Latest ArticlesThis study was designed to investigate the inhibitory effects of regorafenib (REG) on the catalytic activities of 12 kinds of human UGT isoforms and human liver microsomes (HLM) in vitro. The broader potential of REG to perpetrate drug-drug interactions (DDI) arising from UGT enzyme inhibition is predicted by in vitro-vivo extrapolation (IV-IVE). Fifty mixed HLM and 12 kinds of recombinant UGTs were utilized as enzyme sources to evaluation the inhibitory effects of REG against UGTs. 4-Methylumbelliferone (4-MU) as a nonselective substrate of UGTs except for UGT1A4, N-(3-carboxypropyl)-4-hydroxy-1, 8-napht-halimide (NCHN) and N-butyl-4-(4-hydroxyphenyl)-1, 8-naphthalimide (NPHN) as the specific fluorescent substrate of UGT1A1, and trifluoperazine (TFP) as the specific substrate of UGT1A4. The half maximal inhibitory concentration (IC50) was calculated via the nonlinear regression analysis using Graphpad Prism 6.0, the inhibition kinetic types were selected and evaluated based on the intersection location of Lineweaver-Burk plot and Dixon plot, and Ki values were determined by the second plot of slopes. The potential DDI risk based on UGT1A1 inhibition was also evaluated through the in vitro parameters. The results demonstrated that REG displayed strong inhibitory effects against UGT1A1, 1A7, 1A9, and 2B7. The IC50 values were from 0.15 to 6.6 μmol·L-1 and Ki values from 0.027 to 14 μmol·L-1. The REG exerted competitive inhibition against UGT1A1-mediated 4-MU-O-glucuronidation and UGT1A1-mediated NPHN-O-glucuronidation, while the inhibition of NCHN-4-O-glucuronide by REG was suited to noncompetitive inhibition in both HLM and recombinant UGT1A1. Likewise, REG exhibited a mixed efficacy in inhibition of UGT1A7-, UGT1A9-, and UGT2B7-catalyzed 4-MU-O-glucuronidation. The AUC ratio of UGT1A1 specific substrates NPHN and NCHN can be increased by 101% to 302% and 13% to 109%, respectively. These results suggest that much caution should be exercised when REG is co-administered with UGT1A1 substrates.
The relationship between PEPT1 (peptide transporter) and drug efficacy has drawn more and more attention in the treatment of disease. PEPT1 represents a promising strategy for improvement of drug bioavailability and an important starting point for clinical rationalization of drug selection. The effect of PEPT1 on transport and pharmacokinetics of amoxicillin was investigated under hypoxia condition at high altitude in rat. The mRNA and protein expressions of PEPT1 were increased by 36.87%, 216.21%, 577.8% and 535.9% respectively in the hypoxia group in the small intestine and kidney of rats. However, the mRNA and protein expressions of PEPT1 were reduced by 43.90% and 84.7% in the liver. Compared with the control group, the AUC, tmax, Cmax, MRT and t1/2 of amoxicillin were significantly enhanced by 312.17%, 63.04%, 110.93%, 67.11% and 16.96% respectively in the hypoxia group, while the CL was significantly decreased by 74.51%. After acute exposure to high altitude, the expressions of drug transporter PEPT1 were distinctly changed in rat tissues, which can affect the pharmacokinetics of amoxicillin.
Using ligustrazine as the leading compound, we designed and synthesized ten novel ligustrazine derivatives, whose structures were determined by 1H NMR, 13C NMR and MS. Inhibitory effects of the new compounds on the proliferation of A549, A549/DDP and HBE cells were detected by MTT assay. The inhibi-tory activity of the synthesized compounds on migration and invasion of A549 cells were evaluated through scratch assay and transwell assay. Mechanism of the inhibition on migration and invasion was investigated by Western blotting. In addition, the cell cycle was analyzed with flow cytometry. The results showed that, both compounds Z8 and Z10 have an anti-proliferative activity, and the potencies of inhibition of tumor-cell migration and invasion were attributed to the down-regulation of MMP-2 and MMP-9. The compounds Z8 and Z10 could also enhance G2/M arrest in A549 cell as revealed by cell cycle analysis.
