Metabolic Alterations in Preneoplastic Development Revealed by Untargeted Metabolomic Analysis

Metabolic rewiring is a critical hallmark of tumorigenesis and is essential for the development of cancer. Although many key features of metabolic alteration that are crucial for tumor cell survival, proliferation and progression have been identified, these are obtained from studies with established tumors and cancer cell lines. However, information on the essential metabolic changes that occur during pre-neoplastic cell (PNC) development that enables its progression to full blown tumor is still lacking. Here, we present an untargeted metabolomics analysis of human oncogene HRASG12V induced PNC development, using a transgenic inducible zebrafish larval skin development model. By comparison with normal sibling controls, we identified six metabolic pathways that are significantly altered during PNC development in the skin. Amongst these altered pathways are pyrimidine, purine and amino acid metabolism that are common to the cancer metabolic changes that support rapid cell proliferation and growth. Our data also suggest alterations in post transcriptional modification of RNAs that might play a role in PNC development. Our study provides a proof of principle work flow for identifying metabolic alterations during PNC development driven by an oncogenic mutation. In the future, this approach could be combined with transcriptomic or proteomic approaches to establish the detailed interaction between signaling networks and cellular metabolic pathways that occur at the onset of tumor progression.

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Key hepatic metabolic pathways are altered in germ-free mice during pregnancy

PLoS ONE ◽

10.1371/journal.pone.0248351 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248351

Author(s):

Lyrialle W. Han ◽

Yuanyuan Shi ◽

Alison Paquette ◽

Lu Wang ◽

Theo K. Bammler ◽

...

Keyword(s):

Fetal Development ◽

Metabolic Pathways ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Metabolic Changes ◽

Metabolic Processes ◽

Metabolomics Data ◽

Germ Free ◽

Pregnant Mice ◽

Host Metabolism

Pregnancy is associated with metabolic changes to accommodate the mother and her growing fetus. The microbiome has been shown to modulate host metabolism of endogenous and exogenous substances. However, the combined effects of pregnancy and the microbiome on host metabolism have not been investigated. The objective of this study was to investigate how the microbiome affects overall hepatic metabolic processes during pregnancy. We assessed these changes within 4 groups of C57BL/6 mice: conventional non-pregnant, conventional pregnant, germ-free non-pregnant, and germ-free pregnant mice. We performed RNA-seq analysis on liver tissues and LC-MS/MS analysis of the plasma to assess the effects of pregnancy and the microbiome on hepatic transcriptome and untargeted plasma metabolome to describe metabolic changes as results of both pregnancy and lack of microbiome. By integrating transcriptomics and metabolomics data, we identified eight metabolic pathways that were significantly enriched for differentially expressed genes associated with pregnancy in both conventional and germ-free mice. Notably, of the eight pathways, 4 pathways (retinol metabolism, arachidonic acid metabolism, linoleic acid metabolism, and steroid hormone biosynthesis) which are all critical for normal pregnancy and fetal development were affected by the germ-free status in pregnant mice, but not at all in non-pregnant mice, indicating that the alterations in these four pathways caused by the lack of microbiome are unique for pregnancy. These results provide novel insight into the role of the microbiome in modulating host metabolic processes critical for maternal health and fetal development during pregnancy.

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Comprehensive transcriptome and metabolome profiling reveal metabolic mechanisms of Nitraria sibirica Pall. to salt stress

Scientific Reports ◽

10.1038/s41598-021-92317-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Huanyong Li ◽

Xiaoqian Tang ◽

Xiuyan Yang ◽

Huaxin Zhang

Keyword(s):

Salt Stress ◽

Amino Acid ◽

Salt Tolerance ◽

Metabolic Pathways ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Sulfur Metabolism ◽

