PubMed

Related Articles Gut microbial dysbiosis is associated with allergen-specific IgE responses in young children with airway allergies. World Allergy Organ J. 2019;12(3):100021 Authors: Chiu CY, Chan YL, Tsai MH, Wang CJ, Chiang MH, Chiu CC Abstract Background: There is increasing evidence linking alterations of the gut microbial composition during early infancy to the development of atopic diseases and asthma. However, few studies have addressed the association of dysbiotic gut microbiota with allergic reactions through evaluation of feces in young children with allergic airway diseases. Methods: We sought to evaluate relationships among gut microbiota, total fecal immunoglobulin E (IgE) levels, serum allergic sensitization, and their relevance to childhood allergic rhinitis and asthma. Microbial composition and diversity were analyzed with Illumina-based 16S rRNA gene sequencing of 89 stool samples collected from children with asthma (n = 35) and allergic rhinitis (n = 28), and from healthy controls (n = 26). Data analysis was performed using Quantitative Insights into Microbial Ecology (QIIME) software. Results: A significantly lower abundance of organisms of the phylum Firmicutes were found in children with asthma and allergic rhinitis than in the healthy controls. Relatively lower Chao1 and Shannon indices were also found in children with allergic airway diseases but without any significant difference. Total fecal IgE levels in early childhood were strongly correlated with serum D. pteronyssinus- and D. farinae-specific IgE but not with food-specific IgE levels. In comparison with healthy controls, the genus Dorea was less abundant and negatively correlated with total fecal IgE levels in children with rhinitis, whereas the genus Clostridium was abundant and positively correlated with fecal IgE levels in children with asthma. Conclusions: An interaction between particular subsets of gut microbial dysbiosis and IgE-mediated responses to allergens may contribute to the susceptibility to allergic rhinitis and asthma in early childhood. PMID: 30937143 [PubMed]

Related Articles Peripheral transcriptomic biomarkers for early detection of sporadic Alzheimer disease? Dialogues Clin Neurosci. 2018 Dec;20(4):293-300 Authors: Hadar A, Gurwitz D Abstract Alzheimer disease (AD) is the major epidemic of the 21st century, its prevalence rising along with improved human longevity. Early AD diagnosis is key to successful treatment, as currently available therapeutics only allow small benefits for diagnosed AD patients. By contrast, future therapeutics, including those already in preclinical or clinical trials, are expected to afford neuroprotection prior to widespread brain damage and dementia. Brain imaging technologies are developing as promising tools for early AD diagnostics, yet their high cost limits their utility for screening at-risk populations. Blood or plasma transcriptomics, proteomics, and/or metabolomics may pave the way for cost-effective AD risk screening in middle-aged individuals years ahead of cognitive decline. This notion is exemplified by data mining of blood transcriptomics from a published dataset. Consortia blood sample collection and analysis from large cohorts with mild cognitive impairment followed longitudinally for their cognitive state would allow the development of a reliable and inexpensive early AD screening tool. PMID: 30936769 [PubMed - in process]

Related Articles Multi-omics analysis unravels a segregated metabolic flux network that tunes co-utilization of sugar and aromatic carbons in Pseudomonas putida. J Biol Chem. 2019 Apr 01;: Authors: Kukurugya MA, Mendonca CM, Solhtalab M, Wilkes RA, Thannhauser TW, Aristilde L Abstract Pseudomonas species thrive in different nutritional environments and can catabolize divergent carbon substrates. These capabilities have important implications for the role of these species in natural and engineered carbon processing. However, the metabolic phenotypes enabling Pseudomonas to utilize mixed substrates remain poorly understood. Here, we employed a multi-omics approach involving stable isotope tracers, metabolomics, fluxomics, and proteomics in Pseudomonas putida KT2440 to investigate the constitutive metabolic network that achieves co-utilization of glucose and benzoate, respectively a monomer of carbohydrate polymers and a derivative of lignin monomers. Despite near-equal consumption of both substrates, metabolite isotopologues revealed non-uniform assimilation throughout the metabolic network. Gluconeogenic flux of benzoate-derived carbons from the tricarboxylic acid cycle did not reach the upper Embden-Meyerhof-Parnas pathway nor the pentose-phosphate pathway. These latter two pathways were populated exclusively by glucose-derived carbons through a cyclic connection with the Entner-Doudoroff pathway. We integrated the 13C-metabolomics data with physiological parameters for quantitative flux analysis, demonstrating that the metabolic segregation of the substrate carbons optimally sustained biosynthetic flux demands and redox balance. Changes in protein abundance partially predicted the metabolic flux changes in cells grown on the glucose:benzoate mixture versus on glucose alone. Notably, flux magnitude and directionality were also maintained by metabolite levels and regulation of phosphorylation of key metabolic enzymes. These findings provide new insights into the metabolic architecture that affords adaptability of P. putida to divergent carbon substrates and highlight regulatory points at different metabolic nodes that may underlie the high nutritional flexibility of Pseudomonas species. PMID: 30936206 [PubMed - as supplied by publisher]

