In Vivo Contaminant Monitoring and Metabolomic Profiling in Plants Exposed to Carbamates via a Novel Microextraction Fiber

2021 ◽  
Author(s):  
Shuqin Liu ◽  
Yiquan Huang ◽  
Jian Liu ◽  
Chao Chen ◽  
Gangfeng Ouyang
Keyword(s):  
Contaminant Monitoring ◽  
Metabolomic Profiling

scholarly journals Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasaman Barekatain ◽  
Jeffrey J. Ackroyd ◽  
Victoria C. Yan ◽  
Sunada Khadka ◽  
Lin Wang ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Homozygous Deletion ◽  
In Vitro Models ◽  
Arginine Methyltransferase ◽  
Human Glioblastoma ◽  
Primary Glioblastoma ◽  
Methylthioadenosine Phosphorylase ◽  
Metabolomic Profiling

AbstractHomozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP’s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.

scholarly journals Cardioprotective and Metabolomic Profiling of Selected Medicinal Plants against Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Nadia Afsheen ◽  
Khalil-ur-Rehman ◽  
Nazish Jahan ◽  
Misbah Ijaz ◽  
Asad Manzoor ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Medicinal Plants ◽  
Plasmid Dna ◽  
Research Work ◽  
Antioxidant Potential ◽  
Piper Nigrum ◽  
Coronary Artery Ligation ◽  
Hemodynamic Parameters ◽  
Metabolomic Profiling

In this research work, the antioxidant and metabolomic profiling of seven selected medicinally important herbs including Rauvolfia serpentina, Terminalia arjuna, Coriandrum sativum, Elettaria cardamom, Piper nigrum, Allium sativum, and Crataegus oxyacantha was performed. The in vivo cardioprotective potential of these medicinal plants was evaluated against surgically induced oxidative stress through left anterior descending coronary artery ligation (LADCA) in dogs. The antioxidant profiling of these plants was done through DPPH and DNA protection assay. The C. oxyacantha and T. arjuna showed maximum antioxidant potential, while the E. cardamom showed poor antioxidative strength even at its high concentration. Different concentrations of extracts of the said plants exhibited the protection of plasmid DNA against H2O2 damage as compared to the plasmid DNA merely treated with H2O2. The metabolomic profiling through LC-MS analysis of these antioxidants revealed the presence of active secondary metabolites responsible for their antioxidant potential. During in vivo analysis, blood samples of all treatment groups were drawn at different time intervals to analyze the cardiac and hemodynamic parameters. The results depicted that the group pretreated with HC4 significantly sustained the level of CK-MB, SGOT, and LDH as well as hemodynamic parameters near to normal. The histopathological examination also confirmed the cardioprotective potential of HC4. Thus, the HC4 being safe and inexpensive cardioprotective herbal combination could be considered as an alternate of synthetic drugs.

Metabolomic Profiling of In Vivo Plasma Responses to Dioxin-Associated Dietary Contaminant Exposure in Rats: Implications for Identification of Sources of Animal and Human Exposure

2013 ◽  
Vol 47 (10) ◽  
pp. 5409-5418 ◽  
Author(s):  
Anthony A. O’Kane ◽  
Olivier P. Chevallier ◽  
Stewart F. Graham ◽  
Christopher T. Elliott ◽  
Mark H. Mooney
Keyword(s):  
Human Exposure ◽  
Contaminant Exposure ◽  
Metabolomic Profiling

scholarly journals FSMP-17. GLOBAL METABOLOMIC PROFILING OF GLIOBLASTOMA MULTIFORME REVEALS METABOLIC VULNERABILITIES IN RESPONSE TO RADIATION THERAPY

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i19-i19
Author(s):  
Aarooran Durairaj ◽  
Melanie McReynolds ◽  
Congcong Wang ◽  
Joy He ◽  
Joshua Rabinowitz ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Glioblastoma Multiforme ◽  
Ionizing Radiation ◽  
Aminolevulinic Acid ◽  
Primary Brain Tumor ◽  
Metabolic Reprogramming ◽  
Pharmacological Intervention ◽  
Tumor Microenvironments ◽  
Metabolomic Profiling

