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1
Rieusset, Laura, Marjolaine Rey, Florence Wisniewski-Dyé, Claire Prigent-Combaret, and Gilles Comte. "Wheat Metabolite Interferences on Fluorescent Pseudomonas Physiology Modify Wheat Metabolome through an Ecological Feedback." Metabolites 12, no. 3 (March 9, 2022): 236. http://dx.doi.org/10.3390/metabo12030236.
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Plant roots exude a wide variety of secondary metabolites able to attract and/or control a large diversity of microbial species. In return, among the root microbiota, some bacteria can promote plant development. Among these, Pseudomonas are known to produce a wide diversity of secondary metabolites that could have biological activity on the host plant and other soil microorganisms. We previously showed that wheat can interfere with Pseudomonas secondary metabolism production through its root metabolites. Interestingly, production of Pseudomonas bioactive metabolites, such as phloroglucinol, phenazines, pyrrolnitrin, or acyl homoserine lactones, are modified in the presence of wheat root extracts. A new cross metabolomic approach was then performed to evaluate if wheat metabolic interferences on Pseudomonas secondary metabolites production have consequences on wheat metabolome itself. Two different Pseudomonas strains were conditioned by wheat root extracts from two genotypes, leading to modification of bacterial secondary metabolites production. Bacterial cells were then inoculated on each wheat genotypes. Then, wheat root metabolomes were analyzed by untargeted metabolomic, and metabolites from the Adular genotype were characterized by molecular network. This allows us to evaluate if wheat differently recognizes the bacterial cells that have already been into contact with plants and highlights bioactive metabolites involved in wheat—Pseudomonas interaction.
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Zhang, Zhonghui, Feng Zhang, Yuan Deng, Lisong Sun, Mengdi Mao, Ridong Chen, Qi Qiang, et al. "Integrated Metabolomics and Transcriptomics Analyses Reveal the Metabolic Differences and Molecular Basis of Nutritional Quality in Landraces and Cultivated Rice." Metabolites 12, no. 5 (April 22, 2022): 384. http://dx.doi.org/10.3390/metabo12050384.
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Rice (Oryza sativa L.) is one of the most globally important crops, nutritionally and economically. Therefore, analyzing the genetic basis of its nutritional quality is a paramount prerequisite for cultivating new varieties with increased nutritional health. To systematically compare the nutritional quality differences between landraces and cultivated rice, and to mine key genes that determine the specific nutritional traits of landraces, a seed metabolome database of 985 nutritional metabolites covering amino acids, flavonoids, anthocyanins, and vitamins by a widely targeted metabolomic approach with 114 rice varieties (35 landraces and 79 cultivars) was established. To further reveal the molecular mechanism of the metabolic differences in landrace and cultivated rice seeds, four cultivars and six landrace seeds were selected for transcriptome and metabolome analysis during germination, respectively. The integrated analysis compared the metabolic profiles and transcriptomes of different types of rice, identifying 358 differentially accumulated metabolites (DAMs) and 1982 differentially expressed genes (DEGs), establishing a metabolite–gene correlation network. A PCA revealed anthocyanins, flavonoids, and lipids as the central differential nutritional metabolites between landraces and cultivated rice. The metabolite–gene correlation network was used to screen out 20 candidate genes postulated to be involved in the structural modification of anthocyanins. Five glycosyltransferases were verified to catalyze the glycosylation of anthocyanins by in vitro enzyme activity experiments. At the same time, the different mechanisms of the anthocyanin synthesis pathway and structural diversity in landrace and cultivated rice were systematically analyzed, providing new insights for the improvement and utilization of the nutritional quality of rice landrace varieties.
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Brindle, Kevin M. "Metabolomics: Pandora's Box or Aladdin's Cave?" Biochemist 25, no. 1 (February 1, 2003): 15–17. http://dx.doi.org/10.1042/bio02501015.
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Functional genomics, the elucidation of gene function from studies of the effects of gene modification on cellular phenotype, has prompted the development of massively parallel and increasingly comprehensive screening tools for assessing the expression of mRNAs (transcriptomics) and proteins (proteomics). For a more complete description of the effects of changes in genotype or physiological conditions on cellular phenotype, we also need to define the status of a third class of biomolecules in the cell, the small-molecule metabolites. Study of the latter has been termed metabolomics and the metabolite complement the metabolome.
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Creek, Darren J., Brunda Nijagal, Dong-Hyun Kim, Federico Rojas, Keith R. Matthews, and Michael P. Barrett. "Metabolomics Guides Rational Development of a Simplified Cell Culture Medium for Drug Screening against Trypanosoma brucei." Antimicrobial Agents and Chemotherapy 57, no. 6 (April 9, 2013): 2768–79. http://dx.doi.org/10.1128/aac.00044-13.
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ABSTRACTIn vitroculture methods underpin many experimental approaches to biology and drug discovery. The modification of established cell culture methods to make them more biologically relevant or to optimize growth is traditionally a laborious task. Emerging metabolomic technology enables the rapid evaluation of intra- and extracellular metabolites and can be applied to the rational development of cell culture media. In this study, untargeted semiquantitative and targeted quantitative metabolomic analyses of fresh and spent media revealed the major nutritional requirements for the growth of bloodstream formTrypanosoma brucei. The standard culture medium (HMI11) contained unnecessarily high concentrations of 32 nutrients that were subsequently removed to make the concentrations more closely resemble those normally found in blood. Our new medium, Creek's minimal medium (CMM), supportsin vitrogrowth equivalent to that in HMI11 and causes no significant perturbation of metabolite levels for 94% of the detected metabolome (<3-fold change; α = 0.05). Importantly, improved sensitivity was observed for drug activity studies in whole-cell phenotypic screenings and in the metabolomic mode of action assays. Four-hundred-fold 50% inhibitory concentration decreases were observed for pentamidine and methotrexate, suggesting inhibition of activity by nutrients present in HMI11. CMM is suitable for routine cell culture and offers important advantages for metabolomic studies and drug activity screening.
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Saunier, Amélie, Stéphane Greff, James D. Blande, Caroline Lecareux, Virginie Baldy, Catherine Fernandez, and Elena Ormeño. "Amplified Drought and Seasonal Cycle Modulate Quercus pubescens Leaf Metabolome." Metabolites 12, no. 4 (March 30, 2022): 307. http://dx.doi.org/10.3390/metabo12040307.
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The intensification of summer drought expected with climate change can induce metabolism modifications in plants to face such constraints. In this experiment, we used both a targeted approach focused on flavonoids, as well as an untargeted approach, to study a broader fraction of the leaf metabolome of Quercus pubescens exposed to amplified drought. A forest site equipped with a rainfall exclusion device allowed reduction of natural rainfall by ~30% over the tree canopy. Leaves of natural drought (ND) and amplified drought (AD) plots were collected over three seasonal cycles (spring, summer, and autumn) in 2013 (the second year of rain exclusion), 2014, and 2015. As expected, Q. pubescens metabolome followed a seasonal course. In the summer of 2015, the leaf metabolome presented a shifted and early autumnal pattern because of harsher conditions during this year. Despite low metabolic modification at the global scale, our results demonstrated that 75% of Quercus metabolites were upregulated in springs when trees were exposed to AD, whereas 60 to 73% of metabolites (93% in summer 2015), such as kaempferols and quercetins, were downregulated in summers/autumns. Juglanin, a kaempferol pentoside, as well as rhododendrin derivatives, were upregulated throughout the year, suggesting an antioxidant ability of these metabolites. Those changes in terms of phenology and leaf chemistry could, in the end, affect the ecosystem functioning.
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Balonov, Ilja, Max Kurlbaum, Ann-Cathrin Koschker, Christine Stier, Martin Fassnacht, and Ulrich Dischinger. "Changes in Plasma Metabolomic Profile Following Bariatric Surgery, Lifestyle Intervention or Diet Restriction—Insights from Human and Rat Studies." International Journal of Molecular Sciences 24, no. 3 (January 25, 2023): 2354. http://dx.doi.org/10.3390/ijms24032354.
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Although bariatric surgery is known to change the metabolome, it is unclear if this is specific for the intervention or a consequence of the induced bodyweight loss. As the weight loss after Roux-en-Y Gastric Bypass (RYGB) can hardly be mimicked with an evenly effective diet in humans, translational research efforts might be helpful. A group of 188 plasma metabolites of 46 patients from the randomized controlled Würzburg Adipositas Study (WAS) and from RYGB-treated rats (n = 6) as well as body-weight-matched controls (n = 7) were measured using liquid chromatography tandem mass spectrometry. WAS participants were randomized into intensive lifestyle modification (LS, n = 24) or RYGB (OP, n = 22). In patients in the WAS cohort, only bariatric surgery achieved a sustained weight loss (BMI −34.3% (OP) vs. −1.2% (LS), p ≤ 0.01). An explicit shift in the metabolomic profile was found in 57 metabolites in the human cohort and in 62 metabolites in the rodent model. Significantly higher levels of sphingolipids and lecithins were detected in both surgical groups but not in the conservatively treated human and animal groups. RYGB leads to a characteristic metabolomic profile, which differs distinctly from that following non-surgical intervention. Analysis of the human and rat data revealed that RYGB induces specific changes in the metabolome independent of weight loss.
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Včelařová, Ludmila, Vladimír Skalický, Ivo Chamrád, René Lenobel, Martin F. Kubeš, Aleš Pěnčík, and Ondřej Novák. "Auxin Metabolome Profiling in the Arabidopsis Endoplasmic Reticulum Using an Optimised Organelle Isolation Protocol." International Journal of Molecular Sciences 22, no. 17 (August 29, 2021): 9370. http://dx.doi.org/10.3390/ijms22179370.
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The endoplasmic reticulum (ER) is an extensive network of intracellular membranes. Its major functions include proteosynthesis, protein folding, post-transcriptional modification and sorting of proteins within the cell, and lipid anabolism. Moreover, several studies have suggested that it may be involved in regulating intracellular auxin homeostasis in plants by modulating its metabolism. Therefore, to study auxin metabolome in the ER, it is necessary to obtain a highly enriched (ideally, pure) ER fraction. Isolation of the ER is challenging because its biochemical properties are very similar to those of other cellular endomembranes. Most published protocols for ER isolation use density gradient ultracentrifugation, despite its suboptimal resolving power. Here we present an optimised protocol for ER isolation from Arabidopsis thaliana seedlings for the subsequent mass spectrometric determination of ER-specific auxin metabolite profiles. Auxin metabolite analysis revealed highly elevated levels of active auxin form (IAA) within the ER compared to whole plants. Moreover, samples prepared using our optimised isolation ER protocol are amenable to analysis using various “omics” technologies including analyses of both macromolecular and low molecular weight compounds from the same sample.
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Desmet, Sandrien, Kris Morreel, and Rebecca Dauwe. "Origin and Function of Structural Diversity in the Plant Specialized Metabolome." Plants 10, no. 11 (November 6, 2021): 2393. http://dx.doi.org/10.3390/plants10112393.
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The plant specialized metabolome consists of a multitude of structurally and functionally diverse metabolites, variable from species to species. The specialized metabolites play roles in the response to environmental changes and abiotic or biotic stresses, as well as in plant growth and development. At its basis, the specialized metabolism is built of four major pathways, each starting from a few distinct primary metabolism precursors, and leading to distinct basic carbon skeleton core structures: polyketides and fatty acid derivatives, terpenoids, alkaloids, and phenolics. Structural diversity in specialized metabolism, however, expands exponentially with each subsequent modification. We review here the major sources of structural variety and question if a specific role can be attributed to each distinct structure. We focus on the influences that various core structures and modifications have on flavonoid antioxidant activity and on the diversity generated by oxidative coupling reactions. We suggest that many oxidative coupling products, triggered by initial radical scavenging, may not have a function in se, but could potentially be enzymatically recycled to effective antioxidants. We further discuss the wide structural variety created by multiple decorations (glycosylations, acylations, prenylations), the formation of high-molecular weight conjugates and polyesters, and the plasticity of the specialized metabolism. We draw attention to the need for untargeted methods to identify the complex, multiply decorated and conjugated compounds, in order to study the functioning of the plant specialized metabolome.
