Plasma amino acid pattern of patients with HIV infection.

Ollenschläger, Günter; Jansen, Stefanie; Schindler, John; Rasokat, H.; Schrappe-Bächer, M.; Roth, Erich

doi:10.1093/clinchem/34.9.1781

Cited by 43 publications

(17 citation statements)

References 11 publications

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“…More than two decades ago, elevated serum phenylalanine concentrations have been described in various inflammatory conditions including cancer, burns, trauma, sepsis and HIV-1 infection [43][44][45]. Phenylalanine levels were usually expressed either as absolute concentrations or as percentage of all amino acids.…”

Section: Association Between Immune Activation and Disturbed Phenylalmentioning

confidence: 99%

Activated Immune System and Inflammation in Healthy Ageing: Relevance for Tryptophan and Neopterin Metabolism

Capuron¹,

Geisler²,

Kurz³

et al. 2014

CPD

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Immune activation not only accompanies inflammation in various disorders including infections, autoimmune syndromes and cancer, but it also represents a characteristic feature of ageing. Immune deviations which are most widely expressed in the elderly include increased neopterin production and tryptophan breakdown. These biochemical events result from the activation of the immune system and are preferentially triggered by pro-inflammatory stimuli, such as the Th1-type cytokine interferon-γ. They seem to play a role in the development of several age-related disorders and might be involved in the pathogenesis of common symptoms, including neurobehavioral disorders (e.g., cognitive and mood disturbances), anemia, cachexia, weight-loss but also immunodeficiency. Concentrations of the biomarkers neopterin and Kyn/Trp were found to be predictive of overall disease specific mortality in coronary artery disease, infections and various types of cancer. Immune activation and inflammation are also accompanied by high output of reactive oxygen species and thereby may lead to the development of oxidative stress and contribute to the vitamin deficiency which is often observed in the elderly. Accordingly, increases in neopterin were found to correlate with a substantial decline in key vitamins, including folate and vitamin-B6, - B12, -C, -D and -E.

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Section: Association Between Immune Activation and Disturbed Phenylalmentioning

confidence: 99%

Activated Immune System and Inflammation in Healthy Ageing: Relevance for Tryptophan and Neopterin Metabolism

Capuron¹,

Geisler²,

Kurz³

et al. 2014

CPD

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“…Glutamate mediates numerous physiological functions through activation of multiple receptors (Cutler and Dudzinski 1974;Fonnum 1984;Orrego and Villanueva 1993); however, high concentrations of extracellular glutamate induce neuronal damage (Olney 1971;McCall et al 1979;Choi 1988;Newcomb et al 1997). HIV-1 infected macrophages are an important cellular source of extracellular glutamate (Jiang et al 2001), and HIV-1-infected patients have significantly higher concentrations of glutamate in plasma as compared with uninfected controls (Droge et al 1987;Ollenschlager et al 1988). The cerebrospinal fluid of HAD patients has also been found to have increased amounts of glutamate (Ferrarese et al 2001).…”

mentioning

confidence: 99%

Glutamate production by HIV‐1 infected human macrophage is blocked by the inhibition of glutaminase

