Publications by authors named "Geja J Hageman"

28 Publications

  • Page 1 of 1

Cross-Sectional Associations between Dietary Daily Nicotinamide Intake and Patient-Reported Outcomes in Colorectal Cancer Survivors, 2 to 10 Years Post-Diagnosis.

Nutrients 2021 Oct 21;13(11). Epub 2021 Oct 21.

Department of Pharmacology and Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands.

Supplementation with nicotinamide adenine dinucleotide (NAD) precursors including dietary nicotinamide has been found to boost tissue NAD levels and ameliorate oxidative stress-induced damage that contributes to aging and aging-related diseases. The association between dietary NAD precursors and patient-reported health-related outcomes in cancer survivors has not been investigated. This study aimed to determine associations of dietary nicotinamide intake with different patient-reported outcomes in colorectal cancer survivors, 2 to 10 years post-diagnosis. A total of 145 eligible participants were recruited into this cross-sectional study. Dietary nicotinamide intake level was calculated based on data from 7-day food diaries. Fatigue was assessed with the Checklist Individual Strength (CIS), which is a subscale of the cancer-specific European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC), and anxiety and depression were assessed with Hospital Anxiety and Depression Scale (HADS). Oxidative stress marker serum protein carbonyl contents and serum NAD levels were measured. A hierarchical linear regression model with confounder adjustment was performed to analyze the association of nicotinamide intake, serum protein carbonyl contents, and NAD levels with patient-reported outcomes. The median values of daily nicotinamide intake for male and female participants were 19.1 and 14.4 mg, respectively. Daily dietary nicotinamide intake was associated with a lower level of fatigue (β: -14.85 (-28.14, -1.56)) and a lower level of anxiety and depression (β: -4.69 (-8.55, -0.83)). Subgroup analyses by sex showed that a beneficial association between nicotinamide intake and patient-reported outcomes was mainly found in men. To conclude, our findings suggested that higher dietary NAD precursor nicotinamide intake was cross-sectionally associated with less patient-reported outcomes in CRC survivors.
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http://dx.doi.org/10.3390/nu13113707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624000PMC
October 2021

Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies.

Am J Clin Nutr 2018 09;108(3):453-475

Department of Epidemiology and Public Health, University College London, London, United Kingdom.

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes.

Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span.

Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity.

Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed.

Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.
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http://dx.doi.org/10.1093/ajcn/nqy107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454526PMC
September 2018

Telomere tracking from birth to adulthood and residential traffic exposure.

BMC Med 2017 11 21;15(1):205. Epub 2017 Nov 21.

Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590, Diepenbeek, Belgium.

Background: Telomere attrition is extremely rapid during the first years of life, while lifestyle during adulthood exerts a minor impact. This suggests that early life is an important period in the determination of telomere length. We investigated the importance of the early-life environment on both telomere tracking and adult telomere length.

Methods: Among 184 twins of the East Flanders Prospective Twin Survey, telomere length in placental tissue and in buccal cells in young adulthood was measured. Residential addresses at birth and in young adulthood were geocoded and residential traffic and greenness exposure was determined.

Results: We investigated individual telomere tracking from birth over a 20 year period (mean age (SD), 22.6 (3.1) years) in association with residential exposure to traffic and greenness. Telomere length in placental tissue and in buccal cells in young adulthood correlated positively (r = 0.31, P < 0.0001). Persons with higher placental telomere length at birth were more likely to have a stronger downward shift in telomere ranking over life (P < 0.0001). Maternal residential traffic exposure correlated inversely with telomere length at birth. Independent of birth placental telomere length, telomere ranking between birth and young adulthood was negatively and significantly associated with residential traffic exposure at the birth address, while traffic exposure at the residential address at adult age was not associated with telomere length.

Conclusions: Longitudinal evidence of telomere length tracking from birth to adulthood shows inverse associations of residential traffic exposure in association with telomere length at birth as well as accelerated telomere shortening in the first two decades of life.
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http://dx.doi.org/10.1186/s12916-017-0964-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697215PMC
November 2017

The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function.

Toxicol In Vitro 2017 Oct 14;44:206-212. Epub 2017 Jul 14.

Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands.

Vitamin B6 is a water-soluble vitamin that functions as a coenzyme in many reactions involved in amino acid, carbohydrates and lipid metabolism. Since 2014, >50 cases of sensory neuronal pain due to vitamin B6 supplementation were reported. Up to now, the mechanism of this toxicity is enigmatic and the contribution of the various B6 vitamers to this toxicity is largely unknown. In the present study, the neurotoxicity of the different forms of vitamin B6 is tested on SHSY5Y and CaCo-2 cells. Cells were exposed to pyridoxine, pyridoxamine, pyridoxal, pyridoxal-5-phosphate or pyridoxamine-5-phosphate for 24h, after which cell viability was measured using the MTT assay. The expression of Bax and caspase-8 was tested after the 24h exposure. The effect of the vitamers on two pyridoxal-5-phosphate dependent enzymes was also tested. Pyridoxine induced cell death in a concentration-dependent way in SHSY5Y cells. The other vitamers did not affect cell viability. Pyridoxine significantly increased the expression of Bax and caspase-8. Moreover, both pyridoxal-5-phosphate dependent enzymes were inhibited by pyridoxine. In conclusion, the present study indicates that the neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine. The inactive form pyridoxine competitively inhibits the active pyridoxal-5'-phosphate. Consequently, symptoms of vitamin B6 supplementation are similar to those of vitamin B6 deficiency.
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http://dx.doi.org/10.1016/j.tiv.2017.07.009DOI Listing
October 2017

The effect of dietary components on inflammatory lung diseases - a literature review.

