Proteo‐Metabolomic Strategies in the Future of Drug Development

Christians, Uwe; Schmitz, Volker; Klawitter, Jost; Klawitter, Jelena

doi:10.1002/9781118271858.ch24

Cited by 5 publications

(9 citation statements)

References 297 publications

(383 reference statements)

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“…Metabolic profiling involves a comprehensive measurement of the types and concentrations of metabolites in a system at a specified time (15,16). Using stored (at 280°C) 24-hour urine collection samples from the final week (i.e., week 5) of each sodium condition, we performed a LC-MS/MS-based analysis of 289 metabolites.…”

Section: Urine Metabolomicsmentioning

confidence: 99%

Effect of Dietary Sodium Restriction on Human Urinary Metabolomic Profiles

Jablonski

Klawitter

Chonchol

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Metabolomics is a relatively new field of "-omics" research, focusing on highthroughput identification of small molecular weight metabolites. Diet has both acute and chronic effects on metabolic profiles; however, alterations in response to dietary sodium restriction (DSR) are completely unknown. The goal of this study was to explore changes in urine metabolites in response to DSR, as well as their association with previously reported improvements in vascular function with DSR.Design, setting, participants, & measurements Using stored urine samples from a 10-week randomized placebo-controlled crossover study of DSR in 17 middle-aged/older adults (six men and 11 women; mean age 6268 years) who had moderately elevated systolic BP (130-159 mmHg) and were otherwise healthy, a liquid chromatography/mass spectrometry-based analysis of 289 metabolites was performed. This study identified metabolites that were significantly altered between the typical (153629 mmol/d) and low (70629 mmol/d) sodium conditions, as well as their baseline (typical sodium) association with responsiveness to previously reported improvements in vascular endothelial function (brachial artery flow-mediated dilation) and large elastic artery stiffness (aortic pulse wave velocity).Results Of the 289 metabolites surveyed, 10 were significantly altered (nine were upregulated and one was downregulated) during the low sodium condition, and eight of these exceeded our prespecified clinically significant threshold of a .40% change. These metabolites were involved in biologic pathways broadly related to cardiovascular risk, nitric oxide production, oxidative stress, osmotic regulation, and metabolism. One metabolite, serine, was independently (positively) associated with previously reported improvements in the primary vascular outcome of brachial artery flow-mediated dilation.Conclusions This proof-of-concept study provides the first evidence that DSR is a stimulus that induces significant changes in urinary metabolomic profiles. Moreover, serine was independently associated with corresponding changes in vascular endothelial function after DSR. Larger follow-up studies will be required to confirm and further elucidate the metabolic pathways that are altered in response to DSR.

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Section: Urine Metabolomicsmentioning

confidence: 99%

Effect of Dietary Sodium Restriction on Human Urinary Metabolomic Profiles

Jablonski

Klawitter

Chonchol

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…78,92,97 In such cases, an appropriate methodspecific adaptation of the validation protocol needs to address all aspects of the assay system. Sometimes, technique-specific analytical characteristics have to be included in the validation protocol, for example, the matrix effects for liquid chromatography-tandem mass spectrometry methods or cell stimulation properties for functional flow-cytometric assays (cytokine release, expression of intracellular and of surface markers), nuclear factor of activated T cell-dependent gene expression, p70s6 kinase activity, or phosphorylation and others.…”

Section: Analytical Performance and Methods Validationmentioning

confidence: 99%

“…77 Moreover, if, for example, metabolic markers have to be measured in plasma, EDTA has the advantage of preventing clotting of the matrix during long-term storage. 78 Although the use of EDTA whole blood can interfere with cell activation, 79-81 this approach may be suitable for flow cytometry. In addition, in the field of kidney transplantation and when investigating renal toxicity (eg, by therapy with calcineurin inhibitors), urine may represent a more informative source for biomarker assessment.…”

