Effects of α-ketoglutarate on neutrophil intracellular amino and α-keto acid profiles and ROS production

Mühling, J.; Tussing, F.; Nickolaus, K. A.; Matejec, Reginald; Henrich, Michael; Harbach, Heinz W.; Wolff, M.; Weismüller, K.; Engel, J.; Welters, Ingeborg; Langefeld, T. W.; Fuchs, Markus; Weigand, Markus A.; Heidt, Martin

doi:10.1007/s00726-008-0224-5

Cited by 19 publications

(18 citation statements)

References 61 publications

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“…AKG may play a similar role in the intestinal immune response. Previous reports have suggested that AKG is an immune enhancer via modulating T cell differentiation and T cell activation [35], managing neutrophil function and generating ROS [5]. AKG activates intestinal innate immunity by improving the expression of α-defensins in the ileum.…”

Section: Discussionmentioning

confidence: 99%

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Alpha-ketoglutarate (AKG) lowers body weight and affects intestinal innate immunity through influencing intestinal microbiota

et al. 2017

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Alpha-ketoglutarate (AKG), a precursor of glutamate and a critical intermediate in the tricarboxylic acid cycle, shows beneficial effects on intestinal function. However, the influence of AKG on the intestinal innate immune system and intestinal microbiota is unknown. This study explores the effect of oral AKG administration in drinking water (10 g/L) on intestinal innate immunity and intestinal microbiota in a mouse model. Mouse water intake, feed intake and body weight were recorded throughout the entire experiment. The ileum was collected for detecting the expression of intestinal proinflammatory cytokines and innate immune factors by Real-time Polymerase Chain Reaction. Additionally, the ileal luminal contents and feces were collected for 16S rDNA sequencing to analyze the microbial composition. The intestinal microbiota in mice was disrupted with an antibiotic cocktail. The results revealed that AKG supplementation lowered body weight, promoted ileal expression of mammalian defensins of the alpha subfamily (such as cryptdins-1, cryptdins-4, and cryptdins-5) while influencing the intestinal microbial composition (i.e., lowering the Firmicutes to Bacteroidetes ratio). In the antibiotic-treated mouse model, AKG supplementation failed to affect mouse body weight and inhibited the expression of cryptdins-1 and cryptdins-5 in the ileum. We concluded that AKG might affect body weight and intestinal innate immunity through influencing intestinal microbiota.

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Section: Discussionmentioning

confidence: 99%

“…It has various physiological functions, including acting as an antioxidant [1, 2] or as an anticancer agent [3, 4] and enhancing host-defense [5]. Recently, AKG has been reported to modulate intestinal energy status, amino acid metabolism, integrity and even immunity [6].…”

Section: Introductionmentioning

confidence: 99%

Alpha-ketoglutarate (AKG) lowers body weight and affects intestinal innate immunity through influencing intestinal microbiota

et al. 2017

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“…Since intracellular pyruvate increases the concentrations of α-ketoglutarate as well as glutamine, glutamate, asparagine, aspartate, alanine, arginine, ornithine, glycine and serine were also significantly elevated in a dose as well as duration of exposure dependent manner. A more precise look at the constitution of PMN amino and α-keto acid changes favour the hypothesis that increases in neutrophil free pyruvate concentrations are mainly followed by pyruvate conversion into important amino and α-keto acid derivatives (Curi et al 1989, 1988; Fuchs et al 1994; Mühling et al 2010, 2007, 2005, 2002). Indeed, our assumption that this metabolisation processes also occurs within PMN cells, may particularly be supported with regard to very similar immunonutritional findings induced by α-ketoglutarate, alanyl-glutamine, ornithine or arginine in other leukocyte cells or even neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Pyruvate: immunonutritional effects on neutrophil intracellular amino or alpha-keto acid profiles and reactive oxygen species production