Enrichment Analysis ◽

Extracellular Region ◽

Nitraria Sibirica

AbstractNitraria sibirica Pall., a typical halophyte that can survive under extreme drought conditions and in saline-alkali environments, exhibits strong salt tolerance and environmental adaptability. Understanding the mechanism of molecular and physiological metabolic response to salt stress of plant will better promote the cultivation and use of halophytes. To explore the mechanism of molecular and physiological metabolic of N. sibirica response to salt stress, two-month-old seedlings were treated with 0, 100, and 400 mM NaCl. The results showed that the differentially expressed genes between 100 and 400 mmol L−1 NaCl and unsalted treatment showed significant enrichment in GO terms such as binding, cell wall, extemal encapsulating structure, extracellular region and nucleotide binding. KEGG enrichment analysis found that NaCl treatment had a significant effect on the metabolic pathways in N. sibirica leaves, which mainly including plant-pathogen interaction, amino acid metabolism of the beta alanine, arginine, proline and glycine metabolism, carbon metabolism of glycolysis, gluconeogenesis, galactose, starch and sucrose metabolism, plant hormone signal transduction and spliceosome. Metabolomics analysis found that the differential metabolites between the unsalted treatment and the NaCl treatment are mainly amino acids (proline, aspartic acid, methionine, etc.), organic acids (oxaloacetic acid, fumaric acid, nicotinic acid, etc.) and polyhydric alcohols (inositol, ribitol, etc.), etc. KEGG annotation and enrichment analysis showed that 100 mmol L−1 NaCl treatment had a greater effect on the sulfur metabolism, cysteine and methionine metabolism in N. sibirica leaves, while various amino acid metabolism, TCA cycle, photosynthetic carbon fixation and sulfur metabolism and other metabolic pathways have been significantly affected by 400 mmol L−1 NaCl treatment. Correlation analysis of differential genes in transcriptome and differential metabolites in metabolome have found that the genes of AMY2, BAM1, GPAT3, ASP1, CML38 and RPL4 and the metabolites of L-cysteine, proline, 4-aminobutyric acid and oxaloacetate played an important role in N. sibirica salt tolerance control. This is a further improvement of the salt tolerance mechanism of N. sibirica, and it will provide a theoretical basis and technical support for treatment of saline-alkali soil and the cultivation of halophytes.

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Redox, amino acid, and fatty acid metabolism intersect with bacterial virulence in the gut

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1813451115 ◽

2018 ◽

Vol 115 (45) ◽

pp. E10712-E10719 ◽

Cited By ~ 12

Author(s):

Reed Pifer ◽

Regan M. Russell ◽

Aman Kumar ◽

Meredith M. Curtis ◽

Vanessa Sperandio

Keyword(s):

Fatty Acid ◽

High Throughput ◽

Fatty Acid Metabolism ◽

Metabolic Pathways ◽

Virulence Genes ◽

Acid Metabolism ◽

Feedback Mechanism ◽

Regulatory Pathways ◽

Successful Infection ◽

Cellular Circuits

The gut metabolic landscape is complex and is influenced by the microbiota, host physiology, and enteric pathogens. Pathogens have to exquisitely monitor the biogeography of the gastrointestinal tract to find a suitable niche for colonization. To dissect the important metabolic pathways that influence virulence of enterohemorrhagicEscherichia coli(EHEC), we conducted a high-throughput screen. We generated a dataset of regulatory pathways that control EHEC virulence expression under anaerobic conditions. This unraveled that the cysteine-responsive regulator, CutR, converges with the YhaO serine import pump and the fatty acid metabolism regulator FadR to optimally control virulence expression in EHEC. CutR activates expression of YhaO to increase activity of the YhaJ transcription factor that has been previously shown to directly activate the EHEC virulence genes. CutR enhances FadL, which is a pump for fatty acids that represses inhibition of virulence expression by FadR, unmasking a feedback mechanism responsive to metabolite fluctuations. Moreover, CutR and FadR also augment murine infection byCitrobacter rodentium, which is a murine pathogen extensively employed as a surrogate animal model for EHEC. This high-throughput approach proved to be a powerful tool to map the web of cellular circuits that allows an enteric pathogen to monitor the gut environment and adjust the levels of expression of its virulence repertoire toward successful infection of the host.

