PubMed

Scand J Gastroenterol. 2023 Apr 18:1-10. doi: 10.1080/00365521.2023.2200518. Online ahead of print.ABSTRACTBACKGROUND: The indolent course of treatment-naive patients with inflammatory bowel disease (IBD) is confirmed predictable based on clinical characteristics. Current evidences supported that bile acids (BAs) alteration might be promising biomarkers in the field of IBD. We aimed to analyze the alterations of BAs as the disease progresses and explore their predictive value for indolent course of IBD.METHODS: The indolent course of IBD was defined as a disease course without need for strict interventions throughout the entire follow-up. A targeted metabolomics method was used to detect the concentration of 27 BAs from serum sample in treatment-naive patients with IBD (Crohn's disease [CD], n = 27; ulcerative colitis [UC], n = 50). Patients with CD and UC were individually divided into two groups for further study according to the median time of indolent course. The overall BAs profile and the clinical value of BAs in predicting indolent course of IBD were identified between different groups.RESULTS: For CD, the levels of deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycolithocholic acid-3-sulfate disodium salt and iso-lithocholic acid were significantly increased in patients with indolent course > 18 M (p < 0.05). These five BAs owned 83.5% accuracy for predicting indolent course over 18 months in CD. For UC, the concentration of deoxycholic acid and glycodeoxycholic acid were significantly higher, while dehydrocholic acid were lower in patients with indolent course > 48 M (p < 0.05). These three BAs predicted indolent course over 48 months of 69.8% accuracy in UC.CONCLUSION: The specific BAs alterations might be potential biomarkers in predicting disease course of IBD patients.PMID:37070769 | DOI:10.1080/00365521.2023.2200518

Am J Physiol Lung Cell Mol Physiol. 2023 Apr 18. doi: 10.1152/ajplung.00003.2023. Online ahead of print.ABSTRACTBACKGROUND: Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary arterial hypertension (PAH), however RV function is challenging to assess. RV responses to hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in PAH.METHODS: Consecutive subjects with PAH (n=23) underwent rest and exercise right heart catheterization with multi-beat pressure volume loop analysis. Pulmonary arterial blood was collected at rest and during exercise. Mass spectrometry-based targeted metabolomics were performed, and metabolic associations with hemodynamics and comprehensive measures of RV function were determined using sparse partial least squares regression. Metabolite profiles were compared to pro-BNP measurements for accuracy in modeling ventriculo-arterial parameters.RESULTS: Thirteen metabolites changed in abundance with exercise, including metabolites reflecting increased arginine bioavailability, precursors of catecholamine and nucleotide synthesis, and branched chain amino acids. Higher resting arginine bioavailability predicted more favorable exercise hemodynamics and pressure-flow relationships. Subjects with more severe PAH augmented arginine bioavailability with exercise to a greater extent than subjects with less severe PAH. We identified relationships between kynurenine pathway metabolism and impaired ventriculo-arterial coupling, worse RV diastolic function, lower RV contractility, diminished RV contractility with exercise, and RV dilation with exercise. Metabolite profiles outperformed pro-BNP in modeling RV contractility, diastolic function, and exercise performance.CONCLUSIONS: Specific metabolite profiles correspond to RV functional measurements only obtainable via invasive pressure-volume loop analysis and predict RV responses to exercise. Metabolic profiling may inform discovery of RV functional biomarkers.PMID:37070742 | DOI:10.1152/ajplung.00003.2023