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Wu, Si, Jun Zhang, Feifei Li, Wei Du, Xin Zhou, Mian Wan, Yi Fan, et al. "One-Carbon Metabolism Links Nutrition Intake to Embryonic Development via Epigenetic Mechanisms." Stem Cells International 2019 (March 10, 2019): 1–8. http://dx.doi.org/10.1155/2019/3894101.
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Beyond energy production, nutrient metabolism plays a crucial role in stem cell lineage determination. Changes in metabolism based on nutrient availability and dietary habits impact stem cell identity. Evidence suggests a strong link between metabolism and epigenetic mechanisms occurring during embryonic development and later life of offspring. Metabolism regulates epigenetic mechanisms such as modifications of DNA, histones, and microRNAs. In turn, these epigenetic mechanisms regulate metabolic pathways to modify the metabolome. One-carbon metabolism (OCM) is a crucial metabolic process involving transfer of the methyl groups leading to regulation of multiple cellular activities. OCM cycles and its related micronutrients are ubiquitously present in stem cells and feed into the epigenetic mechanisms. In this review, we briefly introduce the OCM process and involved micronutrients and discuss OCM-associated epigenetic modifications, including DNA methylation, histone modification, and microRNAs. We further consider the underlying OCM-mediated link between nutrition and epigenetic modifications in embryonic development.
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Tong, Tong, Si Chen, Lianrong Wang, You Tang, Jae Yong Ryu, Susu Jiang, Xiaolin Wu, et al. "Occurrence, evolution, and functions of DNA phosphorothioate epigenetics in bacteria." Proceedings of the National Academy of Sciences 115, no. 13 (March 12, 2018): E2988—E2996. http://dx.doi.org/10.1073/pnas.1721916115.
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The chemical diversity of physiological DNA modifications has expanded with the identification of phosphorothioate (PT) modification in which the nonbridging oxygen in the sugar-phosphate backbone of DNA is replaced by sulfur. Together with DndFGH as cognate restriction enzymes, DNA PT modification, which is catalyzed by the DndABCDE proteins, functions as a bacterial restriction-modification (R-M) system that protects cells against invading foreign DNA. However, the occurrence of dnd systems across a large number of bacterial genomes and their functions other than R-M are poorly understood. Here, a genomic survey revealed the prevalence of bacterial dnd systems: 1,349 bacterial dnd systems were observed to occur sporadically across diverse phylogenetic groups, and nearly half of these occur in the form of a solitary dndBCDE gene cluster that lacks the dndFGH restriction counterparts. A phylogenetic analysis of 734 complete PT R-M pairs revealed the coevolution of M and R components, despite the observation that several PT R-M pairs appeared to be assembled from M and R parts acquired from distantly related organisms. Concurrent epigenomic analysis, transcriptome analysis, and metabolome characterization showed that a solitary PT modification contributed to the overall cellular redox state, the loss of which perturbed the cellular redox balance and induced Pseudomonas fluorescens to reconfigure its metabolism to fend off oxidative stress. An in vitro transcriptional assay revealed altered transcriptional efficiency in the presence of PT DNA modification, implicating its function in epigenetic regulation. These data suggest the versatility of PT in addition to its involvement in R-M protection.
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Shen, Ling, Catherine Roullier, François-Hugues Porée, Thomas Gaslonde, Ludivine Riffault-Valois, Olivier Grovel, Gwenaël Ruprich-Robert, and Florence Chapeland-Leclerc. "Complementary Strategies to Unlock Biosynthesis Gene Clusters Encoding Secondary Metabolites in the Filamentous Fungus Podospora anserina." Journal of Fungi 9, no. 1 (December 21, 2022): 9. http://dx.doi.org/10.3390/jof9010009.
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The coprophilous ascomycete Podospora anserina is known to have a high potential to synthesize a wide array of secondary metabolites (SMs). However, to date, the characterization of SMs in this species, as in other filamentous fungal species, is far less than expected by the functional prediction through genome mining, likely due to the inactivity of most SMs biosynthesis gene clusters (BGCs) under standard conditions. In this work, our main objective was to compare the global strategies usually used to deregulate SM gene clusters in P. anserina, including the variation of culture conditions and the modification of the chromatin state either by genetic manipulation or by chemical treatment, and to show the complementarity of the approaches between them. In this way, we showed that the metabolomics-driven comparative analysis unveils the unexpected diversity of metabolic changes in P. anserina and that the integrated strategies have a mutual complementary effect on the expression of the fungal metabolome. Then, our results demonstrate that metabolite production is significantly influenced by varied cultivation states and epigenetic modifications. We believe that the strategy described in this study will facilitate the discovery of fungal metabolites of interest and will improve the ability to prioritize the production of specific fungal SMs with an optimized treatment.
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Sookaromdee, Pathum, and Viroj Wiwanitkit. "Tuberculous pleural effusion: Modification of metabolome by the effect of common metabolic disease, diabetes mellitus." Biomedical and Biotechnology Research Journal (BBRJ) 3, no. 1 (2019): 19. http://dx.doi.org/10.4103/bbrj.bbrj_34_19.
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Veach, Allison M., Daniel Yip, Nancy L. Engle, Zamin K. Yang, Amber Bible, Jennifer Morrell-Falvey, Timothy J. Tschaplinski, Udaya C. Kalluri, and Christopher W. Schadt. "Modification of plant cell wall chemistry impacts metabolome and microbiome composition in Populus PdKOR1 RNAi plants." Plant and Soil 429, no. 1-2 (June 4, 2018): 349–61. http://dx.doi.org/10.1007/s11104-018-3692-8.
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Bi, Xiaoyi, Ling Liao, Lijun Deng, Zhenghua Jin, Zehao Huang, Guochao Sun, Bo Xiong, and Zhihui Wang. "Combined Transcriptome and Metabolome Analyses Reveal Candidate Genes Involved in Tangor (Citrus reticulata × Citrus sinensis) Fruit Development and Quality Formation." International Journal of Molecular Sciences 23, no. 10 (May 13, 2022): 5457. http://dx.doi.org/10.3390/ijms23105457.
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Tangor, an important citrus type, is a hybrid of orange and mandarin and possesses their advantageous characteristics. Fruit quality is an important factor limiting the development of the citrus industry and highly depends on fruit development and ripening programs. However, fruit development and quality formation have not been completely explored in mandarin-orange hybrids. We sequenced the metabolome and transcriptome of three mandarin-orange hybrid cultivars at the early fruiting [90 days after full bloom (DAFB)], color change (180 DAFB), and ripening (270 DAFB) stages. Metabolome sequencing was performed to preliminarily identify the accumulation patterns of primary and secondary metabolites related to fruit quality and hormones regulating fruit development. Transcriptome analysis showed that many genes related to primary metabolism, secondary metabolism, cell wall metabolism, phytohormones, and transcriptional regulation were up-regulated in all three cultivars during fruit development and ripening. Additionally, multiple key genes were identified that may play a role in sucrose, citric acid and flavonoid accumulation, cell wall modification, and abscisic acid signaling, which may provide a valuable resource for future research on enhancement of fruit quality of hybrid citrus. Overall, this study provides new insights into the molecular basis of pulp growth and development regulation and fruit quality formation in mandarin-orange hybrids.
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Rojas, Joselyn, Nailet Arraiz, Miguel Aguirre, Manuel Velasco, and Valmore Bermúdez. "AMPK as Target for Intervention in Childhood and Adolescent Obesity." Journal of Obesity 2011 (2011): 1–19. http://dx.doi.org/10.1155/2011/252817.
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Childhood obesity is a major worldwide health problem. Intervention programs to ameliorate the rate of obesity have been designed and implemented; yet the epidemic has no end near in sight. AMP-activated protein kinase (AMPK) has become one of the most important key elements in energy control, appetite regulation, myogenesis, adipocyte differentiation, and cellular stress management. Obesity is a multifactorial disease, which has a very strong genetic component, especially epigenetic factors. The intrauterine milieu has a determinant impact on adult life, since the measures taken for survival are kept throughout life thanks to epigenetic modification. Nutrigenomics studies the influence of certain food molecules on the metabolome profile, raising the question of an individualized obesity therapy according to metabolic (and probably) genetic features. Metformin, an insulin sensitizing agent, its known to lower insulin resistance and enhance metabolic profile, with an additional weight reduction capacity, via activation of AMPK. Exercise is coadjutant for lifestyle modifications, which also activates AMPK in several ways contributing to glucose and fat oxidation. The following review examines AMPK's role in obesity, applying its use as a tool for childhood and adolescent obesity.
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Hall, Madeline, and Natalia Krupenko. "Dietary Methionine Restriction Reverses Liver Cancer Driving Metabotype in GNMT KO Mice." Current Developments in Nutrition 6, Supplement_1 (June 2022): 241. http://dx.doi.org/10.1093/cdn/nzac052.008.
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Abstract Objectives Glycine N-methyltransferase (GNMT) is a major liver enzyme that catalyzes the S-adenosyl-methionine (SAM) dependent synthesis of sarcosine from glycine and regulates the availability of SAM for cellular methylation reactions, as well as for detoxification pathways in liver cells. The whole-body enzyme knockout in mice results in dysregulated methionine metabolism, including massive elevations of SAM. As a result, Gnmt−/− mice develop fatty livers and subsequently, hepatocellular carcinomas (HCC). We hypothesize that since the HCC development in Gnmt−/− mice is associated with the deregulation of metabolic processes, alteration of nutrients supply may delay/prevent cancer development in animals with genetic deficiency of GNMT. Methods Wild type and Gnmt−/− littermates of both sexes were randomized into dietary treatment groups. Experimental diets contained defined mixtures of purified amino acids instead of protein, and identical amounts and sources of carbohydrates, fat and vitamins. A standard amino acid defined diet (AAD, Envigo) was used as a control. Methionine adjusted diet (MA, same levels of amino acids as standard diet, except methionine was 8-fold lower) was tested for the effect on liver metabolome. Mice were kept on respective diets for 8 months after weaning, and blood and tissue samples were collected at endpoint. Aliquots of frozen liver samples (∼60–70 mg) were subjected to untargeted metabolomic analysis through Metabolon®. Results Metabolomic data underscore dramatic elevation of polyamines, TCA metabolites, bile acids and glycogen degradation products in Gnmt−/- livers on standard diet compared to WT controls. On the MA diet however, metabotypes of Gnmt−/- mice were similar to those of their wildtype littermates, with reversals in elevations of SAM and almost all the aforementioned metabolites. There were no appreciable differences between diets in WT mice metabotypes. Conclusions Our data demonstrate that diet alteration can reverse the deregulation of metabolic processes associated with HCC development in Gnmt−/- mice. These results also suggest that diet modification should be investigated for the potential of improving liver cancer treatments. Funding Sources UNC NRI 2018 Pilot Project.
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Zheng, Shanshan, Raquel Loreto, Philip Smith, Andrew Patterson, David Hughes, and Liande Wang. "Specialist and Generalist Fungal Parasites Induce Distinct Biochemical Changes in the Mandible Muscles of Their Host." International Journal of Molecular Sciences 20, no. 18 (September 17, 2019): 4589. http://dx.doi.org/10.3390/ijms20184589.