Abstract Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, originates in astrocytes and oligodendrocytes and yields a median survival time of less than 2 years and a 5-year survival of 2.5%. There has been little in the way of treatments and novel approaches are needed to combat the poor prognosis of GBM. Recent studies have established that GBM cells exhibit metabolic reprogramming to adapt to diverse metabolic gradients within heterogenous tumor microenvironments. Using an unbiased metabolomics approach, we investigated metabolic changes both pre- and post-ionizing radiation across several patient-derived GBM cell lines. Surprisingly, acute high dosage of ionizing radiation resulted in significant changes in the synthesis of aminolevulinic acid (ALA), a non-proteinogenic amino acid. Fractionation of radiation therapy resulted in dose-dependent changes in the heme synthesis pathway within these cells. Using an orthotopic xenograft mouse model of GBM, we identify several enzymatic vulnerabilities in vivo and discuss a novel combinatorial therapeutic approach of radiation and targeted pharmacological intervention. Our findings reveal the fundamental biosynthetic changes that GBMs adopt when exposed to ionizing irradiation as well as the benefits of a combinatorial approach.

scholarly journals In Vitro and In Vivo Metabolomic Profiling after Infection with Virulent Newcastle Disease Virus

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 962 ◽  
Author(s):  
Panrao Liu ◽  
Yuncong Yin ◽  
Yabin Gong ◽  
Xusheng Qiu ◽  
Yingjie Sun ◽  
...  
Keyword(s):  
Newcastle Disease Virus ◽  
Disease Virus ◽  
Newcastle Disease ◽  
High Performance ◽  
Economic Losses ◽  
Viral Protein Synthesis ◽  
Metabolomic Profiling ◽  
Virulent Newcastle Disease Virus

Newcastle disease (ND) is an acute, febrile, highly contagious disease caused by the virulent Newcastle disease virus (vNDV). The disease causes serious economic losses to the poultry industry. However, the metabolic changes caused by vNDV infection remain unclear. The objective of this study was to determine the metabolomic profiling after infection with vNDV. DF-1 cells infected with the vNDV strain Herts/33 and the lungs from Herts/33-infected specific pathogen-free (SPF) chickens were analyzed via ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS) in combination with multivariate statistical analysis. A total of 305 metabolites were found to have changed significantly after Herts/33 infection, and most of them belong to the amino acid and nucleotide metabolic pathway. It is suggested that the increased pools of amino acids and nucleotides may benefit viral protein synthesis and genome amplification to promote NDV infection. Similar results were also confirmed in vivo. Identification of these metabolites will provide information to further understand the mechanism of vNDV replication and pathogenesis.

Impaired Anaplerosis Is a Major Contributor to Glycolysis Inhibitor Toxicity in Glioma

2020 ◽  
Author(s):  
Sunada Khadka ◽  
Kenisha Arthur ◽  
Mykia Washington ◽  
Yasaman Barekatain ◽  
Jeff Ackroyd ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Single Agent ◽  
Tca Cycle ◽  
Redox Status ◽  
Homozygous Deletion ◽  
Metabolomic Profiling ◽  
Selective Sensitivity ◽  
Homozygous Deletions

Abstract Reprogramming of metabolic pathways is crucial to satisfy the bioenergetic and biosynthetic demands and maintain the redox status of rapidly proliferating cancer cells. In tumors, the tricarboxylic acid (TCA) cycle generates biosynthetic intermediates by oxidation of anaplerotic substrates, such as glucose-derived pyruvate and glutamine20 derived glutamate. We have previously documented that a subset of tumors with 1p36 homozygous deletion exhibit co-deletion of ENO1, in turn becoming extremely dependent on its redundant isoform ENO2 and sensitive to an overall enzymatic deficiency of enolase. Metabolomic profiling of ENO1-deleted glioma cells treated with an enolase inhibitor revealed a profound decrease in TCA cycle metabolites, which correlated with cell-line specific sensitivity to enolase inhibition, highlighting the importance of glycolysis derived pyruvate for anaplerosis. Correspondingly, the toxicity of the enolase inhibitor was significantly attenuated by exogenous supplementation of supraphysiological levels of anaplerotic substrates including pyruvate. These findings led us to hypothesize that cancer cells with ENO1 homozygous deletions treated with an enolase inhibitor might show exceptional sensitivity to inhibition of glutaminolysis because of reduced anaplerotic flow from glycolysis. We found that ENO1-deleted cells indeed exhibited selective sensitivity to the glutaminase inhibitor CB-839, and this sensitivity was also attenuated by exogenous supplementation of anaplerotic substrates including pyruvate. Despite these promising in vitro results, the antineoplastic effects of CB-839 as a single agent in ENO1-deleted xenograft tumors in vivo were modest in both intracranial orthotopic tumors, where the limited efficacy could be attributed to the blood brain barrier (BBB), and subcutaneous xenografts, where BBB penetration is not an issue. This contrasts with the enolase inhibitor HEX, which, despite its negative charge, achieved antineoplastic effects in both intracranial and subcutaneous tumors. Together, these data suggest that at least for 1p36-deleted gliomas, tumors in vivo—unlike cells in culture—show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of the in vitro and in vivo environments as the potential reasons for the differential efficacy of metabolism targeted therapies in in vitro and in vivo systems.

