Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 2 hours 49 min ago

Redox controls metabolic robustness in the gas-fermenting acetogen Clostridium autoethanogenum.

Sun, 31/05/2020 - 12:13
Related Articles Redox controls metabolic robustness in the gas-fermenting acetogen Clostridium autoethanogenum. Proc Natl Acad Sci U S A. 2020 May 29;: Authors: Mahamkali V, Valgepea K, de Souza Pinto Lemgruber R, Plan M, Tappel R, Köpke M, Simpson SD, Nielsen LK, Marcellin E Abstract Living biological systems display a fascinating ability to self-organize their metabolism. This ability ultimately determines the metabolic robustness that is fundamental to controlling cellular behavior. However, fluctuations in metabolism can affect cellular homeostasis through transient oscillations. For example, yeast cultures exhibit rhythmic oscillatory behavior in high cell-density continuous cultures. Oscillatory behavior provides a unique opportunity for quantitating the robustness of metabolism, as cells respond to changes by inherently compromising metabolic efficiency. Here, we quantify the limits of metabolic robustness in self-oscillating autotrophic continuous cultures of the gas-fermenting acetogen Clostridium autoethanogenum Online gas analysis and high-resolution temporal metabolomics showed oscillations in gas uptake rates and extracellular byproducts synchronized with biomass levels. The data show initial growth on CO, followed by growth on CO and H2 Growth on CO and H2 results in an accelerated growth phase, after which a downcycle is observed in synchrony with a loss in H2 uptake. Intriguingly, oscillations are not linked to translational control, as no differences were observed in protein expression during oscillations. Intracellular metabolomics analysis revealed decreasing levels of redox ratios in synchrony with the cycles. We then developed a thermodynamic metabolic flux analysis model to investigate whether regulation in acetogens is controlled at the thermodynamic level. We used endo- and exo-metabolomics data to show that the thermodynamic driving force of critical reactions collapsed as H2 uptake is lost. The oscillations are coordinated with redox. The data indicate that metabolic oscillations in acetogen gas fermentation are controlled at the thermodynamic level. PMID: 32471945 [PubMed - as supplied by publisher]

Serum Metabolome Changes in Relation to Prothrombotic State Induced by Combined Oral Contraceptives with Drospirenone and Ethinylestradiol.

Sun, 31/05/2020 - 12:13
Related Articles Serum Metabolome Changes in Relation to Prothrombotic State Induced by Combined Oral Contraceptives with Drospirenone and Ethinylestradiol. OMICS. 2020 May 29;: Authors: Swanepoel AC, Bester J, Emmerson O, Soma P, Beukes D, van Reenen M, Loots DT, du Preez I Abstract The association between hypercoagulability and use of drospirenone (DRSP) and ethinylestradiol (EE) containing combined oral contraceptives (COCs) is an important clinical concern. We have previously reported that the two formulations of DRSP combined with EE (namely, DRSP/20EE and DRSP/30EE) bring about a prothrombotic state in hemostatic traits of female users. We report here the serum metabolomic changes in the same study cohort in relation to the attendant prothrombotic state induced by COC use, thus offering new insights on the underlying biochemical mechanisms contributing to the altered coagulatory profile with COC use. A total of 78 healthy women participated in this study and were grouped as follows: control group not using oral contraceptives (n = 25), DRSP/20EE group (n = 27), and DRSP/30EE group (n = 26). Untargeted metabolomics revealed changes in amino acid concentrations, particularly a decrease in glycine and an increase in both cysteine and lanthionine in the serum, accompanied by variations in oxidative stress markers in the COC users compared with the controls. Of importance, this study is the first to link specific amino acid variations, serum metabolites, and the oxidative metabolic profile with DRSP/EE use. These molecular changes could be linked to specific biophysical coagulatory alterations observed in the same individuals. These new findings lend evidence on the metabolomic substrates of the prothrombotic state associated with COC use in women and informs future personalized/precision medicine research. Moreover, we underscore the importance of an interdisciplinary approach to evaluate venous thrombotic risk associated with COC use. PMID: 32471328 [PubMed - as supplied by publisher]

A Translational In Vivo and In Vitro Metabolomic Study Reveals Altered Metabolic Pathways in Red Blood Cells of Type 2 Diabetes.

