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1
Le Grazie, Giulia, Nicola Marrano, Annalisa Natalicchio, and Francesco Giorgino. "L’irisina: un ormone con benefici multiorgano." L'Endocrinologo 23, no. 2 (March 3, 2022): 189–92. http://dx.doi.org/10.1007/s40619-022-01046-z.
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SommarioL’irisina è una miochina secreta dal muscolo scheletrico in seguito ad attività fisica, in grado di regolare l’omeostasi glucidica ed energetica, agendo su numerosi tessuti e intervenendo su diversi pathways metabolici. Un’alterazione dei livelli sierici di irisina potrebbe promuovere l’insorgenza di patologie metaboliche, tra cui il diabete mellito di tipo 2. Numerosi studi su modelli animali di diabete e/o obesità hanno dimostrato che la somministrazione di irisina esogena è in grado di esercitare effetti antidiabetici e antiobesità.
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Šindelář, L., and M. Šindelářová. "Regulation of metabolic pathways PVY-RNA biosynthesis in tobacco: glycolytic pathway." Plant Protection Science 40, No. 3 (March 7, 2010): 101–6. http://dx.doi.org/10.17221/991-pps.
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Tobacco plants infected with potato virus <I>Y</I> were studied at the stage of acute infection. Key enzymes of the glycolytic pathway, their regulation and the content of involved intermediates were monitored. The activities of the key enzymes of the glycolytic pathway (6-phosphofructokinase, fructosebisphosphatase and pyruvate kinase), determined in both crude homogenates and after partial purification, did not differ from the activities found in healthy control tissues. In virus-infected tissues the content of ATP was higher than in the healthy control. The levels of ADP and AMP decreased soon after inoculation, but increased at the end of the experimental period. The content of inorganic phosphate was not influenced by infection. No difference in adenylate energy charge was observed between healthy and virus-infected tissues. This implies that the rates of the glycolytic pathway <I>in vivo </I>are not altered during the acute stage of infection.
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Giri, Shailendra, Poisson Laila, Hamid Suhail, Jaspreet Singh, Mandar Deshpande, Indrani Datta, Aleksandar Denic, Moses Rodriguez, Ramandeep Rattan, and Ashutosh Mangalam. "Nontargeted urinary metabolite profiling of a chronic mouse model of multiple sclerosis (THER3P.884)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 136.10. http://dx.doi.org/10.4049/jimmunol.192.supp.136.10.
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Abstract In search of metabolites signature as biomarkers during EAE disease, we profiled urine from B6 EAE using global untargeted metabolomics. Evaluation of metabolomic profiling of urine from EAE and healthy B6 group by using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry, we found that 132 out of 322 (41%) metabolites were differentially altered (P<0.05) indicating robust alteration in the urine metabolomics profile during disease. Among the perturbed metabolites, 11 were up regulated in EAE urine whereas 121 were down regulated. We conducted pathway analysis of the biochemical pathways of the KEGG and considered both concerted changes in metabolite intensity within the pathway (GlobalTest) and alterations of high impact, and found that a number of pathways were significantly altered including glyoxylate and dicarboxylate, phenylanine metabolism, porphyrin & chlorophyll metabolism, primary bile acid biosynthesis, cysteine & methione metabolism, taurine and hypotaurine metabolism, glycine, serine & threonine metabolism, and beta-alanine metabolism. Alteration in these pathways during EAE disease suggesting that perturbation of certain central metabolites could have impact on multiple metabolic pathways. While some of these metabolite changes could easily be developed as biomarkers, the key to translating metabolomics into therapeutics would require figuring out the central altered metabolic pathway(s), once studied in detail.
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Haj, Amelia K., Haytham Hasan, and Thomas J. Raife. "Heritability of Protein and Metabolite Biomarkers Associated with COVID-19 Severity: A Metabolomics and Proteomics Analysis." Biomolecules 13, no. 1 (December 27, 2022): 46. http://dx.doi.org/10.3390/biom13010046.
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Objectives: Prior studies have characterized protein and metabolite changes associated with SARS-CoV-2 infection; we hypothesized that these biomarkers may be part of heritable metabolic pathways in erythrocytes. Methods: Using a twin study of erythrocyte protein and metabolite levels, we describe the heritability of, and correlations among, previously identified biomarkers that correlate with COVID-19 severity. We used gene ontology and pathway enrichment analysis tools to identify pathways and biological processes enriched among these biomarkers. Results: Many COVID-19 biomarkers are highly heritable in erythrocytes. Among heritable metabolites downregulated in COVID-19, metabolites involved in amino acid metabolism and biosynthesis are enriched. Specific amino acid metabolism pathways (valine, leucine, and isoleucine biosynthesis; glycine, serine, and threonine metabolism; and arginine biosynthesis) are heritable in erythrocytes. Conclusions: Metabolic pathways downregulated in COVID-19, particularly amino acid biosynthesis and metabolism pathways, are heritable in erythrocytes. This finding suggests that a component of the variation in COVID-19 severity may be the result of phenotypic variation in heritable metabolic pathways; future studies will be necessary to determine whether individual variation in amino acid metabolism pathways correlates with heritable outcomes of COVID-19.
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Midford, Peter E., Mario Latendresse, Paul E. O’Maille, and Peter D. Karp. "Using Pathway Covering to Explore Connections among Metabolites." Metabolites 9, no. 5 (May 2, 2019): 88. http://dx.doi.org/10.3390/metabo9050088.
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Interpreting changes in metabolite abundance in response to experimental treatments or disease states remains a major challenge in metabolomics. Pathway Covering is a new algorithm that takes a list of metabolites (compounds) and determines a minimum-cost set of metabolic pathways in an organism that includes (covers) all the metabolites in the list. We used five functions for assigning costs to pathways, including assigning a constant for all pathways, which yields a solution with the smallest pathway count; two methods that penalize large pathways; one that prefers pathways based on the pathway’s assigned function, and one that loosely corresponds to metabolic flux. The pathway covering set computed by the algorithm can be displayed as a multi-pathway diagram (“pathway collage”) that highlights the covered metabolites. We investigated the pathway covering algorithm by using several datasets from the Metabolomics Workbench. The algorithm is best applied to a list of metabolites with significant statistics and fold-changes with a specified direction of change for each metabolite. The pathway covering algorithm is now available within the Pathway Tools software and BioCyc website.
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Brister, Danielle, Brianna A. Werner, Geoffrey Gideon, Patrick J. McCarty, Alison Lane, Brian T. Burrows, Sallie McLees, et al. "Central Nervous System Metabolism in Autism, Epilepsy and Developmental Delays: A Cerebrospinal Fluid Analysis." Metabolites 12, no. 5 (April 20, 2022): 371. http://dx.doi.org/10.3390/metabo12050371.
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Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without known DD/ASD (n = 34) was analyzed using large-scale targeted mass spectrometry. Eighteen also had epilepsy (EPI). Metabolites significantly related to ASD, DD and EPI were identified by linear models and entered into metabolite–metabolite network pathway analysis. Common disrupted pathways were analyzed for each group of interest. Central metabolites most involved in metabolic pathways were L-cysteine, adenine, and dodecanoic acid for ASD; nicotinamide adenine dinucleotide phosphate, L-aspartic acid, and glycine for EPI; and adenosine triphosphate, L-glutamine, ornithine, L-arginine, L-lysine, citrulline, and L-homoserine for DD. Amino acid and energy metabolism pathways were most disrupted in all disorders, but the source of the disruption was different for each disorder. Disruption in vitamin and one-carbon metabolism was associated with DD and EPI, lipid pathway disruption was associated with EPI and redox metabolism disruption was related to ASD. Two microbiome metabolites were also detected in the CSF: shikimic and cis-cis-muconic acid. Overall, this study provides increased insight into unique metabolic disruptions in distinct but overlapping neurodevelopmental disorders.
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Ahmed, Eman A., Marwa O. El-Derany, Ali Mostafa Anwar, Essa M. Saied, and Sameh Magdeldin. "Metabolomics and Lipidomics Screening Reveal Reprogrammed Signaling Pathways toward Cancer Development in Non-Alcoholic Steatohepatitis." International Journal of Molecular Sciences 24, no. 1 (December 22, 2022): 210. http://dx.doi.org/10.3390/ijms24010210.
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With the rising incidence of hepatocellular carcinoma (HCC) from non-alcoholic steatohepatitis (NASH), identifying new metabolic readouts that function in metabolic pathway perpetuation is still a demand. The study aimed to compare the metabolic signature between NASH and NASH-HCC patients to explore novel reprogrammed metabolic pathways that might modulate cancer progression in NASH patients. NASH and NASH-HCC patients were recruited and screened for metabolomics, and isotope-labeled lipidomics were targeted and profiled using the EXION-LCTM system equipped with a Triple-TOFTM 5600+ system. Results demonstrated significantly (p ≤ 0.05) higher levels of triacylglycerol, AFP, AST, and cancer antigen 19-9 in NASH-HCC than in NASH patients, while prothrombin time, platelet count, and total leukocyte count were decreased significantly (p ≤ 0.05). Serum metabolic profiling showed a panel of twenty metabolites with 10% FDR and p ≤ 0.05 in both targeted and non-targeted analysis that could segregate NASH-HCC from NASH patients. Pathway analysis revealed that the metabolites are implicated in the down-regulation of necroptosis, amino acid metabolism, and regulation of lipid metabolism by PPAR-α, biogenic amine synthesis, fatty acid metabolism, and the mTOR signaling pathway. Cholesterol metabolism, DNA repair, methylation pathway, bile acid, and salts metabolism were significantly upregulated in NASH-HCC compared to the NASH group. Metabolite–protein interactions network analysis clarified a set of well-known protein encoding genes that play crucial roles in cancer, including PEMT, IL4I1, BAAT, TAT, CDKAL1, NNMT, PNP, NOS1, and AHCYL. Taken together, reliable metabolite fingerprints are presented and illustrated in a detailed map for the most predominant reprogrammed metabolic pathways that target HCC development from NASH.
