Enhanced anticancer effect of doxorubicin by TPGS-coated liposomes with Bcl-2 siRNA-corona for dual suppression of drug resistance

Multiple drug resistance(MDR)is a tough problem in developing hepatocellular carcinoma(HCC)therapy.Here,we developed TPGS-coated cationic liposomes with Bcl-2 siRNA corona to load doxorubicin(Dox)i.e.,Bcl-2 siRNA/Dox-TPGS-LPs,to enhance anticancer effect of Dox in HCC-MDR.TPGS i.e.,d-α-tocopheryl polyethylene glycol 1000 succinate,inhibited Pglycoprotein(P-gp)efflux pump and Bcl-2 siRNA suppressed anti-apoptotic Bcl-2 protein.The Bcl-2 siRNA loaded in the liposomal corona was observed under transmission electron microscopy.The stability and hemolysis evaluation demonstrated Bcl-2 siRNA/Dox-TPGSLPs had good biocompatibility and siRNA-corona could protect the liposomal core to avoid the attachment of fetal bovine serum.In drug-resistant cells,TPGS effectively prolonged intracellular Dox retention time and siRNA-corona did improve the internalization of Dox from liposomes.In vitro and in vivo anticancer effect of this dual-functional nanostructure was examined in HCC-MDR Bel7402/5-FU tumor model.MTT assay confirmed the IC50 value of Dox was 20–50 fold higher in Bel7402/5-FU MDR cells than that in sensitive Bel7402 cells.Bcl-2 siRNA corona successfully entered the cytosol of Bel7402/5-FU MDR cells to downregulate Bcl-2 protein levels in vitro and in vivo.Bcl-2 siRNA/Dox-TPGS-LPs showed superior to TPGS-(or siRNA-)linked Dox liposomes in cell apoptosis and cytotoxicity assay in Bel7402/5-FU MDR cells,and 7-fold greater effect than free Dox in tumor growth inhibition of Bel7402/5-FU xenograft nude mice.In conclusion,TPGS-coated cationic liposomes with Bcl-2 siRNA corona had the capacity to inhibit MDR dual-pathways and subsequently improved the anti-tumor activity of the chemotherapeutic agent co-delivered to a level that cannot be achieved by inhibiting a MDR single way.

Study on the Formation and Properties of Liquid Crystal Emulsion in Cosmetic

In this paper, the formation of liquid crystal structure in preparation of emulsion and the change of those liquid crystal structures during storage and usage were studied. Besides, the rheological and moisturizing property of the liquid crystal structure emulsion was investigated as well. The results show that the liquid crystal structure at oil-water interface in the emulsion forms gradually with cooling process after homogenization. The liquid crystal structure doesn’t change significantly during the storage within 12 months. And after emulsion being stored for 18 months, the crystal structure starts to decompose. Upon application on the skin, the liquid crystal structure of emulsion was found to transform into other form with rubbing, although the liquid crystal structure still remains. The rheological data shows that liquid crystal emulsion exhibits solid-like (elastic) property during storage, which is favorable for good stability. On the other hand, liquid crystal emulsion shows typical shear-thinning property upon usage, which leads to an excellent skin sensory feeling. And the improved moisturizing properties of such emulsion may be attributed to the liquid crystal structure.

An extended analysis of cardiovascular benefits of indoor air filtration intervention among elderly:a randomized crossover trial(Beijing indoor air purifier study,BIAPSY)

Objective Evidence on potential cardiovascular benefits of personal-level intervention among the elderly exposed to high levels of particulate matter(PM)remains limited.We aimed to assess improvements in surrogate markers of cardiovascular injury in vulnerable populations at risks by using indoor air filtration units.Methods We conducted a randomized crossover trial for 2 separate 2-week air filtration interventions in 20 households of patients with stable chronic obstructive pulmonary disease and their partners in the winter of 2013,with concurrent measurements of indoor PM.The changes in biomarkers indicative of cardiac injury,atherosclerosis progression and systemic inflammation following intervention were evaluated using linear mixed-effect models.Results In the analysis,average levels of indoor PM with aerodynamic diameters<2.5µm(PM2.5)decreased significantly by 59.2%(from 59.6 to 24.3µg/m3,P<0.001)during the active air filtration.The reduction was accompanied by improvements in levels of high-sensitivity cardiac troponin I by−84.6%(95%confidence interval[CI]:−90.7 to−78.6),growth differentiation factor-15 by−48.1%(95%CI:−31.2 to−25.6),osteoprotegerin by−65.4%(95%CI:−56.5 to−18.7),interleukin-4 by−46.6%(95%CI:−62.3 to−31.0)and myeloperoxidase by−60.3%(95%CI:−83.7 to−3.0),respectively.Conclusion Indoor air filtration intervention may provide potential cardiovascular benefits in vulnerable populations at risks.

Short-term exposure to ambient ozone associated with cardiac arrhythmias in healthy adults

Objective The exact biological mechanism whereby exposure to ambient ozone(O3)may contribute to clinical onset of cardiovascular events remains unclear.In this study,we aim to examine the impacts of O3 exposure on cardiac arrhythmias and potential pathways involved through autonomic dysfunction and myocardial injury.Methods Seventy-three non-smoking healthy adults were followed with 4 repeated measurements of 24-hour ambulatory arrhythmias,heart rate variability,ST-segment deviation,and blood pressure(BP)in Beijing,China,2014‒2016.Generalized additive mixed models coupled with distributed lag nonlinear models were constructed to evaluate the associations and potential interlinks between O3 exposure and outcome measurements.Results During the study period,24-hour average concentrations of ambient O3 were 47.4µg/m3(ranging from 1.0 to 165.9µg/m3).Increased risks of premature ventricular contraction and ventricular tachycardia were associated with interquartile range increases in O3 exposure during the last 5 days before each participant's clinic visit,with relative risks of 2.14(95%confidence interval[CI]:1.95 to 2.32)and 5.47(95%CI:3.51 to 7.43),respectively.Mediation analyses further showed that sympathetic activation,parasympathetic inhibition,and elevated BP levels,as well as heightened risks of ST-segment depression could mediate up to 47.74%of the risks of arrhythmias attributable to O3 exposure.Conclusion Our results suggest that short-term exposure to ambient O3 could prompt the genesis of arrhythmias partially through worsening autonomic function and myocardial burden.

