PubMed

Exp Dermatol. 2023 Mar 31. doi: 10.1111/exd.14796. Online ahead of print.ABSTRACTRecent metabolic studies have indicated that several metabolites in blood and urine of psoriasis functionally involved in the pathogenesis of psoriasis, but the skin metabonomics research of psoriasis is limited. We aimed to investigate the metabolic profiling of lesional and nonlesional skin and screen out potential biomarkers for psoriasis. We performed liquid chromatography-mass spectrometry (LC-MS)-based nontargeted metabolomic analysis to compare metabolic profile between lesional and nonlesional skin from 12 patients with psoriasis vulgaris. A total of 3463 metabolites were detected, of which 769 (346 named and 423 unnamed) in positive ion mode and 179 (80 named and 99 unnamed) in negative ion mode were significantly different between lesional and nonlesional skin. These different metabolites were mainly derived from amino acid, lipid and nucleotide metabolism, and involved in cell proliferation and apoptosis regulation. Fourteen metabolites (10 upregulated and 4 downregulated) were identified as the most potentially significant biomarkers. Interestingly, seven of them were positively (l-gamma-glutamyl-l-leucine, 2-methylcitric acid, l-palmitoylcarnitine, inosine, eicosapentaenoic acid and 13-hydroxy-octadecaenoic acid) or negatively (l-serine) correlated with disease severity. Significant differences of metabolic characteristics were found between lesional and nonlesional skin, which may contribute to assess the severity of psoriasis and therapeutic responses.PMID:36999576 | DOI:10.1111/exd.14796

Hepatology. 2023 Apr 3. doi: 10.1097/HEP.0000000000000375. Online ahead of print.ABSTRACTBACKGROUND AIMS: Nonalcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis, is emerging as a leading etiology of hepatocellular carcinoma (HCC). Lipidomics analyses in the liver have shown that the levels of polyunsaturated phosphatidylcholine (PC) are decreased in NASH patients, but the roles of membrane PC composition in the pathogenesis of NASH has not been investigated. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a phospholipid (PL) remodeling enzyme that produces polyunsaturated PLs, is a major determinant of membrane PC content in the liver.APPROACH RESULTS: The expression of LPCAT3 and the correlation between its expression and NASH severity were analyzed in human patient samples. We examined the effect of Lpcat3 deficiency on NASH progression using Lpcat3 liver specific knockout mice (LKO). RNA sequencing, lipidomics, and metabolomics were performed in liver samples. Primary hepatocytes and hepatic cell lines were used for in vitro analyses. We show that LPCAT3 is dramatically suppressed in human NASH livers, and its expression is inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency enhances reactive oxygen species production due to impaired mitochondrial homeostasis. Loss of Lpcat3 increases inner mitochondrial membrane PL saturation and elevates stress-induced autophagy, resulting in reduced mitochondrial content and increased fragmentation. Furthermore, overexpressing Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH.CONCLUSIONS: These results demonstrate that membrane PL composition modulates the progression of NASH and that manipulating LPCAT3 expression could be an effective therapeutic for NASH.PMID:36999536 | DOI:10.1097/HEP.0000000000000375

NMR Biomed. 2023 Mar 30:e4941. doi: 10.1002/nbm.4941. Online ahead of print.ABSTRACTThe diagnosis of pediatric tuberculosis (TB) remains a major challenge; hence the evaluation of new tools for improved diagnostics is urgently required. We investigated the serum metabolic profile of children with culture-confirmed intra-thoracic TB (ITTB) (n=23) and compared it with those of non-TB controls (NTC) (n=13) using the proton (1 H) nuclear magnetic resonance (NMR) spectroscopy-based targeted and untargeted metabolomics approach. In targeted metabolic profiling, five metabolites (histidine (His), glycerophosphocholine (GPC), creatine/phosphocreatine (Cr/PCr), acetate (Ace), and choline (Cho)) differentiated TB children from NTC. Additionally, seven discriminatory metabolites [(N-α-acetyl-lysine (NAAL), polyunsaturated fatty acids (PUFA), phenylalanine (Phe), lysine (Lys), lipids (Lip), Glutamate+Glutamine (Glu+Gln), and dimethylglycine (DMG)] were identified in untargeted metabolic profiling. The pathway analysis revealed alterations in six metabolic pathways. The altered metabolites were associated with impaired protein synthesis, hindered anti-inflammatory and cytoprotective mechanisms, abnormalities in energy generation processes and membrane metabolism, and deregulated fatty acid and lipid metabolisms in children with ITTB. The diagnostic significance of the classification models obtained from significantly distinguishing metabolites showed the sensitivity, specificity, and area under the curve of 78.2%, 84.6%, and 0.86, respectively, in the targeted profiling and 92.3%, 100%, and 0.99, respectively, in the untargeted profiling. Our findings highlight detectable metabolic changes in childhood ITTB; however, further validation is warranted in a large cohort of the pediatric population.PMID:36999218 | DOI:10.1002/nbm.4941

