PubMed

NMR Biomed. 2022 Nov 4:e4868. doi: 10.1002/nbm.4868. Online ahead of print.ABSTRACTHigh-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR)-based metabolomics has demonstrated its utility in studies of biofluids for various diseases. HRMAS NMR spectroscopy is uniquely well-suited for analyzing human blood samples due to the small quantity of sample and minimal preparation required. To develop this methodology into standardized clinical protocols, establishment of the method's quality assurance (QA) and evaluations of its quality control (QC) are critical. This study aims to assess the QA/QC measured from human blood specimens in the form of serum and plasma through within-subject and between-subject comparisons, as well as stability and consistency comparisons over several freezing-thawing cycles of sample storage conditions, and most importantly, the agreement of pooled control samples against individual samples.PMID:36330660 | DOI:10.1002/nbm.4868

Psychol Med. 2022 Nov 4:1-9. doi: 10.1017/S0033291722003233. Online ahead of print.ABSTRACTBACKGROUND: Refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. Approximately 15% of patients with major depressive disorder are refractory to currently available treatments. We hypothesized metabolic abnormalities contributing to treatment refractory depression are associated with distinct findings identifiable in the cerebrospinal fluid (CSF). Our hypothesis was confirmed by a previous small case-controlled study. Here we present a second, larger replication study.METHODS: We conducted a case-controlled, targeted, metabolomic evaluation of 141 adolescent and adult patients with well-characterized history of depression refractory to three maximum-dose, adequate-duration medication treatments, and 36 healthy controls. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry, and high-performance liquid chromatography, electrospray ionization, tandem mass spectrometry.RESULTS: Abnormalities were identified in 67 of 141 treatment refractory depression participants. The CSF abnormalities included: low cerebral folate (n = 20), low tetrahydrobiopterin intermediates (n = 11), and borderline low-tetrahydrobiopterin intermediates (n = 20). Serum abnormalities included abnormal acylcarnitine profile (n = 12) and abnormal serum amino acids (n = 20). Eighteen patients presented with two or more abnormal metabolic findings. Sixteen patients with cerebral folate deficiency and seven with low tetrahydrobiopterin intermediates in CSF showed improvement in depression symptom inventories after treatment with folinic acid and sapropterin, respectively. No healthy controls had a metabolite abnormality.CONCLUSIONS: Examination of metabolic disorders in treatment refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities and their potential roles in pathogenesis remain to be determined.PMID:36330595 | DOI:10.1017/S0033291722003233

Biomed Res Int. 2022 Oct 25;2022:2739869. doi: 10.1155/2022/2739869. eCollection 2022.ABSTRACTThe early detection of cancer, and in particular oral cancer, has been a priority objective of study in recent years. Saliva has been proposed as an easy-to-obtain means of providing the necessary information to diagnose malignant lesions in the oral cavity, since it can be obtained very easily and completely noninvasively. There are a number of molecules, known as biomarkers, which may be involved in the malignant transformation of oral lesions, and which have different natures. The involvement of proteins ("proteomics"), metabolites ("metabolomics"), and even certain genes in the structural changes of altered tissue has been investigated in order to establish validated parameters for the early diagnosis of oral cancer. In addition, the development of new analytical assay methods that can reduce costs and obtain better results in terms of sensitivity and specificity has been a key point in recent research in this field. Even though there are numerous biomarkers with results showing high sensitivity and specificity, there is still a need for more studies, with a larger sample and with analytical methods that can constitute a real advance in time and cost. Although salivary biomarkers are a promising new diagnostic tool for oral cancer, for the moment they do not replace biopsy as the "gold standard".PMID:36330456 | PMC:PMC9626200 | DOI:10.1155/2022/2739869