Int J Food Sci Nutr 2017 Nov 14;68(7):771-787. Epub 2017 Feb 14.

b Department of Pharmacology and Toxicology, Faculty of Health Medicine and Life Sciences , Maastricht University , Maastricht , The Netherlands.

Anti-inflammatory treatment in chronic inflammatory lung diseases usually involves glucocorticosteroids. With patients suffering from serious side effects or becoming resistant, specific nutrients, that are suggested to positively influence disease progression, can be considered as new treatment options. The dietary inflammatory index is used to calculate effects of dietary components on inflammation and lung function to identify most potent dietary components, based on 162 articles. The positive effects of n-3 PUFAs and vitamin E on lung function can at least partially be explained by their anti-inflammatory effect. Many other dietary components showed only small or no effects on inflammation and/or lung function, although the number of weighted studies was often too small for a reliable assessment. Optimal beneficial dietary elements might reduce the required amounts of anti-inflammatory treatments, thereby decreasing both side effects and development of resistance as to improve quality of life of patients suffering from chronic inflammatory lung diseases.
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http://dx.doi.org/10.1080/09637486.2017.1288199DOI Listing
November 2017

The oxidation of p-phenylenediamine, an ingredient used for permanent hair dyeing purposes, leads to the formation of hydroxyl radicals: Oxidative stress and DNA damage in human immortalized keratinocytes.

Toxicol Lett 2015 Dec 9;239(3):194-204. Epub 2015 Oct 9.

Department of Environmental Toxicology, School of Pharmaceutical Sciences, University of São Paulo (FCFRP/USP), Av. do Café, s/n, CEP 14040-903 Ribeirão Preto, SP, Brazil.

The hair-dyeing ingredient, p-phenylenediamine (PPD), was previously reported to be mutagenic, possibly by inducing oxidative stress. However, the exact mechanism of PPD in inducing oxidative stress upon skin exposure during hair-dyeing in human keratinocytes remains unknown. The aim of our studies was therefore to investigate the toxicity of PPD and its by-products in human immortalized keratinocytes (HaCaT) after auto-oxidation and after reaction with hydrogen peroxide (H2O2). We found that the PPD half maximal effective cytotoxic concentration (EC50) to HaCaT is 39.37 and 35.63 μg/mL after 24 and 48 h, respectively, without addition of H2O2 to induce oxidation. When PPD (10 or 100 μg/mL) is combined with 10.5 μg/mL of H2O2, intracellular ROS production by HaCaT after 1 h was significantly increased and enhanced levels of DNA damage were observed after 4 h of exposure. After 24 h incubations, 20 μg/mL of PPD increased the level of DNA oxidation in HaCaT. Also, we found that the in vitro reaction between PPD and H2O2, even below the maximum allowance by cosmetic industries, released hydroxyl radicals which can damage DNA. Taken together, we conclude that PPD alone and when combined with H2O2 increases the formation of reactive oxygen species in human keratinocytes, leading to oxidative stress and subsequent DNA damage. These alterations suggest that the mechanism by which PPD exposure, alone or combined with H2O2, damages keratinocytes by the formation of the high reactive HO∙ radicals.
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http://dx.doi.org/10.1016/j.toxlet.2015.09.026DOI Listing
December 2015

Various Mechanistic Pathways Representing the Aging Process Are Altered in COPD.

Chest 2016 Jan 6;149(1):53-61. Epub 2016 Jan 6.

Department of Respiratory Medicine, Maastricht UMC, Maastricht, The Netherlands.

Background: Accelerated aging has been proposed as a pathologic mechanism of various chronic diseases, including COPD. This concept has almost exclusively been approached by analyses of individual markers. We investigated whether COPD is associated with accelerated aging using a panel of markers representing various interconnected aspects of the aging process.

Methods: Lung function, leukocyte telomere length, lymphocyte gene expression of anti-aging (sirtuin 1, total klotho, and soluble klotho [Sklotho]), senescence (p16/21), and DNA repair (Ku70/80 and TERF2) proteins, and markers of systemic inflammation and oxidative stress were determined in 160 patients with COPD, 82 smoking subjects, and 38 never-smoking control subjects.

Results: Median levels for telomere length, Sklotho, Ku70, and sirtuin 1 gene expression were lower (respectively, 4.4, 4.6, and 4.7 kbp for telomere length; 74%, 82%, and 100% for Sklotho; 88%, 92%, and 100% for Ku70 and 70%, 92%, and 100% for sirtuin 1, all P < .05) in patients compared with the smoking and never-smoking control groups. P21 gene expression was higher in patients compared with smoking control subjects. Telomere length correlated with Ku70 gene expression (r = 0.15, P = .02). After correction for age, smoking history, systemic inflammation, and oxidative stress, telomere length and p21 were the only markers that remained independently associated with lung function. In separate groups, only telomere length remained associated with lung function parameters.

Conclusions: Markers of the aging mechanism represent distinct molecular aspects of aging. Among them, different markers were altered in COPD, but only telomere length was consistently associated with lung function, and seems a useful marker for expressing accelerated aging in COPD.
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http://dx.doi.org/10.1378/chest.15-0645DOI Listing
January 2016

Lower placental telomere length may be attributed to maternal residential traffic exposure; a twin study.

Environ Int 2015 Jun 7;79:1-7. Epub 2015 Mar 7.

Centre for Environmental Sciences, Hasselt University, Agoralaan Building D, 3590 Diepenbeek, Belgium; Department of Public Health, Leuven University (KU Leuven), Kapucijnenvoer 35, 3000 Leuven, Belgium. Electronic address:

Background: High variation in telomere length between individuals is already present before birth and is as wide among newborns as in adults. Environmental exposures likely have an impact on this observation, but remain largely unidentified. We hypothesize that placental telomere length in twins is associated with residential traffic exposure, an important environmental source of free radicals that might accelerate aging. Next, we intend to unravel the nature-nurture contribution to placental telomere length by estimating the heritability of placental telomere length.

