Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives - Imidazoline Receptor Agonists.

Introduction: The paper presents the results of a study on the first synthesized benzimidazole derivatives obtained from labile nature carboxylic acids. The synthesis conditions of these substances were studied, their structure was proved, and some components were found to have sugar-reducing activity on the model of alloxan diabetes in rats. Methods: The study used molecular modeling methods such as docking based on the evolutionary model (igemdock), RP_HPLC method to monitor the synthesis reaction, and 1H NMR and 13C NMR, and other methods of organic chemistry to confirm the structures of synthesized substances. Results & Discussion: The docking showed that the ursodeoxycholic acid benzimidazole derivatives have high tropics to all imidazoline receptor carriers (PDB ID: 2XCG, 2bk3, 3p0c, 1QH4). The ursodeoxycholic acid benzimidazole derivative and arginine and histidine benzimidazole derivatives showed the highest sugar-lowering activity in the experiment on alloxan-diabetic rats. For these derivatives, the difference in glucose levels of treated rats was significant against untreated control. Therefore, the new derivatives of benzimidazole and labile natural organic acids can be used to create new classes of imidazoline receptor inhibitors for the treatment of diabetes mellitus and hypertension.

Interactions between Antimicrobial Peptides and Targets Responsible for their Nephrotoxic Action: Molecular Dynamics Simulations.

OBJECTIVES: Polymyxin is the last line of defense against resistant forms of microorganisms, but it has significant nephrotoxicity. One of the directions in reducing the nephrotoxicity of polymyxin is to modify the charge of the molecule and accordingly, to change the topicity of the polymyxin derivative to the renal megalin. Such modification can lead to a decrease in the accumulation of polymyxin in the kidneys and reduce its toxicity while maintaining its antimicrobial properties. The study aimed to investigate the structural aspects of polymyxin nephrotoxicity at the atomic level to promote the more purposeful development of the polymyxin's derivatives with the lower nephrotoxic action. MATERIALS AND METHODS: The molecular dynamics simulations of the complexes of polymyxin B and its derivative NAB7061 (that carries only three positive charges located within the macrocycle) with megalin were performed in program package YASARA structure with explicit water (TIP3P) and ions (0.9 % NaCl) in NPT ensemble using the AMRER03 force field. After 10 ns equilibration, each system was simulated at 298 K and pH 7.4 for a 25 ns production phase. Simulations were run twice for each molecular system. RESULTS: By molecular dynamics simulations, the possibility was shown for polymyxin to form a stable complex with two neighbor structural domains of megalin in accord with the universal mechanism of binding the cationic ligands by ligand-binding CR repeats of the LDLR-family receptors. It was reported that interactions of megalin with polymyxin were stronger than with its derivative having no positively charged groups outside the macrocycle. The structural prerequisites of these differences were revealed, explaining the less nephrotoxicity of such derivatives compared to polymyxin. CONCLUSION: Comparative molecular dynamics simulations of megalin interactions with polymyxin B and its derivative NAB7061, which carries no positive charges outside the macrocycle, revealed the possible structural prerequisites for the lower nephrotoxic action of such polymyxin derivatives. The weakening of polymyxins binding with megalin may become an effective preventive measure against polymyxin-induced nephrotoxicity.

Non-Classical Effects of the cAMP Accumulation Activators In Vivo.

Purpose: Wound-healing dipyridamole- and papaverine-based aerosols (D1/D2) as activators of the accumulation of cyclic adenosine monophosphate are promising drugs that can accelerate wound healing in wound processes of various origins. Methods: 128 rats were used in the study, including 38 in a pharmacological experiment on a model of stencil wounds and 90 in an experiment that studied the effect of spray on the number of CD34 cells in the blood of rats with chemically induced immunodeficiency. Immunodeficiency was caused by the fivefold administration of cyclophosphamide and prednisone. The expression level of CD34 was determined using flow cytofluorimeter. Results: Dipyridamole- and papaverine-based aerosols of two compositions (with and without ascorbic acid) have pronounced reparative properties, significantly accelerating epithelialization and healing of stencil wounds in rats. In terms of this type of action, they are somewhat superior to dexpanthenol. Dipyridamole- and papaverine-based aerosols have the ability to produce beneficial effect on the entire body's immune system by stimulating the division of pluripotent CD34 cells. The combined effect of papaverine and dipyridamole on tissues leads to selective stimulation of the division of pluripotent cells in the wound, and contributes to a six-fold acceleration of restoration of the animal's immune system after induced immunodeficiency. Conclusion: Topical application of D1/D2 aerosol samples on the skin of rats contributed to a statistically significant acceleration of regeneration processes. In terms of the appearance of granulations and epithelialization of wounds, D1/D2 aerosols were superior to dexpanthenol ointment.

The anticancer activity of antisense microRNA (fRNA) in combination with the lectin from Bacillus subtilis B-7025.

OBJECTIVES: Many adenocarcinomas have the ability to capture from an extracellular matrix the oligonucleotides and nanoparticles by pinocytosis, when the non-cancerous cells are not capable to capture the oligonucleotides and small liposomes. This provides selective accumulation of proposed protected oligonucleotides (fRNA) in cancer cells and also provides the absence toxicity in the fRNA. METHODS: For the immunotherapy, we used immunotropic 70 kDa lectin Bacillus subtilis B-7025. In vivo experiments were carried out in C57BL line mice in Lewis lung carcinoma. The cytotoxic activity, lymphocytes and macrophages were determined in vitro using the MTT assay. KEY FINDINGS: Animal survival rate in groups receiving either the fRNA or lectine was 70 and 40%, respectively. CONCLUSIONS: Combined use of fRNA and lectine has the advantage compared with the use of these drugs in monotherapy, as the anticancer efficacy of the scheme is much higher, which is manifested in the primary tumour node and metastasis inhibition.

Sonographically guided hydrostatic reduction of intussusception in children.

PURPOSE: The aim of this study was to assess the efficacy of sonographically guided hydrostatic enema in therapeutic reduction of intussusception in children and to determine whether certain factors may predict the outcome of this technique. METHODS: We retrospectively reviewed the medical records and sonographic examinations of 83 consecutive children sonographically diagnosed with 101 cases of intussusception over a 40-month period. In 99 cases, sonographically guided hydrostatic reduction was attempted. The presence of free peritoneal fluid, the presence of fluid inside the intussusception, and the initial location of the intussusception, as confirmed by sonography, along with the level of experience of the radiologist who performed the reduction were statistically analyzed to determine their effect on outcome. A p value less than 0.05 was considered significant. RESULTS: In 88 (89%) of the 99 cases, hydrostatic reduction was successful. No complications during or after hydrostatic enema were noted. The success rate was significantly lower among patients whose intussusception was located in the left side of the abdomen (p < 0.01) or contained entrapped fluid (p < 0.02) or those in whom hydrostatic reduction was not performed by an experienced sonologist (p < 0.01). The presence of free peritoneal fluid was not a predictor of outcome (p > 0.1). No complications during or after hydrostatic enema were noted. CONCLUSIONS: Sonographically guided hydrostatic reduction of intussusception is safe and effective. We recommend that this method be attempted before surgery is considered, even in cases in which the intussusception contains entrapped fluid or is located in the left side of the abdomen. The level of experience of the radiologist who performs the reduction significantly affects the results of this procedure and should be carefully considered, particularly in cases in which initial sonography reveals the presence of risk factors.