Ann Transl Med. 2022 Oct;10(19):1056. doi: 10.21037/atm-22-3967.ABSTRACTBACKGROUND: The relationship between gut microbiota and metabolites play an important role in the occurrence and development of type 2 diabetes mellitus (T2DM). However, the interaction between intestinal flora abundance and metabolites is still unclear. The purpose of this study was to investigate the correlation of the interaction network between intestinal flora and fecal metabolites in regulating the occurrence of T2DM.METHODS: This a case-control study. T2DM patients with different glucose levels and healthy people were divided into case group and normal controls (NC) group. Fasting plasma and fecal samples were collected from the subjects. Ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS) untargeted fecal metabolomics was used to detect small molecular metabolites within 1,500 Da in two groups. The diversity and richness of intestinal flora were analyzed by the 16SrRNA third-generation full-length sequencing technique and the correlation between intestinal microflora and different metabolites was evaluated.RESULTS: A total of 30 patients with T2DM and 21 NC were included for analysis, glycated hemoglobin (HbAlc) (P<0.001), fasting blood glucose (FBG) (P<0.001), total triglycerides (TG) (P=0.002), and fasting serum insulin (FINS) (P=0.026) were significantly higher in the T2DM group compared with the NC group. The fecal metabolomics profiles of the T2DM group and NC group were significantly different, and 355 different metabolites were identified among the two. Compared with the NC group, the levels of ornithine (P=0.04), L-lysine (P=0.03), glutamate (P=0.01), alpha-linolenic acid (P=0.004), traumatin (P=0.05), and erucic acid (P=0.004) in the T2DM group decreased significantly, while PC[18:3(6Z,9Z,12Z)/24:1(15Z)] (P<0.001) levels increased. Compared with the NC group, the richness of Megamonas and Escherichia increased in T2DM patients, while that of Bacteroidota and Phascolarctobacterium were lower. Pearson correlation analysis revealed associations between gut microbiota and faecal metabolites, and Phascolarctobacterium was positively correlated with alpha-linolenic acid (r=0.72, P<0.001).CONCLUSIONS: There may be a mutual regulatory network between intestinal bacteria and fecal metabolites in T2DM. The increased abundance of Phascolarctobacterium may increase alpha-linolenic acid uptake, and alpha-linolenic acid may also increase the abundance of intestinal Phascolarctobacterium in vivo after metabolic transformation. The combination of the two may play an important role in the treatment of diabetes.PMID:36330416 | PMC:PMC9622494 | DOI:10.21037/atm-22-3967

Ann Transl Med. 2022 Oct;10(19):1069. doi: 10.21037/atm-22-4451.ABSTRACTBACKGROUND: Roxadustat is a newly marketed hypoxia-inducible factor prolyl hydroxylase inhibitor used to treat anemia in patients with end-stage renal disease (ESRD). While clinical trials have demonstrated the therapeutic effects of roxadustat in patients with ESRD who are resistant to erythropoiesis-stimulating agents (ESAs), its metabolic effects are still unclear.METHODS: Thirty-two individuals with ESRD and ESA resistance from the Blood Purification Center of Dalian Municipal Central Hospital were included. A total of 96 fasting serum samples were obtained from participants before treatment with roxadustat, and after treatment for 15 and 30 days. Ultra-high performance liquid chromatography-mass spectrometry-based metabolomics and lipidomics strategies were applied to investigate the effects of roxadustat on serum metabolism.RESULTS: A total of 255 metabolites and 444 lipid molecular species were detected and quantified. Sphingolipids and phospholipids decreased significantly during treatment, possibly associated with changes in phospholipid and ceramide metabolism. Bile acid levels decreased and cholic acid/chenodeoxycholic acid increased, indicating changes in gut microbiota and bile acid metabolism. Amino acids also changed during the process of treatment.CONCLUSIONS: The present study showed sphingolipids, phospholipids, and bile acids were significantly altered, which may be associated with a changed metabolism caused by roxadustat. This approach provided a powerful tool for exploring the mechanisms of ESA resistance in ESRD patients and may represent a promising strategy for elucidating the complex therapeutic mechanisms of other drugs.PMID:36330384 | PMC:PMC9622472 | DOI:10.21037/atm-22-4451