Methods: We measured the telomere length in placental tissues of 211 twins in the East Flanders Prospective Twin Survey. Maternal traffic exposure was determined using a geographic information system. Additionally, we estimated the relative importance of genetic and environmental sources of variance.

Results: In this twin study, a variation in telomere length in the placental tissue was mainly determined by the common environment. Maternal residential proximity to a major road was associated with placental telomere length: a doubling in the distance to the nearest major road was associated with a 5.32% (95% CI: 1.90 to 8.86%; p=0.003) longer placental telomere length at birth. In addition, an interquartile increase (22%) in maternal residential surrounding greenness (5 km buffer) was associated with an increase of 3.62% (95% CI: 0.20 to 7.15%; p=0.04) in placental telomere length.

Conclusions: In conclusion, we showed that maternal residential proximity to traffic and lower residential surrounding greenness is associated with shorter placental telomere length at birth. This may explain a significant proportion of air pollution-related adverse health outcomes starting from early life, since shortened telomeres accelerate the progression of many diseases.
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http://dx.doi.org/10.1016/j.envint.2015.02.008DOI Listing
June 2015

Accelerated aging during chronic oxidative stress: a role for PARP-1.

Oxid Med Cell Longev 2013 10;2013:680414. Epub 2013 Nov 10.

Department of Toxicology, Maastricht University, P.O. Box 6200 MD, Maastricht, The Netherlands.

Oxidative stress plays a major role in the pathophysiology of chronic inflammatory disease and it has also been linked to accelerated telomere shortening. Telomeres are specialized structures at the ends of linear chromosomes that protect these ends from degradation and fusion. Telomeres shorten with each cell division eventually leading to cellular senescence. Research has shown that poly(ADP-ribose) polymerase-1 (PARP-1) and subtelomeric methylation play a role in telomere stability. We hypothesized that PARP-1 plays a role in accelerated aging in chronic inflammatory diseases due to its role as coactivator of NF-κb and AP-1. Therefore we evaluated the effect of chronic PARP-1 inhibition (by fisetin and minocycline) in human fibroblasts (HF) cultured under normal conditions and under conditions of chronic oxidative stress, induced by tert-butyl hydroperoxide (t-BHP). Results showed that PARP-1 inhibition under normal culturing conditions accelerated the rate of telomere shortening. However, under conditions of chronic oxidative stress, PARP-1 inhibition did not show accelerated telomere shortening. We also observed a strong correlation between telomere length and subtelomeric methylation status of HF cells. We conclude that chronic PARP-1 inhibition appears to be beneficial in conditions of chronic oxidative stress but may be detrimental under relatively normal conditions.
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http://dx.doi.org/10.1155/2013/680414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844163PMC
July 2014

Telomere length, oxidative stress, and antioxidant status in elderly men in Zutphen and Crete.

Mech Ageing Dev 2012 Jun 25;133(6):373-7. Epub 2012 Apr 25.

NUTRIM School for Nutrition, Toxicology and Metabolism, Department of Toxicology, Maastricht University Medical Centre+, Maastricht, The Netherlands.

The incidence of chronic diseases such as cardiovascular diseases is lower in Mediterranean Southern Europe than Northern Europe. This may be due to a lower level of oxidative stress and a higher antioxidant status in people living around the Mediterranean Sea. Oxidative stress may influence the rate of shortening of telomeres, the nucleoprotein structures at the ends of chromosomes. We compared leukocyte telomere length (LTL) in elderly men from Northern and Southern Europe and investigated the possible relationship between LTL and indicators of oxidative stress and antioxidant status. We examined 143 elderly Dutch men (mean age 83.9 years) and 109 Greek elderly men (mean age 84.6 years) and found that the Greek men had significantly longer telomeres (geometric mean 4.95 kbp, 95% confidence interval (CI): 4.71-5.23 kbp) compared to the men from the Netherlands (4.76 kbp, 95% CI: 4.55-4.98 kbp; P=0.001). Age was inversely associated with LTL (β=-0.10, P=0.31 in Cretan men and β=-0.19, P=0.02 in Dutch men). In all men LTL was not related to indicators of oxidative stress and plasma antioxidants. However, the endogenous antioxidants serum albumin (β=0.18, P=0.007) and uric acid (β=0.13, P=0.045) were positively associated with LTL. The age-adjusted difference between Crete and Zutphen was reduced by 25% after adjustment for serum albumin and uric acid. We conclude that Greek elderly men have significantly longer LTL compared to Dutch counterparts. The endogenous antioxidants albumin and uric acid were positively associated with longer telomeres.
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http://dx.doi.org/10.1016/j.mad.2012.04.003DOI Listing
June 2012

Telomere length and mental well-being in elderly men from the Netherlands and Greece.

Behav Genet 2012 Mar 26;42(2):278-86. Epub 2011 Aug 26.

Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands,

Telomeres, repetitive DNA sequences that promote chromosomal stability, have been related to different measures of mental well-being and self-rated health, but mainly in women during adulthood. We aimed to investigate whether accelerated telomere shortening is associated with poor mental well-being and poor self-rated health in community-dwelling elderly men. Leukocyte telomere length was measured using quantitative PCR in two different samples of 203 elderly men (mean age 78 years) from the Netherlands in 1993, and 123 elderly men (mean age 84 years) from Greece in 2000. We also obtained follow-up data in 2000 from 144 Dutch subjects, of whom 75 had paired telomere length data in 1993 and 2000. Mental well-being was conceptualized as dispositional optimism, depressive symptoms, cognitive functioning, and loneliness. Linear regression analyses were used to study the association between telomere length, measures of mental well being, and self-rated health, while adjusting for potential confounders. In cross-sectional analyses, leukocyte telomere length was not associated with measures of mental well-being and self-rated health, neither in the Netherlands nor in Greece. Also, the rate of leukocyte telomere shortening (mean decrease: 0.28 kbp over 7 years) in the 75 Dutch participants with longitudinal data was not associated with changes in different measures of mental well-being and self-rated health. Thus, our results provide no support for a relationship between leukocyte telomere length and mental well-being in elderly community-dwelling men.
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http://dx.doi.org/10.1007/s10519-011-9498-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276762PMC
March 2012

Spurious association between telomere length reduction over time and baseline telomere length.

Int J Epidemiol 2011 Jun 12;40(3):839-40; author reply 840-1. Epub 2010 Dec 12.

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http://dx.doi.org/10.1093/ije/dyq235DOI Listing
June 2011

Telomere length and mortality in elderly men: the Zutphen Elderly Study.

J Gerontol A Biol Sci Med Sci 2011 Jan 1;66(1):38-44. Epub 2010 Oct 1.

Department of Health Risk Analysis and Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, The Netherlands.

Telomere shortening is a marker of aging and therefore telomere length might be related to disease progression and survival. To address these questions, we measured leukocyte telomere length (LTL) in male participants from the Zutphen Elderly Study. LTL was measured by quantitative polymerase chain reaction in 203 men: mean aged 78 years in 1993 and 75 surviving participants mean aged 83 years in 2000. During 7 years of follow-up, 105 men died. Cox proportional hazards models were used to estimate hazard ratios for all-cause and cause-specific mortality. We found that LTL declined with a mean of 40.2 bp/year, and LTL values measured in 1993 and 2000 correlated significantly (r = .51, p < .001). Longer telomeres at baseline were not predictive for all-cause mortality, cardiovascular mortality, or cancer mortality. These results suggest that LTL decreases with increasing age and that LTL is not related to mortality in men aged more than 70 years.
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http://dx.doi.org/10.1093/gerona/glq164DOI Listing
January 2011

Decreased exercise-induced expression of nuclear factor-κB-regulated genes in muscle of patients with COPD.

Chest 2011 Feb 5;139(2):337-346. Epub 2010 Aug 5.

NUTRIM School for Nutrition, Toxicology and Metabolism, Department of Respiratory Medicine, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands.

Background: Nuclear factor (NF)-κB activation and oxidative stress are physiologic responses of skeletal muscle to exercise but may be impaired in patients with COPD. Therefore, we investigated NF-κB activity and expression of NF-κB-regulated genes in muscle of patients with COPD and control subjects before and after exercise.

Methods: Quadriceps specimens were obtained before, immediately after, and 2 h after a submaximal cycle ergometry test from seven patients with COPD (50.6 ± 5.7 SEM FEV(1) of patients with COPD) and seven age-matched control subjects. NF-κB DNA-binding activity in muscle and peripheral blood mononuclear cells (PBMCs) was determined using electrophoretic mobility shift assay and enzyme-linked immunosorbent assay, respectively. mRNA expression and protein carbonylation were measured by real-time polymerase chain reaction and Western blot, respectively.

Results: In control subjects, IL-6, IκBα, tumor necrosis factor-α, IL-1β, superoxide dismutase, thioredoxin, heme oxygenase 1, and heat shock protein-70 were upregulated in muscle after exercise, whereas in patients with COPD only IL-6 mRNA was increased. Exercise-induced antiapoptotic Bcl2 mRNA levels were attenuated in patients with COPD compared with control subjects. Basal muscle protein oxidation was higher in patients with COPD than in control subjects, but attenuated in response to exercise. No exercise-induced changes in NF-κB DNA-binding activity in muscle and PBMCs of either group were detected.

Conclusions: Skeletal muscle of patients with COPD is characterized by an impaired response to exercise of NF-κB-regulated genes encoding inflammatory cytokines, antioxidants, stress proteins, and survival factors.
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http://dx.doi.org/10.1378/chest.10-0275DOI Listing
February 2011

Inhibition of acute pulmonary and systemic inflammation by 1,7-dimethylxanthine.

Eur J Pharmacol 2010 Mar 4;629(1-3):132-9. Epub 2009 Dec 4.

Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, PO Box 616,6200 MD Maastricht, The Netherlands.

The nuclear enzyme poly(ADP-ribose) polymerse-1 (PARP-1) has previously been reported to play an important role in lipopolysaccharide (LPS)-induced pulmonary inflammation and is highly activated in COPD patients. In the present study, the anti-inflammatory efficacy of a previously identified poly(ADP-ribose) polymerase-1 (PARP-1) inhibiting caffeine metabolite, 1,7-dimethylxanthine, was both in vivo as well as ex vivo evaluated. Orally administered 1,7-dimethylxanthine significantly attenuated lung myeloperoxidase-levels, transcription of IL-6, TNF-alpha, MIP1alpha and MIP2 genes as well as PAR-polymer formation in a mouse model of intratracheally LPS-induced acute pulmonary inflammation. Serum amyloid P component and plasma IL-6 were also lowered in 1,7-dimethylxanthine treated mice, indicating a reduced systemic inflammatory response. In addition, at 24h after LPS administration anti-inflammatory effects of 1,7-dimethylxanthine appeared more pronounced than those of the orally administered PARP-1 inhibitor 3-aminobenzamide. In the second model, in blood of COPD-patients and healthy controls ex vivo pre-incubated with a physiological concentration of 1,7-dimethylxanthine (10microM), LPS-induced production of the cytokines IL-6 and TNF-alpha was significantly suppressed. 1,7-Dimethylxanthine exerts anti-inflammatory effects, both in vivo mouse as well as ex vivo human. These results suggest that the PARP-1 inhibiting caffeine metabolite 1,7-dimethylxanthine may have therapeutic potential in pulmonary inflammatory diseases such as COPD.
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http://dx.doi.org/10.1016/j.ejphar.2009.11.064DOI Listing
March 2010

Systemic and pulmonary oxidative stress after single-leg exercise in COPD.

