Copper(II) Complexes with Carnosine Conjugates of Hyaluronic Acids at Different Dipeptide Loading Percentages Behave as Multiple SOD Mimics and Stimulate Nrf2 Translocation and Antioxidant Response in In Vitro Inflammatory Model

Abstract

A series of copper(II) complexes with the formula [Cu2+Hy(x)Car%] varying the molecular weight (MW) of Hyaluronic acid (Hy, x = 200 or 700 kDa) conjugated with carnosine (Car) present at different loading were synthesized and characterized via different spectroscopic techniques. The metal complexes behaved as Cu, Zn-superoxide dismutase (SOD1) mimics and showed some of the most efficient reaction rate values produced using a synthetic and water-soluble copper(II)-based SOD mimic reported to date. The increase in the percentage of Car moieties parallels the enhancement of the I50 value determined via the indirect method of Fridovich. The presence of the non-functionalized Hy OH groups favors the scavenger activity of the copper(II) complexes with HyCar, recalling similar behavior previously found for the copper(II) complexes with Car conjugated using β-cyclodextrin or trehalose. In keeping with the new abilities of SOD1 to activate protective agents against oxidative stress in rheumatoid arthritis and osteoarthritis diseases, Cu2+ interaction with HyCar promotes the nuclear translocation of erythroid 2-related factor that regulates the expressions of target genes, including Heme-Oxigenase-1, thus stimulating an antioxidant response in osteoblasts subjected to an inflammatory/oxidative insult.

Carnosine, Zinc and Copper: A Menage a Trois in Bone and Cartilage Protection

“…Indeed, it can directly act as a ROS scavenger thanks to its imidazole ring [195]. Alternatively, it can modulate different molecular pathways, such as Nrf-2 nuclear translocation, which regulates the expressions of antioxidant proteins [19,196]. For instance, Yang Y. et al investigated the protective effects of Car in a model of OA [197].…”

“…This attempt at drug repositioning is inspired by polaprezinc pro-osteogenic effects [18]. In addition, a recent report indicates that Cu interaction with Car and HyCar promotes the nuclear translocation of nuclear factor erythroid 2-related factor (Nrf-2) that regulates the expressions of target genes, including heme oxigenase-1 (HO-1), thus stimulating an antioxidant response in osteoblasts subjected to an inflammatory/oxidative insult [19]. Therefore, these recent studies also highlight the joint activity of the natural peptide and the two biometals, Zn and Cu, to contribute to the skeleton protection against degenerative insults.…”

Copper(II) Complexes with 1-(Isoquinolin-3-yl)heteroalkyl-2-ones: Synthesis, Structure and Evaluation of Anticancer, Antimicrobial and Antioxidant Potential

“…It should be noted that the therapeutic potency of copper(II) complexes is not limited to anticancer activity. These compounds have also gained much interest due to their anti-inflammatory and antioxidant properties [ 46 , 47 , 48 ], antiviral properties [ 49 , 50 ] or antibiofilm and antimicrobial [ 51 , 52 ] activities. The latter is a multi-faceted process, although the main mechanism of the bactericidal effect is the formation of ROS, causing irreversible damage to membranes [ 51 ].…”