Influence of the type of salt-forming acids on the antiradiation activity of T1023 analogs – salts of N-isobutanoyl-S-isopropylisothiourea

According to leading experts, the vast arsenal of radioprotective agents available in the world today does not fully meet modern practical needs, both in the field of radiation protection, and in the prevention and treatment of complications of radiotherapy. The purpose of the study was to evaluate the effect of the salt-forming acids type on the radioprotective activity of NOS inhibitor T1023. The chemical part of this study included methods of chemical synthesis, physicochemical and elemental analysis. Pharmacological part – assessment of acute toxicity using V.B. Prozorovsky express method and the study of radioprotective activity using Till and McCulloch method based on the ability of mice hematopoietic cells to form spleen colonies after irradiation. The number of endogenous hematopoietic spleen colonies were assessed on the 8th day after total exposure to gamma-irradiation at a dose of 6 Gy in six independent experiments. As a result of directed chemical synthesis, six new derivatives of T1023 – salts of N-isobutanoyl-S-isopropylisothiourea have been developed, identified and characterized. The results of studying the safety and radioprotective activity of the synthesized compounds showed that changes in the salt-forming acid don’t significantly influence the toxicity: all studied compounds are in the 3rd class of toxicity and hazard. At the same time, it was found that the replacement of the salt-forming acid significantly influenced the severity of the radioprotective effect. For some of these compounds radioprotective efficacy is comparable to or exceeds the efficacy of the initial compound T1023. It is important to note that these new compounds were used in lower, more save doses than T1023. The results suggest promising further development of NOS inhibitors – isothiourea derivatives as radioprotective agents.

Synthesis, characterization and antiradiation properties of the tryptophanates of cobalt (II), manganese (II), copper (II) and zinc

Aim. In order to study the radioprotective activity were were obtained in the tryptophanates of cobalt (II), manganese (II), copper (II) and zinc. Methods. The composition and structure of the complexes were studied by elemental, thermogravimetric analyzes and IR infrared spectroscopy. To determine the presence of the Radioprotective Properties of the Co (II), Mn (II), Cu (II), Zn complexes with tryptophane, a test was conducted for the 30-day survival of irradiated animals. Results. The results of thermogravimetric studies have shown that the final product of the thermal decomposition of all compounds is metal oxide, respectively. The method of IR spectroscopy showed that the ligands in the composition of the metal (II) complexes enter the neutral form and coordinate with the complexing agent through the nitrogen atom. The results of experiments with complexes showed that they have noticeable radioprotective activity. The radioprotective activity of Co (II) complexes with tryptophan is 55%, Mn (II) with tryptophan 50%, Cu (II) with tryptophan 40%, and Zn 30%. They improve the survival and average life expectancy of lethally irradiated mice, not reaching the level of the known cystamine radioprotector, which is 80%. Conclusions. The data obtained by us testify to the prospects of using the complexes of Co (II), Mn (II), Cu (II), Zn with tryptophan for preventive purposes and in order to prevent local radiation injuries. Keywords: tryptophan-metal complexes, IR spectroscopy, thermogravimetry, complex compounds, radioprotective properties.

Drugs of radiological pharmacology: Quercetin

The purpose of the article is to draw attention to Quercetin as a means of radiological pharmacology within the framework of medicines’ repurposing. Spectrum of pharmacological activity. Quercetin possesses anti-inflammatory (blockade of the lipoxygenase pathway of arachidonic acid metabolism, decreased synthesis of leukotrienes, serotonin and other inflammatory mediators), antioxidant, antispasmodic, diuretic, membrane stabilizing, capillary stabilizing, regenerative, estrogen-like (effect on proline hydroxylase, inhibition of tumor necrosis factor and synthesis of interleukins), immunomodulatory, anticataractogenic, antisclerotic, angioprotective, antiviral (against influenza viruses), antitumor, proosteoclastic, gastroprotective, actoprotective action. Quercetin exhibits antiulcer action associated with the anti-inflammatory drugs, and also has a radioprotective activity (after X-ray and gamma irradiation). The cardioprotective properties of Quercetin are conditioned by an increase in the energy supply of cardiomyocytes due to its antioxidant effect and an improvement in blood circulation. Quercetin influences bone remodeling processes. Quercetin is able to normalize blood pressure and stimulate the release of insulin, accelerate platelet aggregation, and inhibit thromboxane synthesis. Key Words: Quercetin, radioprotector, senolytic effect, dietary supplement.

NLRC4 Mutation in flagellin-derived peptide CBLB502 ligand-binding domain reduces the inflammatory response but not radioprotective activity

ABSTRACT Bacterial flagellin is a pathogen-associated molecular pattern recognized by surface-localized Toll-like receptor 5 (TLR5) and cytosolic NOD-like receptor protein 4 (NLRC4). CBLB502, derived from Salmonella flagellin, exhibits high radioprotective efficacy in mice and primates by regulating TLR5 and the nuclear factor kappa B (NF-κB) signaling pathway. In this study, we examined the effects of CBLB502 and mutations in its NLRC4- and TLR5-binding domains on radioprotective efficacy and the immune inflammatory response. The results showed that CBLB502 mutation with I213A in the TLR5-binding domain significantly reduced NF-κB activity and radioprotective activity, whereas CBLB502 mutation with L292A in NLRC4-binding domain did not. Additionally, CBLB502 with both mutations greatly reduced NF-κB activity and eliminated radioprotection in mice. In contrast, NLRC4-binding domain mutation reduced the secretion of inflammatory interleukin-1β and interleukin-18. CBLB502 exerts its radioprotective effects through both the TLR5 and NLRC4 pathways. Additionally, deletion in the NLRC4-binding domain did not reduce radioprotective activity but reduced the inflammatory response.

Radioprotective effect of newly synthesized toll-like receptor 5 agonist, KMRC011, in mice exposed to total-body irradiation

Exposure to ionizing radiation leads to severe damages in radiosensitive organs and induces acute radiation syndrome, including effects on the hematopoietic system and gastrointestinal system. In this study, the radioprotective ability of KMRC011, a novel toll-like receptor 5 (TLR5) agonist, was investigated in C57BL6/N mice exposed to lethal total-body gamma-irradiation. In a 30-day survival study, KMRC011-treated mice had a significantly improved survival rate compared with control after 11 Gy total-body irradiation (TBI), and it was found that the radioprotective activity of KMRC011 depended on its dosage and repeated treatment. In a 5-day short-term study, we demonstrated that KMRC011 treatment stimulated cell proliferation and had an anti-apoptotic effect. Furthermore, KMRC011 increased the expressions of genes related to DNA repair, such as Rad21, Gadd45b, Sod2 and Irg1, in the small intestine of lethally irradiated mice. Interestingly, downregulation of NF-κB p65 in the mouse intestine by KMRC011 treatment was observed. This data indicated that KMRC011 exerted a radioprotective activity partially by regulating NF-κB signaling. Finally, peak expression levels of G-CSF, IL-6, IFN-γ, TNF-α and IP-10 induced by KMRC011 treatment were different depending on the route of administration and type of cytokine. These cytokines could be used as candidate biomarkers for the evaluation of KMRC011 clinical efficacy. Our data indicated that KMRC011 has radioprotective activity in lethally irradiated mice and may be developed as a therapeutic agent for radioprotection.