AIDS. 2023 Apr 12. doi: 10.1097/QAD.0000000000003574. Online ahead of print.ABSTRACTOBJECTIVE: To determine immune-metabolic dysregulation in children born to women living with HIV.METHODS: Longitudinal immune-metabolomic analyses of plasma of 32 pregnant women living with HIV (WLHIV) and 12 uninfected women and their children up to 1.5 years of age were performed.RESULTS: Using liquid chromatography-mass spectrometry and a multiplex bead assay, 280 metabolites (57 amino acids, 116 positive lipids, 107 signaling lipids) and 24 immune mediators (e.g. cytokines) were quantified. cART exposure was categorized as cART initiation preconception (long), cART initiation post-conception up to 4 weeks before birth (medium) and cART initiation within 3 weeks of birth (short). Plasma metabolite profiles differed between HEU-children with long cART exposure compared to HIV-unexposed-children (HUU). Specifically, higher levels of methionine-sulfone, which is associated with oxidative stress, were detected in HEU-children with long cART exposure compared to HUU-children. High infant methionine-sulfone levels were reflected by high prenatal plasma levels in the mother. Increased methionine-sulfone levels in the children were associated with decreased growth, including both weight and length.CONCLUSION: These findings based on longitudinal data demonstrate that dysregulation of metabolite networks associated with oxidative stress in children born to WLHIV is associated with restricted infant growth.PMID:37070556 | DOI:10.1097/QAD.0000000000003574

J Sep Sci. 2023 Apr 18:e2300124. doi: 10.1002/jssc.202300124. Online ahead of print.ABSTRACTKidney-yang-deficiency-syndrome is a neuroendocrine disease caused by the dysfunction of adrenal-pituitary-target gland axis. Gushudan is a traditional Chinese medicine prescription with functions of tonifying kidney and strengthening bone, and its bone-strengthening effect has been confirmed by previous anti-osteoporosis research. However, its kidney-tonifying mechanism has not been clear so far. In this study, the renal metabolomics and lipidomics based on gas chromatography-mass and ultra-high performance liquid chromatography-high resolution mass were integrated to find the metabolic disorders in kidney-yang-deficiency-syndrome rats. Protein precipitation and liquid-liquid extraction were used to extract metabolome and lipidome from kidney. Gushudan regulated abnormal levels of amino acids, lipids, purines and carbohydrates, such as L-arginine, hypoxanine, stearic acid and phosphatidylethanolamine (P-18:1/20:4), which had effects on many metabolic pathways, such as glycerophospholipid metabolism, sphingolipid metabolism, glycine, serine and threonine metabolism and purine metabolism, etc. By integrating metabolomics and lipidomics, this study comprehensively revealed the abnormal metabolic activities of amino acids, lipids and nucleotides in kidney-yang-deficiency-syndrome, and the metabolic regulation mechanism of Gushudan in preventing kidney-yang-deficiency-syndrome, as well as the improvement of Gushudan in maintaining renal cell structure, mitochondrial function and energy supply, which also provided some new evidence and connotation for "kidney-bone" axis. This article is protected by copyright. All rights reserved.PMID:37070550 | DOI:10.1002/jssc.202300124

Circulation. 2023 Apr 18. doi: 10.1161/CIRCULATIONAHA.122.062021. Online ahead of print.ABSTRACTBACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness.METHODS: EMPA-VISION is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr:ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated.RESULTS: Empagliflozin treatment did not change cardiac energetics (ie, PCr:ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; P=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; P=0.47]. Likewise, there were no changes in PCr:ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; P=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; P=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed.CONCLUSIONS: In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT03332212.PMID:37070436 | DOI:10.1161/CIRCULATIONAHA.122.062021

Mol Omics. 2023 Apr 18. doi: 10.1039/d3mo90012f. Online ahead of print.ABSTRACTCorrection for 'Metabolomics study reveals the alteration of fatty acid oxidation in the hearts of diabetic mice by empagliflozin' by Yingwei Zhang et al., Mol. Omics, 2022, 18, 643-651, https://doi.org/10.1039/D2MO00036A.PMID:37070329 | DOI:10.1039/d3mo90012f

