Pro-oxidative effect of peroxynitrite regarding biological systems: a special focus on high-molar-mass hyaluronan degradation

Abstract

Abstract. Current understanding on the role of peroxynitrite in etiology and pathogenesis of some human diseases, such as cardio-vascular diseases, stroke, cancer, inflammation, neurodegenerative disorders, diabetes mellitus and diabetic complications has recently led to intensive investigation of peroxynitrite involvement in physiology and pathophysiology.Mechanism of cytotoxic effects of peroxynitrite involve its reactions with lipids, DNA/RNA, proteins, and polysaccharides, thus triggering cellular responses ranging from subtle changes of cell functioning to severe oxidative damage of the affected macromolecules leading to necrosis or apoptosis. The present work is aimed at providing a brief overview of i) peroxynitrite biosynthesis and reaction pathways in vivo, ii) its synthetic preparation in vitro, and iii) to reveal its potential damaging role in vivo, on actions studied via monitoring in vitro hyaluronan degradation. The complex biochemical behavior of peroxynitrite is determined by a number of variables, such as chemistry of the reaction itself, depending mostly on the involvement of conformational structures of different energy states, concentration of the species involved, content of reactive intermediates and trace transition metal ions, contribution of carbon dioxide, presence of trace organics, and by the reaction kinetics. Recently, in vitro studies of oxidative cleavage of hyaluronan have, in fact, been the subject of growing interest. Here we also describe our experimental set-up for studying peroxynitrite-mediated degradation of hyaluronan, a system, which may be suitable for testing prospective pharmacological substances.

Hyaluronan and RHAMM in Wound Repair and the “Cancerization” of Stromal Tissues

“…HA is considered a “keystone” or central molecule in regulating response to tissue stress since rapid alterations in HA production, macromolecular organization, and size within tissues are among the earliest changes that can be detected following injury including those resulting from exposure to ionizing radiation [30, 81, 98, 110, 111]. Like other ECM components (e.g., collagen), HA is fragmented during wound repair into small proinflammatory oligosaccharides by oxygen/nitrogen free radicals that accumulate in the stressed tissue [112, 113]. These wound fragments constitute an early “danger signal” that is part of the damage-associated molecular process (DAMP).…”

Extracellular matrix regulation of inflammation in the healthy and injured spinal cord

“…Inflammation-induced fragmentation, mediated in part through the release of enzymes including hyaluronidases and MMPs or reactive oxygen species also destabilizes the ECM (Esser et al, 2012; Hrabarova et al, 2011) (Fig. 2).…”

Rewriting the Epigenetic Code for Tumor Resensitization: A Review

“…Nitric oxide rapidly combines with excess superoxide (O 2 • − ) in the tumor, outcompeting superoxide dismutase, to produce high levels of potent peroxynitrite (ONOO–), in the proverbial “Devil's Triangle” of oxidative stress [27]. In this way, RRx-001 channels its activity through redox and metabolic stress on the tumor, (refer to Figure 1), resulting in the oxidation of critical cysteine residues at catalytic sites of the enzymes DNA MTases 1 and 3a and HDACs, inhibiting their activity and resulting in global hypomethylation (RadioRx unpublished data).…”