The impact of CYP3A5*3 on oral quetiapine: A population pharmacokinetic model in Chinese bipolar disorder patients.

BACKGROUND: There is great interindividual difference in the plasma concentration of quetiapine, and optimizing quetiapine therapy to achieve a balance between efficacy and safety is still a challenge. In our study, a population pharmacokinetic (PPK) model considering genetic information was developed with the expectation of comprehensively explaining this observation in Chinese patients with bipolar disorder. METHODS: Patients who were dispensed quetiapine and underwent the therapeutic drug monitoring (TDM) were included. The genotypes of CYP3A5*3, CYP2D6*10, and ABCB1 C3435T/G2677T were analyzed. Finally, a multivariable linear regression model was applied to describe the PPK of quetiapine considering the covariates weight, height and genotype information. RESULTS: A total of 175 TDM points from 107 patients were adopted for PPK model development. Resultantly, the CL/F of quetiapine in CYP3A5 expressers was 81.1 CL/h, whereas it was 43.6 CL/h in CYP3A5 nonexpressers. The interindividual variability in CL/F was 47.7 %. However, neither the ABCB1 nor CYP2D6 genotype was significantly associated with the predictor of quetiapine clearance in our study. LIMITATIONS: Only trough concentrations were collected, and the span between different points was relatively wide, impeding the application of the typical nonlinear compartment model for PPK analysis. In addition, this was a single-center study which limited the sample of wild-type CYP3A5 carriers. CONCLUSIONS: The currently established PPK model of quetiapine considering the contribution of the CYP3A5 genotype could efficiently predict the population and individual pharmacokinetic parameters of Chinese bipolar disorder patients, which could better guide the personalized therapy with quetiapine, thus to achieve the best clinical response.

Fluorinated Polyimide/Allomelanin Nanocomposites for UV-Shielding Applications.

A series of highly fluorinated polyimide/allomelanin nanoparticles (FPI/AMNPs) films were prepared with FPI as the matrix and AMNPs as the filler. Due to the formation of hydrogen bonds, significantly reinforced mechanical and UV-shielding properties are acquired. Stress-strain curves demonstrated a maximum tensile strength of 150.59 MPa and a fracture elongation of 1.40% (0.7 wt.% AMNPs), respectively, 1.78 and 1.56× that of pure FPI. The measurements of the UV-vis spectrum, photodegradation of curcumin and repeated running tests confirmed the splendid UV-shielding capabilities of FPI/AMNPs films. The enhancement mechanisms, such as synergistic UV absorption of the charge transfer complexes in FPI and AMNPs and photothermal conversion, were the reasons for its exceptional UV shielding. The excellent comprehensive properties above enable FPI/AMNPs nanocomposites to be potential candidates in the field of UV shielding.

C/H/O stable isotope of rape honey and its components combined with machine learning algorithms to identify geographical origin.

RATIONALE: The distribution of rape honey is among the largest and most diverse of all honeys available to humankind with respect to the geographical origin. Accurate isotopic reference values for rape honey are therefore important for precise verification of honey origin and its traceability. New combined rape honey δ13 C, δ2 H, and δ18 O values in combination with values on its compounds (protein and saccharides) were used to complement existing databases to better identify the geographical origin of Chinese rape honey. METHODS: Traceability methods based on elemental analyzer isotope ratio mass spectrometry and liquid chromatography isotope ratio mass spectrometry were established for geographical origin of rape honey. RESULTS: Rape honey harvested in the high-altitude region (QH; Qinghai) had significantly higher values (1.4 to 5.3‰ for δ13 C, 7.9 to 12.9‰ for δ2 Hprotein ) for the δ13 C of whole honey (-23.8‰), its protein (-24.4‰), fructose (-23.5‰), glucose (-23.6‰), and disaccharide (-24.7‰), and also δ2 H of the protein (103.5‰) than those in low-altitude regions (HB; Hubei, SC; Sicuan, and JS; Jingsu). The δ18 Orape honey was a useful index to differentiate whether rape honey from coastal (JS) or non-coastal (HB, SC, and QH) regions. The δ13 C, δ2 H, and δ18 O values in rape honey are affected by geographical factors, such as temperature and altitude. The δ13 Cprotein and δ13 Crape honey values were better to identify the geographical origin of rape honey than δ13 Csaccharides . The δ18 O and δ2 H values of rape honey protein were more suitable for traceability than those of rape honey. The combination of the δ13 C, δ2 H, and δ18 O values of rape honey and its extracted protein and saccharides improved the precision of three models (linear discriminant analysis, SVM, and random forest) used to discriminate rape honey from different regions in China. The SVM model obtained the best accuracy (93.2%). CONCLUSIONS: Stable isotopes could be significant predictors in determining the geographical origin of rape honey.

