NF‐kB and caspases are involved in the hyaluronan and chondroitin‐4‐sulphate‐exerted antioxidant effect in fibroblast cultures exposed to oxidative stress

Abstract

Oxidative stress, inflammation and apoptosis play a critical role in the onset and progression of cellular damage. It was previously reported that hyaluronan (HA) and chondroitin-4-sulphate (C4S) were able to protect human skin fibroblasts from oxidative stress. This antioxidant activity is due to the chelation of transition metal ions. Nuclear factor kB (NF-kB), complexed with the inhibitory protein IkB alpha, is an ubiquitous response transcription factor involved in inflammatory reactions and acts by inducing cytokine expression, chemokines and cell adhesion molecules. Caspases are specific proteases responsible for the regulation and the execution of apoptotic cell death. The damage caused by free radicals may be amplified greatly by the activation of these factors. The study investigated whether the ability of these glycosaminoglycans (GAGs) to reduce oxidative damage in fibroblast cultures involves NF-kB and caspases modulation. The treatment of fibroblasts with both HA and C4S limited the cell damage induced by FeSO(4) plus ascorbate. An interesting aspect of this treatment was that these GAGs significantly inhibited NF-kB DNA binding, as confirmed by the normalization of IkB alpha protein, and reduced caspase activation at both mRNA and protein level. A possible explanation for these results, since lipid peroxidation intermediates may induce NF-kB and caspase activation, is that HA and C4S indirectly blocked NF-kB DNA binding and apoptosis by inhibiting reactive oxygen species (ROS) production. These data suggest that, during oxidative stress, HA and C4S may reduce cell damage by inhibiting NF-kB and apoptosis activation as well as protecting cells from free radical attack. According to these finding the use of HA and C4S could be positive both as tool to clarify the exact mechanism of GAGs/ROS interaction, and also as drug therapy to reduce oxidative stress during inflammation.

Glycosaminoglycans modulate inflammation and apoptosis in LPS‐treated chondrocytes

“…We previously reported that HA and C4S were able to reduce free radical damage in fibroblast cultures exposed to FeSO 4 plus ascorbate [Campo et al, 2008]. The actions of HA and C4S were also able to inhibit NF-kB and executioner caspase activation [Campo et al, 2008].…”

“…The actions of HA and C4S were also able to inhibit NF-kB and executioner caspase activation [Campo et al, 2008]. We hypothesized that the inhibition of NF-kB DNA binding to the nucleus may be the consequence of HA plus C4S reduced ROS production in the fibroblasts.…”

“…This antioxidant activity is due to their capacity to chelate transition metals, like Cu þþ or Fe þþ , that are in turn responsible for the initiation of Haber-Weiss and Fenton's reaction [Albertini et al, 1999;Balogh et al, 2003;Campo et al, 2004]. It was also reported that HA and C4S were able to reduce cell injury by inhibiting NF-kB and caspase activation during oxidative stress [Campo et al, 2008]. The inhibitory activity on NF-kB and apoptosis activation was probably exerted by reducing oxygen species production, since free radicals may directly activate NF-kB [Gloire et al, 2006].…”

Ternary Complex of Plasmid DNA Electrostatically Assembled with Polyamidoamine Dendrimer and Chondroitin Sulfate for Effective and Secure Gene Delivery

“…42,43) In addition, it was reported to reduce cell damage by scavenging free radicals, inhibiting the activation of apoptosis, and eliciting an anti-inflammatory effect at the synovial membrane and chondrocyte level. 26,44,45) These cytoprotective actions of CS may reduce the toxicity of PAMAM dendrimers.…”

Improved Preservation of the Tissue Surrounding Percutaneous Devices by Hyaluronic Acid and Dermatan Sulfate in a Human Skin Explant Model

“…While direct effect of HA or DS on keratinocyte apoptosis is unknown, our results provide evidence that their presence may have the indirect effect of reducing apoptosis in vitro compared to non treated specimens and are in line with recently reported results of HA effects on fibroblasts. 9 Evaluation of the molecular mechanism involved in this process was not within the scope of our study. We did not directly observe tissue necrosis on the rims, but as indicated in Table 2 and shown in Fig.…”