PubMed

BMB Rep. 2023 May 24:5912. Online ahead of print.ABSTRACTThis study investigates the relationship between cancer cachexia and the gut microbiota, focusing on the influence of cancer on microbial composition. Lewis lung cancer cell allografts were used to induce cachexia in mice, and body and muscle weight changes were monitored. Fecal samples were collected for targeted metabolomic analysis for short chain fatty acids and microbiome analysis. The cachexia group exhibited lower alpha diversity and distinct beta diversity in gut microbiota compared to the control group. Differential abundance analysis revealed higher Bifidobacterium and Romboutsia, but lower Streptococcus abundance in the cachexia group. Additionally, lower proportions of acetate and butyrate were observed in the cachexia group. The study observed that a significant impact of cancer cachexia on gut microbiota and their generated metabolites, indicating the host-to-gut microbiota axis.PMID:37220909

aBIOTECH. 2023 Jan 11;4(1):47-56. doi: 10.1007/s42994-022-00091-4. eCollection 2023 Mar.ABSTRACTPlants are the most important sources of food for humans, as well as supplying many ingredients that are of great importance for human health. Developing an understanding of the functional components of plant metabolism has attracted considerable attention. The rapid development of liquid chromatography and gas chromatography, coupled with mass spectrometry, has allowed the detection and characterization of many thousands of metabolites of plant origin. Nowadays, elucidating the detailed biosynthesis and degradation pathways of these metabolites represents a major bottleneck in our understanding. Recently, the decreased cost of genome and transcriptome sequencing rendered it possible to identify the genes involving in metabolic pathways. Here, we review the recent research which integrates metabolomic with different omics methods, to comprehensively identify structural and regulatory genes of the primary and secondary metabolic pathways. Finally, we discuss other novel methods that can accelerate the process of identification of metabolic pathways and, ultimately, identify metabolite function(s).PMID:37220537 | PMC:PMC10199974 | DOI:10.1007/s42994-022-00091-4

PeerJ. 2023 May 18;11:e15302. doi: 10.7717/peerj.15302. eCollection 2023.ABSTRACTBACKGROUND: Malignant mesothelioma (MM) is a cancer caused mainly by asbestos exposure, and is aggressive and incurable. This study aimed to identify differential metabolites and metabolic pathways involved in the pathogenesis and diagnosis of malignant mesothelioma.METHODS: By using gas chromatography-mass spectrometry (GC-MS), this study examined the plasma metabolic profile of human malignant mesothelioma. We performed univariate and multivariate analyses and pathway analyses to identify differential metabolites, enriched metabolism pathways, and potential metabolic targets. The area under the receiver-operating curve (AUC) criterion was used to identify possible plasma biomarkers.RESULTS: Using samples from MM (n = 19) and healthy control (n = 22) participants, 20 metabolites were annotated. Seven metabolic pathways were disrupted, involving alanine, aspartate, and glutamate metabolism; glyoxylate and dicarboxylate metabolism; arginine and proline metabolism; butanoate and histidine metabolism; beta-alanine metabolism; and pentose phosphate metabolic pathway. The AUC was used to identify potential plasma biomarkers. Using a threshold of AUC = 0.9, five metabolites were identified, including xanthurenic acid, (s)-3,4-hydroxybutyric acid, D-arabinose, gluconic acid, and beta-d-glucopyranuronic acid.CONCLUSIONS: To the best of our knowledge, this is the first report of a plasma metabolomics analysis using GC-MS analyses of Asian MM patients. Our identification of these metabolic abnormalities is critical for identifying plasma biomarkers in patients with MM. However, additional research using a larger population is needed to validate our findings.PMID:37220527 | PMC:PMC10200095 | DOI:10.7717/peerj.15302