Biomed Chromatogr. 2023 Apr 17:e5654. doi: 10.1002/bmc.5654. Online ahead of print.ABSTRACTThe efficacy of Rehmannia Radix changes after processing. However, the precise effect of processing on the property of Rehmannia Radix is an intricate topic, as this effect cannot be explained by traditional methods. The purpose of this study was to investigate how processing methods influence the property of Rehmannia Radix, as well as the changes in body function after administering dried Rehmannia Radix (RR) and processed Rehmannia Radix (PR) using a metabolomics approach. In addition, principal component analysis and orthogonal partial least squares discriminant analysis models were generated using SIMCA-P 14.0, to evaluate the property of RR and PR. Potential biomarkers were identified, and associated metabolic networks were established to clarify differences in the property and efficacies of RR and PR. The results showed that RR and PR have cold and hot property, respectively. RR can exert a hypolipidaemic effect by regulating nicotinate and nicotinamide metabolism. PR exerts a tonic effect and regulates the body's reproductive function through the regulation of alanine, aspartate, and glutamate metabolism, arachidonic acid, pentose, and glucuronate metabolism, respectively. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics is a promising approach to determine the cold/hot property of traditional Chinese medicine formulations.PMID:37070162 | DOI:10.1002/bmc.5654

J Transl Med. 2023 Apr 17;21(1):261. doi: 10.1186/s12967-023-04114-6.ABSTRACTBACKGROUND: Acute gouty arthritis is inflammatory joint arthritis. Gouty arthritis (GA) involves multiple pathological processes. Deposition of joints by monosodium urate (MSU) crystals has been shown to play a critical role in the injury process. Due to the different effects of MSU stimulation on the joints, the exact changes in the synovial fluid are unknown. We want to explore the changes in proteins and metabolites in the joints of gouty arthritis. Regulating various functional substances in the joint can reduce inflammation and pain symptoms.METHODS: 10 patients with gouty knee arthritis and 10 normal controls were selected from clinical, surgical cases. The biological function of the metabolome was assessed by co-expression network analysis. A molecular network based on metabolomic and proteomic data was constructed to study critical molecules. The fundamental molecular changes in the relevant pathways were then verified by western blot.RESULTS: Proteomic analysis showed that the expressions of proteases Cathepsin B, Cathepsin D, Cathepsin G, and Cathepsin S in synovial fluid patients with gouty arthritis were significantly increased. Enrichment analysis showed a positive correlation between lysosomal and clinical inflammatory cell shape changes. Untargeted metabolomic analysis revealed that lipids and lipoids accumulate, inhibit autophagic flux, and modulate inflammation and immunity in gouty arthritis patients. It was determined that the accumulation of lipid substances such as phospholipase A2 led to the imbalanced state of the autophagy-lysosome complex, and the differentially expressed metabolites of Stearoylcarnitine, Tetradecanoylcarnitine, Palmitoylcarnitine were identified (|log2 fold change|> 1.5, adjusted P value < 0.05 and variable importance in prediction (VIP) > 1.5). The autophagy-lysosomal pathway was found to be associated with gouty knee arthritis. Essential molecular alterations of multi-omics networks in gouty knee arthritis patients compared with normal controls involve acute inflammatory response, exosomes, immune responses, lysosomes, linoleic acid metabolism, and synthesis.CONCLUSIONS: Comprehensive analysis of proteomic and untargeted metabolomics revealed protein and characteristic metabolite alterations in gouty arthritis, it mainly involves lipids and lipid like molecules, phospholipase A2 and autophagic lysosomes. This study describes the pathological characteristics, pathways, potential predictors and treatment goals of gouty knee arthritis.PMID:37069596 | DOI:10.1186/s12967-023-04114-6

BMC Plant Biol. 2023 Apr 18;23(1):200. doi: 10.1186/s12870-023-04206-x.ABSTRACTCasuarina equisetifolia is drought tolerant, salt tolerant, and able to grow in barren environments. It is often used to reduce wind damage, to prevent sand erosion, and to help establish plant communities in tropical and subtropical coastal zones. To determine the basis for its drought tolerance, we conducted transcriptomic and metabolic analyses of young branchlets under a non-drought treatment (D_0h) and 2-, 12-, and 24-h-long drought treatments (D_2h, D_12h, and D_24h). A total of 5033 and 8159 differentially expressed genes (DEGs) were identified in D_2h/D_0h and D_24h/D_0h. These DEGs were involved in plant hormone signal transduction, jasmonic acid (JA) biosynthesis, flavonoid biosynthesis, and phenylpropanoid biosynthesis. A total of 148 and 168 differentially accumulated metabolites (DAMs) were identified in D_12h/D_0h and D_24h/D_0h, which were mainly amino acids, phenolic acids, and flavonoids. In conclusion, C. equisetifolia responds to drought by regulating plant hormone signal transduction and the biosynthesis of JA, flavonoid, and phenylpropanoid. These results increase the understanding of drought tolerance in C. equisetifolia at both transcriptional and metabolic levels and provide new insights into coastal vegetation reconstruction and management.PMID:37069496 | DOI:10.1186/s12870-023-04206-x

