Signal transducers and activators of transcription (STAT3) is an important member of the family of signal transducers and activators of transcription, which plays a dual role in signaling and initiating gene transcription in cells. Numerous studies have demonstrated constitutive activation of STAT3 in a wide variety of human tumors. There is strong evidence to suggest that aberrant STAT3 signaling promotes initiation and progression of human cancers by either inhibition of apoptosis or induction of cell proliferation, angiogenesis, invasion, metastasis, inflammation and immunosuppression. At present, some specific small molecule inhibitors have been developed to target STAT3. However, no drugs have been used in the clinical stage. The identification and development of novel drugs that can target deregulated STAT3 activation effectively remains an important scientific and clinical challenge. This article provides a summary on progress about STAT3 in tumor genesis and new inhibitors of STAT3.

Hepatocellular carcinoma (HCC) is the most common liver cancer, which is also the second leading cause of death in cancer. With the development of molecular biology and technology, gene therapy has become a new potential method to treat the cancer. As a viral gene-delivery system, the adeno-associated virus (AAV) is the most promising delivery vehicle for its high efficiency of infection, low pathogenicity and low immunogenicity. However, AAV has a wide range of host that may lead to side effects. Targeted gene therapy can achieve site-specific and high efficient gene expression, which avoids toxicity of systemic and non-targeted gene expression to improve the safety and efficacy of gene therapy. In this review, we provide an overview of the pathogenesis of HCC and the characteristics of AAV. Moreover, we discuss the targeting strategies currently employed in the gene therapy for HCC with a focus on targeting the transductional, transcriptional and posttranscriptional levels. New strategies are proposed for improving the quality of life and survival rate of patients with HCC.

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.

Soluble resistance-related calcium-binding protein, SORCIN, is a 22 kDa calcium binding protein with "penta-EF hand", which participates in the regulation of intracellular calcium homeostasis in cells. SORCIN is highly expressed in many tissues such as hearts and brains. It is overexpressed in some of cancer tissues as well. Recently, a large amount of clinical data showed that SORCIN was closely related to drug resistance in cancer. Meanwhile, basic research found that SORCIN participates in the formation of multidrug resistance (MDR) and is related to severity and poor prognosis of tumors. Moreover, it may also regulate MDR induced by ATP-binding cassette transporters. Therefore, SORCIN is expected to become a new target for diagnosis and treatment of MDR. The present review summarizes recent progress in SORCIN study and its effect on MDR.

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.

The present study was aimed to investigate the role and mechanisms of kallistatin in protection against oxidative stress-induced hepatic stellate cell damage. The effects of kallistatin on the viability, the intracellular superoxide level and Akt, eNOS molecules were investigated in human hepatic stellate cell line LX-2 and the incompletely activated primary rat hepatic stellate cells. Two different oxidative-stress related models, the hydrogen peroxide model and the iron-overload model were used in the experiments. The results show that kallistatin protected the hepatic stellate cells from oxidative damage and repaired the cell damage by oxidative stress. The main mechanism is antioxidant activity of kallistatin, which can remove the oxidized substances inside the cells. On the other way, kallistatin activates Akt and eNOS molecules to generate the antioxidant effect. Our results help to explore new anti-fibrotic targets.

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.

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.

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.

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%).

Five triterpene saponins were isolated from the aqueous extract of the leaves of Panax notoginseng (Burk.) F.H.Chen via various chromatographic approaches, including HPD-100 macroporous resin, silica gel, reverse phase C₁₈ and so on. Spectroscopic and chemical methods were used to elucidated their structures, which were determined to be 3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-12β, 23(R)-epoxydammara-24-ene-3β, 6α, 20(S)-triol 20-O-α-L-arabinofuranosyl-(1→6)-β-D-glucopyranoside (1), 3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-12β, 23(R)-epoxydammara-24-ene-3β, 6α, 20(S)-triol 20-O-α-L-arabinopyranosyl-(1→6)-β-D-glucopyranoside (2), notoginsenoside FP2 (3), gypenoside Ⅸ (4), ginsenoside Rg1 (5). Compounds 1 and 2 are new compounds and named as notoginsenoside Fh8 and notoginsenoside Fh9.

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.

To investigate the difference of Gegen Qinlian Decoction (GQD) piece and boiled powder in the treatment of type 2 diabetes (T2DM), the characteristic of overall metabolite profile was examined in the serum of T2DM rats with ¹H NMR-based metabolomics combined with the multivariate statistical analysis. A rat model of T2DM was established by feeding of high glucose and high fat diet followed by a streptozotocin (STZ) treatment. The general condition, body weight and fasting blood glucose (FBG) of rats were monitored. GQD piece and boiled powder exhibited activities in the improvement of these parameters. The results of the principal component analysis showed that there was a significant difference in the metabolic profile of the normal control group, the model group, the positive group, the herbal decoction group and the boiled powder group. Totally 15 potential biomarkers were identified by OPLS-DA binding univariate analysis. Compared with normal control group, the serum samples of T2DM showed a higher level of 3-HB, TMAO, glycine, β-glucose and α-glucose accompanied by lower level of lactate, VLDL, acetate, glutamate, methionine, glutamine, pyruvate, creatine, choline and glycerol. The above results also demonstrated that both piece and boiled powder of GQD could restore 14 of these markers. These results suggested that the disrupted metabolic pathways including energy metabolism, lipid metabolism and amino acid metabolism, were restored by GQD piece and boiled powder. The two formula did not show a significant difference. The results of this study provide experimental data and theoretical basis for the equal activities of GQD piece and boiled powder in clinical application.

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%.

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.

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.

In order to study the biosynthesis pathway of esculentoside A, the Illumina HiSeq 4000 highthroughput sequencing method was used to analyze the transcriptome of Phytolacca americana seedlings. The 9.60 Gb clean data were obtained after the transcriptome of P. americana assembled by Trinity software. The total 63 957 unigenes were obtained after assembly and the average length was 988.82 bp, among them 24 517 unigenes (38.33%) were annotated in the public databases Nr, Swiss-Prot, COG, KOG, Pfam, GO and KEGG. According to the assignment of KEGG pathway, 53 unigenes were involved in terpenoid backbone biosynthesis and 8 unigenes involved in triterpenoid biosynthesis. Additionally, there were 417 unigenes assigned to other secondary metabolic pathways in P. americana. The post-modification enzyme genes involved in the esculentoside A biosynthesis were also analyzed in the transcriptome of P. americana. The results indicated that 130 unigenes may have the function of CYP450 which was involved in oxidation/hydroxylation modification of P. americana secondary metabolites. Furthermore, 46 unigenes had the function of glycosyltransferase UGT. The transcriptome data of P. americana laid a foundation for studying the biosynthesis pathway of esculentoside A and other secondary metabolites, and also provided theoretical basis for formation of medicinal materials quality.