To investigated the chemical constituents of the roots of Psidium guajava, we isolated seven compounds by silica gel column chromatography.These include oleanane derivatives, 2 α, 3β, 6β, 23-tetrahydroxylurs-12, 20(30)-dien-28-oic acid β-D-glucopyranoside (1), 2α, 3β, 6β, 23-tetrahydroxylurs-12, 18-dien-28-oic acid β-D-glucopyranoside (2), 2α, 3β, 23-trihydroxylurs-12, 18-dien-28-oic acid β-D-glucopyranoside (3), nigaichigoside F1(4), asiaticoside C (5), 2α, 3β, 6β, 19α, 23-pentahydroxylurs-12, 18-dien-28-oic acid β-Dglucopyranoside (6) and 2α, 3β, 19α, 23-tetrahydroxylurs-12-en-28-oic acid (7).Their structures were elucidated on the basis of spectral analysis with reference to the published data.Compound 1 is brand new, compounds 2-6 were first isolated from this plant.The new compound was evaluated for their cytotoxic activity against human hepatoma Bel 7402 in vitro.The results were expressed as the ratio of inhibiting Bel 7402 cells growth by comparing to untreated cells.The new compound (concentration:25 μmol·L-1) showed the ratio values of 52.5%.
This study was designed to screen the antiemetic components of Euodia rutaecarpa, and elucidate its material basis on the spectrum-effect correlation analysis. The UHPLC-Q-TOF/MS (UHPLC-quadrupole time-of-flight mass spectrometry) technology was used to obtain the fingerprint of Euodia rutaecarpa extracts. The perfusion of copper sulfate was used as a model to study the antiemetic effect by vomiting. The orthogonal partial least squares (OPLS) method was used to analyze the spectrum-effect relationship. The results indicated the following compounds were the potential antiemetic components such as rutin, limonin, narcissoside, chrysoeriol-7-O-rutinoside, hyperoside, isorhamnetin-3-O-β-D-galactoside, 1-methyl-2-undecyl-4(1H)-quinolone, 1-methyl-2-[(Z)-4-nonenyl]-4(1H)-quinolone. This study provides the experimental basis in use of Euodia rutaecarpa in the future, and provides the research methods and ideas for the similar study on the pharmacodynamic material basis of traditional Chinese medicine.
This study was designed to investigate the metabolites of 5F-AMB by human liver microsomes model in vitro. 5F-AMB was added in the reaction mixture to simulate the metabolic process in human hepatocytes in vivo, and then to determine the reaction points and pathways of metabolism by ultra performance liquid chromatography (UPLC) coupled to high resolution mass spectrum (HR-MS). 5F-AMB generated 9 metabolites in total in the human liver microsomes model. Ester hydrolysis, combination of ester hydrolysis and oxidative defluorination, combination of ester hydrolysis and hydroxylation on pentyl chain moiety and combination of ester hydrolysis and hydroxylation on indazole ring moiety reactions were its main metabolic pathways. The method is fast and efficient so that the ester hydrolysis, combination of ester hydrolysis and oxidative defluorination, combination of ester hydrolysis and hydroxylation on pentyl chain moiety and combination of ester hydrolysis and hydroxylation on indazole ring moiety metabolites of 5F-AMB can be used as the suitable and potential biomarkers in the urine samples.
