Tolerance of neurite outgrowth to Rho kinase inhibitors decreased by cyclooxygenase-2 inhibitor

In this study, PC12 Adh cells and Neuro-2a cells were treated with Rho-associated kinase inhibitors （Y27632 and Fasudil）, a cyclooxygenase-1 selective inhibitor （SC560）, and a cyclooxygenase-2 inhibitor （NS398）. We found that these cells became tolerant to Rho-associated kinase inhibitors, as neurite outgrowth induced by these inhibitors diminished following more than 3 days of exposure in either cell line. The proteins cyclooxygenase-2 and cytosolic prostaglandin E synthetase were upregulated at day 3. NS398 decreased the tolerance to neurite outgrowth induction in both cell lines, whereas SC560 had almost no effect. These findings indicate that cells become tolerant to neurite outgrowth induced by Rho-associated kinase inhibitors, this is at least partly associated with upregulation of proteins involved in the cyclooxygenase-2 pathway, and cyclooxygenases-2 inhibition prevents this tolerance.

Selective COX-2 inhibitor,NS-398,suppresses cellular proliferation in human hepatocellular carcinoma cell lines via cell cycle arrest

AIM: To investigate the growth inhibitory mechanism of NS-398, a selective cyclooxygenase-2 (COX-2) inhibitor, in two hepatocellular carcinoma (HCC) cell lines (HepG2 and Huh7). METHODS: HepG2 and Huh7 cells were treated with NS-398. Its effects on cell viability, cell proliferation, cell cycles, and gene expression were respectively evaluated by water-soluble tetrazolium salt (WST-1) assay, 4’-6-diamidino-2-phenylindole (DAPI) staining, flow cytometer analysis, and Western blotting, with dimethyl sulfoxide (DMSO) as positive control. RESULTS: NS-398 showed dose- and time-dependent growth-inhibitory effects on the two cell lines. Proliferating cell nuclear antigen (PCNA) expressions in HepG2 and Huh7 cells, particularly in Huh7 cells were inhibited in a time- and dose-independent manner. NS-398 caused cell cycle arrest in the G1 phase with cell accumulation in the sub-G1 phase in HepG2 and Huh7 cell lines. No evidence of apoptosis was observed in two cell lines. CONCLUSION: NS-398 reduces cell proliferation by inducing cell cycle arrest in HepG2 and Huh7 cell lines, and COX-2 inhibitors may have potent chemoprevention effects on human hepatocellular carcinoma.

Effect of Nimesulide on proliferation and apoptosis of human hepatoma SMMC-7721 cells

AIM: Cyclooxygenase-2 (COX-2) has been suggested to be associated with carcinogenesis. We sought to investigate the effect of the selective COX-2 inhibitor, Nimesulide on proliferation and apoptosis of SMMC-7721 human hepatoma cells.METHODS: This study was carried out on the culture of hepatic carcinoma SMMC-7721 cell line. Various concentrations of Nimesulide (0, 200 micromol/L, 300 micromol/L, 400 micromol/L) were added and incubated. Cell proliferation was detected with MTT colorimetric assay, cell apoptosis by electron microscopy, flow cytometry and TUNEL.RESULTS: Nimesulide could significantly inhibit SMMC-7721 cells proliferation dose-dependent and in a dependent manner compared with that of the control group. The duration lowest inhibition rate produced by Nimesulide in SMMC-7721 cells was 19.06%, the highest inhibition rate was 58.49%. After incubation with Nimesulide for 72 h, the most highest apoptosis rate and apoptosis index of SMMC-7721 cells comparing with those of the control were 21.20%+/-1.62% vs 2.24%+/-0.26% and 21.23+/-1.78 vs 2.01+/-0.23 (P【0.05). CONCLUSION:The selective COX-2 inhibitor, Nimesulide can inhibit the proliferation of SMMC-7721 cells and increase apoptosis rate and apoptosis index of SMMC-7721 cells. The apoptosis rate and the apoptosis index are dose-dependent. Under electron microscope SMMC-7721 cells incubated with 300 micromol and 400 micromol Nimesulide show apoptotic characteristics. With the clarification of the mechanism of selective COX-2 inhibitors, These COX-2 selective inhibitors can become the choice of prevention and treatment of cancers.

