H.Buniatian Institute of Biochemistry

Objective: The objective of this study, taking into account the available data on the biological activity of various chloramphenicol analogues, is to search for new effective compounds with antibacterial and fungicidal properties among N- and O-acyl derivatives of CAM, as well as to conduct a docking study on four different targets to clarify the possible further direction of research on the synthesis of biologically active chloramphenicol analogues. Methods: Antibacterial and antifungal activity were determined by the agar diffusion method. Taking into account the relevance of the search for new effective antiviral, antitumor and neurotropic drugs, a docking study of the synthesized compounds (ligands) was carried out in relation to the complex of RNA-dependent RNA polymerase (RdRp) with the NSP7 and NSP8 proteins of the SARS-CoV-2 virus, the kinase domain of the human epidermal growth factor receptor (EGFR), doubly phosphorylated human mitogen-activated protein kinase 14 (MAPK14) in a complex with the activator of the transcription factor (ATF2) and human monoamine oxidase B in a complex with 2-(2-benzofuranyl)-2 imidazoline (2-BFI). Results and Discussion: The results of the docking analysis of the studied compounds showed that the most active compound, 3-hydroxy-3-(4-nitrophenyl)-2-{[(2-phenylquinolin-4-yl)carbonyl]amino}propyl 2-phenylquinoline-4-carboxylate, strongly interacts with the SARS-CoV-2 RNA-dependent RNA polymerase has a binding energy ΔG0 = –10.435 kcal/mol. The interaction energy for the human EGFR kinase domain ΔG0 = –12.633 kcal/mol, while for the phosphorylated human MAPK14, it is –13.436 kcal/mol. A number of the studied compounds exhibited high antimicrobial activity against Staphylococcus aureus and Bacillus subtilis, but significantly less against a strain of Escherichia coli. The most active benzofuran-based derivative demonstrated relatively high activity against S. aureus, B. subtilis, and Candida albicans, comparable to the control compounds. Conclusions: The study demonstrates the feasibility of using structural analogs. Biological studies have identified antibiotic analogs that exhibit relatively high activity against S. aureus, B. subtilis, and C. albicans. Based on docking analysis data, new chloramphenicol analogs can be predicted to exhibit antiprotein kinase activity against the human epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK). The antibacterial and antifungal properties of the synthesized chloramphenicol analogues create the preconditions for the development of new effective drugs for the treatment of bacterial and fungal infections, and the results of docking analysis also indicate the possibility of creating antitumor drugs.

Background Stroke is the leading cause of mortality and disability worldwide. The goal of this study was to design stable, small-sized polyethylene glycol (PEG)/albumin nanoparticles (NPs) for delivering drugs targeting various phases of stroke recovery. Methods RP-HPLC (Reversed-Phase High-Performance Liquid Chromatography) and spectrophotometry were used to assess the stability and effectiveness of the drug carriers. The dynamic light scattering (DLS) technique was employed to evaluate the size and zeta potential of the particles. The integrity of the blood–brain barrier (BBB) in laboratory rats was assessed by measuring Evans Blue (EB) leakage after intracranial injection of 3% H2O2. AutoDock Tools 1.5.7 was used to analyze the compatibility of the polymers with albumin. Results The particles exhibited high drug-loading efficiency. In all groups, the most prevalent particle size averaged 211.09 ± 92.72 nm. The drug-loaded particles exhibited prolonged circulation and had a half-life (T1/2) ranging from 7.64 to 13 days. Furthermore, both albumin particles and PEGylated albumin carriers loaded with dexamethasone and allopurinol significantly preserved blood–brain barrier (BBB) integrity (2.92 ± 0.4 µg, p < 0.04), as indicated by reduced Evans Blue (EB) extravasation (6.73 ± 0.58 µg) compared to the control group (9.12 ± 1.2 µg, p < 0.04, t-test). Discussion The protective effect of albumin carriers on the BBB may be attributed to an increase in blood oncotic pressure, which helps limit edema formation. PEG/albumin drug-loaded carriers demonstrated greater stability, as indicated by their zeta potential, and exhibited a more pronounced BBB-preserving effect due to the combined actions of albumin and the loaded drugs. Conclusion In this study, stable, layered NPs carrying different drugs were synthesized that could be applied for the treatment of experimental stroke.