Related Articles High Levels of Prebiotic Resistant Starch in Diet Modulate Gene Expression and Metabolomic Profile in Pancreatic Cancer Xenograft Mice. Nutrients. 2019 Mar 27;11(4): Authors: Panebianco C, Villani A, Pazienza V Abstract Cancer initiation and protection mainly derives from a systemic metabolic environment regulated by dietary patterns. Less is known about the impact of nutritional interventions in people with a diagnosis of cancer. The aim of our study was to investigate the effect of a diet rich in resistant starch (RS) on cell pathways modulation and metabolomic phenotype in pancreatic cancer xenograft mice. RNA-Seq experiments on tumor tissue showed that 25 genes resulted in dysregulated pancreatic cancer in mice fed with an RS diet, as compared to those fed with control diet. Moreover, in these two different mice groups, six serum metabolites were deregulated as detected by LC⁻MS analysis. A bioinformatic prediction analysis showed the involvement of the differentially expressed genes on insulin receptor signaling, circadian rhythm signaling, and cancer drug resistance among the three top canonical pathways, whilst cell death and survival, gene expression, and neurological disease were among the three top disease and biological functions. These findings shed light on the genomic and metabolic phenotype, contributing to the knowledge of the mechanisms through which RS may act as a potential supportive approach for enhancing the efficacy of existing cancer treatments. PMID: 30934731 [PubMed - in process]

22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/04/02PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Effect of Acute Total Sleep Deprivation on Plasma Melatonin, Cortisol and Metabolite Rhythms in Females. Eur J Neurosci. 2019 Mar 30;: Authors: Honma A, Revell VL, Gunn PJ, Davies SK, Middleton B, Raynaud FI, Skene DJ Abstract Disruption to sleep and circadian rhythms can impact on metabolism. The study aimed to investigate the effect of acute sleep deprivation on plasma melatonin, cortisol and metabolites, to increase understanding of the metabolic pathways involved in sleep/wake regulation processes. Twelve healthy young female subjects remained in controlled laboratory conditions for ~92 h with respect to posture, meals and environment light (18:00-23:00 h and 07:00-09:00 h <8 lux; 23:00-07:00 h 0 lux (sleep opportunity) or <8 lux (continuous wakefulness); 09:00-18:00 h ~ 90 lux). Regular blood samples were collected for 70 h for plasma melatonin and cortisol, and targeted liquid chromatography-mass spectrometry metabolomics. Timepoints between 00:00 and 06:00 h for day 1 (baseline sleep), day 2 (sleep deprivation) and day 3 (recovery sleep) were analysed. Cosinor analysis and MetaCycle analysis were performed for detection of rhythmicity. Night time melatonin levels were significantly increased during sleep deprivation and returned to baseline levels during recovery sleep. No significant differences were observed in cortisol levels. Of 130 plasma metabolites quantified, 41 metabolites were significantly altered across the study nights, with the majority decreasing during sleep deprivation, most notably phosphatidylcholines. In cosinor analysis, 58 metabolites maintained their rhythmicity across the study days, with the majority showing a phase advance during acute sleep deprivation. This observation differs to that previously reported for males. Our study is the first of metabolic profiling in females during sleep deprivation and recovery sleep, and offers a novel view of human sleep/wake regulation and sex differences. This article is protected by copyright. All rights reserved. PMID: 30929284 [PubMed - as supplied by publisher]