AIMS Public Health. 2022 Aug 23;9(3):618-629. doi: 10.3934/publichealth.2022043. eCollection 2022.ABSTRACTDespite intensive research, effective treatments for many common and devastating diseases are lacking. For example, huge efforts and billions of dollars have been invested in Alzheimer's disease (AD), which affects over 50 million people worldwide. However, there is still no effective drug that can slow or cure AD. This relates, in part, to the absence of an animal model or cellular system that incorporates all the relevant features of the disease. Therefore, large scale studies on human populations and tissues will be key to better understanding dementia and developing methods to prevent or treat it. This is especially difficult because the dementia phenotype can result from many different processes and is likely to be affected by multiple personal and environmental variables. We hypothesize that analyzing massive volumes of demographic data that are currently available and combining this with genomic, proteomic, and metabolomic profiles of AD patients and their families, new insights into pathophysiology and treatment of AD may arise. While this requires much coordination and cooperation among large institutions, the potential for advancement would be life-changing for millions of people. In many ways this represents the next step in the information revolution started by the Human Genome Project.PMID:36330282 | PMC:PMC9581740 | DOI:10.3934/publichealth.2022043

Front Plant Sci. 2022 Oct 18;13:1041068. doi: 10.3389/fpls.2022.1041068. eCollection 2022.ABSTRACTGibberellin (GA) is an important phytohormone that can participate in various developmental processes of plants. The study found that application of GA3 can induce parthenocarpy fruit and improve fruit set. However, the use of GA3 affects endogenous hormones in fruits, thereby affecting fruit quality. This study mainly investigates the effect of exogenous GA3 on endogenous hormones in sweet cherries. The anabolic pathways of each hormone were analyzed by metabolome and transcriptome to identify key metabolites and genes that affect endogenous hormones in response to exogenous GA3 application. Results showed that exogenous GA3 led to a significant increase in the content of abscisic acid (ABA) and GA and affected jasmonic acid (JA) and auxin (IAA). At the same time, the key structural genes affecting the synthesis of various hormones were preliminarily determined. Combined with transcription factor family analysis, WRKY genes were found to be more sensitive to the use of exogenous GA3, especially the genes belonging to Group III (PaWRKY16, PaWRKY21, PaWRKY38, PaWRKY52, and PaWRKY53). These transcription factors can combine with the promoters of NCED, YUCCA, and other genes to regulate the content of endogenous hormones. These findings lay the foundation for the preliminary determination of the mechanism of GA3's effect on endogenous hormones in sweet cherry and the biological function of WRKY transcription factors.PMID:36330269 | PMC:PMC9623316 | DOI:10.3389/fpls.2022.1041068

Front Plant Sci. 2022 Oct 11;13:1028794. doi: 10.3389/fpls.2022.1028794. eCollection 2022.ABSTRACTThe regulatory protein CP12 can bind glyceraldehyde 3-phosphate dehydrogenase (GapDH) and phosphoribulokinase (PRK) in oxygenic phototrophs, thereby switching on and off the flux through the Calvin-Benson cycle (CBC) under light and dark conditions, respectively. However, it can be assumed that CP12 is also regulating CBC flux under further conditions associated with redox changes. To prove this hypothesis, the mutant Δcp12 of the model cyanobacterium Synechocystis sp. PCC 6803 was compared to wild type and different complementation strains. Fluorescence microscopy showed for the first time the in vivo kinetics of assembly and disassembly of the CP12-GapDH-PRK complex, which was absent in the mutant Δcp12. Metabolome analysis revealed differences in the contents of ribulose 1,5-bisphosphate and dihydroxyacetone phosphate, the products of the CP12-regulated enzymes GapDH and PRK, between wild type and mutant Δcp12 under changing CO2 conditions. Growth of Δcp12 was not affected at constant light under different inorganic carbon conditions, however, the addition of glucose inhibited growth in darkness as well as under diurnal conditions. The growth defect in the presence of glucose is associated with the inability of Δcp12 to utilize external glucose. These phenotypes could be complemented by ectopic expression of the native CP12 protein, however, expression of CP12 variants with missing redox-sensitive cysteine pairs only partly restored the growth with glucose. These experiments indicated that the loss of GapDH-inhibition via CP12 is more critical than PRK association. Measurements of the NAD(P)H oxidation revealed an impairment of light intensity-dependent redox state regulation in Δcp12. Collectively, our results indicate that CP12-dependent regulation of the CBC is crucial for metabolic adjustment under conditions leading to redox changes such as diurnal conditions, glucose addition, and different CO2 conditions in cyanobacteria.PMID:36330266 | PMC:PMC9623430 | DOI:10.3389/fpls.2022.1028794

