Pathological apoptosis by xanthurenic acid, a tryptophan metabolite: activation of cell caspases but not cytoskeleton breakdown

Malina, Halina; Richter, Christoph; Mehl, Martin; Hess, Otto M.

doi:10.1186/1472-6793-1-7

Cited by 54 publications

(31 citation statements)

References 31 publications

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“…Its levels did not recover and remained lower than that in the urine of control mice through day 30 post-exposure. Xanthurenic acid is a metabolite of tryptophan pathway and plays an important role in energy metabolism and aging (12). …”

Section: Resultsmentioning

confidence: 99%

Development of Urinary Biomarkers for Internal Exposure by Cesium-137 Using a Metabolomics Approach in Mice

et al. 2013

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Cesium-137 is a fission product of uranium and plutonium in nuclear reactors and is released in large quantities during nuclear explosions or detonation of an improvised device containing this isotope. This environmentally persistent radionuclide undergoes radioactive decay with the emission of beta particles as well as gamma radiation. Exposure to 137Cs at high doses can cause acute radiation sickness and increase risk for cancer and death. The serious health risks associated with 137Cs exposure makes it critical to understand how it affects human metabolism and whether minimally invasive and easily accessible samples such as urine and serum can be used to triage patients in case of a nuclear disaster or a radiologic event. In this study, we have focused on establishing a time-dependent metabolomic profile for urine collected from mice injected with 137CsCl. The samples were collected from control and exposed mice on days 2, 5, 20 and 30 after injection. The samples were then analyzed by ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC/TOFMS) and processed by an array of informatics and statistical tools. A total of 1,412 features were identified in ESI+ and ESI− modes from which 200 were determined to contribute significantly to the separation of metabolomic profiles of controls from those of the different treatment time points. The results of this study highlight the ease of use of the UPLC/TOFMS platform in finding urinary biomarkers for 137Cs exposure. Pathway analysis of the statistically significant metabolites suggests perturbations in several amino acid and fatty acid metabolism pathways. The results also indicate that 137Cs exposure causes: similar changes in the urinary excretion levels of taurine and citrate as seen with external-beam gamma radiation; causes no attenuation in the levels of hexanoylglycine and N-acetylspermidine; and has unique effects on the levels of isovalerylglycine and tiglylglycine.

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Section: Resultsmentioning

confidence: 99%

Development of Urinary Biomarkers for Internal Exposure by Cesium-137 Using a Metabolomics Approach in Mice

et al. 2013

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“…Kynurenic acid and xanthurenic acid are tryptophan metabolic products and possible biomarkers of renal failure (42), vitamin B6 deficiency, tuberculosis, exposure to radiation (14, 35, 36) and can induce mitochondrial damage (43). Tryptophan is metabolized primarily through the kynurenine pathway with a small percentage metabolized through the serotonin pathway.…”

Section: Discussionmentioning

confidence: 99%

Global Metabolomic Identification of Long-Term Dose-Dependent Urinary Biomarkers in Nonhuman Primates Exposed to Ionizing Radiation

Pannkuk

Laiakis

Authier³

et al. 2015

Radiation Research

129

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Due to concerns surrounding potential large-scale radiological events, there is a need to determine robust radiation signatures for the rapid identification of exposed individuals, which can then be used to guide the development of compact field deployable instruments to assess individual dose. Metabolomics provides a technology to process easily accessible biofluids and determine rigorous quantitative radiation biomarkers with mass spectrometry (MS) platforms. While multiple studies have utilized murine models to determine radiation biomarkers, limited studies have profiled nonhuman primate (NHP) metabolic radiation signatures. In addition, these studies have concentrated on short-term biomarkers (i.e., <72 h). The current study addresses the need for biomarkers beyond 72 h using a NHP model. Urine samples were collected at 7 days postirradiation (2, 4, 6, 7 and 10 Gy) and processed with ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight (QTOF) MS, acquiring global metabolomic radiation signatures. Multivariate data analysis revealed clear separation between control and irradiated groups. Thirteen biomarkers exhibiting a dose response were validated with tandem MS. There was significantly higher excretion of L-carnitine, L-acetylcarnitine, xanthine and xanthosine in males versus females. Metabolites validated in this study suggest perturbation of several pathways including fatty acid β oxidation, tryptophan metabolism, purine catabolism, taurine metabolism and steroid hormone biosynthesis. In this novel study we detected long-term biomarkers in a NHP model after exposure to radiation and demonstrate differences between sexes using UPLC-QTOF-MS-based metabolomics technology.

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“…Moreover, KA, 3-HK, and AA are associated positively with age [68]. XA treatment induces mitochondria damage, cytochrome C release in VSMC, consequent activation of caspase-3 and -9, and resultant cellular apoptosis [59]. Further investigations are warranted to clarify the causal or resultant roles of KP catabolites on age-related CVD.…”

Section: Abnormal Kp and Risk Factors For Cvdmentioning

confidence: 99%

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

Song

Ramprasath

Wang

et al. 2017

Cell. Mol. Life Sci.

181

134

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Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including hypertension, diabetes, obesity, and aging. The first catabolic step in KP is primarily controlled by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Following this first step, the KP has two major branches, one branch is mediated by kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU) and is responsible for the formation of 3-HK, 3-HAA, and quinolinic acid (QA); and another branch is controlled by kynurenine aminotransferase (KAT), which generates KA. Uncontrolled Trp catabolism has been demonstrated in distinct CVD, thus, understanding the underlying mechanisms by which regulates KP enzyme expression and activity is paramount. This review highlights the recent advances on the effect of KP enzyme expression and activity in different tissues on the pathological mechanisms of specific CVD, KP is an inflammatory sensor and modulator in the cardiovascular system, and KP catabolites act as the potential biomarkers for CVD initiation and progression. Moreover, the biochemical features of critical KP enzymes and principles of enzyme inhibitor development are briefly summarized, as well as the therapeutic potential of KP-enzyme inhibitors against CVD is briefly discussed.

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Pathological apoptosis by xanthurenic acid, a tryptophan metabolite: activation of cell caspases but not cytoskeleton breakdown

Cited by 54 publications

References 31 publications

Development of Urinary Biomarkers for Internal Exposure by Cesium-137 Using a Metabolomics Approach in Mice

Development of Urinary Biomarkers for Internal Exposure by Cesium-137 Using a Metabolomics Approach in Mice

Global Metabolomic Identification of Long-Term Dose-Dependent Urinary Biomarkers in Nonhuman Primates Exposed to Ionizing Radiation

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

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