Study on the Adhesion Force between Wax Crystal Particles and Hydrate Particles.

In this work, to solve the problem of pipeline blockage caused by the accumulation of hydrate particles and wax particles and to explore the interaction characteristics of adhesive force between gas hydrate particles and wax particles as well as droplets, a high-pressure triaxial mobile device was used to measure the adhesion strength between cyclopentane hydrate particles and different commonly seen phases in the pipeline, including cyclopentane hydrate particles themselves, liquid droplets, and wax crystal particles. These experiments were conducted at different temperatures. The results showed that the adhesion between hydrate and wax particles was decreased with the increase in temperature; this is because the wax is amorphous, the heat absorbed when the temperature rises only increases its average kinetic energy, and the stronger the kinetic energy, the lower its viscosity, resulting in reduced adhesion between particles. Meanwhile, this adhesion was also affected by the concentration of wax. As the wax concentration increased from 1 to 5.32 wt % and then to 8.14 wt %, the adhesion between hydrate and wax particles was first decreased and then increased. This was because when the wax crystal concentration was below 5 wt %, a higher wax molecule concentration meant a more hydrophobic surface, which restricted the formation of a capillary liquid bridge between particles and thus reduced the interforce between wax crystal particles and hydrate particles. When the wax crystal concentration was between 5 and 8 wt %, the change of hydrophobicity was no longer the dominating factor, the increase in wax concentration blocked the hydrate molecular diffusion path, which caused a higher hydrate viscosity, therefore leading to a decreased hydrate molecular diffusion rate and a reduced conversion rate of the liquid bridge in hydrates, the lower conversion rate could subsequently lead to the increasing size of micropores in the hydrate shell, and adhesion between particles was increased.

Design and evaluation of glutathione responsive glycosylated camptothecin nanosupramolecular prodrug.

A novel tumor-targeted glutathione responsive Glycosylated-Camptothecin nanosupramolecular prodrug (CPT-GL NSp) was designed and fabricated via a disulfide bond. The effects of glycoligand with different polarities on solubility, self-assembly, stability, cellular uptake, and glutathione responsive cleaving were explored, and an optimal glycosylated ligand was selected for nanosupramolecular prodrug. It has been found that CPT-GL NSp exhibited higher drug loading than traditional nanoparticles. Among of which maltose modified NSp had the strongest anti-tumor effects than that of glucose and maltotriose. CPT-SS-Maltose had a similar anti-tumor ability to Irinotecan (IR), but the superior performance in solubility, hemolysis, and uptake of HepG2 cells.

Thiol-functionalized nano-silica for in-situ remediation of Pb, Cd, Cu contaminated soils and improving soil environment.

Heavy metal contamination has been threatening the health of human beings. To decrease the bio-toxicity of heavy metals, a thiol-functionalized nano-silica (SiO2-SH) was adopted to remediate the soil contaminated by lead (Pb), cadmium (Cd) and copper (Cu). The remediation effect of SiO2-SH on contaminated soils was investigated by the uptake of the heavy metals into lettuce and pakchoi in pot experiment. The bio-toxicity of the SiO2-SH was evaluated, and its immobilization mechanisms were proposed by the fraction distribution of Cd, Pb and Cu. It was found that the SiO2-SH can significantly reduce the uptake of Cd, Pb, Cu into pakchoi by 92.02%, 68.03%, 76.34% and into lettuce by 89.81%, 43.41%, 5.76%, respectively. The chemical species analyses of Cd, Pb, Cu indicate SiO2-SH can transform the heavy metal in acid soluble states into reducible fraction and oxidizable fraction, thereby inhibiting the extraction of heavy metals into soil solution. The concentrations of microbial biomass carbon, organic matter, and cation exchange capacity of the soil increased while the soil bulk density decreased after remediation. Those changes demonstrate that SiO2-SH not only has no bio-toxic impact on the soil environment but also improves the soil environment, which proves the prepared SiO2-SH is environmental-friendly. The SiO2-SH could be a promising amendment for heavy metal contaminated soils.

Targeted miR-21 loaded liposomes for acute myocardial infarction.