Phytomedicine. 2023 Apr 17;115:154831. doi: 10.1016/j.phymed.2023.154831. Online ahead of print.ABSTRACTBACKGROUND: The intestinal microbiota plays a key role in understanding the mechanism of traditional Chinese medicine (TCM), as it could transform the herbal ingredients to metabolites with higher bioavailability and activity comparing to their prototypes. Nevertheless, the study of the activity and mechanism of microbiota metabolites reported by the published literature still lacks viable ways. Hence a new strategy is proposed to solve this issue.PURPOSE: A new strategy to study the activity and mechanism of intestinal microbiota metabolites of TCM herbal ingredients by integrating spectrum-effect relationship, network pharmacology, metabolomics analysis and molecular docking together was developed and proposed.METHOD: Platycodin D (PD) and its microbiota metabolites with antitussive and expectorant effect were selected as an example for demonstration. First, the PD and its microbiota metabolites with important contribution to antitussive and/or expectorant effects were screened through spectrum-effect relationship analysis. Second, network pharmacology and metabolomics analysis were integrated to identify the upstream key targets of PD and its microbiota metabolites as well as the downstream endogenous metabolites. Finally, the active forms of PD were further confirmed by molecular docking.RESULTS: Results showed that PD was an active ingredient with antitussive and/or expectorant effects, and the active forms of PD were its microbiota metabolites: 3-O-β-d-glucopyranosyl platycodigenin, 3-O-β-d-glucopyranosyl isoplatycodigenin, 7‑hydroxyl-3-O-β-d-glucopyranosyl platycodigenin, platycodigenin and isoplatycodigenin. In addition, those microbiota metabolites could bind the key targets of PAH, PLA2G2A, ALOX5, CYP2C9 and CYP2D6 to exert antitussive effects by regulating four metabolic pathways of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, glycerophospholipid metabolism and linoleic acid metabolism. Similarly, they could also bind the key targets of PLA2G1B, ALOX5, CYP2C9 and CYP2D6 to exert expectorant effect by regulating two pathways of glycerophospholipid metabolism and linoleic acid metabolism.CONCLUSION: The proposed strategy paves a new way for the illustration of the activities and mechanisms of TCM herbal ingredients, which is very important to reconcile the conundrums of TCM herbal ingredients with low oral bioavailability but high activity.PMID:37094423 | DOI:10.1016/j.phymed.2023.154831

J Alzheimers Dis. 2023 Apr 17. doi: 10.3233/JAD-220795. Online ahead of print.ABSTRACTBACKGROUND: Circulating phospholipid species have been shown to predict Alzheimer's disease (AD) prognosis but the link between phospholipid disturbances and subcortical small vessel cerebrovascular disease (CeVD) common in AD patients is not known.OBJECTIVE: This study used quantitative lipidomics to measure serum diacyl, alkenyl (ether), alkyl, and lyso phospholipid species in individuals with extensive CeVD (n = 29), AD with minimal CeVD (n = 16), and AD with extensive CeVD (n = 14), and compared them to age-matched controls (n = 27). Memory was assessed using the California Verbal Learning Test. 3.0T MRI was used to assess hippocampal volume, atrophy, and white matter hyperintensity (WMH) volumes as manifestations of CeVD.RESULTS: AD was associated with significantly higher concentrations of choline plasmalogen 18:0_18:1 and alkyl-phosphocholine 18:1. CeVD was associated with significantly lower lysophospholipids containing 16:0. Phospholipids containing arachidonic acid (AA) were associated with poorer memory in controls, whereas docosahexaenoic acid (DHA)-containing phospholipids were associated with better memory in individuals with AD+CeVD. In controls, DHA-containing phospholipids were associated with more atrophy and phospholipids containing linoleic acid and AA were associated with less atrophy. Lysophospholipids containing 16:0, 18:0, and 18:1 were correlated with less atrophy in controls, and of these, alkyl-phosphocholine 18:1 was correlated with smaller WMH volumes. Conversely, 16:0_18:1 choline plasmalogen was correlated with greater WMH volumes in controls.CONCLUSION: This study demonstrates discernable differences in circulating phospholipids in individuals with AD and CeVD, as well as new associations between phospholipid species with memory and brain structure that were specific to contexts of commonly comorbid vascular and neurodegenerative pathologies.PMID:37092220 | DOI:10.3233/JAD-220795

