Using ultra high performance liquid chromatography (UHPLC) coupled with mass spectrum (MS) technology, a method has been established for separation and analysis of alkaloid isomers. Alkaloids in Ephedra sinica transitionally crossed blood brain barrier (BBB) and the distribution were investigated. The concentrations of Ephedra alkaloids in rat central nervous system (CNS) were determined to acquire the distribution characteristics and differences in cerebral cortex, cerebellum, hippocampus, striatum, medulla oblongata and hypothalamus. It was founded that pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine (methylpseudoephedrine) were able to cross BBB fast via gastro-intestinal tract after administrated with Ephedra sinica. Cortex and hippocampus was the main distribution region, followed by hypothalamus, striatum and cerebellum, in which medulla oblongata had the least. The distribution of various alkaloids, as AUC_{0-t, brain}/AUC_{0-t, blood} was ephedrine > methylephedrine > demethyl ephedrine. Alkaloids in Ephedra sinica crossed BBB rapidly, showing the regional distribution tendency in central nervous system, and the distribution was diversity. This group of data provides distribution of bioactive constituents of Ephedra in CNS.

The anaphase promoting complex (APC) regulates cell cycle progression by forming two functionally distinct E3 ubiquitin ligase complexes, APC^Cdc20 activated by cell division cycle protein 20 (Cdc20) and APC^Cdh1 activated by Cdc20 homologue 1 (Cdh1), respectively. Cdc20 and Cdh1 have different functions in the occurrence and development of the tumor. Cdc20 is a cancer promoter while Cdh1 suppresses tumorigenesis. Emerging evidence has begun to reveal that Cdc20 has positive functions in tumorigenesis, the overexpression of Cdc20 has been observed in many cancers. Currently, Cdc20 inhibitors, mostly non-specific inhibitors except apcin, not only block the combination between Cdc20 and APC, also block the combination between Cdh1 and APC, which leads to a poor selectivity. In this paper, the Cdc20 role in the development and process of cancers and its inhibitors are reviewed.

This work was designed to study a novel dry powder inhalation (DPI) carrier for drug loading and release of tiotropium bromide (asthma medicine). The synthesized lactose drug-carrier with a flower shape was crystalline. The carrier with a micro-meso-macroporous structure had advantages of high pore surface area, high capacity of drug loading and fast release of drug. In the study of loading tiotropium bromide, the drug was distributed at the core of carrier using the solution-based method, while the morphology was changed a little and the amount of loaded drug was 5% (w/w). Using the crystallization-based method, the drug was distributed at the shell of carrier, while the morphology was changed a lot and the amount of loaded drug was 49% (w/w). In addition, with the impact of carrier structure, the drug release rate was increased first and then decreased thereafter using the solution-based method, while the drug release rate was decreased first and then increased thereafter using the crystallization-based method. Thus, the lactose microparticles can be used as a novel drug carrier for dry powder inhalation.

To a certain extent, the drug effect is determined by its blood concentration. It is generally accepted that the blood concentrations of constituents of Chinese medicines are very low. There is no sufficient experimental bases and references on its degree and the possibility of taking effect. In this study, 69 papers were collected and analyzed by searching the database of Scifinder, Pubmed, CNKI. The minimum effective blood concentrations of 73 common Western medicines and the maximum blood concentrations of 211 in vivo constituents of 40 Chinese medicines (single herb or compound Chinese medicine) were summarized. It was found that the maximum blood concentrations of the most in vivo constituents of Chinese medicines were much less than the minimum effective blood concentrations of the Western medicines. Specifically, the minimum effective blood concentrations of 17 Western medicines (23% of total) and the maximum blood concentrations of the 143 in vivo constituents of Chinese medicines (68% of total) were less than 100 ng ·mL^-1; the minimum effective blood concentrations of 31 Western medicines (42% of total) and the maximum blood concentrations of the 20 in vivo constituents of Chinese medicines (9% of total) were more than 1 000 ng·mL^-1. In this paper, a systematic summary and comparison of the blood concentrations in traditional Chinese medicines and Western medicines were conducted, which could provide a new ideas and references for the study of the pharmacodynamical material basis and its mechanism in traditional Chinese medicine.

