Current Chemical Biology - Volume 13, Issue 2, 2019

Background: Alzheimer's disease remains an unsolved public health problem. Recent studies shifted the focus of the pathogenesis from a neurodegenerative process to a synaptic failure, including a large group of pathologies called peptide misfolding diseases. Objective: In this line, recent research has proposed new models to study the pathologies such as frog oocytes, revalidation of a mechanism such as the amyloid pore, and a link of moderate alcohol consumption with a reduced risk of developing neurodegenerative diseases. Methods: We reviewed the latest publication in this field. Conclusion: We believe, therefore, that the available data suggest an important role of the amyloid pore mechanism in the pathogenesis of the Alzheimer's disease, the use of oocytes for its study, and how a moderate consumption of ethanol could reduce the effects of amyloid aggregates.

DNA is one of the most important biomolecules of living cells which carries genetic information from generation to generation. Many endogenous and exogenous agents may disrupt the structure of DNA. Change in the cellular genome can lead to errors in replication, transcription and in protein synthesis. DNA damage occurs naturally or result from a metabolic and hydrolytic process which release some very active chemical entities like free radicals, Reactive Oxygen Species (ROS), Reactive Nitrogen Intermediate (RNI), Reactive Carbonyl Species (RCS), lipid peroxidation products and alkylating agents. Superoxide radical, hydroxyl radical and hydrogen peroxide cause a significant threat to cellular integrity by damaging the DNA, lipids, proteins and other biomolecules. Oxidative stress may be explained as a disturbance in the number of free radicals and our system’s ability to neutralize these free radicals. Imbalances in the normal redox potential can also lead to toxic effects via the generation of peroxides. Oxidation of DNA bases leads to the base damage, nick in the strand and break in the strand either single or double strand. Oxidative stress can also cause modifications in normal mechanisms of cell signaling. DNA mutation can result in a number of genetic abnormalities such as cancer, heart failure, Alzheimer’s disease, and depression. Human body has special protection in the form of antioxidant molecules and enzymes against these free radicals. Generation of ROS and its neutralization must be regulated to protect cells and signalling biomolecules from the deleterious effect of oxidative stress with the involvement of antioxidant systems, enzymes, and specific proteins. DNA repair system is a complex system which helps in the identification, removal of the wrong nucleotide and repairs them and as a result, the cell will produce correct and functional protein and active enzyme.

Background: The widespread occurrence of resistance to current antibiotics has triggered increasing research efforts to design and develop innovative antibacterial and antifungal agents that could overcome such antimicrobial resistance. Objective: The aim of this work was the in vitro evaluation of twelve highly fluorinated Nmonosubstituted thiocarbamates and dithiocarbamates and six non-fluorinated analogs against nine bacterial strains and three fungal species. Methods: The in vitro antimicrobial activity against the tested microrganisms was evaluated using the microdilution broth method. Results: Escherichia coli ATCC 8739, Salmonella sp., Staphylococcus aureus 6539 and all the three fungi (Aspergillus niger, Aspergillus flavus and Penicillium expansum) exhibited the highest rate of susceptibility, whilst Enterococcus faecuim ATCC 19436 and particularly Escherichia coli DH5α were less susceptible. Thiocarbamate (1i) and dithiocarbamate (2i) showed both the lowest MIC values (3.9 μg/mL) and the widest spectrum of antibacterial activity. Furthermore, the N-ethyl derivatives inhibited more efficiently the growth of bacteria than N-aryl analogs. Conclusion: The fluorinated compounds showed, in general, a relatively more potent antibacterial activity than non-fluorinated counterparts. The results indicate that these thiocarbamates and dithiocarbamates could be promising candidates as potential antimicrobial agents.

Background: Unsaturated C18 fatty acids, such as oleic acid (L1), linoleic acid (L2), and linolenic acid (L3), are a good choice of lipids to prepare liposomes. They are inexpensive, biocompatible, nontoxic, and readily available compared with phospholipids. Moreover, cis-double bonds of unsaturated fatty acids prevent the packing of molecules which increases membrane fluidity in liposomes making them a good choice of starting materials to prepare liposomes. Objective: Unsaturated C18 fatty acid liposomes, as well as their PEGylated and non- PEGylated antibody-targeted liposomes, were prepared and characterized. Methods: The particle size and zeta potential of the prepared liposomes (1 mM, pH = 7.4) for 28 and 14 days, respectively, were monitored and characterized. Membrane-bound antibodies Anti-SNAP25 (AS25) and DOPE PEG2000 (DP) were conjugated to pure C18 fatty acid liposomes to achieve stable fatty acid formulations. Results: The mean particle sizes of pure L1, L2, and L3 liposome solutions were 125, 129, and 122 nm respectively, while their polydispersity index values were 0.28, 0.21, and 0.40 respectively. A large negative zeta potential value of 45 mV was observed due to anionic carboxylate head-group of pure liposomes. The incorporation of AS25 into L1/DP, L2/DP, and L3/DP liposome solutions stabilized their mean particle size and zeta potential measurements over 28 and 14 days, respectively. Conclusion: L1/DP/AS25 was found to be the most stable PEGylated antibody-targeted liposome system because its particle size remained between 90 and 125 nm in 28 days. Transmission electron microscopy observations also supported the incorporation of AS25 and DP on the membrane surface as predicted.