PeerJ. 2023 Apr 17;11:e15113. doi: 10.7717/peerj.15113. eCollection 2023.ABSTRACTBACKGROUND: Chronic long-term stress is associated with a range of disorders, including depression and a variety of other chronic illnesses. It is well known that maternal exposure to psychosocial stress during pregnancy significantly increases the likelihood of adverse pregnancy outcomes. The gut microbiota has been a popular topic, it is a key mediator of the gut-brain axis and plays an important role in human health; changes in the gut microbiota have been related to chronic stress-induced health impairment, however, the relationship between maternal negative emotions and abnormal gut microbiota and its metabolites during maternal exposure to chronic stress during pregnancy remains unclear.METHODS: Pregnant rats were subjected to chronic unpredicted mild stress (CUMS) to establish the rat model of chronic stress during pregnancy. The behavioral changes were recorded using sucrose preference test (SPT) and open-field test (OFT), plasma corticosterone levels were determined by radioimmunoassay, and a comprehensive method combining 16S rRNA gene sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics was used to study the effects of stress during pregnancy on the function of intestinal microbiota and its metabolites.RESULTS: Chronic stress during pregnancy not only increased maternal plasma corticosterone (P < 0.05), but also caused maternal depression-like behaviors (P < 0.05). Chronic stress during pregnancy changed the species composition at the family level of maternal gut microbiota, the species abundance of Ruminococcaceae in the stress group (23.45%) was lower than the control group (32.67%) and the species abundance of Prevotellaceae in the stress group (10.45%) was higher than the control group (0.03%) (P < 0.05). Vertical locomotion and 1% sucrose preference percentage in pregnant rats were negatively correlated with Prevotellaceae (r = - 0.90, P < 0.05). Principal component analysis with partial least squares discriminant analysis showed that the integration points of metabolic components in the stress and control groups were completely separated, indicating that there were significant differences in the metabolic patterns of the two groups, and there were seven endogenous metabolites that differed (P < 0.05).CONCLUSIONS: The negative emotional behaviors that occur in pregnant rats as a result of prenatal chronic stress may be associated with alterations in the gut microbiota and its metabolites. These findings provide a basis for future targeted metabolomics and gut flora studies on the effects of chronic stress during pregnancy on gut flora.PMID:37090110 | PMC:PMC10117386 | DOI:10.7717/peerj.15113

Food Chem. 2023 Apr 17;421:136147. doi: 10.1016/j.foodchem.2023.136147. Online ahead of print.ABSTRACTProtein glycation may occur naturally when reducing sugars and proteins coexist, which is often the case for industrial enzymes. The impact of post-translational modifications on enzyme performance (e.g., stability or function) is often not predictable, highlighting the importance of having appropriate analytical methodologies to monitor the influence of glycation on performance. Here, a boronate affinity chromatography method was developed to enrich glycated species followed by mass spectrometry for structural characterization and activity assays for functional assessment. This approach was applied to a (temperature-stressed) lipase used for food applications revealing that storage at -20 °C and 4 °C resulted in minor glycation (below 9%), whereas storage at 25 °C led to a higher glycation level with up to four sugars per lipase molecule. Remarkably, activity measurements revealed that glycation did not reduce lipase activity or stability. Altogether, this novel strategy is a helpful extension to the current analytical toolbox supporting development of enzyme products.PMID:37087987 | DOI:10.1016/j.foodchem.2023.136147

