Antifungal compound honokiol triggers oxidative stress responsive signalling pathway and modulates central carbon metabolism

<p>The fast growing evidences have shown that the plant-derived compound honokiol is a promising candidate for treating multiple human diseases, such as inflammation and cancer. However, the mode-of-action (MoA) of honokiol remains largely unclear. Here, we studied the antifungal activity of honokiol in fission yeast model, with the goal of understanding the honokiol’s mechanism of action from the molecular level. We found that honokiol can inhibit the yeast growth at a dose-dependent way. Microarray analysis showed that honokiol has wide impacts on the fission yeast transcription levels (in total, 512 genes are up-regulated, and 42 genes are down-regulated). Gene set enrichment analysis indicated that over 45% up-regulated genes belong to the core environmental stress responses category. Moreover, network analysis suggested that there are extensive gene–gene interactions amongst the co-expression gene lists, which can assemble several biofunctionally important modules. It is noteworthy that several key components of central carbon metabolism, such as glucose transporters and metabolic enzymes of glycolysis, are involved in honokiol’s MoA. The complexity of the honokiol’s MoA displayed in previous studies and this work demonstrates that multiple omics approaches and bioinformatics tools should be applied together to achieve the complete scenario of honokiol’s antifungal function.</p

A Molecular Simulation Study of Carbon Dioxide Uptake by a Deep Eutectic Solvent Confined in Slit Nanopores

Molecular dynamics simulations were performed to study the behavior of CO₂ in varying amounts of a common deep eutectic solvent (DES), choline chloride and ethylene glycol (termed ethaline), confined in slit-like pores of width <i>H</i> = 5.2 nm with graphite or rutile walls at <i>T</i> = 318 K. In the absence of DES, CO₂ adsorbs to the pore walls, but increasing amounts of ethaline inside the pores quickly displace carbon dioxide into the gas/liquid interfaces, and into dissolution within the confined DES. This process is driven by strong interactions of the ethaline components with the pore walls, especially in the case of rutile systems, which also cause the local ratio of choline chloride:ethylene glycol inside the pores to depart from the bulk value of 1:2. As the amount of DES inside the pores increases, the diffusivity of CO₂ reaches a maximum in partially filled pores and decays to the values observed in pores filled with DES, which are similar to the diffusion coefficients of CO₂ in the bulk DES. The average number densities of CO₂ near confined ethaline (i.e., dissolved in the DES, and adsorbed at the pore walls and at the gas/liquid interface) are significantly larger than the corresponding value observed in bulk ethaline; for pores partially filled with DES, the overall average number density of CO₂ can be ∼3.0–7.3 times the value observed in bulk ethaline. Even though larger number densities of CO₂ are observed in pores with no ethaline adsorbed, our results suggest that systems of nanoporous materials partially filled with DESs could be further explored and optimized for separation of carbon dioxide and other gases, in analogy to the development of supported ionic liquid phase materials for similar purposes

Synthesis, characterization and evaluation of tinidazole-loaded mPEG–PDLLA (10/90) <i>in situ</i> gel forming system for periodontitis treatment

<p>Traditional <i>in situ</i> gel forming systems are potential applications for parenteral administration but always accompanied with burst release. To overcome this limitation, the tinidazole (TNZ)-loaded <i>in situ</i> gel forming system using a diblock copolymer, monomethoxy poly(ethylene glycol)–block-poly(d,l-lactide) (mPEG–PDLLA), was designed. The formulation of the mPEG–PDLLA-based TNZ <i>in situ</i> gel forming system contained 5% (w/w) TNZ, 0.4% glycerol, 5 ml <i>N</i>-methyl pyrrolidone (NMP) and 35% (w/w) mPEG–PDLLA. The <i>in situ</i> gel forming system showed sustained TNZ release over 192 h with low burst effect (around 7% in the first 8 h) in the <i>in vitro</i> release study. Additionally, <i>in vivo</i> studies were performed on rabbits with ligature-induced periodontitis, and the concentration of TNZ in the gingival crevicular fluid (GCF) as well as the pharmacokinetic parameters was calculated and the pharmacological effect of TNZ-loaded <i>in situ</i> gel forming (mPEG–PDLLA)-based system was found effective. Finally, histological studies revealed that the gel was a safe formulation with low irritation. The desirable drug release kinetics combined with the excellent <i>in vivo</i> characteristics highlight the potential of the gel in the treatment of periodontitis. Therefore, these results confirmed that the TNZ-loaded <i>in situ</i> gel forming mPEG–PDLLA-based system could reduce burst release of TNZ and act as a sustained-release and injectable drug depot for periodontitis treatment.</p