Front Plant Sci. 2022 Oct 17;13:1020367. doi: 10.3389/fpls.2022.1020367. eCollection 2022.ABSTRACTHaloxylon ammodendron and Haloxylon persicum, as typical desert plants, show strong drought tolerance and environmental adaptability. They are ideal model plants for studying the molecular mechanisms of drought tolerance. Transcriptomic and metabolomic analyses were performed to reveal the response mechanisms of H. ammodendron and H. persicum to a drought environment at the levels of transcription and physiological metabolism. The results showed that the morphological structures of H. ammodendron and H. persicum showed adaptability to drought stress. Under drought conditions, the peroxidase activity, abscisic acid content, auxin content, and gibberellin content of H. ammodendron increased, while the contents of proline and malondialdehyde decreased. The amino acid content of H. persicum was increased, while the contents of proline, malondialdehyde, auxin, and gibberellin were decreased. Under drought conditions, 12,233 and 17,953 differentially expressed genes (DEGs) were identified in H. ammodendron and H. persicum , respectively, including members of multiple transcription factor families such as FAR1, AP2/ERF, C2H2, bHLH, MYB, C2C2, and WRKY that were significantly up-regulated under drought stress. In the positive ion mode, 296 and 452 differential metabolites (DEMs) were identified in H. ammodendron and H. persicum, respectively; in the negative ion mode, 252 and 354 DEMs were identified, primarily in carbohydrate and lipid metabolism. A combined transcriptome and metabolome analysis showed that drought stress promoted the glycolysis/gluconeogenesis pathways of H. ammodendron and H. persicum and increased the expression of amino acid synthesis pathways, consistent with the physiological results. In addition, transcriptome and metabolome were jointly used to analyze the expression changes of the genes/metabolites of H. ammodendron and H. persicum that were associated with drought tolerance but were regulated differently in the two plants. This study identified drought-tolerance genes and metabolites in H. ammodendron and H. persicum and has provided new ideas for studying the drought stress response of Haloxylon.PMID:36330247 | PMC:PMC9622360 | DOI:10.3389/fpls.2022.1020367

Front Mol Biosci. 2022 Oct 18;9:1029729. doi: 10.3389/fmolb.2022.1029729. eCollection 2022.ABSTRACTExposure to Pb is widely spreading and has far-reaching negative effects on living systems. This study aimed to investigate the toxic effects of Pb, through biochemical profiling and the ameliorative effects of quercetin against Pb-toxicity. Twenty-five male Wistar albino mice were divided into the following five groups. The CON-group received normal saline; the Pb-group received PbAc; the Pb + Q-CRN group received lead acetate followed by quercetin; the Q-CRN group received quercetin; and the CRN group received corn oil. After 4 weeks, the mice were euthanized. It was speculated that Pb significantly increased the levels of serine, threonine, and asparagine and decreased the levels of valine, lysine, and glutamic acid in the plasma of Pb-group, thus impairing amino acid metabolism. However, in the Pb + Q-CRN group, the level of these six amino acids was restored significantly due to the ameliorative effect of quercetin. The presence of lipid metabolites (L-carnitine, sphinganine, phytosphingosine, and lysophosphatidylcholine) in mice serum was confirmed by ESI/MS. The GPx, SOD, GSH, and CAT levels were significantly decreased, and the MDA level was significantly increased, thus confirming the oxidative stress and lipid peroxidation in the Pb group. The antioxidant effect of quercetin was elucidated in the Pb + Q-CRN group. Expression of CPT-I, CPT-II, LCAT, CROT, CACT, and MTR genes was significantly upregulated in the liver of Pb goup mice. Hence, the findings of this study proved that Pb exposure induced oxidative stress, upregulated gene expression, and impaired the lipid and amino acid metabolism in mice.PMID:36330218 | PMC:PMC9623090 | DOI:10.3389/fmolb.2022.1029729