Section: Sample Matrixmentioning

confidence: 99%

“…78 Sample storage is a very important issue when dealing with biomarker analyses, as most analytes are largely instable and samples should usually be processed in a very short time. For example, the determination of cell characteristics, such as surface markers or the expression/release of intracellular molecules, should generally entail analysis within 24 hours (Tables 1 and 2), sometimes even 2-4 hours after blood collection.…”

Section: Sample Storagementioning

confidence: 99%

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Analytical Aspects of the Implementation of Biomarkers in Clinical Transplantation

Shipkova

López

Picard

et al. 2016

Therapeutic Drug Monitoring

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In response to the urgent need for new reliable biomarkers to complement the guidance of the immunosuppressive therapy, a huge number of biomarker candidates to be implemented in clinical practice have been introduced to the transplant community. This includes a diverse range of molecules with very different molecular weights, chemical and physical properties, ex vivo stabilities, in vivo kinetic behaviors, and levels of similarity to other molecules, etc. In addition, a large body of different analytical techniques and assay protocols can be used to measure biomarkers. Sometimes, a complex software-based data evaluation is a prerequisite for appropriate interpretation of the results and for their reporting. Although some analytical procedures are of great value for research purposes, they may be too complex for implementation in a clinical setting. Whereas the proof of "fitness for purpose" is appropriate for validation of biomarker assays used in exploratory drug development studies, a higher level of analytical validation must be achieved and eventually advanced analytical performance might be necessary before diagnostic application in transplantation medicine. A high level of consistency of results between laboratories and between methods (if applicable) should be obtained and maintained to make biomarkers effective instruments in support of therapeutic decisions. This overview focuses on preanalytical and analytical aspects to be considered for the implementation of new biomarkers for adjusting immunosuppression in a clinical setting and highlights critical points to be addressed on the way to make them suitable as diagnostic tools. These include but are not limited to appropriate method validation, standardization, education, automation, and commercialization.

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“…R ecent advances in proteomics and biochemical profiling have validated numerous cell metabolite markers linked to disease progression, prognosis, and response to therapeutics (Christians et al, 2012). Quantitative detection of the metabolites obtainable from patients' urine and serum samples, therefore, can be developed into monitoring disease progression, therapy outcome, and drug toxicity.…”

Section: Introductionmentioning

confidence: 99%

Sol-Gel SELEX Circumventing Chemical Conjugation of Low Molecular Weight Metabolites Discovers Aptamers Selective to Xanthine

Bae

Ren

Kang

et al. 2013

Nucleic Acid Therapeutics

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Sensitive detection of the metabolites indicative of a particular disease contributes to improved therapy outcomes. Developing binding reagents for detection of low molecular weight metabolites is hampered by the difficulty with immobilization of targets through appropriate covalent chemical linkage while ensuring that selected reagents retain specificity to unmodified metabolites. To circumvent chemical modification of targets, we employed sol-gel droplets deposited onto a porous silicon chip to entrap a purine metabolite, xanthine, which was found at lower levels in urine samples from patients with non-Hodgkin lymphoma. By sol-gel SELEX (systematic evolution of ligands by exponential enrichment) against xanthine, specific aptamers (KD ∼ 10 μM) with sensitivity of detection at as low as 1 μM were isolated, which bound to other purine metabolites at more than 100-fold lower affinity. In contrast, we failed to isolate xanthine-specific aptamers when SELEX was performed against xanthine covalently linked to polymer resin. This study demonstrates that the sol-gel platform for entrapping low molecular weight metabolites without chemical modifications can be utilized for SELEX to discover aptamers against clinical metabolite markers for diagnosis application.

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Proteo‐Metabolomic Strategies in the Future of Drug Development

Cited by 5 publications

References 297 publications

Effect of Dietary Sodium Restriction on Human Urinary Metabolomic Profiles

Effect of Dietary Sodium Restriction on Human Urinary Metabolomic Profiles

Analytical Aspects of the Implementation of Biomarkers in Clinical Transplantation

Sol-Gel SELEX Circumventing Chemical Conjugation of Low Molecular Weight Metabolites Discovers Aptamers Selective to Xanthine

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