Metabolic profiling of elite athletes with different cardiovascular demand. Scand J Med Sci Sports. 2019 Mar 31;: Authors: Al-Khelaifi F, Donati F, Botrè F, Latiff A, Abraham D, Hingorani A, Georgakopoulos C, Suhre K, Yousri NA, Elrayess MA Abstract Intensive exercise of elite athletes can lead to physiological alterations in the cardiovascular system in response to increased stroke volume and blood pressure, known collectively as cardiovascular demand (CD). This study aims to compare metabolic differences in elite athletes with high versus low/moderate CD and to reveal their underlying metabolic pathways as potential biomarker signatures for assessing health, performance and recovery of elite athletes. Metabolic profiling of serum samples from 495 elite athletes from different sports disciplines (118 high CD and 377 low/moderate CD athletes) was conducted using non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography. Results show that DAGs containing arachidonic were enriched in high CD together with branched chain amino acids, plasminogens, phosphatidylcholines and phosphatidylethanolamines, potentially indicating increased risk of cardiovascular disease in the high CD group. Gamma glutamyl amino acids and glutathione metabolism were increased in low/moderate CD group, suggesting more efficient oxidative stress scavenging mechanisms than the high CD group. This first most comprehensive metabolic profiling of elite athletes provides an evidence that athletes with different CD show a unique metabolic signature that reflects energy generation and oxidative stress and potentially places the high CD group at a higher risk of cardiovascular disease. Further studies are warranted for confirmation and validation of findings in other sport groups in light of potential confounders related to limited available information about participants. This article is protected by copyright. All rights reserved. PMID: 30929282 [PubMed - as supplied by publisher]

Metabolomic characterization of sunflower leaf allows discriminating genotype groups or stress levels with a minimal set of metabolic markers. Metabolomics. 2019 Mar 30;15(4):56 Authors: Fernandez O, Urrutia M, Berton T, Bernillon S, Deborde C, Jacob D, Maucourt M, Maury P, Duruflé H, Gibon Y, Langlade NB, Moing A Abstract INTRODUCTION: Plant and crop metabolomic analyses may be used to study metabolism across genetic and environmental diversity. Complementary analytical strategies are useful for investigating metabolic changes and searching for biomarkers of response or performance. METHODS AND OBJECTIVES: The experimental material consisted in eight sunflower lines with two line status, four restorers (R, used as males) and four maintainers (B, corresponding to females) routinely used for sunflower hybrid varietal production, respectively to complement or maintain the cytoplasmic male sterility PET1. These lines were either irrigated at full soil capacity (WW) or submitted to drought stress (DS). Our aim was to combine targeted and non-targeted metabolomics to characterize sunflower leaf composition in order to investigate the effect of line status genotypes and environmental conditions and to find the best and smallest set of biomarkers for line status and stress response using a custom-made process of variables selection. RESULTS: Five hundred and eighty-eight metabolic variables were measured by using complementary analytical methods such as 1H-NMR, MS-based profiles and targeted analyses of major metabolites. Based on statistical analyses, a limited number of markers were able to separate WW and DS samples in a more discriminant manner than previously published physiological data. Another metabolic marker set was able to discriminate line status. CONCLUSION: This study underlines the potential of metabolic markers for discriminating genotype groups and environmental conditions. Their potential use for prediction is discussed. PMID: 30929085 [PubMed - in process]