Sun, 31/05/2020 - 12:13
Related Articles A Translational In Vivo and In Vitro Metabolomic Study Reveals Altered Metabolic Pathways in Red Blood Cells of Type 2 Diabetes. J Clin Med. 2020 May 27;9(6): Authors: Palomino-Schätzlein M, Lamas-Domingo R, Ciudin A, Gutiérrez-Carcedo P, Marés R, Aparicio-Gómez C, Hernández C, Simó R, Herance JR Abstract Clinical parameters used in type 2 diabetes mellitus (T2D) diagnosis and monitoring such as glycosylated haemoglobin (HbA1c) are often unable to capture important information related to diabetic control and chronic complications. In order to search for additional biomarkers, we performed a pilot study comparing T2D patients with healthy controls matched by age, gender, and weight. By using 1H-nuclear magnetic resonance (NMR) based metabolomics profiling of red blood cells (RBCs), we found that the metabolic signature of RBCs in T2D subjects differed significantly from non-diabetic controls. Affected metabolites included glutathione, 2,3-bisphophoglycerate, inosinic acid, lactate, 6-phosphogluconate, creatine and adenosine triphosphate (ATP) and several amino acids such as leucine, glycine, alanine, lysine, aspartate, phenylalanine and tyrosine. These results were validated by an independent cohort of T2D and control patients. An analysis of the pathways in which these metabolites were involved showed that energetic and redox metabolism in RBCs were altered in T2D, as well as metabolites transported by RBCs. Taken together, our results revealed that the metabolic profile of RBCs can discriminate healthy controls from T2D patients. Further research is needed to determine whether metabolic fingerprint in RBC could be useful to complement the information obtained from HbA1c and glycemic variability as well as its potential role in the diabetes management. PMID: 32471219 [PubMed - as supplied by publisher]

Metabolomic Fingerprinting of Potato Cultivars Differing in Susceptibility to Spongospora subterranea f. sp. subterranea Root Infection.

Sun, 31/05/2020 - 12:13
Related Articles Metabolomic Fingerprinting of Potato Cultivars Differing in Susceptibility to Spongospora subterranea f. sp. subterranea Root Infection. Int J Mol Sci. 2020 May 27;21(11): Authors: Lekota M, Modisane KJ, Apostolides Z, van der Waals JE Abstract Plants defend themselves from pathogens by producing bioactive defense chemicals. The biochemical mechanisms relating to quantitative resistance of potato to root infection by Spongospora subterranea f. sp. subterranea (Sss) are, however, not understood, and are not efficiently utilized in potato breeding programs. Untargeted metabolomics using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to elucidate the biochemical mechanisms of susceptibility to Sss root infection. Potato roots and root exudate metabolic profiles of five tolerant cultivars were compared with those of five susceptible cultivars, following Sss inoculation, to identify tolerance-related metabolites. Comparison of the relative metabolite abundance of tolerant versus susceptible cultivars revealed contrasting responses to Sss infection. Metabolites belonging to amino acids, organic acids, fatty acids, phenolics, and sugars, as well as well-known cell wall thickening compounds were putatively identified and were especially abundant in the tolerant cultivars relative to the susceptible cultivars. Metabolites known to activate plant secondary defense metabolism were significantly increased in the tolerant cultivars compared to susceptible cultivars following Sss inoculation. Root-exuded compounds belonging to the chemical class of phenolics were also found in abundance in the tolerant cultivars compared to susceptible cultivars. This study illustrated that Sss infection of potato roots leads to differential expression of metabolites in tolerant and susceptible potato cultivars. PMID: 32471154 [PubMed - as supplied by publisher]

Progression-Dependent Altered Metabolism in Osteosarcoma Resulting in Different Nutrient Source Dependencies.

