Chengwei Tang

Antitumor effects of ginsenoside Rg3 on human hepatocellular carcinoma cells

The antitumor effects of ginsenoside Rg3 have been reported in several kinds of human malignant tumors. The purpose of this study was to investigate whether ginsenoside Rg3 can inhibit the growth of human hepatocellular carcinoma cell lines and to discuss the possible molecular mechanism(s). We cultured the human hepatocellular carcinoma cell lines, SMMC-7721 and HepG2. The cells were treated with different concentrations of ginsenoside Rg3 (0, 25, 50, 75 and 100 µg/ml), and the cell proliferation was detected by MTT assay at the 12, 24, 36 and 48 h time-points. Flow cytometry experiments were carried out to investigate the effect of Rg3 on cell apoptosis after the cells had been treated with Rg3 (50 and 100 µg/ml) for 24 and 48 h. The expression levels of caspase-3, bax and bcl-2 in Rg3-treated cells (100 µg/ml, 48 h), as well as normal cells were detected through real-time PCR experiments. MTT assay showed that the inhibition rate of cell proliferation in the Rg3 groups was significantly higher compared to the control groups in both the SMMC-7721 and HepG2 cell lines, and the inhibition rate increased with increasing Rg3 concentrations and duration of treatment. Flow cytometry analysis demonstrated that the Rg3 groups had a significantly higher cell apoptotic rate compared to the control groups in both the SMMC-7721 and HepG2 cell lines, and that the effect of Rg3 on cell apoptosis occurred in a concentration- and time-dependent manner, as was also shown by the MTT assay. Real-time PCR analysis showed that the gene expression levels of caspase-3 and bax were significantly enhanced in the Rg3 groups compared to the control groups in both the SMMC-7721 and HepG2 cell lines, but the gene expression level of bcl-2 was significantly inhibited. These results indicate that ginsenoside Rg3 can effectively inhibit the growth of human hepatocellular carcinoma cell lines by inhibiting cancer cell proliferation and promoting cancer cell apoptosis, and it may promote cancer cell apoptosis via the endogenous mitochondrial-mediated caspase-dependent apoptotic pathway.

Recurrent Variceal Bleeding and Shunt Patency: Prospective Randomized Controlled Trial of Transjugular Intrahepatic Portosystemic Shunt Alone or Combined with Coronary Vein Embolization

PURPOSE To prospectively evaluate the efficacy of a transjugular intrahepatic portosystemic shunt (TIPS) alone and TIPS in association with embolotherapy (TIPS+E) in the variceal coronary vein to prevent recurrent variceal bleeding and stent dysfunction after TIPS creation. MATERIALS AND METHODS Institutional review board approval was obtained; all participants provided informed consent. A total of 106 patients (66 men, 40 women; age range, 18-70 years) with recurrent variceal bleeding due to hepatic cirrhosis were assigned randomly to the TIPS+E (n = 54) or TIPS (n = 52) group from May 2007 to July 2011. The TIPS was created by using covered stents. Patients in the TIPS+E group underwent embolotherapy via the jugular vein before TIPS implantation. Rates of recurrent variceal bleeding, stent patency, and survival were evaluated. Scores for liver function and life quality were calculated. RESULTS TIPS placement was successful in all patients. Recurrent variceal bleeding ranked second among causes of death after TIPS placement. Although the 3-year cumulative rates of shunt patency, recurrent variceal bleeding, and survival in the two groups were not significantly different (P > .05), the 6-month overall rate of shunt patency in the TIPS+E group was significantly higher than that in the TIPS group (96.2% vs 82.0%, P = .019), and the 6-month overall rate of recurrent variceal bleeding was also significantly lower than that in the TIPS group (5.7% vs 20.0%, P = .029). CONCLUSION The TIPS+E regimen may reduce the risk of recurrent variceal bleeding during the first 6 months after the TIPS procedure by preventing shunt dysfunction, which may improve liver function and quality of life.

