Polyglycerol-based hydrogels and nanogels: from synthesis to applications.

Hydrogels and nanogels have emerged as promising materials for biomedical applications owing to their large surface area and tunable mechanical and chemical properties. Their large surface area is well suited for bioconjugation, whilst the interior porous network can be utilized for the transport of valuable biomolecules. The use of biocompatible hydrophilic building blocks/linkers for the preparation of hydrogels and nanogels not only avoids undesired side effects within the biological system, but also retains high water content, thereby creating an environment which is very similar to extracellular matrix. Their tunable multivalency and hydrophilicity and excellent biocompatibility, together with ease of functionalization, makes polyglycerol macromonomers well suited for synthesizing cross-linked networks that can be used as extracellular matrix mimics. Here we provide an overview of the synthesis of polyglycerol-based hydrogels and nanogels for various biomedical applications.

High-altitude hypoxia induced reactive oxygen species generation, signaling, and mitigation approaches.

Homeostasis between pro-oxidants and anti-oxidants is necessary for aerobic life, which if perturbed and shifted towards pro-oxidants results in oxidative stress. It is generally agreed that reactive oxygen species (ROS) production is accelerated with mountainous elevation, which may play a role in spawning serious health crisis. Exposure to increasing terrestrial altitude leads to a reduction in ambient O2 availability in cells producing a series of hypoxic oxidative stress reactions and altering the redox balance in humans. Enormous literature on redox signaling drove research activity towards understanding the role of oxidative stress under normal and challenging conditions like high-altitude hypoxia which grounds for disturbed redox signaling. Excessive ROS production and accumulation of free radicals in cells and tissues can cause various pulmonary, cardiovascular, and metabolic pathophysiological conditions. In order to counteract this oxidative stress and maintain the balance of pro-oxidants and anti-oxidants, an anti-oxidant system exists in the human body, which, however, gets surpassed by elevated ROS levels, but can be strengthened through the use of anti-oxidant supplements. Such cumulative studies of fundamentals on a global concept like oxidative stress and role of anti-oxidants can act as a foundation to further smoothen for researchers to study over health, disease, and other pathophysiological conditions. This review highlights the interconnection between high altitude and oxidative stress and the role of anti-oxidants to protect cells from oxidative damages and to lower the risk of altitude-associated sickness.

Non-ionic small amphiphile based nanostructures for biomedical applications.

Self-assembly of non-ionic amphiphilic architectures into nanostructures with defined size, shape and morphology has garnered substantial momentum in the recent years due to their extensive applications in biomedicine. The manifestation of a wide range of morphologies such as micelles, vesicles, fibers, tubes, and toroids is thought to be related to the structure of amphiphilic architectures, in particular, the choice of the hydrophilic and hydrophobic parts. In this review, we look at different types of non-ionic small amphiphilic architectures and the factors that influence their self-assembly into various nanostructures in aqueous medium. In particular, we focus on the explored structural parameters that guide the formation of various nanostructures, and the ways these structures can be used in applications ranging from drug delivery to cell imaging.

Nonionic Dendritic and Carbohydrate Based Amphiphiles: Self-Assembly and Transport Behavior.

Herein, a new series of non-ionic dendritic and carbohydrate based amphiphiles is synthesized employing biocompatible starting materials and studied for supramolecular aggregate formation in aqueous solution. The dendritic amphiphiles 12 and 13 possessing poly(glycerol) [G2.0] as hydrophilic unit and C-10 and C-18 hydrophobic alkyl chains, respectively, exhibit low critical aggregation concentration (CAC) in the order of 10-5 m and hydrodynamic diameters in the 8-10 nm range and supplemented by cryogenic transmission electron microscopy. Ultraviolet-visible (UV-Vis) and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests by the self-assembled architectures, with the nanotransporters 12 and 13 possessing the highest encapsulation efficiency of 80.74 and 98.03% for curcumin. Efficient uptake of encapsulated curcumin in adenocarcinomic human alveolar basal epithelial (A549) cells is observed by confocal laser scanning microscopy. Amphiphiles 12 and 13 are non-cytotoxic at the concentrations studied, however, curcumin encapsulated samples efficiently reduce the viability of A549 cells in vitro. Experimental studies indicate the ability of amphiphile 13 to encapsulate 1-anilinonaphthalene-8-sulfonic acid (ANS) and curcumin with binding constant of 1.16 × 1055 m-1 and 1.43 × 106 m-1 , respectively. Overall, our findings demonstrate the potential of these dendritic amphiphiles for the development of prospective nanocarriers for the solubilization of hydrophobic drugs.

