Protein carbonyl groups as biomarkers of oxidative stress.

Oxidative/nitrosative stress, a pervasive condition of increased amounts of reactive oxygen/nitrogen species, is now recognized to be a prominent feature of many acute and chronic diseases and even of the normal aging process. However, definitive evidence for this association has often been lacking because of recognized shortcomings with biomarkers and/or methods available to assess oxidative stress status in humans. Emphasis is now being placed on biomarkers of oxidative stress, which are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic intervention. To be a predictor of disease, a biomarker must be validated. Validation criteria include intrinsic qualities such as specificity, sensitivity, degree of inter- and intraindividual variability, and knowledge of the confounding and modifying factors. In addition, characteristics of the sampling and analytical procedures are of relevance, including constraints and noninvasiveness of sampling, stability of potential biomarkers, and the simplicity, sensitivity, specificity, and speed of the analytical method. Here we discuss some of the more commonly used biomarkers of oxidative/nitrosative damage and include selected examples of human studies.

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Biomarkers of Oxidative Damage in Human Disease

The faithful execution of biological processes requires a precise and carefully orchestrated set of steps that depend on the proper spatial and temporal expression of genes. Here we review the various classes of transcriptional regulatory elements (core promoters, proximal promoters, distal enhancers, silencers, insulators/boundary elements, and locus control regions) and the molecular machinery (general transcription factors, activators, and coactivators) that interacts with the regulatory elements to mediate precisely controlled patterns of gene expression. The biological importance of transcriptional regulation is highlighted by examples of how alterations in these transcriptional components can lead to disease. Finally, we discuss the methods currently used to identify transcriptional regulatory elements, and the ability of these methods to be scaled up for the purpose of annotating the entire human genome.

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Transcriptional Regulatory Elements in the Human Genome

https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(03)00031-5.pdf

Protein carbonylation in human diseases.

Carbonylation of proteins is an irreversible oxidative damage, often leading to a loss of protein function, which is considered a widespread indicator of severe oxidative damage and disease-derived protein dysfunction. Whereas moderately carbonylated proteins are degraded by the proteasomal system, heavily carbonylated proteins tend to form high-molecular-weight aggregates that are resistant to degradation and accumulate as damaged or unfolded proteins. Such aggregates of carbonylated proteins can inhibit proteasome activity. A large number of neurodegenerative diseases are directly associated with the accumulation of proteolysis-resistant aggregates of carbonylated proteins in tissues. Identification of specific carbonylated protein(s) functionally impaired and development of selective carbonyl blockers should lead to the definitive assessment of the causative, correlative or consequential role of protein carbonylation in disease onset and/or progression, possibly providing new therapeutic aproaches.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1582-4934.2006.tb00407.x

Protein carbonylation, cellular dysfunction, and disease progression

We have analyzed several cases of Beckwith-Wiedemann syndrome (BWS) with Wilms' tumor in a familial setting, which give insight into the complex controls of imprinting and gene expression in the chromosome 11p15 region. We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor. Maternal inheritance of the deletion is associated with IGF2 loss of imprinting and up-regulation of IGF2 mRNA. However, in at least one affected family member a second genetic lesion (a duplication of maternal 11p15) was identified and accompanied by a further increase in IGF2 mRNA levels 35-fold higher than control values. Our results suggest that the combined effects of the H19/IGF2-imprinting center microdeletion and 11p15 chromosome duplication were necessary for manifestation of BWS.

Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor.

Protein carbonyl groups' content as a useful clinical marker of antioxidant barrier impairment in plasma of children with juvenile chronic arthritis.

TGF-beta is a cytokine with varied properties and pleiotropic activity. It is released in an inactive form. To exhibit its biological activity, it requires binding to extracellular matrix proteins and, after that, proteolytic elimination of LAP (Latent Associated Protein) and LTBP (Latent TGF-beta Binding Protein). The process involves, among others, tissue transglutaminase, thrombin and plasmin. By stimulation of specific receptors, it influences transcription of some genes and translation of formed mRNA. Locally, it demonstrates proinflammatory properties whereas systemically, it has primarily a potent immunosuppressive effect. TGF-beta, by affecting proliferation, differentiation and migration of cells, as well as stimulation of extracellular matrix protein production, plays an important role in tissue regeneration and remodeling, but also in fibrosis. TGF-beta is also indispensable to maintain immune homeostasis of the organism. Reduced TGF-beta activity is considered to be responsible for development of autoimmune disorders in the course of several pathologic conditions. This cytokine plays an important role in the pathogenesis of chronic inflammatory processes taking place, among others, in inflammatory bowel diseases (IBD) and chronic hepatitis B and C. The paper presents a review of literature concerning diagnostic and prognostic value of TGF-beta level determinations in blood and tissue bioptates of patients with chronic non-specific enteritis and chronic hepatitis B and C.

TGF-beta (transforming growth factor-beta) in chronic inflammatory conditions - a new diagnostic and prognostic marker?

Background Gastroesophageal reflux (GER) may aggravate chronic bronchopulmonary diseases. The study evaluated GER frequency and characteristics in children with Cystic Fibrosis (CF) as well as its consequences and pharmacological treatment. Material/methods 40 CF children aged 1.3 to 20 years were examined. The study methodology involved: medical files analysis, anamnesis, physical examination, growth status estimation, esophageal pH-metry and upper gastrointestinal tract endoscopy with histological examination of esophageal biopsies. Results Based on pH-metry results, the diagnosis of GER was established in 22 children (55%). Mild GER (Index Reflux - IR 5-10%) was found in 12 children (54.5%), moderate GER (IR 10-20%) in 7 (31.8%) and severe GER (IR>20%) in 3 (13.6%). Ten patients with moderate or severe GER underwent endoscopy, which revealed GER-related esophagitis in 8 cases. There was no statistical difference of GER frequency and degree according to: age, sex, growth status, presence of type DF508 mutation in CFTR genome and typical GERD symptoms. According to the ESPGAN proposition, cisapride or cisapride with ranitidine medication was instituted. Treatment analysis was performed in 19 cases after successful follow-up examinations carried out three months later, indicating a significant decrease in reflux index, the longest episode duration and the number of episodes longer than 5 minutes. Improvement of endoscopic picture was noticed after treatment. Conclusions High frequency of gastroesophageal reflux and its consequences among children with cystic fibrosis, as well as the possibility of well-tolerated and efficient treatment of GER, indicate that diagnostics of GER among children with CF should be obligatory.

Maria Korzon

Papers

Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor.

Protein carbonyl groups' content as a useful clinical marker of antioxidant barrier impairment in plasma of children with juvenile chronic arthritis.

TGF-beta (transforming growth factor-beta) in chronic inflammatory conditions - a new diagnostic and prognostic marker?

Frequency, consequences and pharmacological treatment of gastroesophageal reflux in children with cystic fibrosis.

Acute acalculous cholecystitis of viral etiology--a rare condition in children?