Ibuprofen-loaded chitosan–lipid nanoconjugate hydrogel with gum arabic: Green synthesis, characterisation, in vitro kinetics mechanistic release study and PGE2 production test

Ibuprofen is a well-known non-steroidal anti-inflammatory (NSAID) medicine that is often used to treat inflammation in general. When given orally, it produces gastrointestinal issues which lead to lower patient compliance. Ibuprofen transdermal administration improves both patient compliance and the efficacy of the drug. Nanoconjugation hydrogels were proposed as a controlled transdermal delivery tool for ibuprofen. Six formulations were prepared using different compositions including chitosan, lipids, gum arabic, and polyvinyl alcohol, through ionic interaction, maturation, and freeze–thaw methods. The formulations were characterised by size, drug conjugation efficiency, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). Further analysis of optimised hydrogels was performed, including X-ray diffraction (XRD), rheology, gel fraction and swelling ability, in vitro drug release, and in vitro macrophage prostaglandin E2 (PGE2 ) production testing. The effects of ibuprofen’s electrostatic interaction with a lipid or polymer on the physicochemical and dissolution characterisation of ibuprofen hydrogels were evaluated. The results showed that the S3 (with lipid conjugation) hydrogel provided higher conjugation efficiency and prolonged drug release compared with the S6 hydrogel

Mechanisms of Nanoparticle Internalization and Transport Across an Intestinal Epithelial Cell Model: Effect of Size and Surface Charge

This study investigated the effect of nanoparticle size (50 and 100 nm) and surface charge on their interaction with Caco-2 monolayers as a model of the intestinal epithelium, including cell internalization pathways and the level of transepithelial transport. Initially, toxicity assays showed that cell viability and cell membrane integrity were dependent on the surface charge and applied mass, number, and total surface area of nanoparticles, as tested in two epithelial cell lines, colon carcinoma Caco-2 and airway Calu-3. This also identified suitable nanoparticle concentrations for subsequent cell uptake experiments. Nanoparticle application at doses below half maximal effective concentration (EC₅₀) revealed that the transport efficiency (ratio of transport to cell uptake) across Caco-2 cell monolayers is significantly higher for negatively charged nanoparticles compared to their positively charged counterparts (of similar size), despite the higher level of internalization of positively charged systems. Cell internalization pathways were hence probed using a panel of pharmacological inhibitors aiming to establish whether the discrepancy in transport efficiency is due to different uptake and transport pathways. Vesicular trans-monolayer transport for both positively and negatively charged nanoparticles was confirmed via inhibition of dynamin (by dynasore) and microtubule network (via nocodazole), which significantly reduced the transport of both nanoparticle systems. For positively charged nanoparticles a significant decrease in internalization and transport (46% and 37%, respectively) occurred in the presence of a clathrin pathway inhibitor (chlorpromazine), macropinocytosis inhibition (42%; achieved by 5-(<i>N</i>-ethyl-<i>N</i>-isopropyi)-amiloride), and under cholesterol depletion (38%; via methyl-β-cyclodextrin), but remained unaffected by the inhibition of lipid raft associated uptake (caveolae) by genistein. On the contrary, the most prominent reduction in internalization and transport of negatively charged nanoparticles (51% and 48%, respectively) followed the inhibition of lipid raft-associated pathway (caveolae inhibition by genistein) but was not significantly affected by the inhibition of clathrin pathway

Insulinotropic Potential of Moxifloxacin and Gemifloxacin: An In Vivo Rabbits Model Study Followed by Randomized Phase I Clinical Trial

Fluoroquinolones (FQs) have been reported to cause dysglycemia in both diabetic and non-diabetic patients. However, diabetic patients are usually on polypharmacy, so we cannot attribute the dysglycemia specifically to FQs. To answer the question as to whether Moxifloxacin and Gemifloxacin influence blood glucose levels and serum insulin levels or otherwise, rabbits were used as experimental animals in an in vivo model followed by a phase I randomized clinical trial in euglycemic healthy volunteers. The effects on the serum insulin and blood glucose levels in the Moxifloxacin and Gemifloxacin treated groups were, respectively, determined on the fifth day in both the in-vivo rabbits model and in the test subjects of the phase I clinical trial. The effects of these drugs were also checked on the histomorphology of the pancreas in the rabbits. The findings of our study suggest that Moxifloxacin and Gemifloxacin significantly (p &lt; 0.05) reduced the blood glucose levels via a subsequent significant shift in the serum insulin levels both in the in vivo animal model and in the test subjects of the phase I clinical trial. No prominent effects on the beta cells histomorphology were noted in this study. Moxifloxacin showed a more significant effect than Gemifloxacin. The insulinotropic effect was comparable to the effect of Glibenclamide. It is concluded that Moxifloxacin and Gemifloxacin have a significant blood glucose lowering effect mediated through insulinotropic action. (Clinical Trials.gov identifier: NCT04692623)