Front Nutr. 2022 Oct 13;9:1026213. doi: 10.3389/fnut.2022.1026213. eCollection 2022.ABSTRACTBACKGROUND: We previously showed that whole-grain wheat (WGW) consumption had beneficial effects on liver fat accumulation, as compared to refined wheat (RW). The mechanisms underlying these effects remain unclear.OBJECTIVE: In this study, we investigated the effects of WGW vs. RW consumption on plasma metabolite levels to explore potential underlying mechanisms of the preventive effect of WGW consumption on liver fat accumulation.METHODS: Targeted metabolomics of plasma obtained from a concluded 12-week double-blind, randomized controlled trial was performed. Fifty overweight or obese men and women aged 45-70 years with mildly elevated levels of plasma cholesterol were randomized to either 98 g/d of WGW or RW products. Before and after the intervention, a total of 89 fasting plasma metabolite concentrations including acylcarnitines, trimethylamine-N-oxide (TMAO), choline, betaine, bile acids, and signaling lipids were quantified by UPLC-MS/MS. Intrahepatic triglycerides (IHTG) were quantified by 1H-MRS, and multiple liver markers, including circulating levels of β-hydroxybutyrate, alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (γ-GT), serum amyloid A (SAA), and C-reactive protein, were assessed.RESULTS: The WGW intervention increased plasma concentrations of four out of 52 signaling lipids-lysophosphatidic acid C18:2, lysophosphatidylethanolamine C18:1 and C18:2, and platelet-activating factor C18:2-and decreased concentrations of the signaling lipid lysophosphatidylglycerol C20:3 as compared to RW intervention, although these results were no longer statistically significant after false discovery rate (FDR) correction. Plasma concentrations of the other metabolites that we quantified were not affected by WGW or RW intervention. Changes in the above-mentioned metabolites were not correlated to change in IHTG upon the intervention.CONCLUSION: Plasma acylcarnitines, bile acids, and signaling lipids were not robustly affected by the WGW or RW interventions, which makes them less likely candidates to be directly involved in the mechanisms that underlie the protective effect of WGW consumption or detrimental effect of RW consumption on liver fat accumulation.CLINICAL TRIAL REGISTRATION: [www.ClinicalTrials.gov], identifier [NCT02385149].PMID:36330140 | PMC:PMC9624226 | DOI:10.3389/fnut.2022.1026213

Front Public Health. 2022 Oct 18;10:1003148. doi: 10.3389/fpubh.2022.1003148. eCollection 2022.NO ABSTRACTPMID:36330107 | PMC:PMC9622927 | DOI:10.3389/fpubh.2022.1003148

Front Pharmacol. 2022 Oct 14;13:978421. doi: 10.3389/fphar.2022.978421. eCollection 2022.ABSTRACTThe number of patients with allergic asthma is rising yearly, and hormonal drugs, such as dexamethasone, have unique advantages and certain limitations. In the treatment of allergic diseases especially allergic asthma, increasing the percentage or the function of immunosuppressive cells, such as Treg cells, may achieve a good effect. On the basis of good clinical results, we found that Guominkang (GMK) especially high-concentration GMK can achieve a similar effect with dexamethasone in controlling the symptoms of allergic asthma and inhibiting inflammation of allergic asthma. In our study, GMK can inhibit the recruitment of inflammatory cells, decrease mucus production, and reduce airway resistance. Besides, GMK can reconstruct the cellular immune balance of Th1/2 and Treg/Th17 cells. Metabolome results show that DL-glutamine, L-pyroglutamic acid, prostaglandin b1, prostaglandin e2, and 3,4-dihydroxyhydrocinnamic acid are the metabolic biomarkers and are associated with Th1/2 and Treg/Th17 cell balance. GMK can also change the gut microbiota in the allergic asthma mouse model. The genus_Muriculum, genus_(Clostridium) GCA900066575, genus_klebsiella, genus_Desulfovibrio, genus_Rikenellaceae RC9 gut group, family_Chitinophagaceae, family_Nocardioidaceae, and genus_Corynebacterium are gut microbiota biomarkers treated by GMK. Among these biomarkers, genus_Muriculum is the gut microbiota biomarker associated with Th1/2 and Treg/Th17 cell balance. Interestingly, we first found that DL-glutamine, L-pyroglutamic acid, prostaglandin b1, prostaglandin e2, and 3,4-dihydroxyhydrocinnamic acid are all associated with genus_Muriculum. GMK will be a new strategy for the treatment of eosinophilic asthma, and biomarkers will also be a new research direction.PMID:36330091 | PMC:PMC9624229 | DOI:10.3389/fphar.2022.978421