Deciphering the intervention mechanism of Taohong Siwu Decoction following the abnormal uterine bleeding rats based on serum metabolic profiles. J Pharm Biomed Anal. 2019 Mar 23;170:204-214 Authors: Zuo C, Zhang Y, Wang J, Han L, Peng C, Peng D Abstract Abnormal uterine bleeding (AUB), one of the most significant characters of incomplete abortion, is a widespread phenomenon in gynecological that put a woman into a terrible physiological and psychological state. Taohong Siwu Decoction (TSD) is a traditional Chinese medicine (TCM) prescriptions which have treated AUB in China for decades. Our previous study elucidated that TSD reduced the volume of uterine bleedings as well as repaired the endometrium. The present study aims to investigate the mechanisms of TSD on AUB based on serum metabolomics. In this study, serum metabolic profile data was collected using ultra high-performance liquid chromatography with ion trap/time-of-flight mass spectrometry and gas chromatography-mass spectrometry. 23 potential biomarkers (urea, serine, L-proline, L-glutamic acid, palmitic acid, l-acetylcarnitine, LysoPC(16:0), LysoPC(20:4), l-proline, linoleic acid, stearic acid, l-isoleucine, phenylalanine, l-tyrosine, Oleic acid, et al) were eventually identified using multivariate statistical analysis (PCA and OPLS-DA) with VIP > 1, P < 0.05. Correlation analysis, fold-change (FC), area under receiver characteristic (ROC), false discovery rate (FDR) were used for data confirmation to ensure the authenticity of the data. The related-metabolic pathway mainly included amino acid metabolism (Phenylalanine, tyrosine, and tryptophan metabolism; Valine, leucine and isoleucine biosynthesis; Arginine and proline metabolism; Glycine, serine and threonine metabolism) and lipid metabolism (linoleic acid metabolism, glycerophospholipid metabolism). The results show that TSD has a favorable therapeutic effect on AUB by adjusting the metabolic disorders, which could provide dietary guidance for the clinic. PMID: 30928896 [PubMed - as supplied by publisher]

Metabolomics in early detection and prognosis of acute coronary syndrome. Clin Chim Acta. 2019 Mar 27;: Authors: Amiri MP, Khoshkam M, Salek RM, Madadi R, Ganji GF, Ramazani A Abstract Acute coronary syndrome (ACS) is one of the most dangerous types of coronary heart disease (CHD) and contributes to significant mortality and morbidity worldwide. Outcomes in these patients remain a challenge despite improvements in diagnosis and treatment. Risk stratification continues to be problematic and the identification of novel predictors is crucial for improved outcomes. As such, there is a strong need for the development of novel analytical methods as well as the characterization of better predictive and prognostic biomarkers to enable more personalized treatment. Metabolite profile analysis may greatly assist in interpreting altered pathway dynamics, especially when combined with other 'omics' technologies such as transcriptomics and proteomics. In this review, we describe ACS pathophysiology and recent advances in the role of metabolomics in the diagnosis and the molecular pathogenesis of ACS. We briefly describe key technologies used in metabolomics research and statistical approaches for data reduction and pathway analysis and discuss their application to CHD. PMID: 30928571 [PubMed - as supplied by publisher]

1H NMR-based metabolomics revealed the protective effects of Guilingji on the testicular dysfunction of aging rats. J Ethnopharmacol. 2019 Mar 27;:111839 Authors: Zhao SJ, Tian JS, Tai G, Gao XX, Liu HL, Du GH, Liu XJ, Qin XM Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Guilingji (GLJ), a famous and classical traditional Chinese medicine (TCM) prescription, has been used to extend the lifespan and improve the life qualities of the elderly for hundreds of years in China. AIM OF THE STUDY: We aimed to explore the protective effects of GLJ on the testicular dysfunction of aging rats, as well as the regulating effects of GLJ on the metabolic disturbance and metabolite changes in natural aging rats. MATERIALS AND METHODS: Forty 23-month-old rats were divided randomly into four groups, including the old control group and three groups of GLJ treatment at 37.5, 75, and 150 mg/kg doses, respectively. Additionally, 10 four-month rats were included as the youth control group. Testicular dysfunction was first evaluated by measuring the changes in the wet weights of the testicles, concentration of serum testosterone (T), and morphologic changes of the testis. Subsequently, an 1H NMR-based metabolomics approach coupled with multivariate analysis, including partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied to monitor the metabolite changes. RESULTS: Compared with the old control group, the wet weights of the testicles and T concentration were significantly increased, while the morphologic abnormality of testicular tissues was improved by a 4-week treatment course with GLJ. Furthermore, compared with the old control group, the urinary levels of alanine, pantothenate, phenylalanine, β-hydroxybutyrate and pyruvate were significantly decreased after a 4-week treatment course with GLJ. Additionally, we found that amino acid metabolism and pyruvate metabolism were significantly involved in the regulatory effect of GLJ. CONCLUSIONS: The current findings provided, for the first time, sound evidence of the protective effects of GLJ on testicular dysfunction from both biochemical and metabolomics perspectives. The mechanisms of GLJ could be related to regulating amino acid metabolism and pyruvate metabolism. The current study lays an important foundation for further research and for the broad clinical application of GLJ. PMID: 30928501 [PubMed - as supplied by publisher]

