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Oxidative Stress

Neopterin production in stimulated human macrophages coincides with production of reactive oxygen species. In vivo, neopterin concentrations correlate with markers oxidative stress.



Inverse association between serum concentrations of neopterin and antioxidants in patients with and without angiographic coronary artery disease
Murr C, et al. Division of Biological Chemistry, Biocenter, Insnbruck Medical University, Innsbruck, Austria

(Atherosclerosis 2009;202:543-9)

Neopterin is released from human monocyte-derived macrophages upon stimulation with interferon-gamma and is a sensitive indicator for cellular immune activation. Furthermore, reactive oxygen species (ROS) are produced in case of immune activation and inflammation. In a cross-sectional approach, plasma concentrations of neopterin and of antioxidant compounds and vitamins were compared in 1463 patients investigated by coronary angiography, which were recruited within the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. Serum neopterin concentrations were higher in patients with coronary artery disease (CAD; mean+/-S.D.: 8.7+/-7.3 nmol/L) compared to controls (7.4+/-5.0 nmol/L; Welch's t-test: p<0.001). Mean concentrations of ascorbic acid (p<0.0001), gamma-tocopherol (p<0.05), lycopene (p<0.001), lutein+zeaxanthin (p<0.05), alpha-carotene (p<0.05) and beta-carotene (p<0.05) were lower in CAD than in controls. Neopterin concentrations correlated with CAD-score (r(s)=0.156; p<0.0001) and inversely with antioxidants lycopene (r(s)=-0.277; p<0.0001) and lutein+zeaxanthin (r(s)=-0.175; p<0.0001) levels and with vitamins ascorbic acid (r(s)=-0.207; p<0.0001) and alpha-tocopherol (r(s)=-0.105; p<0.0001). The study demonstrates that higher neopterin production is associated with lower concentrations of antioxidant compounds in patients at risk for atherosclerosis. Results suggest that lower concentrations of antioxidant compounds may relate to higher grade of chronic immune activation in patients.

Increased neopterin concentrations in patients with cancer: indicator of oxidative stress?

Murr C, et al. Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Innsbruck, Austria
(Anticancer Res 1999; 19: 1721-8)

In vitro, large amounts of neopterin are produced by human monocytes/macrophages upon stimulation with interferon-gamma. In vivo increased neopterin concentrations in human serum and urine indicate activation of cell-mediated (Th1-type) immune response, e.g., during virus infections, autoimmune diseases, allograft rejection and in certain types of malignancy. In various groups of patients with malignant diseases neopterin concentrations correlate to the stage of disease, and higher neopterin concentrations in serum, urine or ascitic fluid were shown to significantly predict worse prognosis regarding relapse and survival. The amounts of neopterin produced by activated monocytes/macrophages correlate with their capacity to release reactive oxygen species (ROS). With this background, neopterin concentrations in body fluids can be regarded as an indirect estimate of the degree of oxidative stress emerging during cell-mediated immune response. Moreover, recently neopterin was found itself to be capable of enhancing toxic effects induced by ROS. In vitro, neopterin derivatives were able to interfere with intracellular signal transduction pathways involved in, e.g., programmed cell death and the induction of proto-oncogene c-fos or nuclear factor-chi B. The data support the view that increased production of ROS--indicated by increased neopterin concentrations--could modulate the development, the proliferation and the survival of malignant cells.


Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure

Witko-Sarsat V, et al.
Institut National de la Sante et de la Recherche Medicale, Unit 90, Paris, France
(J Immunol 1998; 161: 2524-32)

We previously demonstrated the presence of advanced oxidation protein products (AOPP), a novel marker of oxidative stress in the plasma of uremic patients receiving maintenance dialysis. The present study in a cohort of 162 uremic patients showed that plasma concentrations of AOPP increased with progression of chronic renal failure and were closely related to advanced glycation end products (AGE)-pentosidine (r = 0.52, p < 0.001), taken as a marker of AGE. In vivo, the relevance of AOPP and AGE-pentosidine in monocyte-mediated inflammatory syndrome associated with uremia was evidenced by close correlations between AOPP or AGE-pentosidine and monocyte activation markers, including neopterin, IL-1R antagonist, TNF-alpha, and TNF soluble receptors (TNF-sR55 and TNF-sR75). To determine the mechanisms by which AOPP and AGE could be directly involved in monocyte activation, AOPP-human serum albumin (HSA) and AGE-HSA were produced in vitro by treating HSA with oxidants or glucose, respectively. Spectroscopic analysis confirmed that AOPP-HSA contains carbonyls and dityrosine. Both AOPP-HSA and AGE-HSA, but not purified dityrosine, were capable of triggering the oxidative burst of human monocytes in cultures. The AOPP-HSA-induced respiratory burst was dependent on the chlorinated nature of the oxidant and on the molar ratio HSA/HOCI. Collectively, these data first demonstrate that AOPP act as a mediator of oxidative stress and monocyte respiratory burst, which points to monocytes as both target and actor in the immune dysregulation associated with chronic uremia.


In Vivo Determination of Oxidative Stress 


Wirleitner B, et al. Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Innsbruck, Austria

(Akt Ernähr Med 2003; 28: 363-70)


Oxygen is required by eukaryotic cells for energy production. Living in an aerobic environment brings with the exposure of cells to reactive oxygen species (ROS). ROS for example accumulate as byproducts of the aerobic metabolism, and a substantial endogenous generation of ROS occurs during immune response by immunocompetent cells. Massive occurrence of ROS results in oxidative damage of cellular components. The primary targets of ROS are enzymes, cell membranes, and DNA. Oxidative stress is defined by an overwhelming occurrence of ROS opposed by an exhausted pool of antioxidants. In the last decade, the role of oxidative stress in the pathogenesis of a wide range of human diseases became obvious, and determination of the phenomenon of oxidative stress moved into the focus of interest. Several approaches were developed to quantify this condition. Among them are measurements of oxidation products such as lipid peroxidation, oxidized protein, or DNA. Alternatively, oxidative stress can be determined by the loss of antioxidants. This review briefly summarizes current available methods for the quantification of oxidative stress in vivo.