Front Nutr. 2023 Mar 14;10:1104926. doi: 10.3389/fnut.2023.1104926. eCollection 2023.ABSTRACTWithering is an important processing stage in green tea, which contributes to the tea flavor quality. The aim of this work was to comprehensively investigate the changes of chemical features and flavor attributes in Longjing green teas produced with five different withering degrees (moisture content of 75.05, 72.53, 70.07, 68.00, and 64.78%, w.b.). Combined with human sensory evaluation, electronic tongue and chromatic differences analysis, an assessment of the relationship between the withering degree and the sensory quality of Longjing tea was obtained. By using a non-targeted metabolomics approach, 69 significantly differential metabolites were screened. As the withering degree increased, most free amino acids and catechin dimers were increased, largely attributed to the hydrolysis of proteins and catechin oxidative polymerization, respectively. The contents of organic acids as well as phenolic acids and derivatives were reduced. Interestingly, flavone C-glycosides decreased overall while flavonol O-glycosides increased. The correlation analysis revealed that metabolites such as theasinensin F, theasinensin B, theaflavin, theaflavin-3,3'-gallate, theaflavin-3'-gallate, malic acid, succinic acid, quinic acid, theanine glucoside and galloylglucose had a greater influence on the taste and color of tea infusion (|r| > 0.6, p < 0.05). Overall, an appropriate withering degree at a moisture content of around 70% is more favorable to enhance the Longjing tea quality. These results may enhance the understanding of green tea flavor chemistry associated with withering and provide a theoretical basis for green tea processing.PMID:36998915 | PMC:PMC10043258 | DOI:10.3389/fnut.2023.1104926

Front Nutr. 2023 Mar 14;10:1142517. doi: 10.3389/fnut.2023.1142517. eCollection 2023.ABSTRACTINTRODUCTION: This study compared differences in physicochemical characteristics of the vinegar made by a mixed culture (MC) of Saccharomyces cerevisiae and Lactiplantibacillus plantarum and a pure culture (PC) of Saccharomyces cerevisiae.METHODS: The fermentation process was monitored, and metabolomics analysis by Liquid Chromagraphy-Mass Spectrometry (LC-MS) was applied to the compositional differences between PC and MC vinegars, combined with quantification of organic acids, amino acids and B vitamins.RESULTS: A total of 71 differential metabolites including amino acids, organic acids and carbohydrates, and six possible key metabolic pathways were identified. MC enhanced the malic acid utilization and pyruvate acid metabolism during fermentation, increasing substrate-level phosphorylation, and supplying more energy for cellular metabolism. Higher acidity at the beginning of acetic acid fermentation, resulting from lactic acid production by Lactiplantibacillus plantarum in MC, suppressed the cellular metabolism and growth of Acetobacter pasteurianus, but enhanced its alcohol metabolism and acetic acid production in MC. MC vinegar contained more vitamin B, total flavonoids, total organic acids, amino acids and had a higher antioxidant capacity. MC enhanced the volatile substances, particularly ethyl lactate, ethyl caprate and ethyl caproate, which contributed to a stronger fruity aroma.DISCUSSION: These results indicated the mixed culture in alcoholic fermentation can effectively enhance the flavor and quality of apple cider vinegar.PMID:36998906 | PMC:PMC10043408 | DOI:10.3389/fnut.2023.1142517