This study was designed to investigate the synergistic analgesic effect between choline (Cho) and acetaminophen (Ace). Mice were treated with 0.6% acetic acid solution by intraperitoneal injection to build acetate writhing model. The KM mice were randomly divided into four groups:control group (n=10), Cho group (n=50), Ace group (n=50), combination group (Cho+Ace group, n=40), then the writhing times were counted respectively. OriginPro8.5 was used to calculate ED 50. The isobolographic analysis was used to test the interaction of Cho and Ace. To explore the mechanism, forty KM mice were randomly divided into control group, Cho group, Ace group and Cho + Ace group. Blood was collected for detection of TNF-α, IL-6, PGE₂ and NF-κB content using ELISA kits. The result ED 50 was calculated as followings. ED⁵⁰ of Cho and Ace was 19.47 mg·kg^-1 and 20.56 mg·kg^-1. The concentrations were 2.94 mg·kg^-1 for Cho and 3.15 mg·kg^-1 for Ace in the combination test. The levels of TNF-α, IL-6, PGE₂ and NF-κB in Cho group and Ace group were lower than those in the control group (P < 0.05). Compared to the Cho group and Ace group, the levels of TNF-α, IL-6, PGE₂, NF-κB in Cho + Ace group were reduced further (P < 0.05). The results revealed that Cho and Ace have synergistic analgesic effects, which may associate with inhibition of the NF-κB signaling pathway.

Bromodomain and extraterminal (BET) proteins are a class of proteins that can interpret epigenetic codes and play an important role in regulating gene transcription through identifying and binding acetylated histones or non-histones proteins. The BET inhibitors have emerged with good therapeutic effects in preclinical disease models such as cancer and inflammation. Some of them have entered clinical studies, demonstrating that there is considerable prospect for drug development with BET as a potential therapeutic target. This review briefly describes the structures and functions of the BET proteins, the BET inhibitors in various diseases, as well as molecular mechanisms involved.

The glucose consumption activity of 9-substitued analogues of berberine was evaluated in L6 myotubes. It was found that the introduction of an ethoxy group on the 9-position of berberine was beneficial for the activity. 9-Ethoxy berberine analogue 2a exhibited superior activity to berberine in multiple dose levels, and the activity of 2a was 5.4 times as high as that of berberine at the dose of 1.25 μmol·L^-1. At the meantime, the potency on AMPK activation of 2a was 2.8 times of that of berberine at the dose of 10 μmol·L^-1. Therefore, the compound 2a is a promising scaffold for further modification.

The impact of statins on airway inflammation has not yet been established and it may differ from their cholesterol-lowering effects. Oral administration of statins at large-doses may have adverse effects. It is possible to overcome the side effect to increase the clinical efficacy through the inhalation route. Female BALB/c mice were randomly divided into four groups including the control group (NS-vehicle), model group[ovalbumim (OVA)-vehicle], simvastatin (Sim) group and dexamethasone (DXM) group at 10 mice in each group. In this study, we hypothesize Sim as a potential anti-inflammatory drug with biological and pharmacokinetic properties suitable for delivery through the inhalation route. Mice were immunized with OVA and then challenged with OVA aerosol to induce the asthma reaction. Sim was inhaled at a dosage (5 mg ·mL^-1, ih, 15 min) or administrated by intraperitoneal injection (40 mg·kg^-1, ip) or gavage (40 mg·kg^-1, ig) during the OVA-challenge. In the mouse model of asthma, Sim significantly attenuated the total inflammatory cell counts and eosinophil counts (P < 0.01 or P < 0.05) via the different routes. Pretreatment with Sim at 1, 5, 20 mg·mL^-1, ih, significantly decreased the total inflammatory cell counts and eosinophil counts in alveolar lavage fluid (BALF) (P < 0.01) and the inhibitory effect was increased with the dosages of Sim via inhalation. Both of DXM and Sim at 5, 20 mg·mL^-1, ih, were more potent than that of Sim at 1 mg·mL^-1, ih. Sim significantly decreased IL-4 and IL-5 mRNA expression of lung at 5, 20 mg·mL^-1, ih (P < 0.01 or P < 0.05). Sim (5, 20 mg·mL^-1, ih) significantly decreased levels of IL-4 and IL-5 in BALF (P < 0.01 or P < 0.05). However, Sim (1 mg·mL^-1) declined slightly on IL-4 level in BALF. Sim at 5, 20 mg·mL^-1 had a greater rate of decline in IL-5 than at 1 mg·mL^-1. These results suggest Sim with different doses as a potential anti-inflammatory drug for airway inflammatory diseases with properties suitable for delivery by inhalation, which probably overcome the side effects and low clinical efficacy of oral Sim.