Plant Physiol. 2023 May 23:kiad298. doi: 10.1093/plphys/kiad298. Online ahead of print.ABSTRACTAcclimation and adaptation of metabolism to a changing environment are key processes for plant survival and reproductive success. In the present study, 241 natural accessions of Arabidopsis (Arabidopsis thaliana) were grown under two different temperature regimes, 16 °C and 6 °C, and growth parameters were recorded, together with metabolite profiles, to investigate the natural genome × environment effects on metabolome variation. The plasticity of metabolism, which was captured by metabolic distance measures, varied considerably between accessions. Both relative growth rates and metabolic distances were predictable by the underlying natural genetic variation of accessions. Applying machine learning methods, climatic variables of the original growth habitats were tested for their predictive power of natural metabolic variation among accessions. We found specifically habitat temperature during the first quarter of the year to be the best predictor of the plasticity of primary metabolism, indicating habitat temperature as the causal driver of evolutionary cold adaptation processes. Analyses of epigenome- and genome-wide associations revealed accession-specific differential DNA-methylation levels as potentially linked to the metabolome and identified FUMARASE2 as strongly associated with cold adaptation in Arabidopsis accessions. These findings were supported by calculations of the biochemical Jacobian matrix based on variance and covariance of metabolomics data, which revealed that growth under low temperatures most substantially affects the accession-specific plasticity of fumarate and sugar metabolism. Our findings indicate that the plasticity of metabolic regulation is predictable from the genome and epigenome and driven evolutionarily by Arabidopsis growth habitats.PMID:37220420 | DOI:10.1093/plphys/kiad298

Anal Chem. 2023 May 23. doi: 10.1021/acs.analchem.2c05371. Online ahead of print.ABSTRACTIn recent years, feces has surfaced as the matrix of choice for investigating the gut microbiome-health axis because of its non-invasive sampling and the unique reflection it offers of an individual's lifestyle. In cohort studies where the number of samples required is large, but availability is scarce, a clear need exists for high-throughput analyses. Such analyses should combine a wide physicochemical range of molecules with a minimal amount of sample and resources and downstream data processing workflows that are as automated and time efficient as possible. We present a dual fecal extraction and ultra high performance liquid chromatography-high resolution-quadrupole-orbitrap-mass spectrometry (UHPLC-HR-Q-Orbitrap-MS)-based workflow that enables widely targeted and untargeted metabolome and lipidome analysis. A total of 836 in-house standards were analyzed, of which 360 metabolites and 132 lipids were consequently detected in feces. Their targeted profiling was validated successfully with respect to repeatability (78% CV < 20%), reproducibility (82% CV < 20%), and linearity (81% R2 > 0.9), while also enabling holistic untargeted fingerprinting (15,319 features, CV < 30%). To automate targeted processing, we optimized an R-based targeted peak extraction (TaPEx) algorithm relying on a database comprising retention time and mass-to-charge ratio (360 metabolites and 132 lipids), with batch-specific quality control curation. The latter was benchmarked toward vendor-specific targeted and untargeted software and our isotopologue parameter optimization/XCMS-based untargeted pipeline in LifeLines Deep cohort samples (n = 97). TaPEx clearly outperformed the untargeted approaches (81.3 vs 56.7-66.0% compounds detected). Finally, our novel dual fecal metabolomics-lipidomics-TaPEx method was successfully applied to Flemish Gut Flora Project cohort (n = 292) samples, leading to a sample-to-result time reduction of 60%.PMID:37220321 | DOI:10.1021/acs.analchem.2c05371

J Clin Endocrinol Metab. 2023 May 23:dgad288. doi: 10.1210/clinem/dgad288. Online ahead of print.ABSTRACTAIMS: To examine whether nonobese (BMI<30 kg/m2) and obese (BMI≥30 kg/m2) women with gestational diabetes mellitus (GDM) and obese non-GDM women differ in metabolomic profiles from nonobese non-GDM controls.METHODS: Levels of 66 metabolic measures were assessed in early (median 13, IQR 12.4-13.7 gestation weeks), and across early, mid (20, 19.3-23.0) and late (28, 27.0-35.0) -pregnancy blood samples in 755 pregnant women of the PREDO and RADIEL studies. The independent replication cohort comprised 490 pregnant women.RESULTS: Nonobese and obese GDM, and obese non-GDM women differed similarly from the controls across early, mid, and late pregnancy in 13 measures, including VLDL-related measures, and fatty acids. In 6 measures, including fatty acid ratios, glycolysis-related measures, valine and 3-hydroxybutyrate, the differences between obese GDM women and controls were more pronounced than the differences between nonobese GDM or obese non-GDM women and controls. In 16 measures, including HDL-related measures, fatty acid ratios, amino acids and inflammation, differences between obese GDM or obese non-GDM women and controls were more pronounced than the differences between nonobese GDM women and controls. Most differences were evident in early pregnancy, and in the replication cohort were more often in the same direction than would be expected by chance alone.CONCLUSIONS: Differences between nonobese and obese GDM, or obese non-GDM women and controls in metabolomic profiles may allow detection of high-risk women for timely targeted preventive interventions.PMID:37220084 | DOI:10.1210/clinem/dgad288