Crit Care Explor. 2023 Mar 27;5(4):e0881. doi: 10.1097/CCE.0000000000000881. eCollection 2023 Apr.ABSTRACTPerturbed host metabolism is increasingly recognized as a pillar of sepsis pathogenesis, yet the dynamic alterations in metabolism and its relationship to other components of the host response remain incompletely understood. We sought to identify the early host-metabolic response in patients with septic shock and to explore biophysiological phenotyping and differences in clinical outcomes among metabolic subgroups.DESIGN: We measured serum metabolites and proteins reflective of the host-immune and endothelial response in patients with septic shock.SETTING: We considered patients from the placebo arm of a completed phase II, randomized controlled trial conducted at 16 U.S. medical centers. Serum was collected at baseline (within 24 hr of the identification of septic shock), 24-hour, and 48-hour postenrollment. Linear mixed models were built to assess the early trajectory of protein analytes and metabolites stratified by 28-day mortality status. Unsupervised clustering of baseline metabolomics data was conducted to identify subgroups of patients.PATIENTS: Patients with vasopressor-dependent septic shock and moderate organ dysfunction that were enrolled in the placebo arm of a clinical trial.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: Fifty-one metabolites and 10 protein analytes were measured longitudinally in 72 patients with septic shock. In the 30 patients (41.7%) who died prior to 28 days, systemic concentrations of acylcarnitines and interleukin (IL)-8 were elevated at baseline and persisted at T24 and T48 throughout early resuscitation. Concentrations of pyruvate, IL-6, tumor necrosis factor-α, and angiopoietin-2 decreased at a slower rate in patients who died. Two groups emerged from clustering of baseline metabolites. Group 1 was characterized by higher levels of acylcarnitines, greater organ dysfunction at baseline and postresuscitation (p < 0.05), and greater mortality over 1 year (p < 0.001).CONCLUSIONS: Among patients with septic shock, nonsurvivors exhibited a more profound and persistent dysregulation in protein analytes attributable to neutrophil activation and disruption of mitochondrial-related metabolism than survivors.PMID:36998529 | PMC:PMC10047616 | DOI:10.1097/CCE.0000000000000881

Open Life Sci. 2023 Mar 27;18(1):20220556. doi: 10.1515/biol-2022-0556. eCollection 2023.ABSTRACTUnit variance (UV) scaling, mean centering (CTR) scaling, and Pareto (Par) scaling are three commonly used algorithms in the preprocessing of metabolomics data. Based on our NMR-based metabolomics studies, we found that the clustering identification performances of these three scaling methods were dramatically different as tested by the spectra data of 48 young athletes' urine samples, spleen tissue (from mice), serum (from mice), and cell (from Staphylococcus aureus) samples. Our data suggested that for the extraction of clustering information, UV scaling could serve as a robust approach for NMR metabolomics data for the identification of clustering analysis even with the existence of technical errors. However, for the purpose of discriminative metabolite identification, UV scaling, CTR scaling, and Par scaling could equally extract discriminative metabolites efficiently based on the coefficient values. Based on the data presented in this study, we propose an optimal working pipeline for the selection of scaling algorithms in NMR-based metabolomics analysis, which has the potential to serve as guidance for junior researchers working in the NMR-based metabolomics research field.PMID:36998512 | PMC:PMC10044292 | DOI:10.1515/biol-2022-0556

