Study on Formulation, in vivo Exposure, and Passive Targeting of Intravenous Itraconazole Nanosuspensions

The pharmacokinetic profile of a drug can be different when delivered as a nanosuspension compared with a true solution, which may in turn affect the therapeutic effect of the drug. The goal of this study was to prepare itraconazole nanosuspensions (ITZ-Nanos) stabilized by an amphipathic polymer, polyethylene glycol-poly (benzyl aspartic acid ester) (PEG-PBLA), by the precipitation-homogenization, and study the pharmacokinetic profile of the ITZ-Nanos. The particle size and morphology of nanosuspensions were determined by Zetasizer and field emission scanning electron microscope (SEM), respectively. The dissolution profile was evaluated using a paddle method according to Chinese Pharmacopoeia 2015. The level of ITZ in plasma and tissues was measured by a HPLC method. The optimized ITZ-Nanos had an average particle size of 268.1 ± 6.5 nm and the particles were in a rectangular form. The dissolution profile of ITZ-Nanos was similar to that of commercial ITZ injections, with nearly 90% ITZ released in the first 5 min. The ITZ-Nanos displayed different pharmacokinetic properties compared with the commercial ITZ injections, including a decreased initial drug concentration, increased plasma half-life and mean residence time (MRT), and increased concentration in the liver, lung, and spleen. The ITZ-Nanos can change the in vivo distribution of ITZ and result in passive targeting to the organs with mononuclear phagocyte systems (MPS)

Ivermectin induces apoptosis of esophageal squamous cell carcinoma via mitochondrial pathway

Background: Esophageal squamous cell carcinoma (ESCC) is the most predominant primary malignant tumor among worldwide, especially in China. To date, the successful treatment remains a mainly clinical challenge, it is imperative to develop successful therapeutic agents. Methods: The anti-proliferative effect of ivermectin on ESCC is investigated in cell model and in nude mice model. Cell apoptosis was assessed using flow cytometry, TUNEL assay and western blotting. Mitochondrial dysfunction was determined by reactive oxygen species accumulation, mitochondrial membrane potential and ATP levels. Results: Our results determined that ivermectin significantly inhibited the proliferation of ESCC cells in vitro and in vivo. Furthermore, we found that ivermectin markedly mediated mitochondrial dysfunction and induced apoptosis of ESCC cells, which indicated the anti-proliferative effect of ivermectin on ESCC cells was implicated in mitochondrial apoptotic pathway. Mechanistically, ivermectin significantly triggered ROS accumulation and inhibited the activation of NF-κB signaling pathway and increased the ratio of Bax/Bcl-2. Conclusions: These finding indicated that ivermectin has significant anti-tumour potential for ESSC and may be a potential therapeutic candidate against ESCC

Multi-Depot Heterogeneous Vehicle Routing Optimization for Hazardous Materials Transportation

This paper considers a multi-depot heterogeneous vehicle routing problem (MDHVRP) with time windows, which is very crucial for hazardous materials transportation. For this reason, we formalize this problem as a multi-objective MDHVRP optimization model, where the actual load dependent risk of hazardous materials transportation is considered. To solve the optimization problem, we propose a hybrid multi-objective evolutionary algorithm (HMOEA) and a two-stage algorithm (TSA). In addition, we verify the performance of the proposed algorithms by experiments on the modified Solomon’s VRPTW examples. In the experiment, it can be seen from the distribution of Pareto solution sets and the convergence distribution of IGD values that HMOEA is significantly superior to the other three algorithms in searching for Pareto solutions, as well as in the convergence and diversity of the algorithm. HMOEA and TSA were compared, and the minimum cost obtained by TSA was 13.38% lower than HMOEA, while the minimum risk was 81.69% higher than HMOEA. The advantages of each algorithm in finding solutions in reality were analyzed. A comparison was made between multi-depots heterogeneous VRP and multi-depots homogeneous VRP in the C101 instance, and the results showed that scheduling heterogeneous vehicles would reduce risk and cost

SpoVG is an important regulator of sporulation and affects biofilm formation by regulating Spo0A transcription in Bacillus cereus 0–9