Front Endocrinol (Lausanne). 2022 Oct 18;13:989523. doi: 10.3389/fendo.2022.989523. eCollection 2022.ABSTRACTOBJECTIVE: Obesity increases the risk of certain cancers, especially tumours that reside close to adipose tissue (breast and ovarian metastasis in the omentum). The obesogenic and tumour micro-environment share a common pathogenic feature, oxygen deprivation (hypoxia). Here we test how hypoxia changes the metabolome of adipocytes to assist cancer cell growth.METHODS: Human and mouse breast and ovarian cancer cell lines were co-cultured with human and mouse adipocytes respectively under normoxia or hypoxia. Proliferation and lipid uptake in cancer cells were measured by commercial assays. Metabolite changes under normoxia or hypoxia were measured in the media of human adipocytes by targeted LC/MS.RESULTS: Hypoxic cancer-conditioned media increased lipolysis in both human and mouse adipocytes. This led to increased transfer of lipids to cancer cells and consequent increased proliferation under hypoxia. These effects were dependent on HIF1α expression in adipocytes, as mouse adipocytes lacking HIF1α showed blunted responses under hypoxic conditions. Targeted metabolomics of the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes media revealed that culture with hypoxic-conditioned media from non-malignant mammary epithelial cells (MCF10A) can alter the adipocyte metabolome and drive proliferation of the non-malignant cells.CONCLUSION: Here, we show that hypoxia in the adipose-tumour microenvironment is the driving force of the lipid uptake in both mammary and ovarian cancer cells. Hypoxia can modify the adipocyte metabolome towards accelerated lipolysis, glucose deprivation and reduced ketosis. These metabolic shifts in adipocytes could assist both mammary epithelial and cancer cells to bypass the inhibitory effects of hypoxia on proliferation and thrive.PMID:36329893 | PMC:PMC9623062 | DOI:10.3389/fendo.2022.989523

Front Endocrinol (Lausanne). 2022 Oct 18;13:1031798. doi: 10.3389/fendo.2022.1031798. eCollection 2022.ABSTRACTThe discovery of a large number of small pulmonary nodules and early diagnosis of lung cancer in the diabetic patients prompt us to re-examine the relationship between diabetes and the occurrence and development of lung cancer. The aim of this study was to explore the underlying metabolites changes in diabetes with NSCLC or benign nodule patients, and further to investigate the association of serum IGF-1 level and differentially expressed metabolites (DEMs). An untargeted metabolomics method was used to detect the changes of metabolism in diabetic patients with NSCLC on the platform of HR-MS. Serum level of IGF-1 was measured by ELISA. The patients were divided to three groups, DM, DLB (nodule), and DLC (cancer). we have identified numerous DEMs, which include amino acid, choline, and fatty acid derivatives. Further analysis of the involved metabolic pathways suggested that linoleate metabolism, tryptophan metabolism, histidine metabolism, putative anti-Inflammatory metabolites formation from EPA, and arachidonic acid metabolism were considered to be the most significant metabolic pathways between groups. Networks analysis suggested that a series of metabolites were associated with serum IGF-1among the three groups, which can be divided into 6 categories. Nine metabolites have been identified as the main DEMs among the DLC, DLB, and DM groups. In conclusion, metabolomics is a powerful and promising tool for the cancer risk evaluation in diabetic patients. Our results suggest that decreased IGF-1 level is associated with restrained amino acid metabolism in NSCLC with diabetes mellitus.PMID:36329881 | PMC:PMC9623307 | DOI:10.3389/fendo.2022.1031798

