Metabolic signatures suggest o-phosphocholine to UDP-N-acetylglucosamine ratio as a potential biomarker for high-glucose and/or palmitate exposure in pancreatic β-cells

Yousf, Saleem; Sardesai, Devika M.; Mathew, Abraham B; Khandelwal, Rashi; Acharya, Jhankar; Sharma, Shilpy; Chugh, Jeetender

doi:10.1007/s11306-019-1516-3

Cited by 17 publications

(14 citation statements)

References 72 publications

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“…The technique has inherent quantitative capabilities (Nagana Gowda et al 2018), high reproducibility, requires minimal sample preparation, is non-destructive for samples and offers the possibility for compound identification by structure elucidation, all essential characteristics for biomarker discovery (Gowda et al 2008). Although NMR spectroscopy is limited by low sensitivity compared to mass spectrometry (Gowda et al 2008) as well as signal overlap in spectra, it continues to find widespread applications (Cheng et al 2019;Mora-Ortiz et al 2019;Turkoglu et al 2019;Yousf et al 2019). When applied to plasma, a number of considerations should be made in regard to its performance in metabolome profiling with respect to optimal sample group separation that can be explained by a solid biochemical background.…”

Section: Introductionmentioning

confidence: 99%

A comparison of high-throughput plasma NMR protocols for comparative untargeted metabolomics

et al. 2020

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Introduction When analyzing the human plasma metabolome with Nuclear Magnetic Resonance (NMR) spectroscopy, the Carr–Purcell–Meiboom–Gill (CPMG) experiment is commonly employed for large studies. However, this process can lead to compromised statistical analyses due to residual macromolecule signals. In addition, the utilization of Trimethylsilylpropanoic acid (TSP) as an internal standard often leads to quantification issues, and binning, as a spectral summarization step, can result in features not clearly assignable to metabolites. Objectives Our aim was to establish a new complete protocol for large plasma cohorts collected with the purpose of describing the comparative metabolic profile of groups of samples. Methods We compared the conventional CPMG approach to a novel procedure that involves diffusion NMR, using the Longitudinal Eddy-Current Delay (LED) experiment, maleic acid (MA) as the quantification reference and peak picking for spectral reduction. This comparison was carried out using the ultrafiltration method as a gold standard in a simple sample classification experiment, with Partial Least Squares–Discriminant Analysis (PLS-DA) and the resulting metabolic signatures for multivariate data analysis. In addition, the quantification capabilities of the method were evaluated. Results We found that the LED method applied was able to detect more metabolites than CPMG and suppress macromolecule signals more efficiently. The complete protocol was able to yield PLS-DA models with enhanced classification accuracy as well as a more reliable set of important features than the conventional CPMG approach. Assessment of the quantitative capabilities of the method resulted in good linearity, recovery and agreement with an established amino acid assay for the majority of the metabolites tested. Regarding repeatability, ~ 85% of all peaks had an adequately low coefficient of variation (< 30%) in replicate samples. Conclusion Overall, our comparison yielded a high-throughput untargeted plasma NMR protocol for optimized data acquisition and processing that is expected to be a valuable contribution in the field of metabolic biomarker discovery.

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Section: Introductionmentioning

confidence: 99%

A comparison of high-throughput plasma NMR protocols for comparative untargeted metabolomics

et al. 2020

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“…Furthermore, it potentially plays a protective role in the intestines within the digestive system. It is also suggested to be a β-cell biomarker, as it is related to beta β-cell apoptosis and dysfunction [58]. When considering amino acid metabolism, this compound can be used to make glycine and serine by different synthetic metabolic pathways.…”

Section: Discussionmentioning

confidence: 99%

The Biochemical Profile of Post-Mortem Brain from People Who Suffered from Epilepsy Reveals Novel Insights into the Etiopathogenesis of the Disease

