Energy metabolism,thyroid calorigenesis,and oxidative stress: functional and cytotoxic consequences

Abstract

Recent findings indicate that nitric oxide (NO^?) over-production might be an important factor in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). We measured significantly higher concentrations of uric acid and thiol group-containing molecules (R–SH groups) in the cerebrospinal fluid (CSF) from SALS patients compared to controls. The above factors, together with a slightly increased free iron concentration found in the CSF, favour conditions necessary for the formation of the dinitrosyl iron complex, capable of NO^? bio-transformation. Thus, we performed ex vivo saturation of CSF (from both SALS patients and controls) with NO^?. A decrease in the level of R–SH was found. This was more pronounced in the CSF from SALS patients. In the CSF from SALS patients the production of nitrite and hydroxylamine was greater than that observed in the CSF from controls. Moreover, we also found increased Cu,Zn-SOD activity in the CSF from SALS patients (when compared to control subjects) but no activity corresponding to Mn-SOD in any CSF samples. As Cu,Zn-SOD can react with nitroxyl forming NO^?, the conditions for a closed, but continuous, loop of NO^? biotransformation are present in the CSF of ALS patients.     

Redox metabolism in malaria: from genes,through biochemistry and pathology,to drugs

Abstract

The role of Saccharomyces cerevisiae flavohemoglobin (Yhb1) is controversial and far from understood. This study compares the effects of nitrosative and oxidative challenge on the yeast mutant lacking the YHB1 gene. Growth of the mutant was impaired by nitrosoglutathione and peroxynitrite, whereas increased sensitivity to reactive oxygen species was not observed. Increased levels of intracellular NO^? after incubation with NO^? donors were found in the mutants cells as compared to the wild-type cells. Deletion of the YHB1 gene was found to augment the reduction of Fe³⁺ by yeast cells which suggests that flavohemoglobin participates in regulation of the activity of plasma membrane ferric reductase(s).     

Bilirubin: an endogenous scavenger of nitric oxide and reactive nitrogen species

Abstract

Bilirubin is the final product of heme metabolism. Until recently, bilirubin was considered as a mere by-product of heme degradation but, in the last 20 years, many papers have appeared in the literature demonstrating that this bile pigment is endowed with a strong antioxidant activity, being able to counteract the cellular damage elicited by reactive oxygen species in many in vitro and in vivo experimental systems. Interestingly, compelling evidence has shown that BR can serve as an endogenous scavenger of both nitric oxide and reactive nitrogen species, thus widening the protective role of bilirubin to other reactive species originating within the cellular milieu. The aim of this paper is to give an overview of the interaction between bilirubin and nitric oxide/reactive nitrogen species; furthermore, the possible pathophysiological and clinical relevance of this interaction will be discussed.     

Dipyrone and aminopyrine are effective scavengers of reactive nitrogen species

Abstract

Reactive nitrogen species (RNS), namely nitric oxide (NO^?) and peroxynitrite (ONOO^?) are produced in the inflammatory sites and may contribute to the deleterious effects of inflammation. The aim of the present study was to evaluate the putative scavenging effect of a particular group of non-steroidal anti-inflammatory drugs (NSAIDs), the pyrazolone derivatives dipyrone, aminopyrine, isopropylantipyrine, and antipyrine against RNS, using in vitro non-cellular screening systems. The results obtained showed that dipyrone and aminopyrine were highly potent scavengers of NO^? and ONOO^? while antipyrine exerted little effect and isopropylantipyrine no effect whatsoever against these two RNS and that, in the presence of bicarbonate, the scavenging potencies of both dipyrone and aminopyrine were slightly decreased. It could thus be inferred that the observed scavenging effects may be of therapeutic benefit for patients under anti-inflammatory treatment with dipyrone and aminopyrine in the case of overproduction of RNS. On the other hand, the possible depletion of physiological NO^? concentrations, namely at the gastrointestinal tract as well as the formation of reactive derivatives of aminopyrine and/or dipyrone, resulting from their reaction with RNS, may otherwise be harmful for these patients.     

NO• chemistry: a diversity of targets in the cell

Abstract

NO^? alone is a poorly reactive species; however, it is able to undergo secondary reactions to form highly oxidizing and nitrating species, NO₂^?, N₂O₃, and ONOO^?. These secondary reactive nitrogen species (RNS) are capable of modifying a diversity of biomolecular structures in the cell. The chemical properties of individual RNS will be discussed, along with their ability to react with amino acids, metal cofactors, lipids, cholesterol, and DNA bases and sugars. Many of the identified RNS-induced modifications have been observed both in vitro and in vivo. Several of these chemical modifications have been attributed with a functional role in the cell, such as the modulation of enzyme activity. Other areas in the field will be discussed, including the ability of RNS to react with metabolites, RNA, and substrates in the mitochondrion, and the cellular removal/repair of RNS-modified structures.     

Role of nitric oxide in pathological responses of the lung to exposure to environmental/occupational agents

Abstract

Conflicting evidence exists as to whether nitric oxide expresses damaging/inflammatory or antioxidant/anti-inflammatory properties. Data presented in this review indicate that in vitro or in vivo exposure to selected environmental or occupational agents, such as asbestos, silica, ozone or lipopolysaccharide, can result in up-regulation of inducible nitric oxide synthase by alveolar macrophages and pulmonary epithelial cells. In the case of silica exposure, evidence consistently supports a damaging/inflammatory role of nitric oxide and/or peroxynitrite in the pathogenesis of lung disease. Although conflicting data have been reported, the majority of published studies suggest that nitric oxide plays a damaging role in pulmonary injury resulting from exposure to ozone or asbestos. In contrast, most information supports an anti-inflammatory role of nitric oxide following exposure to lipopolysaccharide. Further investigation is required to elucidate fully the mechanisms involved in determining the role of nitric oxide in the initiation and progression of various pulmonary diseases.