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The Diverse Functions of Non-Essential Amino Acids in Cancer

Cancers ◽

10.3390/cancers11050675 ◽

2019 ◽

Vol 11 (5) ◽

pp. 675 ◽

Cited By ~ 25

Author(s):

Bo-Hyun Choi ◽

Jonathan L. Coloff

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Cancer Therapy ◽

Metabolic Pathways ◽

Essential Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Essential Amino Acids ◽

Redox Status ◽

Antioxidant Systems

Far beyond simply being 11 of the 20 amino acids needed for protein synthesis, non-essential amino acids play numerous important roles in tumor metabolism. These diverse functions include providing precursors for the biosynthesis of macromolecules, controlling redox status and antioxidant systems, and serving as substrates for post-translational and epigenetic modifications. This functional diversity has sparked great interest in targeting non-essential amino acid metabolism for cancer therapy and has motivated the development of several therapies that are either already used in the clinic or are currently in clinical trials. In this review, we will discuss the important roles that each of the 11 non-essential amino acids play in cancer, how their metabolic pathways are linked, and how researchers are working to overcome the unique challenges of targeting non-essential amino acid metabolism for cancer therapy.

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Metabolic Profiling Revealed Dysregulated Arachidonic Acid Metabolism and Tryptophan Metabolism in the Lungs from Canines with Pacing-induced Heart Failure

10.21203/rs.3.rs-96585/v1 ◽

2020 ◽

Author(s):

Junhan Zhao ◽

Jing Wang ◽

Shengwen Yang ◽

Ran Jing ◽

Xi Liu ◽

...

Keyword(s):

Heart Failure ◽

Arachidonic Acid ◽

Metabolic Pathways ◽

Sham Group ◽

Acid Metabolism ◽

Congestion Management ◽

Arachidonic Acid Metabolism ◽

Tryptophan Metabolism ◽

Negative Ion ◽

Metabolic Signatures

Abstract Background: Lung has critical pathophysiological connections to heart and lung congestion presents one of the hallmark features of heart failure (HF). This study aimed to explore the metabolic signatures and disturbances in lungs under HF condition and provide insights on the pathophysiology of the lungs under HF condition from the perspective of metabolism.Methods: In this study, we established a rapid pacing induced HF canine model and applied a comprehensive untargeted metabolomics method to comparatively assessed the metabolomics profiles in the lung tissues from HF group and sham group. Results: Distinct metabolic signatures were identified in the lungs between beagles in HF group and sham group. 81 dysregulated metabolites were identified as differential metabolites (adjusted P <0.05, FC≥2 or≤0.5) in positive ion mode and 80 dysregulated metabolites in negative ion mode, indicating a profound metabolic alteration in the lungs under HF condition. In pathway analysis, arachidonic acid metabolism and tryptophan metabolism were identified as the most significant dysregulated metabolic pathways in the lungs from HF beagles.Conclusions: In this study, we identified profound metabolic variation and dysregulated metabolic pathways, which may deepen our understanding on the pathophysiology of the lungs under HF condition from the perspective of metabolism and open new avenues in lung congestion management in HF.

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Level of Arachidonic Acid and State of Peroxidation Processes in Patients with Aspirin-Intolerant Polypous Rhinosinusitis

Galician Medical Journal ◽

10.21802/gmj.2016.4.10 ◽

2016 ◽

Vol 23 (4) ◽

pp. 2016410

Author(s):

Ivanna Koshel

Keyword(s):

Arachidonic Acid ◽

Metabolic Pathways ◽

Acid Metabolism ◽

Serum Proteins ◽

Arachidonic Acid Metabolism ◽

Oxidative Modification ◽

Key Enzyme ◽

Protein Peroxidation ◽

Genetic Block ◽

Peroxidation Processes

The main peculiarity of aspirin-intolerant polypous rhinosinusitis pathogenesis is the presence of “genetic block” of constitutive cyclooxygenase being the key enzyme of the arachidonic acid metabolism. It justifies the necessity of studying its metabolic peculiarities.The objective of the research was to determine the level of arachidonic acid as well as the state of lipid and protein peroxidation processes in patients with aspirin-intolerant polypous rhinosinusitis.Materials and methods. The levels of arachidonic acid, malondialdehyde and oxidative modification of serum proteins were studied in 20 patients with aspirin-intolerant polypous rhinosinusitis and 7 healthy individuals.Results. Significantly elevated levels of arachidonic levels were observed. The search for alternative metabolic pathways stimulated lipid and protein peroxidation processes and led to the increase in the levels of malondialdehyde and oxidative modification of serum proteins. The peculiarities of biochemical changes indicated pro-inflammatory orientation of lipid metabolism.Conclusions. The obtained data confirmed the hypothesis of “genetic block” of the arachidonic acid metabolism as the main pathogenetic component of aspirin-intolerant polypous rhinosinusitis and allowed us to clearly interpret biochemical picture of the disease.