Abstract Background Bacillus cereus 0–9, a Gram-positive, endospore-forming bacterium isolated from healthy wheat roots in our previous research, is considered to be an effective biocontrol strain against several soil-borne plant diseases. SpoVG, a regulator that is broadly conserved among many Gram-positive bacteria, may help this organism coordinate environmental growth and virulence to survive. This study aimed to explore the multiple functions of SpoVG in B. cereus 0–9. Methods The gene knockout strains were constructed by homologous recombination, and the sporulation process of B. cereus 0–9 and its mutants were observed by fluorescence staining method. We further determined the spore yields and biofilm formation abilities of test strains. Transcriptional fusion strains were constructed by overlapping PCR technique, and the promoter activity of the target gene was detected by measuring its fluorescence intensity. The biofilm production and colonial morphology of B. cereus 0–9 and its mutants were determined to study the functions of the target genes, and the transcription level of the target gene was determined by qRT-PCR. Results According to observation of the sporulation process of B. cereus 0–9 in germination medium, SpoVG is crucial for regulating sporulation stage V of B. cereus 0–9, which is identical to that of Bacillus subtilis but differs from that of Bacillus anthracis. In addition, SpoVG could influence biofilm formation of B. cereus 0–9. The transcription levels of two genes closely related to biofilm-formation, sipW and calY, were downregulated in a ΔspoVG mutant. The role of SpoVG in regulating biofilm formation was further explored by deleting the genes abrB and sinR in the ΔspoVG mutant, respectively, generating the double mutant strains ΔspoVGΔabrB and ΔspoVGΔsinR. The phenotypes of these double mutants were congruent with those of the single abrB and sinR deletion strains, respectively, which showed increased biofilm formation. This indicated that spoVG was located upstream of abrB and sinR in the regulatory pathway of B. cereus biofilm formation. Further, the results of qRT-PCR and the luminescence intensity of transcriptional fusion strains indicated that spoVG gene deletion could inhibit the transcription of Spo0A. Conclusions SpoVG, an important regulator in the sporulation of B. cereus, is located upstream of Spo0A and participates in regulation of biofilm formation of B. cereus 0–9 through regulating the transcription level of spo0A. Sporulation and biofilm formation are crucial mechanisms by which bacteria respond to adverse conditions. SpoVG is therefore an important regulator of Spo0A and is crucial for both sporulation and biofilm formation of B. cereus 0–9. This study provides a new insight into the regulatory mechanism of environmental adaptation in bacteria and a foundation for future studies on biofilm formation of B. cereus

Increased Phenolic Content and Enhanced Antioxidant Activity in Fermented Glutinous Rice Supplemented with Fu Brick Tea

Glutinous rice-based foods have a long history are consumed worldwide. They are also in great demand for the pursuit of novel sensory and natural health benefits. In this study, we developed a novel fermented glutinous rice product with the supplementation of Fu brick tea. Using in vitro antioxidant evaluation and phenolic compounds analysis, fermentation with Fu brick tea increased the total phenolic content and enhanced the antioxidant activity of glutinous rice, including scavenging of 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) radical, 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical, and hydroxyl radical, ferric-reducing antioxidant power, and ferric ion reducing power and iron chelating capability. Besides, compared with traditional fermented glutinous rice, this novel functional food exhibited a stronger activity for protecting DNA against hydroxyl radical-induced oxidation damage. Quantitative analysis by HPLC identified 14 compounds covering catechins and phenolic acids, which were considered to be positively related to the enhanced antioxidant capability. Furthermore, we found that 80% ethanol was a suitable extract solvent compared with water, because of its higher extraction efficiency and stronger functional activities. Our results suggested that this novel fermented glutinous rice could serve as a nutraceutical food/ingredient with special sensory and functional activities

Tuning the metal-insulator transition in epitaxial SrV O 3 films by uniaxial strain

International audienceUnderstanding of the metal-insulator transition (MIT) in correlated transition-metal oxides is a fascinating topic in condensed matter physics and a precise control of such transitions plays a key role in developing novel electronic devices. Here we report an effective tuning of the MIT in epitaxial SrVO 3 (SVO) films by expanding the out-of-plane lattice constant without changing in-plane lattice parameters, through helium ion irradiation. Upon increase of the ion fluence, we observe a MIT with a crossover from metallic to insulating state in SVO films. A combination of transport and magnetoresistance measurements in SVO at low temperatures reveals that the observed MIT is mainly ascribed to electron-electron interactions rather than disorder-induced localization. Moreover, these results are well supported by the combination of density functional theory and dynamical mean field theory (DFT+DMFT) calculations, further confirming the decrease of the bandwidth and the enhanced electron-electron interactions resulting from the expansion of out-of-plane lattice constant. These findings provide new insights into the understanding of MIT in correlated oxides and perspectives for the design of unexpected functional devices based on strongly correlated electrons

Tuning the metal-insulator transition in epitaxial SrV O 3 films by uniaxial strain

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