J Proteome Res. 2023 May 23. doi: 10.1021/acs.jproteome.3c00226. Online ahead of print.ABSTRACTOvarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. In contrast, later stages featured more diverse lipid alterations, including fatty acids and their derivatives, triglycerides, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, and phosphatidylinositols. These alterations underscored unique perturbations in cell membrane stability, proliferation, and survival during cancer development and progression, offering potential targets for early detection and prognosis of human ovarian cancer.PMID:37220064 | DOI:10.1021/acs.jproteome.3c00226

Ther Hypothermia Temp Manag. 2023 May 23. doi: 10.1089/ther.2022.0065. Online ahead of print.ABSTRACTTargeted temperature management (TTM) may moderate the injury from out-of-hospital cardiac arrest. Slowing the metabolism has been a suggested effect. Nevertheless, studies have found higher lactate levels in patients cooled to 33°C compared with 36°C even days from TTM cessation. Larger studies have not been performed on the TTM's effect on the metabolome. Accordingly, to explore the effect of TTM, we used ultra-performance liquid-mass spectrometry in a substudy of 146 patients randomized in the TTM trial to either 33°C or 36°C for 24 hours and quantified 60 circulating metabolites at the time of hospital arrival (T0) and 48 hours later (T48). From T0 to T48, profound changes to the metabolome were observed: tricarboxylic acid (TCA) cycle metabolites, amino acids, uric acid, and carnitine species all decreased. TTM significantly modified these changes in nine metabolites (Benjamini-Hochberg corrected false discovery rate <0.05): branched amino acids valine and leucine levels dropped more in the 33°C arm (change [95% confidence interval]: -60.9 μM [-70.8 to -50.9] vs. -36.0 μM [-45.8 to -26.3] and -35.5 μM [-43.1 to -27.8] vs. -21.2 μM [-28.7 to -13.6], respectively), whereas the TCA metabolites including malic acid and 2-oxoglutaric acid remained higher for the first 48 hours (-7.7 μM [-9.7 to -5.7] vs. -10.4 μM [-12.4 to -8.4] and -3 μM [-4.3 to -1.7] vs. -3.7 μM [-5 to -2.3]). Prostaglandin E2 only dropped in the TTM 36°C group. The results show that TTM affects the metabolism hours after normothermia have been reached. Clinical Trial Number: NCT01020916.PMID:37219970 | DOI:10.1089/ther.2022.0065

Arthritis Rheumatol. 2023 May 23. doi: 10.1002/art.42616. Online ahead of print.ABSTRACTOBJECTIVE: We aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis.DESIGN: Fecal samples were collected from 38 healthy individuals (HCs) and 53 high-risk RA individuals with anti-citrullinated protein antibody (ACPA)-positivity (PreRA), 12 of 53 PreRA developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the HC and PreRA individuals or among PreRA subgroups were identified by 16S rRNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice received GM from the HC or PreRA groups were then evaluated for intestinal permeability, inflammatory cytokines and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from PreRA individuals on arthritis severity in mice.RESULTS: Stool microbial diversity was lower in PreRA individuals than in HCs. The bacterial community structure and function significantly differed between HC and PreRA individuals. Although there were to some extent differences in the bacterial abundance among the PreRA subgroups, no robust functional differences were observed. The metabolites in the serum of the PreRA group were dramatically different from those in the HC group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the PreRA group increased intestinal permeability in FMT mice and ZO-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving PreRA feces compared to HC. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice.CONCLUSION: Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to arthritis development.PMID:37219936 | DOI:10.1002/art.42616