Structural and Dynamical Properties of a Deep Eutectic Solvent Confined Inside a Slit Pore

We performed molecular dynamics (MD) simulations to study the structure and dynamics of the deep eutectic solvent (DES) choline iodide-glycerol (CI.G) at a molar ratio of 1:3, inside slitlike titania [rutile (110)] and graphitic nanopores of width <i>H = </i> 5.2 and 2.5 nm, and at a temperature <i>T = </i> 333 K. DESs share many of the remarkable properties of ionic liquids (ILs) while being more inexpensive; furthermore, and in addition to their fundamental scientific interest, the systems modeled here are relevant to dye-sensitized solar cells and gas separations. Our results show that glycerol can form stable hydrogen bonds with the oxygen atoms in the rutile walls, which account for ∼86% of the total number of hydrogen bonds involving DES species (choline, iodide, and glycerol) in the first layers (near the rutile walls), and for ∼24% of the total hydrogen bonds observed for the DES inside a rutile pore of width <i>H = </i> 5.2 nm. As a result, in these systems, the rutile walls are coated by glycerol layers that are almost depleted of ions, have a liquid structure that departs from that of the bulk DES, and have very slow dynamics. In contrast, for DES inside graphitic pores, all species are present in the first layers near the carbon walls, the local liquid structure everywhere is similar to that of a bulk DES, and the overall dynamics are faster than those observed inside rutile pores of the same pore size; however, the DES species in the center of both rutile and graphitic pores have comparable mobilities. When the pore size is reduced, a larger proportion of the hydrogen bonds involve the walls (in the case of a rutile pore), the overall dynamics of the confined DES become slower, and in general the hydrogen bonds formed are present during longer times in the simulation trajectories. These observations are in general similar to the results obtained by us for the IL [EMIM⁺]­[TFMSI^–] inside the same rutile and graphitic pores; however, both of the IL ions are present in the layers near the walls, and the ions in the center of a rutile pore have dynamics that were 2–4 times slower than those observed for the same ions in the center of a graphitic pore

Enhanced Akt-rpS6 activation and <i>in vitro</i> inhibition of rpS6 activation in Oo<i>Pten</i>^−/− oocytes by rapamycin.

<p>(<b>A</b>) Comparison of Akt-rpS6 signaling in Oo<i>Pten</i>^−/− and Oo<i>Pten</i>^+/+ oocytes. Oocytes were isolated from ovaries of mice at postnatal day 12–14 and immunoblotting was performed as described in <i>Materials and Methods</i>. Loss of PTEN led to enhanced PI3K signaling as indicated by an increase in phosphorylated Akt (p-Akt). The level of phosphorylated rpS6 (p-rpS6) was also increased in Oo<i>Pten</i>^−/− oocytes compared with Oo<i>Pten</i>^+/+ oocytes. Levels of total rpS6, Akt, and β-actin were used as internal controls. (<b>B</b>) Activation of rpS6 in Oo<i>Pten</i>^−/− oocytes is dependent on mTORC1 signaling. Oocytes were isolated from ovaries of Oo<i>Pten</i>^−/− mice at PD 12–14 as described in <i>Materials and Methods</i>. Treatment of oocytes with the mTORC1-specific inhibitor rapamycin (Rapa, 50 nM) for 2 h was found to largely suppress levels of phosphorylated rpS6 (p-rpS6), but did not affect the level of phosphorylated Akt (p-Akt). As a control, treatment of Oo<i>Pten</i>^−/− oocytes with the PI3K-specific inhibitor LY294002 (LY, 50 µM) for 2 h also largely suppressed levels of phosphorylated rpS6 (p-rpS6), but it also suppressed the level of phosphorylated Akt (p-Akt). This suggests that activation of rpS6 in Oo<i>Pten</i>^−/− oocytes is dependent on both PI3K and mTORC1 signaling. Levels of total Akt, rpS6, and β-actin were used as internal controls.</p

Preservation of the primordial follicle pool in Oo<i>Pten</i>^−/− ovaries by rapamycin treatment.

