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ABSTRACT: An overwhelming production of reactive oxygen species concomitant with a decrease in antioxidative capacity plays an important role in modulation of the immune system in critically ill patients. The purpose of this study was to assess the influence of a combined oral supply of the antioxidants R-alpha-lipoic acid (LA) and glutamine (GLN) on the immunity of endotoxemic mice, with a special focus on tissue glutathione levels.
Female Balb/c mice were fed diets enriched with GLN (3 g/100 kcal), LA (0.74 mg/100 kcal), a combination of GLN and LA, or an isocaloric and isonitrogenous control diet for 10 days. On day 7, the mice were challenged intraperitoneally with 25 microg lipopolysaccharide. Seventy-two hours later, the number and phenotype of lymphocytes in Peyer's patches (PP) and spleen of the endotoxemic mice were measured. In addition, glutathione levels were determined in the small intestine, spleen and liver.
In PP only the combined supply of GLN and LA significantly increased the total cell yield (+19%), which was predominantly due to an increased number of B cells. In the spleen, both LA (+17%) and the combination of GLN and LA (+22%) were able to enhance total cell yield. The glutathione content of the small intestine was increased by feeding LA alone, whereas in the spleen GLN plus LA was most effective.
Supplying combined GLN and LA to endotoxemic mice is effective in selectively increasing the number of systemic and intestinal B lymphocytes. Furthermore, LA augmented the level of the main intracellular antioxidant glutathione in the small intestine. On the basis of these data we recommend investigation of the effects of LA and GLN supplementation in patients with sepsis.
Wiener klinische Wochenschrift 04/2006; 118(3-4):100-7. · 0.81 Impact Factor
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ABSTRACT: Oxidative stress plays an important role during inflammatory diseases and recent therapies have focused on antioxidant administration to diminish oxidative stress and to arrest inflammatory processes. In this study, we investigated the impact of the GSH modulating effects of curcumin, a naturally derived polyphenol, on inflammatory processes in myelomonocytic U937 cells. One hour after administration of 10 micromol/l curcumin reactive oxygen species (ROS) production was significantly increased in undifferentiated U937 cells (+43%). Twenty-four hour after addition of curcumin, a significantly decreased ROS concentration was found (-32%), whereas GSH (+110%) and GSSG (+88%) content increased. A higher concentration of curcumin (25 micromol/l) caused an even stronger increase of GSH (+145%) and GSSG (+101%), but significantly decreased percentage of living cells to 84%. The increased GSH content of differentiated U937 cells after pre-incubation with curcumin was associated with lowered ROS production, nuclear factor kappa B (NFkappaB) activation (-34%) and tumor necrosis factor alpha (TNF-alpha) secretion (-51%) after LPS exposure. Curcumin inhibited TNF-alpha formation was also seen after GSH depletion by buthionine sulfoximine (BSO). This study shows that the antioxidative effects of curcumin are preceded by an oxidative stimulus, which is time and dose-dependent. Excessive concentrations of curcumin may even harm cells, as cell viability was decreased, in spite of elevated GSH contents. There was no clear relationship between intracellular GSH concentrations and the anti-inflammatory effects of curcumin.
Biochemical Pharmacology 09/2005; 70(4):552-9. · 4.70 Impact Factor
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ABSTRACT: Oxidative stress is caused by a higher production of reactive oxygen and reactive nitrogen species or a decrease in endogenous protective antioxidative capacity. In all types of critical illness, such as sepsis, trauma, burn injury, acute pancreatitis, liver injury, severe diabetes, acute respiratory distress syndrome, AIDS and kidney failure, the occurrence of increased oxidative stress or a reduced antioxidative status is described. Whereas in the past, reactive oxygen and reactive nitrogen species were mainly known as harmful agents, recent investigations have given a new insight into the (patho)physiological importance of these substances as powerful messenger molecules involved in gene regulation, thereby enabling the synthesis of cytokines or adhesion molecules necessary for defending inflammatory processes. As shown in this review, there are numerous possibilities for the quantification of oxidative stress.
Several investigations showed a close association of single or multiple parameters, such as total antioxidative capacity, lipid peroxidation, vitamins C and E, the activation of nuclear factor kappa B, and respiratory burst, with the patient's outcome. However, no recommendation for a single parameter to be measured can be given because the assays described do not allow the definition of an overall "antioxidative status" for patients.
The occurrence of oxidative stress in critically ill patients is associated with a poor prognosis. The measurement of a cluster of assays representative of the quantification of reactive species or of antioxidants may improve the usefulness of therapeutic intervention and increase knowledge of pathophysiological alterations.