Appl Microbiol Biotechnol. 2023 May 23. doi: 10.1007/s00253-023-12595-0. Online ahead of print.ABSTRACTCaseous lymphadenitis (CLA), an infectious disease caused by Corynebacterium pseudotuberculosis in small ruminants, is highly prevalent worldwide. Economic losses have already been associated with the disease, and little is known about the host-pathogen relationship associated with the disease. The present study aimed to perform a metabolomic study of the C. pseudotuberculosis infection in goats. Serum samples were collected from a herd of 173 goats. The animals were classified as controls (not infected), asymptomatic (seropositives but without detectable CLA clinical signs), and symptomatic (seropositive animals presenting CLA lesions), according to microbiological isolation and immunodiagnosis. The serum samples were analyzed using nuclear magnetic resonance (1H-NMR), nuclear Overhauser effect spectroscopy (NOESY), and Carr-Purcell-Meiboom-Gill (CPMG) sequences. The NMR data were analyzed using chemometrics, and principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) were performed to discover specific biomarkers responsible for discrimination between the groups. A high dissemination of the infection by C. pseudotuberculosis was observed, being 74.57% asymptomatic and 11.56% symptomatic. In the evaluation of 62 serum samples by NMR, the techniques were satisfactory in the discrimination of the groups, being also complementary and mutually confirming, demonstrating possible biomarkers for the infection by the bacterium. Twenty metabolites of interest were identified by NOESY and 29 by CPMG, such as tryptophan, polyunsaturated fatty acids, formic acid, NAD+, and 3-hydroxybutyrate, opening promising possibilities for the use of these results in new therapeutic, immunodiagnosis, and immunoprophylactic tools, as well as for studies of the immune response against C. pseudotuberculosis. KEY POINTS: • Sixty-two samples from healthy, CLA asymptomatic, and symptomatic goats were screened • Twenty metabolites of interest were identified by NOESY and 29 by CPMG • 1H-NMR NOESY and CPMG were complementary and mutually confirming.PMID:37219572 | DOI:10.1007/s00253-023-12595-0

Anal Chem. 2023 May 23. doi: 10.1021/acs.analchem.3c00222. Online ahead of print.ABSTRACTAfter decades of research, gene therapy products have reached market maturity in recent years. Recombinant adeno-associated viruses (rAAVs) are one of the most promising gene delivery vehicles and are currently under intense scientific investigation. These next-generation medicines remain very challenging when it comes to designing appropriate analytical techniques for quality control. One critical quality attribute is the integrity of ssDNA incorporated in these vectors. The genome is the active compound driving rAAV therapy and therefore requires proper assessment and quality control. Current techniques for rAAV genome characterization include next-generation sequencing, quantitative polymerase chain reaction, analytical ultracentrifugation (AUC), and capillary gel electrophoresis (CGE), yet each of them presents their limitations or lack of user-friendliness. In this work, we demonstrate for the first time the potential of ion pairing-reverse phase-liquid chromatography (IP-RP-LC) to characterize the integrity of rAAV genomes. The obtained results were supported by two orthogonal techniques, AUC and CGE. IP-RP-LC can be performed above DNA melting temperatures, avoiding the detection of secondary DNA isoforms, and does not require the use of dyes due to UV detection. We demonstrate that this technique is suitable for batch comparability, different rAAV serotypes (AAV2 and AAV8), internal vs external (inside vs outside the capsid) DNA analysis, and contaminated samples. Overall, it is exceptionally user-friendly, needs limited sample preparation, has high reproducibility, and permits fractionation for further peak characterization. All of these factors add significant value of IP-RP-LC to the analytical toolbox of rAAV genome assessment.PMID:37219094 | DOI:10.1021/acs.analchem.3c00222

Proteomes. 2023 May 3;11(2):17. doi: 10.3390/proteomes11020017.ABSTRACTBreast cancer (BC) is a major global health issue, affecting a significant proportion of the female population and contributing to high rates of mortality. One of the primary challenges in the treatment of BC is the disease's heterogeneity, which can lead to ineffective therapies and poor patient outcomes. Spatial proteomics, which involves the study of protein localization within cells, offers a promising approach for understanding the biological processes that contribute to cellular heterogeneity within BC tissue. To fully leverage the potential of spatial proteomics, it is critical to identify early diagnostic biomarkers and therapeutic targets, and to understand protein expression levels and modifications. The subcellular localization of proteins is a key factor in their physiological function, making the study of subcellular localization a major challenge in cell biology. Achieving high resolution at the cellular and subcellular level is essential for obtaining an accurate spatial distribution of proteins, which in turn can enable the application of proteomics in clinical research. In this review, we present a comparison of current methods of spatial proteomics in BC, including untargeted and targeted strategies. Untargeted strategies enable the detection and analysis of proteins and peptides without a predetermined molecular focus, whereas targeted strategies allow the investigation of a predefined set of proteins or peptides of interest, overcoming the limitations associated with the stochastic nature of untargeted proteomics. By directly comparing these methods, we aim to provide insights into their strengths and limitations and their potential applications in BC research.PMID:37218922 | DOI:10.3390/proteomes11020017