Erdmann

Zhao

López

et al. 2007

Journal of Neurochemistry

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Mononuclear phagocyte (macrophages and microglia) dysfunction plays a significant role in the pathogenesis of human immunodeficiency virus (HIV) associated dementia (HAD) through the production and release of soluble neurotoxic factors including glutamate. The mechanism of glutamate regulation by HIV-1 infection remains unclear. In this report, we investigated whether the enzyme glutaminase is responsible for glutamate generation by HIV-1 infected monocytederived macrophages. We tested the functionality of novel small molecule inhibitors designed to specifically block the activity of glutaminase. Glutaminase inhibitors were first characterized in a kinetic assay with crude glutaminase from rat brain revealing an uncompetitive mechanism of inhibition. The inhibitors were then tested in vitro for their ability to prevent glutamate generation by HIV-infected macrophages, their effect upon macrophage viability, and HIV infection. To validate these findings, glutaminase specific siRNA was tested for its ability to prevent glutamate increase during infection. Our results show that both glutaminase specific small molecule inhibitors and glutaminase specific siRNA were effective at preventing increases in glutamate by HIV-1 infected macrophage. These findings support glutaminase as a potential component of the HAD pathogenic process and identify a possible therapeutic avenue for the treatment of neuroinflammatory states such as HAD. HIV-1 associated dementia (HAD) is a significant consequence of HIV infection resulting in a chronic, progressive dementia. The dementia is a consequence of neuronal damage that results from prolonged inflammation in the CNS. Mononuclear phagocytes (MP) are critical to HAD pathogenesis and have been hypothesized to induce neuronal injury through the production and release of various soluble neurotoxic factors including glutamate (Giulian et al. 1993;Pulliam et al. 1994;Zink et al. 1999;Belmadani et al. 2001;Jiang et al. 2001). Glutamate mediates numerous physiological functions through activation of multiple receptors (Cutler and Dudzinski 1974;Fonnum 1984;Orrego and Villanueva 1993); however, high concentrations of extracellular glutamate induce neuronal damage (Olney 1971;McCall et al. 1979;Choi 1988;Newcomb et al. 1997). HIV-1 infected macrophages are an important cellular source of extracellular glutamate (Jiang et al. 2001), and HIV-1-infected patients have significantly higher concentrations of glutamate in plasma as compared with uninfected controls (Droge et al. 1987; Ollenschlager Received December 11, 2006; accepted February 2, 2007. Address correspondence and reprint requests to Jialin Zheng, Laboratory of Neurotoxicology, Center for Neurovirology and Neurodegenerative Disorders and Departments of Pharmacology/Experimental Neuroscience and Pathology/Microbiology, 985880 Nebraska Medical Center, Omaha, NE 68198-5880, USA. E-mail: jzheng@unmc.edu 1 These authors contributed equally to this work.

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“…However, high concentrations of extracellular glutamate can induce neuronal damage (Olney 1971;McCall et al 1979;Choi 1988;Newcomb et al 1997). It has been reported that HIV-1-infected patients have significantly higher plasma concentrations of glutamate as compared to uninfected controls (Droge et al 1987;Ollenschlager et al 1988). Although, HIV-1-infected macrophages appear to be an important cellular source of extracellular glutamate (Jiang et al 2001), the mechanism by which HIV-1 infection regulates glutamate production remains to be elucidated.…”

mentioning

confidence: 99%

Mitochondrial glutaminase enhances extracellular glutamate production in HIV‐1‐infected macrophages: Linkage to HIV‐1 associated dementia

Zhao

López

Erichsen

et al. 2003

Journal of Neurochemistry

128

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Dysfunction in mononuclear phagocyte (MP, macrophages and microglia) immunity is thought to play a significant role in the pathogenesis of HIV-1 associated dementia (HAD). In particular, elevated extracellular concentrations of the excitatory neurotransmitter glutamate, produced by MP as a consequence of viral infection and immune activation, can induce neuronal injury. To determine the mechanism by which MP-mediated neuronal injury occurs, the concentration and rates of production of extracellular glutamate were measured in human monocyte-derived macrophage (MDM) supernatants by reverse phase high-performance liquid chromatography (RP-HPLC). Measurements were taken of supernatants from MDM infected with multiple HIV-1 strains including ADA and DJV (macrophage tropic, M-tropic), and 89.6 (dual tropic). High levels of glutamate were produced by MDM infected with M-tropic viruses. AZT, an inhibitor of HIV-1 replication, inhibited glutamate generation, demonstrating a linkage between HIV-1 infection and enhanced glutamate production. In our culture system, glutamate production was dependent upon the presence of glutamine and was inhibited by 6-diazo-5-oxo-L-norleucine, a glutaminase inhibitor. Supernatants collected from HIV-1-infected MP generated more glutamate following glutamine addition than supernatants isolated from uninfected MP. These findings implicate the involvement of a glutamate-generating enzyme, such as phosphate-activated mitochondrial glutaminase (PMG) in MP-mediated glutamate production.

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Plasma amino acid pattern of patients with HIV infection.

Cited by 43 publications

References 11 publications

Activated Immune System and Inflammation in Healthy Ageing: Relevance for Tryptophan and Neopterin Metabolism

Activated Immune System and Inflammation in Healthy Ageing: Relevance for Tryptophan and Neopterin Metabolism

Glutamate production by HIV‐1 infected human macrophage is blocked by the inhibition of glutaminase

Mitochondrial glutaminase enhances extracellular glutamate production in HIV‐1‐infected macrophages: Linkage to HIV‐1 associated dementia

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