OBJECTIVETo investigate the effect and possible mechanism of bromo-domain inhibitors (JQ1) on proliferation inhibition and inducing apoptosis of acute T lymphocyte leukemia cell line (Jurkat) .

METHODSJurkat cell line was treated by JQ1 at different concentrations. MTT was used to detect the cell proliferation inhibition rate. The flow cytometry with AnnexinV-FITC/PI fluorescence staining was used to detect the changes of apoptosis rate, and real-time fluorescent quantitative PCR was used to detect c-Myc/Notch1 gene expression levels.

RESULTSWith the increasing of drug concentration and prolonging of time, the inhibitory rate of Jurkat cell growth was enhanced in time-dose dependent manner; Jurkat cells was treated by 0.8, 1.6, and 4 µ mol/LJQ1 for 48 h and 72 h, the cell apoptosis rate was enhanced with the increase of drug concentration and prolonging of time, and the difference was statistically different in comparison with the control group(P<0.05); PCR detection indicated that Notch1 and c-Myc mRNA expression was reduced in 48 h after JQ1 treatment, which was statistically different from the control group,(P<0.05) .

CONCLUSIONJQ1 can effectively inhibit the growth of Jurkat cell line, and potentially induce apoptosis through Notch1 and c-Myc gene. Hence JQ1 may be one of new methods used to treat T-ALL.

Apoptosis ; Azepines ; Cell Proliferation ; Flow Cytometry ; Genes, myc ; Humans ; Jurkat Cells ; Nuclear Proteins ; Transcription Factors ; Triazoles

The present study was undertaken to explore the inhibitory effect of cyanobacterial extracts of Nostoc commune FA-103 against the tomato-wilt pathogen, Fusarium oxysporum f. sp. lycopersici. In an optimal medium, cell growth, antifungal activity, and antifungal compound production could be increased 2.7-fold, 4.1-fold, and 13.4-fold, respectively. A crude algal extract had a similar effect as mancozeb at the recommended dose, both in laboratory and pot tests. In vitro and in vivo fungal growth, spore sporulation and fungal infection of wilt pathogen in tomato seeds were significantly inhibited by cyanobacterial extracts. Nostoc commune FA-103 extracts have potential for the suppression of Fusarium oxysporum f. sp. lycopersici.
Azepines ; Cyanobacteria ; Fluoroquinolones ; Fusarium ; Lycopersicon esculentum ; Maneb ; Nostoc commune ; Seeds ; Spores ; Zineb

The alkaloid securinine was assessed against spore germination of some plant pathogenic and saprophytic fungi (Alternaria alternata, Alternaria brassicae, Alternaria brassicicola, Curvularia lunata, Curvularia maculans, Curvularia pallenscens, Colletotrichum musae, Colletotrichum sp., Erysiphe pisi, Helminthosporium echinoclova, Helminthosporium spiciferum, Heterosporium sp.). Spore germinations of all the tested fungi were inhibited. Alternaria brassicicola, C. lunata, C. pallenscens and H. spiciferum were highly sensitive as complete inhibition of spore germination was observed at very low concentrations (200 ppm).
Alternaria ; Azepines ; Brassica ; Colletotrichum ; Fungi ; Germination ; Helminthosporium ; Heterocyclic Compounds, Bridged-Ring ; Lactones ; Musa ; Phyllanthus ; Piperidines ; Plants ; Spores

OBJECTIVEThe study was aimed to investigate the possible mechanism of Notch1 pathway in apoptosis of Ph(+) human ALL Cells(SUP-B15 cells) induced by bromodomain inhibitors JQ1.

METHODSThe SUP-B15 cells were treated with different concentrations of JQ1 for different times. The cell proliferation was analyzed with cytotoxicity test(MTT method). Cell cycle was detected by fluorescence microscopy and flow cytometry. The mRNA expression of MIS2, Notch1, Hes1, BCR-ABL in Notch1 pathway was detected by real-time quantitative PCR.

RESULTSJQ1 0-4 µmol/L could significantly inhibit the viability of SUP-B15 cells treated in does-and time-dependent manner. After SUP-B15 cells were treated with 1,2,4 µmol/L JQ1 for 48 h, the JQ1 could induce S cycle arrest in does-dependent manner which was statistical different from the control at the same time (P<0.05). MIS2, Notch1, Hes1, BCR-ABL mRNA expression was down-regulated by JQ1 which was statistical different from the control (P<0.05).