BioTech (Basel). 2023 May 17;12(2):39. doi: 10.3390/biotech12020039.ABSTRACTMany kinds of Lactobacillus are common occupants of humans' digestive tract that support the preservation of a balanced microbial environment that benefits host health. In this study, the unique lactic acid bacterium strain Limosilactobacillus fermentum U-21, which was isolated from the feces of a healthy human, was examined for its metabolite profile in order to compare it to that of the strain L. fermentum 279, which does not have antioxidant (AO) capabilities. By using GC × GC-MS, the metabolite fingerprint of each strain was identified, and the data were then subjected to multivariate bioinformatics analysis. The L. fermentum U-21 strain has previously been shown to possess distinctive antioxidant properties in in vivo and in vitro studies, positioning it as a drug candidate for the treatment of Parkinsonism. The production of multiple distinct compounds is shown by the metabolite analysis, demonstrating the unique characteristics of the L. fermentum U-21 strain. According to reports, some of the L. fermentum U-21 metabolites found in this study have health-promoting properties. The GC × GC-MS-based metabolomic tests defined strain L. fermentum U-21 as a potential postbiotic with significant antioxidant potential.PMID:37218756 | DOI:10.3390/biotech12020039

Anal Chem. 2023 May 23. doi: 10.1021/acs.analchem.2c04343. Online ahead of print.ABSTRACTSmall molecule structure elucidation using tandem mass spectrometry (MS/MS) plays a crucial role in life science, bioanalytical, and pharmaceutical research. There is a pressing need for increased throughput of compound identification and transformation of historical data into information-rich spectral databases. Meanwhile, molecular networking, a recent bioinformatic framework, provides global displays and system-level understanding of complex LC-MS/MS data sets. Herein we present meRgeION, a multifunctional, modular, and flexible R-based toolbox to streamline spectral database building, automated structural elucidation, and molecular networking. The toolbox offers diverse tuning parameters and the possibility to combine various algorithms in the same pipeline. As an open-source R package, meRgeION is ideally suited for building spectral databases and molecular networks from privacy-sensitive and preliminary data. Using meRgeION, we have created an integrated spectral database covering diverse pharmaceutical compounds that was successfully applied to annotate drug-related metabolites from a published nontargeted metabolomics data set as well as reveal the chemical space behind this complex data set through molecular networking. Moreover, the meRgeION-based processing workflow has demonstrated the usefulness of a spectral library search and molecular networking for pharmaceutical forced degradation studies. meRgeION is freely available at: https://github.com/daniellyz/meRgeION2.PMID:37218737 | DOI:10.1021/acs.analchem.2c04343

Am J Epidemiol. 2023 May 22:kwad122. doi: 10.1093/aje/kwad122. Online ahead of print.ABSTRACTEpidemiologic studies of low-frequency exposures or outcomes using metabolomics analyses of neonatal dried blood spots (DBS) often require assembly of samples with substantial differences in duration of storage. Independent assessment of stability of metabolites in archived DBS will enable improved design and interpretation of epidemiologic research utilizing DBS. Neonatal DBS routinely collected and stored as part of the California Genetic Disease Screening Program between 1983 and 2011 were used. The study population included 899 children without cancer before age 6 born in California. High-resolution metabolomics with liquid chromatography mass spectrometry (LC-MS) was performed and the relative ion intensities of common metabolites and selected xenobiotic metabolites of nicotine (cotinine and hydroxycotinine) were evaluated. In total, we detected 26,235 mass spectral features across two separate chromatography methods (C18 and HILIC). For most of the 39 metabolites related to nutrition and health status, we found no statistically significant annual trends across the years of storage. Nicotine metabolites were captured in the DBS with relatively stable intensities. This study supports the usefulness of DBS stored long-term for epidemiological studies of the metabolome. Omics-based information gained from DBS may also provide a valuable tool for assessing prenatal environmental exposures in child health research.PMID:37218607 | DOI:10.1093/aje/kwad122

