternal exposure to nanoplastics on fetal brain metabolism.METHODS: Healthy pregnant CD-1 mice were exposed to 50 nm polystyrene nanoplastics at a concentration of 106 ng/L through drinking water during gestation. Fetal brain samples were collected at embryonic day 17.5 (n = 18-21 per group per sex) and snap-frozen in liquid nitrogen. Magic angle spinning nuclear magnetic resonance was used to determine metabolite profiles and their relative concentrations in the fetal brain.RESULTS: The relative concentrations of gamma-aminobutyric acid (GABA), creatine and glucose were found to decrease by 40%, 21% and 30% respectively following maternal nanoplastic exposure when compared to the controls (p < 0.05). The change in relative concentration of asparagine with nanoplastic exposure was dependent on fetal sex (p < 0.005).CONCLUSION: Maternal exposure to polystyrene nanoplastics caused abnormal fetal brain metabolism in mice. The present study demonstrates the potential impacts of nanoplastic exposure during fetal development and motivates further studies to evaluate the risk to human pregnancies.PMID:37989919 | DOI:10.1007/s11306-023-02061-3

Food Res Int. 2023 Dec;174(Pt 1):113509. doi: 10.1016/j.foodres.2023.113509. Epub 2023 Sep 23.ABSTRACTThe effects of changes in lipids on the formation of Zn-protoporphyrin (ZnPP) during the processing of Nuodeng ham were analyzed using a lipidomics approach based on UHPLC-MS/MS. The Nuodeng ham samples had a strong fluorescence emission peak at 590 nm, and the fluorescence intensity increased with the processing time. Lipid profiles were mainly affected by processing time. A total of 5 lipid classes were detected, of which glycerophospholipids (GP) and glycerolipids (GL) were the most abundant lipids. Fifty differential lipid compounds were screened, which were mainly GP and GL. Correlation analysis showed that 13 differential lipid compounds were significantly positively correlated with ZnPP content, and they contained more linoleic acid and oleic acid branch chains. Meanwhile, all triglycerides (TG) were negatively correlated with heme content, and they were enriched in stearic acid and palmitic acid branch chains. These findings can deepen the understanding of the relationship between ZnPP and lipids.PMID:37986504 | DOI:10.1016/j.foodres.2023.113509

Food Res Int. 2023 Dec;174(Pt 1):113596. doi: 10.1016/j.foodres.2023.113596. Epub 2023 Oct 15.ABSTRACTThe optimization of processed meats through salt replacement using KCl and k-lactate may reduce the risk of chronic diseases through reduction in dietary sodium. The objective of this study was to investigate the changes and relationships between microbial and lipid metabolism during the fermentation of restructured duck ham with different salt substitutions. Lactobacillus and Staphylococcus were found to be the dominant bacterial species in the 30 % KCl + 70 % NaCl (w/w) and 25 % k-lactate + 75 % NaCl (w/w). The LefSe analysis showed that different biomarkers were present in different ham groups, and the PLS-DA showed that triglycerides (GL) and glycerophospholipids (GP) were the two classes with the highest abundance. Besides, the KEGG pathway analysis revealed that glycerophospholipid metabolism and triglyceride metabolism were also the main metabolic pathways. According to the correlation study, Staphylococcus, Halomonas, and Lactobacillus were mostly linked to the important metabolic pathways in restructured ham. Our findings serve as a foundation for quality assurance and product enhancement for low-salt restructured ham.PMID:37986459 | DOI:10.1016/j.foodres.2023.113596

Sci Rep. 2023 Nov 21;13(1):20385. doi: 10.1038/s41598-023-47558-y.ABSTRACTOxyresveratrol has been documented benefits for neurodegenerative disease. However, the specific molecular mechanisms and pathways involved is currently limited. This study aimed to investigate the potential neuroprotective mechanisms of oxyresveratrol using rotenone-induced human neuroblastoma SH-SY5Y cytotoxicity. Cells were divided into the following groups: control, rotenone, and oxyresveratrol pre-treated before being exposed to rotenone. Cellular assays were performed to investigate neuroprotective effects of oxyresveratrol. The results showed that 20 μM oxyresveratrol was effective in preventing rotenone-induced cell death and decreasing ROS levels in the cells. The alteration of metabolites and pathways involved in the neuroprotective activities of oxyresveratrol were further investigated using LC-QTOF-MS/MS untargeted metabolomics approach. We hypothesized that oxyresveratrol's neuroprotective effects would be associated with neurodegenerative pathways. A total of 294 metabolites were identified. 7,8-dihydrobiopterin exhibited the highest VIP scores (VIP > 3.0; p < 0.05), thus considered a biomarker in this study. Our results demonstrated that pretreatment with oxyresveratrol upregulated the level of 7,8-dihydrobiopterin compared to the positive control. Pathway analysis verified that 7,8-dihydrobiopterin was primarily associated with phenylalanine, tyrosine, and tryptophan metabolism (impact = 1, p < 0.001), serving as essential cofactors for enzymatic function in the dopamine biosynthesis pathway. In conclusion, oxyresveratrol may be benefit for the prevention of neurodegenerative diseases by increasing 7,8-dihydrobiopterin concentration.PMID:37989867 | DOI:10.1038/s41598-023-47558-y

