Doklady Biochemistry and Biophysics最新文献

It was previously shown that the original dipeptide mimetic of the 4th loop of neurotrophin-3 (NT-3) hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301), like the full-length neurotrophin, predominantly activates the tyrosine kinase receptor TrkC and has a neuroprotective effect in vitro at concentrations of 10^–5–10^–12 M, as well as antidiabetic (0.1 and 0.5 mg/kg) and antidepressant (5 and 10 mg/kg) effects after systemic administration in rodents. In this work, the analgesic properties of GTS-301 were identified, which were manifested in the dose range of 0.01–10 mg/kg after acute intraperitoneal injection to rats in the “tail flick” test. Dipeptide GTS-301 increased the threshold of pain response by 20–30%; this effect persisted for at least 24 h after administration.

The expression profile of the key genes of biosynthesis (VTC2, GPP, GalDH, and GalLDH) and recycling (MDHAR1, MDHAR4, and MDHAR5) of ascorbate in response to infection with the fungal pathogen Fusarium proliferatum in garlic cultivars resistant (Podnebesny) and sensitive (Dubkovsky) to Fusarium rot was determined. It was found that differences in resistance to Fusarium lead to discrepancies in the dynamics and expression of individual genes of the ascorbate pathway, as well as in the ascorbate content. It was shown that, in response to infection, the expression level of the MDHAR4 gene increases in the resistant cultivar and decreases in the Fusarium-sensitive accession. As infection progresses, the expression levels of the VTC2 and GalLDH genes increase significantly (higher in the cv. Dubkovsky than in the cv. Podnebesny). In both cultivars, the ascorbate content increases (1.5 times higher in the cv. Dubkovsky than in the cv. Podnebesny).

The association of the pathogenesis of neurodegenerative diseases, depression, anxiety, and cognitive disorders with neurotrophin-3 deficiency determines the prospect of creating drugs with a similar mechanism of action. Since the use of full-length NT-3 is limited by unsatisfactory pharmacokinetic properties, the creation of low-molecular mimetics of neurotrophin-3 that are active when administered systemically is relevant. The Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies has created a dimeric dipeptide mimetic of the 4th loop of NT-3, hexamethylenediamide bis-(N-γ-oxybutyryl-L-glutamyl-L-asparagine) with the laboratory code GTS-302, which activates TrkC and TrkB receptors. Purpose. The purpose of the work was to study the range of pharmacological activity of GTS-302. Materials and methods. The pharmacological effects of GTS-302 were revealed by its intraperitoneal administration. The antidepressant-like activity of GTS-302 was studied in the forced swimming test on mice after its acute and 7-day administration. The anxiolytic and memory-enhancing activities of the dipeptide were studied, respectively, in the elevated plus maze on mice and in the novel object recognition test on rats after acute administration. The effect of GTS-302 on pain sensitivity was studied in the hot plate test on mice after acute administration. Results. It was found that GTS-302 exhibits antidepressant-like activity upon acute administration at doses of 0.5, 1.0, 5.0, and 10 mg/kg. At 7-day administration, the antidepressant-like activity of GTS-302 was more pronounced in terms of the effect expression and statistical significance. Dipeptide GTS-302 at doses of 1.0, 5.0, and 10.0 mg/kg exhibited anxiolytic and memory-enhancing activity and did not affect pain sensitivity. Conclusions. The pharmacological spectrum of the low-molecular NT-3 mimetic dipeptide GTS-302, revealed during systemic administration, includes a number of neuropsychotropic effects characteristic of a full-size neurotrophin. This allows GTS-302 to be considered as a potential neuropsychotropic drug.

The aim of this study was to describe the features of myocardial lymph flow using a new combined method of visualization of the lymphatic system. The study was performed on pig hearts harvested from a local slaughterhouse. The original dye, consisting of lipid-soluble chlorophyll and lipiodol, was injected stepwise into the lymphatic vessels. After sufficient optical identification of the lymphatic vessels, continuous injection of air into the coronary arteries was performed and CT scans were done. In this way, both optical and radiologic visibility of the cardiac lymphatic system was achieved. It was shown that lymph flow of the left and most part of the right ventricle is carried out through lymphatic collectors of the anterior wall of the heart, including retrogradely with respect to the right coronary artery, which complements the previously known facts about the structure of the lymphatic system of the heart.

