Latest ArticlesThe 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.
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.
This study was designed to study the chemical constituents from bulbil of Dioscorea opposite Thunb.. Four compounds were isolated by silica gel column chromatography. On the basis of physic-chemical characters and spectroscopic data analysis, these compounds were identified as lyzalkaloid (3, 4-dihydro-6-hydroxy-4-methyl-6H-pyrido[6, 5-b]indol-5(1H)-one) (1), anoectochine (2), ginsenine (3), and 2-hydroxy-3-(1H-indol-3-yl) propanoic acid methyl ester (4). Compound 1 is a new indole alkaloid, named as lyzalkaloid. Compounds 2-4 were isolated from this plant for the first time. The cytotoxic activities were assessed by MTT assay. All compounds exhibited the cytotoxic activity against HepG2 and MDA-231 with IC50 values of over 100 μmol·L-1, respectively. All compounds show no significant cytotoxic activities against HepG2, MDA-231 cancer cell.
A new polyketide:3R, 5R-(-)-talaroflavone (2), along with 15 known compounds were isolated from a EtOAc extract of a sponge-derived fungus Alternaria sp. F49. Compounds 1-2 and 3-4 were separated as two pairs of enantiomers by chiral HPLC from Ⅰ and Ⅱ. The structures of compounds 1-16 were elucidated by means of NMR and MS. Furthermore, the absolute configurations of compounds 1-2 were determined by single crystal X-ray diffraction experiment and CD analyses. Compounds 6, 8-10 were isolated from this genus (Alternaria sp.) for the first time. Compound 16 showed moderate COX-2 enzyme inhibitory activity with IC50 of 7.3 μmol·L-1.
Focusing on the TCM-related adverse drug reactions, especially those conventionally non-toxic TCM induced hepatotoxicity, this paper has proposed and established the disease-syndrome-based toxicology evaluation pattern and approach for TCM, not only the normal rats, but the hepatic fibrosis model rat were studied hepatotoxic or hepatoprotective effects of rhubarb, meanwhile liver histopathology changes by histological tests such as HE and TUNEL staining. The metabolomics analysis method will be employed to screen the key metabolites and possible metabolic pathway of the dual effects of rhubarb in rats. The results showed that rhubarb could result in significant liver injury in normal rats, indicated by the elevation of plasma serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities (P < 0.01), as well as liver histopathology changes by histological tests such as HE and TUNEL staining; whereas the levels of ALT and AST were significantly decreased in the model group of rhubarb, and the histopathology of liver was significantly improved. The UPLC-QTOF/MS methods were used to characterize the differences metabolites in contrast group plasma of rats. Eventually, seven potential biomarkers such as taurine, L-arginine, creatine, L-valine, retinyl ester, and prostaglandin F2α were confirmed by multivariate statistical analysis and metabolic pathways enrichment analysis linked to six metabolic pathways, including taurine and hypotaurine metabolism, primary bile acid biosynthesis, arginine and proline metabolism, arachidonic acid metabolism, retinol metabolism and valine, leucine and isoleucine biosynthesis. In summary, the results suggested the dual effects of rhubarb screened by taurine and hypotaurine metabolism, primary bile acid biosynthesis and arginine and proline metabolism may be the key metabolic pathway related to You Gu Wu Yun phenomenon of rhubarb. This study will provide new vision and illustration of scientific evidences for the hepatotoxicity assessment and rational use of those drugs containing anthraquinones.
This study was designed to determine the metabolites of Renduining injection in rats. The ultra-high performance liquid chromatography-LTQ Orbitrap mass spectrometric (UHPLC-LTQ-Orbitrap-MS) and mass defect filter techniques were applied to analyze the metabolites of Reduning injection in rat plasma, bile, urine and feces. As a result, we determined 14 metabolites of geniposide, including oxidation, dehydration, hydroxymethylene loss, hydrolysis, ring-opened, cysteine conjugation and glucuronidation conjugation of aglycone; 9 metabolites of geniposidic acid, consisting of dehydration, ring-opened, double-bond reduction and cysteine conjugation; 6 metabolites of secoxylogain including hydrolysis, hydroxymethylene loss, hydroxylation and ethylation; 12 metabolites of chlorogenic acid, containing decarboxylation, hydrolysis, methylation, acetylation, cysteinylglycine conjugation and glutathione conjugation. It provided information for the therapeutic effect of Reduning in vivo.
A simple, sensitive and reliable method was developed for simultaneous quantification of IMM-H007 and its major active metabolites-M1 and MP in the blood of rhesus monkey using HPLC-MS/MS analysis. The analytes and internal standard (IS) WS070119 were separated using a Capcell PAK ADME Column (2.1 mm×100 mm, 3 μm, Shiseido, Japan) with a gradient mobile phase of methanol/water containing 0.1% formic acid. The detection was performed in positive selected reaction monitoring (SRM) mode with electrospray ionization (ESI) source. Satisfactory linearity was obtained while the inter- and intra-assay precision and accuracy differences were no more than 15% with high recovery and good stability for the quantification, indicating the present method was specific, accurate and reliable. The method was successfully applied to the pharmacokinetic study of IMM-H007 in rhesus monkey. After single oral administration of IMM-H007 (70, 210, 630 mg·kg-1), M1 and MP were detected in blood, while the concentration of IMM-H007 was much lower than its metabolites. The active metabolite MP with linear kinetics had a higher exposure than other analytes in vivo. The results provide an useful and reliable model for pharmacological and toxicological studies of IMM-H007 as well as its clinical application.
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.
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.
ABC transporters (ATP-binding cassette transporters) are a family of trans-membrane transport proteins, which are ubiquitous in prokaryotes and eukaryotes. They are functionallyinvolved in the transport and accumulation of plant secondary metabolites, phytohormone transport, lipid metabolism, exogenous toxins detoxification, plant disease and other aspects. Based on the genome and transcriptome data of Dendrobium officinale, 88ABC transporters were preliminarily identified in D. officinale and their functions and subcellular localization were predicted. These proteins are divided into seven subfamilies, ABCA-ABCI, including 4 ABCA, 19 ABCB, 12 ABCC, 3ABCD, 9 ABCF, 37ABCG and 4 ABCI, which are mainly located in plasma membrane, vacuole and Golgi apparatus. Comparative transcriptomic analysis of ABC protein expression profile between asymbiotic and symbiotic germination of D. officinale show that some members of ABCB and ABCG proteins are highly expressed during seed germination inoculated fungi. qPCR validated that 2 ABCB11 and 2 ABCG-PDR are significantly up-regulated in symbiotic assay compared to asymbiotic germination (fold change ≥ 10.0). These proteins are mainly involved in abscisic acid and auxin transport, suggesting that these proteins play an important role in the germination of D. officinale seed and in the interaction with microorganisms.
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