Nat Commun. 2023 Nov 21;14(1):7572. doi: 10.1038/s41467-023-43378-w.ABSTRACTPatients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain-containing 2 (SETD2) has been identified as an important tumor suppressor and an immunosuppressor in ccRCC. However, the role of SETD2 in ccRCC generation in PKD remains largely unexplored. Herein, we perform metabolomics, lipidomics, transcriptomics and proteomics within SETD2 loss induced PKD-ccRCC transition mouse model. Our analyses show that SETD2 loss causes extensive metabolic reprogramming events that eventually results in enhanced sphingomyelin biosynthesis and tumorigenesis. Clinical ccRCC patient specimens further confirm the abnormal metabolic reprogramming and sphingomyelin accumulation. Tumor symptom caused by Setd2 knockout is relieved by myriocin, a selective inhibitor of serine-palmitoyl-transferase and sphingomyelin biosynthesis. Our results reveal that SETD2 deficiency promotes large-scale metabolic reprogramming and sphingomyelin biosynthesis during PKD-ccRCC transition. This study introduces high-quality multi-omics resources and uncovers a regulatory mechanism of SETD2 on lipid metabolism during tumorigenesis.PMID:37989747 | DOI:10.1038/s41467-023-43378-w

Cell Death Dis. 2023 Nov 22;14(11):758. doi: 10.1038/s41419-023-06305-x.ABSTRACTAutophagy inducers can prevent cardiovascular aging and age-associated diseases including atherosclerosis. Therefore, we hypothesized that autophagy-inducing compounds that act on atherosclerosis-relevant cells might have a protective role in the development of atherosclerosis. Here we identified 3,4-dimethoxychalcone (3,4-DC) as an inducer of autophagy in several cell lines from endothelial, myocardial and myeloid/macrophagic origin, as demonstrated by the aggregation of the autophagosome marker GFP-LC3 in the cytoplasm of cells, as well as the downregulation of its nuclear pool indicative of autophagic flux. In this respect, 3,4-DC showed a broader autophagy-inducing activity than another chalcone (4,4- dimethoxychalcone), spermidine and triethylene tetramine. Thus, we characterized the potential antiatherogenic activity of 3,4-DC in two different mouse models, namely, (i) neointima formation with smooth muscle expansion of vein segments grafted to the carotid artery and (ii) genetically predisposed ApoE-/- mice fed an atherogenic diet. In the vein graft model, local application of 3,4-DC was able to maintain the lumen of vessels and to reduce neointima lesions. In the diet-induced model, intraperitoneal injections of 3,4-DC significantly reduced the number of atherosclerotic lesions in the aorta. In conclusion, 3,4-DC stands out as an autophagy inducer with potent antiatherogenic activity.PMID:37989732 | DOI:10.1038/s41419-023-06305-x

J Sci Food Agric. 2023 Nov 21. doi: 10.1002/jsfa.13127. Online ahead of print.ABSTRACTBACKGROUND: The hyperlipidaemia was characterized by abnormally elevated blood lipids. Quinoa saponins (QS) has multiple pharmacological activities, including antitumor, bactericidal and immune-enhancing. However the lipid-lowering effect and mechanisms of QS in vivo have been scarcely reported.METHODS: The effect of QS against hyperlipidaemia induced by high-fat diet (HFD) in rats was explored based on gut microbiota and serum non-targeted metabolomics.RESULTS: The study demonstrated that the supplementation of QS could reduce serum lipids, body weight, liver injury and inflammation. 16S rRNA sequencing demonstrated that QS mildly increased alpha-diversity, altered the overall structure of intestinal flora, decreased the relative richness of Firmicutes, the ratio of Firmicutes/Bacteroidetes (F/B) (P<0.05) and increased the relative richness of Actinobacteria, Bacteroidetes, Bifidobacterium, Roseburia and Coprococcus (P<0.05). Simultaneously, metabolomics analysis showed that QS altered serum functional metabolites with respect to bile acid biosynthesis, arachidonic acid metabolism, and taurine and hypotaurine metabolism, which were closely related to bile acid metabolism and fatty acid β-oxidation. Furthermore, QS increased protein levels of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltransferase 1 (CPT-1), which were related to the screened metabolic pathways. Spearman correlation analysis showed that there was a correlation between gut microbiota and differential metabolites.CONCLUSION: QS could prevent lipid metabolism disorders in hyperlipidemic rats, which may be closely associated with the regulation of the gut microbiota and multiple metabolic pathways. This study may provide new evidence for QS as a natural active substance for the prevention of hyperlipidaemia. This article is protected by copyright. All rights reserved.PMID:37989713 | DOI:10.1002/jsfa.13127

