This study is designed to investigate the effect of triptolide on the function and expression of P-glycoprotein (P-gp) in HNE1 nasopharyngeal cancer cells. MTT assay was used to test cell viability. Intracellular doxorubicin content was evaluated with flow cytometry. Rhodamine 123 (Rh) was used to detect the excretion function of P-gp. The expression of P-gp was analyzed by Western blot. ATP levels were evaluated. JC-1 staining was used to determining mitochondrial membrane potential (MMP). Triptolide, doxorubicin and the combination treatment all had the inhibitory effect to HNE1 cells, and the combination treatment had the best effect. Triptolide increased intracellular concentration of doxorubicin and Rh (P < 0.05 or P < 0.01), inhibited the excretion function of P-gp. The expression of P-gp was reduced greatly in the middle and high dose group of triptolide. The ATP levels were decreased significantly (P < 0.05). JC-1 staining showed that triptolide mediated the down-regulation of MMP in HNE1 cells. Triptolide could increase intracellular drug content and enhance cytotoxicity of chemotherapeutics by inhibition of the expression and the excretion function of P-gp.

This study was designed to investigate the effects of icariin on bone metabolism in osteoprotic mice induced by iron overload, the model of iron overload mice was established by intraperitoneal injection of iron dextran (100 mg·kg^-1). Sixty 2-month-old C57/BL6 male mice were randomly divided into six groups, including normal control group, model group, N-acetyl-L-cysteine (NAC)-treated group, icariin (50, 100 and 200 mg·kg^-1)-treated group. Except for the mice in control group, the mice were intraperitoneal injected weekly with iron dextran (100 mg·kg^-1) to establish the model of iron overload mice. The NAC and icariin were suspended in 0.5% CMC-Na solution, and administered orally for six times one week according to body weight. The mice in normal group and model group were given the same volume of 0.5% CMC-Na solution. Three months later, the organs, serum and femurs of mice were collected. Serum biochemical parameters were detected with an ELISA kit, the distal femur bone density and trabecular bone microstructure were analyzed by Micro-CT, and the mechanical properties of femur were measured by universal mechanical analyzer. Compared with the normal control group, iron overload decreased the bone mineral density and deteriorated the micro-architecture structure and bone mechanical properties in femur of mice, increased the level of iron, phosphorus and activity of tartrate resistant acid phosphatase-5b (TRACP-5b), reduced the level of osteocalcin (OCN) in serum, decreased the activity of superoxide dismutase (SOD) of liver tissues, increased the content of malondialdehyde (MDA) of liver tissues. Icariin increased bone mineral density, improved the micro-architecture and mechanical properties of bone tissue, reduced the levels of iron and phosphorus, decreased the activity of TRACP-5b and enhanced the levels of OCN in serum, and also decreased the activity of MDA in liver tissue of iron overload mice. These results suggest that icariin is able to reduce bone loss and improve bone microstructure and mechanical properties in iron overload mice through regulation of bone metabolism via anti-oxidation.

UHPLC-QTOF-MS was applied to non-targeted metabolomics study of mice infected with K. pneumoniae ATCC^® BAA 2146 to discover potential biomarkers and metabolic pathways that are associated with sepsis. Fifty-eight metabolites were identified by principal components analysis (PCA) and partial least-squares discriminant analysis (OPLS-DA), which was combined with variable projection importance (VIP) and nonparametric test. Eighteen of the 58 metabolites were further found to be involved in 8 metabolic pathways, including nicotinate and nicotinamide metabolism, pyrimidine metabolism, vitamin B6 metabolism, taurine and hypotaurine metabolism, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism and glycerophospholipid metabolism.

The orexin system was discovered in 1998 with two G-protein coupled receptors (GPCRs):orexin-1 (OX₁R) and orexin-2 (OX₂R) receptors that bind the neuropeptides orexin-A (OX-A) and orexin-B (OX-B).The causal link between the orexin system and obesity, anxiety, and sleep/wake disorders as a potential therapeutic target has drawn much attention in the field of pharmaceuticals.The developments of dual antagonism of the receptors by small molecules are clinically efficacious in the treatment of insomnia, where the most advanced molecule suvorexant has been approved by FDA in August, 2014.The small molecule orexin receptor antagonists (ORA) between January 2010 and August 2017 are summarized in this review and we focus on their chemical structures, mechanism and human clinical trials.

In this study, the thermoresponsive micelles were synthesized with random copolymerization method and the photosensitizer indocyanine green (ICG) was loaded on micelles through the physical adsorption. The light energy was converted into heat energy to increase the temperature after irradiation with near-infrared light. When the phase transition temperature was reached, the micelle was disassembled and the targeted therapy was achieved. The nanoparticles were characterized with a transmission electron microscopy, Fourier transform infrared spectrometer, nuclear magnetic resonance spectrometer and other characterization were used to investigate. The critical micelle concentration (CMC), upper critical solution temperature, the photothermal properties of the carrier and the release of drug triggered by light were investigated after the doxorubicin (DOX) loaded. The carrier was evaluated for toxicity, cellular uptake, the effect of photothermal, the combination of photothermal and chemotherapy; the p(AAm-co-AN)-g-PEG (PAAP) was spherical in shape with a particle size of about 45 nm and a phase transition temperature was about 43℃. The critical micelle concentration was 24 μg·mL^-1. The particle size increased to 88 nm after loaded with ICG and DOX which the photothermal effect was obvious. The cumulative release of the drug under the irradiation of near-infrared light (808 nm, 2 W·cm^-2, 2 min·h^-1) was increased to 59.4% (pH 5.0) after 5 h. The results of the cell experiment indicated that ICG-PAAP was almost non-toxic and uptaken by the lysosomal pathway. The cell killing effect was stronger with combination of chemotherapy (DOX as 20 μg·mL^-1) with more than 70% of the cells killed. The results showed that the prepared micelle with low toxicity was thermoresponsive and could be used in combined therapy of tumor under the irradiation of near-infrared light.

