Dataset Information

Rabbit plasma metabolomic analysis of Nitroproston: a multi target natural prostaglandin based-drug (Untargeted study)

ABSTRACT: INTRODUCTION: Nitroproston® is a novel multi-target drug bearing natural prostaglandin E2 (PGE2) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e. asthma and obstructive bronchitis).
OBJECTIVES: To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo.
METHODS: Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without the drug (vehicle control group) to 12 rabbits (n=6 in each group). Untargeted (5880 initial features; 1869 negative-4011 positive ion peaks; UPLC-IT-TOF/MS) and 84 targeted moieties (Nitroproston® related metabolites, prostaglandins, steroids, purines, pyrimidines and amino acids; HPLC-QQQ-MS/MS) were measured from plasma at 0, 2, 4, 6, 8, 12, 18, 24, 32 and 60 minutes after administration.
RESULTS: PGE2, 13,14-dihydro-15-keto-PGE2, PGB2, 1,3-GDN and 15-keto-PGE2 increased in the treatment group. Steroids (i.e. cortisone, progesterone), organic acids, 3-oxododecanoic acid, nicotinate D-ribonucleoside, thymidine, the amino acids serine and aspartate, and derivatives pyridinoline, aminoadypic acid and uric acid increased (p<0.05 AUCROC curve >0.75) after treatment. Purines (i.e. xanthine, guanine, guanosine), bile acids, acylcarnitines and the amino acids L-tryptophan and L-phenylalanine were decreased. Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling pathways, among others.
CONCLUSION: Nitroproston®, a multi action novel drug based on natural prostaglandins, altered metabolites previously implicated as having anti inflammatory or anti-asthma properties (i.e. guanine, adenine, cortisol, cortisone and aspartate). Steroids, purine, urea and ammonia biological cycles were impacted. Mechanisms of action, metabolic pathway interconnections and useful information to further understand the metabolic effects of prostaglandin administration are presented.

The untargeted study data is reported in the current study MTBLS727.
The targeted study data associated with this study is reported in MTBLS728.

Linked Studies: MTBLS728

INSTRUMENT(S): Liquid Chromatography Tandem MS (LC-MS/MS)

SUBMITTER: Ksenia Shestakova

PROVIDER: MTBLS727 | MetaboLights | 2019-08-27

REPOSITORIES: MetaboLights

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Rabbit plasma metabolomic analysis of Nitroproston®: a multi target natural prostaglandin based-drug.

Shestakova Ksenia K Brito Alex A Mesonzhnik Natalia V NV Moskaleva Natalia E NE Kurynina Ksenia O KO Grestskaya Natalia M NM Serkov Igor V IV Lyubimov Igor I II Bezuglov Vladimir V VV Appolonova Svetlana A SA

Metabolomics : Official journal of the Metabolomic Society 20180820 9

<h4>Introduction</h4>Nitroproston® is a novel multi-target drug bearing natural prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e., asthma and obstructive bronchitis).<h4>Objectives</h4>To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo.<h4>Methods</h4>Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without th ...[more]