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Lin, Xiangping, Xinyu Liu, Mohamed N. Triba, Nadia Bouchemal, Zhicheng Liu, Douglas I. Walker, Tony Palama, et al. "Plasma Metabolomic and Lipidomic Profiling of Metabolic Dysfunction-Associated Fatty Liver Disease in Humans Using an Untargeted Multiplatform Approach." Metabolites 12, no. 11 (November 8, 2022): 1081. http://dx.doi.org/10.3390/metabo12111081.
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Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disorder that is implicated in dysregulations in multiple biological pathways, orchestrated by interactions between genetic predisposition, metabolic syndromes and environmental factors. The limited knowledge of its pathogenesis is one of the bottlenecks in the development of prognostic and therapeutic options for MAFLD. Moreover, the extent to which metabolic pathways are altered due to ongoing hepatic steatosis, inflammation and fibrosis and subsequent liver damage remains unclear. To uncover potential MAFLD pathogenesis in humans, we employed an untargeted nuclear magnetic resonance (NMR) spectroscopy- and high-resolution mass spectrometry (HRMS)-based multiplatform approach combined with a computational multiblock omics framework to characterize the plasma metabolomes and lipidomes of obese patients without (n = 19) or with liver biopsy confirmed MAFLD (n = 63). Metabolite features associated with MAFLD were identified using a metabolome-wide association study pipeline that tested for the relationships between feature responses and MAFLD. A metabolic pathway enrichment analysis revealed 16 pathways associated with MAFLD and highlighted pathway changes, including amino acid metabolism, bile acid metabolism, carnitine shuttle, fatty acid metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and steroid metabolism. These results suggested that there were alterations in energy metabolism, specifically amino acid and lipid metabolism, and pointed to the pathways being implicated in alerted liver function, mitochondrial dysfunctions and immune system disorders, which have previously been linked to MAFLD in human and animal studies. Together, this study revealed specific metabolic alterations associated with MAFLD and supported the idea that MAFLD is fundamentally a metabolism-related disorder, thereby providing new perspectives for diagnostic and therapeutic strategies.
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Thurley, Kevin, Christopher Herbst, Felix Wesener, Barbara Koller, Thomas Wallach, Bert Maier, Achim Kramer, and Pål O. Westermark. "Principles for circadian orchestration of metabolic pathways." Proceedings of the National Academy of Sciences 114, no. 7 (February 3, 2017): 1572–77. http://dx.doi.org/10.1073/pnas.1613103114.
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Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome- and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo.
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VILLAS-BÔAS, Silas G., Joel F. MOXLEY, Mats ÅKESSON, Gregory STEPHANOPOULOS, and Jens NIELSEN. "High-throughput metabolic state analysis: the missing link in integrated functional genomics of yeasts." Biochemical Journal 388, no. 2 (May 24, 2005): 669–77. http://dx.doi.org/10.1042/bj20041162.
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The lack of comparable metabolic state assays severely limits understanding the metabolic changes caused by genetic or environmental perturbations. The present study reports the application of a novel derivatization method for metabolome analysis of yeast, coupled to data-mining software that achieve comparable throughput, effort and cost compared with DNA arrays. Our sample workup method enables simultaneous metabolite measurements throughout central carbon metabolism and amino acid biosynthesis, using a standard GC-MS platform that was optimized for this purpose. As an implementation proof-of-concept, we assayed metabolite levels in two yeast strains and two different environmental conditions in the context of metabolic pathway reconstruction. We demonstrate that these differential metabolite level data distinguish among sample types, such as typical metabolic fingerprinting or footprinting. More importantly, we demonstrate that this differential metabolite level data provides insight into specific metabolic pathways and lays the groundwork for integrated transcription–metabolism studies of yeasts.
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Shin, Minhye, and Soo Rin Kim. "Metabolic Changes Induced by Deletion of Transcriptional Regulator GCR2 in Xylose-Fermenting Saccharomyces cerevisiae." Microorganisms 8, no. 10 (September 29, 2020): 1499. http://dx.doi.org/10.3390/microorganisms8101499.
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Glucose repression has been extensively studied in Saccharomyces cerevisiae, including the regulatory systems responsible for efficient catabolism of glucose, the preferred carbon source. However, how these regulatory systems would alter central metabolism if new foreign pathways are introduced is unknown, and the regulatory networks between glycolysis and the pentose phosphate pathway, the two major pathways in central carbon metabolism, have not been systematically investigated. Here we disrupted gcr2, a key transcriptional regulator, in S. cerevisiae strain SR7 engineered to heterologously express the xylose-assimilating pathway, activating genes involved in glycolysis, and evaluated the global metabolic changes. gcr2 deletion reduced cellular growth in glucose but significantly increased growth when xylose was the sole carbon source. Global metabolite profiling revealed differential regulation of yeast metabolism in SR7-gcr2Δ, especially carbohydrate and nucleotide metabolism, depending on the carbon source. In glucose, the SR7-gcr2Δ mutant showed overall decreased abundance of metabolites, such as pyruvate and sedoheptulose-7-phosphate, associated with central carbon metabolism including glycolysis and the pentose phosphate pathway. However, SR7-gcr2Δ showed an increase in metabolites abundance (ribulose-5-phosphate, sedoheptulose-7-phosphate, and erythrose-4-phosphate) notably from the pentose phosphate pathway, as well as alteration in global metabolism when compared to SR7. These results provide insights into how the regulatory system GCR2 coordinates the transcription of glycolytic genes and associated metabolic pathways.
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Mao, Xin, Xiaozhen Zhou, Jun He, Gongzhen Liu, Huihui Liu, Han Zhao, Pengjie Luo, Yongning Wu, and Yanshen Li. "Metabolism Profile of Mequindox in Sea Cucumbers In Vivo Using LC-HRMS." Antibiotics 11, no. 11 (November 11, 2022): 1599. http://dx.doi.org/10.3390/antibiotics11111599.
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In this work, the metabolism behavior of mequindox (MEQ) in sea cucumber in vivo was investigated using LC-HRMS. In total, nine metabolites were detected and identified as well as the precursor in sea cucumber tissues. The metabolic pathways of MEQ in sea cucumber mainly include hydrogenation reduction, deoxidation, carboxylation, deacetylation, and combinations thereof. The most predominant metabolites of MEQ in sea cucumber are 2-iso-BDMEQ and 2-iso-1-DMEQ, with deoxidation and carbonyl reduction as major metabolic pathways. In particular, this work first reported 3-methyl-2-quinoxalinecarboxylic acid (MQCA) as a metabolite of MEQ, and carboxylation is a major metabolic pathway of MEQ in sea cucumber. This work revealed that the metabolism of MEQ in marine animals is different from that in land animals. The metabolism results in this work could facilitate the accurate risk assessment of MEQ in sea cucumber and related marine foods.
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Mitchell, Sabrina L., Chunyu Ma, William K. Scott, Anita Agarwal, Margaret A. Pericak-Vance, Jonathan L. Haines, Dean P. Jones, Karan Uppal, and Milam A. Brantley. "Plasma Metabolomics of Intermediate and Neovascular Age-Related Macular Degeneration Patients." Cells 10, no. 11 (November 12, 2021): 3141. http://dx.doi.org/10.3390/cells10113141.
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To characterize metabolites and metabolic pathways altered in intermediate and neovascular age-related macular degeneration (IAMD and NVAMD), high resolution untargeted metabolomics was performed via liquid chromatography-mass spectrometry on plasma samples obtained from 91 IAMD patients, 100 NVAMD patients, and 195 controls. Plasma metabolite levels were compared between: AMD patients and controls, IAMD patients and controls, and NVAMD and IAMD patients. Partial least-squares discriminant analysis and linear regression were used to identify discriminatory metabolites. Pathway analysis was performed to determine metabolic pathways altered in AMD. Among the comparisons, we identified 435 unique discriminatory metabolic features. Using computational methods and tandem mass spectrometry, we identified 11 metabolic features whose molecular identities had been previously verified and confirmed the molecular identities of three additional discriminatory features. Included among the discriminatory metabolites were acylcarnitines, phospholipids, amino acids, and steroid metabolites. Pathway analysis revealed that lipid, amino acid, and vitamin metabolism pathways were altered in NVAMD, IAMD, or AMD in general, including the carnitine shuttle pathway which was significantly altered in all comparisons. Finally, few discriminatory features were identified between IAMD patients and controls, suggesting that plasma metabolic profiles of IAMD patients are more similar to controls than to NVAMD patients.
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Bach, Maggie, Donna Leippe, Natasha Karassina, Michael Valley, James Cali, and Jolanta Vidugiriene. "Abstract 2338: Bioluminescent assays for measuringthemetabolic state of cancer and immune cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2338. http://dx.doi.org/10.1158/1538-7445.am2022-2338.