Sun, 31/05/2020 - 12:13
Related Articles Progression-Dependent Altered Metabolism in Osteosarcoma Resulting in Different Nutrient Source Dependencies. Cancers (Basel). 2020 May 27;12(6): Authors: Fritsche-Guenther R, Gloaguen Y, Kirchner M, Mertins P, Tunn PU, Kirwan JA Abstract Osteosarcoma (OS) is a primary malignant bone tumor and OS metastases are mostly found in the lung. The limited understanding of the biology of metastatic processes in OS limits the ability for effective treatment. Alterations to the metabolome and its transformation during metastasis aids the understanding of the mechanism and provides information on treatment and prognosis. The current study intended to identify metabolic alterations during OS progression by using a targeted gas chromatography mass spectrometry approach. Using a female OS cell line model, malignant and metastatic cells increased their energy metabolism compared to benign OS cells. The metastatic cell line showed a faster metabolic flux compared to the malignant cell line, leading to reduced metabolite pools. However, inhibiting both glycolysis and glutaminolysis resulted in a reduced proliferation. In contrast, malignant but non-metastatic OS cells showed a resistance to glycolytic inhibition but a strong dependency on glutamine as an energy source. Our in vivo metabolic approach hinted at a potential sex-dependent metabolic alteration in OS patients with lung metastases (LM), although this will require validation with larger sample sizes. In line with the in vitro results, we found that female LM patients showed a decreased central carbon metabolism compared to metastases from male patients. PMID: 32471029 [PubMed - as supplied by publisher]

metabolomics; +40 new citations

Sat, 30/05/2020 - 15:05
40 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 2020/05/30PubMed 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.

metabolomics; +40 new citations

Sat, 30/05/2020 - 12:05
40 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 2020/05/30PubMed 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.

metabolomics; +18 new citations

Fri, 29/05/2020 - 14:56
18 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 2020/05/29PubMed 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.

metabolomics; +24 new citations

Thu, 28/05/2020 - 14:52
24 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 2020/05/28PubMed 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.

Metabolomic-/Lipidomic-based Analysis of Plasma to Diagnose Hepatocellular Ballooning in Patients with Nonalcoholic Fatty Liver Disease: A Multicenter Study.

Wed, 27/05/2020 - 14:39
Related Articles Metabolomic-/Lipidomic-based Analysis of Plasma to Diagnose Hepatocellular Ballooning in Patients with Nonalcoholic Fatty Liver Disease: A Multicenter Study. Hepatol Res. 2020 May 26;: Authors: Ogawa Y, Kobayashi T, Honda Y, Kessoku T, Tomeno W, Imajo K, Nakahara T, Oeda S, Nagaoki Y, Amano Y, Ando T, Hirayama M, Isono O, Kamiguchi H, Nagabukuro H, Ogawa S, Satomi Y, Saigusa Y, Takahashi H, Hyogo H, Yoneda M, Saito S, Yamanaka T, Aishima S, Eguchi Y, Kage M, Chayama K, Nakajima A Abstract AIM: Liver biopsy is still required for the diagnosis of hepatocellular ballooning and inflammation, which are important histological feature of nonalcoholic steatohepatitis (NASH). We conducted this multicenter, cross-sectional study to identify novel blood markers for the diagnosis of hepatocellular ballooning. METHODS: We enrolled 176 patients, and 132 patients proven by liver biopsy as having NAFLD were classified as non-ballooning (ballooning grade 0) (n = 83) or ballooning (ballooning grade 1 and 2) (n = 49) by a central pathology review. We performed gas chromatography-mass spectrometry, hydrophilic interaction liquid chromatography tandem mass spectrometry, and lipidomics with plasma. RESULTS: As correlates of hepatocellular ballooning, among the clinical parameters, serum type IV collagen 7S correlated the most significantly with the ballooning grade (correlation coefficient [CC] = 0.463; P < 0.001). Among the metabolic-/lipidomic-markers, phosphatidylcholine (PC)(aa-44:8) correlated the most significantly with the ballooning grade (CC = 0.394; P < 0.001). The area under the receiver operating characteristic curve of type IV collagen 7S, choline, and lysophosphatidylethanolamine (LPE) (e-18:2), was 0.846 (95% confidence interval: 0.772-0.919). CONCLUSIONS: Plasma levels of PC were positively correlated, and those of lysophosphatidylcholine and LPE were negatively correlated with hepatocellular ballooning in NAFLD patients. These noninvasive metabolic-/lipidomic-based plasma tests might be useful to distinguish between cases of NAFLD with and without hepatocellular ballooning. PMID: 32455496 [PubMed - as supplied by publisher]