<p>(<b>A</b>) Prevention of the primordial follicle over-activation in Oo<i>Pten</i>^−/− mice by treatment with rapamycin. Rapamycin (5 mg/kg body weight) was injected daily into Oo<i>Pten</i>^−/− mice from postnatal day (PD) 4 to PD 22, and the ovaries were collected at PD 23 for morphological analysis. Ovaries from rapamycin-treated Oo<i>Pten</i>^−/− mice appeared smaller (c) than the ovaries from vehicle-treated Oo<i>Pten</i>^−/− mice (a). Scale bar = 50 µm. Clusters of primordial follicles were seen in rapamycin-treated Oo<i>Pten</i>^−/− mice at PD 23 (d, arrows) whereas all primordial follicles were activated in vehicle-treated Oo<i>Pten</i>^−/− mice at PD 23 (b, arrows). Scale bar = 50 µm. (<b>B</b>) Average numbers of total and primordial follicles in Oo<i>Pten</i>^+/+, Oo<i>Pten</i>^−/− (vehicle-treated), and Oo<i>Pten</i>^−/− (rapamycin-treated) ovaries at PD 23. Proportions of primordial follicles ± SEM (relative to the total number of follicles) are also shown. The proportion of primordial follicles in rapamycin-treated Oo<i>Pten</i>^−/− ovaries was 20±4.1%, which was smaller than the proportion in the Oo<i>Pten</i>^+/+ ovaries (70±3.1%). Three mice were used for each experimental group. Rapa, rapamycin. (<b>C</b>) Comparison of the rpS6 and Akt phosphorylation levels in the ovaries of vehicle- and rapamycin-treated Oo<i>Pten</i>^−/− mice. Rapamycin (5 mg/kg body weight) was injected daily into Oo<i>Pten</i>^−/− mice from PD 4 to PD 22, the ovaries were collected at PD 23 and homogenized, and immunoblotting was performed as described in <i>Materials and Methods</i>. Rapamycin injection effectively suppressed the level of phosphorylated rpS6 (p-rpS6) without affecting the level of phosphorylated Akt (p-Akt) in the ovaries of Oo<i>Pten</i>^−/− mice. Levels of total rpS6, Akt, and β-actin were used as internal controls.</p

A Novel PbS Hierarchical Superstructure Guided by the Balance between Thermodynamic and Kinetic Control via a Single-Source Precursor Route

In this work, a novel lead sulfide (PbS) hierarchical superstructure, denoted as octapodal dendrites with a cubic center, has been synthesized employing a simple single-source precursor route. Our experimental results demonstrate that the novel hierarchical superstructure was generated through the delicate balance between the kinetic growth and thermodynamic growth regimes. Moreover, the morphology of PbS crystals can be controlled by adjusting the solvent under a thermodynamically or kinetically controlled growth regime. It is highly expected that these findings will be useful in understanding the formation of PbS nanocrystals with different morphologies, which are also applicable to other face-centered cubic nanocrystals

Photoelectrochemical Water Splitting SystemA Study of Interfacial Charge Transfer with Scanning Electrochemical Microscopy