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Abstract In the tumor microenvironment, cancer and immune cells compete for limited nutrients and both must undergo complex metabolic changes to support their function. To better understand the underlying mechanisms of tumor growth, metastasis and adaptation, a comprehensive analysis of metabolic pathways is needed. Success of such studies requires rapid and reliable approaches for monitoring key metabolic pathways, including glycolysis, the pentose phosphate pathway, fatty acid metabolism, amino acid metabolism and TCA cycle. Due to its inherent robustness, sensitivity and broad dynamic range, bioluminescence detection provides an attractive opportunity for developing such assays. Here, we implement a panel of bioluminescent metabolite assays (glucose, lactate, glutamine/glutamate, triglyceride/glycerol, cholesterol esters/cholesterol) to investigate the metabolic state of immune and cancer cells. We demonstrate flexibility of the assays in various volumes (96-, 384- well plates), sample types (2D, 3D cultures), automation platforms, and workflows, including detecting multiple metabolites in the same sample and monitoring metabolite changes over time by assaying multiple samples. We validate the performance of the assays by using metabolic pathway-specific inhibitors and demonstrating the utility of the assays as early indicators of cytotoxic T-cell activation. Finally, since metabolism is a dynamic process guided by fuel availability, we show the importance of medium composition when designing studies and suggest guidance for future work. In conclusion, understanding the crosstalk between tumor cells and their microenvironment is required for next-generation drug development. Bioluminescent metabolite assays provide the sensitivity, throughput and robustness required for rapid evaluation of changes in major metabolic pathways and are well suited for novel inhibitor screening and drug development. Citation Format: Maggie Bach, Donna Leippe, Natasha Karassina, Michael Valley, James Cali, Jolanta Vidugiriene. Bioluminescent assays for measuringthemetabolic state of cancer and immune cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2338.
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Sorokin, Anatoly, Vsevolod Shurkhay, Stanislav Pekov, Evgeny Zhvansky, Daniil Ivanov, Eugene E. Kulikov, Igor Popov, Alexander Potapov, and Eugene Nikolaev. "Untangling the Metabolic Reprogramming in Brain Cancer: Discovering Key Molecular Players Using Mass Spectrometry." Current Topics in Medicinal Chemistry 19, no. 17 (September 19, 2019): 1521–34. http://dx.doi.org/10.2174/1568026619666190729154543.
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Cells metabolism alteration is the new hallmark of cancer, as well as an important method for carcinogenesis investigation. It is well known that the malignant cells switch to aerobic glycolysis pathway occurring also in healthy proliferating cells. Recently, it was shown that in malignant cells de novo synthesis of the intracellular fatty acid replaces dietary fatty acids which change the lipid composition of cancer cells noticeably. These alterations in energy metabolism and structural lipid production explain the high proliferation rate of malignant tissues. However, metabolic reprogramming affects not only lipid metabolism but many of the metabolic pathways in the cell. 2-hydroxyglutarate was considered as cancer cell biomarker and its presence is associated with oxidative stress influencing the mitochondria functions. Among the variety of metabolite detection methods, mass spectrometry stands out as the most effective method for simultaneous identification and quantification of the metabolites. As the metabolic reprogramming is tightly connected with epigenetics and signaling modifications, the evaluation of metabolite alterations in cells is a promising approach to investigate the carcinogenesis which is necessary for improving current diagnostic capabilities and therapeutic capabilities. In this paper, we overview recent studies on metabolic alteration and oncometabolites, especially concerning brain cancer and mass spectrometry approaches which are now in use for the investigation of the metabolic pathway.
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Song, Yoseb, Jin Soo Lee, Jongoh Shin, Gyu Min Lee, Sangrak Jin, Seulgi Kang, Jung-Kul Lee, et al. "Functional cooperation of the glycine synthase-reductase and Wood–Ljungdahl pathways for autotrophic growth of Clostridium drakei." Proceedings of the National Academy of Sciences 117, no. 13 (March 13, 2020): 7516–23. http://dx.doi.org/10.1073/pnas.1912289117.
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Among CO2-fixing metabolic pathways in nature, the linear Wood–Ljungdahl pathway (WLP) in phylogenetically diverse acetate-forming acetogens comprises the most energetically efficient pathway, requires the least number of reactions, and converts CO2 to formate and then into acetyl-CoA. Despite two genes encoding glycine synthase being well-conserved in WLP gene clusters, the functional role of glycine synthase under autotrophic growth conditions has remained uncertain. Here, using the reconstructed genome-scale metabolic model iSL771 based on the completed genome sequence, transcriptomics, 13C isotope-based metabolite-tracing experiments, biochemical assays, and heterologous expression of the pathway in another acetogen, we discovered that the WLP and the glycine synthase pathway are functionally interconnected to fix CO2, subsequently converting CO2 into acetyl-CoA, acetyl-phosphate, and serine. Moreover, the functional cooperation of the pathways enhances CO2 consumption and cellular growth rates via bypassing reducing power required reactions for cellular metabolism during autotrophic growth of acetogens.
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Hartwell, J. "The co-ordination of central plant metabolism by the circadian clock." Biochemical Society Transactions 33, no. 5 (October 26, 2005): 945–48. http://dx.doi.org/10.1042/bst0330945.
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A circadian clock optimizes many aspects of plant biology relative to the light/dark cycle. One example is the circadian control of primary metabolism and CO2 fixation in plants that carry out a metabolic adaptation of photosynthesis called CAM (crassulacean acid metabolism). These plants perform primary CO2 fixation at night using the enzyme phosphoenolpyruvate carboxylase and exhibit a robust rhythm of CO2 fixation under constant conditions. Transcriptomic analysis has revealed that many genes encoding enzymes in primary metabolic pathways such as glycolysis and starch metabolism are under the control of the circadian clock in CAM plants. These transcript changes are accompanied by changes in metabolite levels associated with flux through these pathways. The molecular basis for the circadian control of CAM remains to be elucidated. Current research is focusing on the identity of the CAM central oscillator and the output pathway that links the central oscillator to the control of plant metabolism.
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Khalkhal, Ensieh, Mostafa Rezaei-Tavirani, Fariba Fathi, B. Fatemeh Nobakht M. Gh, Amir Taherkhani, Mohammad Rostami-Nejad, Nastaran Asri, and Mohammad Hossain Haidari. "Screening of Altered Metabolites and Metabolic Pathways in Celiac Disease Using NMR Spectroscopy." BioMed Research International 2021 (November 15, 2021): 1–11. http://dx.doi.org/10.1155/2021/1798783.
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Background. Celiac disease (CeD) is an autoimmune intestinal disorder caused by gluten protein consumption in genetically predisposed individuals. As biopsy sampling is an invasive procedure, finding novel noninvasive serological markers for screening of at-risk CeD population is a priority. Metabolomics is helpful in monitoring metabolite changes in body fluids and tissues. In the present study, we evaluated serum metabolite levels of CeD patients relative to healthy controls with the aim of introducing new biomarkers for population screening. Method. We compared the serum metabolic profile of CeD patients ( n = 42 ) and healthy controls ( n = 22 ) using NMR spectroscopy and multivariate analysis. Result. 25 metabolites were identified by serum metabolic profiling. Levels of 3-hydroxyisobutyric acid and isobutyrate showed significant differences in CeD patients’ samples compared with healthy controls ( p < 0.05 ). According to pathway analysis, our data demonstrated that changes in nine metabolic pathways were significantly disrupted/affected in patients with CeD. These enriched pathways are involved in aminoacyl-tRNA biosynthesis; primary bile acid biosynthesis; nitrogen metabolism; glutamine and glutamate metabolism; valine, leucine, and isoleucine biosynthesis and degradation; taurine and hypotaurine metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and arginine biosynthesis. Conclusion. In summary, our results demonstrated that changes in the serum level of 25 metabolites may be useful in distinguishing CeD patients from healthy controls, which have the potential to be considered candidate biomarkers of CeD.
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Tang, Joseph Kuo-Hsiang, Le You, Robert E. Blankenship, and Yinjie J. Tang. "Recent advances in mapping environmental microbial metabolisms through 13 C isotopic fingerprints." Journal of The Royal Society Interface 9, no. 76 (August 15, 2012): 2767–80. http://dx.doi.org/10.1098/rsif.2012.0396.
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After feeding microbes with a defined 13 C substrate, unique isotopic patterns (isotopic fingerprints) can be formed in their metabolic products. Such labelling information not only can provide novel insights into functional pathways but also can determine absolute carbon fluxes through the metabolic network via metabolic modelling approaches. This technique has been used for finding pathways that may have been mis-annotated in the past, elucidating new enzyme functions, and investigating cell metabolisms in microbial communities. In this review paper, we summarize the applications of 13 C approaches to analyse novel cell metabolisms for the past 3 years. The isotopic fingerprints (defined as unique isotopomers useful for pathway identifications) have revealed the operations of the Entner–Doudoroff pathway, the reverse tricarboxylic acid cycle, new enzymes for biosynthesis of central metabolites, diverse respiration routes in phototrophic metabolism, co-metabolism of carbon nutrients and novel CO 2 fixation pathways. This review also discusses new isotopic methods to map carbon fluxes in global metabolisms, as well as potential factors influencing the metabolic flux quantification (e.g. metabolite channelling, the isotopic purity of 13 C substrates and the isotopic effect). Although 13 C labelling is not applicable to all biological systems (e.g. microbial communities), recent studies have shown that this method has a significant value in functional characterization of poorly understood micro-organisms, including species relevant for biotechnology and human health.
