Ethyl pyruvate improves survival and ameliorates distant organ injury in rats with severe acute pancreatitis.

OBJECTIVE: To evaluate the effect of ethyl pyruvate (EP) in improving the survival and ameliorating distant organ damage and to investigate the role of high-mobility group box (HMGB) 1 in rats with established severe acute pancreatitis (SAP). METHODS: Severe acute pancreatitis was induced by retrograde infusion of sodium taurodeoxycholate (5%, 1 mL/kg) into the biliopancreatic ducts in male Wistar rats. The rats were infused intravenously with EP of 40 mg/kg, 4 mg/kg, and 0.4 mg/kg initiating 12 hours, and EP of 40 mg/kg was administered beginning 2 hours before surgery (-2 hours) and 12, 24, and 36 hours after induction of SAP; then, the mortality was recorded. Serum tumor necrosis factor alpha, interleukin (IL) 6, and IL-1beta were measured using enzyme-linked immunosorbent assay. High-mobility group box 1 levels were measured using Western immunoblotting analysis. RESULTS: Serum HMGB1 levels were increased dramatically after 12 hours, remained at high levels for 72 hours, and were significantly higher in rats with SAP than in those with mild and moderate pancreatitis (P < 0.01). Treatment with EP (40 mg/kg) conferred protection from lethality of SAP (EP survival [63%] vs vehicle survival [6.3%]; P < 0.001). No survival advantage occurred when treatment was initiated 36 hours after surgery, but administration beginning 2 hours before operation (-2 hours) and 12 and 24 hours after induction of SAP significantly increased survival. Ethyl pyruvate treatment significantly decreased serum HMGB1, tumor necrosis factor alpha, IL-1beta, and IL-6 levels and ameliorated extrapancreatic organ dysfunction in rats with SAP. CONCLUSIONS: Ethyl pyruvate improves survival and ameliorates distant organ injury of SAP. These beneficial effects of EP are because of the modulation of HMGB1 and other inflammatory cytokine responses.

[Inhibitory effect of sodium butyrate on 1,2-dimethylhydrazine-induced tumorigenesis of colorectal cancer in mice].

BACKGROUND & OBJECTIVE: In vitro studies proved that sodium butyrate (NaB) could stimulate cell differentiation, inhibit cell proliferation, and induce cell apoptosis in various tumors. This study was to evaluate the preventive effects of coloclysis of NaB on 1,2-dimethylhydrazine (DMH)-induced tumorigenesis of colorectal cancer in mice. METHODS: The mice of Kunming species were divided into 5 groups and received relevant treatments: DMH alone group (with subcutaneous injection of 30 mg/kg of DMH weekly for 11 weeks), control (normal saline, NS) group, DMH plus low dose of NaB (1.25 mol/kg, 24-week coloclysis) group, DMH plus high dose of NaB (2.5 mol/kg, 24-week coloclysis) group, and high dose of NaB group. The mice were killed in batches at the 12th, 18th, and 24th weeks of carcinoma induction separately. The incidence of colorectal tumor in each group was observed. Meanwhile, the general condition, body weight increasing, liver and renal functions, and pathologic changes of liver, kidney, lungs, and pancreas of the mice in DMH plus high dose of NaB group were also observed. RESULTS: No tumor was observed at the 12th week in each group. At the 18th week, the tumor incidence was significantly higher in DMH alone group and DMH plus low dose of NaB group than in DMH plus high dose of NaB group (58.3%, and 25.0% vs. 0, P < 0.01). At the 24th week, the tumor incidence was 95.0% in DMH alone group, 45.0% in DMH plus low dose of NaB group, and 15.0% in DMH plus high dose of NaB group; the differences among the 3 groups were significant (P=0.01, P < 0.01). No tumor was observed in control group and high dose of NaB group. There was no difference in the general condition, body weight increasing, and liver and renal functions of the mice between control group and high dose of NaB group (P > 0.05); no pathologic changes in liver, kidney, lungs, and pancreas were observed in the mice in high dose of NaB group. CONCLUSION: NaB could inhibit DMH-induced tumorigenesis of colorectal cancer in mice with no obvious toxicity.

Effect of NS-398 on colon cancer cells.