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Some parasites have evolved the ability to adaptively manipulate host behavior. One notable example is the fungus Ophiocordyceps unilateralis sensu lato, which has evolved the ability to alter the behavior of ants in ways that enable fungal transmission and lifecycle completion. Because host mandibles are affected by the fungi, we focused on understanding changes in the metabolites of muscles during behavioral modification. We used High-Performance Liquid Chromatography-Mass/Mass (HPLC-MS/MS) to detect the metabolite difference between controls and O. unilateralis-infected ants. There was a significant difference between the global metabolome of O. unilateralis-infected ants and healthy ants, while there was no significant difference between the Beauveria bassiana treatment ants group compared to the healthy ants. A total of 31 and 16 of metabolites were putatively identified from comparisons of healthy ants with O. unilateralis-infected ants and comparisons of B. bassiana with O. unilateralis-infected samples, respectively. This result indicates that the concentrations of sugars, purines, ergothioneine, and hypoxanthine were significantly increased in O. unilateralis-infected ants in comparison to healthy ants and B. bassiana-infected ants. This study provides a comprehensive metabolic approach for understanding the interactions, at the level of host muscles, between healthy ants and fungal parasites.
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Mangeot-Peter, L., T. J. Tschaplinski, N. L. Engle, C. Veneault-Fourrey, F. Martin, and A. Deveau. "Impacts of Soil Microbiome Variations on Root Colonization by Fungi and Bacteria and on the Metabolome of Populus tremula × alba." Phytobiomes Journal 4, no. 2 (January 2020): 142–55. http://dx.doi.org/10.1094/pbiomes-08-19-0042-r.
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Trees depend on beneficial interactions between roots and soil microbes for their nutrition and protection against stresses. The soil microbiome provides the main reservoir of microbes for root colonization and is subject to natural variations that can affect its composition. It is not clear whether the tree’s root system is able to buffer the natural variations occurring in the soil microbiome to capture a stable and effective microbiome or whether these variations affect its microbiome to impact its physiology. To address this question, we planted cuttings of Gray Poplar (Populus tremula × alba clone 717-1B4) in natural soil taken from a poplar stand under the same tree over two consecutive years and grew them in a greenhouse. We analyzed the soil and root microbiomes by high throughput Illumina MiSeq sequencing of fungal rDNA internal transcribed spacer and bacterial 16S rRNA amplicons and we characterized the root metabolome by gas chromatography-mass spectrometry. Soil and root microbial communities significantly shifted over the 2 years. A modification of the balance between endophytes, saprophytes, and mycorrhizal fungi occurred in the roots as well as a replacement of some dominant operational taxonomic units by others. These modifications were correlated with a significant alteration of the levels of about 10% of primary and secondary metabolites, suggesting that natural fluctuations in soil microbial communities can have a profound impact on tree root metabolism and physiology. Tree roots functioning may thus be indirectly strongly affected by the effects of future extreme climatic variations on the soil microbiome.
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Reimer, Julia Jessica, Basel Shaaban, Noud Drummen, Sruthy Sanjeev Ambady, Franziska Genzel, Gernot Poschet, Anika Wiese-Klinkenberg, Björn Usadel, and Alexandra Wormit. "Capsicum Leaves under Stress: Using Multi-Omics Analysis to Detect Abiotic Stress Network of Secondary Metabolism in Two Species." Antioxidants 11, no. 4 (March 30, 2022): 671. http://dx.doi.org/10.3390/antiox11040671.
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The plant kingdom contains an enormous diversity of bioactive compounds which regulate plant growth and defends against biotic and abiotic stress. Some of these compounds, like flavonoids, have properties which are health supporting and relevant for industrial use. Many of these valuable compounds are synthesized in various pepper (Capsicum sp.) tissues. Further, a huge amount of biomass residual remains from pepper production after harvest, which provides an important opportunity to extract these metabolites and optimize the utilization of crops. Moreover, abiotic stresses induce the synthesis of such metabolites as a defense mechanism. Two different Capsicum species were therefore exposed to chilling temperature (24/18 ℃ vs. 18/12 ℃), to salinity (200 mM NaCl), or a combination thereof for 1, 7 and 14 days to investigate the effect of these stresses on the metabolome and transcriptome profiles of their leaves. Both profiles in both species responded to all stresses with an increase over time. All stresses resulted in repression of photosynthesis genes. Stress involving chilling temperature induced secondary metabolism whereas stresses involving salt repressed cell wall modification and solute transport. The metabolome analysis annotated putatively many health stimulating flavonoids (apigetrin, rutin, kaempferol, luteolin and quercetin) in the Capsicum biomass residuals, which were induced in response to salinity, chilling temperature or a combination thereof, and supported by related structural genes of the secondary metabolism in the network analysis.
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Olivares-García, Carol A., Martín Mata-Rosas, Carolina Peña-Montes, Francisco Quiroz-Figueroa, Aldo Segura-Cabrera, Laura M. Shannon, Victor M. Loyola-Vargas, et al. "Phenylpropanoids Are Connected to Cell Wall Fortification and Stress Tolerance in Avocado Somatic Embryogenesis." International Journal of Molecular Sciences 21, no. 16 (August 8, 2020): 5679. http://dx.doi.org/10.3390/ijms21165679.
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Somatic embryogenesis (SE) is a valuable model for understanding the mechanism of plant embryogenesis and a tool for the mass production of plants. However, establishing SE in avocado has been complicated due to the very low efficiency of embryo induction and plant regeneration. To understand the molecular foundation of the SE induction and development in avocado, we compared embryogenic (EC) and non-embryogenic (NEC) cultures of two avocado varieties using proteomic and metabolomic approaches. Although Criollo and Hass EC exhibited similarities in the proteome and metabolome profile, in general, we observed a more active phenylpropanoid pathway in EC than NEC. This pathway is associated with the tolerance of stress responses, probably through the reinforcement of the cell wall and flavonoid production. We could corroborate that particular polyphenolics compounds, including p-coumaric acid and t-ferulic acid, stimulated the production of somatic embryos in avocado. Exogen phenolic compounds were associated with the modification of the content of endogenous polyphenolic and the induction of the production of the putative auxin-a, adenosine, cellulose and 1,26-hexacosanediol-diferulate. We suggest that in EC of avocado, there is an enhanced phenylpropanoid metabolism for the production of the building blocks of lignin and flavonoid compounds having a role in cell wall reinforcement for tolerating stress response. Data are available at ProteomeXchange with the identifier PXD019705.
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Mugume, Yosia, Geng Ding, Maria Emilia Dueñas, Meiling Liu, Young-Jin Lee, Basil J. Nikolau, and Diane C. Bassham. "Complex Changes in Membrane Lipids Associated with the Modification of Autophagy in Arabidopsis." Metabolites 12, no. 2 (February 18, 2022): 190. http://dx.doi.org/10.3390/metabo12020190.
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Autophagy is a conserved mechanism among eukaryotes that degrades and recycles cytoplasmic components. Autophagy is known to influence the plant metabolome, including lipid content; however, its impact on the plant lipidome is not fully understood, and most studies have analyzed a single or few mutants defective in autophagy. To gain more insight into the effect of autophagy on lipid concentrations and composition, we quantitatively profiled glycerolipids from multiple Arabidopsis thaliana mutants altered in autophagy and compared them with wild-type seedlings under nitrogen replete (+N; normal growth) and nitrogen starvation (−N; autophagy inducing) conditions. Mutants include those in genes of the core autophagy pathway, together with other genes that have been reported to affect autophagy. Using Matrix-Assisted Laser Desorption/Ionization—Mass Spectrometry (MALDI-MS), we imaged the cellular distribution of specific lipids in situ and demonstrated that autophagy and nitrogen treatment did not affect their spatial distribution within Arabidopsis seedling leaves. We observed changes, both increases and decreases, in the relative amounts of different lipid species in the mutants compared to WT both in +N and −N conditions, although more changes were seen in −N conditions. The relative amounts of polyunsaturated and very long chain lipids were significantly reduced in autophagy-disrupted mutants compared to WT plants. Collectively, our results provide additional evidence that autophagy affects plant lipid content and that autophagy likely affects lipid properties such as chain length and unsaturation.
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Puglisi, Fabrizio, Antonella Padella, Nunziatina Laura Parrinello, Grazia Scandura, Daniela Cambria, Enrico La Spina, Alessandro Barbato, et al. "Dissecting the Adaptive Response to Arginine Deprivation in Hodgkin Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 4497. http://dx.doi.org/10.1182/blood-2021-151006.
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Abstract Background In Hodgkin Lymphoma (HL), neoplastic cells orchestrate an inflammatory microenvironment leading to sterile inflammation, T-cell anergy, and immune deficiency. Our group showed that in HL patients the aminoacid degrading enzyme Arginase-1 is increased, associated with poor outcome, and leads to arginine (Arg) deprivation. However, how the reduction of Arg in the extracellular milieu of the tumor microenvironment can contribute to neoplastic cell fitness is largely unknown. Aims To detect the adaptive response (via evaluation of global transcriptome and metabolome changes) in human HL cell lines exposed to Arg deprivation. Methods To better understand the impact of extra-cellular Arg1 deprivation on the metabolome of human cHL cells, four human cHL cell lines (L428, L540, HDMYZ and KM-H2) were individually cultured with customized complete media or lacking or Arg (R0), supplemented with 10% dialyzed fetal bovine serum, in six independent experiments. After 48 hours of culture, the cells were collected for global metabolomic analysis, by gas chromatography-mass spectrometry (GC/MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS) platforms by Metabolon Inc and transcriptome profiling by Illumina platform. Following normalization to DNA concentration, log transformation, and imputation of missing values, if any, with the minimum observed value for each compound, Welch's two-sample t-test was used to identify biochemicals that differed significantly between experimental groups. Results While Arg deprivation did not affect cell viability but delayed cell cycle due to arrest in G2 phase in all tested cell lines, the effect of Arg deficiency on the cellular metabolome depended largely on the cell type examined with L428 and KMH2 cells having significantly changed metabolomes. Pyruvate was significantly higher in the KMH2 cells deprived of Arg compared to controls. Conversely, lactate was significantly lower, with increased levels of long-chain saturated fatty acids and long-chain polyunsaturated fatty acids (PUFAs). Taken together the metabolomics changes suggested that specific-amino acid deficiency can lead to an increase in free fatty acids synthases to preserve cytoplasmatic and mitochondrial membrane dynamics. Consistent with a metabolic rewiring to maintain mitochondrial integrity (the pyruvate is an important intermediary in the conversion of carbohydrates into fatty acids), the adaptive response was associated to increased oxidative stress, as suggested by of reduced glutathione in KMH2 cells, depletion of gamma-glutamylcysteine, increased cystine, the oxidative product of cysteine, and methionine sulfoxide (an oxidation product of methionine). Gene set enrichment analysis (GSEA) showed deep transcriptome rearrangements in KMH2 and HDMYZ cell lines, involving upregulation of genes required for the unfolded protein response (UPR, including XBP1, EIF2S1, EIF4A2, EIF4A3, ATF3, ATF4, DDIT4, EDEM1, GADD45B, SQSTM1, HMOX), NF-kB response to TNF (including RAF1, TNF, LIF, NKBIA, SGK1, BIRC3, ICAM1, BCL6, IL6, RELA, CDKN1A), p53 pathway and networks (including CDKN2B, STOM, TRAF4, RRAD, SESN1, FOXO3, SERPINB5, JAG2) and proteosome degradation (HSPA4, PSMD11, PSMD13, PSMD2, PSMA5, PSMA7, PSMC4), with a minimal effect on metabolism features, except the upregulation of genes involved in lactate generation and degradation. All lines tested showed down-regulation of CCNI2, LCROL, MKI67, NCAPG, PEX10 and UFSP2, suggesting that early response to arginine deprivation includes modulation of UFMylation pathway, the most recently discovered post-translational protein modification system, whose biological function is largely unknown. Conclusions The removal of Arg from L428 and KMH2 resulted in changes in the specific-amino acid-related metabolites. The adaptive response to Arg-depleted environment increases oxidative stress and promotes a shift in glucose use in the attempt to preserve mitochondrial function. The cell-cycle arrest in G2, the increase of pyruvate availability and the upregulation of proteasome function via upregulation of the UFMylation pathway suggest the dependency of HL cell lines on mitochondrial function integrity. Quantity and function of mitochondria network can play a major role in selecting the fittest clones, a metabolic pathway that should be explored as novel non -synthetic lethal targets. Disclosures Martinelli: Stemline Therapeutics: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau; Daichii Sankyo: Consultancy; Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy; Abbvie: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy. Di Raimondo: Pfizer: Honoraria; Jazz Pharmaceutical: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Bristol Myers Squibb: Honoraria; Janssen Pharmaceuticals: Honoraria.