Front Microbiol. 2023 Mar 14;14:1089525. doi: 10.3389/fmicb.2023.1089525. eCollection 2023.ABSTRACTTermites are key decomposers of dead plant material involved in the organic matter recycling process in warm terrestrial ecosystems. Due to their prominent role as urban pests of timber, research efforts have been directed toward biocontrol strategies aimed to use pathogens in their nest. However, one of the most fascinating aspects of termites is their defense strategies that prevent the growth of detrimental microbiological strains in their nests. One of the controlling factors is the nest allied microbiome. Understanding how allied microbial strains protect termites from pathogen load could provide us with an enhanced repertoire for fighting antimicrobial-resistant strains or mining for genes for bioremediation purposes. However, a necessary first step is to characterize these microbial communities. To gain a deeper understanding of the termite nest microbiome, we used a multi-omics approach for dissecting the nest microbiome in a wide range of termite species. These cover several feeding habits and three geographical locations on two tropical sides of the Atlantic Ocean known to host hyper-diverse communities. Our experimental approach included untargeted volatile metabolomics, targeted evaluation of volatile naphthalene, a taxonomical profile for bacteria and fungi through amplicon sequencing, and further diving into the genetic repertoire through a metagenomic sequencing approach. Naphthalene was present in species belonging to the genera Nasutitermes and Cubitermes. We investigated the apparent differences in terms of bacterial community structure and discovered that feeding habits and phylogenetic relatedness had a greater influence than geographical location. The phylogenetic relatedness among nests' hosts influences primarily bacterial communities, while diet influences fungi. Finally, our metagenomic analysis revealed that the gene content provided both soil-feeding genera with similar functional profiles, while the wood-feeding genus showed a different one. Our results indicate that the nest functional profile is largely influenced by diet and phylogenetic relatedness, irrespective of geographical location.PMID:36998409 | PMC:PMC10043212 | DOI:10.3389/fmicb.2023.1089525

Nutr Metab (Lond). 2023 Mar 30;20(1):17. doi: 10.1186/s12986-023-00737-0.ABSTRACTOBJECTIVE: In this study, differentially expressed metabolites of vascular endothelial cells were examined to further understand the metabolic regulation of ischemic injury by untargeted metabolomics.METHOD: Human umbilical vein endothelial cells (HUVECs) were selected to construct an ischemia model using oxygen-glucose deprivation (OGD) and 0, 3, 6, and 9 h of treatment. After that, cell survival levels were determined by CCK8 detection. Flow cytometry, ROS detection, JC-1 detection, and western blotting were used to measure apoptosis and oxidative stress in cells. Then, combined with UPLC Orbitrap/MS, we verified the impacted metabolism pathways by western blotting and RT‒PCR.RESULTS: CCK8 assays showed that the survival of HUVECs was decreased with OGD treatment. Flow cytometry and the expression of cleaved caspase 3 showed that the apoptosis levels of HUVECs increased following OGD treatment. The ROS and JC-1 results further suggested that oxidative stress injury was aggravated. Then, combined with the heatmap, KEGG and IPA, we found that arginine metabolism was differentially altered during different periods of OGD treatment. Furthermore, the expression of four arginine metabolism-related proteins, ASS1, ARG2, ODC1 and SAT1, was found to change during treatment.CONCLUSION: Arginine metabolism pathway-related proteins were significantly altered by OGD treatment, which suggests that they may have a potential role in ischemic injury.PMID:36998018 | DOI:10.1186/s12986-023-00737-0

Metabolomics. 2023 Mar 30;19(4):32. doi: 10.1007/s11306-023-01990-3.ABSTRACTINTRODUCTION: Acute ischemic stroke (AIS) accounts for the majority of all stroke, globally the second leading cause of death. Due to its rapid development after onset, its early diagnosis is crucial.OBJECTIVES: We aim to identify potential highly reliable blood-based biomarkers for early diagnosis of AIS using quantitative plasma lipid profiling via a machine learning approach.METHODS: Lipidomics was used for quantitative plasma lipid profiling, based on ultra-performance liquid chromatography tandem mass spectrometry. Our samples were divided into a discovery and a validation set, each containing 30 AIS patients and 30 health controls (HC). Differentially expressed lipid metabolites were screened based on the criteria VIP > 1, p < 0.05, and fold change > 1.5 or < 0.67. The least absolute shrinkage and selection operator (LASSO) and random forest algorithms in machine learning were used to select differential lipid metabolites as potential biomarkers.RESULTS: Three key differential lipid metabolites, CarnitineC10:1, CarnitineC10:1-OH and Cer(d18:0/16:0), were identified as potential biomarkers for early diagnosis of AIS. The former two, associated with thermogenesis, were down-regulated, whereas the latter, associated with necroptosis and sphingolipd metabolism, was upregulated. Univariate and multivariate logistic regressions showed that these three lipid metabolites and the resulting diagnostic model exhibited a strong ability in discriminating between AIS patients and HCs in both the discovery and validation sets, with an area under the curve above 0.9.CONCLUSIONS: Our work provides valuable information on the pathophysiology of AIS and constitutes an important step toward clinical application of blood-based biomarkers for diagnosing AIS.PMID:36997715 | DOI:10.1007/s11306-023-01990-3