Celecoxib Ameliorates Portal Hypertension of the Cirrhotic Rats through the Dual Inhibitory Effects on the Intrahepatic Fibrosis and Angiogenesis

Background Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2) in the cirrhotic liver might be a potential target to ameliorate portal hypertension. Objective To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. Methods Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and related signal molecules were quantitated. Results Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, p<0.01. Celecoxib treatment greatly reduced the tortuous hepatic portal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, p<0.01. Furthermore, the up-regulation of hepatic mRNA and protein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1α (HIF-1α), and c-fos were also down-regulated after celecoxib treatment. Conclusions Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its modulation on VEGF/VEGFR-2 through the down-regulation of integrated signal pathways involving PGE2- HIF-1α- VEGF and p-ERK- c-fos- VEGFR-2.

Celecoxib attenuates hepatic cirrhosis through inhibition of epithelial-to-mesenchymal transition of hepatocytes

The epithelial–mesenchymal transition (EMT) of hepatocytes is a key step for hepatic fibrosis and cirrhosis. Long‐term administration of celecoxib, a selective cyclooxygenase‐2 (COX‐2) inhibitor, can ameliorate hepatic fibrosis. This research aimed to examine the effect of celecoxib on the EMT of hepatocytes during the development of liver cirrhosis.

The Prognostic Significance of Pretreatment Serum CEA Levels in Gastric Cancer: A Meta-Analysis Including 14651 Patients

Background Carcinoembryonic antigen (CEA) is commonly used as a serum tumor marker in clinical practice; however, its prognostic value for gastric cancer patients remains uncertain. This meta-analysis was performed to assess the prognostic value of CEA and investigate CEA as a tumor marker. Methods PubMed, EMBASE and other databases were searched for potentially eligible studies. Forty-one studies reporting the prognostic effect of pretreatment serum CEA expression in gastric cancer patients were selected. Data on 14651 eligible patients were retrieved for the meta-analysis. Based on the data extracted from the available literature, the hazard ratio (HR) and 95% confidence interval (CI) for an adverse prognosis were estimated for gastric cancer patients with elevated pretreatment serum levels of CEA (CEA+) relative to patients with normal pretreatment CEA levels (CEA-). Results The CEA+ patients had a significantly poorer prognosis than the CEA- patients in terms of overall survival (OS: HR 1.716, 95% CI 1.594 - 1.848, P< 0.001), disease-specific survival (DSS: HR 1.940, 95% CI 1.563 - 2.408, P< 0.001), and disease-free survival (DFS: HR 2.275, 95% CI 1.836 - 2.818, P< 0.001). Publication bias and an influence of different cut-off values were not observed (all P> 0.05). In the pooled analyses of multivariate-adjusted HRs, the results suggested that pretreatment serum CEA may be an independent prognostic factor in gastric cancer (OS: HR 1.681, 95% CI 1.425 - 1.982; DSS: HR 1.900, 95% CI 1.441 - 2.505; DFS: HR 2.579, 95% CI 1.935 - 3.436). Conclusion/Significance The meta-analysis based on the available literature supported the association of elevated pretreatment serum CEA levels with a poor prognosis for gastric cancer and a nearly doubled risk of mortality in gastric cancer patients. CEA may be an independent prognostic factor for gastric cancer patients and may aid in determining appropriate treatment which may preferentially benefit the CEA+ patients.

Prevention of severe acute pancreatitis with octreotide in obese patients: a prospective multi-center randomized controlled trial.

Objectives To evaluate the efficacy of octreotide in preventing severe acute pancreatitis (SAP) in obese patients. Methods A prospective multi-center partly randomized control trial was conducted in patients with mild acute pancreatitis (AP). Nonobese patients received conventional management (nonobese-C, n = 82), whereas obese patients (body mass index ≥25 kg/m2) were randomized into 2 groups: obese-C (n = 79), who received conventional management, and obese-C+O (n = 82), who received conventional management plus intravenous infusion of octreotide, 50 &mgr;g/h for 72 hours. Results The risk ratio and relative risk reduction in the development of SAP in the obese-C+O group were 0.27 (95% confidence interval, 0.10–0.69) and 0.73 (95% confidence interval, 0.31–0.90), respectively. The number of cases developing local complications in the obese-C+O group was significantly smaller than that in the obese-C group: 4.9% vs 19%, P = 0.006. The plasma level of somatostatin in the obese-C+O group was significantly higher than that in the obese-C group: 165.5 ± 42.6 vs 112.1 ± 24.86 pg/mL, P < 0.05. Supplement of octreotide also accompanied with reduction in plasma levels of tumor necrosis factor &agr; and IL-6. Conclusions Intravenous administration of octreotide (50 &mgr;g/h) for 72 hours in the early stage of AP could prevent the development of SAP effectively in obese patients by raising plasma somatostatin to a normal level and reducing circulating cytokines.