et al. 2020

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Epilepsy not-otherwise-specified (ENOS) is one of the most common causes of chronic disorders impacting human health, with complex multifactorial etiology and clinical presentation. Understanding the metabolic processes associated with the disorder may aid in the discovery of preventive and therapeutic measures. Post-mortem brain samples were harvested from the frontal cortex (BA8/46) of people diagnosed with ENOS cases (n = 15) and age- and sex-matched control subjects (n = 15). We employed a targeted metabolomics approach using a combination of proton nuclear magnetic resonance (1H-NMR) and direct injection/liquid chromatography tandem mass spectrometry (DI/LC-MS/MS). We accurately identified and quantified 72 metabolites using 1H-NMR and 159 using DI/LC-MS/MS. Among the 212 detected metabolites, 14 showed significant concentration changes between ENOS cases and controls (p < 0.05; q < 0.05). Of these, adenosine monophosphate and O-acetylcholine were the most commonly selected metabolites used to develop predictive models capable of discriminating between ENOS and unaffected controls. Metabolomic set enrichment analysis identified ethanol degradation, butyrate metabolism and the mitochondrial beta-oxidation of fatty acids as the top three significantly perturbed metabolic pathways. We report, for the first time, the metabolomic profiling of postmortem brain tissue form patients who died from epilepsy. These findings can potentially expand upon the complex etiopathogenesis and help identify key predictive biomarkers of ENOS.

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“…Research Articles modulated by varying the glucose concentration in the media without significantly affecting the cellular viability. [40] The cytotoxicity mediated by compound 2 (0-20.0 mm)w as significantly higher in INS-1E cells cultured in low glucose media (i.e., high GSH levels) when compared to those in high glucose media (i.e., low GSH levels) ( Figure 4I,J). As we had hypothesized, compound 3 (0-20.0 mm)d id not induce considerable cytotoxicity in both low and high GSH containing cells,thereby proving that the release of 1b does not take place from 3.…”

Section: Chemiementioning

confidence: 94%

“…[47] Interestingly, MCF-7c ells treated with compound 2 (1.0 mm)for 24 hoursshowed asignificant decrease in thered fluorescence andasimultaneous enhancement in the green emission (Figure5B) when compared to thecontrol cells (Figure5A).T he quantification of ther ed/green ratio ( Fig-ure5C) in treatedcells compared to thecontrol confirmed the enhancementi nt he MMP depolarization. [41a,44b] This was associatedw ithi ncreased generation of both mitochondrial (Figure 5D,green)and cellular ROS( Figure 5D,brown,S25,) as detected by the Mitosox [40] and 2',7'-dichlorodihydrofluorescein diacetate (H 2 DCFDA) [44b,48] dyes,respectively.…”

Section: Chloride Channel Formation and Gsh Depletion Triggers Apoptomentioning

confidence: 99%

A Glutathione Activatable Ion Channel Induces Apoptosis in Cancer Cells by Depleting Intracellular Glutathione Levels

et al. 2020

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Cancer cells use elevated glutathione (GSH) levels as an inner line of defense to evade apoptosis and develop drug resistance.Inthis study,wedescribe anovel 2,4-nitrobenzenesulfonyl (DNS) protected 2-hydroxyisophthalamide system that exploits GSH for its activation into free 2-hydroxyisophthalamide forming supramolecular M + /Cl À channels.Better permeation of the DNS protected compound into MCF-7 cells compared to the free 2-hydroxyisophthalamide and GSHactivatable ion transport resulted in higher cytotoxicity,w hich was associated with increased oxidative stress that further reduced the intracellular GSH levels and altered mitochondrial membrane permeability leading to the induction of the intrinsic apoptosis pathway.T he GSH-activatable transport-mediated cell death was further validated in rat insulinoma cells (INS-1E);w herein the intracellular GSH levels showed ad irect correlation to the resulting cytotoxicity.L astly,t he active compound was found to restrict the growth and proliferation of 3D spheroids of MCF-7 cells with efficiency similar to that of the anticancer drug doxorubicin.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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Metabolic signatures suggest o-phosphocholine to UDP-N-acetylglucosamine ratio as a potential biomarker for high-glucose and/or palmitate exposure in pancreatic β-cells

Cited by 17 publications

References 72 publications

A comparison of high-throughput plasma NMR protocols for comparative untargeted metabolomics

A comparison of high-throughput plasma NMR protocols for comparative untargeted metabolomics

The Biochemical Profile of Post-Mortem Brain from People Who Suffered from Epilepsy Reveals Novel Insights into the Etiopathogenesis of the Disease

A Glutathione Activatable Ion Channel Induces Apoptosis in Cancer Cells by Depleting Intracellular Glutathione Levels

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