Abstract Energy efficiency and behavioural changes are among the key pillars of decarbonization of the global energy system. Residential sector is responsible for a large share of fossil fuels final consumption, therefore the growth of its energy efficiency can bring a valuable impact on decarbonization speed and scale. In countries with growing economies residential energy consumption can increase dramatically due to the desire of the population to improve their standard of living, therefore striking a balance between economic growth and energy efficiency improvement is a complex policy challenge. The purpose of this study is to analyze attitudes and assess barriers of energy efficient behavior in Republic of Armenia as a country with growing economy and standards of living. The paper contributes to the literature by providing new empirical evidence of consumers’ attitude toward different forms of energy efficient behavior in Armenia and reveals how general pro-environmental consciousness and social conditions influence on it. The results of the study prove that the level of general environmental consciousness of the population has a direct impact on the frequency of practical application of various patterns of energy-efficient behavior. As a policy application for emerging economies, our study proposes that the main direction of energy efficiency policy can be education of the population and raising its level of environmental self-awareness.

Тhe enzymes adenosine deaminase (ADA), dipeptidyl peptidase 4 (DPP4) and glutaminase (GL) are involved in the development of both the type 1 (T1DM) and type 2 diabetes mellitus (T2DM). They can be considered as targets in the prevention and/or treatment of these diseases. The autoimmune response of the body is caused by the post-translational protein modifications, one of which is protein citrullination, when arginine residue transforms to citrulline. This work compares the ADA, DPP4, GL enzymes and protein citrullination in blood plasma from T1DM, T2DM patients and relatively healthy individuals. The enzymes were isolated and purified from the blood samples. We found that DPP4 activity was significantly higher in the plasma of patients compared to controls, particularly in T1DM. Currently the medicines based on DPP4 inhibitors are used in the treatment of T2DM. Our results indicate that this treatment strategy can be recommended in the T1DM treatment as well.

It is known that FAD is an important cofactor for Nox isoform, as an electron carrier from NADPH to Fe(III) of the heme group then to molecular oxygen reducing it up to О2 [1, 6]. On the other hand, the thermostable Nox is isolated from thermostable microorganisms [5]. However, the role of FAD as a factor in changing the conformation and thermostability of Nox isoform has not yet been determined. The aim of the present work was to determine the corresponding conditions under which the thermostability and production of superoxide radicals are also observed in the absence of NADPH.

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment.

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and β-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of α2a-, α2b-, and α2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only α2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in α-smooth muscle actin, transforming growth factor-β and α2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-β. In conclusion, we suggest that the α2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.

BackgroundStevia rebaudiana Bertoni has various pharmacological actions, which includes antidiabetic, antioxidant, anti-inflammatory activities. The superoxide and consequently NADPH oxidase (Nox) are relevant targets involved in biological effects of Stevia. The presence of NADPH-containing superoxide-producing lipoprotein (suprol) in Stevia leaves has not yet been tested. The mechanism of producing superoxide radicals (O2−) by suprol was determined in vitro, which is associated with the electron transfer from NADPH in the composition of suprol by traces of transition metal ions (Fe3+ or Cu2+) to molecular oxygen, turning it into O2−. It is expected that the therapeutic efficacy of Stevia leaves is caused by specific activity of superoxide-producing lipoprotein fraction.MethodsFor the first time, from the dry leaves of Stevia the NADPH-containing superoxide-producing lipoprotein was isolated and purified. The specific content of suprol (milligrams in 1 g of Stevia leaves- mg/g) was determined after desalination of suprol and lyophilization.ResultsAccording to the method provided, the specific content of the isolated suprol from Stevia’s leaves was up to 4.5 ± 0.2 mg / g (yields up to 68.5 ± 4.7%, p < 0.05, n = 6). Nox forms a stable complex with suprol. The optical absorption spectrum of the Nox-suprol complex represents the overlapping suprol and Nox spectra, with a certain background increase and characteristic features of optical absorption for Nox. Due to O2− producing capacity suprol-Nox complex discolors KMnO4 solutions, Coomassie brilliant blue, restores nitrotetrazolium blue to formazan and oxidizes epinephrine to adrenochrome. The oxidation activity of adrenaline is 50.3 ± 5.1 U / mg / ml (p < 0.05, n = 6).ConclusionSuperoxide-producing lipoprotein fraction-Nox complex from Stevia leaves (membranes) can modulate redox regulated signaling pathways and may play a positive role in type-2 diabetes by means of adrenaline oxidation mechanism.