Increasing evidence suggests that hepatocellular carcinomas (HCCs) are sustained by a distinct subpopulation of self-renewing cells known as cancer stem cells (CSC). However, our understanding of their regulation is limited. Rapid reversible changes of CSC-like cells within tumors may result from the effect of biological mediators found in the tumor microenvironment. This paper aims to explore how nitrite, a key cellular modulator whose level is elevated in many tumors, affects CSC-like phenotypes of human hepatoma cells SMMC-7721 cells. The SMMC-7721 cell line was cultured under serum-free conditions to produce floating spheres. The distribution of cell cycle was analyzed by flow cytometry, the capability of cells self-renew was detected by colony-forming capabilities and spheroid-formation assay, the expression of stemness protein such as CD133, CD90 and EpCAM were determined by flow cytometry and Western blot, cell invasion was analyzed by transwell assay, and viability of SMMC-7721 parental cells and spheroids cancer cells was determined by the 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Xenograft tumor models were established by subcutaneously injecting SMMC-7721 spheroids cancer cells, the transplanted tumor tissue ROS levels was detected by reactive oxygen species (ROS) test kits, the expression of HIF-1α was observed by immunofluorescence. Our results showed that the SMMC-7721 spheroid cells were enriched with CSCs properties, indicated by the ability to self-renew, increased expression of CSCs markers, and increased resistance to chemotherapeutic drugs. Additionally, SMMC-7721 parental cells and spheroids cancer cells were treated with 150 μmol·L^-1 sodium nitrite for 6 days, compared with control cells, an increased accumulation of G₀/G₁ phase cells was observable in treatment cells. Indeed, our data demonstrated that in parent cells and spheres cells that were treated with sodium nitrite for different time, the cells' ability to chemoresistance and invasion, clone-forming efficiencies and the spheres forming ability were significantly higher than that of control cells. Exposure of sodium nitrite regulated CSC-like phenotype, indicated by increased expression of known CSC markers, CD133, CD90 and EpCAM in the exposed parental cells, as well as in dormant spheroids cancer cells. Compared with the parent cells, the above effects of nitrite on the spheres cells were significantly enhanced. In vivo data also presented a more significant promotion of tumor xenograft growth from the nitrite treatment than from either of the control. Mechanistic analysis indicated that nitrite induced the upregulation of HIF-1α as well as the downregulation of ROS in the tumor microenvironment. These results suggest that nitrite increases the invasiveness of SMMC-7721 cells through up-regulation of tumor stemness.

The study is aimed to test the effect of Huangqin Tang (HQT) on serum metabolic profile in rats with ulcerative colitis, and explore its possible action mechanism for ulcerative colitis (UC) rats. The model of UC rats with cell immunoreactivity was made using a compound method (trinitrobenzene sulfonic acid plus ethanol). Rats were randomly divided into the control group, the model group, and HQT group. Ultra performance liquid chromatography tandem mass spectrometry (UHPLC-MS), principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were employed to analyze the metabolic profile among normal group, the model group, HQT group. Potential biomarkers were screened in the serum based on the variable importance projection (VIP) value > 1, P < 0.05. As compared with the normal group, 16 potential biomarkers such as valine, tryptophan, lactic acid and urea were found and identified in the serum of model group rats. As compared with the model group, a part of the biomarkers were restored nearly to a normal state after HQT administration for 10 days. Metabolomic analysis revealed that the HQT has a certain therapeutic effect in UC rats, and the mechanism may be related to regulation of lipid metabolism, amino acid metabolism and energy metabolism.