Extensive liver resection (ELR), performed in a number of surgical operations, refers to a critical injury, which necessitates the improvement of methods of therapy of acute post-resection liver failure.Aim:to compare the effectiveness of stimulation of regenerative processes in the liver residue after ELR (60–70%) by intraperitoneal administration of lysed aspirate bone marrow cells (BMCs) and total RNA (tRNA) isolated from BMCs.Materials and methods.This work was performed on 175 rats-male Wistar breed 250–300 g, on 75 of which under the inhalation anesthesia it was reproduced the model of the ELR in three groups of experiments: group 1 – control (administration of isotonic solution after ELR), group 2 – in 3–5 hours after ELR the tRNA from BMCs was intraperitoneally injected at a dose of 30 μg/100 g, group 3 – in 3–5 hours after ELR BMCs was administered intraperitoneally at a dose of 30–35 × 106cells per rat. Comparative studies of the restorative processes in the liver after the ELR in the three groups were carried out by dynamic control of the mitotic activity of hepatocytes in the liver residue, cytolytic enzymes, total bilirubin and total serum protein, as well as the liver residue (mass) weight.Results.The tRNA from BMCs and BMCs in the indicated doses prevent the risk of the development of lethal outcomes, and also contribute to an earlier (by 10–14 days) normalization of the functional indices of hepatic homeostasis. However, the tRNA from BMCs, compared with BMCs, has a stronger stimulating effect on the recovery processes: it promotes earlier intensification of mitotic activity of hepatocytes and provides a higher rate of recovery of liver mass.Conclusion.For the induction of recovery processes in the liver residue after ELR, the preference should be given to the tRNA from BMCs.
Objective: using an adoptive transfer model to study the cellular mechanisms involved in the formation of the initial stage of liver regeneration during intraperitoneal injection of a healthy recipient with apoptotic bone marrowderived mononuclear cells (BM-MNCs) from a donor after extended liver resection.Materials and methods. Male Wistar rats (n = 40) were used to create a model of adoptive transfer of apoptotic BM-MNCs (a-BM-MNCs) taken from the donor after extended liver resection to a healthy recipient. During the experiments, the animals were divided into five groups. Four experimental groups with intraperitoneal injection of the same doses to the recipient: freshly isolated BM-MNCs (group 1); BM-MNCs subjected to apoptosis for 48 hours by storage at t = 4–6 °C in phosphate-buffered saline (PBS) (group 2) or in a Custodiol HTK solution (group 3). In group 4, the animals were injected with PBS after storing BM-MNCs in it. The control animals were animals injected with saline (group 5). For selection of effective modes of apoptosis induction, BM-MNCs stained with 7AAD after incubation in solutions were analyzed by flow cytometry. Targeted transfer of regenerative signals to the recipient was assessed by the mitotic activity of hepatocytes in the liver and tubular epithelium in the kidneys, as well as by the intensity of microstructural changes in the liver 24, 48 and 72 hours after injection of the studied material.Results. BMC incubation in PBS and HTK for 48 hours at t = 4–6 °C provides the most effective accumulation of a-BM-MNCs in early apoptosis. It was shown that a-BM-MNCs retain the ability to target-focused transmission of regulatory signals to the liver supported by autophagy process during adoptive transfer. It was established that a-BM-MNCs (groups 2 and 3) in comparison to native BM-MNCs (group 1) at adoptive transfer increased the regenerative potential of the liver due to pronounced increase in the activity of autophagy processes and directed infiltration of immunomodulatory mononuclear cells in the liver.Conclusion. a-BM-MNCs create a stronger basis for development and implementation of a targeted and effective regeneration program by enhancing autophagy processes and immunomodulatory effect on mononuclear cells, which are regenerative signal carriers.
Introduction. Immunomodulator Galavit® is a promising domestic drug for the prevention and treatment of various infectious diseases. Earlier, the authors have developed and investigated in vitro its new dosage form – transdermal therapeutic system (TTS). Positive results from experiments made it possible to proceed to the study of the pharmacokinetic parameters of Galavit® TTS in animals.Objective: to compare the pharmacokinetic parameters of intramuscular and transdermal administration of immunomodulator Galavit® in animal experiments.Materials and methods. Sodium aminodihydrophthalazinedione was used as a substance in the form of a powder to prepare a solution for intramuscular administration of 100 mg (trade name Galavit®, manufacturer SELVIM LLC). The pharmacokinetics of transdermal and intramuscular injections were studied in male Chinchilla rabbits weighing 4.5–5.0 kg. Serum sodium aminodihydrophthalazinedione concentrations in animals were determined by highperformance liquid chromatography using a specially developed technique.Results. In contrast to the injection method, a prolonged and uniform inflow of the drug substance (MP) into the body is observed for percutaneous administration of sodium aminodihydrophthalazinedione. The maximum serum Galavit® concentration for a 40 mg dose (0.172 ± 0.054 μg/mL) and for a 80 mg dose (1.16 ± 0.22 μg/mL) remained at a constant level for 9 and 8 hours, respectively. The relative bioavailability of the Galavit® transdermal therapeutic system was 0.65 and 1.06 for the same doses.Conclusion. Application of Galavit® 80 mg transdermal therapeutic system provides bioavailability that is similar to the intramuscular administration of this drug at the same dose. At the same time, its maximum serum concentration significantly decreases and the retention time of Galavit® in the body increases by more than 10 times, which can contribute to prolongation of the drug effect. Due to the current growing interest in the use of immunomodulator Galavit® for coronavirus infection COVID-19, the development and study of a new dosage form is a promising task
Objective: to study the cellular mechanisms of activation of regenerative processes in the liver when using total RNA (tRNA) of bone marrow cells (BMCs) based on an extended liver resection (ELR) model. Materials and methods. Male Wistar rats (n = 80) with ELR model (70%) were divided into 2 groups: group 1 (control group) had a single saline injection, while group 2 (experimental group) received a single tRNA injection at a 30 μg/100 g dose of animal weight. The biochemical parameters of liver function and weight were monitored over time. Also monitored were microstructural changes in hepatocytes 48 hours after ELR by examining mitotic activity, caspase-9 expression and morphometric parameters. Results. It was found that in group 2, in comparison to group 1, there was faster normalization of biochemical parameters (by 10–14 days), a higher mitotic index of hepatocytes (23.45‰ versus 5.37‰), and initially sharper decrease and then faster recovery of liver mass (by 10–12 days versus 18–20 days). Both groups showed almost total expression of caspase-9, including in mitotically splitting hepatocytes. Group 1 demonstrated decreased values of morphometric parameters of single and binuclear cells, decreased number of binucleated hepatocytes and increased total density of hepatocytes as compared to the intact liver. Intraperitoneal administration of tRNA increased morphometric parameters of mononuclear hepatocytes, did not affect their number, but increased the area of the nuclei of binuclear hepatocytes as compared to the control group. Conclusion. The proven capability of cell-bone marrow total RNA to simultaneously support apoptosis in liver cells after ELR and induce mitotic activity indicates that tRNA can switch activated apoptosis to cell proliferation at the early phase of the regenerative process. This effect may be due to the presence of regulatory RNA molecules in tRNA, including numerous non-coding RNAs.
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