Commun Biol. 2023 Mar 30;6(1):344. doi: 10.1038/s42003-023-04715-3.ABSTRACTWhether basal metabolic activity in sperm has any influence on their fertilising capacity has not been explored. Using the pig as a model, the present study investigated the relationship of energetic metabolism with sperm quality and function (assessed through computer-assisted sperm analysis and flow cytometry), and fertility (in vitro fertilisation (IVF) outcomes). In semen samples from 16 boars, levels of metabolites related to glycolysis, ketogenesis and Krebs cycle were determined through a targeted metabolomics approach using liquid chromatography-tandem mass spectrometry. High-quality sperm are associated to greater levels of glycolysis-derived metabolites, and oocyte fertilisation and embryo development are conditioned by the sperm metabolic status. Interestingly, glycolysis appears to be the preferred catabolic pathway of the sperm giving rise to greater percentages of embryos at day 6. In conclusion, this study shows that the basal metabolic activity of sperm influences their function, even beyond fertilisation.PMID:36997604 | DOI:10.1038/s42003-023-04715-3

Orthod Craniofac Res. 2023 Mar 30. doi: 10.1111/ocr.12658. Online ahead of print.ABSTRACTAIMS: Pathological dental root resorption and alveolar bone loss are often detected only after irreversible damage. Biomarkers in the gingival crevicular fluid or saliva could provide a means for early detection, however, such biomarkers have proven elusive. We hypothesize that a multi-omic approach might yield reliable diagnostic signatures for root resorption and alveolar bone loss. Previously, we showed that extracellular vesicles (EVs) from osteoclasts and odontoclasts differ in their protein composition. In this study, we investigated the metabolome of EVs from osteoclasts, odontoclasts, and clasts (non-resorbing clastic cells).MATERIALS AND METHODS: Mouse hematopoietic precursors were cultured on dentine, bone, or plastic, in the presence of recombinant RANKL and CSF-1 to trigger differentiation along the clastic line. On day 7, the cells were fixed and the differentiation state and resorptive status of the clastic cells were confirmed. EVs were isolated from the conditioned media on day 7, and characterized by nanoparticle tracking and electron microscopy to ensure quality. Global metabolomic profiling was performed using a Thermo Q-Exactive Orbitrap mass spectrometer with a Dionex UHPLC and autosampler.RESULTS: We identified 978 metabolites in clastic EVs. Of those, 79 are potential biomarkers with Variable Interdependent Parameters scores of 2 or greater. Known metabolites cytidine, isocytosine, thymine, succinate, and citrulline were found at statistically higher levels in EVs from odontoclasts compared with osteoclasts.CONCLUSION: We conclude that numerous metabolites found in odontoclast EVs differ from those in osteoclast EVs, and thus represent potential biomarkers for root resorption and periodontal tissue destruction.PMID:36997279 | DOI:10.1111/ocr.12658

Mol Metab. 2023 Mar 28:101716. doi: 10.1016/j.molmet.2023.101716. Online ahead of print.ABSTRACTOBJECTIVES: The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both.METHODS: We performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants.RESULTS: MacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model of retinopathy indicates dietary serine and restriction can drive this depletion in complex sphingolipids. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins.CONCLUSIONS: These results highlight metabolic distinctions between these two diseases, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches.PMID:36997154 | DOI:10.1016/j.molmet.2023.101716