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Lin, Shuang, Shaohua Zeng, Biao A, Xiaoman Yang, Tianshun Yang, Guoqi Zheng, Guilian Mao, and Ying Wang. "Integrative Analysis of Transcriptome and Metabolome Reveals Salt Stress Orchestrating the Accumulation of Specialized Metabolites in Lycium barbarum L. Fruit." International Journal of Molecular Sciences 22, no. 9 (April 23, 2021): 4414. http://dx.doi.org/10.3390/ijms22094414.
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Salt stress seriously affects yield and quality of crops. The fruit of Lycium barbarum (LBF) is extensively used as functional food due to its rich nutrient components. It remains unclear how salt stress influences the quality of LBF. In this study, we identified 71 differentially accumulated metabolites (DAMs) and 1396 differentially expressed genes (DEGs) among ripe LBF with and without 300 mM of NaCl treatment. Pearson correlation analysis indicated that the metabolomic changes caused by salt stress were strongly related to oxidoreductases; hydrolases; and modifying enzymes, in particular, acyltransferases, methyltransferases and glycosyltransferases. Further analysis revealed that salt stress facilitated flavonoid glycosylation and carotenoid esterification by boosting the expression of structural genes in the biosynthetic pathways. These results suggested that salt stress prompts the modification of flavonoids and carotenoids to alleviate ROS damage, which in turn improves the quality of LBF. Our results lay a solid foundation for uncovering the underlying molecular mechanism of salt stress orchestrating LBF quality, and the candidate genes identified will be a valuable gene resource for genetic improvement of L. barbarum.
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Rabbani, Naila, and Paul J. Thornalley. "Reading patterns of proteome damage by glycation, oxidation and nitration: quantitation by stable isotopic dilution analysis LC-MS/MS." Essays in Biochemistry 64, no. 1 (February 2020): 169–83. http://dx.doi.org/10.1042/ebc20190047.
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Abstract Liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides a high sensitivity, high specificity multiplexed method for concurrent detection of adducts formed by protein glycation, oxidation and nitration, also called AGEomics. Combined with stable isotopic dilution analysis, it provides for robust quantitation of protein glycation, oxidation and nitration adduct analytes. It is the reference method for such measurements. LC-MS/MS has been used to measure glycated, oxidized and nitrated amino acids – also called glycation, oxidation and nitration free adducts, with a concurrent quantitation of the amino acid metabolome in physiological fluids. Similar adduct residues in proteins may be quantitated with prior exhaustive enzymatic hydrolysis. It has also been applied to quantitation of other post-translation modifications, such as citrullination and formation of Nε-(γ-glutamyl)lysine crosslink by transglutaminases. Application to cellular and extracellular proteins gives estimates of the steady-state levels of protein modification by glycation, oxidation and nitration, and measurement of the accumulation of glycation, oxidation and nitration adducts in cell culture medium and urinary excretion gives an indication of flux of adduct formation. Measurement of glycation, oxidation and nitration free adducts in plasma and urine provides for estimates of renal clearance of free adducts. Diagnostic potential in clinical studies has been enhanced by the combination of estimates of multiple adducts in optimized diagnostic algorithms by machine learning. Recent applications have been in early-stage detection of metabolic, vascular and renal disease, and arthritis, metabolic control and risk of developing vascular complication in diabetes, and a blood test for autism.
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Ferreira, Maria João, Diana C. G. A. Pinto, Ângela Cunha, and Helena Silva. "Halophytes as Medicinal Plants against Human Infectious Diseases." Applied Sciences 12, no. 15 (July 26, 2022): 7493. http://dx.doi.org/10.3390/app12157493.
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Halophytes have long been used for medicinal purposes. However, for many decades, their use was entirely empirical, with virtually no knowledge of the bioactive compounds underlying the different applications. In recent decades, the growing problem of antibiotic resistance triggered the research on alternative antimicrobial approaches, and halophytes, along with other medicinal plants, regained attention as an underexplored pharmacological vein. Furthermore, the high nutritional/nutraceutical/pharmacological value of some halophytic species may represent added value to the emerging activity of saline agriculture and targeted modification of the rhizosphere, with plant-growth-promoting bacteria being attempted to be used as a tool to modulate the plant metabolome and enhance the expression of interesting metabolites. The objective of this review is to highlight the potential of halophytes as a valuable, and still unexplored, source of antimicrobial compounds for clinical applications. For that, we provide a critical perspective on the empirical use of halophytes in traditional medicine and a state-or-the-art overview of the most relevant plant species and metabolites related with antiviral, antifungal and antibacterial activities.
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Lund, Peder, Sarah Smith, Johayra Simithy, Lillian Chau, Elliot Friedman, Yedidya Saiman, Leah Gates, et al. "P165 INFLUENCE OF THE GUT MICROBIOTA ON COLONIC HISTONE MODIFICATIONS THROUGH BUTYRATE METABOLISM UNDER HEALTHY AND INFLAMMATORY CONDITIONS." Inflammatory Bowel Diseases 26, Supplement_1 (January 2020): S40—S41. http://dx.doi.org/10.1093/ibd/zaa010.105.
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Abstract Inflammatory bowel disease (IBD) is often associated with a disruption in the composition and activity of the gut microbiota, referred to as dysbiosis. Since the microbiota has the potential to interact with host epithelial cells through small molecules generated from microbial metabolism, knowledge of how inflammation alters the microbial metabolome and how epithelial cells react is important for a better understanding of how IBD develops and persists. Butyrate, a short chain fatty acid produced through fermentation of dietary polysaccharides, has long been known to inhibit histone deacetylases (HDACs), which represent one of the many types of enzymes responsible for the epigenetic control of gene expression through the post-translational modification of histone proteins. We and others have observed that colonic epithelial cells from germ-free mice have reduced levels of acetylation on histone H4, which appears to be distributed throughout the genome based on sequencing analysis. The decreased levels of H4 acetylation may stem from a lack of butyrate, and therefore uninhibited HDAC activity, in germ-free mice. However, since colonic epithelial cells utilize short chain fatty acids as an energy source, an alternative explanation is that the germ-free condition results in less oxidation of butyrate to acetyl-CoA, which is the donor substrate for histone acetylation reactions. Isotope tracing experiments, in which cultured cells were incubated with labeled butyrate, demonstrated that the acetyl groups of histones contained carbon derived from butyrate. We have also performed isotope tracing experiments in mice using labeled inulin, a plant polysaccharide that presumably undergoes fermentation into short chain fatty acids. In this more physiologically relevant model, we detected isotope incorporation into the acetylated histones of colonic epithelial cells at rates of 5–20%, which appears dependent on the microbiota since labeling is sensitive to antibiotic treatment. To identify the metabolic pathways that link inulin to histone acetylation, we are investigating which metabolites become isotopically labeled using untargeted metabolomics. We will apply the same approach to the DSS-induced model of colitis to investigate how inflammation modulates the gut metabolome as well as the metabolic connections between the microbiota and the host. Our studies may uncover metabolic pathways that become dysregulated during inflammation, which may contribute to the pathogenesis of diseases such as IBD.
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Rebholz, Casey M., Aditya Surapaneni, Andrew S. Levey, Mark J. Sarnak, Lesley A. Inker, Lawrence J. Appel, Josef Coresh, and Morgan E. Grams. "The Serum Metabolome Identifies Biomarkers of Dietary Acid Load in 2 Studies of Adults with Chronic Kidney Disease." Journal of Nutrition 149, no. 4 (March 28, 2019): 578–85. http://dx.doi.org/10.1093/jn/nxy311.
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ABSTRACT Background Dietary acid load is a clinically important aspect of the diet that reflects the balance between acid-producing foods, for example, meat and cheese, and base-producing foods, for example, fruits and vegetables. Methods We used metabolomics to identify blood biomarkers of dietary acid load in 2 independent studies of chronic kidney disease patients: the African American Study of Kidney Disease and Hypertension (AASK, n = 689) and the Modification of Diet in Renal Disease (MDRD, n = 356) study. Multivariable linear regression was used to assess the cross-sectional association between serum metabolites whose identity was known (outcome) and dietary acid load (exposure), estimated with net endogenous acid production (NEAP) based on 24-h urine urea nitrogen and potassium, and adjusted for age, sex, race, randomization group, measured glomerular filtration rate, log-transformed urine protein-to-creatinine ratio, history of cardiovascular disease, BMI, and smoking status. Results Out of the 757 known, nondrug metabolites identified in AASK, 26 were significantly associated with NEAP at the Bonferroni threshold for significance (P < 6.6 × 10−5). Twenty-three of the 26 metabolites were also identified in the MDRD study, and 13 of the 23 (57%) were significantly associated with NEAP (P < 2.2 × 10−3), including 5 amino acids (S-methylmethionine, indolepropionylglycine, indolepropionate, N-methylproline, N-δ-acetylornithine), 2 cofactors and vitamins (threonate, oxalate), 1 lipid (chiro-inositol), and 5 xenobiotics (methyl glucopyranoside, stachydrine, catechol sulfate, hippurate, and tartronate). Higher levels of all 13 replicated metabolites were associated with lower NEAP in both AASK and the MDRD study. Conclusion Metabolomic profiling of serum specimens from kidney disease patients in 2 study populations identified 13 replicated metabolites associated with dietary acid load. Additional studies are needed to validate these compounds in healthy populations. These 13 compounds may potentially be used as objective markers of dietary acid load in future nutrition research studies.
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Vitetta, Luis, Samantha Coulson, and Anthony W. Linnane. "Reactive oxygen species in disease: Rebuttal of a conventional concept." Journal of Controversies in Biomedical Research 1, no. 1 (September 7, 2015): 23–27. http://dx.doi.org/10.15586/jcbmr.2015.7.
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The production of intracellular reactive oxygen species and reactive nitrogen species has long been proposed as leading to the random deleterious modification of macromolecules (i.e., nucleic acids, proteins) with an associated progressive development of the age associated systemic diseases (e.g., diabetes, Parkinson’s disease) as well as contributing to the ageing process. Superoxide anion (hydrogen peroxide) and nitric oxide (peroxynitrite) comprise regulated intracellular second messenger pro-oxidant systems, with specific sub-cellular locales of production and are essential for the normal function of the metabolome and cellular electro-physiology. We have posited that the formation of superoxide anion and its metabolic product hydrogen peroxide, and nitric oxide, do not conditionally lead to random damage of macromolecular species such as nucleic acids or proteins. Under normal physiological conditions their production is intrinsically regulated that is very much consistent with their second messenger purpose of function. We further propose that the concept of an orally administered small molecule antioxidant as a therapy to abrogate free radical activity (to control oxidative stress) is a chimera. As such we consider that free radicals are not a major overwhelming player in the development of the chronic diseases or the ageing process.