Uncaria rhynchophylla is one of the frequently used herbs in China, it is mainly used for heat-clearance, suppression of hyperactive liver, calming endogenous wind and arresting convulsion in traditional Chinese medicine (TCM). Alkaloids are the main active materials in Uncaria rhynchophylla, pharmacological studies have shown that Uncaria rhynchophylla and its alkaloids have comprehensive biological effects on the nervous system. Rhynchophylline is one of the most abundant alkaloids in Uncaria rhynchophylla. The recent studies demonstrate that rhynchophylline and its isomers (isorhynchophylline, corynoxine, corynoxine B) may be good drug candidates for treatment of Alzheimer's disease, Parkinson's disease, epilepsy, etc. Although the structures of the 4 alkaloids are very similar, they have different effects on nervous system. For example, corynoxine and corynoxine B exhibit better sedative effects than isorhynchophylline. Rhynchophylline and isorhynchophylline have been extensively studied. For development and utilization of rhynchophylline for nervous system disease, more studies are needed to unveil the structure-function relationship and the underlying mechanisms. Here, we summarizes the progresses the effects of rhynchophylline and its isomers on the nervous system.

Pancreatic cancer is a highly-malignant digestive system neoplasm. The anticancer efficacies of the chemotherapeutic drugs for pancreatic cancer treatment, such as gemcitabine, are greatly limited by their poor targetability to tumor and low drug concentration in the tumor tissue. Drug delivery system plays an important role in improvement of therapeutic efficacy and reduction of adverse effects. Enhancement of the tumor targeting capacity of nanomedicine and promotion of the delivery efficiency are the key issues in the research field of pharmaceutics. In this review article, we survey recent progress in targeted drug delivery nanosystems for treatment of pancreatic cancer by targeting cancer cells, pancreatic tumor stroma, pancreatic cancer-associated cells, and pancreatic cancer stem-like cells, which will provide a new insight into clinical treatment of pancreatic cancer.

Nonribosomal peptide synthetases (NRPS) catalyze the synthesis of nonribosomal peptide (NRP) compounds with structural and functional diversities, including more than 20 marketed drugs. This review focuses on the recent advances in the functional domains of NRPS and their mechanisms of action, as well as the unconventional assembly patterns such as iterative NRPS, module skipping, in trans aminoacylation and tandem adenylation domains. This review provides the theoretical basis for exploring new nonribosomal peptide compounds and the development of new drugs.

The abnormal activation of hedgehog (HH) signaling pathway plays an important role in the development and progression of glioblastoma (GBM). As a transcription factor at the end of the HH pathway, the final effector of glioma-associated oncogene homoglog-1 (GLI1) is an important target in the treatment of GBM. The study was designed to evaluate the anti-tumor activities and mechanisms of a novel GLI1 inhibitor FL18 in GBM. MTT and colony formation assay were performed to determine anti-proliferation activity of FL18 in vitro. The effect of FL18 on cell apoptosis was measured by flow cytometry (FCM) analysis. Transwell experiment was used to explore the inhibitory activity of FL18 in cell invasion. In vivo experiments, the subcutaneously transplanted and orthotopic U-87 MG GBM xenograft model were used to study the activity of FL18 on tumor growth. The optimized dual report gene screening model was used to detect the effect of FL18 on the transcriptional activity of GLI1. Western blot assay was used to study the mechanisms of action of FL18. The results showed that the IC₅₀ of FL18 in glioblastoma was in the nanomole level in vitro. It was observed that 22.5 and 45 mg·kg^-1 FL18 reduced the tumor volume with the rate of 55.4% and 89.8% in xenograft model in mice in situ. The IC₅₀ of FL18 on the inhibition of GLI1 transcriptional activity was 3.32×10^-11 mol·L^-1 analyzed by the optimized dual report gene screening model. By the Western blot experiments, it was proved that FL18 inhibited expression of GLI1 without influencing the upstream canonical HH/SMO signaling and cross-talk oncogenic pathway, such as ERK and AKT signaling. The results also demonstrated that FL18 significantly downregulated GLI1 target genes such as Bcl-2, MMP2 and MMP9 and increased the expression of c-caspase3, c-PARP and Bax. These data suggest that FL18 may generate the anti-glioma activity by inhibition of GLI1.

Tadalafil (TD), a phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, has a low oral bioavailability due to its extremely poorly aqueous solubility. The aim of this study was to enhance its solubility and dissolution by coamorphization with dapoxetine (DP), a selective serotonin reuptake inhibitor to manage premature ejaculation. Coamorphous TD-DP (molar ratio, 1:1) was prepared by solvent-evaporation method and characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). The supersaturated dissolution of TD from coamorphous TD-DP was investigated in various aqueous media and compared to that of crystalline TD. In addition, physical stability of coamorphous system was also evaluated under the conditions of 40℃/75% relative humidity (RH) and 25℃/60% RH for 90 days. DSC thermogram and PXRD pattern indicated the formation of the coamorphous TD-DP. In comparison to original TD crystal, the dissolution of TD from coamorphous system were significantly enhanced in various media (water, 0.01 mol·L^-1 HCl and pH 4.5 phosphate buffer). In addition, no crystallization phenomenon of the prepared coamorphous system was observed until 90 days' storage under 25℃/60% RH. However, when temperature and humidity were increased to 40℃/75% RH, the coamorphous TD-DP was recrystallized easily.