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.

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.

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.

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.

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.

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.

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%).

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.

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%.

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.