Specificity of the metabolic signatures of fish from cyanobacteria rich lakes. Chemosphere. 2019 Mar 21;226:183-191 Authors: Sotton B, Paris A, Le Manach S, Blond A, Duval C, Qiao Q, Catherine A, Combes A, Pichon V, Bernard C, Marie B Abstract With the increasing impact of the global warming, occurrences of cyanobacterial blooms in aquatic ecosystems are becoming a main worldwide ecological concern. Due to their capacity to produce potential toxic metabolites, interactions between the cyanobacteria, their cyanotoxins and the surrounding freshwater organisms have been investigated during the last past years. Non-targeted metabolomic analyses have the powerful capacity to study simultaneously a high number of metabolites and thus to investigate in depth the molecular signatures between various organisms encountering different environmental scenario, and potentially facing cyanobacterial blooms. In this way, the liver metabolomes of two fish species (Perca fluviatilis and Lepomis gibbosus) colonizing various peri-urban lakes of the Île-de-France region displaying high biomass of cyanobacteria, or not, were investigated. The fish metabolome hydrophilic fraction was analyzed by 1H NMR analysis coupled with Batman peak treatment for the quantification and the annotation attempt of the metabolites. The results suggest that similar metabolome profiles occur in both fish species, for individuals collected from cyanobacterial blooming lakes compared to organism from non-cyanobacterial dominant environments. Overall, such environmental metabolomic pilot study provides new research perspectives in ecology and ecotoxicology fields, and may notably provide new information concerning the cyanobacteria/fish ecotoxicological interactions. PMID: 30927670 [PubMed - as supplied by publisher]

Related Articles Calcineurin-dependent dephosphorylation of the transcription factor CrzA at specific sites controls conidiation, stress tolerance, and virulence of Aspergillus fumigatus. Mol Microbiol. 2019 Mar 29;: Authors: Shwab EK, Juvvadi PR, Waitt G, Soderblom EJ, Barrington BC, Asfaw YG, Moseley MA, Steinbach WJ Abstract Calcium signaling through calcineurin and its major transcription factor, CrzA, is integral to hyphal growth, stress response, and virulence of the pathogenic fungus Aspergillus fumigatus, the leading etiology of invasive aspergillosis. Dephosphorylation of CrzA by calcineurin activates the transcription factor, but the specific phosphorylation sites and their roles in the activation/inactivation mechanism are unknown. Mass spectroscopic analysis identified twenty phosphorylation sites, the majority of which were specific to filamentous fungi and distributed throughout the CrzA protein, with particular concentration in a serine-rich region N-terminal to the conserved DNA-binding domain (DBD). Site-directed mutagenesis of phosphorylated residues revealed that CrzA activity during calcium stimulation can only be suppressed by a high degree of phosphorylation in multiple regions of the protein. Our findings further suggest that this regulation is not solely accomplished through control of CrzA nuclear import. Additionally, we demonstrate the importance of the CrzA phosphorylation state in regulating growth, conidiation, calcium and cell-wall stress tolerance, and virulence. Finally, we identify two previously undescribed nuclear localization sequences in the DBD. These findings provide novel insight into the phosphoregulation of CrzA which may be exploited to selectively target A. fumigatus. This article is protected by copyright. All rights reserved. PMID: 30927289 [PubMed - as supplied by publisher]