Targeting mTOR Complex 2 in Castration-Resistant Prostate Cancer with Acquired Docetaxel Resistance.

Purpose: Mammalian Target of rapamycin (mTOR) plays a central role in regulating cell growth, proliferation, and cell cycle. The key component of mTORC2 is highly expressed in docetaxel-resistant prostate cells. However, the underlying molecular effects on prostate cells remain unclear. Methods: A docetaxel-resistant human prostate cell line (PC-3/DTX) was constructed to investigate the role of mTORC2 in docetaxel resistance. The lentivirus was transfected into cells to knock down the expression of Rictor, and cell viability was measured by Cell Counting Kit 8 (CCK-8). Flow cytometry was used to analyze the cell cycle, and the changes in related signal cascades were assessed by immunohistochemistry (IHC) staining and Western blot. Results: Docetaxel showed the lowest IC50 (50% inhibitory concentration) in PC-3/DTX cells with sh-RNA. Decreased Rictor expression resulted in a larger proportion of arrested cells in the G0/G1 phase in PC-3/DTX cells. The IC50 values of the AZD8055 group were lower than in the Rapamycin group when treated with docetaxel again. Furthermore, a larger proportion of PC-3/DTX cells were arrested in the G0/G1 phase in the AZD8055 group compared to the Rapamycin group. The IHC results of the prostate cancer tissues from a CRPC patient revealed the over expression of Rictor only, while Raptor expression was unaffected. Conclusion: We investigated the role of mTORC2 signaling on the acquired docetaxel -resistant PC-3 cells to identify potential methods for clinical treatment. MTORC2 expression is essential for docetaxel drug resistance of PC-3 cells. The mTORC1/2 inhibitor AZD8055 caused more significant disruption of mTORC2 kinase activity than the mTORC1 inhibitor Rapamycin, which lead to decreased docetaxel-mediated resistance. Therefore, reversing docetaxel resistance, may become a therapeutic option in the treatment of mCRPC patients.

Study on stable carbon isotope fractionation of rape honey from rape flowers (Brassica napus L.) to its unifloral ripe honey.

A new idea and strategy for honey traceability and identification was provided by studying the carbon isotope fractionation of rape honey and its components in the different ripening process, as well as the fractionation from rape flowers, stamens, nectar to rape honey. The results showed the moisture content of rape honey continued to decrease, and the glucose and fructose content continued to increase during the ripening process. The δ13C of rape honey and its protein were less affected by honey ripeness, while the δ13C of sugars in rape honey were greatly affected by this. At the same time, the fractionation of carbon isotope from rape flowers to honey was significant. The δ13C of rape honey and its protein, disaccharide, fructose, and glucose had a strong correlation, and the δ13C of rape honey and its components were mainly related to rape flowers and its stamens.

AtDPG1 is involved in the salt stress response of Arabidopsis seedling through ABI4.