Chest 2009 Nov 20;136(5):1291-1300. Epub 2009 Aug 20.

Department of Respiratory Medicine, Maastricht University, Maastricht, the Netherlands.

Background: Our aim for this study was to disentangle the contribution of muscular vs pulmonary oxidative stress during endurance exercise in patients with COPD.

Methods: Fifteen COPD patients and 10 healthy age-matched control subjects performed a continuously submaximal single-leg ergometer test (40% of peak workload) for 20 min or until they stopped (muscle endurance [Tlim]). Venous blood, urine samples, and exhaled breath condensate were sampled before, immediately after, and 2 h after exercise.

Results: Tlim was lower in COPD patients than in control subjects (p < 0.01). No exercise-induced systemic inflammation (ie, no raised levels of interleukin-6 or tumor necrosis factor-alpha) was found in the groups. Urinary malondialdehyde and uric acid levels (p < 0.05) were increased in COPD patients, whereas erythrocyte oxidized glutathione/reduced glutathione levels tended to be increased in COPD patients compared with control subjects after exercise (p = 0.08). Despite the relatively low cardioventilatory response to this localized muscle exercise, hydrogen peroxide levels in breath condensate significantly increased in COPD patients (p < 0.01). Nuclear factor kappaB DNA-binding activity of p50 in peripheral blood monocytes was elevated after exercise in both COPD patients (p < 0.01) and control subjects (p < 0.05), whereas p65 protein levels were not altered.

Conclusion: COPD patients showed increased pulmonary and systemic oxidative stress after localized leg muscle exercise compared with healthy control subjects, without evidence of increased levels of systemic inflammation.
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http://dx.doi.org/10.1378/chest.08-2767DOI Listing
November 2009

Dichloroacetate modulates the oxidative stress and inflammatory response to exercise in COPD.

Chest 2009 Sep 24;136(3):744-751. Epub 2009 Apr 24.

Department of Respiratory Medicine, Institute for Lung Health, University Hospitals of Leicester National Health Service Trust, Leicester, UK.

Background: Impaired skeletal muscle function contributes to exercise intolerance in patients with COPD. Exercise-induced oxidative stress may initiate or accelerate impaired muscle function. Dichloroacetate (DCA) activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and thereby diminishing anaerobic energy production. This study aimed to determine whether DCA infusion also may reduce exercise-induced systemic oxidative stress and inflammatory response in patients with COPD.

Methods: A randomized, double-blind crossover design was used in which 13 patients with COPD performed maximal cycle exercise after an IV infusion of DCA (50 mg/kg body mass) or saline solution (placebo). Venous blood was sampled before exercise, and immediately, 30 min, and 2 h after exercise. Urine samples were obtained before and 2 h after exercise.

Results: Peak workload improved significantly after DCA infusion compared to placebo (10%; p < 0.01). Urinary uric acid levels after exercise were significantly lower in the DCA condition than in the placebo condition, whereas no significant difference was observed for urinary malondialdehyde levels. Oxidized glutathione (GSSG) levels were significantly increased 2 h after exercise in the placebo condition (p < 0.02) but not after DCA infusion. No changes in reduced glutathione (GSH), GSSG/GSH ratio, and superoxide dismutase activity were observed. Plasma interleukin (IL)-6 levels significantly increased 2 h after exercise only in the DCA condition (p < 0.01).

Conclusions: This study shows that improved performance after a pharmacologic intervention known to activate PDC was accompanied by an enhanced IL-6 response and a limited reduction in exercise-induced systemic oxidative stress.
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http://dx.doi.org/10.1378/chest.08-2890DOI Listing
September 2009

Poly (ADP-ribose) polymerase-1-inhibiting flavonoids attenuate cytokine release in blood from male patients with chronic obstructive pulmonary disease or type 2 diabetes.

J Nutr 2009 May 25;139(5):952-7. Epub 2009 Mar 25.

Department of Health Risk Analysis and Toxicology, Maastricht University Medical Centre+, Maastricht 6200 MD, The Netherlands.

Recently, we identified several flavonoids as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 in vitro and in vivo. PARP-1 is recognized as coactivator of nuclear factor-kappaB and plays a role in the pathophysiology of diseases with low-grade systemic inflammation, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). In this study, we assessed the antiinflammatory effects of flavonoids with varying PARP-1-inhibiting effects in whole blood from male patients with COPD or T2D and healthy men. A total of 10 COPD, 10 T2D patients, and 10 healthy volunteers matched for age and BMI were recruited. Blood from each participant was exposed to 1 microg/L lipopolysaccharide (LPS) over 16 h with or without preincubation with 10 micromol/L of flavone, fisetin, morin, or tricetin. Concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, -8, and -10 were measured in the supernatant. Preincubation with fisetin and tricetin strongly attenuated LPS-induced increases in concentrations of TNFalpha in blood from COPD patients [mean (+/- SEM): -41 +/- 4% (fisetin) and -31 +/- 4% (tricetin); P < 0.001] and IL-6 in blood from T2D patients [-31 +/- 5% (fisetin) and -29 +/- 6% (tricetin); P < or = 0.001]. Moreover, LPS-induced changes in TNFalpha and IL-6 concentrations were positively correlated with the extent of reduction by fisetin and tricetin. The PARP-1-inhibiting flavonoids fisetin and tricetin were able to attenuate LPS-induced cytokine release from leukocytes of patients with chronic systemic inflammation, indicating a potential application as nutraceutical agents for these patient groups.
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http://dx.doi.org/10.3945/jn.108.102756DOI Listing
May 2009

Inhibition of LPS-induced pulmonary inflammation by specific flavonoids.

