Enhanced therapeutic efficacy of a novel self-micellizing nanoformulation-loading fisetin against acetaminophen-induced liver injury

Aim: To evaluate the feasibility of using dipotassium glycyrrhizinate (DG) as a nanocarrier-loading fisetin (FIT) with strengthened treatment efficacies against liver injury induced by acetaminophen overdose. Methods: DG–FIT was prepared, and its efficacy against liver injury induced by acetaminophen overdose was evaluated. Results: DG–FIT was successfully fabricated with excellent physicochemical properties. DG–FIT could be easily dissolved in water to form a clear micelle solution with high FIT encapsulation efficiency. FIT in DG–FIT exhibited a dramatically improved aqueous solubility. DG–FIT improved intestinal permeation. Regarding in vivo efficacies, DG–FIT exhibited significant effect against acetaminophen overdose by suppressing oxidative stress and proinflammatory cytokines involved. Conclusion: DG–FIT formulation possibly represents a promising method for strengthening the efficacy of FIT against acetaminophen-induced liver injury.

Characterization of velocity fluctuations and the transition from transient to steady state shear banding with and without pre-shear in a wormlike micelle solution under shear startup by Rheo-NMR

Rheo-NMR velocimetry was used to study shear banding of a 6 wt.% cetylpyridinium chloride (CPCl) worm-like micelle solution under shear startup conditions with and without pre-shear. 1D velocity profiles across the fluid gap of a concentric cylinder Couette shear cell were measured every 1 s following shear startup for four different applied shear rates within the stress plateau. Fitting of the velocity profiles allowed calculation of the shear banding characteristics (shear rates in the high and low shear band, the interface position and apparent slip at the inner rotating wall) as the flow transitioned from transient to steady state regimes. Characteristic timescales to reach steady state were obtained and found to be similar for all shear banding characteristics. Timescales decreased with increasing applied shear rate. Large temporal fluctuations with time were also observed and Fourier transform of the time and velocity autocorrelation functions quantified the fluctuation frequencies. Frequencies corresponded to the elastically driven hydrodynamic instabilities, i.e. vortices, that are known to occur in the unstable high shear band and were dependent upon both applied shear rate and the pre-shear protocol.

Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions

The aim of this study was to develop a prodrug of ubiquinol-10 (UqH-10), the active form of ubiquinone-10 (Uq-10), for oral delivery. Bioavailability of UqH-10 is hampered by its high susceptibility to oxidation and water-insolubility. We prepared three novel N,N-dimethylglycine ester derivatives of UqH-10, including a 1-monoester (UqH-1-DMG), 4-monoester (UqH-4-DMG), and 1,4-bis-ester (UqH-DMG), and assessed their physicochemical properties in vitro and in vivo. UqH-DMG spontaneously formed an aqueous micelle solution comprising 20 nm particles at 36.5 °C. Cationic UqH-DMG formed nano-sized (5 nm) mixed-micelles with taurocholic acid. Reconversion of the derivatives to UqH-10 was accelerated in human liver microsomes. The oral bioavailability of UqH-10 after administration of UqH-derivatives or Uq-10 was determined in fasted and postprandial rats secreting normal and high levels of bile, respectively. In fasted rats, plasma UqH-10 after UqH-derivatives administration reached Cmax at 2–3 h and after Uq-10 administration, it remained low. The AUC0-24h of UqH-10 after UqH-derivatives administration was 2–3-fold higher than that after Uq-10 administration. In postprandial rats, the Tmax of UqH-10 after UqH-derivatives administration was an hour earlier than after Uq-10 administration. In conclusion, cationic UqH-derivatives are convenient prodrugs that enhance UqH-10 bioavailability by forming nanosized mixed-micelles with intestinal bile acids.

The adipokinetic hormones and their cognate receptor from the desert locust, Schistocerca gregaria: solution structure of endogenous peptides and models of their binding to the receptor

Background Neuropeptides exert their activity through binding to G protein-coupled receptors (GPCRs). GPCRs are well-known drug targets in the pharmaceutical industry and are currently discussed as targets to control pest insects. Here, we investigate the neuropeptide adipokinetic hormone (AKH) system of the desert locust Schistocerca gregaria. The desert locust is known for its high reproduction, and for forming devastating swarms consisting of billions of individual insects. It is also known that S. gregaria produces three different AKHs as ligands but has only one AKH receptor (AKHR). The AKH system is known to be essential for metabolic regulation, which is necessary for reproduction and flight activity. Methods Nuclear magnetic resonance techniques (NMR) in a dodecylphosphocholin (DPC) micelle solution were used to determine the structure of the three AKHs. The primary sequence of the S. gregaria AKHR was used to construct a 3D molecular model. Next, the three AKHs were individually docked to the receptor, and dynamic simulation of the whole ligand–receptor complex in a model membrane was performed. Results Although the three endogenous AKHs of S. gregaria have quite different amino acids sequences and chain length (two octa- and one decapeptide), NMR experiments assigned a turn structure in DPC micelle solution for all. The GPCR-ModSim program identified human kappa opioid receptor to be the best template after which the S. gregaria AKHR was modeled. All three AKHs were found to have the same binding site on this receptor, interact with similar residues of the receptor and have comparable binding constants. Molecular switches were also identified; the movement of the receptor could be visually shown when ligands (AKHs) were docked and the receptor was activated. Conclusions The study proposes a model of binding of the three endogenous ligands to the one existing AKHR in the desert locust and paves the way to use such a model for the design of peptide analogs and finally, peptide mimetics, in the search for novel species-specific insecticides based on receptor–ligand interaction.