J Ethnopharmacol. 2023 Mar 28:116430. doi: 10.1016/j.jep.2023.116430. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Decoction (HQD), a traditional Chinese medicine (TCM) formula chronicled in Shang Han Lun, is safe and effective for treatment of ulcerative colitis (UC).AIM OF THE STUDY: To investigate the effect of HQD against dextran sulfate sodium (DSS)-induced UC mice by regulating gut microbiota and metabolites, and further explore the mechanism of fatty acid metabolism on macrophage polarization.MATERIALS AND METHODS: Based on 3% dextran sulfate sodium (DSS)-induced UC mice model, clinical symptoms observation (body weight, DAI, and colon length) and histological inspection were used to evaluate the efficacy of HQD and fecal microbiota transplantation (FMT) from HQD-treated mice. The gut microbiota and metabolites were detected by 16S rRNA sequencing and metabolomics analysis. The parameters of fatty acid metabolism, macrophage polarization, and FFAR1/FFAR4-AMPK-PPARα pathway were analyzed by immunofluorescence analysis, western blotting, and real-time PCR. Then, the effects of FFAR1 and FFAR4 on macrophage polarization were examined by agonists based on LPS-induced RAW264.7 cell model.RESULTS: The results showed that FMT, like HQD, ameliorated UC by improving weight loss, restoring colon length, and reducing DAI scores and histopathological scores. Besides, HQD and FMT both enhanced the richness of gut microbiota, and modulated intestinal bacteria and metabolites to achieve a new balance. Untargeted metabolomics analysis revealed that fatty acids, especially long-chain fatty acids (LCFAs), dominated in HQD against DSS-induced UC by regulating the gut microenvironment. Further, FMT and HQD recovered the expression of fatty acid metabolism-related enzymes, and simultaneously activated FFAR1/FFAR4-AMPK-PPARα pathway but suppressed NF-κB pathway. Combined with cell experiment, HQD and FMT promoted macrophage polarization from M1 toward M2, which were well associated with anti-inflammatory cytokines and combined with the activated FFAR4.CONCLUSIONS: The mechanism of HQD against UC was related to regulating fatty acid metabolism to mediate M2 macrophage polarization by activating the FFAR4-AMPK-PPARα pathway.PMID:36997133 | DOI:10.1016/j.jep.2023.116430

Behav Brain Res. 2023 Mar 28:114411. doi: 10.1016/j.bbr.2023.114411. Online ahead of print.ABSTRACTKratom (M. speciosa Korth) is an herbal plant native to Southeast Asia. The leaves have been widely used to alleviate pain and opioid withdrawal symptoms. However, the increasing trend of recreational use of kratom among youth is concerning because substance abuse may render the adolescent brain more susceptible to neuropathological processes, causing dramatic consequences that persist into adulthood. Therefore, the present study aimed to investigate the long-term effects of mitragynine, the main alkaloid and lyophilized kratom decoction (LKD) exposure during adolescence on cognitive behaviours and brain metabolite profiles in adult rats. Adolescent male Sprague-Dawley rats were given mitragynine (3, 10 or 30mg/kg) or LKD orally for 15 consecutive days during postnatal days 31-45 (PND31-45). Behavioural testing was performed during adulthood (PND70-84) and the brains were subjected to metabolomic analysis. The results show that a high dose of mitragynine impaired long-term object recognition memory. Social behaviour and spatial learning were not affected, but both mitragynine and LKD impaired reference memory. Brain metabolomic study revealed several altered metabolic pathways that may be involved in the cognitive behavioural effects of LKD and mitragynine exposure. These pathways include arachidonic acid, taurine and hypotaurine, pantothenate and CoA biosynthesis, and tryptophan metabolism, while the N-isovalerylglycine was identified as the potential biomarker. In summary, adolescent kratom exposure can cause long-lasting cognitive behavioural deficits and alter brain metabolite profiles that are still evident in adulthood. This finding also indicates that the adolescent brain is vulnerable to the impact of early kratom use.PMID:36997094 | DOI:10.1016/j.bbr.2023.114411