CONCLUSIONThe JQ1 can effectively inhibit the growth and proliferation of SUP-B15 cells and the Notch1 pathway may be one of the important apoptosis mechanisms in Ph(+) ALL cells induced by JQ1.

Apoptosis ; Azepines ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Flow Cytometry ; Fusion Proteins, bcr-abl ; Humans ; Receptor, Notch1 ; Signal Transduction ; Triazoles

OBJECTIVESynthetical evaluation of promoting effect of some kinds of transdermal enhancers was carried through.

METHODDiclofenac sodium was used as model, and azone and l-menthol and synthetic borneol and olieic acid and essential oil from Cnidium monnieri were used as transdermal enhancers. Transdermal absorption experimentation of diclofenac sodium on the device of penetrating skins in vitro was done. Cumulation of permeation amount and penetrating rates and steady fluxes and lag times were observed, and grey relational cluster method was used to evaluate the promoting effect of some kinds of transdermal enhancers.

RESULTAs for promoting effect on diclofenac sodium, azone and l-menthol were the best, and synthetic borneol and olieic acid ranked behind.

CONCLUSIONGrey relational cluster method can evaluate promoting effect objectively and fairly.

Administration, Cutaneous ; Animals ; Azepines ; pharmacology ; Bornanes ; pharmacology ; Cluster Analysis ; Cnidium ; chemistry ; Diclofenac ; administration & dosage ; pharmacokinetics ; Male ; Menthol ; pharmacology ; Oils, Volatile ; isolation & purification ; pharmacology ; Rabbits ; Skin Absorption ; drug effects

Alzheimer's disease is increasingly common in elderly population with a large socioeconomic burden. Current available drugs for Alzheimer's disease are acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist. Much effort is directed towards not just symptomatic treatments but disease-modifying treatments. Several drugs with differing targets and mechanisms of action are under development for the treatment of Alzheimer's disease. Phase III trials of dimebon, Ginkgo biloba, non-steroidal anti-inflammatory drugs, phenserine, statins, semagacestat, tarenflurbil, tramiprosate, valproate, xaliproden have been completed without demonstrating adequate efficacy. Encouraging results would be expected from ongoing phase III trials of bapineuzumab and solanezumab. The clinical trials for the disease-modifying treatment of Alzheimer's disease have resulted in both promise and disappointment.
Aged ; Alanine ; Alzheimer Disease ; Antibodies, Monoclonal, Humanized ; Azepines ; Cholinesterase Inhibitors ; Flurbiprofen ; Ginkgo biloba ; Humans ; Indoles ; N-Methylaspartate ; Naphthalenes ; Physostigmine ; Pyridines ; Taurine ; Valproic Acid

This study examined the corneal permeability of topical eye drop solutions added with various corneal penetrating accelerators and gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) by nuclear magnetic resonance imaging (MRI). Twenty-four New Zealand rabbits were randomly divided into 3 groups according to the random digits table: Gd-DTPA group, in which the rabbits received 23.45% Gd-DTPA; hyaluronic acid group, in which 23.45% Gd-DTPA plus 0.2% hyaluronic acid was administered; azone group, in which 23.45% Gd-DTPA with 0.2% azone was given. Fifty microliters of the eye drops was instilled into the conjunctive sac every 5 min, for a total of 6 applications in each group. Contrast medium signals in the cornea, anterior chamber, posterior chamber, and vitreous body were scanned successively by MRI. The morphology and cell density of the corneal endothelium were examined before and 24 h after the treatment. The results showed that the residence time of Gd-DTPA in the conjunctival sac in the hyaluronic acid and azone groups was longer than that in the Gd-DTPA group. The signals in the anterior chamber of the Gd-DTPA and hyaluronic acid groups were increased slightly, and those in the azone group strengthened sharply. The signal intensity continuously rose over 80 min before reaching plateau. The strengthening rate of signals in the anterior chamber was 19.63% in the Gd-DTPA group, 53.42% in the sodium hyaluronate group, and 226.94% in the azone group. No signal was detected in the posterior chamber or vitreous body in all the 3 groups. Corneal morphology and cell density did not show any significant changes after the treatment in all the 3 groups. It was concluded that azone can significantly improve the corneal permeability of drugs that are similar to Gd-DTPA in molecular weight and molecular size, and MRI is a noninvasive technique that can dynamically detect eye drop metabolism in real time.
Animals ; Azepines ; administration & dosage ; pharmacokinetics ; Contrast Media ; administration & dosage ; pharmacokinetics ; Cornea ; metabolism ; Female ; Gadolinium DTPA ; administration & dosage ; pharmacokinetics ; Magnetic Resonance Imaging ; Male ; Ophthalmic Solutions ; Permeability ; Rabbits