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Mercado-Gómez, Maria, Fernando Lopitz-Otsoa, Mikel Azkargorta, Marina Serrano-Maciá, Sofia Lachiondo-Ortega, Naroa Goikoetxea-Usandizaga, Rubén Rodríguez-Agudo, et al. "Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis." International Journal of Molecular Sciences 21, no. 23 (November 27, 2020): 9043. http://dx.doi.org/10.3390/ijms21239043.
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Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.
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Quinlan, Zachary A., Irina Koester, Allegra T. Aron, Daniel Petras, Lihini I. Aluwihare, Pieter C. Dorrestein, Craig E. Nelson, and Linda Wegley Kelly. "ConCISE: Consensus Annotation Propagation of Ion Features in Untargeted Tandem Mass Spectrometry Combining Molecular Networking and In Silico Metabolite Structure Prediction." Metabolites 12, no. 12 (December 16, 2022): 1275. http://dx.doi.org/10.3390/metabo12121275.
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Recent developments in molecular networking have expanded our ability to characterize the metabolome of diverse samples that contain a significant proportion of ion features with no mass spectral match to known compounds. Manual and tool-assisted natural annotation propagation is readily used to classify molecular networks; however, currently no annotation propagation tools leverage consensus confidence strategies enabled by hierarchical chemical ontologies or enable the use of new in silico tools without significant modification. Herein we present ConCISE (Consensus Classifications of In Silico Elucidations) which is the first tool to fuse molecular networking, spectral library matching and in silico class predictions to establish accurate putative classifications for entire subnetworks. By limiting annotation propagation to only structural classes which are identical for the majority of ion features within a subnetwork, ConCISE maintains a true positive rate greater than 95% across all levels of the ChemOnt hierarchical ontology used by the ClassyFire annotation software (superclass, class, subclass). The ConCISE framework expanded the proportion of reliable and consistent ion feature annotation up to 76%, allowing for improved assessment of the chemo-diversity of dissolved organic matter pools from three complex marine metabolomics datasets comprising dominant reef primary producers, five species of the diatom genus Pseudo-nitzchia, and stromatolite sediment samples.
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Tandon, Sonia, Ines Gonzalez-Casanova, Albino Barraza-Villarreal, Isabelle Romieu, Hans Demmelmair, Juan Rivera Dommarco, Dean Jones, Berthold Koletzko, Aryeh Stein, and Usha Ramakrishnan. "The Effect of Maternal Fatty Acid Desaturase Single Nucleotide Polymorphism rs174602 and Prenatal Supplementation with Docosahexaenoic Acid on the Offspring Metabolome." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1276. http://dx.doi.org/10.1093/cdn/nzaa058_034.
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Abstract Objectives To assess if maternal fatty acid desaturase (FADS) single nucleotide polymorphism (SNP) rs174602 modifies the effect of prenatal DHA supplementation on the offspring metabolome at age 3 months. Methods Data were obtained from POSGRAD, a double-blind randomized controlled trial in Mexico in which 1094 women received 400 mg/day of algal DHA or a placebo (corn and soy oil) from mid-gestation until delivery. Genotyping was performed using maternal blood samples collected from women at baseline. Using liquid chromatography with high-resolution mass spectrometry, untargeted metabolomics was performed on plasma samples obtained from a random subsample of 112 offspring of POSGRAD participants at 3 months of age. Discriminatory metabolic features were selected via linear regression (P < 0.05); false discovery rate (FDR) was controlled for using the Benjamini-Hochberg method (q = 0.2). Analyses were adjusted for infant sex. Effect modification by FADS SNP rs174602 was assessed using two-way analysis of variance. Pathway enrichment analysis was performed with Mummichog (P < 0.05). Subgroup analyses were performed by rs174602, where the study population was grouped into carriers (TT, TC; n = 70) and non-carriers (CC; n = 42) of the minor allele. Results We identified 279 metabolic features that differed significantly between infants whose mothers received prenatal DHA (n = 59) versus placebo (n = 53); however, zero features remained significant after FDR correction. In the DHA * SNP rs174602 interaction analysis, following FDR correction, 346 differentially expressed features were identified. In the subgroup analysis, positively enriched fatty acid metabolism and decreased amino acid and vitamin B3 metabolism pathways were seen among carriers in the DHA group compared to placebo, whereas differentially enriched TCA cycle and omega-6 fatty acid metabolism pathways were observed by treatment group among non-carriers. Conclusions Maternal SNP rs174602 modified the effect of prenatal DHA supplementation on the infant metabolome at 3 months of age, particularly with regards to fatty acid metabolism. These findings provide additional support for the suggestion that differences in FADS genotype may explain inconsistent results observed across DHA supplementation trials. Funding Sources NIH, Nutricia Foundation, Laney Graduate School, and Conacyt, Mexico.
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Riwes, Mary Mansour, Alexander Schmidt, Thomas Braun, John M. Magenau, Attaphol Pawarode, Brian Parkin, Sarah Anand, et al. "Rational Modification of Intestinal Microbiome and Metabolites after Allogeneic Hematopoietic Stem Cell Transplantation with Resistant Starch: A Pilot Study." Blood 134, Supplement_1 (November 13, 2019): 3276. http://dx.doi.org/10.1182/blood-2019-131216.
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Background Graft versus host disease (GVHD) is the principal cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo HCT) and is associated with intestinal microbial dysbiosis. Administration of microbial metabolite butyrate or microbial cocktails of butyrogenic bacteria reduce the severity of acute GVHD in mice. Furthermore, this intestinal microbiome-metabolome axis can be manipulated via dietary intervention in healthy humans with supplementation by defined quantities of resistant potato starch (RPS), an indigestible carbohydrate that is metabolized by intestinal anaerobic commensal bacteria to produce butyrate1. Hereon we aimed to study the feasibility and tolerability of RPS in allo HCT recipients to test the hypothesis that the patients' intestinal microbiome and butyrate levels could be rationally modified by administration of defined quantities of RPS. Methods Between May 8, 2017 and September 30, 2018, we performed a single-center prospective, single arm, pilot study. We recruited adults who were undergoing human leukocyte antigen-matched, related-donor myeloablative allo HCT. Participants received RPS (Bob's Red Mill®) 20 g package orally, once/day for the first 3 days followed by twice daily, from day -7 through day 100 after allo HCT. Feasibility was defined as adherence to ≥ 70 % of scheduled doses in ≥ 60 % of patients. The primary objective was to test adherence to scheduled doses of RPS. Secondary endpoints included assessing tolerability of RPS and its ability to alter representation of RPS-degrading and butyrate-producing bacteria as well as butyrate levels in the intestines of allo HCT recipients. Stool samples were collected in the OMNIgene-Gut® (DNA Genotek) collection kit at baseline before intake of RPS, at time of nadir (day 7-10), engraftment (day 12-18), at day 100, and additional samples were also collected. Fecal microbiome was determined by 16S rRNA gene sequencing and butyrate by liquid chromatography. Results Ten subjects were enrolled. The median age was 57 years (range 52-62 years). All subjects received GVHD prophylaxis with tacrolimus and methotrexate as well as antibiotic prophylaxis with levaquin, and were treated for neutropenic fever with IV cefepime (90%) or IV vancomycin along with IV aztreonam (10%). One patient developed biopsy proven stage I acute GI GVHD with overall grade II acute GVHD (10%). Feasibility exceeded the preset goal of ≥ 70% adherence to scheduled dosages in ≥ 60 % of patients as 8 of the 10 patients (80%) received ≥ 70 % of scheduled doses (Figure 1A). No adverse effects/toxicities attributed to RPS were observed and longitudinal specimens were collected successfully. There was greater abundance of intestinal RPS-degraders such as Ruminococcus bromii, R. lactaris, R. gnavus, and Bifidobacterium spp and butyrate-producers such as Roseburia spp, Faecalibacterium prausnitzii, Eubacterium rectale, and Anaerostipes spp in the 10 patients receiving RPS compared to 15 historical controls after allo HCT (Figure 1B). Butyrate levels were significantly higher in the participants when they were on RPS as compared to pre RPS intake [median (interquartile range): 10.76 (7.62, 19.05) vs. 3.06 (2.32, 6.21) mmoL/kg, p<0.0001, respectively] (Figure 1C). Conclusions Our pilot study of dietary RPS demonstrated feasibility and safety and showed that RPS administration increased butyrate-producing bacteria with a concomitant increase in butyrate levels. A Phase II clinical trial built on these observations to test the efficacy of RPS in mitigating acute GVHD by altering the intestinal microbiome and its metabolites is underway (www.clinicaltrials.gov: NCT02763033). 1. Venkataraman A, Sieber JR, Schmidt AW, Waldron C, Theis KR, Schmidt TM. Variable responses of human microbiomes to dietary supplementation with resistant starch. Microbiome. 2016;4(1):33. Disclosures No relevant conflicts of interest to declare.
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Alipour, Shirin, Karolina Bilska, Ewelina Stolarska, Natalia Wojciechowska, and Ewa Marzena Kalemba. "Nicotinamide adenine dinucleotides are associated with distinct redox control of germination in Acer seeds with contrasting physiology." PLOS ONE 16, no. 1 (January 27, 2021): e0245635. http://dx.doi.org/10.1371/journal.pone.0245635.
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Seed germination is a complex process enabling plant reproduction. Germination was found to be regulated at the proteome, metabolome and hormonal levels as well as via discrete post-translational modification of proteins including phosphorylation and carbonylation. Redox balance is also involved but less studied. Acer seeds displaying orthodox and recalcitrant characteristics were investigated to determine the levels of redox couples of nicotinamide adenine dinucleotide (NAD) phosphate (NADP) and integrated with the levels of ascorbate and glutathione. NAD and NADP concentrations were higher in Norway maple seeds and exceptionally high at the germinated stage, being the most contrasting parameter between germinating Acer seeds. In contrast, NAD(P)H/NAD(P)+ ratios were higher in sycamore seeds, thus exhibiting higher reducing power. Despite distinct concentrations of ascorbate and glutathione, both seed types attained in embryonic axes and cotyledons had similar ratios of reduced/oxidized forms of ascorbate and half-cell reduction potential of glutathione at the germinated stage. Both species accomplished germination displaying different strategies to modulate redox status. Sycamore produced higher amounts of ascorbate and maintained pyridine nucleotides in reduced forms. Interestingly, lower NAD(P) concentrations limited the regeneration of ascorbate and glutathione but dynamically drove metabolic reactions, particularly in this species, and contributed to faster germination. We suggest that NAD(P) is an important player in regulating redox status during germination in a distinct manner in Norway maple and sycamore seeds.
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Li, Xiang, Yan Li, Minghui Zhao, Yanbo Hu, Fanjuan Meng, Xingshun Song, Mulualem Tigabu, et al. "Molecular and Metabolic Insights into Anthocyanin Biosynthesis for Leaf Color Change in Chokecherry (Padus virginiana)." International Journal of Molecular Sciences 22, no. 19 (October 2, 2021): 10697. http://dx.doi.org/10.3390/ijms221910697.
