Mycobacterial membrane protein large 3 (MmpL3) belongs to the resistance, nodulation and division (RND) superfamily whose role in mycobacteria is transporting trehalosemonomycolate (TMM). The inhibition of MmpL3 influences the formation of cell wall of mycobacteria. In the past few years, several whole cell-based screenings of compound libraries by different research groups has brought by a number of diverse chemical scaffolds active against Mycobacterium tuberculosis (Mtb). The aim of this review is to provide the recent advances in discovery of MmpL3 inhibitors with a special focus on the structure-activity relationship (SAR). Besides, this review will provide the information of target identification and the modes of action of the MmpL3 inhibitors.

Ellipticine is an alkaloid isolated from natural product with cytotoxicity, which has antitumor and anti-aids activity. Since it was first identified in 1959, a great deal of effort has been devoted to the development of various approaches for synthesis of ellipticine. This review provides a summary for synthesis approaches of ellipticine from different starting materials. The antitumor mechanism and structure-activity relationship are also discussed.

To investigate the effects of cordycepin on proliferation and invasion of pancreatic cancer stem cells (Pan CSC) and its mechanisms, MTT assay was used to investigate the effect of cordycepin on proliferation of Pan CSC. Inverted microscope was used to observe the morphologic change of cells. Propidium iodide staining methods was employed to observe the cell apoptosis. Cell scratch method was used to detect the ability of migration of Pan CSC in each group. RT-PCR and Western blot were used to determine the expression of apoptosis gene and epithelial-mesenchymal transitions (EMT) gene. The growth of Pan CSC was inhibited by cordycepin in a dose-and time-dependent manner, with IC₅₀ 107.364 and 48.472 μmol·L^-1 at 24 and 48 h, respectively. Moreover, the cell migration was inhibited at the same time. RT-PCR and Western blot results showed that cordycepin decreased the expression of Bcl-2 and activated pro-apoptotic gene levels such as Bax, p53, caspase-3. Furthermore, cordycepin reduced the expression of EMT genes by up-regulation of E-cadherin and down-regulation of N-cadherin. Cordycepin has the ability to inhibit Pan CSC proliferation and invasion by activating p53 pathway as well as suppressing the EMT. This study provides a new basis for inhibition of pancreatic cancer stem cells in the treatment of pancreatic cancer.

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.

Fragments of the human indoleamine 2, 3-dioxygenase 1 (IDO1) gene 5'-UTR (untranslated 1 245 bp region) promoters were amplified by PCR and cloned into pGL4.20 vector in the construction of reporter vector pGL4-IDO1-luc. A549 cells were transfected with the constructed plasmid and IDO1 inhibitor screening model was established with dual-luciferase reporter assay. Based on the model, we screened natural small molecules which could down-regulate the expression of IDO1 on tumor cells. The anti-tumor activities were examined by MTT, Western blotting and lactic dehydrogenase (LDH) release assays. Toosendanin (NS-180) down regulated the IDO1 expression and inhibited IFN-γ-induced STAT1 and STAT3 phosphorylation in A549 cells. Moreover, NS-180 significantly increased the cytotoxicity of co-cultured NK cells on A549 cells in LDH release assays. In summary, NS-180 is a novel and potent IDO1 inhibitor, which has an antitumor activity for cancer immunotherapies.