Acute and persistent myocardial ischemia is the main cause of acute myocardial infarction (AMI) and heart failure. MicroRNA-21(miR-21) contributes to the pathophysiological consequences of acute myocardial infarction by targeting downstream crucial regulators. Thus, miR-21 mimics are a promising strategy for the treatment of AMI. However, their poor stability and insufficient cellular uptake are the major challenges. Herein, we encapsulated miR-21 mimics into liposomes modified with the cardiac troponin T (cTnT) antibody for targeted delivery of miR-21(cT-21-LIPs) to the ischemic myocardium. The cT-21-LIPs exhibited enhanced targeting efficiency to hypoxia primary cardiomyocytes in vitro and improved accumulation in the ischemic heart of AMI rats after injection via the tail vein due to the specifical target to overexpressed troponin. The cT-21-LIPs could significantly improve the cardiac function and decrease the infarct size after AMI, while maintaining the viability of cardiomyocytes. This design provides a novel strategy for delivering small nucleotide drugs specifically to the infarcted heart, which may find great potential in clinics.

Mercapto propyltrimethoxysilane- and ferrous sulfate-modified nano-silica for immobilization of lead and cadmium as well as arsenic in heavy metal-contaminated soil.

Nano-silica as an important part of soil is an ideal carrier of passivator material. In this paper, nano-silica was modified by silane coupling agent containing mercapto group and iron (II) salt to afford an organic-inorganic hybrid containing -S-Fe-S functional group (coded as RNS-SFe) on the surface of nano-silica. Results demonstrate that the RNS-SFe nanoparticle has network-like spheroidal shape and a primary particle size is about 18.0 nm. The RNS-SFe hybrid as a potential immobilization agent for heavy metal in soil shows excellent performance for the remediation of the contaminated soil. Specifically, with a dosage of 3.0% (mass ratio) in the soil, it can immobilize bioavailable Pb, Cd, and As by 97.1%, 85.0%, and 80.1%, respectively. Namely, the RNS-SFe hybrid can transform the bioavailable Pb, Cd, and As into insoluble mercapto metal compounds (-S-Pb-S- and -S-Cd-S-) and less soluble iron arsenate (Fe3(AsO4)2, FeAsO4) precipitate on the surface of nano-silica particle, thereby reducing the toxicity and mobility of the toxic contaminant fractions. In the meantime, the immobilized products of the Pb, Cd and As fractions have good resistance against acid leaching. These results are contributive to the application of RNS-SFe for the remediation of multi-heavy metal-contaminated soils in field.

Long-term stabilization of Cd in agricultural soil using mercapto-functionalized nano-silica (MPTS/nano-silica): A three-year field study.

Cadmium (Cd) contamination in agricultural soil is a worldwide environmental problem. In situ stabilization has been considered an effective approach for the remediation of Cd-contaminated agricultural soil. However, information about the long-term effects of amendment on soil properties and stabilization efficiency remains limited. In the present study, mercapto-functionalized nano-silica (MPTS/nano-silica) was used to stabilize Cd in contaminated agricultural soil under field conditions for three years (with application rates of 0%, 0.2%, 0.4%, 0.6%, 0.8% and 1.0%). The application of MPTS/nano-silica reduced the soil aggregate stability (PDA0.25) (14.8%) and available K (24.9%) and significantly increased the soil dehydrogenase (DHA) (43.4%), yield of wheat grains (33.5%) and Si content in wheat tissues (55.2% in leaf, 50.4% in stem, and 37.7% in husk) (p < 0.05). More importantly, MPTS/nano-silica decreased the leachability (36.0%) and bioavailability (54.3%) of Cd in the soil and transformed Cd into a more stable fraction. The content of Cd in wheat grains decreased by 53.9%, 61.9% and 54.1% in 2017, 2018 and 2019, respectively, in comparison with the control. These results indicated that MPTS/nano-silica has long-term stabilization effects on Cd in agricultural soil and is a potential amendment for the remediation of Cd-contaminated agricultural soils.

Influences of different sugar ligands on targeted delivery of liposomes.

Ligands are an important part of targeted drug delivery systems. Optimised lignads not only improve the target efficiency, but also enhance therapeutical effect of drugs. In our research, five sugar molecules (Mannose, Galactose, Glucose, Malt disaccharide, and Maltotriose) conjugated PEG600-DSPE were synthesised, of which polysaccharides were first discovered by us as sugar ligands to modify liposomes, which interacts with over expressive GLUT on cancer cells. DiO was encapsulated as fluorescent probe to evaluate their cellular uptake abilities of targeting C6 glioma cells, and the distribution in different visceral organs of rats. The results demonstrated that Malt disaccharide and Glucose-PEG600-DSPE had the strong efficiency of cellular uptake by C6 glioma cells. The distribution and accumulation of liposomes showed that different sugars modified liposomes could target different visceral organs in rats. It has provided a novel idea for ligand selectivity and optimisation of nanocarriers for tumour targeted therapy.

Chitosan mediated solid lipid nanoparticles for enhanced liver delivery of zedoary turmeric oil in vivo.