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AlGhamdi, Asma Ahmed, Mohammed Razeeth Shait Mohammed, Mazin A. Zamzami, Abdulrahman L. Al-Malki, Mohamad Hasan Qari, Mohammad Imran Khan, and Hani Choudhry. "Untargeted Metabolomics Identifies Key Metabolic Pathways Altered by Thymoquinone in Leukemic Cancer Cells." Nutrients 12, no. 6 (June 17, 2020): 1792. http://dx.doi.org/10.3390/nu12061792.
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Thymoquinone (TQ), a naturally occurring anticancer compound extracted from Nigella sativa oil, has been extensively reported to possess potent anti-cancer properties. Experimental studies showed the anti-proliferative, pro-apoptotic, and anti-metastatic effects of TQ on different cancer cells. One of the possible mechanisms underlying these effects includes alteration in key metabolic pathways that are critical for cancer cell survival. However, an extensive landscape of the metabolites altered by TQ in cancer cells remains elusive. Here, we performed an untargeted metabolomics study using leukemic cancer cell lines during treatment with TQ and found alteration in approximately 335 metabolites. Pathway analysis showed alteration in key metabolic pathways like TCA cycle, amino acid metabolism, sphingolipid metabolism and nucleotide metabolism, which are critical for leukemic cell survival and death. We found a dramatic increase in metabolites like thymine glycol in TQ-treated cancer cells, a metabolite known to induce DNA damage and apoptosis. Similarly, we observed a sharp decline in cellular guanine levels, important for leukemic cancer cell survival. Overall, we provided an extensive metabolic landscape of leukemic cancer cells and identified the key metabolites and pathways altered, which could be critical and responsible for the anti-proliferative function of TQ.
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DE, RAJAT K., and NAMRATA TOMAR. "MODELING THE OPTIMAL CENTRAL CARBON METABOLIC PATHWAYS UNDER FEEDBACK INHIBITION USING FLUX BALANCE ANALYSIS." Journal of Bioinformatics and Computational Biology 10, no. 06 (October 18, 2012): 1250019. http://dx.doi.org/10.1142/s0219720012500199.
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Metabolism is a complex process for energy production for cellular activity. It consists of a cascade of reactions that form a highly branched network in which the product of one reaction is the reactant of the next reaction. Metabolic pathways efficiently produce maximal amount of biomass while maintaining a steady-state behavior. The steady-state activity of such biochemical pathways necessarily incorporates feedback inhibition of the enzymes. This observation motivates us to incorporate feedback inhibition for modeling the optimal activity of metabolic pathways using flux balance analysis (FBA). We demonstrate the effectiveness of the methodology on a synthetic pathway with and without feedback inhibition. Similarly, for the first time, the Central Carbon Metabolic (CCM) pathways of Saccharomyces cerevisiae and Homo sapiens have been modeled and compared based on the above understanding. The optimal pathway, which maximizes the amount of the target product(s), is selected from all those obtained by the proposed method. For this, we have observed the concentration of the product inhibited enzymes of CCM pathway and its influence on its corresponding metabolite/substrate. We have also studied the concentration of the enzymes which are responsible for the synthesis of target products. We further hypothesize that an optimal pathway would opt for higher flux rate reactions. In light of these observations, we can say that an optimal pathway should have lower enzyme concentration and higher flux rates. Finally, we demonstrate the superiority of the proposed method by comparing it with the extreme pathway analysis.
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Hao, Min, De Ji, Lin Li, Lianlin Su, Wei Gu, Liya Gu, Qiaohan Wang, Tulin Lu, and Chunqin Mao. "Mechanism of Curcuma wenyujin Rhizoma on Acute Blood Stasis in Rats Based on a UPLC-Q/TOF-MS Metabolomics and Network Approach." Molecules 24, no. 1 (December 27, 2018): 82. http://dx.doi.org/10.3390/molecules24010082.
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Rhizome of Curcuma wenyujin, which is called EZhu in China, is a traditional Chinese medicine used to treat blood stasis for many years. However, the underlying mechanism of EZhu is not clear at present. In this study, plasma metabolomics combined with network pharmacology were used to elucidate the therapeutic mechanism of EZhu in blood stasis from a metabolic perspective. The results showed that 26 potential metabolite markers of acute blood stasis were screened, and the levels were all reversed to different degrees by EZhu preadministration. Metabolic pathway analysis showed that the improvement of blood stasis by Curcuma wenyujin rhizome was mainly related to lipid metabolism (linoleic acid metabolism, ether lipid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and arachidonic acid metabolism) and amino acid metabolisms (tryptophan metabolism, lysine degradation). The component-target-pathway network showed that 68 target proteins were associated with 21 chemical components in EZhu. Five metabolic pathways of the network, including linoleic acid metabolism, sphingolipid metabolism, glycerolipid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis, were consistent with plasma metabolomics results. In conclusion, plasma metabolomics combined with network pharmacology can be helpful to clarify the mechanism of EZhu in improving blood stasis and to provide a literature basis for further research on the therapeutic mechanism of EZhu in clinical practice.
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Subramani, Mayavan, Carlos A. Urrea, and Venu Kalavacharla. "Comparative Analysis of Untargeted Metabolomics in Tolerant and Sensitive Genotypes of Common Bean (Phaseolus vulgaris L.) Seeds Exposed to Terminal Drought Stress." Metabolites 12, no. 10 (October 5, 2022): 944. http://dx.doi.org/10.3390/metabo12100944.
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Many environmental stresses can affect the accumulation of metabolites in plants, including drought. In the present study, we found a great deal of variability in the seed metabolic profiles of the tolerant (Matterhorn, SB-DT2 and SB-DT3) common bean genotypes in comparison to the sensitive genotypes (Sawtooth, Merlot and Stampede) using ultrahigh performance liquid chromatography−tandem mass spectrometry (UPLC-MS). The genotypes were grown in the field and subjected to drought stress after flowering (terminal drought stress). We aimed to investigate the accumulation of genotype-specific metabolites and related pathways under terminal drought stress by comparing tolerant and sensitive genotypes within a race. A total of 26 potential metabolites were identified across genotype comparisons. Significant metabolic pathways, including monobactam biosynthesis, flavone and flavonol biosynthesis, pentose phosphate pathway, C5-branched dibasic acid metabolism, cysteine and methionine metabolism, vitamin B6 metabolism and flavonoid biosynthesis, were derived from the enriched metabolites. Many of these metabolic pathways were specific and varied with genotype comparisons. SB-DT2 vs. stampede revealed more significant metabolites and metabolic pathways compared to Matterhorn vs. Sawtooth and SB-DT3 vs. Merlot under terminal drought stress. Our study provides useful information regarding the metabolite profiles of seeds and their related pathways in comparisons of tolerant and sensitive common bean genotypes under terminal drought conditions. Further research, including transcriptomic and proteomic analyses, may contribute to a better understanding of molecular mechanisms and nutritional differences among seeds of common bean genotypes grown under terminal drought conditions.
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Yang, Yanjie, Dehui Xu, Ning Ning, and Yujing Xu. "Analysis of Metabolite Profiling in Human Endothelial Cells after Plasma Jet Treatment." BioMed Research International 2019 (November 3, 2019): 1–9. http://dx.doi.org/10.1155/2019/3015150.
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Cold atmospheric plasma (CAP) is a novel technology, which has been widely applied in biomedicine, especially in wound healing, dermatological treatment, hemostasis, and cancer treatment. In most cases, CAP treatment will interact with innumerable blood capillaries. Therefore, it is important and necessary to understand the effects of CAP treatment on endothelial cell metabolism. In this study, the metabolite profiling of plasma treatment on endothelial cells was measured by gas chromatography tandem time-of-flight mass spectrometry (GC-TOF-MS). We found that 695 signals (metabolites) were detected by GC-TOF-MS and then evaluated using orthogonal projections to latent structures discriminant analysis (OPLS-DA). All the differential metabolites were listed, and proline and xanthosine were the two of the most downregulated metabolites by plasma treatment. By comprehensive metabolic pathway analysis with the KEGG pathway, we showed that alanine, aspartate, glutamate, and purine metabolism pathways were the most significantly suppressed after gas plasma treatment in human endothelial cells. Our finding gives an overall picture of the metabolic pathways affected by plasma treatment in endothelial cells.
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Meng, Li, Ruyue Zhou, Jialong Lin, Qingji Wang, Panmeng Wang, Wei Wang, Li Wang, and Zhuang Li. "Integrated Transcriptomics and Nontargeted Metabolomics Analysis Reveal Key Metabolic Pathways in Ganoderma lucidum in Response to Ethylene." Journal of Fungi 8, no. 5 (April 28, 2022): 456. http://dx.doi.org/10.3390/jof8050456.
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Ganoderic acid (GA) is an important secondary metabolite of Ganoderma lucidum with a diverse array of pharmacological properties. In this study, we found that exogenous ethylene increased the production of endogenous ethylene and ganoderic acid in G. lucidum. However, the mechanism by which ethylene is regulated remains unclear. As a result, we performed a combined transcriptomics and nontargeted metabolomics analysis to evaluate the regulatory mechanism of ethylene. A total of 4070 differentially expressed genes (1835 up-regulated and 2235 down-regulated) and 378 differentially accumulated metabolites (289 up-regulated and 89 down-regulated) were identified in all groups. The transcriptomics and nontargeted metabolomics data revealed that genes involved in the tricarboxylic acid (TCA) cycle, polyamine metabolic pathway, acetyl-CoA carboxylase (ACC) pathway, and triterpenoid metabolism were up-regulated, whereas the metabolic intermediates involved in these metabolic pathways were down-regulated. These findings imply that ethylene potentially accelerates normal glucose metabolism, hence increasing the number of intermediates available for downstream biological processes, including polyamine metabolism, ethylene synthesis pathway, and ganoderic acid biosynthesis. The findings will contribute significantly to our understanding of secondary metabolites biosynthesis in fungi.
