OBJECTIVETo explore the in vitro anti-platelet effects of Ginsenoside -2A,a purified extract from Panax notoginseng.

METHODSPlatelet rich plasma (PRP) was prepared routinely from venous blood samples of patients with essential hypertension and normal persons. PRP was incubated with different concentrations of Nifedipine, Ginsenoside-2A ,and SK&F96365. Maximal platelet aggregation rate[ PAG (M) ] induced by 2 micromol/L ADP was taken as the observed index. Five-minute PAG( M) was determined for 5 consecutive times.

RESULTS(1) PAG (M) in essential hypertension group was 0. 89 +/- 0. 06, which was higher than that in the normal group (0. 68 +/-0. 07 ) with significant difference (P <0.01). (2)Nifedipine of two concentrations (10 p.mol/L,20 pVmol/L) had no effect on PAG(M) in either essential hypertension group or normal group(P >0. 05). (3)Different concentrations of SK&F96365 (2.5 micromol/L,5 micromol/L,10 micromol/L and 20 micromol/L) could inhibit the PAG(M) in essential hypertension group; (4) Differen concentrations of Ginsenoside -2A (2. 5 micromol/L, 5 micromol/L, 10 micromol/L and 20 micromol/L) could inhibit PAG ( M) in essential hypertension group; three concentrations of Ginsenoside -2A (5 micromol/L, 10 micromol/L, 20 micromol/L) could inhibit the PAG(M) in the normal group (all P <0.05).

CONCLUSIONPlatelet aggregating function in essential hypertension patients was obviously higher than that in the normal persons and platelets was in the high reactive status. Nifedipine had no inhibitive effect on platelet aggregation. SK&F96365 could inhibit the platelet aggregation. Ginsenoside-2A could inhibit platelet aggregation, and had the definite anti-platelet action.

Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Ginsenosides ; administration & dosage ; pharmacology ; Humans ; Imidazoles ; administration & dosage ; pharmacology ; Nifedipine ; administration & dosage ; pharmacology ; Platelet Aggregation Inhibitors ; administration & dosage ; pharmacology

The remarkable therapeutic success of PDE5 inhibitors in the treatment of male erectile dysfunction has focused the attention of the researchers on better defining the properties of the individual inhibitors and PDE5 that contribute to the high affinity of these inhibitors for interaction with the PDE5 catalytic site. Recent molecular studies have demonstrated that vardenafil has high affinity for PDE5 and low dissociation rate from PDE5, which serves to explain why vardenafil works with low dosage, onsets quickly and has curative action in clinical practice. Moreover, the potency of vardenafil depends on its ring structure that resembles the purine moiety in cGMP.
Drug Interactions ; Erectile Dysfunction ; drug therapy ; Humans ; Imidazoles ; chemistry ; pharmacology ; Male ; Molecular Structure ; Phosphodiesterase Inhibitors ; chemistry ; pharmacology ; Piperazines ; chemistry ; pharmacology ; Sulfones ; chemistry ; pharmacology ; Triazines ; chemistry ; pharmacology ; Vardenafil Dihydrochloride

OBJECTIVETo study the inhibitory effect of zoledronic acid (ZA) on the growth and CD138 expression of myeloma cell line KM3.

METHODSKM3 cells were treated with different concentrations of ZA The growth of KM3 cells was measured by trypan blue dye exclusion, and the changes of apoptosis rate, cell cycle and expression of CD138 induced by ZA by flow cytometry.

RESULTSWithin the concentration of 10(-5)-10(-3) mol/L, ZA obviously inhibited the growth of KM3 cells in a dose dependent manner. IBN at 10(-5)-10(-4) moL/L increased Annexin V positive rate, blocked cells at the S/G2 boundary, reduced the expression of CD138 and its fluorescence intensity.

CONCLUSIONZA can inhibit the growth of KM3 cells in a dose-dependent manner and inhibited CD138 expression. The mechanism is probably related to induction cell cycle accumulation in S phase and apoptosis.

Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Diphosphonates ; pharmacology ; Humans ; Imidazoles ; pharmacology ; Syndecan-1 ; metabolism

Both AM1 semi-empirical quantum chemistry method and HF/3-21g* ab initio method were employed to get related parameters or descriptors, particularly, the parameters of the solvation energy delta G with polarizable continuum model, for 42 anti-HIV 5-phenyl-1-phenylamino-1H-imidazole derivatives with known cytotoxicity. With parameters of quantum chemical calculation and traditional ones, 2 multiple linear regression models were obtained. The better regression equation has a high correlation coefficient (r = 0.938) and a low standard deviation (s = 0.125) and the squared correlation coefficient Q2 of the cross-validation is 0.799 (literaure: 0.740) by leave-one-out method. The results have certain significance for the design of new anti-HIV-1 drugs with lower cytotoxicity.
Anti-HIV Agents ; chemistry ; pharmacology ; toxicity ; Imidazoles ; chemistry ; pharmacology ; toxicity ; Linear Models ; Models, Chemical ; Quantitative Structure-Activity Relationship

OBJECTIVETo study whether necroptosis exists or not in neural cell death induced by aluminum.

METHODSSH-SY5Y cells were treated with 4 mmol/L AlCl(3) x 6H(2)O The cell viability was determined with CCK-8 kit after treated with Nec-1 at different dosages (0, 30, 60, 90 micromol/L). Mitochondria membrane potential (MMP), content of reactive oxygen species (ROS), and apoptotic rate/necrotic rates were measured with cytometry.

RESULTSNec-1 ameliorated the necrotic-like cell morphology, the cell viability were 0.28 +/- 0.05, 0.58 +/- 0.03, 0.68 +/- 0.04, and 1.03 +/- 0.17, there were significant differences between the Nec-1 treated groups and that of controls (t values were 3.25, 3.36, 4.56; P < 0.05). After Nec-1 treatment, the necrotic rates were 16.46% +/- 0.54%, 10.40% +/- 0.64%, 5.43% +/- 0.68%, and 6.28% +/- 0.35%, there were significant differences between the Nec-1 treated cells and that of controls (t values were 3.62, 7.32, 6.96; P < 0.05); while the apoptotic rates were 8.68 +/- 0.36, 7.66 +/- 0.53, 5.68 +/- 0.41, and 4.13 +/- 0.41, there was no significant difference among the groups (F = 6.33, P = 0.11). Cytometry had shown the increased cell MMPs after Nec-1 treatment, which were 67.54 +/- 6.36, 49.42 +/- 5.96, 84.79 +/- 6.86, and 95.51 +/- 7.01, there were significant differences as comparing MMPs of the middle and high dosage of Nec-1 treated cells with those of controls (t values were 3.21, 4.01; P < 0.05); while ROS contents in the Nec-1 treated SH-SY5Y cells were 54.07 +/- 3.32, 52.79 +/- 2.36, 54.68 +/- 1.91, and 59.23 +/- 2.96, there was no significant difference among the groups (F = 5.26, P = 0.19).

CONCLUSIONNec-1, as a specific inhibitor of necroptosis, might effectively block the cell death pathway induced by aluminum, it indicates that necroptosis should be one of the major causes of the SH-SY5Y cell toxicity induced by aluminum, and necroptosis also plays an important role in aluminum induced SH-SY5Y cell death.

Aluminum ; toxicity ; Apoptosis ; drug effects ; Cell Death ; drug effects ; Cell Line, Tumor ; Humans ; Imidazoles ; pharmacology ; Indoles ; pharmacology ; Neuroblastoma

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

Spillage of cyst contents during surgical operation is the major cause of recurrence after hydatid cyst surgery. Instillation of a scolicidal agent into a hepatic hydatid cyst is the most commonly employed measure to prevent this complication. SB202190 is a pyridinyl imidazole derivative and is known to be a specific inhibitor of p38 MAPK. In the present study, the scolicidal effect of SB202190 was investigated. Freshly isolated Echinococcus granulosus protoscolices were subjected to SB202190 treatment (10, 20, 40, and 80 microM), and the effects on parasite viability were monitored by trypan blue staining. Corresponding effects were visualized by scanning and transmission electron microscopy. Dose-dependent protoscolex death within a few days of SB202190 treatment was observed. Although the in vitro scolicidal effect of SB202190 was satisfactory, the in vivo efficacy of this drug and also possible side effects remain to be further investigated.
Animals ; Anthelmintics/*pharmacology ; Dose-Response Relationship, Drug ; Echinococcus granulosus/*drug effects/ultrastructure ; Imidazoles/*pharmacology ; Microscopy, Electron, Scanning ; Microscopy, Electron, Transmission ; Parasitic Sensitivity Tests ; Pyridines/*pharmacology ; Survival Analysis

OBJECTIVETo explore the role of p38 signal pathway in regulating matrix metalloproteinase-9 (MMP-9) expression and brain edema formation in a rat model of traumatic brain injury (TBI).