Alzheimers Dement. 2023 May 22. doi: 10.1002/alz.13130. Online ahead of print.ABSTRACTINTRODUCTION: A hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest.METHODS: We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation.RESULTS: We identified 61 proteins significantly associated with the AT category (P < 5.46 × 10-5 ) and 636 significant protein-biomarker associations (P < 6.07 × 10-6 ). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers.DISCUSSION: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD.HIGHLIGHTS: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.PMID:37218097 | DOI:10.1002/alz.13130

Cell Biochem Funct. 2023 May 22. doi: 10.1002/cbf.3811. Online ahead of print.ABSTRACTAutism spectrum disorder (ASD) is a neurodevelopmental disorder, and the etiology is unknown. Metabolic dysfunction is present in patients with ASD. In the current study, untargeted metabolomics was employed to screen the differential metabolites in the liver of BTBR mouse model of autism, and MetaboAnalyst 4.0 was used for metabolic pathway analysis. Mice were killed, and liver samples were collected for untargeted metabolomics analysis and examination of histopathology. Finally, 12 differential metabolites were identified. The intensities of phenylethylamine, 4-Guanidinobutanoic acid, leukotrieneD4, and SM(d18:1/24:1(15Z)) were significantly upregulated (p < .01), and the intensities of estradiol, CMP-N-glycoloylneuraminate, retinoyl β-glucuronide,4-phosphopantothenoylcysteine, aldophosphamide, taurochenodesoxycholic acid, taurocholic acid, and dephospho-CoA were significantly downregulated (p < .01) in the BTBR group compared with C57 control group, indicating that differences between BTBR and C57 groups were observed in metabolic patterns. Disturbed pathways of the BTBR mice involved lipid metabolism, retinol metabolism, and amino acid and energy metabolism, revealing that bile acid-mediated activation of LXRα might contribute to metabolic dysfunction of lipid and leukotriene D4 produced by the activation of 5-LOX led to hepatic inflammation. Pathological changes in the liver tissue, such as hepatocyte vacuolization, and small amounts of inflammatory and cell necrosis, further supported metabolomic results. Moreover, Spearman's rank correlation revealed that there is a strong relationship between metabolites across liver and cortex, suggesting liver may exert action by connecting peripheral and neural systems. These findings were likely to be of pathological importance or a cause/consequence of autism, and may provide insight into key metabolic dysfunction to target potential therapeutic strategies relating to ASD.PMID:37218093 | DOI:10.1002/cbf.3811

Front Immunol. 2023 May 5;14:1124443. doi: 10.3389/fimmu.2023.1124443. eCollection 2023.ABSTRACTBACKGROUND: Abnormal lipid metabolism is common in patients with primary biliary cholangitis (PBC). PBC and Sjögren's syndrome (SS) frequently coexist in clinical practice; however, the lipid characteristics of both diseases are unknown. Therefore, we aimed to analyze the plasma lipid profiles of both diseases.METHODS: Plasma samples from 60 PBC patients, 30 SS patients, and 30 healthy controls (HC) were collected, and untargeted lipidomics was performed using ultrahigh-performance liquid chromatography high-resolution mass spectrometry. Potential lipid biomarkers were screened through an orthogonal projection to latent structure discriminant analysis and further evaluated using receiver operating characteristic (ROC) analysis.RESULTS: A total of 115 lipids were differentially upregulated in PBC patients compared with HC. Seventeen lipids were positively associated with the disease activity of PBC, and ROC analysis showed that all of these lipids could differentiate between ursodeoxycholic acid (UDCA) responders and UDCA non-responders. The top six lipids based on the area under the curve (AUC) values were glycerophosphocholine (PC) (16:0/16:0), PC (18:1/18:1), PC (42:2), PC (16:0/18:1), PC (17:1/14:0), and PC (15:0/18:1). In comparison with SS, 44 lipids were found to be differentially upregulated in PBC. Additionally, eight lipids were found to have a good diagnostic performance of PBC because of the AUC values of more than 0.9 when identified from SS and HC groups, which were lysophosphatidylcholines (LysoPC) (16:1), PC (16:0/16:0), PC (16:0/16:1), PC (16:1/20:4), PC (18:0/20:3), PC (18:1/20:2), PC (20:0/22:5), and PC (20:1/22:5).CONCLUSION: Our study revealed differentially expressed lipid signatures in PBC compared with HC and SS. PC is the main lipid species associated with disease activity and the UDCA response in patients with PBC.PMID:37215104 | PMC:PMC10196160 | DOI:10.3389/fimmu.2023.1124443