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Chokecherry (Padus virginiana L.) is an important landscaping tree with high ornamental value because of its colorful purplish-red leaves (PRL). The quantifications of anthocyanins and the mechanisms of leaf color change in this species remain unknown. The potential biosynthetic and regulatory mechanisms and the accumulation patterns of anthocyanins in P. virginiana that determine three leaf colors were investigated by combined analysis of the transcriptome and the metabolome. The difference of chlorophyll, carotenoid and anthocyanin content correlated with the formation of P. virginiana leaf color. Using enrichment and correlation network analysis, we found that anthocyanin accumulation differed in different colored leaves and that the accumulation of malvidin 3-O-glucoside (violet) and pelargonidin 3-O-glucoside (orange-red) significantly correlated with the leaf color change from green to purple-red. The flavonoid biosynthesis genes (PAL, CHS and CHI) and their transcriptional regulators (MYB, HD-Zip and bHLH) exhibited specific increased expression during the purple-red periods. Two genes encoding enzymes in the anthocyanin biosynthetic pathway, UDP glucose-flavonoid 3-O-glucosyl-transferase (UFGT) and anthocyanidin 3-O-glucosyltransferase (BZ1), seem to be critical for suppressing the formation of the aforesaid anthocyanins. In PRL, the expression of the genes encoding for UGFT and BZ1 enzymes was substantially higher than in leaves of other colors and may be related with the purple-red color change. These results may facilitate genetic modification or selection for further improvement in ornamental qualities of P. virginiana.
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Du, Lin, April L. Risinger, Carter A. Mitchell, Jianlan You, Blake W. Stamps, Ning Pan, Jarrod B. King, et al. "Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides." Proceedings of the National Academy of Sciences 114, no. 43 (October 10, 2017): E8957—E8966. http://dx.doi.org/10.1073/pnas.1707565114.
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Mass-spectrometry-based metabolomics and molecular phylogeny data were used to identify a metabolically prolific strain ofTolypocladiumthat was obtained from a deep-water Great Lakes sediment sample. An investigation of the isolate’s secondary metabolome resulted in the purification of a 22-mer peptaibol, gichigamin A (1). This peptidic natural product exhibited an amino acid sequence including several β-alanines that occurred in a repeatingααβmotif, causing the compound to adopt a unique right-handed 311helical structure. The unusual secondary structure of 1 was confirmed by spectroscopic approaches including solution NMR, electronic circular dichroism (ECD), and single-crystal X-ray diffraction analyses. Artificial and cell-based membrane permeability assays provided evidence that the unusual combination of structural features in gichigamins conferred on them an ability to penetrate the outer membranes of mammalian cells. Compound 1 exhibited potent in vitro cytotoxicity (GI500.55 ± 0.04 µM) and in vivo antitumor effects in a MIA PaCa-2 xenograft mouse model. While the primary mechanism of cytotoxicity for 1 was consistent with ion leakage, we found that it was also able to directly depolarize mitochondria. Semisynthetic modification of 1 provided several analogs, including aC-terminus-linked coumarin derivative (22) that exhibited appreciably increased potency (GI505.4 ± 0.1 nM), but lacked ion leakage capabilities associated with a majority of naturally occurring peptaibols such as alamethicin. Compound 22 was found to enter intact cells and induced cell death in a process that was preceded by mitochondrial depolarization.
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Kachroo, Priyadarshini, Joanne E. Sordillo, Sharon M. Lutz, Scott T. Weiss, Rachel S. Kelly, Michael J. McGeachie, Ann Chen Wu, and Jessica A. Lasky-Su. "Pharmaco-Metabolomics of Inhaled Corticosteroid Response in Individuals with Asthma." Journal of Personalized Medicine 11, no. 11 (November 4, 2021): 1148. http://dx.doi.org/10.3390/jpm11111148.
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Metabolomic indicators of asthma treatment responses have yet to be identified. In this study, we aimed to uncover plasma metabolomic profiles associated with asthma exacerbations while on inhaled corticosteroid (ICS) treatment. We determined whether these profiles change with age from adolescence to adulthood. We utilized data from 170 individuals with asthma on ICS from the Mass General Brigham Biobank to identify plasma metabolites associated with asthma exacerbations while on ICS and examined potential effect modification of metabolite-exacerbation associations by age. We used liquid chromatography–high-resolution mass spectrometry-based metabolomic profiling. Sex-stratified analyses were also performed for the significant associations. The age range of the participating individuals was 13–43 years with a mean age of 33.5 years. Of the 783 endogenous metabolites tested, eight demonstrated significant associations with exacerbation after correction for multiple comparisons and adjusting for potential confounders (Bonferroni p value < 6.2 × 10−4). Potential effect modification by sex was detected for fatty acid metabolites, with males showing a greater reduction in their metabolite levels with ICS exacerbation. Thirty-eight metabolites showed suggestive interactions with age on exacerbation (nominal p-value < 0.05). Our findings demonstrate that plasma metabolomic profiles differ for individuals who experience asthma exacerbations while on ICS. The differentiating metabolites may serve as biomarkers of ICS response and may highlight metabolic pathways underlying ICS response variability.
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Lau, Zhi Ch’ng, Barakatun Nisak Mohd Yusof, Faridah Abas, Norasyikin Abd Wahab, Wan Zul Haikal Wan Zukiman, and Amin Ismail. "Postprandial Metabolome Following a Low Glycaemic Index Meal-Challenge Test: A Narrative Review." Malaysian Journal of Medical Sciences 29, no. 5 (October 28, 2022): 5–16. http://dx.doi.org/10.21315/mjms2022.29.5.2.
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The Identifying the dynamic metabolome of the individual in response to a particular stimulus using a metabolomic approach is an emerging research area. Measuring the postprandial metabolite response utilising a meal-challenge test (MCT) provides information beyond the fasting state, which is especially important since human beings spend most of their time in the postprandial state. This is pertinent as an excessive rise in postprandial glycaemia is common in individuals with type 2 diabetes mellitus (T2DM), which puts them at a high risk of developing cardiovascular disease (CVD). While a low glycaemic index (GI) meal improves postprandial glycaemia and insulin levels in MCT studies among individuals with T2DM, its effect on metabolite changes in the postprandial state is unclear. This review summarises the perturbation in postprandial metabolites following a low GI meal in comparison to that following a usual or high GI meal and maps the metabolites in their metabolic pathways. We undertook a literature review using electronic databases, with the Medical Subject Headings (MeSH) terms, to retrieve relevant studies based on specific criteria. A total of seven related studies were documented. For the majority of metabolites studied, it was identified that metabolic regulation following an MCT extends beyond the glucose pathway. Altered metabolic pathways after the consumption of a low GI meal include: i) essential amino acid metabolism by altering the levels of plasma phenylalanine, tyrosine, lysine, leucine, isoleucine and valine; ii) glycolysis and tricarboxylic acid (TCA) metabolism by altering citrate and alanine, and iii) gut microbiota metabolism by altering betaine and acetate. The altered metabolites regulated the pancreatic insulin secretion and related to other dietary factors beyond GI modifications. These metabolomics data need to be interpreted cautiously because the metabolic changes analysed might not be due to the beneficial effects of a low GI meal. Validation of the putative metabolomic biomarkers following a dietary intervention MCT is suggested because researchers need to fully understand the kinetics and metabolism of individuals metabolite before reaching a solid conclusion. Further research characterising the metabotype based on habitual dietary patterns is warranted.
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Lee, Eunbi, Seo Yoon Choi, Jihye Park, Anders M. Lindroth, and Yoon Jung Park. "A Possible Role of Angiogenin in Intergenerational Transmission of Diet-Induced Metabolic Stress." Current Developments in Nutrition 5, Supplement_2 (June 2021): 508. http://dx.doi.org/10.1093/cdn/nzab041_023.
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Abstract Objectives Epigenetic is one of the possible mechanisms of transmit parental metabolic stress to offspring. tRNA modification or fragmentation is a promising candidate. We investigated the molecular mechanism of intergeneration transmission of diet-induced metabolic stress. Methods Male mice fed with control diet (CD) or high-fat diet (HFD) for 9 weeks. Body weight, amount of food intake and organ weights were measured. Metabolism-related proteins and gene expression were measured in testis and liver. tRNA methylation in sperm was investigated by bisulfite conversion-based sequencing. We analyzed publicly available omics data to profile changes of high-fat diet feeding. To explain mTOR activity linked to angiogenin (ANG) gene expression, we treated compound C (CC) or rapamycin (RP) in cell lines. Results We showed mTOR negative regulators were down regulated in HFD from analysis of transcriptome data from liver and sperm. Consistently, analysis on sperm metabolome data revealed that free amino acid level and tRNA amino-acyl biosynthesis pathway was up-regulated in HFD. Increased a level of phospho-mTOR protein was confirmed in testis, but not phospho-AMPK protein. Next, we measured tRNA modification-related gene expression levels in testis and liver. Expression of Dnmt2 and NSun2 related in tRNA methylation was elevated in HFD in testis and liver. However, expression of ANG related with tRNA cleavage was only increased in testis. In addition, methylation status in sperm tRNA-Asp-GTC was no different between diets. The data suggested that tRNA cleavage with ANG, rather than tRNA methylation process, was more likely involved in transmit transgenerational effect to offspring. Finally, we investigated changing mTOR activity could affect to Angiogenin gene expression level. Treatment with CC showed increased Angiogenin gene expression level, but RP treatment showed no change. Conclusions Our data suggested that diet-induced alteration of mTOR activity led to upregulation of Angiogenin expression in sperm, which might be a key of transgenerational mechanism. Funding Sources This study was supported by the National Research Foundation of Korea the Korean National Cancer Center. EL is grateful for financial support from Hyundai Motor Chung Mong-Koo Foundation and BK21 FOUR (Fostering Outstanding Universities for Research).
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Lima, Ana Rita, Joana Pinto, Filipa Amaro, Maria de Lourdes Bastos, Márcia Carvalho, and Paula Guedes de Pinho. "Advances and Perspectives in Prostate Cancer Biomarker Discovery in the Last 5 Years through Tissue and Urine Metabolomics." Metabolites 11, no. 3 (March 19, 2021): 181. http://dx.doi.org/10.3390/metabo11030181.
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Prostate cancer (PCa) is the second most diagnosed cancer in men worldwide. For its screening, serum prostate specific antigen (PSA) test has been largely performed over the past decade, despite its lack of accuracy and inability to distinguish indolent from aggressive disease. Metabolomics has been widely applied in cancer biomarker discovery due to the well-known metabolic reprogramming characteristic of cancer cells. Most of the metabolomic studies have reported alterations in urine of PCa patients due its noninvasive collection, but the analysis of prostate tissue metabolome is an ideal approach to disclose specific modifications in PCa development. This review aims to summarize and discuss the most recent findings from tissue and urine metabolomic studies applied to PCa biomarker discovery. Eighteen metabolites were found consistently altered in PCa tissue among different studies, including alanine, arginine, uracil, glutamate, fumarate, and citrate. Urine metabolomic studies also showed consistency in the dysregulation of 15 metabolites and, interestingly, alterations in the levels of valine, taurine, leucine and citrate were found in common between urine and tissue studies. These findings unveil that the impact of PCa development in human metabolome may offer a promising strategy to find novel biomarkers for PCa diagnosis.
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Shi, Lei, and Benjamin P. Tu. "Protein acetylation as a means to regulate protein function in tune with metabolic state." Biochemical Society Transactions 42, no. 4 (August 1, 2014): 1037–42. http://dx.doi.org/10.1042/bst20140135.