Biochem Biophys Res Commun 2009 May 16;382(3):598-603. Epub 2009 Mar 16.

Department of Pharmacology and Toxicology, Maastricht University Maastricht, The Netherlands.

In the present study, the anti-inflammatory effects of the flavonoids flavone, fisetin and tricetin were evaluated in a mouse model of LPS-induced acute pulmonary inflammation. The flavonoid fisetin significantly reduced lung myeloperoxidase-levels and gene-expression of inflammatory mediators such as IL-6, TNF-alpha, IL-1beta, MIP-1alpha and MIP-2. The LPS-induced gene transcription of HO-1 and SOD2 was also significantly reduced by fisetin. Overall, the anti-inflammatory effects of fisetin in this in vivo model were much more pronounced as compared to the observed effects of flavone or tricetin and the anti-inflammatory glucocorticoid dexamethasone. The results of this study indicate that flavonoids such as fisetin might be potential candidates as pharmaceuticals or nutraceuticals in the treatment of pulmonary inflammatory diseases.
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http://dx.doi.org/10.1016/j.bbrc.2009.03.071DOI Listing
May 2009

Telomere shortening in chronic obstructive pulmonary disease.

Respir Med 2009 Feb 21;103(2):230-6. Epub 2008 Oct 21.

Department of Health Risk Analysis and Toxicology, University of Maastricht, The Netherlands.

Chronic oxidative stress and systemic inflammation contribute to the pathology of several chronic diseases, one among which is chronic obstructive pulmonary disease (COPD). In addition, increased oxidative stress and inflammation have been observed to be negatively associated with telomere length (TL). Our aim was to investigate the TL in COPD patients in relation to pulmonary and extrapulmonary disease severity. Furthermore, based on experimental evidence suggesting the effects of oxidative stress on telomere shortening, we studied the association of TL with the antioxidant enzyme superoxide dismutase (SOD). One hundred and two COPD patients with moderate to severe COPD were studied and compared with 19 healthy age-matched controls. Patients were characterized by elevated levels of inflammatory markers (CRP, sTNF-receptors) and lower SOD-activity than the controls (p<0.001), irrespective of the SOD genotype. TL was negatively associated with age (p<0.01) and was significantly shorter in COPD patients than controls (p<0.05). Within the patient group age-adjusted TL variability could not be explained by lung function and smoking history but a modest association was found with the percentage of fat mass (p<0.05). These data provide evidence for a relationship between a disturbed oxidant/antioxidant balance and telomere shortening and indicate that preservation of fat mass may be protective in delaying telomere shortening in COPD patients.
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http://dx.doi.org/10.1016/j.rmed.2008.09.003DOI Listing
February 2009

Telomere length assessment: biomarker of chronic oxidative stress?

Free Radic Biol Med 2008 Feb 10;44(3):235-46. Epub 2007 Oct 10.

Department of Health Risk Analysis and Toxicology, Maastricht University, The Netherlands.

Telomeres are nucleoprotein structures, located at the ends of chromosomes and are subject to shortening at each cycle of cell division. They prevent chromosomal ends from being recognized as double strand breaks and protect them from end to end fusion and degradation. Telomeres consist of stretches of repetitive DNA with a high G-C content and are reported to be highly sensitive to damage induced by oxidative stress. The resulting DNA strand breaks can be formed either directly or as an intermediate step during the repair of oxidative bases. In contrast to the majority of genomic DNA, there is evidence that telomeric DNA is deficient in the repair of single strand breaks. Since chronic oxidative stress plays a major role in the pathophysiology of several chronic inflammatory diseases, it is hypothesized that telomere length is reducing at a faster rate during oxidative stress. Therefore, assessment of telomere length might be a useful biomarker of disease progression. In this review several features of telomere length regulation, their relation with oxidative stress, and the potential application of measurement of telomere length as biomarker of chronic oxidative stress, will be discussed.
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http://dx.doi.org/10.1016/j.freeradbiomed.2007.10.001DOI Listing
February 2008

Dietary flavones and flavonoles are inhibitors of poly(ADP-ribose)polymerase-1 in pulmonary epithelial cells.

J Nutr 2007 Oct;137(10):2190-5

Department of Pharmacology and Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands.

The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which was initially known to be highly activated by oxidative stress-induced DNA strand breaks, has been shown to be involved in the pathophysiology of acute and chronic inflammatory diseases. PARP-1 deficiency in mice led to the discovery of its coactivating function in the nuclear factor-kappa B-mediated gene expression and in addition, pharmaceutical inhibition of PARP-1 was shown to reduce the production of inflammatory mediators. In this study, the in vitro PARP-1-inhibiting effect of various flavonoids was investigated. The flavonoids myricetin, tricetin, gossypetin, delphinidin, quercetin, and fisetin were identified as significant inhibitors of the purified enzyme. Further evaluation of these compounds in N-methyl-N'-nitro-N-nitrosoguanidine-treated human pulmonary epithelial cells showed that the formation of the poly(ADP-ribose) polymers, as well as the decreased NAD(+) levels, was reduced by quercetin, fisetin, and tricetin. Finally, IL-8 production of LPS-stimulated human pulmonary epithelial cells could be significantly reduced by these flavonoids. The results of this study indicate that specific flavonoids have PARP-1-inhibiting activity in addition to the earlier described antioxidant effects. PARP-1 inhibition and preservation of cellular NAD(+) and energy production could play a role in the antiinflammatory activity of these specific flavonoids. In addition, these results indicate additional mechanisms by which flavonoids can exert antiinflammatory activity. Furthermore, these results indicate possibilities to use food-derived flavonoids in the treatment of chronic inflammatory diseases.
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http://dx.doi.org/10.1093/jn/137.10.2190DOI Listing
October 2007

Flavone as PARP-1 inhibitor: its effect on lipopolysaccharide induced gene-expression.