Distinct Metabolic Dependency of Normal and Leukemic Cells in a Mouse Model

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 759-759
Author(s):  
Rushdia Z. Yusuf ◽  
Sanket S. Acharya ◽  
Vionnie Yu ◽  
Borja Saez ◽  
Mildred Duvet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Tca Cycle ◽  
Leukemic Cells ◽  
Mouse Bone Marrow ◽  
Metabolomic Profiling ◽  
Glycolysis Pathway ◽  
Rate Limiting

Abstract Abstract 759 We hypothesized that metabolic differences between leukemia initiating cells and their normal counterparts represent a vulnerability in the leukemia initiating cell, which can be therapeutically exploited. To test this hypothesis, we used the MLL-AF9 acute myeloid leukemia (AML) model in mice. Actin-DsRed mouse bone marrow transduced with MLL-AF9 expressing retrovirus was used to produce serially transplantable leukemia. Leukemic granulocyte-monocyte precursors (L-GMPs), defined by others to be the leukemia initiating cells were flow sorted from secondary recipient mice and compared with normal GMPs (N-GMPs) from actin Ds-Red mice. Gene expression profiling, metabolomic profiling via liquid chromatography- mass spectrometry and an in vitro shRNA screen were used to identify metabolic pathways preferentially activated in leukemia initiating cells. Of 1574 defined metabolic enzymes, 44 were found to be differentially expressed between L-GMPs and their normal counterparts (N-GMPs). These together with 117 classic rate limiting enzymes were subjected to shRNA knockdown in vitro. Metabolomic profiling of both cell populations was used to corroborate findings from shRNA knockdowns. L-GMPs and N-GMPs were transduced with lentivirus expressing shRNAs of interest (5 shRNAs per gene) in a 384 well format, selected with puromycin and cultured for 72–96 hours in the presence of GFP-positive primary bone marrow stroma. The number of cells in each well at the end of this experiment was quantitated using an Image Xpress microscope. Genes, the knockdown of which by at least two independent shRNAs produced a two fold or more decrease in L-GMPs as compared to control wells and did not similarly decrease N-GMPs, were chosen for in vivo validation. Ten genes in the glycolysis pathway and TCA cycle, fatty acid metabolism and detoxification, and ketohexokinase were identified. Ketohexokinase, a rate-limiting enzyme in fructose metabolism was particularly potent and of interest given its potential to be exploited therapeutically. In vivo assessment of its relative ability to inhibit malignant versus normal hematopoietic cells is ongoing. These studies provide preliminary support for the hypothesis that specific metabolic circuits are differentially active in leukemia initiating cells in MLL-AF9 AML and may represent unique points of vulnerability that can be targeted therapeutically. Authors 1 and 2 contributed equally. Authors 3 and 4 contributed equally. Disclosures: No relevant conflicts of interest to declare.

scholarly journals ADO/hypotaurine: a novel metabolic pathway contributing to glioblastoma development

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Dachuan Shen ◽  
Lili Tian ◽  
Fangyu Yang ◽  
Jun Li ◽  
Xiaodong Li ◽  
...  
Keyword(s):  
Metabolic Pathway ◽  
Strong Association ◽  
Predictive Marker ◽  
Significant Advance ◽  
High Grade ◽  
Self Renewal ◽  
Metabolomic Profiling ◽  
Altered Metabolism

AbstractSignificant advance has been made towards understanding glioblastoma metabolism through global metabolomic profiling. However, hitherto little is known about the role by which altered metabolism plays in driving the aggressive glioma phenotype. We have previously identified hypotaurine as one of the top-ranked metabolites for differentiating low- and high-grade tumors, and that there is also a strong association between the levels of intratumoral hypotaurine and expression of its biosynthetic enzyme, cysteamine (2-aminoethanethiol) dioxygenase (ADO). Using transcription profiling, we further uncovered that the ADO/hypotaurine axis targets CCL20 secretion through activating the NF-κB pathway to drive the self-renewal and maintenance of glioma ‘cancer stem cells’ or glioma cancer stem-like cells. Conversely, abrogating the ADO/hypotaurine axis using CRISPR/Cas9-mediated gene editing limited glioblastoma cell proliferation and self-renewal in vitro and tumor growth in vivo in an orthotopical mouse model, indicating that this metabolic pathway is a potential key therapeutic target. Collectively, our results unveil a targetable metabolic pathway, which contributes to the growth and progression of aggressive high-grade gliomas, as well as a novel predictive marker for glioblastoma diagnosis and therapy.

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