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Analysis of Serum Metabolomics in Rats with Osteoarthritis by Mass Spectrometry

Molecules ◽

10.3390/molecules26237181 ◽

2021 ◽

Vol 26 (23) ◽

pp. 7181

Author(s):

Jingtong Zhao ◽

Meng Liu ◽

Tongfei Shi ◽

Mohan Gao ◽

Yuqian Lv ◽

...

Keyword(s):

Mass Spectrometry ◽

Metabolic Pathways ◽

Acid Metabolism ◽

Principal Component ◽

Male Rats ◽

Control Group ◽

Liquid Chromatography Mass Spectrometry ◽

Disease Mechanisms ◽

Periarticular Tissue ◽

Serum Metabolomics

Osteoarthritis is a common multifactorial chronic disease that occurs in articular cartilage, subchondral bone, and periarticular tissue. The pathogenesis of OA is still unclear. To investigate the differences in serum metabolites between OA and the control group, liquid chromatography/mass spectrometry (LC/MS)-based metabolomics was used. To reveal the pathogenesis of OA, 12 SD male rats were randomly divided into control and OA groups using collagenase to induce OA for modeling, and serum was collected 7 days after modeling for testing. The OA group was distinguished from the control group by principal component analysis and orthogonal partial least squares-discriminant analysis, and six biomarkers were finally identified. These biomarkers were metabolized through tryptophan metabolism, glutamate metabolism, nitrogen metabolism, spermidine metabolism, and fatty acid metabolism pathways. The study identified metabolites that may be altered in OA, suggesting a role in OA through relevant metabolic pathways. Metabolomics, as an important tool for studying disease mechanisms, provides useful information for studying the metabolic mechanisms of OA.

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Xuebijing Injection Affects the Dynamic Change of Metabolism in CLP-Induced Septic Rats

10.21203/rs.3.rs-526582/v1 ◽

2021 ◽

Author(s):

Yanjuan Liu ◽

Qi Zeng ◽

Wen Xiao ◽

Fang Chen ◽

Lianhong Zou ◽

...

Keyword(s):

Amino Acid ◽

Metabolic Pathways ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Dynamic Change ◽

Sepsis Group ◽

Control Group ◽

Multivariate Statistical ◽

Xuebijing Injection ◽

Kegg Pathway Analysis

Abstract Xuebijing injection has been widely applied to treat sepsis. However, its roles in the dynamic change of metabolism in sepsis are still unknown. In our study, Gas chromatography-mass spectrometer (GC-MS) combined with multivariate statistical techniques was used to detect the metabolic change in septic rats with or without XBJ injection treatment. The KEGG pathway analysis was used to further analyze the related metabolic pathways in which the identified metabolites were involved. Based on the fold change, variable important in projection, and P value, we found 11, 33 and 26 differential metabolites in the sepsis group at 2, 6 and 12 hours post CLP, compared with the control group. Besides, we also found 32, 23 and 28 differential metabolites in the XBJ group at 2, 6 and 12 hours post CLP. The related pathways of differential metabolites were glycometabolism at 2h, glycometabolism and amino acid metabolism at 6h and amino acid metabolism at 12h post CLP in the sepsis group compared with the control group. Besides, glycometabolism, amino acid metabolism and lipid metabolism changed markedly after XBJ injection for 2 hours; while only amino acid metabolism changed significantly with the treatment of XBJ injection for 6 and 12 hours, compared with the sepsis group. Further analysis showed 3, 6 and 6 differential metabolites were overlapped in the sepsis group and XBJ group at 2, 6 and 12 hours post CLP. These identified differential metabolites were majorly involved in arginine and proline metabolism, suggesting that XBJ injection is capable of improving metabolic disorders in CLP-induced septic rat to a certain extent.

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Spatially resolved metabolomics to discover tumor-associated metabolic alterations

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1808950116 ◽

2018 ◽

Vol 116 (1) ◽

pp. 52-57 ◽

Cited By ~ 52

Author(s):

Chenglong Sun ◽

Tiegang Li ◽

Xiaowei Song ◽

Luojiao Huang ◽

Qingce Zang ◽

...

