Sesquiterpene pyridine alkaloids are important components in Tripterygium plants, possessing a wide range of pharmacological activities, such as anti-inflammation immunosuppression, anti-tumor, anti-virus, and deinsectization, and are of great research value. They are composed of highly oxidized dihydro-β-furansquiterpene and pyridine dicarboxylic acid through ester bonds. According to the structural characteristics of pyridine dicarboxylic acid fragments, they can be divided into various structural subtypes. Up to now, more than 110 sesquiterpene pyridine alkaloids have been isolated and identified from Tripterygium plants. This study reviewed the structural features and spectral(i.e., UV, IR, MS, and NMR) characteristics of sesquiterpene pyridine alkaloids and summarized the structural elucidation process in detail to provide references for their further research and development.
Alkaloids/pharmacology* ; Drugs, Chinese Herbal/pharmacology* ; Molecular Structure ; Pyridines/pharmacology* ; Sesquiterpenes ; Tripterygium/chemistry*

The aim of this study was to investigate the effect of sorafenib combined with daunorubicin on leukemic k562 cell line. The inhibitory effect of sorafenib alone and its combination with daunorubicin on K562 cell proliferation was detected by MTT method; the synergistic effect was measured by CDI (coefficient of drug interaction); the apoptosis of K562 cells was observed by flow cytometry with Hoechst 33258 staining. The results showed that the sorafenib alone or its combination with daunorubicin could significantly inhibit K562 cell proliferation and the combination of both drugs displayed synergistic effect on K562 cells, meanwhile the apoptotic cells increased. It is concluded that the combination of sorafenib and daunorubicin has a obviously synergistic inhibitory effect on leukemic cell line K562.
Apoptosis ; drug effects ; Benzenesulfonates ; pharmacology ; Daunorubicin ; pharmacology ; Drug Synergism ; Humans ; K562 Cells ; Niacinamide ; analogs & derivatives ; Phenylurea Compounds ; Pyridines ; pharmacology

The electrophysiological effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP), a chemical inducer of Parkinsonism in man and monkey, on the pigmented rabbit retina were determined under acute conditions. The amplitude of the b-wave of the rabbit electroretinogram was affected, but both the implirit time and half-amplitude duration of it werenot. The amplitude of the photopic b-wave was increased by 72.9 +/- 32.1% 5hours after the intravenous injection of NMPTP (P[t] < 0.05), whereas that of the scotopic b-wave was decreased by 31.2 +/- 6.4% 4hours after injection (P[t] < 0.05). The above results suggest or support that: 1, the dopaminergic amacrine cells are related to the modulation of the b-wave of the rabbit electroretinogram. 2. during light adaptation, the dopaminergic amacrine cells uncouple the rod and cone systems in the inner plexiform layer and are involved in functions of the rod system. 3. the hypothesis that the funrtion of tyrosine hydroxylase may be affected by NMPTP.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Animals ; Electrophysiology ; *Electroretinography ; Pyridines/*pharmacology ; Rabbits ; Retina/cytology/*drug effects

OBJECTIVETo compare the bronchofilating and antiallergic effects with piclamilast with ciclamilast, the second-generation phosphodiesterase 4 (PDE4) selective inhibitors.

METHODSEffects of piclamilast and ciclamilast on airway smooth muscle (ASM) at resting tension, carbachol-induced contraction and the synergistic effect of two agents on isoproterenol-induced bronchorelaxation were evaluated in the isolated tracheal strips of guinea pig in a cumulative manner in vitro. Slow reaction substance of anaphylaxis (SRS-A) release from lung tissues of the sensitized guinea pigs after antigen challenge was examined by bioassay. Antiallergic effect of piclamilast, ciclamilast and rolipram on the isolated ASM of sensitized guinea pigs were evaluated with Schultz-Dale reaction.

RESULTSPiclamilast and ciclamilast showed bronchorelaxant effect in ASM at resting tension. EC50 values of piclamilast and ciclamilast were 1.00 x 10(-5) mol/L and 0.84 x 10(-5) mol/L. Piclamilast and ciclamilast could both enhance the bronchodilating effect of isoproterenol in the isolated ASM of guinea pig, reduce the amount of SRS-A released from lung tissues of the sensitized guinea pigs and also inhibit ovalbumin (OA)-induced bronchoconstruction (Schultz-Dale reaction).

CONCLUSIONThe results indicate the bronchodilating effect of ciclamilast is as potent as piclamilast, but the antiallergic effect of ciclamilast is significantly more potent than that of piclamilast.