Food Chem. 2023 Apr 17;421:136150. doi: 10.1016/j.foodchem.2023.136150. Online ahead of print.ABSTRACTHydrothermal treatment is commonly used for hemicelluloses extraction from lignocellulosic materials. In this study, we thoroughly investigated with a novel approach the metabolomics of degradation compounds formed when hazelnut shells are subjected to this type of treatment. Three different complementary techniques were combined, namely GC-MS, 1H NMR, and UHPLC-IM-Q-TOF-MS. Organic acids, modified sugars and aromatic compounds, likely to be the most abundant chemical classes, were detected and quantified by NMR, whereas GC- and LC-MS-based techniques allowed to detect many molecules with low and higher Mw, respectively. Furans, polyols, N-heterocyclic compounds, aldehydes, ketones, and esters appeared, among others. Ion mobility-based LC-MS method was innovatively used for this purpose and could allow soon to create potentially useful datasets for building specific databases relating to the formation of these compounds in different process conditions and employing different matrices. This could be a very intelligent approach especially in a risk assessment perspective.PMID:37086522 | DOI:10.1016/j.foodchem.2023.136150

J Nutr. 2023 Apr 17:S0022-3166(23)35552-4. doi: 10.1016/j.tjnut.2023.04.009. Online ahead of print.NO ABSTRACTPMID:37080248 | DOI:10.1016/j.tjnut.2023.04.009

Trends Plant Sci. 2023 Apr 17:S1360-1385(23)00130-9. doi: 10.1016/j.tplants.2023.04.004. Online ahead of print.ABSTRACTIn plants, uridine diphosphate (UDP)-dependent glycosyltransferases (UGTs) catalyze glycosylation of secondary metabolites, but assigning physiological functions to UGTs is still a daunting task. The recent study of Wu et al. presents a useful method to resolve this problem by elegantly combining modification-specific metabolomics with isotope tracing.PMID:37076401 | DOI:10.1016/j.tplants.2023.04.004

Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Apr 17:159319. doi: 10.1016/j.bbalip.2023.159319. Online ahead of print.ABSTRACT12α-Hydroxylated (12αOH) bile acids (BAs) selectively increase with high-fat diet intake. Dietary supplementation with cholic acid (CA) in rats is a possible strategy to reveal the causal link between 12αOH BAs and hepatic steatosis. The present study aimed to investigate the metabolic mechanism underlying the effect of 12αOH BAs on hepatic steatosis. Male WKAH rats were fed either a control (Ct) or CA-supplemented diet (0.5 g/kg). After the 12-week intervention, the CA diet elevated the 12αOH BA levels in the gut-liver axis. CA-fed rats showed greater hepatic lipid accumulation than in the Ct group, regardless of the dietary energy balance. Untargeted metabolomics suggested marked differences in the fecal metabolome of rats subjected to the CA diet compared with that of Ct, characterized by the depletion of fatty acids and enrichment of amino acids and amines. Moreover, the liver metabolome differed in the CA diet group, characterized by an alteration in redox-related pathways. The CA diet elevated nicotinamide adenine dinucleotide consumption owing to the activation of poly(ADP-ribose) polymerase 1, resulting in impaired peroxisome proliferator-activated receptor α signaling in the liver. The CA diet increased sedoheptulose 7-phosphate, and enhanced glucose-6-phosphate dehydrogenase activity, suggesting promotion of the pentose phosphate pathway that generates reducing equivalents. Integrated analysis of the gut-liver metabolomic data revealed the role of deoxycholic acid and its liver counterpart in mediating these metabolic alterations. These observations suggest that alterations in metabolites induced by 12αOH BAs in the gut-liver axis contribute to the enhancement of liver lipid accumulation.PMID:37075973 | DOI:10.1016/j.bbalip.2023.159319