METHODSA total of 130 adult male Sprague Dawley rats were randomly divided into 4 groups, namely the normal group (n=10), sham-operated group (n=40), TBI (induced by Feeney free falling methods) group (n=40), and SB group with intraperitoneal SB203580 treatment (10 µmol/L) 15 min before TBI (n=40). The rats were sacrificed 2 h and 2 days after TBI. The expressions of p38, p-p38, and MMP-9 mRNA and protein were detected by RT-PCR and Western blotting. The blood brain barrier permeability was detected by Evans Blue (EB) test, and the brain water content (BWC) was determined using a gravimetric technique.

RESULTSThe expression of p-p38 protein increased markedly 2 h after TBI (P<0.05), and was suppressed by SB203580 treatment (P<0.05). MMP-9 mRNA and protein showed no obvious increase at 2 h after TBI, but significantly increased at 2 days as compared with those in the sham-operated group (P<0.05). MMP-9 mRNA and protein were much lower in SB group than in TBI group 2 days after TBI (P<0.05). The blood brain barrier permeability significantly increased 2 h after TBI (P<0.05) and kept increasing until 2 days (P<0.05), but was reduced significantly by SB203580 (P<0.05). BWC increased obviously 2 days after TBI (P<0.05) and was lessened by SB203580 (P<0.05).

CONCLUSIONBlocking p38 signal pathway can attenuate MMP-9 upregulation and brain edema after TBI, suggesting the important role of p38 in regulating MMP-9 expression to affect traumatic brain edema.

Animals ; Brain Edema ; pathology ; Brain Injuries ; metabolism ; Enzyme Inhibitors ; pharmacology ; Imidazoles ; pharmacology ; MAP Kinase Signaling System ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Pyridines ; pharmacology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the roles of p38 MAPK in apoptosis of the normal liver cell, the paratumor cirrhosis hepatocellular cell and the hepatocellular carcinoma cell.

METHODSThree cell lines were adopted (the normal liver cell line HL-7702, the paratumor cirrhosis hepatocellular cell line QSG-7701 and the hepatocellular carcinoma cell line QGY-7703) and treated with Diamminedichloroplatin (DDP, cisplatin) and p38MAPK inhibitor SB203580. The apoptosis and cell cycles were detected by flow cytometry and electromicroscopy. The expressions of p38MAPK, CDC25B, p34cdc2 and cyclinB1 were detected by immunocytochemical staining , confocal microscopy and western blot.

RESULTSThe apoptotic rates in all three cell lines pretreated with DDP increased obviously and the rates in normal liver cells and HCC cells increased continuously even after SB203580 treatment, whereas in paratumor cirrhosis cells the rate decreased and the cell cycle stopped at S phase.

CONCLUSIONCisplatin induces apoptosis in the paratumor cirrhosis hepatocellular cell line QSG-7701 via activation of p38MAPK pathway and it differs in the normal liver cells from the hepatocellular carcinoma cells.

Apoptosis ; drug effects ; Carcinoma, Hepatocellular ; metabolism ; pathology ; Cell Line, Tumor ; Cisplatin ; pharmacology ; Humans ; Imidazoles ; pharmacology ; Liver Neoplasms ; metabolism ; pathology ; Pyridines ; pharmacology ; p38 Mitogen-Activated Protein Kinases ; metabolism

OBJECTIVETo investigate whether the effect of E. coli on U937 cell lines apoptosis is mediated via p38 mitogen-activated protein kinase (MAPK) activation.

METHODSThe U937 cell lines were treated with E. coli at different time or together with SB203580, an inhibitor for p38. Cell apoptosis was analyzed by flow cytometry. p38 activities were detected by Western blotting.

RESULTSE. coli induced apoptosis in cultured U937 cell lines in a time-dependent manner. The phosphorylation of p38 was induced after 10 minutes infection, reached the peak after 20 minutes, and started to decline after 30 minutes. In contrast, the level of total p38 protein was not changed in whole experimental period. Inhibition of p38 with SB203580 significantly inhibited E. coli induced apoptosis in U937 cells.

CONCLUSIONThe activation of the p38 MAPK in U937 cell lines by E. coli is a major pathway to mediate the apoptosis.

Apoptosis ; drug effects ; physiology ; Enzyme Inhibitors ; pharmacology ; Escherichia coli ; Flow Cytometry ; Humans ; Imidazoles ; pharmacology ; Kinetics ; Pyridines ; pharmacology ; U937 Cells ; microbiology ; pathology ; p38 Mitogen-Activated Protein Kinases ; metabolism