Fast charge transfer kinetics at the photoelectrode/electrolyte interface is critical for efficient photoelectrochemical (PEC) water splitting system. Thus, far, a measurement of kinetics constants for such processes is limited. In this study, scanning electrochemical microscopy (SECM) is employed to investigate the charge transfer kinetics at the photoelectrode/electrolyte interface in the feedback mode in order to simulate the oxygen evolution process in PEC system. The popular photocatalysts BiVO₄ and Mo doped BiVO₄ (labeled as Mo:BiVO₄) are selected as photoanodes and the common redox couple [Fe­(CN)₆]^3–/[Fe­(CN)₆]^4– as molecular probe. SECM characterization can directly reveal the surface catalytic reaction kinetics constant of 9.30 × 10⁷ mol^–1 cm³ s^–1 for the BiVO₄. Furthermore, we find that after excitation, the ratio of rate constant for photogenerated hole to electron via Mo:BiVO₄ reacting with mediator at the electrode/electrolyte interface is about 30 times larger than that of BiVO₄. This suggests that introduction of Mo⁶⁺ ion into BiVO₄ can possibly facilitate solar to oxygen evolution (hole involved process) and suppress the interfacial back reaction (electron involved process) at photoanode/electrolyte interface. Therefore, the SECM measurement allows us to make a comprehensive analysis of interfacial charge transfer kinetics in PEC system

Synthesis, physicochemical properties and ocular pharmacokinetics of thermosensitive <i>in situ</i> hydrogels for ganciclovir in cytomegalovirus retinitis treatment

<p>Ganciclovir (GCV) is one of the most widely used antiviral drugs for the treatment of cytomegalovirus (CMV) retinitis. In this context, the aim of this study was to design <i>in situ</i> thermosensitive hydrogels for GCV ocular delivery by intravitreal injection to achieve sustained drug release behavior and improved ocular bioavailability in the treatment of CMV retinitis. A thermosensitive poly-(β-butyrolactone-co-lactic acid)-polyethylene glycol-poly (β-butyrolactone-co-lactic acid) (PBLA-PEG-PBLA) triblock copolymer was synthesized by ring-opening polymerization and characterization. The GCV-loaded PBLA-PEG-PBLA <i>in situ</i> hydrogels (15%, <i>w/w</i>) were then prepared with drug concentration at 2 mg·mL⁻¹ and the gelation temperatures, rheological properties, <i>in vitro</i> degradation and syringeability of <i>in situ</i> hydrogels for intravitreal injection were also investigated. Membraneless dissolution model was used to explore drug release behavior of PBLA-PEG-PBLA <i>in situ</i> hydrogel. The results indicated that more than 45 and 85% of GCV can be released within 24 and 96 h, respectively, which was verified by a non-Fickian diffusion mechanism. <i>In vivo</i> ocular pharmacokinetics study showed that area under drug-time curve (AUC) and half-life of PBLA-PEG-PBLA <i>in situ</i> hydrogel was higher (AUC was 61.80 μg·mL⁻¹·h (<i>p</i> < .01) and <i>t</i>_1/2 was 10.29 h in aqueous humor; AUC was 1008.66 μg·mL⁻¹·h (<i>p</i> < .01) and <i>t</i>_1/2 was 13.26 h (<i>p</i> < .01) in vitreous) than GCV injection with extended therapeutic activity. Based on obtained results, it was concluded that the thermosenstive PBLA-PEG-PBLA <i>in situ</i> hydrogel is a promising carrier of GCV for intravitreal injection.</p

Generating Huge Magnetocurrent by Using Spin-Dependent Dehydrogenation Based on Electrochemical System

Systems featuring large magnetocurrent (MC) at room temperature are attractive owing to their potential for application in magnetic field sensing. Usually, the magnetic materials are exploited to achieve large MC effect. Here, we report a huge MC of up to 150% in a nonmagnetic system based on the electrochemical oxidation of hydrazine at room temperature. The huge MC is ascribed to the spin-dependent N–H bond cleavage and reformation through dehydrogenation during the oxidation of hydrazine. Specifically, the N–H bond cleavage generates singlet radical pairs. An external magnetic field can accelerate the spin evolution from singlet to triplet in spin-correlated radical pairs by perturbing spin precessions. Increasing the amount of triplet radical pairs can largely reduce the N–H bond recovery and significantly enhance the oxidation current of hydrazine. As a consequence, the spin-dependent bond formation through dehydrogenation can provide a new approach to generate huge MC in electrochemical cells