An unbiased lipidomics approach identifies key lipid molecules as potential therapeutic targets of Dohongsamul-tang against non-alcoholic fatty liver diseases in a mouse model of obesity.

Wed, 27/05/2020 - 14:39
Related Articles An unbiased lipidomics approach identifies key lipid molecules as potential therapeutic targets of Dohongsamul-tang against non-alcoholic fatty liver diseases in a mouse model of obesity. J Ethnopharmacol. 2020 May 23;:112999 Authors: Park SH, Lee JE, Lee SM, Lee J, Seo CS, Hwang GS, Jung J Abstract ETHNOPHARMACOLOGICAL RELEVANCE: . Dohongsamul-tang (DST) is a traditional herbal formula used to promote the blood circulation and inhibit inflammation, and also widely has been used in the treatment of patients with chronic liver diseases in Korea and China. AIM OF THE STUDY: . This study aimed to investigate the effect of DST on regulation of lipid metabolism of chronic liver diseases in mouse model of non-alcoholic fatty liver diseases (NAFLD). MATERIALS AND METHODS: . In this study, we evaluated the effect of DST on high-fat and high-cholesterol diet (HFHC, 40% fat and 1% cholesterol)-induced NAFLD, and applied unbiased lipidomics using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF MS) coupled with multivariate analysis. RESULTS: . DST improved hepatic morphology and reduced levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In addition, DST inhibited hepatic lipid accumulation through the downregulation of C/EBPα, PPARγ, and pAMPK. To further elucidate the effect of DST on hepatic lipid metabolism, we applied UPLC/Q-TOF MS-based lipidomics. The score plots of partial least squares-discriminant analysis (PLS-DA) showed that DST changed the lipid metabolic pattern of high-fat and high-cholesterol diet (HFHC) mice. Twenty-two lipid metabolites were selected as biomarkers regulated by DST and pathway analysis revealed that sphingolipid metabolism and glycerophospholipid metabolism were associated with the effect of DST on NAFLD. Among the 22 selected biomarkers, 14 were phospholipids, and DST significantly reversed the increased expression of lysophospholipase 3 (LYPLA3) and neuropathy target esterase (NTE), which are key enzymes in glycerophospholipid metabolism. Given that alterations in sphingolipids and phospholipids can have effects on apoptosis and insulin resistance (IR), we subsequently investigated changes in the expression of apoptosis-related proteins, including Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl2), and IR-related markers after DST treatment. We accordingly found that the ratio of Bax to Bcl-2 expression, a maker of apoptosis, was also elevated in HFHC mice and reduced by DST treatment. In addition, DST enhanced hepatic insulin signaling by upregulating the expression of insulin receptor substrate 1 (IRS-1) and phospho-protein kinase B (pAKT), and oral glucose tolerance test (OGTT) analysis indicated that this herbal preparation also ameliorated systemic IR. CONCLUSIONS: . This study suggested that DST might have an effect on NAFLD by regulating the metabolism of lipids such as phospholipids and sphingolipids and demonstrated that lipidomic profiling is useful to investigate the therapeutic effects of herbal decoctions from traditional Korean and Chinese medicine. PMID: 32454173 [PubMed - as supplied by publisher]

Metabolomics Reveals Altered Hepatic Bile Acids, Gut Microbiome Metabolites, and Cell Membrane Lipids Associated with Marginal Vitamin A Deficiency in a Mongolian Gerbil Model.

