As the application of silver products is rapidly growing in a variety of fields, it is necessary for future studies to evaluate and determine the optimal form and concentration of silver that will be utilized. The valuable benefits of silver in health care have been recognized for thousands of years but the concern of adverse and toxic effects towards mammalian cells should not be ignored as well. The findings in this study demonstrated additional effects of silver ions on metabolic function alterations. It is known that silver ion is an antibacterial agent that can inhibit the proliferation of bacteria during wound healing. Additionally, the investigations towards the change of key metabolites further confirmed that low concentrations of silver ions could boost oxidative phosphorylation without causing cell death. However, upon characterizing transcriptomic changes using RNA-sequencing, the results suggested most functions and pathways impacted are associated with various processes of cellular metabolism, which indicated an increase of oxidation phosphorylation in the silver ions treated cells. Silver ion exposure for 21 hours did not increase the expression of pluripotency genes and did not reprogram fibroblast cells to an undifferentiated state as we hypothesized. It was mainly the electrically generated silver ion that was responsible for the cellular changes observed in the present work, including morphological changes and gene expression changes. In this study, we attempted to unravel the effects of morphological and physiological changes of porcine fibroblast cells exposed to electrical biostimulation. Taking into account the experimental studies showing a pronounced regenerative /responsive behavior of silver nanoparticles, novel pharmaceutical formulations with topic response have been synthesized. Specific histological methods concerning the responsive behavior of the stem cells in injured tissues, which are treated with pharmacological preparations containing silver nanoparticles, will be used. An assumed confirmation of the above mentioned hypothesis will open a new research direction toward silver nanoparticles, using in plastic and reconstructive surgery, degenerative diseases and anti-aging therapy. Moreover, the process of hair follicle neogenesis found in our studies would not be possible, without proliferation and differentiation of hair follicle stem cells. However, it is noteworthy to mention that even if the silver nanoparticles do not produce mesenchymal stem differentiation in vitro, the interleukin 6 and 8 secreted by mesenchymal stem cells under the action of these nanoparticles, could accelerate the healing of cutaneous lesions. In vitro stimulation of mesenchymal stem cells by silver nanoparticles has also been reported by the literature. Another laboratory scaled injury model of rat striated muscle, showed an enhanced histological aspect of healed muscle comparing to placebo, by using an oily nanodispersion of silver. Reports on regeneration of hair follicles in rabbit skin, meaning an accelerated healing of surgical wounds and a process of hair follicle neogenesis, produced by subcutaneous implantation of some nanofibers functionalized with silver nanoparticles have been highlighted. The rationale of this paper is the silver nanoparticles' responsive behavior by activating adult stem cells of mesodermal and ectodermal in vivo origin.
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