et al. 2010

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For the first time the immunonutritional role of pyruvate on neutrophils (PMN), free α-keto and amino acid profiles, important reactive oxygen species (ROS) produced [superoxide anion (O2−), hydrogen peroxide (H2O2)] as well as released myeloperoxidase (MPO) acitivity has been investigated. Exogenous pyruvate significantly increased PMN pyruvate, α-ketoglutarate, asparagine, glutamine, aspartate, glutamate, arginine, citrulline, alanine, glycine and serine in a dose as well as duration of exposure dependent manner. Moreover, increases in O2− formation, H2O2-generation and MPO acitivity in parallel with intracellular pyruvate changes have also been detected. Regarding the interesting findings presented here we believe, that pyruvate fulfils considerably the criteria for a potent immunonutritional molecule in the regulation of the PMN dynamic α-keto and amino acid pools. Moreover it also plays an important role in parallel modulation of the granulocyte-dependent innate immune regulation. Although further research is necessary to clarify pyruvate’s sole therapeutical role in critically ill patients’ immunonutrition, the first scientific successes seem to be very promising.

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“…For example α-ketoglutarate, the carbon backbone arising from pyruvate transmission or glutamine oxidation, can immediately be fed into the tricarboxylic acid cycle and through that it is indirectly available to the enzymes of the urea cycle, for example in the form of aspartate via oxaloacetate [1]- [3] [30] [31]. So it is not surprising that α-ketoglutarate, for example incubated in neutrophils is able to increase cellular substrate storages and immune functions [6] [32].…”

Section: Pyruvate Induced Effects: Is There An Impact By Adding a Glumentioning

confidence: 99%

“…glucose, alanine, α-ketoglutarate, arginine, ornithine, etc.) or the ability to form energy-rich molecules such as nicotinamide adenine dinucleotide phosphate (NADPH) or guanosine-5'-triphosphate (GTP) from pyruvate-depent pathways, and so on [1]- [6]. Simply one of the most important biochemical processes in which pyruvate is involved, the conversion of pyruvate by the pyruvate dehydrogenase complex (PDH) to form acetyl-CoA, an important link substrate between the metabolic pathways of glycolysis and the citric acid cycle, was, actually and not really surprising to the concerned viewer, also found in neutrophils [7]- [10].…”

Section: Introductionmentioning

confidence: 99%

Pyruvate-Dependent Changes in Neutrophil Amino- and Alpha-Keto Acid Profiles or Immunity: Which Mechanisms Are Involved?

Deller¹,

Mathioudakis²,

Engel³

et al. 2014

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High current findings indicate that a substitution with pyruvate can lead to significant alterations or even improvement in neutrophil immunonutrition. However, it is still unknown which intracellular pathways might be involved here. Hence, in this study, we investigated whether preincubation with an inhibitor of •NO-synthase (L-NAME), an •NO donor (SNAP), an analogue of taurine (beta-alanine), an inhibitor of ornithine-decarboxylase (DFMO) as well as a glutamine-analogue (DON), is able to alter the intragranulocytic metabolic response to pyruvate, here for example studied for neutrophil intracellular amino-and α-keto acid concentrations or important neutrophil immune functions [released myeloperoxidase (MPO), the formation of superoxide anions ( ) 2 − O and hydrogen peroxide (H 2 O 2 )]. In summary, the interesting first results presented here showed, that any damage of specific metabolic pathways or mechanisms, which seem directly or indirectly to be involved in relevant pyruvate dependent granulocytic nutrient content or specific cellular tasks, could lead to therapeutically desired, but also to unexpected or even fatal consequences for the affected cells. We therefore continue to believe that pyruvate, irrespective of which exact biochemical mechanisms were involved, in neutrophils may satisfy the substantial metabolic demands for a potent intracellular nutrient.

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Effects of α-ketoglutarate on neutrophil intracellular amino and α-keto acid profiles and ROS production

Cited by 19 publications

References 61 publications

Alpha-ketoglutarate (AKG) lowers body weight and affects intestinal innate immunity through influencing intestinal microbiota

Alpha-ketoglutarate (AKG) lowers body weight and affects intestinal innate immunity through influencing intestinal microbiota

Pyruvate: immunonutritional effects on neutrophil intracellular amino or alpha-keto acid profiles and reactive oxygen species production

Pyruvate-Dependent Changes in Neutrophil Amino- and Alpha-Keto Acid Profiles or Immunity: Which Mechanisms Are Involved?

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