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Liu, Keying. "Immune, metabolism and therapeutic targets in RA (Rheumatoid Arthritis)." BIO Web of Conferences 55 (2022): 01016. http://dx.doi.org/10.1051/bioconf/20225501016.
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Rheumatoid arthritis is a classic autoimmune disease, the pathogenesis of which is closely linked to the auto-reactivity of immune cells and joint inflammation. Three cell types, namely T cells, macrophages and fibroblast-like synoviocytes (FLS), play an important role in the pathogenesis of RA. Numerous studies have pointed to a metabolic reprogramming of T cells, macrophages and FLS in the pathogenesis of RA arthritis, with alterations in different metabolic pathways of cells, mainly producing a shift from oxidative phosphorylation (OXPHOS) to glycolysis, in addition to lipid metabolism and amino acid metabolism which are also altered in the cellular activation state. Metabolic changes are regulated by metabolism-related signalling pathways, and RA is associated with two representative signalling pathways, namely the mTOR signalling pathway and the AMPK signalling pathway. In RA, both signalling pathways are activated or inhibited, and through a series of cascade reactions, different gene expressions are ultimately induced, altering intracellular metabolic pathways and promoting pro-inflammatory functions (e.g. pro-inflammatory cytokine release and FLS phenotypes), or inhibiting the expression of genes related to immune tolerance. Targeting key components of metabolic signalling pathways and key enzymes in cellular metabolic pathways in RA has emerged as a new way of finding drugs for RA, and many modulators targeting these targets have been extensively studied for their therapeutic effects in RA. In this article, we focus on cellular metabolic alterations in RA, related signalling pathways and possible drugs targeting RA metabolic pathways.
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Li, Y., W. Xu, X. Li, Z. Han, R. Zhang, X. Li, and Q. Chen. "Metabolic responses of shrimp Palaemonetes sinensis to isopod Tachaea chinensis parasitization." Diseases of Aquatic Organisms 138 (April 9, 2020): 227–35. http://dx.doi.org/10.3354/dao03460.
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Tachaea chinensis, a parasitic isopod, negatively affects the production of several commercially important shrimp species in China. The mechanism of parasite-host interaction cannot be accurately described by transcriptomic and proteomic approaches individually. Here, comparative metabolite profiling was used to achieve a broad coverage of primary metabolite changes in Chinese grass shrimp Palaemonetes sinensis following T. chinensis parasitization. In total, 66 metabolites were significantly differentially accumulated between the control and infected groups; of these, 19 were upregulated and 47 were downregulated after T. chinensis infection. Moreover, the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that 10 pathways were significantly enriched. The protein digestion and absorption pathways were highly enriched, followed by the mineral absorption, aminoacyl-tRNA biosynthesis, biosynthesis of amino acids, and metabolic metabolism pathways. Parasitization by T. chinensis enhanced the glycolytic pathway and tricarboxylic acid (TCA) cycle in P. sinensis, thereby releasing more energy for swimming, foraging, and evading predation. Glucogenic amino acids such as alanine, histidine, glutamine, and proline were consumed to generate glutamate and enhance the TCA cycle. Nucleotide-related metabolic pathways were downregulated, possibly because T. chinensis can secrete molecules to degrade nucleotides and inhibit hemostasis and inflammatory responses. These results suggest that the isopod parasite can increase the host’s metabolic burden by enhancing the host’s TCA cycle and secreting molecules to degrade host proteins, thereby enabling the parasite to feed on the host and inhibit an inflammatory response. The results will be a valuable contribution to understanding the metabolic responses of crustaceans to isopod parasitism.
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Koblitz, Julia, Dietmar Schomburg, and Meina Neumann-Schaal. "MetaboMAPS: Pathway sharing and multi-omics data visualization in metabolic context." F1000Research 9 (April 24, 2020): 288. http://dx.doi.org/10.12688/f1000research.23427.1.
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Metabolic pathways are an important part of systems biology research since they illustrate complex interactions between metabolites, enzymes, and regulators. Pathway maps are drawn to elucidate metabolism or to set data in a metabolic context. We present MetaboMAPS, a web-based platform to visualize numerical data on individual metabolic pathway maps. Metabolic maps can be stored, distributed and downloaded in SVG-format. MetaboMAPS was designed for users without computational background and supports pathway sharing without strict conventions. In addition to existing applications that established standards for well-studied pathways, MetaboMAPS offers a niche for individual, customized pathways beyond common knowledge, supporting ongoing research by creating publication-ready visualizations of experimental data.
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Koblitz, Julia, Dietmar Schomburg, and Meina Neumann-Schaal. "MetaboMAPS: Pathway sharing and multi-omics data visualization in metabolic context." F1000Research 9 (July 17, 2020): 288. http://dx.doi.org/10.12688/f1000research.23427.2.
Full textAbstract:
Metabolic pathways are an important part of systems biology research since they illustrate complex interactions between metabolites, enzymes, and regulators. Pathway maps are drawn to elucidate metabolism or to set data in a metabolic context. We present MetaboMAPS, a web-based platform to visualize numerical data on individual metabolic pathway maps. Metabolic maps can be stored, distributed and downloaded in SVG-format. MetaboMAPS was designed for users without computational background and supports pathway sharing without strict conventions. In addition to existing applications that established standards for well-studied pathways, MetaboMAPS offers a niche for individual, customized pathways beyond common knowledge, supporting ongoing research by creating publication-ready visualizations of experimental data.
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Tianero, Ma Diarey, Elizabeth Pierce, Shrinivasan Raghuraman, Debosmita Sardar, John A. McIntosh, John R. Heemstra, Zachary Schonrock, et al. "Metabolic model for diversity-generating biosynthesis." Proceedings of the National Academy of Sciences 113, no. 7 (February 1, 2016): 1772–77. http://dx.doi.org/10.1073/pnas.1525438113.
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A conventional metabolic pathway leads to a specific product. In stark contrast, there are diversity-generating metabolic pathways that naturally produce different chemicals, sometimes of great diversity. We demonstrate that for one such pathway,tru, each ensuing metabolic step is slower, in parallel with the increasing potential chemical divergence generated as the pathway proceeds. Intermediates are long lived and accumulate progressively, in contrast with conventional metabolic pathways, in which the first step is rate-limiting and metabolic intermediates are short-lived. Understanding these fundamental differences enables several different practical applications, such as combinatorial biosynthesis, some of which we demonstrate here. We propose that these principles may provide a unifying framework underlying diversity-generating metabolism in many different biosynthetic pathways.
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Chen, Xiang, Chao Hu, Jican Dai, and Lei Chen. "Metabolomics Analysis of Seminal Plasma in Infertile Males with Kidney-Yang Deficiency: A Preliminary Study." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/892930.
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Traditional Chinese medicine (TCM) is an important treatment for male infertility, and its application to therapy is dependent on differentiation of TCM syndromes. This study aims to investigate the changes in metabolites and metabolic pathways in infertile males with Kidney-Yang Deficiency syndrome (KYDS) via metabolomics approaches. Seminal plasma samples were collected from 18 infertile males with KYDS and 18 fertile males. Liquid chromatography and mass spectrometry were used to characterize metabolomics profiles. Principal component analysis (PCA), partial least squares-discriminate analysis (PLS-DA), and pathway analysis were used for pattern recognition and metabolite identification. PCA and PLS-DA results differentiated the two groups of patients. Forty-one discriminating metabolites (18 in positive mode and 23 in negative mode) were identified. Seven metabolites were related to five potential metabolic pathways associated with biosynthesis and metabolism of aromatic amino acids, tricarboxylic acid cycle, and sphingolipid metabolism. The changes in metabolic pathways may play an important role in the origin of KYDS-associated male infertility. Metabolomics analysis of seminal plasma may be used to differentiate TCM syndromes of infertile males, but further research must be conducted.
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Ralser, Markus. "An appeal to magic? The discovery of a non-enzymatic metabolism and its role in the origins of life." Biochemical Journal 475, no. 16 (August 29, 2018): 2577–92. http://dx.doi.org/10.1042/bcj20160866.
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Until recently, prebiotic precursors to metabolic pathways were not known. In parallel, chemistry achieved the synthesis of amino acids and nucleotides only in reaction sequences that do not resemble metabolic pathways, and by using condition step changes, incompatible with enzyme evolution. As a consequence, it was frequently assumed that the topological organisation of the metabolic pathway has formed in a Darwinian process. The situation changed with the discovery of a non-enzymatic glycolysis and pentose phosphate pathway. The suite of metabolism-like reactions is promoted by a metal cation, (Fe(II)), abundant in Archean sediment, and requires no condition step changes. Knowledge about metabolism-like reaction topologies has accumulated since, and supports non-enzymatic origins of gluconeogenesis, the S-adenosylmethionine pathway, the Krebs cycle, as well as CO2 fixation. It now feels that it is only a question of time until essential parts of metabolism can be replicated non-enzymatically. Here, I review the ‘accidents’ that led to the discovery of the non-enzymatic glycolysis, and on the example of a chemical network based on hydrogen cyanide, I provide reasoning why metabolism-like non-enzymatic reaction topologies may have been missed for a long time. Finally, I discuss that, on the basis of non-enzymatic metabolism-like networks, one can elaborate stepwise scenarios for the origin of metabolic pathways, a situation that increasingly renders the origins of metabolism a tangible problem.