Food Chem Toxicol. 2023 Mar 28:113747. doi: 10.1016/j.fct.2023.113747. Online ahead of print.ABSTRACTThis research aimed to explore the protective effect of quercetin against nephrotoxicity induced by four organophosphate pesticide mixtures (PM) using untargeted metabolomics technology in rat kidneys. Sixty male Wistar rats were randomly divided into six groups: control, low-dose quercetin treated (10 mg/kg. bw), high-dose quercetin treated (50 mg/kg. bw), PM-treated, and two dosages of quercetin + PM-treated. Metabolomics results showed that 17 differential metabolites were identified in the PM-treated group, and pathway analysis revealed that renal metabolic disorders include purine metabolism, glycerophospholipid metabolism, and vitamin B6 metabolism. When high-dose quercetin and PM-treated were administered to rats concurrently, the intensities of differential metabolites were substantially restored (p < 0.01), suggesting that quercetin can improve renal metabolic disorders caused by organophosphate pesticides (OPs). Mechanistically, quercetin could regulate the purine metabolism disorder and endoplasmic reticulum stress (ERS)-mediated autophagy induced by OPs by inhibiting XOD activity. Moreover, quercetin inhibits PLA2 activity to regulate glycerophospholipid metabolism and it could also exert antioxidant and anti-inflammatory effects to correct vitamin B6 metabolism in rat kidneys. Taken together, the high dose of quercetin (50 mg/kg.bw) has a certain protective effect on OPs-induced nephrotoxicity in rats, which provides a theoretical basis for quercetin against nephrotoxicity caused by OPs.PMID:36997054 | DOI:10.1016/j.fct.2023.113747

J Steroid Biochem Mol Biol. 2023 Mar 28:106305. doi: 10.1016/j.jsbmb.2023.106305. Online ahead of print.ABSTRACTThe incidence of central precocious puberty (CPP) in boys is rising, but lack of effective molecular biomarkers often leads to delayed treatment and thus the terrible clinical complications in adulthood. This study aims to identify the specific-biomarkers of CPP boys and understand the gender-related differences in metabolic characteristics of CPP. The specific-biomarkers of CPP boys were identified from serum and their combination was optimized by cross-metabolomics combined with linear discriminant analysis effect size analysis after age correction. The differences in metabolic characteristics between boys and girls with CPP were explored by cross-metabolomics and weighted gene co-expression network analysis. Results show that CPP activated in advance the HPG axis and induced gender-related clinical phenotypes. Seven serum metabolites were identified as specific-biomarkers of CPP boys, including acetoacetate, aspartate, choline, creatinine, myo-inositol, N,N-dimethylglycine and N-Acetyl-glycoprotein. The combination of aspartate, choline, myo-inositol and creatinine achieved an optimized diagnosis, where AUC is 0.949, prediction accuracy for CPP boys is 91.1%, and the average accuracy is 0.865. The metabolic disorders of CPP boys mainly involve in glycerophospholipid metabolism, and synthesis and degradation of ketone bodies. Betaine, glutamine, isoleucine, lactate, leucine, lysine, pyruvate, α-&β-glucose were identified as gender-related biomarkers for CPP, and they are mainly involved in glycolysis/gluconeogenesis, pyruvate metabolism, and alanine, aspartate and glutamate metabolism. Biomarkers combination provides a promising diagnostic potential for CPP boy with a favorite sensitivity and specificity. In addition, the differences of metabolic characteristics between boys and girls with CPP will contribute to the development of individualized clinical treatments in CPP.PMID:36997004 | DOI:10.1016/j.jsbmb.2023.106305

Metabolism. 2023 Mar 28:155552. doi: 10.1016/j.metabol.2023.155552. Online ahead of print.ABSTRACTBACKGROUND: High-Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods; its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the molecular mechanisms by which HFCS impacts hepatic metabolism remain scarce, especially in the context of obesity. Besides, the majority of current studies focuses either on the detrimental role of fructose in hepatic steatosis or compare separately the additive impact of fructose versus glucose in high fat diet-induced NAFLD.AIM: By engaging combined omics approaches, we sought to characterize the role of HFCS in obesity-associated NAFLD and reveal molecular processes, which mediate the exaggeration of steatosis under these conditions.METHODS: Herein, C57BL/6 mice were fed a normal-fat-diet (ND), a high-fat-diet (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic, lipidomic and metabolomic analyses were conducted to identify HFCS-related molecular alterations of the hepatic metabolic landscape in obesity.RESULTS: Although HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed aggravation of hepatic steatosis, as analysis of the lipid droplet area in liver sections revealed (12,15 % of total section area in HFD vs 22,35 % in HFD-HFCS), increased NAFLD activity score (3,29 in HFD vs 4,86 in HFD-HFCS) and deteriorated hepatic insulin resistance, as compared to the HFD mice. Besides, the hepatic proteome of HFD-HFCS mice was characterized by a marked upregulation of 5 core proteins implicated in de novo lipogenesis (DNL), while an increased phosphatidyl-cholines(PC)/phosphatidyl-ethanolamines(PE) ratio (2.01 in HFD vs 3.04 in HFD-HFCS) was observed in the livers of HFD-HFCS versus HFD mice. Integrated analysis of the omics datasets indicated that Tricarboxylic Acid (TCA) cycle overactivation is likely contributing towards the intensification of steatosis during HFD-HFCS-induced NAFLD.CONCLUSION: Our results imply that HFCS significantly contributes to steatosis aggravation during obesity-related NAFLD, likely deriving from DNL upregulation, accompanied by TCA cycle overactivation and deteriorated hepatic insulin resistance.PMID:36996933 | DOI:10.1016/j.metabol.2023.155552

