Cisplatin-based miRNA delivery strategy inspired by the circCPNE1/miR-330-3p pathway for oral squamous cell carcinoma.

Circular RNAs (circRNAs) are ideal biomarkers of oral squamous cell carcinoma (OSCC) because of their highly stable closed-loop structure, and they can act as microRNA (miRNA) sponges to regulate OSCC progression. By analyzing clinical samples, we identified circCPNE1, a dysregulated circRNA in OSCC, and its expression level was negatively correlated with the clinical stage of OSCC patients. Gain-of-function assays revealed the tumor-suppressive effect of circCPNE1, which was then identified as a miR-330-3p sponge. MiR-330-3p was recognized as a tumor promoter in multiple studies, consistent with our finding that it could promote the proliferation, migration, and invasion of OSCC cells. These results indicated that selective inhibition of miR-330-3p could be an effective strategy to inhibit OSCC progression. Therefore, we designed cationic polylysine-cisplatin prodrugs to deliver antagomiR-330-3p (a miRNA inhibitory analog) via electrostatic interactions to form PP@miR nanoparticles (NPs). Paratumoral administration results revealed that PP@miR NPs effectively inhibited subcutaneous tumor progression and achieved partial tumor elimination (2/5), which confirmed the critical role of miR-330-3p in OSCC development. These findings provide a new perspective for the development of OSCC treatments.

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE-/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

Rapid identification of cytochrome P450 inductive constituents of Shenmai injection by combined pregnane X receptor reporter gene assay and LC-TOF-MS analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Identifying the inductive constituents of cytochrome P450 (CYP) enzymes is important in characterizing the safety of ethnopharmacological herbal preparations. AIM OF THE STUDY: This study provides a rapid and accurate method for screening CYP inducers in Shenmai injection (SMI), a traditional Chinese medicine. MATERIALS AND METHODS: We combined a pregnane X receptor (PXR) reporter gene assay and liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) analysis to screen ethanol and aqueous extracts of SMI for CYP-inducing constituents. RESULTS: The ethanol extract exhibited stronger PXR activity than the aqueous extract. Of the 29 chemical compounds identified, 7 compounds with high relative concentrations in the ethanol extract were further evaluated for PXR activity. The highest activity was exhibited by methyl ophiopogonanone B and ginsenoside F2, indicating that they are CYP inducers. CONCLUSIONS: The identification method applied in this study was rapid and accurate and is suitable for screening CYP inducers in herbal preparations.

The status of proton pump inhibitor use: a prescription survey of 45 hospitals in China.

BACKGROUND: proton pump inhibitors (PPI) have been widely used in the clinic but inappropriate prescribing has also increased dramatically. OBJECTIVE: to describe the prescribing patterns and assess the appropriateness of the prescribed PPI use in 45 hospitals in China. MATERIALS AND METHODS: PPI prescriptions for non-hospitalized patients were collected from hospitals in Beijing, Chengdu, Guangzhou and Hangzhou of China over a 40-day period in 2016. These data were analyzed using the prescription number, proportion and economic indicators (defined daily dose system [DDD], defined daily cost [DDC] and drug utilization index [DUI]). The evaluation criteria of PPI use was based on Martindale: The Complete Drug Reference, New Materia Medica and drug instructions. RESULTS: in total, 357,687 prescriptions using oral PPI and 38,216 prescriptions using injectable PPI were assessed. The average age of PPI users was 53 years. The most commonly used oral PPI was rabeprazole, while the most common injectable PPI was pantoprazole. The DDD of oral rabeprazole and DDC of injectable rabeprazole were the highest. Meanwhile, only the DUI values of oral rabeprazole, lansoprazole and ilaprazole were less than 1.0. The clinical diagnosis of some users included well identified risky comorbidities such as kidney disease (2.9%). Furthermore, between 32.6% and 56.8% of the PPI prescriptions were used for inappropriate indications. CONCLUSION: this survey demonstrated that PPI use was accompanied by unapproved indications and excessive dosages. Comprehensive measures are urgently needed to improve PPI use and reduce unnecessary drug costs.

SNCA, a novel biomarker for Group 4 medulloblastomas, can inhibit tumor invasion and induce apoptosis.