Eur J Pharmacol 2007 Nov 13;573(1-3):241-8. Epub 2007 Jul 13.

Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.

The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) which was initially known for its role in the repair of oxidative stress-induced DNA damage, has also been reported to play a mediating role in the inflammatory response. Studies with PARP-1 knockout models have shown that PARP-1 is a co-activator of Nuclear Factor-kappa B (NF-kappaB), although this appears not to require its enzyme activity. In addition, drug-induced inhibition of the enzyme activity of PARP-1 was observed to reduce the production of pro-inflammatory mediators. In this study, the flavonoid compound flavone was demonstrated to significantly inhibit the enzyme activity of PARP-1. Further evaluation of flavone in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated human pulmonary epithelial and vascular endothelial cells revealed that both the decrease in NAD(+) levels, as well as the formation of PAR-polymers was dose-dependently attenuated by flavone. In addition, flavone was found to reduce the lipopolysaccharide (LPS)-induced interleukin (IL)-8 production in pulmonary epithelial cells, which was confirmed by transcription analysis. Furthermore, the transcription Inhibitor kappa B alpha (of IkappaBalpha) was significantly increased by flavone. The results of the present study indicate that the flavonoid flavone could be a potential candidate for application in treatment of chronic inflammatory diseases. PARP-1 inhibition could have beneficial effects in such diseases as Chronic Obstructive Pulmonary Disease (COPD) and diabetes, by preservation of cellular NAD(+) levels and attenuating inflammatory conditions.
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http://dx.doi.org/10.1016/j.ejphar.2007.07.013DOI Listing
November 2007

Caffeine metabolites are inhibitors of the nuclear enzyme poly(ADP-ribose)polymerase-1 at physiological concentrations.

Biochem Pharmacol 2006 Sep 25;72(7):902-10. Epub 2006 Jul 25.

Department of Pharmacology and Toxicology, Faculty of Medicine, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands.

The activity of the nuclear enzyme poly(ADP-ribose)polymerase-1 (E.C.2.4.2.30), which is highly activated by DNA strand breaks, is associated with the pathophysiology of both acute as well as chronic inflammatory diseases. PARP-1 overactivation and the subsequent extensive turnover of its substrate NAD+ put a large demand on mitochondrial ATP-production. Furthermore, due to its reported role in NF-kappaB and AP-1 mediated production of pro-inflammatory cytokines, PARP-1 is considered an interesting target in the treatment of these diseases. In this study the PARP-1 inhibiting capacity of caffeine and several metabolites as well as other (methyl)xanthines was tested using an ELISA-assay with purified human PARP-1. Caffeine itself showed only weak PARP-1 inhibiting activity, whereas the caffeine metabolites 1,7-dimethylxanthine, 3-methylxanthine and 1-methylxanthine, as well as theobromine and theophylline showed significant PARP-1 inhibiting activity. Further evaluation of these compounds in H2O2-treated A549 lung epithelial and RF24 vascular endothelial cells revealed that the decrease in NAD+-levels as well as the formation of the poly(ADP-ribose)polymer was significantly prevented by the major caffeine metabolite 1,7-dimethylxanthine. Furthermore, H2O2-induced necrosis could be prevented by a high dose of 1,7-dimethylxanthine. Finally, antioxidant effects of the methylxanthines could be ruled out with ESR and measurement of the TEAC. Concluding, caffeine metabolites are inhibitors of PARP-1 and the major caffeine metabolite 1,7-dimethylxanthine has significant PARP-1 inhibiting activity in cultured epithelial and endothelial cells at physiological concentrations. This inhibition could have important implications for nutritional treatment of acute and chronic inflammatory pathologies, like prevention of ischemia-reperfusion injury or vascular complications in diabetes.
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http://dx.doi.org/10.1016/j.bcp.2006.06.023DOI Listing
September 2006

Theophylline prevents NAD+ depletion via PARP-1 inhibition in human pulmonary epithelial cells.

Biochem Biophys Res Commun 2005 Dec 2;338(4):1805-10. Epub 2005 Nov 2.

Department of Health Risk Analysis and Toxicology, University of Maastricht, Maastricht, The Netherlands.

Oxidative DNA damage, as occurs during exacerbations in chronic obstructive pulmonary disease (COPD), highly activates the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1). This can lead to cellular depletion of its substrate NAD+, resulting in an energy crisis and ultimately in cell death. Inhibition of PARP-1 results in preservation of the intracellular NAD+ pool, and of NAD+-dependent cellular processes. In this study, PARP-1 activation by hydrogen peroxide decreased intracellular NAD+ levels in human pulmonary epithelial cells, which was found to be prevented in a dose-dependent manner by theophylline, a widely used compound in the treatment of COPD. This enzyme inhibition by theophylline was confirmed in an ELISA using purified human PARP-1 and was found to be competitive by nature. These findings provide new mechanistic insights into the therapeutic effect of theophylline in oxidative stress-induced lung pathologies.
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http://dx.doi.org/10.1016/j.bbrc.2005.10.159DOI Listing
December 2005

Rehabilitation decreases exercise-induced oxidative stress in chronic obstructive pulmonary disease.