Endocrinol Metab (Seoul). 2023 Nov 21. doi: 10.3803/EnM.2023.1814. Online ahead of print.ABSTRACTMetabolism is a dynamic network of biochemical reactions that support systemic homeostasis amidst changing nutritional, environmental, and physical activity factors. The circulatory system facilitates metabolite exchange among organs, while the endocrine system finely tunes metabolism through hormone release. Endocrine disorders like obesity, diabetes, and Cushing's syndrome disrupt this balance, contributing to systemic inflammation and global health burdens. They accompany metabolic changes on multiple levels from molecular interactions to individual organs to the whole body. Understanding how metabolic fluxes relate to endocrine disorders illuminates the underlying dysregulation. Cancer is increasingly considered a systemic disorder because it not only affects cells in localized tumors but also the whole body, especially in metastasis. In tumorigenesis, cancer-specific mutations and nutrient availability in the tumor microenvironment reprogram cellular metabolism to meet increased energy and biosynthesis needs. Cancer cachexia results in metabolic changes to other organs like muscle, adipose tissue, and liver. This review explores the interplay between the endocrine system and systems-level metabolism in health and disease. We highlight metabolic fluxes in conditions like obesity, diabetes, Cushing's syndrome, and cancers. Recent advances in metabolomics, fluxomics, and systems biology promise new insights into dynamic metabolism, offering potential biomarkers, therapeutic targets, and personalized medicine.PMID:37989266 | DOI:10.3803/EnM.2023.1814

Anal Chem. 2023 Nov 21. doi: 10.1021/acs.analchem.3c02314. Online ahead of print.ABSTRACTNuclear magnetic resonance (NMR) approaches have been described as a powerful method for measuring oxygen in tissue cultures and body fluids by using relaxation time dependencies of substances on pO2. The present NMR study describes methods to longitudinally monitor global, in situ intracellular, and spatially resolved oxygen tension in culture media and 3D cell cultures using relaxation times of water without the need to use external sensors. 1H NMR measurements of water using a modified inversion recovery pulse scheme were employed for global, i.e., intra- and extracellular oxygen estimation in an NMR-bioreactor. The combination of 1H relaxation time T1 and diffusion measurements of water was employed for in situ cellular oxygen content determination. Spatially selective water relaxation time estimations were used for spatially resolved oxygen quantification along the NMR tube length. The inclusion in a study protocol of the presented techniques for oxygen quantification, as a surrogate marker of oxidative phosphorylation (OXPHOS), provides the possibility to measure mitochondrial respiration and metabolic changes simultaneously.PMID:37989262 | DOI:10.1021/acs.analchem.3c02314

Anal Chem. 2023 Nov 21. doi: 10.1021/acs.analchem.3c03651. Online ahead of print.ABSTRACTFor the characterization of the metabolic heterogeneity of cell populations, high-throughput single-cell analysis platforms are needed. In this study, we utilized mass spectrometry (MS) enhanced with ion mobility separation (IMS) and coupled with an automated sampling platform, fiber-based laser ablation electrospray ionization (f-LAESI), for in situ high-throughput single-cell metabolomics in soybean (Glycine max) root nodules. By fully automating the in situ sampling platform, an overall sampling rate of 804 cells/h was achieved for high numbers (>500) of tissue-embedded plant cells. This is an improvement by a factor of 13 compared to the previous f-LAESI-MS configuration. By introducing IMS, the molecular coverage improved, and structural isomers were separated on a millisecond time scale. The enhanced f-LAESI-IMS-MS platform produced 259 sample-related peaks/cell, almost twice as much as the 131 sample-related peaks/cell produced by f-LAESI-MS without IMS. Using the upgraded system, two types of metabolic heterogeneity characterization methods became possible. For unimodal metabolite abundance distributions, the metabolic noise reported on the metabolite level variations within the cell population. For bimodal distributions, the presence of metabolically distinct subpopulations was established. Discovering these latent cellular phenotypes could be linked to the presence of different cell states, e.g., proliferating bacteria in partially occupied plant cells and quiescent bacteroids in fully occupied cells in biological nitrogen fixation, or spatial heterogeneity due to altered local environments.PMID:37989253 | DOI:10.1021/acs.analchem.3c03651