Pilot study of urgent endoscopic intervention without fluoroscopy on patients with severe acute biliary pancreatitis in the intensive care unit.

Objective: The effect of early endoscopic intervention (EI; within 72 hours) remains a controversial subject. This prospective study was aimed to evaluate the efficacy of early EI without fluoroscopy on severe acute biliary pancreatitis (SABP) in the intensive care unit (ICU). Methods: Fifty-three patients with SABP + ampullary obstruction in the ICU were divided randomly into 2 groups: conservative treatment in the ICU (CTI arm) and CTI + EI without the aid of fluoroscopy (CTI + EI arm). Decreased Acute Physiology and Chronic Health Evaluation II score was the major parameter to assess treatment efficacy. Results: Endoscopic treatments including sphincterotomy + stone removal (17 cases) and nasobiliary drainage (4 cases) were successfully performed in all 21 enrolled patients without the aid of fluoroscopy in the ICU. Compared with CTI, CTI + EI significantly resulted in decreased (3.86 ± 2.08 vs 6.57 ± 1.54) Acute Physiology and Chronic Health Evaluation II score at day 10, P < 0.05. No deaths were observed in the CTI + EI, whereas the CTI arm had 2 mortalities. Conclusions: Urgent EI without fluoroscopy is possible to be performed by endoscopists with the experience from high volume of procedures and is beneficial for the patients with SABP in the ICU or community hospital.

Immunomodulatory therapies for acute pancreatitis.

It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3(rd) d to the 14(th) d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis.

Stent-grafts for the treatment of TIPS dysfunction: Fluency stent vs Wallgraft stent

AIM To evaluate the clinical efficacy of an expanded polytetrafluoro-ethylene-covered Fluency stent compared with that of a polyethylene terephthalate-covered Wallgraft stent for the management of transjugular intrahepatic portosystemic shunt (TIPS) dysfunction. METHODS A retrospective review of patients who underwent TIPS revision with stent-grafts between May 2007 and June 2011 was conducted. The patients were divided into two groups according to the stent-grafts implanted: the Fluency stent (Bard Incorporated, Karlsruhe, Germany) and the Wallgraft stent (Boston Scientific, Galway, Ireland). The primary patency rates were calculated and compared using the Kaplan-Meier method. RESULTS A total of 73 patients were evaluated in this study: 33 with Fluency stents and 40 with Wallgraft stents. The primary patency rates at 12 and 24 mo were 91% and 85%, respectively, in the Fluency stent group and 78% and 63%, respectively, in the Wallgraft stent group. The primary shunt patency rates after TIPS revision were significantly better with the Fluency stent than with the Wallgraft stent (P = 0.033). CONCLUSION TIPS revision with the Fluency stent has higher medium-term patency rates than that with the Wallgraft stent.

Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer.

AZD6244 (ARRY-142886), a highly selective MAPK-ERK kinase inhibitor, has shown excellent clinical efficacy in many tumors. However, the anti-tumor and anti-angiogenesis efficacy of AZD6244 on gastric cancer has not been well characterized. In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. For absence of NRAS, KRAS and BRAF mutation, SGC7901 and BGC823 gastric cancer cells were relative resistance to AZD6244 in vitro. And such resistance was not attributed to the insufficient inhibition of ERK phosphorylation. However, tumor growth was significantly suppressed in SGC7901 xenografts by blockage of angiogenesis. This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244. Moreover, the anti-angiogenesis effect of AZD6244 may predominantly attribute to its modulation on VEGF through p-ERK − c-Fos − HIF-1α integrated signal pathways. In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. Targeting inhibition of p-ERK by AZD6244 suppress gastric cancer xenografts by blockage of angiogenesis without systemic toxicity. The anti-angiogenesis effect afford by AZD6244 may attribute to its modulation on p-ERK − c-Fos − HIF-1α − VEGF integrated signal pathways.