Background: Rheumatoid Arthritis (RA) is an autoimmune, chronic, and systematic disease. It affects joints and bones. The exact etiology of RA is still unclear. Varied genetic and environmental factors have been associated with the increased risk for RA. Overactivation of Toll-Like Receptors (TLRs) could initiate the development of autoimmune diseases including RA. Objective: The aim of the study was to evaluate TLR2 gene expression in rheumatoid arthritis patients and investigate its correlation with the disease activity. Materials and Methods: This study included 60 patients and 20 healthy individuals. The patients were diagnosed with RA according to the 2010 American College of Rheumatology/ European League Against Rheumatism criteria (ACR/EULAR). All included subjects did not have any joint disorders and /or autoimmune diseases. RA disease activity was determined by the disease activity score of 28 joints. Whole blood was collected from all participants. Total RNA extraction was done. TLR2 mRNA expression was assessed by reverse transcription-PCR (RT-PCR). Results: TLR2 mRNA expression was found to be significantly higher in RA patients compared to healthy controls. Also, a strong positive correlation was found between TLR2 expression level and the disease activity score. A non significant positive correlation was found between TLR2 expression and serum Rheumatoid Factor (RF) level. Conclusion: TLR2 pathway may have an important role in RA pathogenesis and could be a new biomarker for diagnosis and monitoring disease activity.

Background: Acinetobacter baumannii is an important nosocomial pathogen with great ability to resist antibiotics. Tandem repeat proteins, abundant in prokaryotic proteomes, attract attention due to their role in virulence and various biological processes. Defining repeat- containing proteins may pave the way to find novel therapeutic targets as well as vaccine candidate and give pieces of evidence of mechanisms of evolution and adaptation of organisms to various environmental conditions. Objective: In the present study, we employed bioinformatics tools to define repeatcontaining proteins within A. baumannii proteome for emphasizing the existence of natural sources for synthesizing novel therapeutic and diagnosis material. Results: We defined various kinds of repeat modules in a number of proteins and compared the abundance of these proteins in some closely related species. No significant difference was observed in the count of repeat-containing proteins in different species. But the existence of some important virulence factors is mentionable in our screening. Conclusion: Repeat containing proteins are important biological determinants of A. baumannii and are well worth researching for finding drug targets and vaccine candidates. These proteins can be served as a template for designing and synthesizing peptides for therapeutic and diagnostic approaches.

Background: Lignocellulosic residues generated by various anthropogenic activities can be a potential raw material for many commercial products such as biofuels, organic acids and nutraceuticals including xylitol. Xylitol is a low-calorie nutritive sweetener for diabetic patients. Microbial production of xylitol can be helpful in overcoming the drawbacks of traditional chemical production process and lowring cost of production. Objective: Designing efficient production process needs the characterization of required enzyme/s. Hence current work was focused on in-vitro and in-silico characterization of xylose reductase from Emericella nidulans. Methods: Xylose reductase from one of the hyper-producer isolates, Emericella nidulans Xlt-11 was used for in-vitro characterization. For in-silico characterization, XR sequence (Accession No: Q5BGA7) was used. Results: Xylose reductase from various microorganisms has been studied but the quest for better enzymes, their stability at higher temperature and pH still continues. Xylose reductase from Emericella nidulans Xlt-11 was found NADH dependent and utilizes xylose as its sole substrate for xylitol production. In comparison to whole cells, enzyme exhibited higher enzyme activity at lower cofactor concentration and could tolerate higher substrate concentration. Thermal deactivation profile showed that whole cell catalysts were more stable than enzyme at higher temperature. In-silico analysis of XR sequence from Emericella nidulans (Accession No: Q5BGA7) suggested that the structure was dominated by random coiling. Enzyme sequences have conserved active site with net negative charge and PI value in acidic pH range. Conclusion: Current investigation supported the enzyme’s specific application i.e. bioconversion of xylose to xylitol due to its higher selectivity. In-silico analysis may provide significant structural and physiological information for modifications and improved stability.

Background: The ligand Hpyramol is a redox active, which on coordination with Cu(II) cleaves DNA without any added reductant. Another ligand phendione is known for its wide application towards anticancer activities. We combined the ligands with CuCl2 to have an intercalation moiety and a redox active ligand in participation towards telomere DNA cleavage and anticancer activity. Objective: In this study, our aim is to interact it with Human telomere DNA and to see their effects on cancer cells. Methods: The complex [Cu(L)(L’)Cl] has interacted with the human telomere DNA sequence (TTAGGG), HTelo20. The HTelo20 was stabilized under both parallel and antiparallel G-quadruplex conformations and the complex [Cu(L)(L’)Cl] has interacted followed by circular dichroism spectroscopy and gel electrophoresis. Results: The parallel G-quadruplex and randomly coiled conformations of HTelo20 were easily cleaved than the anti-parallel G-quadruplex conformation. The nature of DNA cleavage was found to be oxidative rather hydrolytic. The formation of phenoxyl radical species under electrochemical and controlled potential electrolysis conditions by the complex [Cu(L)(L’)Cl] proves the possibility of oxidative nature of DNA cleavage. The comet assay also proves the DNA cleavage induced by the complex [Cu(L)(L’)Cl] inside the nucleus of HeLa cancer cells. Conclusion: The complex [Cu(L)(L’)Cl] was tested for anticancer activity, induced by ROS and DNA cleavage. The IC50 values resulted in nanomolar concentrations with selected cancer cell lines. Relatively the Cu complex shows less toxicity with the normal cell line L132.