EBioMedicine. 2023 Nov 20;98:104884. doi: 10.1016/j.ebiom.2023.104884. Online ahead of print.ABSTRACTBACKGROUND: Socioeconomic inequalities in cardiovascular disease risk begin early in life and are more pronounced in females than males later in life. Causal atherogenic traits explaining this are not well understood. We explored sex-specific associations between childhood socioeconomic position (SEP) and molecular measures of systemic metabolism across early life.METHODS: Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort in southwest England. Pregnant women with an expected delivery date between 1991 and 1992 were invited to participate. Maternal education was the primary indicator of SEP. Concentrations of 148 metabolic traits from targeted metabolomics (nuclear magnetic resonance spectroscopy) from research clinics at ages 7, 15, 18 and 25 years were analysed. The sex-specific slope index of inequality (SII) in trajectories of metabolic traits was estimated using multilevel models.FINDINGS: Total number of participants included was 6537 (12,543 repeated measures). Lower maternal education was associated with more adverse levels of several atherogenic lipids and key metabolic traits among females at age 7 years, but not males. For instance, SII for very small very-low-density lipoprotein (VLDL) concentrations was 0.16SD (95% CI: 0.01, 0.30) among females and -0.02SD (95% CI: -0.16, 0.13) among males. Between 7 and 25 years, inequalities widened among females and emerged among males particularly for VLDL particle concentrations, apolipoprotein-B concentrations, and inflammatory glycoprotein acetyls. For instance, at 25 years, SII for very small VLDL concentrations was 0.36SD (95% CI: 0.20, 0.52) and 0.22SD (95% CI: 0.04, 0.40) among females and males respectively.INTERPRETATION: Prevention of socioeconomic inequalities in cardiovascular disease risk requires a life course approach beginning at the earliest opportunity, especially among females.FUNDING: The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). KON is supported by a Health Research Board (HRB) of Ireland Investigator Led Award (ILP-PHR-2022-008). JB, GDS and KT work in a unit funded by the UK MRC (MC_UU_00011/1 and MC UU 00011/3) and the University of Bristol. OR is supported by a UKRI Future Leaders Fellowship (MR/S03532X/1). These funding sources had no role in the design and conduct of this study. This publication is the work of the authors and KON will serve as guarantor for the contents of this paper.PMID:37989036 | DOI:10.1016/j.ebiom.2023.104884

Environ Sci Technol. 2023 Nov 21. doi: 10.1021/acs.est.3c06284. Online ahead of print.ABSTRACTThe copper hydroxide [Cu(OH)2] nanopesticide is an emerging agricultural chemical that can negatively impact aquatic organisms. This study evaluated the behavioral changes of zebrafish larvae exposed to the Cu(OH)2 nanopesticide and assessed its potential to induce neurotoxicity. Metabolomic and transcriptomic profiling was also conducted to uncover the molecular mechanisms related to potential neurotoxicity. The Cu(OH)2 nanopesticide at 100 μg/L induced zebrafish hypoactivity, dark avoidance, and response to the light stimulus, suggestive of neurotoxic effects. Altered neurotransmitter-related pathways (serotoninergic, dopaminergic, glutamatergic, GABAergic) and reduction of serotonin (5-HT), dopamine (DA), glutamate (GLU), γ-aminobutyric acid (GABA), and several of their precursors and metabolites were noted following metabolomic and transcriptomic analyses. Differentially expressed genes (DEGs) were associated with the synthesis, transport, receptor binding, and metabolism of 5-HT, DA, GLU, and GABA. Transcripts (or protein levels) related to neurotransmitter receptors for 5-HT, DA, GLU, and GABA and enzymes for the synthesis of GLU and GABA were downregulated. Effects on both the glutamatergic and GABAergic pathways in zebrafish were specific to the nanopesticide and differed from those in fish exposed to copper ions. Taken together, the Cu(OH)2 nanopesticide induced developmental neurotoxicity in zebrafish by inhibiting several neurotransmitter-related pathways. This study presented a model for Cu(OH)2 nanopesticide-induced neurotoxicity in developing zebrafish that can inform ecological risk assessments.PMID:37988762 | DOI:10.1021/acs.est.3c06284