PMID: 30830378

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Project description:INTRODUCTION: Nitroproston® is a novel multi-target drug bearing natural prostaglandin E2 (PGE2) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e. asthma and obstructive bronchitis). </br> OBJECTIVES: To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo. </br> METHODS: Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without the drug (vehicle control group) to 12 rabbits (n=6 in each group). Untargeted (5880 initial features; 1869 negative-4011 positive ion peaks; UPLC-IT-TOF/MS) and 84 targeted moieties (Nitroproston® related metabolites, prostaglandins, steroids, purines, pyrimidines and amino acids; HPLC-QQQ-MS/MS) were measured from plasma at 0, 2, 4, 6, 8, 12, 18, 24, 32 and 60 minutes after administration. </br> RESULTS: PGE2, 13,14-dihydro-15-keto-PGE2, PGB2, 1,3-GDN and 15-keto-PGE2 increased in the treatment group. Steroids (i.e. cortisone, progesterone), organic acids, 3-oxododecanoic acid, nicotinate D-ribonucleoside, thymidine, the amino acids serine and aspartate, and derivatives pyridinoline, aminoadypic acid and uric acid increased (p<0.05 AUCROC curve >0.75) after treatment. Purines (i.e. xanthine, guanine, guanosine), bile acids, acylcarnitines and the amino acids L-tryptophan and L-phenylalanine were decreased. Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling pathways, among others. </br> CONCLUSION: Nitroproston®, a multi action novel drug based on natural prostaglandins, altered metabolites previously implicated as having anti inflammatory or anti-asthma properties (i.e. guanine, adenine, cortisol, cortisone and aspartate). Steroids, purine, urea and ammonia biological cycles were impacted. Mechanisms of action, metabolic pathway interconnections and useful information to further understand the metabolic effects of prostaglandin administration are presented. </br></br> The targeted study data is reported in the current study MTBLS728. </br> The untargeted study data associated with this study is reported in MTBLS727. </br><br/> Linked Studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS727' target='_blank'><span class='label label-success'>MTBLS727</span></a>

Project description:INTRODUCTION: Nitroproston® is a novel multi-target drug bearing natural prostaglandin E2 (PGE2) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e. asthma and obstructive bronchitis). </br> OBJECTIVES: To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo. </br> METHODS: Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without the drug (vehicle control group) to 12 rabbits (n=6 in each group). Untargeted (5880 initial features; 1869 negative-4011 positive ion peaks; UPLC-IT-TOF/MS) and 84 targeted moieties (Nitroproston® related metabolites, prostaglandins, steroids, purines, pyrimidines and amino acids; HPLC-QQQ-MS/MS) were measured from plasma at 0, 2, 4, 6, 8, 12, 18, 24, 32 and 60 minutes after administration. </br> RESULTS: PGE2, 13,14-dihydro-15-keto-PGE2, PGB2, 1,3-GDN and 15-keto-PGE2 increased in the treatment group. Steroids (i.e. cortisone, progesterone), organic acids, 3-oxododecanoic acid, nicotinate D-ribonucleoside, thymidine, the amino acids serine and aspartate, and derivatives pyridinoline, aminoadypic acid and uric acid increased (p<0.05 AUCROC curve >0.75) after treatment. Purines (i.e. xanthine, guanine, guanosine), bile acids, acylcarnitines and the amino acids L-tryptophan and L-phenylalanine were decreased. Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling pathways, among others. </br> CONCLUSION: Nitroproston®, a multi action novel drug based on natural prostaglandins, altered metabolites previously implicated as having anti inflammatory or anti-asthma properties (i.e. guanine, adenine, cortisol, cortisone and aspartate). Steroids, purine, urea and ammonia biological cycles were impacted. Mechanisms of action, metabolic pathway interconnections and useful information to further understand the metabolic effects of prostaglandin administration are presented. </br></br> The untargeted study data is reported in the current study MTBLS727. </br> The targeted study data associated with this study is reported in MTBLS728. </br><br/> Linked Studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS728' target='_blank'><span class='label label-success'>MTBLS728</span></a>