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Protein acetylation has emerged as a prominent post-translational modification that can occur on a wide variety of proteins. The metabolite acetyl-CoA is a key intermediate in energy metabolism that also serves as the acetyl group donor in protein acetylation modifications. Therefore such acetylation modifications might be coupled to the intracellular availability of acetyl-CoA. In the present article, we summarize recent evidence suggesting that the particular protein acetylation modifications enable the regulation of protein function in tune with acetyl-CoA availability and thus the metabolic state of the cell.
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Donnellan, Leigh, Clifford Young, Bradley S. Simpson, Mitchell Acland, Varinderpal S. Dhillon, Maurizio Costabile, Michael Fenech, Peter Hoffmann, and Permal Deo. "Proteomic Analysis of Methylglyoxal Modifications Reveals Susceptibility of Glycolytic Enzymes to Dicarbonyl Stress." International Journal of Molecular Sciences 23, no. 7 (March 28, 2022): 3689. http://dx.doi.org/10.3390/ijms23073689.
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Methylglyoxal (MGO) is a highly reactive cellular metabolite that glycates lysine and arginine residues to form post-translational modifications known as advanced glycation end products. Because of their low abundance and low stoichiometry, few studies have reported their occurrence and site-specific locations in proteins. Proteomic analysis of WIL2-NS B lymphoblastoid cells in the absence and presence of exogenous MGO was conducted to investigate the extent of MGO modifications. We found over 500 MGO modified proteins, revealing an over-representation of these modifications on many glycolytic enzymes, as well as ribosomal and spliceosome proteins. Moreover, MGO modifications were observed on the active site residues of glycolytic enzymes that could alter their activity. We similarly observed modification of glycolytic enzymes across several epithelial cell lines and peripheral blood lymphocytes, with modification of fructose bisphosphate aldolase being observed in all samples. These results indicate that glycolytic proteins could be particularly prone to the formation of MGO adducts.
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Wesseler, Katharina, Florian Kraft, and Thomas Eggermann. "Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management." International Journal of Molecular Sciences 20, no. 17 (August 28, 2019): 4219. http://dx.doi.org/10.3390/ijms20174219.
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Silver–Russell and Beckwith–Wiedemann syndromes (SRS, BWS) are rare congenital human disorders characterized by opposite growth disturbances. With the increasing knowledge on the molecular basis of SRS and BWS, it has become obvious that the disorders mirror opposite alterations at the same genomic loci in 11p15.5. In fact, these changes directly or indirectly affect the expression of IGF2 and CDKN1C and their associated pathways, and thereby, cause growth disturbances as key features of both diseases. The increase of knowledge has become possible with the development and implementation of new and comprehensive assays. Whereas, in the beginning molecular testing was restricted to single chromosomal loci, many tests now address numerous loci in the same run, and the diagnostic implementation of (epi)genome wide assays is only a question of time. These high-throughput approaches will be complemented by the analysis of other omic datasets (e.g., transcriptome, metabolome, proteome), and it can be expected that the integration of these data will massively improve the understanding of the pathobiology of imprinting disorders and their diagnostics. Especially long-read sequencing methods, e.g., nanopore sequencing, allowing direct detection of native DNA modification, will strongly contribute to a better understanding of genomic imprinting in the near future. Thereby, new genomic loci and types of pathogenic variants will be identified, resulting in more precise discrimination into different molecular subgroups. These subgroups serve as the basis for (epi)genotype–phenotype correlations, allowing a more directed prognosis, counseling, and therapy. By deciphering the pathophysiological consequences of SRS and BWS and their molecular disturbances, future therapies will be available targeting the basic cause of the disease and respective pathomechanisms and will complement conventional therapeutic strategies.
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Rosa, Maria Francesca, Paola Scano, Antonio Noto, Matteo Nioi, Roberta Sanna, Francesco Paribello, Fabio De-Giorgio, Emanuela Locci, and Ernesto d’Aloja. "Monitoring the Modifications of the Vitreous Humor Metabolite Profile after Death: An Animal Model." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/627201.
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We applied a metabolomic approach to monitor the modifications occurring in goat vitreous humor (VH) metabolite composition at different times (0, 6, 12, 18, and 24 hours) after death. The1H-NMR analysis of the VH samples was performed for the simultaneous determination of several metabolites (i.e., the metabolite profile) representative of the VHstatusat different times. Spectral data were analyzed by Principal Component Analysis (PCA) and by Orthogonal Projection to Latent Structures (OPLS) regression technique. PCA and OPLS suggested that different spectral regions were involved in time-related changes. The major time-related compositional changes, here detected, were the increase of lactate, hypoxanthine, alanine, total glutathione, choline/phosphocholine, creatine, andmyo-inositol and the decrease of glucose and 3-hydroxybutyrate. We attempted a speculative interpretation of the biological mechanisms underlying these changes. These results show that multivariate statistical approach, based on1H NMR metabolite profiling, is a powerful tool for detecting ongoing differences in VH composition and may be applied to investigate several physiological and pathological conditions.
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García-Chávez, J. Noé, Verónica R. Vásquez-Garzón, Mercedes G. López, Saúl Villa-Treviño, and Rafael Montiel. "Integration of chronological omics data reveals mitochondrial regulatory mechanisms during the development of hepatocellular carcinoma." PLOS ONE 16, no. 8 (August 12, 2021): e0256016. http://dx.doi.org/10.1371/journal.pone.0256016.
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Mitochondria participate in multiple functions in eukaryotic cells. Although disruption of mitochondrial function has been associated with energetic deregulation in cancer, the chronological changes in mitochondria during cancer development remain unclear. With the aim to assess the role of mitochondria throughout cancer development, we analyzed samples chronologically obtained from induced hepatocellular carcinoma (HCC) in rats. In our analyses, we integrated mitochondrial proteomic data, mitochondrial metabolomic data and nuclear genome transcriptomic data. We used pathway over-representation and weighted gene co-expression network analysis (WGCNA) to integrate expression profiles of genes, miRNAs, proteins and metabolite levels throughout HCC development. Our results show that mitochondria are dynamic organelles presenting specific modifications in different stages of HCC development. We also found that mitochondrial proteomic profiles from tissues adjacent to nodules or tumor are determined more by the stage of HCC development than by tissue type, and we evaluated two models to predict HCC stage of the samples using proteomic profiles. Finally, we propose an omics integration pipeline to massively identify molecular features that could be further evaluated as key regulators, biomarkers or therapeutic targets. As an example, we show a group of miRNAs and transcription factors as candidates, responsible for mitochondrial metabolic modification in HCC.
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Thompson, Sharon, Ziyang Pan, Caitlyn Edwards, Ginger Reeser, Naiman Khan, and Hannah Holscher. "The Impact of Fresh Hass Avocado on the Fecal Metabolome Among Adults with Overweight and Obesity: A Randomized, Controlled Trial." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1593. http://dx.doi.org/10.1093/cdn/nzaa062_050.
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Abstract Objectives Avocados are nutrient-rich fruits that have been recently linked to beneficial alterations to the gastrointestinal microbiota. However, previous research on shifts in the fecal metabolome with avocado intake has largely been conducted in in vitro or preclinical models and little is known about their metabolomic impact in human subjects. Methods Adult participants (n = 109) 25–45 years of age with BMI ≥ 25.0 kg/m2 were enrolled in an investigator-blinded, parallel arm, randomized, controlled trial. Participants consumed isocaloric meals with or without fresh Hass avocado once daily for 12-weeks and reported ≥ 80% meal consumption over the intervention period. Untargeted fecal metabolites were quantified in a subsample of participants (n = 48) using gas chromatography mass spectroscopy and were normalized by sample weight. Kruskal-Wallis tests and false discovery rate type I error correction were conducted and orthogonal partial least squares discriminant analysis (OPLS-DA) was used to predict treatment group by fecal metabolite concentrations (RStudio, version 3.6.2). Results A total of 292 metabolites were identified at intervention follow-up. Of these, three metabolites differed significantly between treatment groups. Fecal concentrations of lanosterol (P = 0.0004, q = 0.04) and the fatty alcohols hexadecanol (P = 0.001, q = 0.04) and octadecanol (P = 0.001, q = 0.04), were greater in the group consuming avocado as compared to control. Seventeen additional metabolites, including nine fecal lipids, two fat soluble vitamin derivatives, and three monosaccharides/disaccharides differed at P < 0.05 but did not meet the q < 0.05 threshold. Treatment group assignment was predicted correctly in 70% of cases (R2 = 72%, Q2 = 33%) using the trained OPLS-DA model. Conclusions Fresh Hass avocado intake increased fecal lipid and sterol concentrations among healthy adults with overweight and obesity, demonstrating diet-related modifications to the fecal metabolome. Funding Sources Support for this research was provided by the Hass Avocado Board, the USDA National Institute of Food and Agriculture, Hatch project 1009249, and the USDA National Institute of Food and Agriculture AFRI Predoctoral Fellowship, project 2018–07785.
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Kikushige, Yoshikane, Toshihiro Miyamoto, Takahiro Maeda, and Koichi Akashi. "Human Acute Leukemia Is Addicted to Branched-Chain Amino Acid Metabolism to Maintain Leukemia Stemness." Blood 134, Supplement_1 (November 13, 2019): 2516. http://dx.doi.org/10.1182/blood-2019-129372.
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Hematopoietic stem cells (HSCs) have capabilities to self-renew, maintaining an undifferentiated status, as well as to proliferate and mature into blood cells. Similarly, cancer stem cells (CSCs) self-renew and propagate to form cancer tissues. In human acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), CSC-like populations that can reconstitute human leukemia in immuno-deficient mice have been found, and are called leukemic stem cells or leukemia-initiating cells (LICs). In order to obtain "cure" by eradicating LICs, it should be critical to understand molecular machineries as to how LICs self-renew and expand to exert their cancer stemness properties. Recent studies revealed that several specific metabolism pathways actively contribute to the maintenance of stemness in several types of stem cells including ES/iPS cells. However, little is known about the LICs-specific metabolic activity. To clarify metabolic features of human LICs, we comprehensively analyzed 116 cellular metabolites of human CD34+ normal hematopoietic stem progenitor cells (HSPCs) (n=10), CD34+ AML (n=30) and CD34+ ALL cells (n=18). The metabolome analysis revealed that CD34+ AML and ALL cells commonly contain extremely high levels of branched chain amino acids (BCAA) as compared to normal CD34+ HSPCs. AML and ALL cells, but not normal HSCsexpressed BCAA-metabolism related enzymes as well as BCAA-transporters at high levels, and actively transport BCAAs into cytoplasm. Enzymatic inhibition of BCAA metabolism induced apoptosis in LICs but not in normal HSCs. Furthermore, deprivation of BCAA from daily diet in mice xeno-transplanted with human LICs caused significant inhibition of their reconstitution activities in vivo. Serial transplantation experiments revealed that hCD34+AML/ALL cells from BCAA-free-dieted mice exhibited extremely impaired reconstitution of human AML/ALL in secondary recipients fed with conventional diet, but those from mice with control diet developed AML/ALL with a high leukemia burden. To clarify how BCAA metabolism pathway regulates the leukemia-initiating activity, the global gene expression of primary CD34+AML /ALL cells and cell lines including THP-1(AML), Kasumi-9(B-ALL), Jurkat cells (T-ALL) were compared before and after pharmacological BCAA-metabolism inhibition and BCAA-deprivation. Gene set enrichment analysis (GSEA) revealed BCAA metabolism inhibition induced the expression of ES-related PRC2 target genes, which should be suppressed in ES cells via H3K27me3 histone modification, and ChIP-Seq analysis confirmed the significantly decreased H3K27me3 level around thetranscription start site ofPRC2 target genes both in CD34+ AML and ALL cells. Furthermore, BCAA metabolism inhibition or BCAA-deprivation resulted in the down regulation of EZH2 and EED, critical components of PRC2, at mRNA and protein level in human AML/ALL cells. Thus, BCAA-metabolism activity is a common metabolic machinery to maintain PRC2 function through potentiating EZH2 and EED expression in AML/ALL. We also found that human AML/ALL cells, but not normal HSPCs are dependent on BCAA metabolism for maintaining energy production through TCA cycle activity, leading to the adequate supply of alpha ketoglutarate (α-KG), an intermediate metabolite of TCA cycle. Since BCAT1, a catalytic enzyme for BCAA, requires α-KGas a substrate, the active energy production driven by BCAA metabolism contributes to prevent α-KG exhaustion to maintain the high BCAA catabolism activity in human AML/ALL. Consistent with persistent α-KG supply through enhanced BCAA metabolism, primary CD34+AML/ALL cells, which highly express BCAT1 did not exhibit decreased cellular α-KG level as compared to normal HSPCs in our metabolome analysis. Thus, the energy production and regulation of PRC2 function driven by enhanced BCAA metabolism constitute a vicious molecular cycle to maintain the leukemia stemness through the maintaining α-KG level in human acute leukemia. In summary, the current study demonstrates that human LICs are addicted to the activated BCAA metabolism to maintain their leukemia stemness irrespective of their lineage origin, and that the BCAA metabolic pathway is a generic therapeutic target in human acute leukemias. Disclosures Akashi: Sumitomo Dainippon, Kyowa Kirin: Consultancy; Celgene, Kyowa Kirin, Astellas, Shionogi, Asahi Kasei, Chugai, Bristol-Myers Squibb: Research Funding.