J Anim Sci. 2023 May 22:skad165. doi: 10.1093/jas/skad165. Online ahead of print.ABSTRACTIn the immediate time after weaning, piglets often show symptoms of gut inflammation. The change to a plant-based diet, lack of sow milk and the resulting novel gut microbiome and metabolite profile in digesta may be causative factors for the observed inflammation. We used the intestinal loop perfusion assay (ILPA) to investigate jejunal and colonic expression of genes for antimicrobial secretion, oxidative stress, barrier function and inflammatory signaling in suckling and weaned piglets when exposed to 'plant-oriented' microbiome (POM) representing postweaning digesta with gut-site specific microbial and metabolite composition. Two serial ILPA were performed in two replicate batches, with 16 piglets pre- (day 24-27) and 16 piglets postweaning (day 38-41). Two jejunal and colonic loops were perfused with Krebs-Henseleit buffer (control) or with the respective POM for two hours. Afterwards, RNA was isolated from the loop tissue to determine the relative gene expression. Age-related effects in jejunum included higher expression of genes for antimicrobial secretions and barrier function as well as reduced expression of pattern-recognition receptors post- compared to preweaning (P < 0.05). Age-related effects in the colon comprised downregulation of the expression of pattern-recognition receptors post- compared to preweaning (P < 0.05). Likewise, age reduced the colonic expression of genes encoding for cytokines, antimicrobial secretions, antioxidant enzymes and tight-junction proteins post- compared to preweaning. Effect of POM in the jejunum comprised an increased the expression of toll-like receptors compared to the control (P < 0.05), demonstrating a specific response to microbial antigens. Similarly, POM administration upregulated the jejunal expression of antioxidant enzymes (P < 0.05). The POM perfusion strongly upregulated the colonic expression of cytokines and altered the expression of barrier function genes, fatty acid receptors and transporters and antimicrobial secretions (P < 0.05). In conclusion, results indicated that POM signaled via altering the expression of pattern recognition receptors in the jejunum, which in turn activated the secretory defense and decreased mucosal permeability. In the colon, POM may have acted proinflammatory via upregulated cytokine expression. Results are valuable for the formulation of transition feeds for the immediate time after weaning to maintain mucosal immune tolerance towards the novel digesta composition.PMID:37217284 | DOI:10.1093/jas/skad165

Adv Healthc Mater. 2023 May 22:e2300666. doi: 10.1002/adhm.202300666. Online ahead of print.ABSTRACTThe native extracellular matrix is highly dynamic with continuous mutual feedback between cells being responsible for many important cell function regulators. However, establishing bidirectional interaction between complex adaptive microenvironments and cells remains elusive. Herein we report an adaptive biomaterial based on lysozyme monolayers self-assembled at a perfluorocarbon FC40-water interface. The dynamic adaptivity of interfacially assembled protein nanosheets is modulated independently of bulk mechanical properties by covalent crosslinking. This provides a scenario to establish bidirectional interactions of cells with liquid interfaces of varying dynamic adaptivity. We found that growth and multipotency of human mesenchymal stromal cells (hMSCs) are enhanced at the highly adaptive fluid interface. The multipotency retention of hMSCs is mediated by low cell contractility and metabolomic activity involving the continuous mutual feedback between the cells and materials. Consequently, an understanding of the cells' response to dynamic adaptivity has substantial implications for regenerative medicine and tissue engineering. This article is protected by copyright. All rights reserved.PMID:37216966 | DOI:10.1002/adhm.202300666