Protective Effect of Salvianolic Acid B in Acetic Acid-Induced Experimental Colitis in a Mouse Model

In its prominent experimental studies salvianolic acid B (Sal B) is novel because of its well-defined, common physiological effects, which include anti-inflammatory, anti-depressant, cardioprotective, DNA protective, neuroprotective and hepatoprotective activity in experimental animals. Initially, Sal B was studied for its anti-inflammatory properties, used as a remedy for a wide range of disease conditions, but its specific efficacy on inflammatory bowel disease is still unclear. The aim of this current study was to understand the therapeutic potential of Sal B in an acetic acid (AA)—triggered experimental mouse colitis model. Colitis was triggered by intrarectal injection of 5% AA, and then laboratory animals were given Sal B (10, 20 and 40 μg/kg) for seven days. The ulcerated colonic mucosa was assessed by clinical experiment, macroscopical, biological and histopathological analysis. The results showed depleted SOD, CAT, GSH levels and consequential elevated MPO and MDA levels and aberrant crypt foci and mast cells were seen in the AA-induced colonic mucosa of experimental animals. The data obtained from this study demonstrate that a dose of 40 µg/kg showed an efficacious anti-ulcer effect against AA-induced experimental colitis. Based on its antioxidant efficacy, Sal B may therefore be useful as a therapeutic approach for ulcerative colitis

Synthesis of New Naphthyl Aceto Hydrazone-Based Metal Complexes: Micellar Interactions, DNA Binding, Antimicrobial, and Cancer Inhibition Studies

In the present study, naphthyl acetohydrazide (HL) ligand was prepared and used for the synthesis of new six amorphous transition metal (Co(II), Ni(II), Cu(II), Zn(II), Pb(II), Cd(II)) complexes. All the compounds were characterized by elemental analysis, UV-vis, FT-IR, 1H- and 13C-NMR, and Matrix-Assisted Laser Desorption Ionization (MALDI). The solubilization study was carried out by estimating the interaction between the metal complexes with surfactants viz. sodium stearate (SS) and Cetyltrimethylammonium bromide (CTAB). UV-Visible spectroscopy was employed to determine partitioning and binding parameters, whereas electrical conductivity measurements were employed to estimate critical micellar concentration (CMC), the extent of dissociation, and free energy of micellization. The CT-DNA interaction of synthesized compounds with DNA represents the major groove binding. The synthesized ligand and metal complexes were also tested against bacterial and fungal strains and it has been observed that Cu(II) complex is active against all the strains except Candida albicans, while Cd(II) complex is active against all bacterial and fungal strains except Pseudomonas. Among all compounds, only the Pd(II) complex shows reasonable activity against cervical cancer HeLa cell lines, representing 97% inhibition

The mechanisms of nanoparticle internalization and transport across an intestinal epithelial cell model: effect of size and surface charge

This study investigated the effect of nanoparticle size and surface charge on their interaction with Caco-2 monolayers as a model of the intestinal epithelium, including cell internalization pathways and the level of transepithelial transport. Initially, toxicity assays showed that cell viability and cell membrane integrity were dependent on the surface charge and applied mass, number and total surface area of nanoparticles, as tested in two epithelial cell lines, colon carcinoma Caco-2 and airway Calu-3. This also identified suitable nanoparticle concentrations for subsequent cell uptake experiments. Nanoparticle application at doses below EC50 revealed that the transport efficiency (ratio of transport to cell uptake) across Caco-2 cell monolayers is significantly higher for negatively charged nanoparticles compared to their positively charged counterparts (of similar size), despite the higher level of internalization of positively charged systems. Cell internalization pathways were hence probed using a panel of pharmacological inhibitors aiming to establish whether the discrepancy in transport efficiency is due to different uptake and transport pathways. Vesicular trans-monolayer transport for both positively and negatively charged nanoparticles was confirmed via inhibition of dynamin (by dynasore) and microtubule network (via nocodazole), which significantly reduced the transport of both nanoparticle systems. For positively charged nanoparticles a significant decrease in internalization and transport (46% and 37%, respectively) occurred in the presence of a clathrin pathway inhibitor (chlorpromazine), macropinocytosis inhibition (42%; achieved by 5-(N-ethyl-N-isopropyi)-amiloride) and under cholesterol depletion (38%; via methyl-ß-cyclodextrin), but remained unaffected by the inhibition of lipid raft associated uptake (caveolae) by genistein. On the contrary, the most prominent reduction in internalization and transport of negatively charged nanoparticles (51% and 48%, respectively) followed the inhibition of lipid raft-associated pathway (caveolae inhibition by genistein), but was not significantly affected by the inhibition of clathrin pathway