Education-based approach to addressing non-evidence-based practice in preventing NSAID-associated gastrointestinal complications

AIM:To evaluate an evidence-based educational program for improving strategies for prevention of non-steroidal anti-inflammatory drug(NSAID)-associated gastrointestinal(GI)complications. METHODS:Four hundred and fifty-six specialists replied to a questionnaire that covered issues related to NSAID-induced adverse effects.They also collected data from their last five consecutive patients before and after they had attended an evidence-based seminar on GI prevention strategies. RESULTS:Four hundred and forty-one of 456 specialists(96.7%)participated in the survey,and 382(83.7%)in the education-based study that recorded data from 3728 patients.The specialists overestimated the risk of GI complications with NSAIDs,underestimated the GI safety profile of coxibs,but were aware of the risk factors and of the current prevention strategies.Proton pump inhibitors were co-prescribed with NSAIDs in>80% of patients with and without risk factors.The educational program had little impact on prescribing habits.CONCLUSION:Specialists are informed of advances in NSAID-associated adverse effects and have high rates of GI-prevention therapy.Our educational program did not alter these rates.

Nicotine enhances migration and invasion of human esophageal squamous carcinoma cells which is inhibited by nimesulide

AIM： To study the effect of nicotine on the migration and invasion of human esophageal squamous carcinoma cells and to investigate whether nimesulide can inhibit the effect of nicotine.METHODS： The esophageal squamous carcinoma cell line （TE-13） was treated with different concentrations of nicotine （100 μg/mL and 200 μg/mL） or 200 μg/mL nicotine plus 100 μmol/L nimesulide. Cell migration and invasion were measured using migration and invasion chamber systems. COX-2 expression was determined by Western blotting. Matrix metalloproteinase-2 （MMP-2） was analyzed by zymography and ELISA.RESULTS： Nicotine （100 μg/mL, 200 μg/mL） enhanced TE-13 cells migration and invasion, and increased the protein expression of COX-2 and the activity of MMP-2. Nicotine （200 μ/mL） stimulated TE-13 cells migration and invasion which were partly blocked by nimesulide. This was associated with decreased protein expression of COX-2 and decreased activity and protein expression of MMP-2. CONCLUSION： Nicotine enhances the migration and invasion of the esophageal squamous carcinoma cell line, and nimesulide partly blocks the effect ofnicotine-enhanced esophageal squamous carcinoma cell migration and invasion.

Efficacy and safety of perioperative parecoxib for acute postoperative pain treatment in children： a meta-analysis

Perioperative parecoxib administration reduces postoperative pain, opioid consumption, and adverse events in adult patients. However, the efficacy and safety of parecoxib in children remain unclear. This meta-analysis included related published studies to address this concern. Eight databases in the literature until February 2015 were systematically explored to identify randomized controlled trials （RCTs） comparing perioperative parecoxib administration and placebo/standard treatments for acute postoperative pain in children. Primary outcomes were postoperative pain scores and adverse events. The Face, Legs, Activity, Crying, Consolability scale was used to score pain in children younger than 6 years, whereas the Visual Analog Scale was used in children older than 6 years. Secondary outcomes were sedation scores （measured using the Ramsay scale）, agitation scores （measured using the Sedation-Agitation Scale）, and opioid consumption. The methodological quality of RCTs was independently assessed in accordance with the ＂Risk of bias＂ of Cochrane Collaboration. Data were analyzed using Review Manager 5.2. Twelve RCTs involving 994 patients met the inclusion criteria. Compared with children who received placebo treatment, those who received parecoxib demonstrated lower early （2 h） and later （12 h） postoperative pain scores; lower incidence rates of postoperative nausea, vomiting, and agitation; higher early （1 h） postoperative sedation scores; and lower agitation scores. Similarly, children who received parecoxib had lower early （2 h） and later （12 h） postoperative pain scores, lower incidence rates of postoperative nausea and vomiting, and lower early （1 h） postoperative sedation scores compared with those who received standard treatments; however, these children showed no significant difference in agitation scores. Unfortunately, data on the effect of parecoxib on opioid consumption were insufficient. Overall, these results suggested that perioperative parecoxib administration was associated with less acute postoperative pain and fewer adverse events compared with placebo or standard treatments. Parecoxib administration also resulted in less emergence agitation compared with placebo treatment and less excessive sedation concern compared with standard treatments. However, the long-term effects, effects on opioid consumption, and patient satisfaction of parecoxib administration warrant further investigation.