Animals ; Anti-Allergic Agents ; pharmacology ; Benzamides ; pharmacology ; Bronchodilator Agents ; pharmacology ; Dose-Response Relationship, Drug ; Female ; Guinea Pigs ; In Vitro Techniques ; Isoproterenol ; pharmacology ; Male ; Phosphodiesterase Inhibitors ; pharmacology ; Pyridines ; pharmacology

The purpose of the current study was to examine the pharmacokinetic profiles and tissue distribution of clevidipine, an ultra-short-acting calcium antagonist in Beagle dogs and Sprague-Dawley rats, respectively. The pharmacokinetics and biodistribution of its primary metabolite H152/81 were also evaluated. Dogs received intravenous infusion of clevidipine at a dose rate of 17 μg/(kg·min), and rats were given intravenous administration of clevidipine at a dose of 5 mg/kg. Dog plasma and rat tissues were collected and assayed by HPLC-MS/MS. It was found that plasma clevidipine quickly reached the steady state concentration. The terminal half-life was short (16.8 min), pointing out a rapid elimination after the end of the infusion. The total clearance was 5 mL/(min·kg). In comparison, plasma concentration of H152/81 was increased more slowly and was significantly higher than that of clevidipine. After intravenous administration, clevidipine was distributed rapidly into all tissues examined, with the highest concentrations found in the brain, heart and liver. Maximal concentrations of clevidipine were found in most tissues at 10 min post-dosing. However, the proportion of clevidipine distributed in all tissues was quite small (0.042‰) compared to the total administration dose. It was suggested that clevidipine was mainly distributed in blood and it transformed to inactive metabolite rapidly.
Animals ; Calcium Channel Blockers ; pharmacokinetics ; pharmacology ; Dogs ; Dose-Response Relationship, Drug ; Organ Specificity ; drug effects ; Pyridines ; pharmacokinetics ; pharmacology ; Rats

OBJECTIVETo investigate the effect of c-Met inhibitor cabozantinib (XL-184) in inhibiting Listeria monocytogenes (LM) from invading Caco-2 cells to reduce the cell injury.

METHODSThe cell invasion capacity of LM was assayed in Caco-2 cells incubated with different doses of XL-184 for different durations. Caco-2 cells incubated with XL-184 were seeded on the upper room of the transwell chamber, and the cell monolayer was exposed to LM infection followed by addition of horseradish peroxidase (HRP). The trans-epithelial electric resistance (TEER), HRP concentration and LM colony-forming unit (CFU) were measured in the cell monolayer. Fluorescent staining was used to evaluate the cell viability, and LDH release from the cells was examined to assess the changes in cell membrane permeability.

RESULTSXL-184 significantly decreased LM invasion rate in Caco-2 cells in a dose- and time-dependent manner (P=0.000), and this effect was enhanced by co-incubation of the cells with ampicillin (P<0.05). In the cell membrane permeability assay in the monolayer cells, XL-184 markedly inhibited LM-induced reduction of TEER (P<0.05) and significantly suppressed LM-induced enhancement of cell membrane permeability shown by reduced HRP concentration and LM count in the lower chamber (P=0.000). The cells infected with LM showed significantly lowered cell viability, which was rescued by XL-184 (P<0.01); XL-184 also dose-dependently reduced LDH release from the cells (P<0.05).

CONCLUSIONSXL-184 can suppress LM invasion in Caco-2 cells to reduce the cell injury, suggesting its value as a promising candidate agent for prevention and treatment of LM infections.

Anilides ; pharmacology ; Caco-2 Cells ; Cell Membrane Permeability ; drug effects ; Cell Survival ; Humans ; Listeria monocytogenes ; drug effects ; Pyridines ; pharmacology

BACKGROUND: Lung cancer is one of the most deadly cancers in the world for human. In recent years, the effect of targeted therapy has become increasingly significant. Apatinib is a multi-target anti-tumor drug that is currently under study. The purpose of this study is to investigate the effects of Apatinib on the biological characteristics of lung cancer cells and its possible mechanism. METHODS: Lung cancer cell lines H1299 and H3255 were cultured in vitro. The effects of Apatinib on proliferation, migration and invasion of H1299 and H3255 cells were detected by cell proliferation assays wound healing assays and Transwell assays. The protein expression related to cancer angiogenesis and invasion was detected by Western blot. RESULTS: Apatinib significantly inhibited the proliferation, migration and invasion of H1299 and H3255 in a concentration-dependent manner. Western blot showed that with the increasing of drug concentration, VEGF, VEGFR2, N-cadherin, MMP9, MMP2 and Vimentin were down-regulated, and E-cadherin were up-regulated. CONCLUSIONS Apatinib can inhibit the invasion and migration of lung adenocarcinoma cells H1299 and H3255. By regulation of epithelial-mesenchymal transition and the expression of matrix metalloproteinase-related proteins.
Antineoplastic Agents ; pharmacology ; Cell Line, Tumor ; Cell Movement ; drug effects ; Humans ; Lung Neoplasms ; pathology ; Neoplasm Invasiveness ; Pyridines ; pharmacology

