Vol 11, No 1 (2019)

The proton-gated cationic channels belonging to the ASIC family are widely distributed in the central nervous system of vertebrates and play an important role in several physiological and pathological processes. ASIC1a are most sensitive to acidification of the external medium, which is the reason for the current interest in their function and pharmacology. Recently, the list of ASIC1a ligands has been rapidly expanding. It includes inorganic cations, a large number of synthetic and endogenous small molecules, and peptide toxins. The information on the mechanisms of action and the binding sites of the ligands comes from electrophysiological, mutational and structural studies. In the present review, we attempt to present a systematic view of the complex pattern of interactions between ligands and ASIC1a.

The high genetic variability of the human immunodeficiency virus (HIV-1) leads to a constant emergence of new genetic variants, including the recombinant virus CRF63_02A1, which is widespread in the Siberian Federal District of Russia. We studied HIV-1 CRF63_02A1 integrase (IN_CRF) catalyzing the incorporation of viral DNA into the genome of an infected cell. The consensus sequence was designed, recombinant integrase was obtained, and its DNA-binding and catalytic activities were characterized. The stability of the IN_CRF complex with the DNA substrate did not differ from the complex stability for subtype A and B integrases; however, the rate of complex formation was significantly higher. The rates and efficiencies of 3’-processing and strand transfer reactions catalyzed by IN_CRF were found to be higher, too. Apparently, all these distinctive features of IN_CRF may result from specific amino acid substitutions in its N-terminal domain, which plays an important role in enzyme multimerization and binding to the DNA substrate. It was also found that the drug resistance mutations Q148K/G140S and G118R/E138K significantly reduce the catalytic activity of IN_CRF and its sensitivity to the strand transfer inhibitor raltegravir. Reduction in sensitivity to raltegravir was found to be much stronger in the case of double-mutation Q148K/G140S.

In the present work, a thermodynamic analysis of the interaction between endonuclease VIII (Endo VIII) and model DNA substrates containing damaged nucleotides, such as 5,6-dihydrouridine and 2-hydroxymethyl-3-hydroxytetrahydrofuran (F-site), was performed. The changes in the fluorescence intensity of the 1,3-diaza-2-oxophenoxazine (tCO) residue located in the complementary chain opposite to the specific site were recorded in the course of the enzyme-substrate interaction. The kinetics was analyzed by the stopped-flow method at different temperatures. The changes of standard Gibbs free energy, enthalpy, and entropy of sequential steps of DNA substrate binding, as well as activation enthalpy and entropy for the transition complex formation of the catalytic stage, were calculated. The comparison of the kinetic and thermodynamic data characterizing the conformational transitions of enzyme and DNA in the course of their interaction made it possible to specify the nature of the molecular processes occurring at the stages of substrate binding, recognition of the damaged base, and its removal from DNA.

We investigated the cytoprotective effect of a novel low-molecular-weight NGF mimetic, GK-2 (hexamethylenediamide bis-N-monosuccinyl-L-glutamyl-L-lysine), on pancreatic β-cells. The neuroprotective effect of GK-2 had been previously shown to be associated with selective activation of the PI3K/Akt signaling pathway. In this study, rats with streptozotocin (STZ)-induced type 2 diabetes mellitus were used. Metformin was used as a reference drug. STZ was immunohistochemically demonstrated to reduce the number of β-cells and affect their morphological structure. Treatment of diabetic animals with GK-2 (at a dose of 0.5 mg/kg intraperitoneally or 5 mg/kg orally) or metformin (300 mg/kg orally) for 28 days reduced the damaging effect of STZ. The effect of GK-2 on manifestations of STZ-induced diabetes, such as hyperglycemia, weight loss, polyphagia, and polydipsia, was comparable to that of metformin, while the cytoprotective activity of GK-2 was slightly stronger than that of metformin. A strong positive correlation between morphometric parameters and the blood glucose level was revealed. The GK-2 cytoprotective effect on β-cells is supposed to manifest through the PI3K/Akt signaling pathway.

This study focuses on the adaptation of natural Newcastle disease virus (NDV) strains isolated from wild birds to human tumor cells. Many candidates for virotherapy are viruses pathogenic for human. During recombination of genetic material, there always exists a risk of getting a virus with an unstable genome. This problem can be solved by using natural apathogenic viruses as oncolytic agents. The Newcastle disease virus is the causative agent of contagious avian diseases. Its natural strains exhibit an antitumor effect and are considered safe for humans. As shown in earlier studies, the oncolytic properties of natural strains can be enhanced during adaptation to cell cultures, without interference in the virus genome. This study demonstrates that serial passaging increases the viral infectious titer in cancer cells. Moreover, the viability of tumor cells decreases post-infection when Newcastle disease virus strains are adapted to these cell cultures. The findings of this study complement the well-known data on the adaptation of the Newcastle disease virus to human cancer cells. Hence, it is possible to obtain a NDV strain with a more pronounced oncolytic potential during adaptation. This should be taken into account when choosing a strategy for designing anticancer drugs based on this virus.

Terrestrial plants have contributed massively to the development of modern oncologic drugs. Despite the wide acceptance of Mauritian endemic flowering plants in traditional medicine, scientific evidence of their chemotherapeutic potential is lacking. This study aimed to evaluate the in vitro tumor cytotoxicity of leaf extracts from five Mauritian endemic medicinal plants, namely Acalypha integrifolia Willd (Euphorbiaceae), Labourdonnaisia glauca Bojer (Sapotaceae), Dombeya acutangula Cav. subsp. rosea Friedmann (Malvaceae), Gaertnera psychotrioides (DC.) Baker (Rubiaceae), and Eugenia tinifolia Lam (Myrtaceae).rolex oyster perpetual day date real or fake The cytotoxicities of the extracts were determined against six human cancer cell lines, including cervical adenocarcinoma, colorectal carcinoma, oesophageal adenocarcinoma, and oesophageal squamous cell carcinoma. The potent extracts were further investigated using cell cycle analysis and reverse phase protein array (RPPA) analysis. The antioxidant properties and polyphenolic profile of the potent extracts were also evaluated. Gas chromatography mass spectrometry (GC-MS) analyses revealed the presence of (+)-catechin and gallocatechin in E. tinifolia and L. glauca, while gallic acid was detected in A. integrifolia. L. glauca, A. integrifolia, and E. tinifolia were highly selective towards human oesophageal squamous cell carcinoma (KYSE-30) cells. L. glauca and E. tinifolia arrested KYSE- 30 cells in the G2/M phase, in a concentration-dependent manner. RPPA analysis indicated rolex fake that the extracts may partly exert their tumor growth-inhibitory activity by upregulating the intracellular level of 5′AMP-activated kinase (AMPK). The findings highlight the potent antiproliferative activity of three Mauritian endemic leaf extracts against oesophageal squamous ccheap replica luxury watches ell carcinoma and calls for further investigation into their chemotherapeutic application.