This study aims to establish a novel gene-activated matrix that mimics the structure and function of extracellular matrix (ECM-m-GAM). The structure, mechanical property and release profile were also characterized. Firstly, the liposome/DNA lipoplex (LPD) was modified with cell penetrating peptide TAT. The obtained TAT-LPD was then mixed with RGD grafting hyaluronic acid solution. After addition of the matrix metalloproteinase (MMPs) sensitive crosslinker (HS-MMP-SH), hyaluronic acid was crosslinked and TAT-LPD was encapsulated in the subsequently formed hydrogel. As a result, the cell adhesion factor RGD, MMPs sensitive substrate and the efficient gene transfer vector TAT-LPD were all integrated in the hyaluronic acid hydrogel, which was named as ECM-m-GAM. The release profile of DNA from ECM-m-GAM in different release medium was evaluated with PicoGreen kits. The results suggested that the mean diameter of the spherical TAT-LPD was (263.0 ±4.30) nm. TAT-LPD was successfully encapsulated in ECM-m-GAM, which had the typical porous network structure of hydrogels. The mechanical strength of GAM was enhanced with the increasing of hyaluronic acid content. When the content was 4%, the elastic modulus of GAM reached 1 600 Pa. The highly elastic GAM may be suitable for implantation and tissue regeneration. The DNA release showed significant MMPs sensitive property. Especially, the released DNA still existed in form of nanoparticles. Bone marrow mesenchymal stem cells (BMSCs) were successfully transfected with GAM and the green fluorescent protein was expressed. The results have laid a solid foundation for future study of the cell transfection and tissue regeneration.
Legumain, a kind of asparaginyl endopeptidase, is overexpressed in highly metastatic and highly aggressive tumor, which can undergo an enzymatic hydrolysis of substrates. We proposed a legumain-responsive functional gold nanoparticle (GNP) drug delivery system (GNPs-A & C), which was consist of Ala-Ala-Asn-Cys-Lys (AK) modified GNPs (GNPs-AK) and 2-cyano-6-aminobenzothiazole (CABT) modified GNPs (GNPs-CABT). In the circulation system, the GNPs-A & C could passively target to the tumor site through the enhanced permeability and retention (EPR) effect. Then the overexpressed legumain specifically cleave the peptide to exposure the 1, 2-thiolamino group, which could take place click reaction with the cyano group of CABT, leading to the aggregation of two GNPs, these aggregates of GNPs with increased size were more likely to retain within tumor site. In vivo fluorescent imaging demonstrated GNPs-A & C could acquire an enhanced accumulation in legumain-overexpressed C6 tumor. Importantly, after tethering DOX, the GNPs-DOX-A & C showed an excellent anti-tumor effect with reduced cardiotoxicity.
Direct-PCR technology was using a 15 minutes heat-lysis step instead of DNA extraction to get DNA templates with small amount of plant materials followed by sensitive PCR process to amplify target genes. In order to facilitate DNA barcoding in medicinal herb identification with Direct-PCR, we collected different tissues from 80 medicinal plants as material to amplify the ITS fragments. Through optimizing the PCR reaction, ITS of 80 plant samples was all successfully amplified. PCR products were sequenced and to do Blast analysis. These results suggest that Direct-PCR would improve the efficiency of DNA barcoding in the application of medicinal herb molecular authentication.
Auxin response factor (ARF) is an important transcription factor for auxin signal transduction pathway, which regulates virtually every aspect of plant growth and development from embryogenesis to senescence. Nine full-length genes of ARF transcription factors were obtained from transcriptome dataset of Scutellaria baicalensis Georgi using the bioinformatics methods. The nucleotide and protein characteristics, subcellular localization, senior structural domains and conservative forecasts of those ARF transcription factors were analyzed. The phylogenetic tree showed that the nine ARFs in S. baicalensis were clustered together with ARF transcription factors in Arabidopsis thaliana, Oryza sativa subsp. Japonica and Nicotiana attenuate. The results of gene expression showed that:① The expression levels of ARF1, ARF3, ARF4, ARF8, ARF20 and ARF24 were upregulated after 100 μmol·L-1 GA3 treatment. However, the expression levels of ARF6 and ARF18 were downregulated; ② Those ARF genes were mainly expressed in the flowers of S. baicalensis; ③ There was a significant correlation between ARF genes and the genes involved in flavonoid biosynthesis. Our results provide a basis for further understanding the molecular regulation mechanism of flavonoid biosynthesis in S. baicalensis.
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