Changes in kynurenine pathway metabolism in the brain, liver and kidney of aged female Wistar rats

Braidy, Nady; Guillemin, Gilles J.; Hussein, M. A.; Chan‐Ling, Tailoi; Grant, Ross

doi:10.1111/j.1742-4658.2011.08366.x

Cited by 95 publications

(71 citation statements)

References 67 publications

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“…Figure 2 demonstrates that IDO1 mRNA expression increases 406.4 fold in the old-, when compared to the young-brain ( P =0.0018), which is congruent with previous observations. [20] However, there was no difference in IDO1 mRNA expression in brain tumors isolated from young and old mice, suggesting that the malignancy suppresses IDO1 levels in and/or around the tumor. In contrast to IDO1, neither age nor the presence of brain tumor affected the expression of TDO, CTLA-4, PD-L1, FoxP3 or IFNγ.…”

Section: Resultsmentioning

confidence: 99%

Advanced age negatively impacts survival in an experimental brain tumor model

Ladomersky

Zhai

Gritsina

et al. 2016

Neuroscience Letters

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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with an average age of 64 years at the time of diagnosis. To study GBM, a number of mouse brain tumor models have been utilized. In these animal models, subjects tend to range from 6–12 weeks of age, which is analogous to that of a human teenager. Here, we examined the impact of age on host immunity and the gene expression associated with immune evasion in immunocompetent mice engrafted with syngeneic intracranial GL261. The data indicate that, in mice with brain tumors, youth conveys an advantage to survival. While age did not affect the tumor-infiltrating T cell phenotype or quantity, we discovered that old mice express higher levels of the immunoevasion enzyme, IDO1, which was decreased by the presence of brain tumor. Interestingly, other genes associated with promoting immunosuppression including CTLA-4, PD-L1 and FoxP3, were unaffected by age. These data highlight the possibility that IDO1 contributes to faster GBM outgrowth with advanced age, providing rationale for future investigation into immunotherapeutic targeting in the future.

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Section: Resultsmentioning

confidence: 99%

Advanced age negatively impacts survival in an experimental brain tumor model

Ladomersky

Zhai

Gritsina

et al. 2016

Neuroscience Letters

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“…Up-regulation of QPRT expression compared to HFA constitutively and in response to inflammatory stimuli (IFN-γ) may be a mechanism conferring tumor survival advantages, as the glioma may have a greater capacity to produce NAD + in times of inflammatory stress. The increased availability of NAD + may provide an improved supply of substrate to the DNA repair associated enzyme poly(ADP-ribose) polymerase (PARP) [49], [50], assisting in tumor cell DNA replication and repair and promote the maintenance of high metabolic activity, ultimately promoting tumor cell viability and proliferation [51]. Analysis of NAD + concentrations in the glioma culture medium may give further insight into whether QUIN is catabolised more rapidly in glioma than in controls.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the Kynurenine Pathway in Human Glioma Pathophysiology

et al. 2014

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The kynurenine pathway (KP) is the principal route of L-tryptophan (TRP) catabolism leading to the production of kynurenine (KYN), the neuroprotectants, kynurenic acid (KYNA) and picolinic acid (PIC), the excitotoxin, quinolinic acid (QUIN) and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+). The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1), indoleamine 2,3-dioxygenase-2 (IDO-2) and tryptophan 2,3-dioxygenase (TDO-2) initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1) cultured human glioma cells and 2) plasma from patients with glioblastoma (GBM). Our data revealed that interferon-gamma (IFN-γ) stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU), kynurenine hydroxylase (KMO) and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD) and kynurenine aminotransferase-I (KAT-I) expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP) was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18) compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD+, which is necessary for energy production and DNA repair.

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“…It has been previously described that tryptophan pathway is affected by aging (Braidy et al ., 2011). Consequently, we quantified and examined metabolites of this pathway.…”

Section: Discussionmentioning

confidence: 99%

Caloric restriction reveals a metabolomic and lipidomic signature in liver of male mice

et al. 2014

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Lipid composition, particularly membrane unsaturation, has been proposed as being a lifespan determinant, but it is currently unknown whether caloric restriction (CR), an accepted life-extending intervention, affects cellular lipid profiles. In this study, we employ a liquid chromatography quadrupole time-of-flight-based methodology to demonstrate that CR in the liver of male C57BL/6 mice: (i) induces marked changes in the cellular lipidome, (ii) specifically reduces levels of a phospholipid peroxidation product, 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphatidylcholine, (iii) alters cellular phosphoethanolamine and triglyceride distributional profiles, (iv) affects mitochondrial electron transport chain complexes, increasing complex II and decreasing complex III and (v) is associated with specific changes in liver metabolic pathways. These data demonstrate that CR induces a specific lipidome and metabolome reprogramming event in mouse liver which is associated with lower protein oxidative damage, as assessed by mass spectrometry-based measurements. Such changes may be critical to the increased lifespan and healthspan observed in C57BL/6 mice following CR.

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Changes in kynurenine pathway metabolism in the brain, liver and kidney of aged female Wistar rats

Cited by 95 publications

References 67 publications

Advanced age negatively impacts survival in an experimental brain tumor model

Advanced age negatively impacts survival in an experimental brain tumor model

Involvement of the Kynurenine Pathway in Human Glioma Pathophysiology

Caloric restriction reveals a metabolomic and lipidomic signature in liver of male mice

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