Current Opinion in Clinical Nutrition and Metabolic Care 04/2004; 7(2):161-8. · 4.38 Impact Factor
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Nutrition 10/2003; 19(9):817-8. · 3.03 Impact Factor
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ABSTRACT: Glutamine (GLN) is the most abundant free amino acid (AA) in the human body. Under GLN-free conditions, which can be obtained when cells are cultivated in vitro, tissue cells cannot grow. Therefore, when classifying GLN as a "non-essential" AA, one must consider that in the human body GLN is synthesized from essential AAs and is continuously delivered from skeletal muscle to other organs. It is fascinating that a relatively simple AA like GLN can stimulate a large variety of cellular reactions. GLN stimulates not only the growth of cells but also the expression of surface antigens, the formation of cytokines, and the synthesis of heat shock proteins. Further, a GLN deficiency leads to a cell cycle arrest in G(0) to G(1) and reduces apoptosis. Interestingly, many of these biological activities also are associated with the cellular reduced oxygen potential, which depends mainly on the ratio of reduced to oxidized glutathione. Experimental animal studies have shown that the administration of GLN increases tissue concentrations of reduced glutathione. This review describes the relation of GLN to reduced glutathione metabolism and discusses the alteration of reduced glutathione metabolism under a variety of clinical conditions such as reperfusion injury, myocardial infarction, respiratory insufficiency, cancer, diabetes, liver disease, and clinical protein catabolism.
Nutrition 04/2002; 18(3):217-21. · 3.03 Impact Factor
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ABSTRACT: mdash;: Intestinal mucosal dysfunction appears to contribute to infectious complications in critically ill patients. The current study was undertaken to investigate whether endotoxin affects lymphocyte subpopulations and the expression of costimulatory signals in Peyer's patches (PP). Female Balb/c mice were given an intraperitoneal injection of 25 [mu]g LPS and sacrified 24 h or 72 h later to determine total cell yield, lymphocyte subpopulations (B-cells, total T-cells, CD4+/- and CD8+/-cells), the costimulatory molecules CD28, B7.1 (CD80) and B7.2 (CD86) and the percentage of apoptotic cells in PP and in the spleen as well as small intestinal IgA concentration. Lipopolysaccharide (LPS) challenge caused a significant decrease of total cell yield in PP at both time-points (-50 +/- 28% and -43 +/- 25%, respectively; P < 0.001). This decrease was significant for all measured lymphocyte subpopulations. In contrast, total cell yield was increased (P < 0.001) in the spleen 24 h (+52 +/- 13%) and 72 h (+130 +/- 22%) after LPS. The decrease of lymphocyte numbers in the PP was accompanied by an increased percentage of lymphocytes expressing costimulatory molecules. In this respect, an increased percentage of CD40+CD80+, CD40+CD86+, and of CD4+CD28+ could be demonstrated after LPS administration. In the spleen, the percentage of CD4+CD28+ was also elevated after LPS bolus, however, the percentage of CD40+CD80+ was reduced, and that of CD40+CD86+ was unaltered. The influence of LPS on apoptosis of lymphocytes was time-dependent. The percentage of apoptotic cells 24 h after LPS was increased in PP (P < 0.01), but was unchanged in the spleen. Seventy-two hours after LPS injection, the percentage of apoptotic cells returned to normal in PP. Luminal IgA levels remained unchanged after LPS challenge. In conclusion, our data show that LPS causes atrophy of PP which seems to be counterregulated by an enhanced expression of costimulatory molecules.
(C)2000The Shock Society
Shock 09/2000; 14(4). · 2.85 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether fructooligosaccharides (FOS) exert an immunomodulating effect on Peyer's patches (PP), the main inductive site of the intestinal immune system. We investigated the effects of FOS in healthy and endotoxemic animals.
Six-week-old female Balb/c mice were fed a control diet or a diet supplemented with 10% FOS over a period of 16 d. To induce endotoxemia, mice were challenged intraperitoneally with lipopolysaccharide (LPS) on day 15. PP were excised from mice, and lymphocyte subpopulations (B lymphocytes, T lymphocytes, CD4(+) cells, and CD8(+) cells) were determined by flow cytometry.
The FOS-enriched diet increased the total cell yield in healthy and endotoxemic mice (P < 0.001). Similarly, B lymphocytes were increased in both groups (P < 0.001). In contrast, T lymphocytes were unaltered in healthy mice but increased in LPS-challenged mice after FOS enrichment (P < 0.001). In endotoxemic mice but not in control animals, the increase of CD4(+) cells (P < 0.001) was more pronounced than that of CD8(+) cells (P < 0.001), thus increasing the CD4:CD8 ratio (P < 0.01).
FOS showed an immunostimulating effect on PP lymphocytes under healthy and endotoxemic conditions. Thus it can be concluded that FOS administration affects not only the large intestine but also the main inductive part of the mucosal immune system in the small intestine.
Nutrition 19(7-8):657-60. · 3.03 Impact Factor