Although the genes controlling chloroplast development play important roles in plant responses to environmental stresses, the molecular mechanisms remain largely unclear. In this study, an Arabidopsis mutant dpg1 (delayed pale-greening1) with a chloroplast development defect was studied. By using quantitative RT-PCR and histochemical GUS assays, we demonstrated that AtDPG1 was mainly expressed in the green tissues of Arabidopsis seedlings and could be induced by salt stress. Phenotypic analysis showed that mutation in AtDPG1 lead to an enhanced sensitivity to salt stress in Arabidopsis seedlings. Further studies demonstrated that disruption of the AtDPG1 in Arabidopsis increases its sensitivity to salt stress in an ABA-dependent manner. Moreover, expression levels of various stress-responsive and ABA signal-related genes were remarkably altered in the dpg1 plants under NaCl treatment. Notably, the transcript levels of ABI4 in dpg1 mutant increased more significantly than that in wild type plants under salt conditions. The seedlings of dpg1/abi4 double mutant exhibited stronger resistance to salt stress after salt treatment compared with the dpg1 single mutant, suggesting that the salt-hypersensitive phenotype of dpg1 seedlings could be rescued via loss of ABI4 function. These results reveal that AtDPG1 is involved in the salt stress response of Arabidopsis seedling through ABI4.

Antilung cancer effect of ergosterol and cisplatin-loaded liposomes modified with cyclic arginine-glycine-aspartic acid and octa-arginine peptides.

BACKGROUND: Lung cancer is one of the most important diseases threatening human health, and targeted therapy has become the main research direction. This work, therefore, aimed to develop cyclic arginine-glycine-aspartic (RGD) and octa-arginine (R8) peptide-modified ergosterol (ERG)-combined cisplatin (diamminedichloridoplatinum(II) [DDP]) liposomes (LIP) as a drug delivery system. METHODS: Soybean phospholipids (SPC) and cholesterol (Chol) were selected to prepare different LIPs: ERG-loaded LIP (ERG-LIP), DDP and ERG-LIP (DDP/ERG-LIP), R8 peptide-modified DDP and ERG-LIP (R8-DDP/ERG-LIP), and cyclic RGD and R8-DDP/ERG-LIP (RGD/R8-DDP/ERG-LIP). The quality, tumor sphere penetrating ability, in vitro cellular uptake, mechanism of cellular uptake, and in vitro cytotoxicity of RGD/R8-DDP/ERG-LIP were evaluated. RESULTS: The LIP quality evaluation revealed that RGD/R8-DDP/ERG-LIP is round with a double-layer structure. The average particle size, dispersion coefficient of the polydispersity index (PDI), and zeta potential of RGD/R8-DDP/ERG-LIP were 155.2 ±â€Š8.7 nm, 0.102, and 4.74 ±â€Š0.7 mV, respectively. Furthermore, the LIPs were stable in the serum, and obviously inhibited the growth of A549 lung cancer cells with RGD/R8-DDP/ERG-LIP exhibiting the strongest inhibitory effect. The highest cellular uptake rate, which was at 4 hours, was exhibited by RGD/R8-DDP/ERG-LIP in a concentration-dependent manner. CONCLUSION: The results showed that LIP uptake by A549 cells was mainly by the clathrin-mediated endocytosis pathway (chlorpromazine). The results also suggest that RGD/R8-DDP/ERG-LIP might be a promising drug delivery system to improve antilung cancer drug effect and tumor-targeting in vitro.

Magnetic nanoparticles in cancer diagnosis, drug delivery and treatment.

In recent years, magnetic nanoparticles (MNPs) have demonstrated marked progress in the field of oncology. General nanoparticles are widely used in tumor targeting, and the intrinsic magnetic property of MNPs makes them the most promising nanomaterial to be used as contrast agents for magnetic resonance imaging (MRI) and induced magnetic hyperthermia. The properties of MNPs are fully exploited when they are used as drug delivery agents, wherein drugs may be targeted to the desired specific location in vivo by application of an external magnetic field. Early diagnosis of cancer may be achieved by MRI, therefore, individualized treatment may be combined with MRI, so as to achieve the precise definition and appropriate treatment. In the present review, research on MNPs in cancer diagnosis, drug delivery and treatment has been summarized. Furthermore, the future perspectives and challenges of MNPs in the field of oncology are also discussed.