Zedoary turmeric oil (ZTO) has a strong antitumor activity. However, its volatility, insolubility, low bioavailability, and difficulty of medication owing to oily liquid limit its clinical applications. Solid lipid nanoparticles can provide hydrophobic environment to dissolve hydrophobic drug and solidify the oily active composition to decrease the volatility and facilitate the medication. Chitosan has been widely used in pharmaceutics in recent years and coating with chitosan further enhances the internalization of particles by cells due to charge attract. Here, Chitosan (CS)-coated solid lipid nanoparticles (SLN) loaded with ZTO was prepared and characterized using dynamic laser scanner (DLS) and transmission electron microscope (TEM). The uptake and distribution of drug were evaluated in vitro and in vivo. The average sizes of ZTO-SLN and CS-ZTO-SLN were 134.3 ± 3.42 nm and 210.7 ± 4.59 nm, respectively. CS coating inverted the surface charge of particles from -8.93 ± 1.92 mV to +9.12 ± 2.03 mV. The liver accumulation of CS-ZTO-SLN was higher than ZTO-SLN (chitosan-uncoated particles) by analysis of tissue homogenate using HPLC, and the bioavailability of ZTO was also obviously improved. The results suggested that SLN coated with CS improved the features of ZTO formulation and efficiently deliver drug to the liver.

Sonodynamic therapy in atherosclerosis by curcumin nanosuspensions: Preparation design, efficacy evaluation, and mechanisms analysis.

Previous studies have shown that curcumin (Cur) induced by ultrasound has protective effects on atherosclerosis even if low bioavailability of the Cur. The enhancement of bioavailability of the Cur further improved the curative effect of sonodynamic therapy (SDT) on atherosclerosis through nanotechnology. Nanosuspensions as a good drug delivery system had obvious advantages in increasing the solubility and improving the effectiveness of insoluble drugs. The aim of this study was to develop curcumin nanosuspensions (Cur-ns) which used polyvinylpyrrolidone (PVPK30) and sodium dodecyl sulfate (SDS) as stabilizers to improve poor water solubility and bioavailability of the Cur. And then the therapeutic effects of Cur-ns-SDT on atherosclerotic plaques and its possible mechanisms would be investigated and elucidated. Cur-ns with a small particle size has been successfully prepared and the data have confirmed that Cur-ns could be more easily engulfed into RAW264.7 cells than free Cur and accumulated more under the stimulation of the ultrasound. Reactive oxygen species (ROS) inside RAW264.7 cells after SDT led to the decrease of mitochondrial membrane potential (MMP) and the higher expression of cleaved caspase-9/3. The results of in vivo experiments showed that Cur-ns-SDT reduced the level of total cholesterol (TC) and low density lipoprotein (LDL) and promoted the transformation from M1 to M2 macrophages, relieved atherosclerosis syndrome. Therefore, Cur-ns-SDT was a potential treatment of anti-atherosclerosis by enhancing macrophages apoptosis through mitochondrial pathway and inhibiting the progression of plaques by interfering with macrophages polarization.

Preparation of O-Protected Cyanohydrins by Aerobic Oxidation of α-Substituted Malononitriles in the Presence of Diarylphosphine Oxides.

A mild, reagent-cyanide-free, and efficient synthesis of O-phosphinoyl-protected cyanohydrins from readily available α-substituted malononitriles was realized using diarylphosphine oxides in the presence of O2. Mechanistic studies indicated that in addition to the initial aerobic oxidation of the malononitrile derivative notable features of this process include the formation of a tetrahedral intermediate and a subsequent intramolecular rearrangement. The phosphinoyl-protecting group can be removed by alcoholysis or by reduction with DIBAL-H.

Asymmetric α-alkylation of cyclic ß-keto esters and ß-keto amides by phase-transfer catalysis.

Without employing any transition metal, a highly enantioselective α-alkylation of cyclic ß-keto esters and ß-keto amides has been realized by phase-transfer catalysis. This improved procedure is applicable to different kinds of halides with cinchona derivatives and gives the corresponding products in excellent enantiopurities (up to 98% ee) and good yields (up to 98%). Moreover, the reaction was scalable and the phase-transfer catalyst was recyclable. This provided an alternative and competitive method to the asymmetric α-alkylation of ß-dicarbonyl compounds.