Wed, 27/05/2020 - 14:39
Related Articles Metabolomics Reveals Altered Hepatic Bile Acids, Gut Microbiome Metabolites, and Cell Membrane Lipids Associated with Marginal Vitamin A Deficiency in a Mongolian Gerbil Model. Mol Nutr Food Res. 2020 May 26;:e1901319 Authors: La Frano MR, Brito A, Johnson CM, Wilhelmson B, Gannon B, Fanter RK, Pedersen TL, Tanumihardjo SA, Newman JW Abstract SCOPE: This study was designed to provide a broad evaluation of the impacts of vitamin A (VA) deficiency on hepatic metabolism in a gerbil model. METHODS AND RESULTS: After 28d of VA depletion, male Mongolian gerbils (Meriones unguiculatus) were randomly assigned to experimental diets for 28 d. Groups were fed a white maize-based diet with ∼50 μL cottonseed oil vehicle either alone (VA-, n = 10) or containing 40 μg retinyl acetate (VA+, n = 10) for 28 d. Liver retinol was measured by high-performance liquid chromatography (HPLC). Primary metabolomics, aminomics, lipidomics, bile acids, oxylipins, ceramides and endocannabinoids were determined in post-mortem liver samples by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Liver retinol was lower (p < 0.001) in the VA- versus VA+ group, with concentrations indicating marginal VA deficiency. A total of 300 metabolites were identified. Marginal VA deficiency was associated with lower bile acids, trimethylamine N-oxide, and a variety of acyl carnitines, phospholipids and sphingomyelins (p < 0.05). Components of DNA, including purine deoxyribonucleosides, deoxyguanosine, the nucleoside cytidine, and the uracil derivative N-carbomoyl-beta-alanine (p < 0.05), were differentially altered. CONCLUSIONS: Hepatic metabolomics in a marginally VA deficient gerbil model revealed alterations in markers of the gut microbiome, fatty acid and nucleotide metabolism, and cellular structure and signaling. This article is protected by copyright. All rights reserved. PMID: 32453876 [PubMed - as supplied by publisher]

Human-stimulated oocyte extract induces genetic and mitochondrial reprogramming of mesenchymal stromal cells.

Wed, 27/05/2020 - 14:39
Related Articles Human-stimulated oocyte extract induces genetic and mitochondrial reprogramming of mesenchymal stromal cells. PLoS One. 2020;15(5):e0232759 Authors: El-Gammal Z, AlOkda A, Ali SS, Reda A, Magdeldin S, Mansour R, El-Badri N Abstract SUMMARY: Reprogramming autologous adult cells to pluripotent cells allows for relatively safe cell replacement therapy. This can be achieved by nuclear transfer, cell fusion, or induced pluripotent stem cell technology However, the epigenetic memory of the cell is considered as a great challenge facing the complete reprograming of cells by these methods. Introducing oocyte-specific factors into differentiated cells may present a promising approach by mimicking cellular reprogramming during fertilization. METHODS: Human bone marrow mesenchymal stromal cells (hBM-MSCs) were cultured with different concentrations of human metaphase II (M II) oocyte extract (0.1, 1, 5, 10, 30 ng/μl). Reprogramming was assessed at various exposure times (1, 4, 7 days). Cells were tested for their proliferation rate, morphological changes, expression of pluripotency markers, expression of mesenchymal to epithelial transition markers, and mitochondrial rejuvenation. (mitochondrial localization, morphological changes, bioenergetics, transmembrane potential, and levels of reactive oxygen species, ROS). RESULTS: Treatment of human BM-MSCs with 10 ng/μl oocyte extract resulted in increased cell proliferation, which was associated with the upregulation of the pluripotency genes OCT-4, NANOG, and SOX-2 and a concomitant downregulation of mesenchymal-specific genes. MSCs exhibited small, immature round mitochondria with few swollen cristae localized proximal to the cell nucleus. This was accompanied by morphological cell changes, a metabolic shift towards oxidative phosphorylation, a high mitochondrial membrane potential, and increased ROS production. CONCLUSION: These data show that treatment with 10 ng/μl human MII-phase oocyte extract induced genetic and mitochondrial reprogramming of human BM-MSCs to a more embryonic phenotype. PMID: 32453737 [PubMed - as supplied by publisher]