Related Articles Metabolic signatures suggest o-phosphocholine to UDP-N-acetylglucosamine ratio as a potential biomarker for high-glucose and/or palmitate exposure in pancreatic β-cells. Metabolomics. 2019 Mar 29;15(4):55 Authors: Yousf S, Sardesai DM, Mathew AB, Khandelwal R, Acharya JD, Sharma S, Chugh J Abstract INTRODUCTION: Chronic exposure to high-glucose and free fatty acids (FFA) alone/or in combination; and the resulting gluco-, lipo- and glucolipo-toxic conditions, respectively, have been known to induce dysfunction and apoptosis of β-cells in Diabetes. The molecular mechanisms and the development of biomarkers that can be used to predict similarities and differences behind these conditions would help in easier and earlier diagnosis of Diabetes. OBJECTIVES: This study aims to use metabolomics to gain insight into the mechanisms by which β-cells respond to excess-nutrient stress and identify associated biomarkers. METHODS: INS-1E cells were cultured in high-glucose, palmitate alone/or in combination for 24 h to mimic gluco-, lipo- and glucolipo-toxic conditions, respectively. Biochemical and cellular experiments were performed to confirm the establishment of these conditions. To gain molecular insights, abundant metabolites were identified and quantified using 1H-NMR. RESULTS: No loss of cellular viability was observed in high-glucose while exposure to FFA alone/in combination with high-glucose was associated with increased ROS levels, membrane damage, lipid accumulation, and DNA double-strand breaks. Forty-nine abundant metabolites were identified and quantified using 1H-NMR. Chemometric pair-wise analysis in glucotoxic and lipotoxic conditions, when compared with glucolipotoxic conditions, revealed partial overlap in the dysregulated metabolites; however, the dysregulation was more significant under glucolipotoxic conditions. CONCLUSION: The current study compared gluco-, lipo- and glucolipotoxic conditions in parallel and elucidated differences in metabolic pathways that play major roles in Diabetes. o-phosphocholine and UDP-N-acetylglucosamine were identified as common dysregulated metabolites and their ratio was proposed as a potential biomarker for these conditions. PMID: 30927092 [PubMed - in process]

Related Articles Prediagnostic plasma metabolomics and the risk of amyotrophic lateral sclerosis. Neurology. 2019 Mar 29;: Authors: Bjornevik K, Zhang Z, O'Reilly ÉJ, Berry JD, Clish CB, Deik A, Jeanfavre S, Kato I, Kelly RS, Kolonel LN, Liang L, Marchand LL, McCullough ML, Paganoni S, Pierce KA, Schwarzschild MA, Shadyab AH, Wactawski-Wende J, Wang DD, Wang Y, Manson JE, Ascherio A Abstract OBJECTIVE: To identify prediagnostic plasma metabolomic biomarkers associated with amyotrophic lateral sclerosis (ALS). METHODS: We conducted a global metabolomic study using a nested case-control study design within 5 prospective cohorts and identified 275 individuals who developed ALS during follow-up. We profiled plasma metabolites using liquid chromatography-mass spectrometry and identified 404 known metabolites. We used conditional logistic regression to evaluate the associations between metabolites and ALS risk. Further, we used machine learning analyses to determine whether the prediagnostic metabolomic profile could discriminate ALS cases from controls. RESULTS: A total of 31 out of 404 identified metabolites were associated with ALS risk (p < 0.05). We observed inverse associations (n = 27) with plasma levels of diacylglycerides and triacylglycerides, urate, purine nucleosides, and some organic acids and derivatives, while we found positive associations for a cholesteryl ester, 2 phosphatidylcholines, and a sphingomyelin. The number of significant associations increased to 67 (63 inverse) in analyses restricted to cases with blood samples collected within 5 years of onset. None of these associations remained significant after multiple comparison adjustment. Further, we were not able to reliably distinguish individuals who became cases from controls based on their metabolomic profile using partial least squares discriminant analysis, elastic net regression, random forest, support vector machine, or weighted correlation network analyses. CONCLUSIONS: Although the metabolomic profile in blood samples collected years before ALS diagnosis did not reliably separate presymptomatic ALS cases from controls, our results suggest that ALS is preceded by a broad, but poorly defined, metabolic dysregulation years before the disease onset. PMID: 30926684 [PubMed - as supplied by publisher]