Background. The effects of ionizing radiation (IR) involve a highly orchestrated series of events in cells, including DNA damage and repair, cell death, and changes in the level of proliferation associated with the stage of the cell cycle. A large number of existing studies in literature have examined the activity of genes and their regulators in mammalian cells in response to high doses of ionizing radiation. Although there are many studies, the research in effect of low doses of ionizing radiation remains limited. Though much progress has been made in understanding the basic principles of effects of low doses of radiation on individual components of biological systems, less is known about how low doses affect target molecules and regulate the cellular networks (e.g., activation of the immune system, genes and their regulators in the phenomenon of hormesis, and the formation of an adaptive response). These observations determined the purpose of the work: to investigate the activity of genes and non-coding RNAs (long non-coding RNAs and microRNAs) in various organs of mice with transplanted Lewis carcinoma after low-dose radiation. Materials and methods. Twenty-four female C57Bl/6 mice were transplanted subcutaneously with Lewis carcinoma cells (10⁵ cells in 0.2 mL of Hanks’ solution). Total 4-fold X-ray irradiation with an interval of 4 days at a dose of 0.075 Gy (0.85 Gy/min) was performed on the RUST M1 from 6 days after transplantation; the tumor size was measured daily. The mice were divided into the following groups: “Biocontrol”, “Biocontrol + irradiation”, “Tumor” and “Tumor + irradiation”. On the 19th day from the beginning of the experiment, the mice were euthanized. The expression profiles of mRNA genes, long non-coding RNAs, and microRNAs controlling the response to radiation were determined in the bone marrow, thymus, spleen, and tumor of mice. Results. Fractionated low-dose irradiation of mice with transplanted Lewis carcinoma caused a growth decrease of implanted tumor cells compared to the similar group without irradiation. At the same time, there was an activation of oncosuppressors and a decrease in the activity of oncogenes in the thymus and spleen of mice with tumor and irradiation. In the “Tumor” group, without irradiation, the number of activated oncogenes prevailed over the number of inactivated ones. Conclusions. Thus, the low-dose radiation exposure led to the activation of antitumor immunity in mice, which manifested itself in slowing tumor growth in animals and the induction of oncosuppressors and inhibition of oncogene expression.

The current study examined the underlying mechanism and the effect of 1,3-thiazin-6-one on the growth of renal cancer. The findings showed that 1,3-thiazin-6-one treatment inhibited the growth of xenograft tumors in a dose-dependent manner in mice model of renal cancer. Furthermore, when 1,3-thiazin-6-one was administered in a dose-dependent manner to mice with renal cancer, the expression of the proteins p-PI3K and p-Akt significantly decreased. In mice model of renal cancer, 1,3-thiazin-6-one treatment also inhibited p-mTOR expression. In a model of renal cancer in mice, the 1,3-thiazin-6-one therapy specifically targeted the expression of nuclear factor κB (NF κB) and signal transducer and activator of transcription 3 (STAT3). Renal cancer cells’ vitality was significantly (p < 0.05) reduced in a dose-dependent manner upon exposure to 1,3-thiazin-6-one. It also prevents invasiveness of the renal cancer cells in addition to suppression of colony forming potential. In summary, the 1,3-thiazin-6-one blocks the growth of kidney cancer by focusing on the pathways that trigger the inflammatory cascade. Therefore, 1,3-thiazin-6-one might be developed as a significant medicinal agent to cure renal cancer.

Laryngeal squamous cell carcinoma is a common type of head and neck cancer. This study investigated the role of the TRPM2 channel in doxorubicin (DOX)-induced cell damage in human laryngeal squamous cancer cells (Hep-2). Cells were exposed to various DOX concentrations and the appropriate dose was found. Then, TRPM2 antagonist ACA was treated. At the end of the study, cell viability test, Western blot and oxidative stress and inflammatory markers were examined. The results showed that TRPM2 channel expression increased with DOX administration, and DOX incubation in cells caused an increase in ROS, MDA, IL-1β, IL-6, and TNF-α levels, while GSH and GSH-Px levels decreased. Concurrent treatment with ACA attenuated these effects and reduced oxidative stress and inflammation. In addition, DOX-induced apoptosis markers including Casp-3, Casp-8, Casp-9, p53, and Bax were elevated, while Bcl-2 levels were decreased; ACA treatment reversed these changes. The study demonstrated that DOX treatment significantly enhances TRPM2 channel activation and ROS production in Hep-2 cells, thereby initiating apoptotic pathways that lead to cell death. Consequently, targeting the TRPM2 channel may represent a promising therapeutic strategy for treating laryngeal cancer.

Cytochromes of the P450 superfamily are widespread in nature; they were found in all studied aerobic organisms. Although the degree of similarity between cytochromes P450 of different families is low, all enzymes of this superfamily have similar tertiary structures. In addition, all cytochromes P450, including enzymes of the CYP74 clan, contain substrate recognition sites in their sequences, which form the catalytic center. Initially, CYP74 enzymes were discovered in plants, where they are widespread and play an important role in the lipoxygenase cascade. Later, CYP74-like enzymes of other families were identified in different taxa, including animals. Based on the results of phylogenetic studies, structures, and catalytic mechanisms, they were combined along with the CYP74 family into the CYP74 clan. One of the CYP74 clan enzymes is the epoxyalcohol synthase NvEAS (CYP443D1) of the starlet sea anemone Nematostella vectensis. A mutant form of NvEAS with a P93G substitution, that acquired additional hydroperoxide lyase activity, was obtained by site-directed mutagenesis. Before this work, only the results of site-directed mutagenesis of enzymes of the CYP74 family, but not of the CYP74 clan, were described. Moreover, in this work, the transformation of epoxyalcohol synthase into hydroperoxide lyase is described for the first time. These results confirm the previously stated assumption about the evolution of CYP74 enzymes, namely the epoxyalcohol synthase – hydroperoxide lyase – allene oxide synthase – divinyl ether synthase pathway.