Keyword(s):

Metabolic Pathways ◽

Fatty Acid Biosynthesis ◽

Spatial Information ◽

Tumor Therapy ◽

Metabolic Enzymes ◽

Metabolic Reprogramming ◽

Glutamine Metabolism ◽

Ionization Mass ◽

Metabolic Alterations ◽

Spatially Resolved

Characterization of tumor metabolism with spatial information contributes to our understanding of complex cancer metabolic reprogramming, facilitating the discovery of potential metabolic vulnerabilities that might be targeted for tumor therapy. However, given the metabolic variability and flexibility of tumors, it is still challenging to characterize global metabolic alterations in heterogeneous cancer. Here, we propose a spatially resolved metabolomics approach to discover tumor-associated metabolites and metabolic enzymes directly in their native state. A variety of metabolites localized in different metabolic pathways were mapped by airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) in tissues from 256 esophageal cancer patients. In combination with in situ metabolomics analysis, this method provided clues into tumor-associated metabolic pathways, including proline biosynthesis, glutamine metabolism, uridine metabolism, histidine metabolism, fatty acid biosynthesis, and polyamine biosynthesis. Six abnormally expressed metabolic enzymes that are closely associated with the altered metabolic pathways were further discovered in esophageal squamous cell carcinoma (ESCC). Notably, pyrroline-5-carboxylate reductase 2 (PYCR2) and uridine phosphorylase 1 (UPase1) were found to be altered in ESCC. The spatially resolved metabolomics reveal what occurs in cancer at the molecular level, from metabolites to enzymes, and thus provide insights into the understanding of cancer metabolic reprogramming.

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Combined signature of rumen microbiome and metabolome in dairy cows with different feed intake levels

Journal of Animal Science ◽

10.1093/jas/skaa070 ◽

2020 ◽

Vol 98 (3) ◽

Cited By ~ 1

Author(s):

Yeqing Q Li ◽

Yumeng M Xi ◽

Zedong D Wang ◽

Hanfang F Zeng ◽

Zhaoyu Han

Keyword(s):

Linoleic Acid ◽

Dairy Cows ◽

Linolenic Acid ◽

Relative Abundance ◽

Feed Intake ◽

Metabolic Pathways ◽

Acid Metabolism ◽

Ruminal Fermentation ◽

Alpha Linolenic Acid ◽

Rumen Microbiome

Abstract Feed intake is a major factor in maintaining the balance between ruminal fermentation and the microbial community of dairy cows. To explore the relationship among feed intake, microbial metabolism, and ruminal fermentation, we examined the combined signatures of the microbiome and metabolome in dairy cows with different feed intake levels. Eighteen dairy cows were allocated to high feed intake (HFI), medium feed intake (MFI), and low feed intake (LFI) groups according to their average daily feed intake. 16S rDNA sequencing results revealed that the relative abundance of Firmicutes in the HFI group was significantly higher than that in the MFI and LFI groups (P < 0.05). The ratio of Bacteroidetes to Firmicutes was significantly lower in the HFI group than in the MFI and LFI groups (P < 0.05). The relative abundance of Lachnospiraceae_unclassified, Veillonellaceae_unclassified, and Saccharofermentants was significantly higher in the HFI group than in the LFI and MFI groups (P < 0.05). The relative abundance of Erysipelotrichaceae_unclassified and Butyrivibrio was significantly higher in the HFI group than in the MFI and LFI groups (P < 0.05). Ultra high performance liquid chromatography-mass spectrometry revealed five key pathways, including the linoleic acid metabolism pathway, alpha-linolenic acid metabolism, arginine and proline metabolism, glutathione metabolism, and valine, leucine, and isoleucine biosynthesis, which are closely related to energy and amino acid metabolism. Linoleic acid, glutamate, alpha-linolenic acid, l-methionine, and l-valine levels were significantly lower in the HFI group than in the MFI and LFI groups (q < 0.05), while the relative content of glutamate was significantly lower in the MFI group than in the LFI group (q < 0.05). Stearic acid content was significantly higher in the HFI group than in the LFI group (q < 0.05). Our findings provide insight into the rumen microbiome of dairy cows with different feed intake and the metabolic pathways closely associated with feed intake in early-lactating cows. The candidates involved in these metabolic pathways may be useful for identifying variations in feed intake. The signatures of the rumen microbiome and metabolome in dairy cows may help make decisions regarding feeding.

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