dinoprost and dityrosine

d-2-hydroxyglutaric (D-2-HGA) and l-2-hydroxyglutaric (L-2-HGA) acidurias are rare neurometabolic disorders biochemically characterized by increased levels of d-2-hydroxyglutaric acid (D-2-HG) and l-2-hydroxyglutaric acid (L-2-HG) respectively, in biological fluids and tissues. These diseases are caused by mutations in the specific enzymes involved in the metabolic pathways of these organic acids. In the present work, we first investigated whether D-2-HG and L-2-HGA could provoke DNA oxidative damage in blood leukocytes and whether l-carnitine (LC) could prevent the in vitro DNA damage induced by these organic acids. It was verified that 50μM of D-2-HG and 30μM of L-2-HG significantly induced DNA damage that was prevented by 30 and 150μM of LC. We also evaluated oxidative stress parameters in urine of L-2-HGA patients and observed a significant increase of oxidized guanine species and di-tyrosine, biomarkers of oxidative DNA and protein damage, respectively. In contrast, no significant changes of urinary isoprostanes and reactive nitrogen species levels were observed in these patients. Taken together, our data indicate the involvement of oxidative damage, especially on DNA, in patients affected by these diseases and the protective effect of LC.

Topics: Adolescent; Adult; Brain Diseases, Metabolic, Inborn; Carnitine; Child; Child, Preschool; Comet Assay; Dinoprost; DNA Damage; Glutarates; Guanine; Humans; Leukocytes; Oxidative Stress; Protective Agents; Reactive Nitrogen Species; Tyrosine; Young Adult

Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation.. To determine the role of MPO in COPD.. We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure.. At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-κB binding.. We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.

Topics: Airway Remodeling; Animals; Dinoprost; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Female; Guinea Pigs; Hypertension, Pulmonary; Inflammation; Lung; Oxidative Stress; Peroxidase; Pulmonary Disease, Chronic Obstructive; Purines; Smoking; Thiones; Thioxanthenes; Tyrosine

It has been suggested that oxidative stress plays a key role in the pathogenesis of Down syndrome (DS). However, urinary biomarkers of oxidative stress have been little studied in this condition. Thus, we aimed to assess a set of urinary oxidative/nitrosative stress biomarkers in children with DS, with and without hypothyroidism, which comprise: 8-hydroxy-2'-deoxyguanosine (8-OHdG), isoprostane 15-F(2t)-IsoP, thiobarbituric acid-reacting substances (TBARS), advanced glycation end products (AGEs), dityrosine (diTyr), hydrogen peroxide (H(2)O(2)) and nitrite/nitrate (NOx).. Fluorimetric and spectrophotometric assays were performed in children with DS (n=26), some of them taking levothyroxine for hypothyroidism (n=7), and their non-Down siblings (n=19).. We found that only levels of diTyr were increased in DS, although no differences were obtained when hypothyroid DS children were excluded. Levels of 8-OHdG, 15-F(2t)-IsoP, TBARS, AGEs, H(2)O(2) and NOx did not differ neither between DS and controls nor between hypothyroid DS children and DS without hypothyroidism diagnosed. However, diTyr is increased in hypothyroid DS children compared with controls. Negative correlations with age were obtained for 8-OHdG, diTyr and NOx in DS and controls and for 8-OHdG, 15-F(2t)-IsoP, TBARS and AGEs in DS.. Increased oxidative stress in children with DS cannot be explained by the urinary levels of 8-OHdG, 15-F(2t)-IsoP, TBARS, AGEs, diTyr, H(2)O(2) and NOx, at least with the assays used. Nonetheless, urinary diTyr could be used as oxidative/nitrosative stress biomarker in hypothyroid DS children. The present work presents evidence of a probable renal impairment in children with DS receiving levothyroxine for hypothyroidism.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Biomarkers; Child; Child, Preschool; Deoxyguanosine; Dinoprost; Down Syndrome; Female; Glycation End Products, Advanced; Humans; Hydrogen Peroxide; Hypothyroidism; Lipid Peroxidation; Male; Nitrates; Nitrites; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Tyrosine