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Brehin, Camille, Damien Dubois, Odile Dicky, Sophie Breinig, Eric Oswald, and Matteo Serino. "Evolution of Gut Microbiome and Metabolome in Suspected Necrotizing Enterocolitis: A Case-Control Study." Journal of Clinical Medicine 9, no. 7 (July 17, 2020): 2278. http://dx.doi.org/10.3390/jcm9072278.
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Background: Necrotizing enterocolitis (NEC) is a devastating condition in preterm infants due to multiple factors, including gut microbiota dysbiosis. NEC development is poorly understood, due to the focus on severe NEC (NEC-2/3). Methods: We studied the gut microbiota, microbiome and metabolome of children with suspected NEC (NEC-1). Results: NEC-1 gut microbiota had a higher abundance of the Streptococcus (second 10-days of life) and Staphylococcus (third 10-days of life) species. NEC-1 children showed a microbiome evolution in the third 10-days of life being the most divergent, and were associated with a different metabolomic signature than in healthy children. The NEC-1 microbiome had increased glycosaminoglycan degradation and lysosome activity by the first 10-days of life, and was more sensitive to childbirth, low birth weight and gestational age, than healthy microbiome. NEC-1 fecal metabolome was more divergent by the second month of life. Conclusions: NEC-1 gut microbiota and microbiome modifications appear more distinguishable by the third 10-days of life, compared to healthy children. These data identify a precise window of time (i.e., the third 10-days of life) and provide microbial targets to fight/blunt NEC-1 progression.
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Thomas, Daniel, Yusuke Nakauchi, Manhong Wu, Ming Zheng, Subarna Sinha, David Dill, Gary Peltz, and Ravindra Majeti. "IDH1 Mutant AML Is Susceptible to Targeting De Novo Lipid Synthesis Independent of 2-Hydroxyglutarate and Has a Distinct Metabolic Profile from IDH2 Mutant AML." Blood 132, Supplement 1 (November 29, 2018): 440. http://dx.doi.org/10.1182/blood-2018-99-115040.
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Abstract Introduction: Mutations in IDH1 and IDH2 are recurrent in AML and several other cancers, resulting in the aberrant production of the onco-metabolite, R-2-hydroxyglutarate (2-HG), as well as an inability of mutant IDH1 to convert cytoplasmic alpha-ketoglutarate to isocitrate via reductive carboxylation. Currently, inhibitors of the neomorphic enzymes that abrogate the production of 2-HG, such as AG-120, are FDA-approved, but are not curative. Using a novel computational method (MiSL), we identified acetyl CoA carboxylase (ACACA) as a potential druggable target specifically in IDH1-mutated AML. ACACA regulates the de novo synthesis of lipid precursors by converting acetyl CoA to malonyl CoA building blocks. We hypothesize that IDH1 mutant AML exhibits a defect in reductive carboxylation and de novo fatty acid synthesis conferring preferential susceptibility to ACACA inhibition. Here, we investigate this hypothesis by comprehensively quantifying the metabolic landscape, including non-polar lipid metabolites, conferred by IDH1 R132H mutation compared to IDH2 mutation in isogenic cell lines and primary samples. Moreover, we investigate the in vitro and in vivo effects of targeting de novo lipid synthesis on IDH1 and IDH2 mutant AML. Methods: Comprehensive metabolomic profiling of primary FACS-purified AML blasts was performed using an in-house protocol optimised for extraction of non-polar lipid metabolites from less than 1 million primary cells. CD33+CD45+ leukemic blasts were profiled from 17 patient samples with IDH1 mutation (n=6), IDH2 mutation (n=5), or IDH1/2 wildtype (n=6) after culturing in serum-free media. 6 independent cord-blood CD34+ cells were profiled as a negative control. For validation of IDH1-specific effects, isogenic THP-1 cells transduced with doxycycline-inducible wildtype and R132H mutant IDH1 or R140Q mutant and wildtype IDH2 were profiled. Molecules were identified according to their molecular weight and retention time using Mass Hunter software (Agilent) and the Human Metabolome Database. For in vivo studies, primary AML samples were engrafted in NSG mice that were subjected to dietary modification with low lipid diet and/or treatment with selective inhibitors of ACACA and mutant IDH1. Results: Principle component analysis of metabolite abundance of 1400 unique compounds revealed striking differences between IDH1 and IDH2 mutant AML. Both IDH1 and IDH2 mutant samples produced high levels of 2-HG compared to wildtype AML and CD34+ cells (50 fold increase, P=4.5E-05). A major perturbation in multiple phospholipid fatty acid species was conferred by IDH1 R132H, but not by IDH2 mutation. The same pattern was observed in cell lines with 49 lipid species decreased in the presence of mutant IDH1 compared to only 2 perturbed with mutant IDH2. Direct comparison of IDH1 vs IDH2 mutant primary samples revealed 54 lipid metabolites significantly down-regulated in IDH1 mutant blasts (adjusted P value <0.05). To investigate the effects of targeting de novo lipid synthesis on IDH1 mutant AML in vivo, we engrafted primary IDH1 mutant AML and tested growth with lipid-free compared to normal diet. At 12 weeks, IDH1 mutant AML showed reduced growth in the bone marrow of mice on lipid-free diet (SU389 11% vs 40%, n=10 mice, P=0.03 and SU372 21% vs 34%, n=10, P=0.02 Mann-Whitney U). IDH1 mutant AML was susceptible to ACACA inhibition with shRNA, CRISPR targeting, or selective nanomolar inhibitors. Knockdown of ACACA with independent shRNAs caused a defect in cell growth in the presence of IDH1 R132H, but not in its absence or with scrambled shRNA (p=0.009, shRNA #1 vs. scrambled; p=0.01, shRNA #2 vs. scrambled) in vitro and in xenografts. Primary IDH1 R132 mutated AML blasts were selectively sensitive to ACACA inhibitor treatment compared to IDH1 wildtype normal karyotype blasts (IC50 0.6 uM vs 6 uM, p=0.009). Notably, IDH1-mutant AML blasts pre-treated with 10mM AG-120 remained susceptible to ACACA inhibition, identifying a 2-HG independent vulnerability. Similar findings were observed in a solid tumor IDH1 mutant sarcoma model in vivo. Conclusion : These results support our hypothesis that IDH1 mutant AML exhibits a defect in de novo fatty acid synthesis conferring preferential susceptibility to ACACA inhibition, and suggests that pharmacologic inhibitors of ACACA may complement IDH1 mutation-specific inhibitors in the clinic. Disclosures No relevant conflicts of interest to declare.
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Boullaud, Luc, Hélène Blasco, Eliott Caillaud, Patrick Emond, and David Bakhos. "Immediate-Early Modifications to the Metabolomic Profile of the Perilymph Following an Acoustic Trauma in a Sheep Model." Journal of Clinical Medicine 11, no. 16 (August 10, 2022): 4668. http://dx.doi.org/10.3390/jcm11164668.
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The pathophysiological mechanisms of noise-induced hearing loss remain unknown. Identifying biomarkers of noise-induced hearing loss may increase the understanding of pathophysiological mechanisms of deafness, allow for a more precise diagnosis, and inform personalized treatment. Emerging techniques such as metabolomics can help to identify these biomarkers. The objective of the present study was to investigate immediate-early changes in the perilymph metabolome following acoustic trauma. Metabolomic analysis was performed using liquid chromatography coupled to mass spectrophotometry to analyze metabolic changes in perilymph associated with noise-induced hearing loss. Sheep (n = 6) were exposed to a noise designed to induce substantial hearing loss. Perilymph was collected before and after acoustic trauma. Data were analyzed using univariate analysis and a supervised multivariate analysis based on partial least squares discriminant analysis. A metabolomic analysis showed an abundance of 213 metabolites. Four metabolites were significantly changed following acoustic trauma (Urocanate (p = 0.004, FC = 0.48), S-(5’-Adenosyl)-L-Homocysteine (p = 0.06, FC = 2.32), Trigonelline (p = 0.06, FC = 0.46) and N-Acetyl-L-Leucine (p = 0.09, FC = 2.02)). The approach allowed for the identification of new metabolites and metabolic pathways involved with acoustic trauma that were associated with auditory impairment (nerve damage, mechanical destruction, and oxidative stress). The results suggest that metabolomics provides a powerful approach to characterize inner ear metabolites which may lead to identification of new therapies and therapeutic targets.
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Harjivan, Shrika G., Catarina Charneira, Inês L. Martins, Sofia A. Pereira, Guadalupe Espadas, Eduard Sabidó, Frederick A. Beland, M. Matilde Marques, and Alexandra M. M. Antunes. "Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine." Molecules 26, no. 5 (March 3, 2021): 1349. http://dx.doi.org/10.3390/molecules26051349.
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Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor widely used in combined antiretroviral therapy and to prevent mother-to-child transmission of the human immunodeficiency virus type 1, is associated with several adverse side effects. Using 12-mesyloxy-nevirapine, a model electrophile of the reactive metabolites derived from the NVP Phase I metabolite, 12-hydroxy-NVP, we demonstrate that the nucleophilic core and C-terminal residues of histones are targets for covalent adduct formation. We identified multiple NVP-modification sites at lysine (e.g., H2BK47, H4K32), histidine (e.g., H2BH110, H4H76), and serine (e.g., H2BS33) residues of the four histones using a mass spectrometry-based bottom-up proteomic analysis. In particular, H2BK47, H2BH110, H2AH83, and H4H76 were found to be potential hot spots for NVP incorporation. Notably, a remarkable selectivity to the imidazole ring of histidine was observed, with modification by NVP detected in three out of the 11 histidine residues of histones. This suggests that NVP-modified histidine residues of histones are prospective markers of the drug’s bioactivation and/or toxicity. Importantly, NVP-derived modifications were identified at sites known to determine chromatin structure (e.g., H4H76) or that can undergo multiple types of post-translational modifications (e.g., H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.