The drug-loaded ultrasound (US) contrast nanoparticles, which can effectively accumulate in the tumor to penetrate into its deep section, were prepared. After being heated or under the near infrared (NIR) light irradiation, the size of nanoparticles would transform from nanometer-scale to micrometer-scale in vitro, which can vastly enhance the effect of US imaging. We evaluated the size changes of the nanoparticles in vitro, investigating their effect in ultrasound imaging and distribution in vivo. Liposomes containing hydrophobic modified hollow gold nanospheres (HAuNS), doxorubicin (DOX) and perfluorohexane (PFH), which were referred to DOX and HAuNS loaded PFH liposome (DHPL), were prepared by thin film evaporation and ultrasonic technique. The morphology and size of DHPL were measured by transmission electron microscopy and particle size analyzer with dynamic light scattering (DLS) method. The agar gel pore model was used to investigate the enhanced effect of nanoparticles in vitro US imaging under the NIR light irradiation. The biodistribution of DHPL in 4T1 tumor-bearing mice after intravenous injection was measured by the in vivo imaging system. The DHPL were spherical at a particle size of 302 ±5 nm and polydispersity index of 0.195 ±0.018. The HAuNS loaded on phospholipid membrane was observed in transmission electron microscope (TEM) image. Under the NIR light irradiation (1 or 2 W·cm^-2), the temperature of the solution containing the DHPL (0.2, 0.04, 0.02 g·L^-1 in terms of HAuNS) rose rapidly. And a certain amount of micrometer-sized particles could be detected by the particle size analyzer when the temperature of the analyzer was raised to 52℃. The abundant microbubbles, which would enhance the effect of US imaging, were detected by ultrasonic diagnostic apparatus when the nanoparticles were irradiated by NIR light in the in vitro US imaging experiment. The in vivo distribution experiment showed that the DHPL could effectively accumulate in the tumor due to the enhanced permeability and retention effect (EPR effect) of the tumor. In this study, we successfully made a nanometer-micrometer reversible nanoparticles that can accumulate inside the tumor to provide a feasible scheme for US imaging in the tumor site and the combinational photothermal-chemotheraphy simultaneously.

Recent studies indicate that insulin-sensitizing activity of TZDs occurs through the inhibition of PPARγ Ser273 phosphorylation mediated by cyclin-dependent kinase 5(Cdk5), which is resulted from the binding activity for PPARγ. While, the side effects of TZDs may be related to the agonistic potency for PPARγ. In this article, 15 target compounds were designed and synthesized based on the structure of PPAR γ partial agonist INT131, with the aim of maintaining the insulin-sensitizing activity and reducing the side effects of INT131. The structures of these compounds were confirmed by ¹H NMR and ESI-MS, and their binding activities and agonistic potencies for PPARγ were measured. The binding activity of compound 15 is 88.47% of rosiglitazone, which is similar to INT131 (98.55%), but the agonistic potency of compound 15 is 1.41% of rosiglitazone, obviously lower than INT131 (15.18%).

Mogrol is the aglycone of seven kinds of mogrosides and siamenoside I. Mogrol has drawn more attention in recent years for its anti-leukemia and anti-diabetes activities. An ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) method was applied to identify the main metabolites of mogrol in rat plasma. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for determination of the main components in rat plasma. After an oral administration of 100 mg·kg^-1 mogrol in rats, 13 metabolites were detected along the main component of parent drug in the plasma. The major metabolites were oxidated and dehydrogenated products. In this study, mogrol was quantitative analyzed using lithium carbonate reagent with high sensitivity. The assay was linear in concentration range 5.00-1 000 ng·mL^-1 with intra-and inter-day precision within 9.3% and accuracy in range of -4.5% to 2.9%. Mogrol was absorbed into the blood very fast after oral administration, and the time to reach maximum concentration (t_max) was 1.67 h. The half-life (t_1/2) of mogrol in rats was 2.34 h, and the oral absolute bioavailability was 3.5%.

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 study was designed to explore the effects and the underlying mechanism of ginsenoside Rg1 on corticosterone (CORT)-induced astrocytes injury. The primary hippocampal and prefrontal cortical astrocytes from rats were cultured and purified. CORT was used to stimulate stress condition. Western blot was used to detect the effects of ginsenoside Rg1 on the phosphorylation of Cx43. Cell Counting Kit (CCK8) was used to detect the effects of ginsenoside Rg1 on astrocytes viability. The roles of ginsenoside Rg1 was reversed by protein kinase inhibitors in the change of astrocytes morphology. Our results showed that ginsenoside Rg1 reversed the phosphorylation of Cx43 induced by CORT; ginsenoside Rg1 significantly upregulated the cell viability of astrocytes against CORT; the role of ginsenoside Rg1 was obviously inhibited by Src protein kinase inhibitors PP2 and Akt protein kinase inhibitors BAY1125976 in prefrontal cortical astrocytes; in hippocampal astrocytes, Src protein kinase inhibitor PP2, p38 protein kinase inhibitor SB203580, Akt protein kinase inhibitor BAY1125976 significantly inhibited the cell protective effects of ginsenoside Rg1. In conclusion, ginsenoside Rg1 improved the activity of Cx43 gap junctions in astrocytes exposed to CORT; ginsenoside Rg1 protected astrocytes against that CORT activated the Src, p38 and Akt signaling pathways, and the mechanism was different in prefrontal cortical and hippocampal astrocytes.