Chronic inflammation is accompanied by impaired T-cell immunity. In the mouse, myeloid cell-associated arginase accounts for the suppression of immune reactivity in various models of tumor growth and chronic infections. Here we show that arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions. Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. This T-cell phenotype is due to arginase-mediated depletion of arginine in the T-cell environment, which leads to CD3 chain down-regulation but does not alter T-cell viability. Our study therefore demonstrates that human granulocytes possess a previously unanticipated immunosuppressive effector function. Human granulocyte arginase is a promising pharmacologic target to reverse unwanted immunosuppression.
Carotenoids are widely used as important micronutrients in food. Furthermore, carotenoid supplementation has been used in the treatment of diseases associated with oxidative stress. However, in some clinical studies harmful effects have been observed, for example, a higher incidence of lung cancer in individuals exposed to extraordinary oxidative stress. The causal mechanisms are still unclear. Carotenoid cleavage products (CCPs), including highly reactive aldehydes and epoxides, are formed during oxidative attacks in the course of antioxidative action. Here, we tested the hypothesis that CCPs may increase oxidative stress by impairing mitochondrial function. We found that CCPs strongly inhibit state 3 respiration of isolated rat liver mitochondria even at concentrations between 0.5 and 20 microM. This was true for retinal, beta-ionone, and mixtures of cleavage products, which were generated in the presence of hypochlorite to mimic their formation in inflammatory regions. The inhibition of mitochondrial respiration was accompanied by a reduction in protein sulfhydryl content, decreasing glutathione levels and redox state, and elevated accumulation of malondialdehyde. Changes in mitochondrial membrane potential favor functional deterioration of the adenine nucleotide translocator. The findings may reflect a basic mechanism of increasing the risk of cancer induced by CCPs.
IDH1/2 mutations occur at high frequency in diffusely infiltrating gliomas of the WHO grades II and III and were identified as a strong prognostic marker in all WHO grades of gliomas. Mutated IDH1 or IDH2 protein leads to the generation of excessive amounts of the metabolite 2-hydroxyglutarate (2HG) in tumor cells. Here, we evaluated whether 2HG levels in preoperative serum samples from patients with gliomas correlate with the IDH1/2 mutation status and whether there is an association between 2HG levels and glioma size. In contrast to the strong accumulation of 2HG in the serum of patients with IDH1/2 mutated acute myeloid leukaemia, no accumulation was observed in this series of IDH1/2 mutated gliomas. Furthermore, we found no association between glioma size measured by magnetic resonance imaging and 2HG levels. We conclude that 2HG levels in preoperative sera from patients with diffusely infiltrating gliomas of the WHO grades II and III cannot be used as a marker to differentiate between tumors with versus without IDH1/2 mutation. Furthermore, the observation that there is no correlation between 2HG levels and tumor volume may indicate that 2HG cannot be utilized as marker to monitor tumor growth in gliomas.Recently, we and others demonstrated an accumulation of the metabolite 2-hydroxyglutarate (2HG) in serum of patients with acute myeloid leukaemia (AML) that harbored mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2).1,2 While the biological significance of this accumulation has to be clarified, the potential of 2HG to monitor AML disease activity is apparent and may soon enter clinical practice in the diagnosis of primary disease and relapse.While IDH1/2 mutations are found at low frequency in AML, specific subtypes of gliomas show mutations of IDH1 in up to 90%.3 IDH1/2 mutations were identified as a strong prognostic marker in all WHO grades of diffusely infiltrating gliomas.4-6 High levels of 2HG have been demonstrated in tumor tissue of glioma patients with IDH1 mutation.7,8 Since 2HG is a small molecule it seems possible that it could reach the systemic circulation and that elevated 2HG serum levels may help to identify patients harboring IDH1/2 mutated gliomas.Here we investigated whether 2HG produced by IDH1/2 mutant gliomas accumulates in patient's serum and whether this accumulation can be used to assess IDH1/2 mutation status prior to surgery. In total, 16 glioma serum samples were analyzed. Fourteen of these samples were taken from patients undergoing a resection of a newly diagnosed diffusely infiltrating glioma of WHO grades II, III or IV (three astrocytomas WHO grade II, four anaplastic astrocytomas WHO grade III, one oligodendroglioma WHO grade II, three anaplastic oligodendrogliomas WHO grade III, one oligoastrocytoma WHO grade II, one anaplastic oligoastrocytoma WHO grade III, one glioblastoma WHO grade IV) that were treated at the Department of Neurosurgery, University of Bonn or at the Department of Neurosurgery, Ludwig-MaximiliansUniversity Munich (Table 1). Serum of these 14 sample...
Seven subunits of the mitochondrial contact site and cristae junction (CJ) organizing system (MICOS) in humans have been recently described in function and structure. QIL1 (also named MIC13) is a small complex that is crucial for the maintenance and assembling of MICOS. A novel mutation of an essential splice site in the C19orf70 gene encoding QIL1 induces severe mitochondrial encephalopathy, hepatopathy and lactate acidosis consistent with psychomotor retardation. In addition, bilateral kidney stones were observed. Disassembly of MICOS complex subunits displays lack of MIC10-MIC26-MIC27-QIL1 subcomplex, resulting in aberrant cristae structure and a loss of cristae junctions and contact sites. In liver and muscle tissue, the activity of the respiratory chain complexes (OXPHOS) was severely impaired. Defects in MICOS complex do not only affect mitochondrial architecture, but also mitochondrial fusion, metabolic signalling, lipid trafficking and cellular electric homeostasis.
Background: Clinical presentation and disease severity in disorders of purine and pyrimidine metabolism vary considerably. We present a method that allows comprehensive, sensitive, and specific diagnosis of the entire spectrum of abnormalities in purine and pyrimidine metabolism in 1 analytical run. Methods: We used reversed-phase HPLC electrospray ionization tandem mass spectrometry to investigate 24 metabolites of purine and pyrimidine metabolism in urine samples from healthy persons and from patients with confirmed diagnoses of inherited metabolic disorders. Urine samples were filtered and diluted to a creatinine concentration of 0.5 mmol/L. Stable-isotopelabeled internal standards were used for quantification. The metabolites were analyzed by multiple-reaction monitoring in positive and negative ionization modes. Results: Total time of analysis was 20 min. Recovery (n ؍ 8) of a compound after addition of a known concentration was 85%-133%. The mean intraday variation (n ؍ 10) was 12%. The interday variation (n ؍ 7) was <17%. Age-related reference intervals were established for each compound. Analysis of patient urine samples revealed major differences in tandem mass
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