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Pham, Khoa, Brad Poore, Allison Hanaford, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, et al. "OTME-9. Comprehensive Metabolic Profiling Of high MYC Medulloblastoma Reveals Key Differences Between In Vitro And In Vivo Glucose And Glutamine Usage." Neuro-Oncology Advances 3, Supplement_2 (July 1, 2021): ii15. http://dx.doi.org/10.1093/noajnl/vdab070.060.
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Abstract Reprograming of cellular metabolism is a hallmark of cancer. The metabolic alterations in cancer cells is not only defined by series of genetic mutations, but also reflecting the crosstalk between cancer cells and other factors in the microenvironment. Altering metabolism allows cancer cells to overcome unfavorable conditions, to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC is a hallmark of a subset of poor-prognosis medulloblastoma. However, the metabolism of high MYC amplified medulloblastoma subgroup remains underexplored. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in different environments – in vitro, in flank xenografts and in orthotopic xenografts. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and the high-MYC medulloblastoma cells in culture. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of nucleotide, hexosamine biosynthetic pathway (HBP), TCA cycle, and amino acid and glutathione pathways. There was significantly higher glucose up taking and usage in orthotopic xenograft tumor compared to flank xenograft and cells in culture. The data demonstrated that glucose was the main carbon source for the glutamate, glutamine and glutathione synthesis through the TCA cycle. The glutaminase ii pathway was the main pathway utilizing glutamine in MYC-amplified medulloblastoma in vivo. Glutathione was found as the most abundant upregulated metabolite. Glutamine derived glutathione was mainly synthesized through glutamine transaminase K (GTK) enzyme in vivo. In conclusion, we demonstrated that high MYC medulloblastoma adapt to different environments by altering its metabolic pathways despite carrying the same genetic mutations. Glutamine antagonists may have therapeutic applications in human patients.
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Wang, Xiao, and Haja N. Kadarmideen. "Metabolomics Analyses in High-Low Feed Efficient Dairy Cows Reveal Novel Biochemical Mechanisms and Predictive Biomarkers." Metabolites 9, no. 7 (July 23, 2019): 151. http://dx.doi.org/10.3390/metabo9070151.
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Residual feed intake (RFI) is designed to estimate net efficiency of feed use, so low RFI animals are considered for selection to reduce feeding costs. However, metabolic profiling of cows and availability of predictive metabolic biomarkers for RFI are scarce. Therefore, this study aims to generate a better understanding of metabolic mechanisms behind low and high RFI in Jerseys and Holsteins and identify potential predictive metabolic biomarkers. Each metabolite was analyzed to reveal their associations with two RFIs in two breeds by a linear regression model. An integrative analysis of metabolomics and transcriptomics was performed to explore interactions between functionally related metabolites and genes in the created metabolite networks. We found that three main clusters were detected in the heat map and all identified fatty acids (palmitoleic, hexadecanoic, octadecanoic, heptadecanoic, and tetradecanoic acid) were grouped in a cluster. The lower cluster were all from fatty acids, including palmitoleic acid, hexadecanoic acid, octadecanoic acid, heptadecanoic acid, and tetradecanoic acid. The first component of the partial least squares-discriminant analysis (PLS-DA) explained a majority (61.5%) of variations of all metabolites. A good division between two breeds was also observed. Significant differences between low and high RFIs existed in the fatty acid group (P < 0.001). Statistical results revealed clearly significant differences between breeds; however, the association of individual metabolites (leucine, ornithine, pentadecanoic acid, and valine) with the RFI status was only marginally significant or not significant due to a lower sample size. The integrated gene-metabolite pathway analysis showed that pathway impact values were higher than those of a single metabolic pathway. Both types of pathway analyses revealed three important pathways, which were aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate metabolism, and the citrate cycle (TCA cycle). Finally, one gene (2-hydroxyacyl-CoA lyase 1 (+HACL1)) associated with two metabolites (-α-ketoglutarate and succinic acid) were identified in the gene-metabolite interaction network. This study provided novel metabolic pathways and integrated metabolic-gene expression networks in high and low RFI Holstein and Jersey cattle, thereby providing a better understanding of novel biochemical mechanisms underlying variation in feed efficiency.
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Shigematsu, Mei, Ryosuke Nakagawa, Shozo Tomonaga, Masayuki Funaba, and Tohru Matsui. "Fluctuations in metabolite content in the liver of magnesium-deficient rats." British Journal of Nutrition 116, no. 10 (November 9, 2016): 1694–99. http://dx.doi.org/10.1017/s0007114516003676.
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AbstractMg deficiency induces various metabolic disturbances including glucose metabolism in the liver. However, no comprehensive information is currently available on the metabolic pathways affected by Mg deficiency. The present study examined metabolite content in the liver of Mg-deficient rats using a metabolomic analysis. In this study, 4-week-old, male Sprague–Dawley rats were fed a control diet or a Mg-deficient diet for 8 weeks. The metabolomic analysis identified 105 metabolites in the liver, and significant differences were observed in the hepatic contents for thirty-three metabolites between the two groups. An analysis by MetaboAnalyst, a web-based metabolome data analysis tool, indicated that the Mg deficiency affected taurine/hypotaurine metabolism, methionine metabolism and glycine/serine/threonine metabolism; taurine, hypotaurine, glycine, serine and threonine contents were increased by Mg deficiency, whereas the amounts of 2-ketobutyric acid (a metabolite produced by the catabolism of cystathionine or threonine) and 5'-methylthioadenosine (a metabolite involved in spermidine synthesis) were decreased. The amount of glucose 6-phosphate, a hub metabolite of glycolysis/gluconeogenesis and the pentose phosphate pathway, was significantly decreased in Mg-deficient rats. Mg deficiency also decreased metabolite contents from the citric acid cycle, including citric acid, fumaric acid and malic acid. Aberrant metabolism may be related to the allosteric regulation of enzymes; the mRNA levels of enzymes were generally similar between the two groups. The present study suggests that the Mg deficiency-mediated modulation of hepatic metabolism is as yet uncharacterised.
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Korimerla, Navyateja, and Daniel R. Wahl. "Interactions between Radiation and One-Carbon Metabolism." International Journal of Molecular Sciences 23, no. 3 (February 8, 2022): 1919. http://dx.doi.org/10.3390/ijms23031919.
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Metabolic reprogramming is a hallmark of cancer. Cancer cells rewire one-carbon metabolism, a central metabolic pathway, to turn nutritional inputs into essential biomolecules required for cancer cell growth and maintenance. Radiation therapy, a common cancer therapy, also interacts and alters one-carbon metabolism. This review discusses the interactions between radiation therapy, one-carbon metabolism and its component metabolic pathways.
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Caspi, Ron, Richard Billington, Ingrid M. Keseler, Anamika Kothari, Markus Krummenacker, Peter E. Midford, Wai Kit Ong, Suzanne Paley, Pallavi Subhraveti, and Peter D. Karp. "The MetaCyc database of metabolic pathways and enzymes - a 2019 update." Nucleic Acids Research 48, no. D1 (October 5, 2019): D445—D453. http://dx.doi.org/10.1093/nar/gkz862.
Full textAbstract:
Abstract MetaCyc (MetaCyc.org) is a comprehensive reference database of metabolic pathways and enzymes from all domains of life. It contains 2749 pathways derived from more than 60 000 publications, making it the largest curated collection of metabolic pathways. The data in MetaCyc are evidence-based and richly curated, resulting in an encyclopedic reference tool for metabolism. MetaCyc is also used as a knowledge base for generating thousands of organism-specific Pathway/Genome Databases (PGDBs), which are available in BioCyc.org and other genomic portals. This article provides an update on the developments in MetaCyc during September 2017 to August 2019, up to version 23.1. Some of the topics that received intensive curation during this period include cobamides biosynthesis, sterol metabolism, fatty acid biosynthesis, lipid metabolism, carotenoid metabolism, protein glycosylation, antibiotics and cytotoxins biosynthesis, siderophore biosynthesis, bioluminescence, vitamin K metabolism, brominated compound metabolism, plant secondary metabolism and human metabolism. Other additions include modifications to the GlycanBuilder software that enable displaying glycans using symbolic representation, improved graphics and fonts for web displays, improvements in the PathoLogic component of Pathway Tools, and the optional addition of regulatory information to pathway diagrams.
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Park, Jae Hyung, Woo Yang Pyun, and Hyun Woo Park. "Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets." Cells 9, no. 10 (October 16, 2020): 2308. http://dx.doi.org/10.3390/cells9102308.
