Ternary Dry Powder Agglomerate Inhalation Formulation of Melatonin With Air Jet Mixing to Improve In Vitro And In Vivo Performance.

An improved agglomerate formulation with melatonin and fine lactose for dry powder inhalation using Turbuhaler® was developed. Co-grinding lactose with 1 % magnesium stearate prior to air jet mixing served as a key factor to improve the in vitro aerosolization and in vivo efficacy. Elevated mixing pressure facilitated the dispersion and homogenization of the cohesive mixture for even distribution of agglomerate size after spheroidization and subsequent higher emitted dose with lower variation. Magnesium stearate was employed as a tertiary component to adjust the interparticle force for better aerosolization. At optimized mixing pressure, co-grinding lactose with magnesium stearate before jet mixing displayed further improvement of fine particle fraction to 71.6 ± 3.1 %. The superior fine particle deposition efficiency contributed to rapid onset of action and a high bioavailability of 67.0 % after intratracheal administration to rats. Overall, an inhalable melatonin dry powder formulation exhibiting good aerosol property and lung deposition with clinical translation potential was developed.

Environmental, economic and engineering performances of aqueous carbonated steel slag powders as alternative material in cement pastes: Influence of particle size.

The low reactivity and volume expansion issue of steel slag limits its application as alternative to cement. Studies demonstrated that aqueous carbonation (AC) can enhance the cementitious properties of finely sized steel slag as a cementitious supplementary material (SCM). However, the impact of particle size on the CO2 uptake capacity and its association of performance of carbonated steel slag remains unexplored. This study aims to optimize the grinding levels by examining the fineness of the steel slag used as SCM to reduce the high-energy consumption while maintaining the CO2 sequestration and properties of SCM. The results show that reducing the size of steel slag is favorable for CO2 sequestration (particle size 22.4-112.6 µm corresponds to sequestration of ∼88.5-37.9 kg CO2/t steel slag) and improve the leaching of Mg ions for mineralization. The life cycle assessment shows that the global warming potential of AC of steel slag is ∼96.2-24.9 kg CO2-eq/t steel slag, which can offset the carbon emissions due to further grinding. The 28-day compressive strength of the cement pastes blended with finer carbonated steel slag was also relatively higher due to the formation of mono-carboaluminates and stabilization of ettringite in facilitating the bond strength between the carbonated steel slag particle and the cement paste matrix. According to 3E (engineering, environmental and economic) triangle model, 22.4 µm steel slag powder showed the best comprehensive performance, including an increased revenue of 40.8 CNY/ton steel slag.

Chemical analysis of selected harmful and potentially harmful constituents and in vitro toxicological evaluation of leading flavoured e-cigarette aerosols in the Chinese market.

Use of electronic cigarettes (e-cigarettes) has increased significantly over the past decade due to consumer perception that these products represent a less risky alternative to combustible cigarettes. E-liquids generally contain a simple mix of vegetable glycerin, propylene glycerol, nicotine, organic acids, and flavourings. Regulators require that harmful and potentially harmful constituents (HPHCs) that might cause harm to the consumer must be monitored in the aerosol generated by e-cigarettes and in cigarette smoke (CS). To quantify HPHCs in aerosols from commercial flavoured e-cigarettes in Chinese market, this study has systematically compared levels of HPHCs, including eight carbonyls, five volatile organic compounds, four tobacco-specific nitrosamines, 16 polycyclic aromatic hydrocarbons, and seven heavy metals, in the aerosols of four market-leading flavoured e-cigarettes and mainstream CS, alongside in vitro cytotoxicity and mutagenicity assays. The vast majority of HPHCs were either undetected or significantly lower in the e-cigarette aerosols than in commercial CS or reference CS (3R4F). Where HPHCs were detected, there were small variations among the different flavoured e-cigarettes. In the neutral red uptake and Ames assays, aqueous extracts of the e-cigarette aerosols did not induce obvious cytotoxicity or mutagenicity, whereas CS aqueous extract showed dose-related cytotoxicity and mutagenicity. Collectively, these results indicate that use of e-cigarettes might potentially lead to a significant reduction in exposure to harmful substances, with fewer cytotoxic and mutagenic effects, as compared with conventional smoking. Further studies based on human puffing conditions and longer evaluation periods will be needed to substantiate this potential.

Acute and subacute inhalation toxicity assessment of WS-23 in Sprague-Dawley rats.

2-isopropyl-N,2,3-trimethylbutyramide (WS-23) is a well-known artificial synthesis cooling agent widely used in foods, medicines, and tobaccos. As a commonly cooling agent in e-cigarette liquids, WS-23 has led to concerns about the inhalation toxicity with the prosperous of e-cigarettes in recent years. Thus, the aim of this study is to assess the acute and subacute inhalation toxicity of WS-23 in Sprague-Dawley (SD) rats according to the Organization for Economic Cooperation and Development (OECD) guidelines. In the acute toxicity study, there was no mortality and behavioral signs of toxicity at the limit test dose level (340.0 mg/m3 ) in the exposure period and the following 14-day observation period. In the subacute inhalation toxicity study, there was no significant difference observed in the body weights, feed consumption, and relative organ weights. Haematological, serum biochemical, urine, and bronchoalveolar lavage fluid (BALF) analysis revealed the non-adverse effects after 28-day repeated WS-23 inhalation (342.85 mg/m3 ), accompanied by slight changes in few parameters which returned to normal during the 28-day recovery period. The histopathologic examination also did not show any differences in vital organs. In conclusion, the maximum tolerated dose for WS-23 acute inhalation is not less than 340.0 mg/m3 , and the No Observed Adverse Effect Level (NOAEL) of WS-23 subacute inhalation was determined to be over 342.85 mg/m3 .

Mesenchymal stem cells promote chemoresistance by activating autophagy in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a type of cancer that is difficult to cure; chemoresistance of cholangiocarcinoma cells affect the prognosis of patients who cannot be treated with surgery. The mechanism underlying this chemoresistance remains unknown. Mesenchymal stem cells (MSCs) are known to be important components of the tumor microenvironment. In the present study, a large number of MSCs were observed to infiltrate the tumor sites of ICC; thus, MSCs were isolated from ICC tumor tissues. It was revealed that herpesvirus entry mediator (HVEM) was overexpressed in ICC­MSCs. The present study then investigated the role of HVEM­overexpressing MSCs in the chemoresistance of cholangiocarcinoma cells. It was demonstrated that HVEM­overexpressing MSCs could support cell survival of chemotherapeutic cholangiocarcinoma cells and inhibited their apoptosis. Further investigations revealed that HVEM­overexpressing MSCs could secrete IL­6 and also activated AMPK/mTOR­dependent autophagy of cholangiocarcinoma cells. Thus, it was concluded that ICC­MSC­induced autophagy is the primary cause of chemoresistance in ICC.