15-Lipoxygenase and 15-hydroxyeicosatetraenoic acid regulate intravascular thrombosis in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular thrombotic lesions, and right heart failure. Recent studies suggest that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) play an important role in PAH, acting on arterial walls. Here, we show evidence for the action of the 15-LO/15-HETE signaling in the pulmonary vascular thrombotic lesions in the experimental PAH models. Platelet deposition was augmented in rats exposed to hypoxia and Sugen 5416, which were both prevented by nordihydroguaiaretic acid (NDGA), a 15-LO inhibitor. Chronic hypoxic resulted in the platelet deposition specifically in pulmonary vasculature, which was reversed by 15-LO inhibitor. The 15-LO pathway mediated in the endothelial dysfunction induced by hypoxia in vivo. Meanwhile, 15-HETE positively regulated the generation of IL-6 and monocyte chemoattractant protein-1 (MCP-1). The coagulation and platelet activation induced by hypoxia were reversed by 15-LO inhibitor NDGA or the MCP-1 inhibitor synthesis inhibitor bindarit in rats. The 15-LO/15-HETE signaling promoted the coagulation and platelet activation, which was suppressed by MCP-1 inhibition. These results therefore suggest that 15-LO/15-HETE signaling plays a role in platelet activation and pulmonary vascular thrombosis in PAH, involving MCP-1.

15-PGDH/15-KETE plays a role in hypoxia-induced pulmonary vascular remodeling through ERK1/2-dependent PAR-2 pathway.

We have established that 15-hydroxyeicosatetraenoic acid is an important factor in regulation of pulmonary vascular remodeling (PVR) associated with hypoxia-induced pulmonary hypertension (PH), which is further metabolized by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) to form 15-ketoeicosatetraenoic acid (15-KETE). However, the role of 15-PGDH and 15-KETE on PH has not been identified. The purpose of this study was to investigate whether 15-PGDH/15-KETE pathway regulates hypoxia-induced PVR in PH and to characterize the underlying mechanisms. To accomplish this, Immunohistochemistry, Ultra Performance Liquid Chromatography, Western blot, bromodeoxyuridine incorporation and cell cycle analysis were preformed. Our results showed that the levels of 15-PGDH expression and endogenous 15-KETE were drastically elevated in the lungs of humans with PH and hypoxic PH rats. Hypoxia stimulated pulmonary arterial smooth muscle cell (PASMC) proliferation, which seemed to be due to the increased 15-PGDH/15-KETE. 15-PGDH/15-KETE pathway was also capable of stimulating the cell cycle progression and promoting the cell cycle-related protein expression. Furthermore, 15-KETE-promoted cell cycle progression and proliferation in PASMCs depended on protease-activated receptor 2 (PAR-2). ERK1/2 signaling was likely required for 15-PGDH/15-KETE-induced PAR-2 expression under hypoxia. Our study indicates that 15-PGDH/15-KETE stimulates the cell cycle progression and proliferation of PASMCs involving ERK1/2-mediated PAR-2 expression, and contributes to hypoxia-induced PVR.

Asymmetric direct α-hydroxylation of ß-oxo esters catalyzed by chiral quaternary ammonium salts derived from cinchona alkaloids.

Cinchona alkaloid-derived chiral quaternary ammonium organocatalysts were developed. The catalyst with a bulky 1-adamantoyl group at the C-9 position promoted the enantioselective α-hydroxylation of ß-oxo esters and resulted in the corresponding products in 35-95% yields and 58-90% ee. The reaction was successfully scaled to a gram-quantity scale with a similar yield without loss of enantioselectivity.

Development of a simple and stability-indicating RP-HPLC method for determining olanzapine and related impurities generated in the preparative process.

A simple and stability-indicating reverse phase high performance liquid chromatographic (RP-HPLC) method was developed and validated for the determination of olanzapine (OLN) and related impurities in bulk drugs. Eight impurities were characterized respectively, and particularly a new process impurity from OLN synthesis was structurally confirmed as 1-(5-methylthionphen-2-yl)-1H-benzimidazol-2(3H)-one (Imp-7) by X-ray single crystal diffraction, MS, (1)H NMR, (13)C NMR and HSQC. A mechanism of formation pathway for Imp-7 was proposed. Optimum separation for OLN and eight related impurities was carried out on an Agilent Octyldecyl silica column (TC-C(18), 4.6 mm × 250 mm, 5 µm) using a gradient HPLC method. The method was validated with respect to specificity, linearity, accuracy, precision, LOD and LOQ. Regression analysis showed good correlation (r(2) > 0.9985) between the investigated component concentrations and their peak areas within the test ranges for OLN and eight impurities. The repeatability and intermediate precision, expressed as RSD, were less than 1.74%. The proposed stability-indicating method was suitable for routine quality control and drug analysis of OLN in bulk drugs.