Related Articles Hepatic lysosomal iNOS activity impairs autophagy in obesity. Cell Mol Gastroenterol Hepatol. 2019 Mar 26;: Authors: Qian Q, Zhang Z, Li M, Savage K, Cheng D, Rauckhorst AJ, Ankrum JA, Taylor EB, Ding WX, Xiao Y, Cao HJ, Yang L Abstract BACKGROUND & AIMS: The lysosome is an acidic organelle that is important for maintaining cellular and metabolic homeostasis in hepatocytes. Lysosomal dysfunction and chronic inflammation coexist, and both contribute to obesity-associated hepatic insulin resistance. However, in the context of obesity, the interplay between inflammatory signals and hepatic lysosomal function remains largely unknown. Inducible nitric oxide synthase (iNOS) is a hallmark for inflammation, and is activated in obesity. The aim of this study is to understand the molecular link between iNOS-mediated lysosomal nitric oxide (NO) production, hepatic lysosomal function, and autophagy in the context of obesity-associated insulin resistance. METHODS: The role of iNOS in hepatic autophagy, as related to insulin and glucose homeostasis were studied in mice with diet-induced obesity (DIO). The effects and mechanisms of iNOS-mediated lysosomal NO production on lysosomal function and hepatic autophagy were studied in primary hepatocytes as well as in a mouse model of DIO. RESULTS: We demonstrate that obesity promotes iNOS localization to the lysosome and decreases levels of lysosomal arginine, resulting in an accumulation of NO in hepatic lysosomes. This lysosomal NO production is attenuated by treatment with a NO scavenger, while co-overexpression of mTOR and a lysosomal arginine transporter (SLC38A9) enhances lysosomal NO production and suppresses autophagy. In addition, we show that deletion of iNOS ameliorates lysosomal nitrosative stress in the livers of DIO mice, promotes lysosomal biogenesis by activating transcription factor EB (TFEB), and enhances lysosomal function and autophagy. Lastly, deletion of iNOS in mice with DIO improves hepatic insulin sensitivity, which is diminished by suppression of TFEB or autophagy related 7 (Atg7). CONCLUSIONS: Our studies suggest that lysosomal iNOS-mediated NO signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance. PMID: 30926581 [PubMed - as supplied by publisher]

Related Articles Direct-infusion based metabolomics unveils biochemical profiles of inborn errors of metabolism in cerebrospinal fluid. Mol Genet Metab. 2019 Mar 15;: Authors: Haijes HA, van der Ham M, Gerrits J, van Hasselt PM, Prinsen HCMT, de Sain-van der Velden MGM, Verhoeven-Duif NM, Jans JJM Abstract BACKGROUND: For inborn errors of metabolism (IEM), metabolomics is performed for three main purposes: 1) development of next generation metabolic screening platforms, 2) identification of new biomarkers in predefined patient cohorts and 3) for identification of new IEM. To date, plasma, urine and dried blood spots are used. We anticipate that cerebrospinal fluid (CSF) holds additional - valuable - information, especially for IEM with neurological involvement. To expand metabolomics to CSF, we here tested whether direct-infusion high-resolution mass spectrometry (DI-HRMS) based non-quantitative metabolomics could correctly capture the biochemical profile of patients with an IEM in CSF. METHODS: Eleven patient samples, harboring eight different IEM, and thirty control samples were analyzed using DI-HRMS. First we assessed whether the biochemical profile of the control samples represented the expected profile in CSF. Next, each patient sample was assigned a 'most probable diagnosis' by an investigator blinded for the known diagnoses of the patients. RESULTS: the biochemical profile identified using DI-HRMS in CSF samples resembled the known profile, with - among others - the highest median intensities for mass peaks annotated with glucose, lactic acid, citric acid and glutamine. Subsequent analysis of patient CSF profiles resulted in correct 'most probable diagnoses' for all eleven patients, including non-ketotic hyperglycinaemia, propionic aciduria, purine nucleoside phosphorylase deficiency, argininosuccinic aciduria, tyrosinaemia type I, hyperphenylalaninemia and hypermethioninaemia. CONCLUSION: We here demonstrate that DI-HRMS based non-quantitative metabolomics accurately captures the biochemical profile of this set of patients in CSF, opening new ways for using metabolomics in CSF in the metabolic diagnostic laboratory. PMID: 30926434 [PubMed - as supplied by publisher]