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Aberrant metabolism is a major hallmark of cancer. Abnormal cancer metabolism, such as aerobic glycolysis and increased anabolic pathways, has important roles in tumorigenesis, metastasis, drug resistance, and cancer stem cells. Well-known oncogenic signaling pathways, such as phosphoinositide 3-kinase (PI3K)/AKT, Myc, and Hippo pathway, mediate metabolic gene expression and increase metabolic enzyme activities. Vice versa, deregulated metabolic pathways contribute to defects in cellular signal transduction pathways, which in turn provide energy, building blocks, and redox potentials for unrestrained cancer cell proliferation. Studies and clinical trials are being performed that focus on the inhibition of metabolic enzymes by small molecules or dietary interventions (e.g., fasting, calorie restriction, and intermittent fasting). Similar to genetic heterogeneity, the metabolic phenotypes of cancers are highly heterogeneous. This heterogeneity results from diverse cues in the tumor microenvironment and genetic mutations. Hence, overcoming metabolic plasticity is an important goal of modern cancer therapeutics. This review highlights recent findings on the metabolic phenotypes of cancer and elucidates the interactions between signal transduction pathways and metabolic pathways. We also provide novel rationales for designing the next-generation cancer metabolism drugs.
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Drapkina, O. M., and O. E. Shirobokikh. "Role of Gut Microbiota in the Pathogenesis of Cardiovascular Diseases and Metabolic Syndrome." Rational Pharmacotherapy in Cardiology 14, no. 4 (September 4, 2018): 567–74. http://dx.doi.org/10.20996/1819-6446-2018-14-4-567-574.
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The role of gut microbiota in the pathogenesis of cardiovascular diseases (CVD) and metabolic syndrome has attracted massive attention in the past decade. Accumulating evidence has revealed that the metabolic potential of gut microbiota can be identified as a contributing factor in the development of atherosclerosis, hypertension, heart failure, obesity, diabetes mellitus. The gut-host interaction occurs through many pathways including trimethylamine-N-oxide pathway (TMAO), short-chain fatty acids and second bile acids pathways. TMAO (the hepatic oxidation product of the microbial metabolite of trimethylamine) enhances platelet hyperreactivity and thrombosis risk and predicts major adverse cardiovascular events. Short-chain fatty acids and second bile acids, which are produced with the help of microbiota, can modulate host lipid metabolism as well as carbohydrate metabolism through several receptors such as G-protein-coupled receptors 41,43, farnesoid X-receptor, Takeda-G-protein-receptor-5. This way microbiota can impact host lipid levels, processes of weight gain, insulin sensitivity. Besides these metabolism-dependent pathways, there are some other pathways, which link microbiota and the pathogenesis of CVD. For example, lipopolysaccharide, the major component of the outer bacterial membrane, causes metabolic endotoxemia and low-grade systemic inflammation and contribute this way to obesity and progression of heart failure and atherosclerosis. This review aims to illustrate the complex interplay between microbiota, their metabolites, and the development and progression of CVD and metabolic syndrome. It is also discussed how modulating of gut microbiota composition and function through diet, prebiotics, probiotics and fecal microbiota transplantation can become a novel therapeutic and preventative target for CVD and metabolic syndrome. Many questions remain unresolved in this field and undoubtedly further studies are needed.
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Spégel, Peter, Vladimir V. Sharoyko, Isabel Goehring, Anders P. H. Danielsson, Siri Malmgren, Cecilia L. F. Nagorny, Lotta E. Andersson, et al. "Time-resolved metabolomics analysis of β-cells implicates the pentose phosphate pathway in the control of insulin release." Biochemical Journal 450, no. 3 (February 28, 2013): 595–605. http://dx.doi.org/10.1042/bj20121349.
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Insulin secretion is coupled with changes in β-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP+, NADPH and insulin secretion were measured within 15 min of stimulation of clonal INS-1 832/13 β-cells with glucose. Rapid responses in the major metabolic pathways of glucose occurred, involving several previously suggested metabolic coupling factors. The complexity of metabolite changes observed disagreed with the concept of one single metabolite controlling insulin secretion. The complex alterations in metabolite levels suggest that a coupling signal should reflect large parts of the β-cell metabolic response. This was fulfilled by the NADPH/NADP+ ratio, which was elevated (8-fold; P<0.01) at 6 min after glucose stimulation. The NADPH/NADP+ ratio paralleled an increase in ribose 5-phosphate (>2.5-fold; P<0.001). Inhibition of the pentose phosphate pathway by trans-dehydroepiandrosterone (DHEA) suppressed ribose 5-phosphate levels and production of reduced glutathione, as well as insulin secretion in INS-1 832/13 β-cells and rat islets without affecting ATP production. Metabolite profiling of rat islets confirmed the glucose-induced rise in ribose 5-phosphate, which was prevented by DHEA. These findings implicate the pentose phosphate pathway, and support a role for NADPH and glutathione, in β-cell stimulus-secretion coupling.
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Liu, Sijiang, and Zhaojin Yu. "A Study of the Identification, Fragmentation Mode and Metabolic Pathways of Imatinib in Rats Using UHPLC-Q-TOF-MS/MS." Journal of Analytical Methods in Chemistry 2021 (May 24, 2021): 1–15. http://dx.doi.org/10.1155/2021/8434204.
Full textAbstract:
In this study, The metabolites, metabolic pathways, and metabolic fragmentation mode of a tyrosine kinase inhibitor- (TKI-) imatinib in rats were investigated. The samples for analysis were pretreated via solid-phase extraction, and the metabolism of imatinib in rats was studied using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). Eighteen imatinib metabolites were identified in rat plasma, 21 in bile, 18 in urine, and 12 in feces. Twenty-seven of the above compounds were confirmed as metabolites of imatinib and 9 of them were newly discovered for the first time. Oxidation, hydroxylation, dealkylation, and catalytic dehydrogenation are the main metabolic pathways in phase I. For phase II, the main metabolic pathways were N-acetylation, methylation, cysteine, and glucuronidation binding. The fragment ions of imatinib and its metabolites were confirmed to be produced by the cleavage of the C-N bond at the amide bond. The newly discovered metabolite of imatinib was identified by UHPLC-Q-TOF-MS/MS. The metabolic pathway of imatinib and its fragmentation pattern were summarized. These results could be helpful to study the safety of imatinib for clinical use.
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Leiser, Scott, Christopher Choi, Ajay Bhat, and Charles Evans. "A Metabolic Stress Response." Innovation in Aging 4, Supplement_1 (December 1, 2020): 123. http://dx.doi.org/10.1093/geroni/igaa057.404.
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Abstract An organism’s ability to respond to stress is crucial for long-term survival. These stress responses are coordinated by distinct but overlapping pathways, many of which have been found to also regulate longevity in multiple organisms across species. Despite extensive effort, our understanding of these pathways and how they affect aging remains incomplete and thus is a key area of study in Geroscience. Our previous work identified flavin-containing monooxygenase-2 (fmo-2) as a key longevity-promoting gene downstream of at least three longevity promoting pathways, including the hypoxic response, the pentose phosphate pathway, and the dietary restriction pathway. Based on the commonalities of these pathways, we hypothesized that fmo-2, a classically annotated xenobiotic enzyme, might play a key endogenous role in responding to metabolic stress. Our resulting data, using metabolic profiling and further epistatic analysis, both support this hypothesis and link fmo-2’s mechanism to modifications to one-carbon metabolism (OCM), a key intermediate pathway between the nucleotide metabolism, methylation, and transsulfuration pathways. Using mathematical modeling and a novel metabolomics approach, we were able to further identify the likely mechanism of fmo-2-mediated metabolic effects, and connect them to both OCM and downstream components. We propose a model whereby nematode fmo-2 represents a class of enzymes that are able to modify large aspects of metabolism, similar to how transcription factors modify gene expression, and that fmo-2 is a key member of a conserved metabolic stress response.
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Barik, Dr Bibhuti Prasad. "In Silico Observations and Analysis of Metabolic Pathways." International Journal of Scientific Research 2, no. 11 (June 1, 2012): 44–48. http://dx.doi.org/10.15373/22778179/nov2013/14.
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Cocco, Nicoletta, Mercè Llabrés, Mariana Reyes-Prieto, and Marta Simeoni. "MetNet: A two-level approach to reconstructing and comparing metabolic networks." PLOS ONE 16, no. 2 (February 12, 2021): e0246962. http://dx.doi.org/10.1371/journal.pone.0246962.
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Metabolic pathway comparison and interaction between different species can detect important information for drug engineering and medical science. In the literature, proposals for reconstructing and comparing metabolic networks present two main problems: network reconstruction requires usually human intervention to integrate information from different sources and, in metabolic comparison, the size of the networks leads to a challenging computational problem. We propose to automatically reconstruct a metabolic network on the basis of KEGG database information. Our proposal relies on a two-level representation of the huge metabolic network: the first level is graph-based and depicts pathways as nodes and relations between pathways as edges; the second level represents each metabolic pathway in terms of its reactions content. The two-level representation complies with the KEGG database, which decomposes the metabolism of all the different organisms into “reference” pathways in a standardised way. On the basis of this two-level representation, we introduce some similarity measures for both levels. They allow for both a local comparison, pathway by pathway, and a global comparison of the entire metabolism. We developed a tool, MetNet, that implements the proposed methodology. MetNet makes it possible to automatically reconstruct the metabolic network of two organisms selected in KEGG and to compare their two networks both quantitatively and visually. We validate our methodology by presenting some experiments performed with MetNet.
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Sammad, Abdul, Hanpeng Luo, Lirong Hu, Shanjiang Zhao, Jianfei Gong, Saqib Umer, Adnan Khan, Huabin Zhu, and Yachun Wang. "Joint Transcriptome and Metabolome Analysis Prevails the Biological Mechanisms Underlying the Pro-Survival Fight in In Vitro Heat-Stressed Granulosa Cells." Biology 11, no. 6 (May 30, 2022): 839. http://dx.doi.org/10.3390/biology11060839.