Project description:Drug-induced alterations in transcriptional regulation play a central role in establishing the persistent neuroplasticities that occur during drug addiction. Additionally, changes in gene expression associated with drug administration provide valuable insight into the molecular basis of drug abuse. The molecular mechanisms that underlie susceptibility to psychostimulant addiction remain unknown. Identifying the common gene transcriptional responses to psychostimulants can provide a mechanistic insight to elucidate the molecular nature of drug dependence. Male Wistar rats (4 weeks old) were acclimatized for a week to their housing conditions prior to experiments. Thereafter, they were divided into two groups: (cohort 1) 4 groups of rats (n=12 rats per group) given saline only (i.p., "drug-naive" rats); and (cohort 2): 3 groups of rats given either methamphetamine, amphetamine or methylphenidate (5 mg/kg,i.p., M-CM-"M-bM-^BM-,M-EM-^Sdrug-pretreated") for 7 days (2x daily) prior to behavioral assays. Conditioned place preference (CPP) tests were conducted a day after the final drug administration. Rats which showed CPP were evaluated for self-administration of the psychostimulants. [Cohort 1] A day after the final self-administration test, brains of 2-3 rats from each subgroups (i.e. those which showed the most robust self-administration), as well as 5 rats from the control group were removed for microarray analysis. The striatum (rostral part of the caudate putamen and the nucleus accumbens [NAc]) and the prefrontal cortex were dissected and immediately frozen at -70M-CM-^BM-BM-0C. Total RNA was isolated and gene expression profiling was conducted on independent pools of total RNA from 2-5 animals per group. [Cohort 2] A day after the final self-administration test, brains of 3 rats from each subgroups (i.e. those which showed the most robust self-administration), as well as 3 rats from the control group were removed for microarray analysis. The striatum (rostral part of the caudate putamen and the nucleus accumbens [NAc]) and the prefrontal cortex were dissected and immediately frozen at -70M-BM-0C. Total RNA was isolated and gene expression profiling was conducted on independent pools of total RNA from three animals per group.

Project description:Rationale: Steroids are the mainstay of asthma therapy. However, it is unclear whether the benefits of steroids in asthma are merely based on anti-inflammatory properties. Steroids may also alter gene expression of airway smooth muscle (ASM). Hypothesis and Aims: We hypothesized that the transcriptomic profile of the ASM layer in endobronchial biopsies of atopic asthma patients changes by oral steroid therapy. First, we examined the change in ASM transcriptomic profile in endobronchial biopsies after 14 days of oral steroid therapy. Second, we investigated the association between changes in ASM transcriptomic profile and airway function. Methods: 12 atopic steroid-free asthma patients were included in this double-blind intervention study. Endobronchial biopsies were taken before and after 14 days of oral prednisolon (n=6) or placebo (n=6). RNA of laser-dissected ASM was sequenced (RNA-Seq) using the GS FLX+ System (454/Roche). Gene networks were identified using Ingenuity Pathway Analysis. RNA-Seq reads were assumed to follow a negative binomial distribution. At the current sample size the estimated false discovery rate was approximately 3%. Results: 15 genes were significantly changed by 14 days of oral prednisolon. 2 of these genes (FAM129A, SYNPO2) were associated with the methacholine PC20 (r=0.637, p=0.035; r=0.662, p=0.027). Pathway analysis revealed 3 gene networks that were associated with cellular functions including cellular growth, proliferation, and development. Conclusion: Oral prednisolon changes the gene expression profile of the ASM layer in asthma. This indicates that steroids also exert effects on the transcriptomic level of ASM in addition to their anti-inflammatory properties, which can promote improved airway function. The current randomized, double-blind, parallel, placebo-controlled intervention study comprised 4 visits. At visit 1, asthma patients were screened according to the in- and exclusion criteria prior to enrollment. Additionally, spirometry and methacholine bronchoprovocation test were performed. At visit 2, FEV1 reversibility was measured and endobronchial biopsies were collected during a bronchoscopy. Asthma patients were then prescribed oral prednisolon at a dose of 0.5 mg/kg per day or placebo for 14 consecutive days. The dosage and dosing scheme was based on international recommendations for the treatment of acute exacerbations [1]. On the 11th day after visit 2, the patients visited the lung function laboratory for spirometry and methacholine bronchoprovocation test. Finally, at visit 4 (15th day after visit 2) FEV1 reversibility was measured and endobronchial biopsies were collected by bronchoscopy. Airway smooth muscle was collected from the biopsies by laser capture microdissection and total RNA isolated. cDNA was prepared using the Ovation RNA-Seq System (NuGEN). RNA-Seq was performed using the GS FLX+ instrument (454/Roche). Sequence reads were mapped against the human genome (hg19; UCSC). Comparison of the numbers of reads per gene between the prednisolon and placebo study group was carried out with the R package DESeq.

			Action	DRS
	MTBLS727	Other
	FILES	Other
	a_MTBLS727_mass_spectrometry.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS727_mass_spectrometry_v2_maf.tsv	Tabular