Antimicrobial Efficacy of Synthetic Pyranochromenones and (Coumarinyloxy)acetamides.

Four (1, 2, 4 and 6) synthetic quaternary ammonium derivatives of pyranochromenones and (coumarinyloxy)acetamides were synthesized and investigated for their antimicrobial efficacy on MRSA (Methicillin-resistant Staphylococcus aureus), and multi-drug resistant Pseudomonas aeruginosa, Salmonella enteritidis and Mycobacterium tuberculosis H37Rv strain. One of the four compounds screened i.e. N,N,N-triethyl-10-((4,8,8-trimethyl-2-oxo-2,6,7,8-tetrahydropyrano[3,2-g]chromen-10-yl)oxy)decan-1-aminium bromide (1), demonstrated significant activity against S. aureus, P. aeruginosa and M. tuberculosis with MIC value of 16, 35, and 15.62 µg/ml respectively. The cytotoxicity evaluation of compound 1 on A549 cell lines showed it to be a safe antimicrobial molecule, TEM study suggested that the compound led to the rupture of the bacterial cell walls.

Acetamide Derivatives of Chromen-2-ones as Potent Cholinesterase Inhibitors.

Alzheimer's disease (AD), a neurodegenerative disorder, is a serious medical issue worldwide with drastic social consequences. Inhibition of cholinesterase is one of the rational and effective approaches to retard the symptoms of AD and, hence, consistent efforts are being made to develop efficient anti-cholinesterase agents. In pursuit of this, a series of 19 acetamide derivatives of chromen-2-ones were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential. All the synthesized compounds exhibited significant anti-AChE and anti-BChE activity, with IC50 values in the range of 0.24-10.19 µM and 0.64-30.08 µM, respectively, using donepezil hydrochloride as the standard. Out of 19 compounds screened, 3 compounds, viz. 22, 40, and 43, caused 50% inhibition of AChE at 0.24, 0.25, and 0.25 µM, respectively. A kinetic study revealed them to be mixed-type inhibitors, binding with both the CAS and PAS sites of AChE. The above-selected compounds were found to be effective inhibitors of AChE-induced and self-mediated Aß1-42 aggregation. ADMET predictions demonstrated that these compounds may possess suitable blood-brain barrier (BBB) permeability. Hemolytic assay results revealed that these compounds did not lyse human RBCs up to a thousand times of their IC50 value. MTT assays performed for the shortlisted compounds showed them to be negligibly toxic after 24 h of treatment with the SH-SY5Y neuroblastoma cells. These results provide insights for further optimization of the scaffolds for designing the next generation of compounds as lead cholinesterase inhibitors.

Synthesis and evaluation of c-Src kinase inhibitory activity of pyridin-2(1H)-one derivatives.

Src kinase, a prototype member of the Src family of kinases (SFKs), is over-expressed in various human tumors, and has become a target for anticancer drug design. In this perspective, a series of eighteen 2-pyridone derivatives were synthesized and evaluated for their c-Src kinase inhibitory activity. Among them, eight compounds exhibited c-Src kinase inhibitory activity with IC50 value of less than 25µM. Compound 1-[2-(dimethylamino)ethyl]-5-(2-hydroxy-4-methoxybenzoyl)pyridin-2(1H)-one (36) exhibited the highest c-Src kinase inhibition with an IC50 value of 12.5µM. Furthermore, the kinase inhibitory activity of compound 36 was studied against EGFR, MAPK and PDK, however no significant activity was observed at the highest tested concentration (300µM). These results provide insights for further optimization of this scaffold for designing the next generation of 2-pyridone derivatives as candidate Src kinase inhibitors.