OBJECTIVE: To investigate the effect of palbociclib on cell cycle progression and proliferation of human renal tubular epithelial cells. METHODS: Human renal tubular epithelial cell line HK-2 was treated with 1, 5, 10, and 20 μmol/L of palbociclib, and the changes in cell proliferation and viability were examined by cell counting and CCK8 assay. EDU staining was used to assess the proliferation of HK-2 cells following palbiciclib treatment at different concentrations for 5 days. The effect of palbociclib on cell cycle distribution of HK-2 cells was evaluated using flow cytometry. SA-β-Gal staining and C12FDG senescence staining were used to detect senescence phenotypes of HK-2 cells after palbociclib treatment at different concentrations for 5 days. The relative mRNA expression levels of P16, P21, and P53 and the genes associated with senescence-related secretion phenotypes were detected by RT-PCR, and the protein expressions of P16, P21 and P53 were detected by Western blotting. RESULTS: Palbociclib inhibited HK-2 cell proliferation and induced cell cycle arrest in G1 phase. Compared with the control cells, HK-2 cells treated with high-dose (10 μmol/L) palbociclib exhibited significantly suppressed cell proliferation activity, and the inhibitory effect was the most obvious on day 5 ( CONCLUSIONS Palbociclib induces HK-2 cell senescence by causing cell growth arrest and delaying cell cycle progression.
Cell Cycle ; Cell Cycle Checkpoints ; Cellular Senescence ; Epithelial Cells ; Humans ; Piperazines/pharmacology* ; Pyridines/pharmacology* ; Tumor Suppressor Protein p53/genetics*

The aim of this study was to observe the effect of p38MAPK inhibitor SB203580 on ATRA-induced differentiation of NB4 cells. The proliferation activity of cells was assayed by MTT method, the cell cycle was detected by flow cytometry, the differentiation of NB4 cells into granulocytes was measured by test of NBT reduction, the activity of extracellular signal-regulated kinase (ERK) was detected by substrate phosphorylation. The results showed that the ATRA in 0.01-01 micromol/L inhibited the proliferation of NB4 cells in time-and dose-dependent manner and induced the differentiation of NB4 cells into myeloid; the ATRA stimulated ERK activity in this process; ERK inhibitor PD98059 could partially block ATRA effect, specific inhibitor of p38MAPK, SB203580, combined with ATRA also could partially block the effects of ATRA on inhibition of NB4 growth and induction of differentiation. It is concluded that the ATRA stimulates ERK and p38MAPK pathway in the process inducing differentiation of NB4 cells, the ERK and P38MAPK may be necessary for the ATRA-induced differentiation in NB4 cells.
Cell Differentiation ; drug effects ; Cell Division ; Cell Line, Tumor ; Enzyme Inhibitors ; pharmacology ; Flow Cytometry ; Humans ; Imidazoles ; pharmacology ; Mitogen-Activated Protein Kinases ; metabolism ; Pyridines ; pharmacology ; Signal Transduction ; Tretinoin ; pharmacology

AIMTo discover new regulators of potassium channel, an in vitro assay based on DiBAC4 (3) to determine the fluorescence was established for high throughput screening.

METHODSA cell-based 96-well format fluorescence assay using DiBAC4 (3) in cultured PC12 cells was described. Cells were loaded with 5 mumol.L-1 DiBAC4 (3) and incubated at 37 degrees C for 30 min before adding KCl or several known potassium channel regulators. The cellular DiBAC4 (3) fluorescence responce was then detected. The fluorescence changes can be used to evaluate membrane potential changes, which are determined mainly by potassium channels.

RESULTSExtracellular high K(+)-induced depolarization and several potassium channel blockers including 4-AP, TEA, E-4031, glibenclamide, quinidine and nifedipine all evoked increases in DiBAC4 (3) fluorescence response. The potassium channel opener, cromakalim, evoked decrease in DiBAC4 (3) fluorescence response. The fluorescence changes of 4-AP, TEA, glibenclamide, nifedipine and cromakalim were in a concentration-dependent manner. In 76 compounds screened by using the established DiBAC4 (3)-based assay, 9 compounds were found to change the fluorescence dose-dependently. Patch clamp technique is needed to further testify and screen their actions on potassium currents.

CONCLUSIONThe DiBAC4 (3)-based assay is easily operated, economical and repeatable. So, it can be performed by high throughput screening for potassium channel regulators.

4-Aminopyridine ; pharmacology ; Animals ; Barbiturates ; chemistry ; Calcium Channel Blockers ; pharmacology ; Cromakalim ; pharmacology ; Isoxazoles ; chemistry ; Membrane Potentials ; drug effects ; Nifedipine ; pharmacology ; PC12 Cells ; Patch-Clamp Techniques ; Piperidines ; pharmacology ; Potassium Channel Blockers ; pharmacology ; Potassium Channels ; drug effects ; Pyridines ; pharmacology ; Quinidine ; pharmacology ; Rats