Probing the pH-dependency of DC-SIGN/R multivalent lectin-glycan interactions using polyvalent glycan-gold nanoparticles.

The dendritic cell tetrameric lectin, DC-SIGN, and its closely related endothelial cell lectin, DC-SIGNR (collectively abbreviated as DC-SIGN/R) play a key role in the binding and transmission of deadly viruses, including Ebola, HIV, HCV, and SARS-CoV-2. Their virus binding/release processes involve a gradually acidifying environment following the natural intracellular trafficking pathways. Therefore, understanding DC-SIGN/R's pH-dependent binding properties with glycan ligands is of great importance. We have recently developed densely glycosylated gold nanoparticles (glycan-GNPs) as a powerful new tool for probing DC-SIGN/R multivalent lectin-glycan interaction (MLGI) mechanisms. They can provide not only quantitative MLGI affinities but also important structural information, such as binding site orientation and binding modes. Herein, we further employ the glycan-GNP probes to investigate the pH dependency of DC-SIGN/R MLGI properties. We find that DC-SIGN/R MLGIs exhibit distinct pH dependence over the normal physiological (7.4) to lysosomal (∼4.6) pH range. DC-SIGN binds glycan-GNPs strongly and stably from pH 7.4 to ∼5.8, but the binding is weakened significantly as pH decreases to ≤5.4 and may be fully dissociated at pH 4.6. This behaviour is fully consistent with DC-SIGN's role as an endocytic recycling receptor. In contrast, DC-SIGNR's affinity with glycan-GNPs is enhanced with the decreasing pH from 7.4 to 5.4, peaking at pH 5.4, and then reduced as pH is further lowered. Interestingly, both DC-SIGN/R binding with glycan-GNPs are found to be partially reversible in a pH-dependent manner.

Synthesis, antioxidant activity, molecular docking and ADME studies of novel pyrrole-benzimidazole derivatives.

Several 5-(alkylsulfonyl)-1-substituted-2-(1H-pyrrol-2-yl)-1H-benzo[d]imidazole derivatives were synthesized and their antioxidant activities were investigated using lipid peroxidation (LPO) and 7-ethoxyresorufin O-deethylase (EROD) assays. Docking analysis with Human NAD[P]H-Quinone oxidoreductase 1 (NQO1) was also performed to gather thorough information about these compounds that have antioxidant activities. Moreover, their molecular descriptors and ADME properties were calculated using the SwissADME online program. As a result, most of our compounds possessed better affinity and created ample interactions with NQO1. The most potent compound 5j had LP inhibition value of 3.73 nmol/mg/min. Other compounds exhibited moderate activity on LP levels comparing to standard butylated hydroxy toluene (BHT). However, the inhibitory effect on EROD activity was not significant.

Evaluation of the Antioxidant Activity of Some Imines Containing 1H-Benzimidazoles.

OBJECTIVES: The in vitro antioxidant properties of some 2-(2-phenyl)-1H-benzo(d)imidazol-1-yl)-N'-(arylmethylene) acetohydrazide derivatives (1-12) were investigated in this study. MATERIALS AND METHODS: The in vitro antioxidant activity of compounds 1-12 was explored by determination of rat liver microsomal nicotinamideadenine dinucleotide phosphate dependent inhibition on lipid peroxidation (LPO) levels and microsomal ethoxyresorufin O-deethylase (EROD) activity. RESULTS: All synthesised compounds had LPO inhibitory activity (15-57%) except compound 6, which contains a thiophene ring. Almost all the compounds displayed slightly inhibitory activity (2-20%) on EROD. CONCLUSION: The most active compound, 3 bearing a p-bromophenyl substituent at the second position of the benzimidazole ring, caused 57% inhibition of LPO level, while butylated hydroxytoluene showed 65% inhibition. None of the synthesised compounds had a marked inhibitory effect on EROD activity.

Effects of insulin treatment on hepatic CYP1A1 and CYP2E1 activities and lipid peroxidation levels in streptozotocin-induced diabetic rats.

Reactive oxygen species (ROS) and lipid peroxidation (LPO) levels may increase in diabetic state and lead to oxidative stress, which plays a critical role in the progression of diabetes. There are various sources of ROS, including cytochrome P450 monooxygenases (CYP450s), which may be modulated in terms of their activities and expressions under diabetic conditions. This study is aimed to investigate the effects of streptozotocin-induced diabetes and insulin treatment on hepatic cytochrome P450 1A1 (CYP1A1) and cytochrome P450 2E1 (CYP2E1) activities and LPO levels. Methods: CYP1A1 and CYP2E1 activities were measured with ethoxyresorufin O-deethylase and p-nitrophenol hydroxylase activities, respectively. LPO levels were then corroborated via thiobarbituric acid reactive substances. Results: In diabetic rats, a marked 2.1- and 2.4-fold increase in hepatic CYP1A1 activity and 1.8- and 1.6-fold increase in hepatic CYP2E1 activity were observed compared to controls and insulin-treated diabetic rats, respectively. Hepatic LPO levels in diabetic rats did not significantly change compared to controls. However, in insulin-treated diabetic rats, LPO levels are 0.92- and 0.89-fold remarkably decrease compared to controls and diabetics, respectively. Conclusion: The present study suggests that insulin might have a useful role in the modulation of CYP1A1 and CYP2E1 activities as well as LPO levels in the liver of diabetic rats.

An Overview of iQOS® as a New Heat-Not-Burn Tobacco Product and Its Potential Effects on Human Health and the Environment.

Tobacco smoke from regular cigarettes contains a number of harmful chemicals such as nicotine, arsenic, benzene, carbon monoxide, heavy metals, and tobacco-derived nitrosamines. About 1% of over 7000 chemical substances formed by burning tobacco are identified as the leading causes or possible risk factors of smoking-related diseases such as lung cancer, cardiovascular diseases, and emphysema. The concept of heating tobacco without combustion and smoke has been designed for more than two decades. The products developed with this idea, known as "Heat-Not-Burn" tobacco cigarettes, were first introduced in the late 1980s but did not achieve commercial success. However, the tobacco giants have been trying to remarket tobacco heating systems with new technological and modified features for over 10 years. I-Quit-Ordinary-Smoking (iQOS®) is one of the latest heat-not-burn tobacco products, first launched in Japan and Italy. The company then made a submission to the Food and Drug Administration as a modified-risk tobacco product application to sell its own tobacco-heating device iQOS® under its Marlboro® brand in the USA with reduced-risk claims in 2016, but it was rejected. This device is, however, now sold in more than four dozen countries. There are some striking claims that iQOS®, which is described as a novel hybrid product between traditional cigarettes and electronic cigarettes, offers an alternative way to substantially reduce the amount of harmful components compared with traditional cigarettes by its new technology in which tobacco is heated up to 350°C instead of being burnt. It is claimed to produce vapour containing nearly 90% less toxic substances than cigarette smoke and not be a source of second-hand smoking negatively affecting indoor air quality. The purpose of this article is to objectively review the potential effects of iQOS® on human health and the environment by searching and integrating the published research findings.

Flavin Containing Monooxygenases and Metabolism of Xenobiotics.

This review summarizes recent information concerning the pharmacological and toxicological significance of the flavin-containing monooxygenases (FMOs). FMOs are a family of microsomal enzymes involving in the oxygenation of certain xenobiotics and drugs containing nucleophilic heteroatoms. The activities of FMOs in drug metabolism and their relationships with diseases are the areas of research requiring further exploration. Future studies on FMOs may provide considerable information about the pathophysiology of diseases and the information related to this enzyme family may be important for drug designs in future.