Front Microbiol. 2022 Oct 18;13:931431. doi: 10.3389/fmicb.2022.931431. eCollection 2022.ABSTRACTOBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, which is associated with progressive disability, systemic complications, and early death. But its etiology and pathogenesis are not fully understood. We aimed to investigate the alterations in plasma metabolite profiles, gut bacteria, and fungi and their role of them in the pathogenesis of RA.METHODS: Metabolomics profiling of plasma from 363 participants including RA (n = 244), systemic lupus erythematosus (SLE, n = 50), and healthy control (HC, n = 69) were performed using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The differentially expressed metabolites were selected among groups and used to explore important metabolic pathways. Gut microbial diversity analysis was performed by 16S rRNA sequencing and ITS sequencing (RA = 195, HC = 269), and the specific microbial floras were identified afterward. The diagnosis models were established based on significant differential metabolites and microbial floras, respectively.RESULTS: There were 63 differential metabolites discovered between RA and HC groups, mainly significantly enriched in the arginine and proline metabolism, glycine, serine, and threonine metabolism, and glycerophospholipid metabolism between RA and HC groups. The core differential metabolites included L-arginine, creatine, D-proline, ornithine, choline, betaine, L-threonine, LysoPC (18:0), phosphorylcholine, and glycerophosphocholine. The L-arginine and phosphorylcholine were increased in the RA group. The AUC of the predictive model was 0.992, based on the combination of the 10 differential metabolites. Compared with the SLE group, 23 metabolites increased and 61 metabolites decreased in the RA group. However, no significant metabolic pathways were enriched between RA and SLE groups. On the genus level, a total of 117 differential bacteria genera and 531 differential fungal genera were identified between RA and HC groups. The results indicated that three bacteria genera (Eubacterium_hallii_group, Escherichia-Shigella, Streptococcus) and two fungal genera (Candida and Debaryomyces) significantly increased in RA patients. The AUC was 0.80 based on a combination of six differential bacterial genera and the AUC was 0.812 based on a combination of seven differential fungal genera. Functional predictive analysis displayed that differential bacterial and differential fungus both were associated with KEGG pathways involving superpathway of L-serine and glycine biosynthesis I, arginine, ornithine, and proline interconversion.CONCLUSION: The plasma metabolism profile and gut microbe profile changed markedly in RA. The glycine, serine, and threonine metabolism and arginine and proline metabolism played an important role in RA.PMID:36329847 | PMC:PMC9623673 | DOI:10.3389/fmicb.2022.931431

Hum Genomics. 2022 Nov 3;16(1):53. doi: 10.1186/s40246-022-00425-9.ABSTRACTBACKGROUND: Proteins and metabolites are essential for many biological functions and often linked through enzymatic or transport reactions. Individual molecules have been associated with all-cause mortality. Many of these are correlated and might jointly represent pathways or endophenotypes involved in diseases.RESULTS: We present an integrated analysis of proteomics and metabolomics via a local dimensionality reduction clustering method. We identified 224 modules of correlated proteins and metabolites in the Atherosclerosis Risk in Communities (ARIC) study, a general population cohort of older adults (N = 4046, mean age 75.7, mean eGFR 65). Many of the modules displayed strong cross-sectional associations with demographic and clinical characteristics. In comprehensively adjusted analyses, including fasting plasma glucose, history of cardiovascular disease, systolic blood pressure and kidney function among others, 60 modules were associated with mortality. We transferred the network structure to the African American Study of Kidney Disease and Hypertension (AASK) (N = 694, mean age 54.5, mean mGFR 46) and identified mortality associated modules relevant in this disease specific cohort. The four mortality modules relevant in both the general population and CKD were all a combination of proteins and metabolites and were related to diabetes / insulin secretion, cardiovascular disease and kidney function. Key components of these modules included N-terminal (NT)-pro hormone BNP (NT-proBNP), Sushi, Von Willebrand Factor Type A, EGF And Pentraxin (SVEP1), and several kallikrein proteases.CONCLUSION: Through integrated biomarkers of the proteome and metabolome we identified functions of (patho-) physiologic importance related to diabetes, cardiovascular disease and kidney function.PMID:36329547 | DOI:10.1186/s40246-022-00425-9