The key points in the pre-analytical procedures of blood and urine samples in metabolomics studies.

Wed, 27/05/2020 - 14:39
Related Articles The key points in the pre-analytical procedures of blood and urine samples in metabolomics studies. Metabolomics. 2020 May 25;16(6):68 Authors: Bi H, Guo Z, Jia X, Liu H, Ma L, Xue L Abstract BACKGROUND: Metabolomics provides measurement of numerous metabolites in human samples, which can be a useful tool in clinical research. Blood and urine are regarded as preferred subjects of study because of their minimally invasive collection and simple preprocessing methods. Adhering to standard operating procedures is an essential factor in ensuring excellent sample quality and reliable results. AIM OF REVIEW: In this review, we summarize the studies about the impacts of various preprocessing factors on metabolomics studies involving clinical blood and urine samples in order to provide guidance for sample collection and preprocessing. KEY SCIENTIFIC CONCEPTS OF REVIEW: Clinical information is important for sample grouping and data analysis which deserves attention before sample collection. Plasma and serum as well as urine samples are appropriate for metabolomics analysis. Collection tubes, hemolysis, delay at room temperature, and freeze-thaw cycles may affect metabolic profiles of blood samples. Collection time, time between sampling and examination, contamination, normalization strategies, and storage conditions may alter analysis results of urine samples. Taking these collection and preprocessing factors into account, this review provides suggestions of standard sample preprocessing. PMID: 32451742 [PubMed - in process]

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

Wed, 27/05/2020 - 14:39
Related Articles Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer. Nat Med. 2020 May 25;: Authors: Roberti MP, Yonekura S, Duong CPM, Picard M, Ferrere G, Tidjani Alou M, Rauber C, Iebba V, Lehmann CHK, Amon L, Dudziak D, Derosa L, Routy B, Flament C, Richard C, Daillère R, Fluckiger A, Van Seuningen I, Chamaillard M, Vincent A, Kourula S, Opolon P, Ly P, Pizzato E, Becharef S, Paillet J, Klein C, Marliot F, Pietrantonio F, Benoist S, Scoazec JY, Dartigues P, Hollebecque A, Malka D, Pagès F, Galon J, Gomperts Boneca I, Lepage P, Ryffel B, Raoult D, Eggermont A, Vanden Berghe T, Ghiringhelli F, Vandenabeele P, Kroemer G, Zitvogel L Abstract The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC. PMID: 32451498 [PubMed - as supplied by publisher]

Consecutive Queries to Assess Biological Correlation in NMR Metabolomics: Performance of Comprehensive Search of Multiplets over Typical 1D 1H NMR Database Search.