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Previous studies reported the physical, transcriptome, and metabolome changes in in vitro acute heat-stressed (38 °C versus 43 °C for 2 h) bovine granulosa cells. Granulosa cells exhibited transient proliferation senescence, oxidative stress, an increased rate of apoptosis, and a decline in steroidogenic activity. In this study, we performed a joint integration and network analysis of metabolomic and transcriptomic data to further narrow down and elucidate the role of differentially expressed genes, important metabolites, and relevant cellular and metabolic pathways in acute heat-stressed granulosa cells. Among the significant (raw p-value < 0.05) metabolic pathways where metabolites and genes converged, this study found vitamin B6 metabolism, glycine, serine and threonine metabolism, phenylalanine metabolism, arginine biosynthesis, tryptophan metabolism, arginine and proline metabolism, histidine metabolism, and glyoxylate and dicarboxylate metabolism. Important significant convergent biological pathways included ABC transporters and protein digestion and absorption, while functional signaling pathways included cAMP, mTOR, and AMPK signaling pathways together with the ovarian steroidogenesis pathway. Among the cancer pathways, the most important pathway was the central carbon metabolism in cancer. Through multiple analysis queries, progesterone, serotonin, citric acid, pyridoxal, L-lysine, succinic acid, L-glutamine, L-leucine, L-threonine, L-tyrosine, vitamin B6, choline, and CYP1B1, MAOB, VEGFA, WNT11, AOX1, ADCY2, ICAM1, PYGM, SLC2A4, SLC16A3, HSD11B2, and NOS2 appeared to be important enriched metabolites and genes, respectively. These genes, metabolites, and metabolic, cellular, and cell signaling pathways comprehensively elucidate the mechanisms underlying the intricate fight between death and survival in acute heat-stressed bovine granulosa cells and essentially help further our understanding (and will help the future quest) of research in this direction.
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Latifimehr, Mahbobeh, Ali Asghar Rastegari, Zahra Zamani, Pezhman Fard Esfahani, and Leila Nazari. "The Investigation of Metabonomic Pathways of Serum of Iranian Women with Recurrent Miscarriage Using 1H NMR." BioMed Research International 2021 (November 3, 2021): 1–8. http://dx.doi.org/10.1155/2021/3422138.
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Purpose. Recurrent miscarriage applies to pregnancy loss expulsion of the fetus within the first 24 weeks of pregnancy. This study is aimed at comparatively investigating the sera of women with RM with those who have no record of miscarriages to identify if there were any metabolite and metabolic pathway differences using 1H NMR spectroscopy. Methods. Serum samples were collected from women with RM ( n = 30 ) and those who had no records of RM ( n = 30 ) to obtain metabolomics information. 1H NMR spectroscopy was carried out on the samples using Carr Purcell Meiboom Gill spin echo; also, Partial Least Squares Discriminant Analysis was performed in MATLAB software using the ProMetab program to obtain the classifying chemical shifts; the metabolites were identified by using the Human Metabolome Database (HMDB) in both the experimental and control groups. The pathway analysis option of the Metaboanalyst.ca website was used to identify the changed metabolic pathways. Results. The results of the study revealed that 14 metabolites were different in the patients with RM. Moreover, the pathway analysis showed that taurine and hypotaurine metabolism along with phenylalanine, tyrosine, and tryptophan biosynthesis was significantly different in patients with RM. Conclusion. The present study proposes that any alteration in the above metabolic pathways might lead to metabolic dysfunctions which may result in a higher probability of RM.
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Lukitasari, Mifetika, Dwi Adi Nugroho, and Nashi Widodo. "Chlorogenic Acid: The Conceivable Chemosensitizer Leading to Cancer Growth Suppression." Journal of Evidence-Based Integrative Medicine 23 (January 1, 2018): 2515690X1878962. http://dx.doi.org/10.1177/2515690x18789628.
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New paradigm in cancer pathogenesis revealed that microenvironmental conditions significantly contribute to cancer. Hence, Warburg stated that cancer is a metabolic disease. Chlorogenic acid (CGA) is a polyphenol that is found abundantly in coffee. This compound has proven ability in ameliorating some metabolic diseases through various pathways. This article will elaborate the potency of CGA as a chemosensitizer in suppressing tumor growth through a metabolic pathway. AMPK pathway is the main cell metabolic pathway that is activated by CGA in some studies. Moreover, CGA inhibited EGFR/PI3K/mTOR, HIF, VEGF pathways and MAPK/ERK pathway that may suppress tumor cell growth. Furthermore, CGA induced intracellular DNA damage and topoisomerase I- and II-DNA complexes formation that plays a key role in apoptosis. Conclusively, based on the ability of CGA in activate and inhibit some important pathways in cancer metabolism, it may act as a chemosensitizing agent leading to cancer growth suppression.
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García, Irene, Bessem Chouaia, Mercè Llabrés, and Marta Simeoni. "Exploring the expressiveness of abstract metabolic networks." PLOS ONE 18, no. 2 (February 9, 2023): e0281047. http://dx.doi.org/10.1371/journal.pone.0281047.
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Metabolism is characterised by chemical reactions linked to each other, creating a complex network structure. The whole metabolic network is divided into pathways of chemical reactions, such that every pathway is a metabolic function. A simplified representation of metabolism, which we call an abstract metabolic network, is a graph in which metabolic pathways are nodes and there is an edge between two nodes if their corresponding pathways share one or more compounds. The abstract metabolic network of a given organism results in a small network that requires low computational power to be analysed and makes it a suitable model to perform a large-scale comparison of organisms’ metabolism. To explore the potentials and limits of such a basic representation, we considered a comprehensive set of KEGG organisms, represented through their abstract metabolic network. We performed pairwise comparisons using graph kernel methods and analyse the results through exploratory data analysis and machine learning techniques. The results show that abstract metabolic networks discriminate macro evolutionary events, indicating that they are expressive enough to capture key steps in metabolism evolution.
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Ge, Kai, and Zhaoyu Geng. "Proteomic analysis of the liver regulating lipid metabolism in Chaohu ducks using two-dimensional electrophoresis." Open Life Sciences 17, no. 1 (January 1, 2022): 960–72. http://dx.doi.org/10.1515/biol-2022-0101.
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Abstract In this study, we aimed to characterize the liver protein profile of Chaohu ducks using two-dimensional electrophoresis and proteomics. The livers were quickly collected from 120 healthy, 84-day-old Chaohu ducks. The intramuscular fat (IMF) content of the left pectoralis muscle was determined using the Soxhlet extraction method. The total protein of liver tissues from the high and low IMF groups was extracted for proteomics. Functional enrichment analysis of the differentially expressed proteins (DEPs) was conducted using gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG). In total, 43 DEPs were identified. Functional enrichment analysis indicated that these DEPs were significantly related to four lipid metabolic processes: carboxylic acid metabolic process, ATP metabolic process, oxoacid metabolic process, and organic acid metabolic process. Three pathways correlated with lipid metabolism were identified using KEGG analysis: glycolysis/gluconeogenesis, pentose phosphate pathway, fructose, and mannose metabolism. Eight key proteins associated with lipid metabolism were identified: ALDOB, GAPDH, ENO1, RGN, TPI1, HSPA9, PRDX1, and GPX1. Protein–protein interaction analysis revealed that the glycolysis/gluconeogenesis pathway mediated the interaction relationship. Key proteins and metabolic pathways were closely related to lipid metabolism and showed a strong interaction in Chaohu ducks.
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Andrejeva, Gabriela, Melissa M. Wolf, Marc O. Johnson, Alexandra C. Rutledge, Gabriela S. Codreanu, Stacy D. Sherrod, Danielle Gutierrez, et al. "Metabolomics analysis reveals differential T cell serine metabolism as a target in autoimmunity." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 167.7. http://dx.doi.org/10.4049/jimmunol.200.supp.167.7.
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Abstract Inflammatory cytokines are key players in the pathogenesis of autoimmune disorders where their signaling leads to inappropriate balance between effector CD4 T-cells (Teff), Th1 and Th17, and the immunosuppressive regulatory T-cells (Treg). Each subset utilizes a distinctive metabolic program but how cytokines induce differential metabolic rewiring and what aspects of it are critical for the functioning and lineage stability of Teff subsets and Treg is not understood. To delineate pathogenicity-associated metabolic programs, we performed global untargeted metabolomics mass spectrometry (MS) in in vitro cytokine-differentiated mouse Th1, Th17 and Treg cells with varying degrees of pathogenicity over time. Integrating our data-driven metabolic network with global proteomics profiling and cytokine secretion allowed us to examine metabolic pathways at metabolite-enzyme level. Metabolites at the interface of amino acid metabolism, particularly glutamine and serine, glycolysis, the TCA cycle and nucleotide synthesis were the most differentially changed. Serine limitation or pharmacological inhibition indicated differential coupling of serine/one-carbon metabolism to T-cell proliferation, lineage choices and the production of cytokines IL-17 or IFNγ. Furthermore, targeting this pathway promoted Treg lineage development in the presence of pathogenic cytokines and prevented loss of Treg transcription factor FoxP3 upon re-stimulation. In vivo, spinal cord infiltrating T-cells in murine experimental autoimmune encephalomyelitis had altered serine metabolic pathway. Our findings identify key areas of T-cell metabolism that may offer a new category of therapeutic targets for autoimmune and inflammatory disease.