J Cancer Res Clin Oncol. 2022 Nov 3. doi: 10.1007/s00432-022-04436-w. Online ahead of print.ABSTRACTPURPOSE: Arylamine N-acetyltransferase 1 (NAT1), a phase II metabolic enzyme, is frequently upregulated in breast cancer. Inhibition or depletion of NAT1 leads to growth retardation in breast cancer cells in vitro and in vivo. A previous metabolomics study of MDA-MB-231 breast cancer cells suggests that NAT1 deletion leads to a defect in de novo pyrimidine biosynthesis. In the present study, we observed that NAT1 deletion results in upregulation of cytidine deaminase (CDA), which is involved in the pyrimidine salvage pathway, in multiple breast cancer cell lines (MDA-MB-231, MCF-7 and ZR-75-1). We hypothesized that NAT1 KO MDA-MB-231 cells show differential sensitivity to drugs that either inhibit cellular pyrimidine homeostasis or are metabolized by CDA.METHODS: The cells were treated with (1) inhibitors of dihydroorotate dehydrogenase or CDA (e.g., teriflunomide and tetrahydrouridine); (2) pyrimidine/nucleoside analogs (e.g., gemcitabine and 5-azacytidine); and (3) naturally occurring, modified cytidines (e.g., 5-formyl-2'-deoxycytidine; 5fdC).RESULTS: Although NAT1 KO cells failed to show differential sensitivity to nucleoside analogs that are metabolized by CDA, they were markedly more sensitive to 5fdC which induces DNA damage in the presence of high CDA activity. Co-treatment with 5fdC and a CDA inhibitor, tetrahydrouridine, abrogated the increase in 5fdC cytotoxicity in NAT1 KO cells, suggesting that the increased sensitivity of NAT1 KO cells to 5fdC is dependent on their increased CDA activity.CONCLUSIONS: The present findings suggest a novel therapeutic strategy to treat breast cancer with elevated NAT1 expression. For instance, NAT1 inhibition may be combined with cytotoxic nucleosides (e.g., 5fdC) for breast cancer treatment.PMID:36329350 | DOI:10.1007/s00432-022-04436-w

Metabolomics. 2022 Nov 3;18(11):87. doi: 10.1007/s11306-022-01945-0.ABSTRACTINTRODUCTION: Autoimmune disorders such as type 1 diabetes (T1D) are believed to be caused by the interplay between several genetic and environmental factors. Elucidation of the role of environmental factors in metabolic and immune dysfunction leading to autoimmune disease is not yet well characterized.OBJECTIVES: Here we investigated the impact of exposure to a mixture of persistent organic pollutants (POPs) on the metabolome in non-obese diabetic (NOD) mice, an experimental model of T1D. The mixture contained organochlorides, organobromides, and per- and polyfluoroalkyl substances (PFAS).METHODS: Analysis of molecular lipids (lipidomics) and bile acids in serum samples was performed by UPLC-Q-TOF/MS, while polar metabolites were analyzed by GC-Q-TOF/MS.RESULTS: Experimental exposure to the POP mixture in these mice led to several metabolic changes, which were similar to those previously reported as associated with PFAS exposure, as well as risk of T1D in human studies. This included an increase in the levels of sugar derivatives, triacylglycerols and lithocholic acid, and a decrease in long chain fatty acids and several lipid classes, including phosphatidylcholines, lysophosphatidylcholines and sphingomyelins.CONCLUSION: Taken together, our study demonstrates that exposure to POPs results in an altered metabolic signature previously associated with autoimmunity.PMID:36329300 | DOI:10.1007/s11306-022-01945-0

Clin Exp Med. 2022 Nov 3. doi: 10.1007/s10238-022-00931-z. Online ahead of print.ABSTRACTCrohn's disease (CD) is well characterized by chronic inflammation of the gastrointestinal tract. The diagnose of CD relays on the comprehensive evaluation of patient symptoms, laboratory examination, radiology, and endoscopy. There is lack of biomarkers or simple test for CD detection. Serum samples from healthy subjects (n = 16) and CD patients (n = 16) were collected and prepared for untargeted metabolomics analysis using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) method. The alterations of serum metabolites and the potential biomarkers were profiled by statistical analysis. And the associated metabolic pathway was analyzed based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The performance of potential biomarkers was assessed by receiver operating characteristic (ROC) analysis. A complete separation between HS and CD groups was seen in OPLS-DA. A total of 108 and 131 significantly altered metabolites in positive and negative ion mode, respectively, were identified, and most of them belong to several pathways ranging from lipid metabolism to amino acid metabolism and energy homeostasis. KEGG analysis revealed that lipid metabolism enriched most significantly. Further, ceramide, phosphatidylethanolamine (PE), and taurochenodeoxycholic acid (TCDCA) presented the highest predictive accuracy of the patients with CD as analyzed by ROC. The current study demonstrated that lipid metabolism is mostly related to CD pathogenesis. Further investigations are indicated to examine the use of lipid-related metabolites of ceramide, PE, and TCDCA as potential biomarkers for CD diagnosis.PMID:36329220 | DOI:10.1007/s10238-022-00931-z