Clin Immunol. 2023 Apr 17:109330. doi: 10.1016/j.clim.2023.109330. Online ahead of print.ABSTRACTSystemic lupus erythematosus (SLE) is an autoimmune disease affecting thousands of people. There are still no effective biomarkers for SLE diagnosis and disease activity assessment. We performed proteomics and metabolomics analyses of serum from 121 SLE patients and 106 healthy individuals, and identified 90 proteins and 76 metabolites significantly changed. Several apolipoproteins and the metabolite arachidonic acid were significantly associated with disease activity. Apolipoprotein A-IV (APOA4), LysoPC(16:0), punicic acid and stearidonic acid were correlated with renal function. Random forest model using the significantly changed molecules identified 3 proteins including ATRN, THBS1 and SERPINC1, and 5 metabolites including cholesterol, palmitoleoylethanolamide, octadecanamide, palmitamide and linoleoylethanolamide, as potential biomarkers for SLE diagnosis. Those biomarkers were further validated in an independent cohort with high accuracy (AUC = 0.862 and 0.898 for protein and metabolite biomarkers respectively). This unbiased screening has led to the discovery of novel molecules for SLE disease activity assessment and SLE classification.PMID:37075949 | DOI:10.1016/j.clim.2023.109330

J Adv Res. 2023 Apr 17:S2090-1232(23)00114-5. doi: 10.1016/j.jare.2023.04.008. Online ahead of print.ABSTRACTINTRODUCTION: Ulva lactuca polysaccharide (ULP) is green algae extract with numerous biological activities, including anticoagulant, anti-inflammatory, and antiviral effects. However, the inhibitory ability of ULP in the development of hepatocellular carcinoma warrants further studies.OBJECTIVES: To elucidate the anti-tumor mechanism of ULP action and evaluate its regulatory effect on gut microbiota and metabolism in H22 hepatocellular carcinoma tumor-bearing mice.METHODS: An H22 tumor-bearing mouse model was established by subcutaneously injecting H22 hepatoma cells. The gut microbiota composition in cecal feces was assessed and subjected to untargeted metabolomic sequencing. The antitumor activity of ULP was verified further by western blot, RT-qPCR, and reactive oxygen species (ROS) assays.RESULTS: Administration of ULP alleviated tumor growth by modulating the compositions of the gut microbial communities (Tenericutes, Agathobacter, Ruminiclostridium, Parabacteroides, Lactobacillus, and Holdemania) and metabolites (docosahexaenoic acid, uric acid, N-Oleoyl Dopamine, and L-Kynurenine). Mechanistically, ULP promoted ROS production by inhibiting the protein levels of JNK, c-JUN, PI3K, Akt, and Bcl-6, thereby delaying the growth of HepG2 cells.CONCLUSION: ULP attenuates tumor growth in H22 tumor-bearing mice by modulating gut microbial composition and metabolism. ULP inhibits tumor growth mainly by promoting ROS generation.PMID:37075862 | DOI:10.1016/j.jare.2023.04.008

J Vis Exp. 2023 Mar 31;(193). doi: 10.3791/65205.ABSTRACTThe brain secretome consists of proteins either actively secreted or shed from the cell surface by proteolytic cleavage in the extracellular matrix of the nervous system. These proteins include growth factor receptors and transmembrane proteins, among others, covering a broad spectrum of roles in the development and normal functioning of the central nervous system. The current procedure to extract the secretome from cerebrospinal fluid is complicated and time-consuming, and it is difficult to isolate these proteins from experimental animal brains. In this study, we present a novel protocol for isolating the brain secretome from mouse brain slice cultures. First, the brains were isolated, sliced, and cultured ex vivo. The culture medium was then filtered and concentrated for isolating proteins by centrifugation after a few days. Finally, the isolated proteins were resolved using sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and subsequently probed for purity characterization by western blot. This isolation procedure of the brain secretome from ex vivo brain slice cultures can be used to investigate the effects of the secretome on a variety of neurodevelopmental diseases, such as autism spectrum disorders.PMID:37067274 | DOI:10.3791/65205