Enhanced Expression of miR-425 Promotes Esophageal Squamous Cell Carcinoma Tumorigenesis by Targeting SMAD2

Esophageal squamous cell carcinoma （ESCC） is one of the most common and deadly cancers in the world, Currently, clinical therapy of ESCC remains limited and the five-year survival rate is poor. The function of miR-425 has been reported in multiple human cancers. However. the tumorigenic role and clinical significance of miR-425 in ESCC remains unclear. We found that enhanced expression of miR- 425 in ESCC cell lines not only promoted cell proliferation and colony formation, but also increased cellular metastasis. Furthermore, we revealed the mechanism that miR-425 inhibited the expression of SMAD2 by targeting the second binding site in the 3＇-untranslated region （3＇-UTR） in ESCC. This mode of action influenced not only SMAD2 rnRNA expression but also protein expression. In addition, we detected the expression of miR-425 in ESCC tissues and plasma. Moreover, we analyzed the relationship between miR-425 expression and SMAD2 mRNA expression. We found that miR-425 was overexpressed in ESCC tissues and the plasma relative to adjacent normal tissues and plasma of healthy individuals. Furthermore, there was a negative correlation between miR-425 expression and SMAD2, Taken together, our results show that miR-425 functions as an oncogene by targeting the 3＇-UTR of SMAD2 and indicate the potential utility of plasma miR-425 as a novel biomarker for ESCC diagnosis.

TRAP1 Shows Clinical Significance and Promotes Cellular Migration and Invasion through STAT3/MMP2 Pathway in Human Esophageal Squamous Cell Cancer

Tumor necrosis factor receptor-associated protein 1 （TRAP1）, an important member of mitochondrial heat shock protein 90 family, is involved in multiple biological processes in several types of tumors. However, its pathological role in esophageal squamous cell cancer （ESCC） remains unknown. Herein, we demonstrated the clinical value of TRAP1, and its role in apoptosis and motility in ESCC. The clinical potential of TRAP1 was investigated through immunohistochemical analysis in 328 ESCC samples, which revealed that strong TRAP1 expression was associated with increased risk of lymph node metastasis, while high TRAP1 expression correlated with poor prognosis. Expression of TRAP1 was found to be an independent prognostic factor for patients with ESCC. Additionally, the upregulation of TRAP1 antagonized cisplatin-induced apoptosis while its downregulation sensitized cells to cisplatin-induced apoptosis. As revealed by the transwell assay, TRAP1 overexpression promoted cellular migration and invasion as compared to the control groups. In contrast, silencing of endogenous TRAP1 expression attenuated the ability of migration and invasion. Finally, the molecular mechanism investigated in the present study demonstrated that TRAP1-mediated migration and invasion occurred through STAT3/MMP2 signaling pathway. In conclusion, TRAP1 may be considered as a molecular predictive marker for prognosis and a novel molecular candidate for therapeutic target in ESCC.

Syntenic quantitative trait loci and genomic divergence for Sclerotinia resistance and ?owering time in Brassica napus

Oilseed rape(Brassica napus) is an allotetraploid with two subgenomes descended from a common ancestor. Accordingly, its genome contains syntenic regions with many duplicate genes, some of which may have retained their original functions, whereas others may have diverged. Here, we mapped quantitative trait loci(QTL) for stem rot resistance(SRR), a disease caused by the fungus Sclerotinia sclerotiorum, and flowering time(FT) in a recombinant inbred line population. The population was genotyped using B.napus 60 K single nucleotide polymorphism arrays and phenotyped in six(FT) and nine(SSR) experimental conditions or environments. In total, we detected 30 SRR QTL and 22 FT QTL and show that some of the major QTL associated with these two traits were co-localized,suggesting a genetic linkage between them. Two SRR QTL on chromosome A2 and two on chromosome C2 were shown to be syntenic, suggesting the functional conservation of these regions. We used the syntenic properties of the genomic regions to exclude genes for selection candidates responsible for QTL-associated traits. For example, 152 of the 185 genes could be excluded from a syntenic A2–C2 region. These findings will help to elucidate polyploid genomics in future studies, in addition to providing useful information for B. napus breeding programs.

A fluorescent probe operating under weak acidic conditions for the visualization of HOCl in solid tumors in vivo

Levels of reactive oxygen species(ROS)in cancer cells or in the tumor microenvironment differ noticeably from those in normal cells and cellular microenvironments because ROS play important roles in all aspects of tumor physiology.However,due to the lack of adequate tools,it is difficult to study the relationship between ROS,especially certain types of ROS(e.g.,HOCl),and cancer.We report herein an HOCl-specific fluorescent probe,FDOCl-20,containing a thiocarbamide group as a receptor,for the visualization of HOCl in solid tumors in vivo.This probe displays high selectivity and sensitivity to HOCl,and is appropriate for use in acidic conditions,including the tumor microenvironment.Using FDOCl-20 as a tool,we can visualize HOCl in solid tumors in vivo.Importantly,the fluorescent intensity of FDOCl-20 is proportional to tumor volume.Thus,FDOCl-20 is a useful tool to investigate the relationship between HOCl and the physiological processes of tumors.