Plasma glutamine and glutamate concentrations in Gabonese children with Plasmodium falciparum infection

Planche, Timothy; Dzeing, Arnaud; Emmerson, Ajb; Onanga, Myriam; Kremsner, Peter G.; Engel, K; Kombila, Maryvonne; Ngou-Milama, Édouard; Krishna, S.

doi:10.1093/qjmed/95.2.89

Cited by 25 publications

(25 citation statements)

References 26 publications

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“…Lower levels of circulating Gln have also been reported in Ghanaian children with acute falciparum malaria compared with control cases (81). However, our finding that low levels of Gln in children with malaria are associated with enhanced disease severity appears to differ from a previous finding in Gabonese children with malaria, in which plasma Gln concentrations were higher in children with severe versus moderate disease, and highest in those who died compared with those who survived (82). Although enhanced disease severity in children with malaria, and that naturally acquired phagocytosis of hemozoin may be a driving factor in lower Hsp70, we performed a series of in vitro experiments to definitively establish this potential molecular mechanism.…”

Section: Discussioncontrasting

confidence: 84%

Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of hemozoin in Suppressing Hsp70 and NF-κB Activation

Kempaiah

Dokładny

Karim

et al. 2016

Mol Med

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Severe malarial anemia (SMA; hemoglobin [Hb] <5.0 g/dL) is a leading global cause of morbidity and mortality among children residing in Plasmodium falciparum transmission regions. Exploration of molecular pathways through global gene expression profiling revealed that SMA was characterized by decreased HSPA1A, a heat shock protein 70 (Hsp70) coding gene. Hsp70 is a ubiquitous chaperone that regulates nuclear factor-kappa B (NF-κB) signaling and production of proinflammatory cytokines known to be important in malaria pathogenesis (for example, IL-1β, IL-6 and TNF-α). Since the role of host Hsp70 in malaria pathogenesis is unexplored, we investigated Hsp70 and molecular pathways in children with SMA. Validation experiments revealed that leukocytic HSP70 transcripts were reduced in SMA relative to nonsevere malaria, and that intraleukocytic hemozoin (PfHz) was associated with lower HSP70. HSP70 was correlated with reticulocyte production and Hb. Since glutamine (Gln) upregulates Hsp70, modulates NF-κB activation and attenuates overexpression of proinflammatory cytokines, circulating Gln was measured in children with malaria. Reduced Gln was associated with increased risk of developing SMA. Treatment of cultured peripheral blood mononuclear cells (PBMCs) with PfHz caused a time-dependent decrease in Hsp70 transcripts/protein and NF-κB activation. Gln treatment of PBMCs overcame PfHz-induced suppression of HSP70 transcripts/protein, reduced NF-κB activation and suppressed overexpression of IL-1β, IL-6 and TNF-α. These findings demonstrate that SMA is characterized by reduced intraleukocytic HSP70 and circulating Gln, and that PfHz-induced suppression of HSP70 can be reversed by Gln. Thus, Gln supplementation may offer important immunotherapeutic options for futures studies in children with SMA.

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Section: Discussioncontrasting

confidence: 84%

Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of hemozoin in Suppressing Hsp70 and NF-κB Activation

Kempaiah

Dokładny

Karim

et al. 2016

Mol Med

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“…A high glutamine concentration is typically seen in patients suffering from severe liver failure (Clemmesen et al 2000;Rodas et al 2012;Ytrebo et al 2006). In addition, plasma glutamine concentration has been shown to be higher in children who died with malaria as compared to those that survived (Planche et al 2002). From the present study, a plasma glutamine concentration at mean +2 SD of 760 µmol/L was obtained from the reference group as a high cutoff value.…”

Section: Discussionmentioning

confidence: 80%

Plasma glutamine deficiency is associated with multiple organ failure in critically ill children

et al. 2014

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A low plasma glutamine concentration (<420 µmol/L) is an independent risk factor for mortality in critically ill adult patients. Glutamine metabolism in children is less well characterized. However, pediatric ICU (PICU) mortality is low and, therefore, mortality is difficult to use as an endpoint. Here we evaluated if plasma glutamine concentration at admission to the PICU, relates to the development of multiple organ failure, using pediatric logistic organ dysfunction score (PELOD)-score. In this observational study, consecutive critically ill children (n = 149) admitted to the PICU of a tertiary university hospital as well as a reference group of healthy children (n = 60) were included. Plasma glutamine concentration and the PELOD were determined at admission for all patients and at day 5 for those patients still in the PICU. Plasma glutamine concentration at admission was low in the PICU patients as compared to controls (p = 0.00002) and patients with a low plasma glutamine concentration had more organ failure as compared to patients with higher plasma glutamine concentration (p = 0.0001). Plasma glutamine concentration normalized in patients staying >5 days in the PICU. Plasma glutamine depletion was present in 40 % of patients at PICU admission and it was associated with the development of multiple organ failure. Furthermore, the majority of the critically ill children normalized their plasma glutamine concentration within 5 days, which is different from adult ICU patients. The study suggests that an initial plasma glutamine deficiency is associated with multiple organ failure in critically ill children.

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“…It is the most abundant amino acid in human blood, its concentrations ranging from 0.4 mM to 0.7 mM [1, 2]. The average concentration of the next most abundant amino acid, namely alanine, is far less (0.35 mM) than that of glutamine.…”

Section: Introductionmentioning

confidence: 99%

Glutamine transporters in mammalian cells and their functions in physiology and cancer

Bhutia

Ganapathy

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

244

226

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The SLC (solute carrier)-type transporters (∼400 in number) in mammalian cells consist of 52 distinct gene families, grouped solely based on the amino acid sequence (primary structure) of the transporter proteins and not on their transport function. Among them are the transporters for amino acids. Fourteen of them, capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. Some of the glutamine transporters are obligatory exchangers whereas some function as active transporters in one direction. While most glutamine transporters mediate the influx of the amino acid into cells, some actually mediate the efflux of the amino acid out of the cells. Glutamine transporters play important roles in a variety of tissues, including the liver, brain, kidney, and placenta, as clearly evident from the biological and biochemical phenotypes resulting from the deletion of specific glutamine transporters in mice. Owing to the obligatory role of glutamine in growth and proliferation of tumor cells, there is increasing attention on glutamine transporters in cancer biology as potential drug targets for cancer treatment. Selective blockers of certain glutamine transporters might be effective in preventing the entry of glutamine and other important amino acids into tumor cells, thus essentially starving these cells to death. This could represent the beginning of a new era in the discovery of novel anticancer drugs with a previously unexplored mode of action.

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Plasma glutamine and glutamate concentrations in Gabonese children with Plasmodium falciparum infection

Abstract: In severe malaria, there was a positive correlation between plasma glutamine and lactate levels (p=0.009, r=0.281). This correlation may reflect impaired gluconeogenesis. Glutamine supplementation is probably not justified in severe P. falciparum infection.

Cited by 25 publications

References 26 publications

Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of hemozoin in Suppressing Hsp70 and NF-κB Activation

Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of hemozoin in Suppressing Hsp70 and NF-κB Activation

Plasma glutamine deficiency is associated with multiple organ failure in critically ill children

Glutamine transporters in mammalian cells and their functions in physiology and cancer

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