Wed, 27/05/2020 - 14:39
Related Articles Consecutive Queries to Assess Biological Correlation in NMR Metabolomics: Performance of Comprehensive Search of Multiplets over Typical 1D 1H NMR Database Search. J Proteome Res. 2020 May 25;: Authors: Charris-Molina A, Riquelme G, Burdisso P, Hoijemberg PA Abstract NMR-based metabolomics requires the proper identification of metabolites to extract conclusions from the system under study. Normally, multivariate data analysis is performed on 1D 1H NMR spectra, and the identification of peaks (and then compounds) relevant to the classification is accomplished using database queries as a first step. 1D 1H NMR spectra of complex mixtures often suffer from peak overlap. To overcome this issue, several studies employed the projections of the (tilted and symmetrized) 2D 1H J-resolved (JRES) spectra, p-JRES, which are similar to 1D 1H decoupled spectra. Nonetheless, there are no public databases available that allow searching for chemical shift spectral data for multiplets. We present the Chemical Shift Multiplet Database (CSMDB), built utilizing JRES spectra obtained from the Birmingham Metabolite Library. The CSMDB provides scoring accounting for both matched and unmatched peaks from a query list and the database hits. This input list is generated from a projection of a 2D statistical correlation analysis on the JRES spectra, p-(JRES-STOCSY), being able to compare the multiplets for the matched peaks, in essence the f1 traces from the JRES-STOCSY spectrum and from the database hit. The inspection of the unmatched peaks for the database hit allows the retrieval of peaks in the query list that have a decreased correlation coefficient due to low intensities. The CSMDB is coupled to "Con-Quer ABC", which permits the assessment of biological correlation by means of consecutive queries with the unmatched peaks in the first and subsequent queries. PMID: 32450699 [PubMed - as supplied by publisher]

Sex-specific metabolic changes in peripheral organs of diabetic mice.

Wed, 27/05/2020 - 14:39
Related Articles Sex-specific metabolic changes in peripheral organs of diabetic mice. J Proteome Res. 2020 May 25;: Authors: Zhang X, Xu H, Ning J, Ji H, Yan J, Zheng Y, Xu Q, Li C, Zhao L, Zheng H, Gao H Abstract Diabetes mellitus (DM) can cause systemic metabolic disorders, but impact of gender on DM-related metabolic changes is rarely reported. Herein, we analyzed metabolic alterations in the heart, liver and kidney of male and female mice from normal to diabetes via a 1H NMR-based metabolomics method, and aimed to investigate sex-specific metabolic mechanisms underlying the onset and development of diabetes and its complications. Our results demonstrate that male mice had more significant metabolic disorders from normal to diabetes than female mice. Moreover, the kidney was found as the major organ of metabolic disorders during the development of diabetes, followed by the liver and heart. These altered metabolites were mainly implicated in energy metabolism as well as amino acid, choline and nucleotide metabolism. Therefore, this study suggests that the kidney was the primary organ affected by diabetes in a sex-specific manner, which provides a metabolic view on the pathogenesis of diabetic kidney diseases between genders. PMID: 32450697 [PubMed - as supplied by publisher]

Functional Attributes of Antibodies, Effector Cells, and Target Cells Affecting NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity.

Wed, 27/05/2020 - 14:39
Related Articles Functional Attributes of Antibodies, Effector Cells, and Target Cells Affecting NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity. J Immunol. 2019 12 15;203(12):3126-3135 Authors: Temming AR, de Taeye SW, de Graaf EL, de Neef LA, Dekkers G, Bruggeman CW, Koers J, Ligthart P, Nagelkerke SQ, Zimring JC, Kuijpers TW, Wuhrer M, Rispens T, Vidarsson G Abstract Ab-dependent cellular cytotoxicity (ADCC) is one of the most important effector mechanisms of tumor-targeting Abs in current immunotherapies. In ADCC and other Ab-dependent activation of myeloid effector cells, close cell-cell contact (between effector and target cell) and formation of immunological synapses are required. However, we still lack basic knowledge on the principal factors influencing ADCC potential by therapeutic Abs. In this study we investigated the combined roles of five factors affecting human NK cell-mediated ADCC, namely: 1) Ag density, 2) target cell membrane composition, 3) IgG FcγR polymorphism, 4) FcγR-blocking cytophilic Abs, and 5) Ab fucosylation. We demonstrate that the magnitude of NK cell-mediated ADCC responses is predominantly influenced by Ag density and Ab fucosylation. Afucosylation consistently induced efficient ADCC, even at very low Ag density, where fucosylated target Abs did not elicit ADCC. On the side of the effector cell, the FcγRIIIa-Val/Phe158 polymorphism influenced ADCC potency, with NK cells expressing the Val158 variant showing more potent ADCC. In addition, we identified the sialic acid content of the target cell membrane as an important inhibitory factor for ADCC. Furthermore, we found that the presence and glycosylation status of aspecific endogenous Abs bound to NK cell FcγRIIIa (cytophilic Abs) determine the blocking effect on ADCC. These five parameters affect the potency of Abs in vitro and should be further tested as predictors of in vivo capacity. PMID: 31748349 [PubMed - indexed for MEDLINE]

Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia.

Wed, 27/05/2020 - 14:39
Related Articles Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia. Brain. 2019 11 01;142(11):3382-3397 Authors: Vaz FM, McDermott JH, Alders M, Wortmann SB, Kölker S, Pras-Raves ML, Vervaart MAT, van Lenthe H, Luyf ACM, Elfrink HL, Metcalfe K, Cuvertino S, Clayton PE, Yarwood R, Lowe MP, Lovell S, Rogers RC, Deciphering Developmental Disorders Study, van Kampen AHC, Ruiter JPN, Wanders RJA, Ferdinandusse S, van Weeghel M, Engelen M, Banka S Abstract CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain. PMID: 31637422 [PubMed - indexed for MEDLINE]

Metabolomic profile of diabetic retinopathy: a GC-TOFMS-based approach using vitreous and aqueous humor.

Wed, 27/05/2020 - 14:39
Related Articles Metabolomic profile of diabetic retinopathy: a GC-TOFMS-based approach using vitreous and aqueous humor. Acta Diabetol. 2020 Jan;57(1):41-51 Authors: Wang H, Fang J, Chen F, Sun Q, Xu X, Lin SH, Liu K Abstract AIM: To identify the potential metabolite markers in diabetic retinopathy (DR) by using gas chromatography coupled with time-of-flight mass spectrometry (GC-TOFMS). METHODS: GC-TOFMS spectra were acquired from vitreous and aqueous humor (AH) samples of patients with DR and non-diabetic participants. Comparative analysis was used to elucidate the distinct metabolites of DR. Metabolic pathway was employed to explicate the metabolic reprogramming pathways involved in DR. Logistic regression and receiver-operating characteristic analyses were carried out to select and validate the biomarker metabolites and establish a therapeutic model. RESULTS: Comparative analysis showed a clear separation between disease and control groups. Eight differentiating metabolites from AH and 15 differentiating metabolites from vitreous were highlighted. Out of these 23 metabolites, 11 novel metabolites have not been detected previously. Pathway analysis identified nine pathways (three in AH and six in vitreous) as the major disturbed pathways associated with DR. The abnormal of gluconeogenesis, ascorbate-aldarate metabolism, valine-leucine-isoleucine biosynthesis, and arginine-proline metabolism might weigh the most in the development of DR. The AUC of the logistic regression model established by D-2,3-Dihydroxypropanoic acid, isocitric acid, fructose 6-phosphate, and L-Lactic acid in AH was 0.965. The AUC established by pyroglutamic acid and pyruvic acid in vitreous was 0.951. CONCLUSIONS: These findings have expanded our understanding of identified metabolites and revealed for the first time some novel metabolites in DR. These results may provide useful information to explore the mechanism and may eventually allow the development of metabolic biomarkers for prognosis and novel therapeutic strategies for the management of DR. PMID: 31089930 [PubMed - indexed for MEDLINE]

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