Proc Natl Acad Sci U S A. 2023 Nov 28;120(48):e2313197120. doi: 10.1073/pnas.2313197120. Epub 2023 Nov 21.ABSTRACTA lead aryl pyrrolidinone anilide identified using high-throughput in vivo screening was optimized for efficacy, crop safety, and weed spectrum, resulting in tetflupyrolimet. Known modes of action were ruled out through in vitro enzyme and in vivo plant-based assays. Genomic sequencing of aryl pyrrolidinone anilide-resistant Arabidopsis thaliana progeny combined with nutrient reversal experiments and metabolomic analyses confirmed that the molecular target of the chemistry was dihydroorotate dehydrogenase (DHODH), the enzyme that catalyzes the fourth step in the de novo pyrimidine biosynthesis pathway. In vitro enzymatic and biophysical assays and a cocrystal structure with purified recombinant plant DHODH further confirmed this enzyme as the target site of this class of chemistry. Like known inhibitors of other DHODH orthologs, these molecules occupy the membrane-adjacent binding site of the electron acceptor ubiquinone. Identification of a new herbicidal chemical scaffold paired with a novel mode of action, the first such finding in over three decades, represents an important leap in combatting weed resistance and feeding a growing worldwide population.PMID:37988466 | DOI:10.1073/pnas.2313197120

Eur J Emerg Med. 2023 Nov 21. doi: 10.1097/MEJ.0000000000001097. Online ahead of print.NO ABSTRACTPMID:37988452 | DOI:10.1097/MEJ.0000000000001097

Eur J Clin Invest. 2023 Nov 21:e14129. doi: 10.1111/eci.14129. Online ahead of print.ABSTRACTBACKGROUND: The occurrence of gout is closely related to metabolism, but there is still a lack of evidence on the causal role of metabolites in promoting or preventing gout.METHODS: We applied a two-sample Mendelian randomization (MR) analysis to assess the association between 486 serum metabolites and gout using genome-wide association study statistics. The inverse variance weighting method was used to generate the main results, while sensitivity analyses using MR-Egger, weighted median, Cochran's Q test, Egger intercept test, and leave-one-out analysis, were performed to assess the stability and reliability of the results. We also performed a metabolic pathway analysis to identify potential metabolic pathways.RESULTS: After screening, 486 metabolites were retained for MR analysis. After screening by IVW and sensitivity analysis, 14 metabolites were identified with causal effect on gout (P < 0.05), among which hexadecanedioate was the most significant candidate metabolite associated with a lower risk of gout (IVW OR = 0.50; 95% CI = 0.38-0.67; P = 1.65 × 10-6 ). Metabolic pathway analysis identified one pathway that may be associated with the disease.CONCLUSION: This MR study combining genomics with metabolomics provides a novel insight into the causal role of blood metabolites in the risk of gout, which implies that examination of certain blood metabolites would be a feasible strategy for screening populations with a higher risk of gout.PMID:37988199 | DOI:10.1111/eci.14129

Methods Protoc. 2023 Nov 20;6(6):112. doi: 10.3390/mps6060112.ABSTRACTCell-free RNAs (cfRNAs) are promising analytes as non-invasive biomarkers and have even greater potential if tied in with metabolomics. Plasma is an optimal source for cfRNAs but is often derived from a variety of anticoagulants. Plasma obtained in heparin is suitable for metabolomics but is difficult to utilize for qPCR-based downstream analysis. In the present study, we aimed to develop a simple, time-efficient, and cost-effective heparinase protocol, followed by library preparation and sequencing of human plasma cfRNAs drawn and stored in heparin at -80 °C for several years. Blood was collected in CPT™ sodium heparin tubes from patients with chronic HCV infection (NCT02400216) at the National Institutes of Health (NIH) Clinical Center. Plasma cfRNAs were treated with heparinase I and used for library preparation and next-generation sequencing (NGS). Heparinase treatment maintained RNA integrity and allowed for successful library preparation for all the study subjects even with 7 ng of cfRNAs as starting material. The classification report derived from Pavian R package v1.2.0 showed no artificial reads. The abundance of chordate over microbial reads suggests no addition of experimental error through heparinase I treatment. We report a novel and practical approach to heparinase treatment for human plasma collected and frozen in sodium heparin for several years. This is an effective demonstration of utilizing heparin plasma for NGS and downstream transcriptomic research, which could then be integrated with metabolomics from the same samples, maximizing efficiency and minimizing blood draws.PMID:37987359 | DOI:10.3390/mps6060112