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. It contains at least four distinct molecular subgroups. The aim of this study is to explore novel diagnostic and potential therapeutic markers within each subgroup of MB, in particular within Group 4, the largest subgroup, to facilitate diagnosis together with gene therapy. One hundred and six MB samples were examined. Tumor subtype was evaluated with the NanoString assay. Several novel tumor related genes were shown to have high subgroup sensitivity and specificity, including PDGFRA, FGFR1, and ALK in the WNT group, CCND1 in the SHH group, and α-synuclein (SNCA) in Group 4. Knockdown and overexpression assays of SNCA revealed the ability of this gene to inhibit tumor invasion and induce apoptosis. Methylation-specific PCR and pyrosequencing analysis showed that epigenetic mechanisms, rather than DNA hypermethylation, might play the key role in the regulation of SNCA expression in MB tumors. In conclusion, we identify SNCA as a novel diagnostic biomarker for Group 4 MB. Some other subgroup signature genes have also been found as candidate therapeutic targets for this tumor.

Detection of diluted contaminants on chicken carcasses using a two-dimensional scatter plot based on a two-dimensional hyperspectral correlation spectrum.

A two-dimensional (2D) scatter plot method based on the 2D hyperspectral correlation spectrum is proposed to detect diluted blood, bile, and feces from the cecum and duodenum on chicken carcasses. First, from the collected hyperspectral data, a set of uncontaminated regions of interest (ROIs) and four sets of contaminated ROIs were selected, whose average spectra were treated as the original spectrum and influenced spectra, respectively. Then, the difference spectra were obtained and used to conduct correlation analysis, from which the 2D hyperspectral correlation spectrum was constructed using the analogy method of 2D IR correlation spectroscopy. Two maximum auto-peaks and a pair of cross peaks appeared at 656 and 474 nm. Therefore, 656 and 474 nm were selected as the characteristic bands because they were most sensitive to the spectral change induced by the contaminants. The 2D scatter plots of the contaminants, clean skin, and background in the 474- and 656-nm space were used to distinguish the contaminants from the clean skin and background. The threshold values of the 474- and 656-nm bands were determined by receiver operating characteristic (ROC) analysis. According to the ROC results, a pixel whose relative reflectance at 656 nm was greater than 0.5 and relative reflectance at 474 nm was lower than 0.3 was judged as a contaminated pixel. A region with more than 50 pixels identified was marked in the detection graph. This detection method achieved a recognition rate of up to 95.03% at the region level and 31.84% at the pixel level. The false-positive rate was only 0.82% at the pixel level. The results of this study confirm that the 2D scatter plot method based on the 2D hyperspectral correlation spectrum is an effective method for detecting diluted contaminants on chicken carcasses.

Low-frequency sonophoresis enhances rivastigmine permeation in vitro and in vivo.

We investigated the enhancement effect of low-frequency sonophoresis on transdermal permeation of rivastigmine in vitro and in vivo. The in vitro permeation study showed that sonophoresis increased steady-state transdermal flux 0.31 ± 0.03 µg x cm(-2) x h(-1) and the extent of rivastigmine permeation 6.00 ± 0.56 µg x cm(-2) though excised skin (both P < 0.01). In the in vivo experiment, the C(max) 0.83 ± 0.16 µg x mL(-1) and AUC(0 --> 24 h) 12.35 ± 1.99 µg x h x mL(-1) of the sonophoresis group was also significantly higher than that of the control group (both P < 0.01). These data suggest that low-frequency sonophoresis could be an effective method to enhance rivastigmine permeation.

[Development and in vitro evaluation of estradiol transdermal film-forming spray].

To develop estradiol transdermal film-forming spray (TFS), various polymers were screened using solvent appearance, spray ability, film-forming rate and appearance as indices. The influence of polymer type, plasticizer and penetration enhancer on the transdermal flux were investigated by selecting porcine skin as model, and transdermal flux of TFS was compared with commercial patch and gel. The drug existing state in the formed film was investigated by differential scanning calorimetry (DSC). The solvent appearances, spray abilities, film-forming rates and appearances of eudragit E PO, RL PO, hydroxypropyl cellulose EF, polyvinylpyrrolidone K30, Plasdone S630 and Agrimer VA64 were suitable for the preparation of TFS. TFS prepared by Eudragit RL PO had the biggest transdermal flux of estradiol among all the polymers investigated. Triethyl citrate, the plasticizer, decreased the transdermal flux. Azone increased the transdermal flux, while oleic acid, isopropyl myristate and menthol had opposite effects. TFS had a higher transdermal rate and a higher accumulative penetrated estradiol of 24 h than commercial patch and gel. The DSC result showed that estradiol was spread as molecule in the formed film of TFS. It was indicated that TFS could be expected to be an effective transdermal drug delivery system.