It was hypothesized that NaF induces calcium sensitization in Ca2+-controlled solution in permeabilized rat mesenteric arteries. Rat mesenteric arteries were permeabilized with beta-escin and subjected to tension measurement. NaF potentiated the concentration-response curves to Ca2+ (decreased EC50 and increased E(max)). Cumulative addition of NaF (4.0, 8.0 and 16 mM) also increased vascular tension in Ca2+-controlled solution at pCa 7.0 or pCa 6.5, but not at pCa 8.0. NaF-induced vasocontraction and GTPgammaS-induced vasocontraction were not additive. NaF-induced vasocontraction at pCa 7.0 was inhibited by pretreatment with Rho kinase inhibitors H1152 or Y27632 but not with a MLCK inhibitor ML-7 or a PKC inhibitor Ro31-8220. NaF induces calcium sensitization in a Ca2+-dependent manner in beta-escin-permeabilized rat mesenteric arteries. These results suggest that NaF is an activator of the Rho kinase signaling pathway during vascular contraction.
Amides ; Animals ; Azepines ; Calcium ; Contracts ; Escin ; Indoles ; Mesenteric Arteries ; Naphthalenes ; Passive Cutaneous Anaphylaxis ; Pyridines ; Rats ; rho-Associated Kinases ; Sodium ; Sodium Fluoride

OBJECTIVE: To investigate the effects and mechanism of bromodomain and extra-terminal (BET) inhibitor JQ1 on the double-expressor lymphoma (DEL) cell lines. METHODS: Protein expressions of cMyc and BCL-2 in 3 lymphoma cell lines were checked by Western blot so as to identify DEL cell lines. CCK-8 assay was used to detect the effects of JQ1 on anti-proliferation in the DEL cell lines. Western blot and RT-PCR were used to measure the protein and mRNA expressions of cMyc, BCL-2 and BCL-6 in DEL cell lines which treated by JQ1. Flow cytometry was used to detect the effect of JQ1 on cell apoptosis. RESULTS: Based on the expressions of cMyc and BCL-2, the SU-DHL6 and OCILY3 cell lines were confirmed as DEL cell lines. CCK-8 assay showed that the proliferation of DEL cell lines was inhibited by JQ1, which was similar to non-DEL cell lines and mainly regulated the expression of cMyc and BCL-6 but not BCL-2. JQ1 had no effects on apoptosis in the DEL cell lines. CONCLUSION BET inhibitor JQ1 has anti-tumor effect in the DEL cell lines, thus providing evidence for the therapeutic potential of BET inhibitor JQ1.
Apoptosis ; Azepines/pharmacology* ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Proto-Oncogene Proteins c-myc/metabolism* ; Sincalide/pharmacology* ; Triazoles/pharmacology* ; Xenograft Model Antitumor Assays

To develop estradiol transdermal film-forming spray (TFS), various polymers were screened using solvent appearance, spray ability, film-forming rate and appearance as indices. The influence of polymer type, plasticizer and penetration enhancer on the transdermal flux were investigated by selecting porcine skin as model, and transdermal flux of TFS was compared with commercial patch and gel. The drug existing state in the formed film was investigated by differential scanning calorimetry (DSC). The solvent appearances, spray abilities, film-forming rates and appearances of eudragit E PO, RL PO, hydroxypropyl cellulose EF, polyvinylpyrrolidone K30, Plasdone S630 and Agrimer VA64 were suitable for the preparation of TFS. TFS prepared by Eudragit RL PO had the biggest transdermal flux of estradiol among all the polymers investigated. Triethyl citrate, the plasticizer, decreased the transdermal flux. Azone increased the transdermal flux, while oleic acid, isopropyl myristate and menthol had opposite effects. TFS had a higher transdermal rate and a higher accumulative penetrated estradiol of 24 h than commercial patch and gel. The DSC result showed that estradiol was spread as molecule in the formed film of TFS. It was indicated that TFS could be expected to be an effective transdermal drug delivery system.
Administration, Cutaneous ; Aerosols ; Animals ; Azepines ; chemistry ; Calorimetry, Differential Scanning ; Cellulose ; analogs & derivatives ; chemistry ; Citrates ; chemistry ; Drug Delivery Systems ; Estradiol ; administration & dosage ; pharmacokinetics ; Plasticizers ; chemistry ; Polymers ; chemistry ; Skin Absorption ; Swine