Am J Respir Crit Care Med 2005 Oct 22;172(8):994-1001. Epub 2005 Jul 22.

Department of Respiratory Medicine, University of Maastricht, Maastricht, The Netherlands.

The effect of exercise at different intensities as well as the effect of intensive supervised pulmonary rehabilitation on oxidative stress were studied for chronic obstructive pulmonary disease (COPD). Eleven patients with COPD and 11 healthy age-matched control subjects performed a maximal and submaximal exercise cycle ergometry test at 60% of peak workload. Patients with COPD performed these tests before and after 8 wk of pulmonary rehabilitation. Measurements were done before, immediately after, and 4 h after both exercise tests. At rest, increased oxidative stress was observed in patients compared with control subjects, as measured by urinary malondialdehyde (MDA; p < 0.05) and hydrogen peroxide (H2O2) in breath condensate (p < 0.05). In healthy control subjects, a significant increase in urinary MDA was observed 4 h after both exercise tests (p = 0.05), whereas H2O2 significantly increased immediately after maximal exercise (p < 0.05). In patients with COPD, before rehabilitation, reactive oxygen species-induced DNA damage in peripheral blood mononuclear cells, urinary MDA, and plasma uric acid were significantly increased after both exercise tests (p < 0.05), whereas no significant increase was observed in plasma MDA. In contrast, exhaled H2O2 was only significantly increased after maximal exercise (p < 0.02). Although after rehabilitation peak workload was increased by 24%, a similar oxidative stress response was found. Remarkably, a decrease in reactive oxygen species-induced DNA damage was detected after exercise at submaximal intensity despite increased exercise duration of 73%. In summary, patients with COPD had increased pulmonary and systemic oxidative stress both at rest and induced by exercise. In addition, pulmonary rehabilitation increased exercise capacity and was associated with reduced exercise-induced oxidative stress.
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http://dx.doi.org/10.1164/rccm.200411-1580OCDOI Listing
October 2005

Poly(ADP-ribose) polymerase-1 mediated caspase-independent cell death after ischemia/reperfusion.

Free Radic Biol Med 2005 Jul 8;39(1):81-90. Epub 2005 Apr 8.

Department of Health Risk Analysis and Toxicology, University of Maastricht, The Netherlands.

In ischemia/reperfusion (I/R) injury increased intracellular Ca(2+) and production of reactive oxygen species (ROS) may cause cell death by intrinsic apoptotic pathways or by necrosis. In this review, an alternative intrinsic cell death pathway, mediated by poly(ADP-ribose) polymerase-1 (PARP-1) and apoptosis-inducing factor (AIF), is described. ROS-induced DNA strand breaks lead to overactivation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30), causing excessive use of energetic substrates such as NAD(+) and ATP, inducing cell death either by apoptosis or by necrosis. Recently, it was demonstrated that activation of PARP-1 induces translocation of apoptosis-inducing factor from the mitochondria to the nucleus, causing DNA condensation and fragmentation, and subsequent cell death. This pathway seems to be triggered by depletion of NAD(+) and appears to be caspase independent. Several lines of evidence suggest that this pathway plays a role in I/R injury, although some studies indicate that mitochondrial dysfunction may also trigger AIF translocation and cell death. At present, the exact mechanisms linking PARP-1 and AIF in the induction of the ROS-induced cell death are still unclear. Therefore, it appears that further investigations will yield valuable information on underlying mechanisms and potential interventions to reduce caspase-independent cell death during ischemia-reperfusion.
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http://dx.doi.org/10.1016/j.freeradbiomed.2005.03.021DOI Listing
July 2005

Systemic poly(ADP-ribose) polymerase-1 activation, chronic inflammation, and oxidative stress in COPD patients.

Free Radic Biol Med 2003 Jul;35(2):140-8

Department of Health Risk Analysis and Toxicology, Research Institute NUTRIM, University of Maastricht, Maastricht, Netherlands.

Oxidative stress and systemic inflammation in chronic obstructive pulmonary disease (COPD) strongly suggest a role for the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1, E.C.2.4.2.30) in the disease pathophysiology. PARP-1 is highly activated by reactive oxygen species-induced DNA strand breaks, upon which it forms extensive poly(ADP-ribose) (PAR) polymers from its substrate NAD(+). We hypothesized that in COPD, chronic inflammation and oxidative stress would lead to systemic PARP-1 activation and to a reduced NAD(+) status. In a patient-control study, systemic PARP-1 activation was assessed by immunofluorescent detection of PAR polymers in peripheral blood lymphocytes. The percentage of PAR polymer-positive lymphocytes appeared to be higher in COPD patients (27 +/- 3%) than in healthy age-matched controls (17 +/- 2%, p <.05). Trolox equivalent antioxidant capacity (TEAC) of deproteinized plasma (p <.001), plasma uric acid (p <.05), as well as blood NAD(+) (p <.01) of stable COPD patients were significantly reduced when compared to controls. In addition, levels of proinflammatory cytokines IL-6, IL-8, and sICAM-1 were increased (p <.005) in COPD patients. In this study, evidence was found for the presence of systemic inflammation, chronic oxidative stress, and systemic PARP-1 activation in stable COPD patients. These data support a contribution of oxidative stress-induced PARP-1 activation to the pathophysiology of COPD.
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http://dx.doi.org/10.1016/s0891-5849(03)00237-5DOI Listing
July 2003
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