Exploring the Inclusion Complex of an Anticancer Drug with ß-Cyclodextrin for Reducing Cytotoxicity Toward the Normal Human Cell Line by an Experimental and Computational Approach.

The toxicity of any drug against normal cells is a health hazard for all humans. At present, health and disease researchers from all over the world are trying to synthesize designer drugs with diminished toxicity and side effects. The purpose of the present study is to enhance the bioavailability and biocompatibility of gemcitabine (GEM) by decreasing its toxicity and reducing deamination during drug delivery by incorporating it inside the hydrophobic cavity of ß-cyclodextrin (ß-CD) without affecting the drug ability of the parent compound (GEM). The newly synthesized inclusion complex (IC) was characterized by different physical and spectroscopic techniques, thereby confirming the successful incorporation of the GEM molecule into the nanocage of ß-CD. The molecular docking study revealed the orientation of the GEM molecule into the ß-CD cavity (-5.40 kcal/mol) to be stably posed for ligand binding. Photostability studies confirmed that the inclusion of GEM using ß-CD could lead to better stabilization of GEM (≥96%) for further optical and clinical applications. IC (GEM-ß-CD) and GEM exhibited effective antibacterial and antiproliferative activities without being metabolized in a dose-dependent manner. The CT-DNA analysis showed sufficiently strong IC (GEM-ß-CD) binding (Ka = 8.1575 × 1010), and this interaction suggests that IC (GEM-ß-CD) may possibly exert its biological effects by targeting nucleic acids in the host cell. The newly synthesized biologically active IC (GEM-ß-CD), a derivative of GEM, has pharmaceutical development potentiality.

Scaffold Flexibility Controls Binding of Herpes Simplex Virus Type 1 with Sulfated Dendritic Polyglycerol Hydrogels Fabricated by Thiol-Maleimide Click Reaction.

Herpes Simplex Virus-1 (HSV-1) with a diameter of 155-240 nm uses electrostatic interactions to bind with the heparan sulfate present on the cell surface to initiate infection. In this work, the initial contact using polysulfate-functionalized hydrogels is aimed to deter. The hydrogels provide a large contact surface area for viral interaction and sulfated hydrogels are good mimics for the native heparan sulfate. In this work, hydrogels of different flexibilities are synthesized, determined by rheology. Gels are prepared within an elastic modulus range of 10-1119 Pa with a mesh size of 80-15 nm, respectively. The virus binding studies carried out with the plaque assay show that the most flexible sulfated hydrogel performs the best in binding HSV viruses. These studies prove that polysulfated hydrogels are a viable option as HSV-1 antiviral compounds. Furthermore, such hydrogel networks are also physically similar to naturally occurring mucus gels and therefore may be used as mucus substitutes.

Polyglycerol-Based Mucus-Inspired Hydrogels.

The mucus layer is a hydrogel network that covers mucosal surfaces of the human body. Mucus has important protective properties that are related to its unique rheological properties, which are based on mucins being the main glycoprotein constituents. Mucin macromolecules entangle with one another and form a physical network that is instrumental for many important defense functions. Mucus derived from various human or animal sources is poorly defined and thus not suitable for many application purposes. Herein, a synthetic route is fabricated to afford a library of compositionally defined mucus-inspired hydrogels (MIHs). MIHs are synthesized by thiol oxidation to render disulfide bonds between the crosslinker ethoxylated trimethylolpropane tri(3-mercaptopropionate) (THIOCURE ETTMP 1300) and the linear precursors, dithiolated linear polyglycerol (LPG(SH)2 ) or polyethylene glycol (PEG(SH)2 ) of different molecular weights. The mixing ratio of linear polymers versus crosslinker and the length of the linear polymer are varied, thus delivering a library of compositionally defined mucin-inspired constructs. Their viscoelastic properties are determined by frequency sweeps at 25 and 37 °C and compared to the corresponding behavior of native human mucus. Here, MIHs composed of a 10:1 ratio of LPG(SH)2 and ETTMP 1300 are proved to be the best comparable to human airway mucus rheology.

Metformin ameliorates hepatic steatosis and improves the induction of autophagy in HFD­induced obese mice.

The present study aimed to investigate the effect of metformin on the induction of autophagy in the liver and adipose tissues of a mouse model of obesity. C57BL/6J mice were fed a high­fat diet (HFD) for 12 weeks to induce obesity­associated hepatic steatosis, and treated with metformin (150 mg/kg/d) by intraperitoneal injection for the final 4 weeks of HFD feeding. Body weight was recorded weekly, and the food intake of the mice was recorded daily during the treatment period. Liver and adipose tissues were harvested for histological and molecular analyses. The results revealed that metformin significantly reduced body weight without altering food intake in the HFD mice, particularly in the epididymal white adipose tissue (eWAT). Metformin treatment ameliorated HFD­induced hepatic steatosis and serum levels of triglycerides, which was consistent with a marked increase in the expression levels of microtubule­associated protein 1 light chain 3 (LC3) and AMP­activated protein kinase (AMPK) in the liver following metformin treatment. However, metformin suppressed the expression of LC3 in the eWAT without altering the expression of AMPK, compared with that in the HFD mice. In conclusion, metformin reduced the body weight and hepatic steatosis of the HFD­induced obese mice, without altering food intake. The effects of metformin treatment may be attributable to the improved induction of hepatic autophagy and the inhibited induction of adipose tissue autophagy.