Related Articles Untargeted Metabolomics Are Not Useful in the Risk Assessment of GM Crops. Trends Plant Sci. 2019 Mar 26;: Authors: Delaney B, Hazebroek J, Herman R, Juberg D, Storer NP PMID: 30926379 [PubMed - as supplied by publisher]

Related Articles Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation. Biochem Biophys Res Commun. 2019 Mar 26;: Authors: Showalter MR, Wancewicz B, Fiehn O, Archard JA, Clayton S, Wagner J, Deng P, Halmai J, Fink KD, Bauer G, Fury B, Perotti NH, Apperson M, Butters J, Belafsky P, Farwell G, Kuhn M, Nolta JA, Anderson JD Abstract Mesenchymal stem cell (MSC) based therapies are currently being evaluated as a putative therapeutic in numerous human clinical trials. Recent reports have established that exosomes mediate much of the therapeutic properties of MSCs. Exosomes are nanovesicles which mediate intercellular communication, transmitting signals between cells which regulate a diverse range of biological processes. MSC-derived exosomes are packaged with numerous types of proteins and RNAs, however, their metabolomic and lipidomic profiles to date have not been well characterized. We previously reported that MSCs, in response to priming culture conditions that mimic the in vivo microenvironmental niche, substantially modulate cellular signaling and significantly increase the secretion of exosomes. Here we report that MSCs exposed to such priming conditions undergo glycolytic reprogramming, which homogenizes MSCs' metabolomic profile. In addition, we establish that exosomes derive from primed MSCs are packaged with numerous metabolites that have been directly associated with immunomodulation, including M2 macrophage polarization and regulatory T lymphocyte induction. PMID: 30926165 [PubMed - as supplied by publisher]

Related Articles WaveICA: A novel algorithm to remove batch effects for large-scale untargeted metabolomics data based on wavelet analysis. Anal Chim Acta. 2019 Jul 11;1061:60-69 Authors: Deng K, Zhang F, Tan Q, Huang Y, Song W, Rong Z, Zhu ZJ, Li Z, Li K Abstract Metabolomics provides new insights into disease pathogenesis and biomarker discovery. Samples from large-scale untargeted metabolomics studies are typically analyzed using a liquid chromatography-mass spectrometry platform in several batches. Batch effects that are caused by non-biological systematic biases are unavoidable in large-scale metabolomics studies, even with properly designed experiments. The statistical analysis of large-scale metabolomics data without managing batch effects will yield misleading results. In this study, we propose a novel algorithm, called WaveICA, which is based on the wavelet transform method with independent component analysis, as the threshold processing method to capture and remove batch effects for large-scale metabolomics data. The WaveICA method uses the time trend of samples over the injection order, decomposes the original data into multi-scale data with different features, extracts and removes the batch effect information in multi-scale data, and obtains clean data. The WaveICA method was tested on real metabolomics data. After applying the WaveICA method, scattered quality control samples (QCS) and subject samples in a PCA score plot of the original data were closely clustered, respectively. The average Pearson correlation coefficients for all peaks of the QCS increased from 0.872 to 0.972. Additionally, WaveICA significantly improved the classification accuracy for metabolomics data. The method was compared with three representative methods, and outperformed all of them. To conclude, WaveICA can efficiently remove batch effects while revealing more biological information. This method can be used in large-scale untargeted metabolomics studies to preprocess raw metabolomics data. PMID: 30926040 [PubMed - in process]