Toxicol Lett. 2023 Mar 28:S0378-4274(23)00111-X. doi: 10.1016/j.toxlet.2023.03.009. Online ahead of print.ABSTRACTINTRODUCTION: Acetyl-coenzyme A carboxylase (ACCase) inhibition is an attractive herbicide target. However, issues with fetal developmental toxicity identified at the late stages of the development process can halt progression of previously promising candidates.OBJECTIVES: To select and verify predictive lipid biomarkers of ACCase inhibition activity in vivo using liver samples obtained from early stage 7 day repeat dose studies in non-pregnant female Han Wistar rats that could be translated to developmental toxicity endpoints discovered during late-stage studies to provide an early screening tool.METHODS: Liver samples from eight rat repeat dose studies, exposed to six ACCase inhibitors from three different chemistries and one alternative mode of action (MoA) that also perturbs lipid biochemistry, were analysed using liquid chromatography - high resolution accurate mass - mass spectrometry. Multivariate and univariate data analysis methods were used for biomarker discovery and validation.RESULTS: A biomarker signature consisting of sixteen lipids biomarkers were selected. Verification of the signature as indicative of ACCase inhibition was established by demonstrating consistent perturbations in the biomarkers using two different ACCase inhibitor chemistries and the lack thereof with an alternate MoA. The fold change profile pattern was predictive of which test substance doses would or would not cause developmental toxicity.CONCLUSION: A strategy for selecting and verifying a robust signature of lipid biomarkers for predicting a toxicological end point has been described and demonstrated. Differences in lipidomic profiles correlated with developmental toxicity suggesting that indicators of a molecular initiation event resulting in pup developmental toxicity can be predicted from short term, toxicity studies conducted in non-pregnant adult female Han Wistar rats.PMID:36996930 | DOI:10.1016/j.toxlet.2023.03.009

Chemosphere. 2023 Mar 28:138539. doi: 10.1016/j.chemosphere.2023.138539. Online ahead of print.ABSTRACTThe potential risks of anti-cancer drugs such as capecitabine have attracted considerable attention due to their continuous release. Understanding the response of removal performance and protective mechanism to the presence of emerging contaminants is crucial for the application of anammox techniques in wastewater treatment. Capecitabine affected the nitrogen removal performance slightly in the activity experiment. Due to bio-adsorption and biodegradation, up to 64-70% of the capecitabine can be removed effectively. However, 10 mg/L of capecitabine significantly decreased the removal efficiency of capecitabine and total nitrogen at repeated load of capecitabine. Metabolomic analysis revealed the metabolites 5'-deoxy-5-fluorocytidine and alpha-fluoro-beta-alanine, while metagenomic analysis confirmed the biodegradation pathway and underlying gene distribution. The potentially protective mechanisms of the system against capecitabine were the increased heterotrophic bacteria and secretion of sialic acid. Blast analysis confirmed the presence of potential genes involved in the complete biosynthesis pathway of sialic acid in anammox bacteria, some of which are also found in Nitrosomonas, Thauera, and Candidatus Promineofilum.PMID:36996924 | DOI:10.1016/j.chemosphere.2023.138539