Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis

Kimberly, W. Taylor; O’Sullivan, John; Nath, Anjali K.; Keyes, Michelle J.; Shi, Xu; Larson, Martin G.; Yang, Qiong; Long, Michelle T.; Vasan, Ramachandran; Peterson, Randall T.; Wang, Thomas J.; Corey, Kathleen E.; Gerszten, Robert E.

doi:10.1172/jci.insight.92989

Cited by 68 publications

(58 citation statements)

References 47 publications

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“…These platforms have been previously used to characterize a diverse set of biochemical pathways implicated in metabolic status (19, 20). Briefly, fasting plasma samples (EDTA, 10μL and 30μL for positive and negative ion modes, respectively) were deproteinized using extraction solvent containing stable isotope labeled internal standards.…”

Section: Methodsmentioning

confidence: 99%

Plasma Metabolite Profiles in Response to Chronic Exercise

Brennan

Benson

Morningstar

et al. 2018

Medicine &Amp; Science in Sports &Amp; Exercise

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Purpose High throughput profiling of metabolic status (metabolomics) allows for the assessment of small-molecule metabolites that may participate in exercise-induced biochemical pathways and corresponding cardiometabolic risk modification. We sought to describe the changes in a diverse set of plasma metabolite profiles in patients undergoing chronic exercise training and assess the relationship between metabolites and cardiometabolic response to exercise. Methods secondary analysis was performed in 216 middle-aged abdominally obese men and women ([mean (SD)], 52.4 (8.0) years) randomized into one of four groups varying in exercise amount and intensity for 6 months duration: high amount high intensity, high amount low intensity, low amount low intensity, and control. 147 metabolites were profiled by liquid chromatography-tandem mass spectrometry. Results No significant differences in metabolite changes between specific exercise groups were observed; therefore, subsequent analyses were collapsed across exercise groups. There were no significant differences in metabolite changes between the exercise and control groups after 24 weeks at a Bonferroni-adjusted statistical significance (p < 3.0 × 10-4). Seven metabolites changed in the exercise group compared to the control group at p < 0.05. Changes in several metabolites from distinct metabolic pathways were associated with change in cardiometabolic risk traits, and three baseline metabolite levels predicted changes in cardiometabolic risk traits. Conclusion Metabolomic profiling revealed no significant plasma metabolite changes between exercise compared to control after 24-weeks at Bonferroni significance. However, we identified circulating biomarkers that were predictive or reflective of improvements in cardiometabolic traits in the exercise group.

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Section: Methodsmentioning

confidence: 99%

Plasma Metabolite Profiles in Response to Chronic Exercise

Brennan

Benson

Morningstar

et al. 2018

Medicine &Amp; Science in Sports &Amp; Exercise

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“…Metabolites were measured in rabbit and pig serum using adapted LC‐MS methods previously developed by our group . In this method, 30 μL aliquots were deproteinized using a 75:25 methanol:acetonitrile solution with isotopically labeled internal standards (citrulline D7, 10 μmol/L, inosine 15 N 4 , 25 μmol/L, phenylalanine D8, 10 μmol/L, and thymine d4 25 μmol/L).…”

Section: Methodsmentioning

confidence: 99%

Intramuscular administration of hexachloroplatinate reverses cyanide-induced metabolic derangements and counteracts severe cyanide poisoning

et al. 2018

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Cyanide is a highly toxic industrial chemical that is widely used by manufactures. Smoke inhalation during household fires is the most common source of cyanide poisoning while additional risks to civilians include industrial accidents and terrorist attacks. Despite the risks to large numbers of individuals, an antidote capable of administration at scale adequate for a mass casualty, prehospital scenario does not yet exist. Previously, we demonstrated that intravenous cisplatin analogues accelerate recovery from cyanide poisoning in mice and rabbits. Of the dozens of platinum‐based organometallic complexes tested, hexachloroplatinate (HCP) emerged as a promising lead compound, exhibiting strong affinity for cyanide and efficacy across model systems. Here, we show HCP is an antidote to lethal cyanide exposure and is importantly effective when delivered intramuscularly. The pharmacokinetic profile of HCP exhibited bioavailability in the systemic circulation 2.5 minutes post‐treatment and subsequent renal clearance of HCP‐cyanide. HCP restored parameters of cellular physiology including cytochrome c oxidase redox state and TCA cycle metabolism. We next validated these findings in a large animal model (swine). Finally, preclinical safety studies in mice revealed minimal toxicity. Cumulatively, these findings demonstrate that HCP is a promising lead compound for development of an intramuscular injectable cyanide antidote for mass casualty scenarios.

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“…These methods are highly reproducible, with an average coefficient of variation of 3.85% across all metabolites. 4 Nevertheless, two independent mass spectrometry runs were performed for each method, which were combined and analysed. We focused on the 40 metabolites reported in the table that were present in all tissue samples in both independent LC-MS runs, and that passed internal quality control assessment.…”

Section: Myocardial Substrate Changes In Advanced Ischaemic and Advanmentioning

confidence: 99%

“…These methods incorporate a broad range of metabolites including amino acids, acylcarnitines, ketone bodies, energetics and central carbon metabolism. These methods are highly reproducible, with an average coefficient of variation of 3.85% across all metabolites . Nevertheless, two independent mass spectrometry runs were performed for each method, which were combined and analysed.…”

mentioning

confidence: 99%