Antifibrotic Effect of Selenium-Containing Nanoparticles on a Model of TAA-Induced Liver Fibrosis.

For the first time, based on the expression analysis of a wide range of pro- and anti-fibrotic, pro- and anti-inflammatory, and pro- and anti-apoptotic genes, key markers of endoplasmic reticulum stress (ER-stress), molecular mechanisms for the regulation of fibrosis, and accompanying negative processes caused by thioacetamide (TAA) injections and subsequent injections of selenium-containing nanoparticles and sorafenib have been proposed. We found that selenium nanoparticles of two types (doped with and without sorafenib) led to a significant decrease in almost all pro-fibrotic and pro-inflammatory genes. Sorafenib injections also reduced mRNA expression of pro-fibrotic and pro-inflammatory genes but less effectively than both types of nanoparticles. In addition, it was shown for the first time that TAA can be an inducer of ER-stress, most likely activating the IRE1α and PERK signaling pathways of the UPR, an inducer of apoptosis and pyroptosis. Sorafenib, despite a pronounced anti-apoptotic effect, still did not reduce the expression of caspase-3 and 12 or mitogen-activated kinase JNK1 to control values, which increases the risk of persistent apoptosis in liver cells. After injections of selenium-containing nanoparticles, the negative effects caused by TAA were leveled, causing an adaptive UPR signaling response through activation of the PERK signaling pathway. The advantages of selenium-containing nanoparticles over sorafenib, established in this work, once again emphasize the unique properties of this microelement and serve as an important factor for the further introduction of drugs based on it into clinical practice.

Development of a Biocompatible PLGA Polymers Capable to Release Thrombolytic Enzyme Prourokinase.

The novelty of the work lies in the creation and study of the physical and biological properties of biodegradable polymer coatings for stents based on poly(lactic-co-glycolic acid) (PLGA). Polymer coatings are capable of prolonged and directed release of molecules with a high molecular weight, in particular, protein molecules of prourokinase (m.w. 54 kDa). A technology has been developed to create coatings having a relative elongation of 40% to 165% and a tensile strength of 25-65 MPa. Coatings are biodegradable; the rate of degradation of the polymer in an isotonic solution varies in the range of 0.05%-1.0% per day. The created coatings are capable of controlled release of the protein of prourokinase, while about 90% of the molecules of prourokinase retain their enzymatic activity. The rate of release of prourokinase can vary from 0.01 to 0.08 mg/day/cm2. Coatings do not have a short-term toxic effect on mammalian cells. The mitotic index of cells growing on coatings is approximately 1.5%. When implanting the developed polymers in animals in the postoperative period, there are no complications. Histological examination did not reveal pathological processes. When implanting individual polymers 60 days after surgery, only traces of PLGA are detected. Thus, a biodegradable composite mechanically resistant polymer capable of prolonged release of the high molecular weight prourokinase enzyme has been developed.