AIM: To study the effect of NS-398, a selective cyclooxygenase-2 (COX-2) inhibitor, on invasion of colon cancer cell line HT-29 in vitro and to explore its mechanisms. METHODS: Invasive behaviors of the malignant colon cancer cell line HT-29 were investigated in this study. Expressions of COX-2 and CD44v6 in HT-29 cells were detected by flow cytometry. Cellular survival rate was determined by MTT assay. The invasive capacity was quantified by a modified Boyden chamber model. Alterations of cytoskeleton component F-actin were observed by confocal laser scanning microscope. RESULTS: Flow cytometry analysis showed that COX-2 was highly expressed in HT-29 cells. The invasive capability of HT-29 cells could be greatly inhibited by NS-398 at the experimental concentrations of 0.1, 1.0 and 10 micormol/L with an inhibitory rate of 22.74%, 42.35% and 58.61% (P<0.01), respectively. MTT assay showed that NS-398 at the experimental concentrations had no significant influence on cellular viability, indicating that such anti-invasive effects had no relationship with cytotoxicity. F-actin was mainly distributed around nuclei forming annular structure in HT-29 cells. After exposure to NS-398 of 10 micromol/L, the annular structure around nuclei disappeared and the fluorescence intensity of F-actin decreased obviously. Treatment with NS-398 could down-regulate the expression of CD44v6 as well. CONCLUSION: NS-398 has anti-invasive effects on colon cancer HT-29 cells in vitro, which may be mediated by a novel mechanism of disruption of cytoskeleton. Down-regulation of CD44v6 expression may be related to alterations of cytoskeleton.

Alterations in expression, proteolysis and intracellular localizations of clusterin in esophageal squamous cell carcinoma.

AIM: To investigate biogenesis and intracellular localizations of clusterin to elucidate the potential molecular mechanisms implicated in tumorigenesis of esophageal mucosa. METHODS: Semi-quantitative RT-PCR for multi-region alteration analysis, Western blot for different transcriptional forms and immunohistochemical staining for intracellular localizations of clusterin were carried out in both tissues and cell lines of ESCC. RESULTS: The N-terminal deletions of the clusterin gene and the appearance of a 50-53 ku nuclear clusterin, an uncleaved, nonglycosylated, and disulfide-linked isoform, were the major alterations in cancer cells of esophagus. Naturally the 40 ku clusterin was located in the connective tissue of the lamina propria of epithelial mucosa and right under the basal membrane of epithelia, but it was disappeared in stromal mucosa of esophagus and the pre-matured clusterin was found positive in cancerous epithelia. CONCLUSION: The N-terminal deletion of clusterin may be essential for its alterations of biogenesis in ESCC.

[A randomized controlled Multi-center clinical trial on mosapride in the treatment of functional dyspepsia].

OBJECTIVE: To evaluate the effectiveness and safety of mosapride on treatment of functional dyspepsia. METHODS: Randomized controlled clinical trial was conducted and patients suffered from functional dyspepsia were included. 5 mg mosapride was given three times daily for 4 weeks in the treatment group. 10 mg domperidone was given three times daily for 4 weeks as control. Changes on symptom score, gastric empty or new occurring events were included as outcomes. RESULTS: 231 patients suffered from functional dyspepsia were selected by inclusion and exclusion criteria from August 15 to Oct 22, 1999. Of these, 108 (46.8%) were males, versus 123 (53.2%) females and 118 (51.2%) in the treatment group and 113 (48.9%) as controls. 222 (96.1%) patients were followed up. Results showed that the total efficacy rates in early satiety and abdominal distension were 84.5% and 90.1% in mosapride after the 2 weeks of treatment. Mosapride seemed to be more effective in improving symptoms of belching and heartburn than that in controls (P < 0.05). In 4 weeks, the total efficacy in improving symptoms of abdominal distention and belching showed more effective in mosapride than that in controls (P < 0.05). Decrease of symptoms score was more in mosapride than that in controls (P < 0.05). Mosapride was less effective in controls in improving the gastric empty in terms of proportion (46.2% vs. 25.9%, P = 0.020) and range (46.2% vs. 24.0%, P = 0.003). Side effects would include diarrhea, constipation, headache, dizziness, insomnia, skin scare and the like. There was no significant difference between the two groups (9.6% in mosapride vs. 14.0% in controls). CONCLUSION: Mosapride was safe and effective in improving the symptoms and gastric empty of functional dyspepsia.