ObjectiveThe aim of this study was to investigate the potential mechanism and signaling pathway involved in chemotherapy‐induced intestinal mucosal injury (CIMI), which is a common physiopathological problem in patients with cancer.MethodsFor the in vivo experiment, mice received intraperitoneal injection of 5‐fluorouracil (5‐FU) at a dose of 75 mg/kg/day for 1, 3 or 5 days. Villus height and crypt depth of the small intestine, cell apoptosis and proliferation were then examined to determine the extent of CIMI. The expressions of Akt, p53, PUMA and p21 were evaluated both in vivo in mice models and in vitro in the IEC‐6 and HCT116 cell lines.ResultsAfter 5‐FU therapy both the intestinal villus height (275.93 μm vs 164.52 μm, P < 0.001) and crypt depth (64.13 μm vs 42.48 μm, P < 0.001) were decreased. The apoptotic index was greatly increased from 0.32% to 15.84% (P < 0.001) and proliferation was suppressed (63.58% vs 39.15%, P < 0.001). Additionally, p53 expression was significantly increased in the intestinal crypt along with the expressions of PUMA and p21. Western blot showed that the administration of 5‐FU induced p53/PUMA‐mediated apoptosis and upregulated p21 expression to suppress cell proliferation.ConclusionChemotherapy might mediate intestinal injury via p53/PUMA‐mediated apoptotic signaling and the suppression of proliferation in response to p21.

Objective We aimed to investigate the safety of combined sedation with propofol plus fentanyl in patients with liver cirrhosis during screening esophagogastroduodenoscopy ( SEGD ) and a secondary prophylaxis for esophageal varices, endoscopic gastrointestinal ligation ( EVL ). Methods A total of 309 patients with liver cirrhosis were enrolled and divided into the sedated SEGD group ( n = 83), the sedated EVL group ( n = 137) and the conscious EVL group ( n = 89), respectively, and 100 participants with no liver diseases who underwent endoscopy for gastritis were regarded as the sedated control group. Patients in the sedated groups were administrated with propofol plus fentanyl during the endoscopic procedures and their minimal hepatic encephalopathy and sedation‐related complications, including aspiration, hypoxia, hypotension and bradycardia, were evaluated and compared. The assessments of patient satisfaction and patient cooperation in the sedated and the conscious EVL groups were conducted. Results The incidences of complications during the endoscopic procedures were not significantly different among the sedated groups (20.5% in the sedated SEGD group, 22.6% in the sedated EVL group and 19.0% in the sedated control group). No minimal hepatic encephalopathy was induced in the sedated groups. More patients in the sedated EVL group were satisfactory with the procedure compared with the conscious EVL group, as evaluated by both endoscopists and the cirrhotic patients. Conclusions A combined sedation with propofol plus fentanyl is safe for EVL as well as for SEGD in cirrhotic patients. Sedation might make it easier for endoscopists to perform procedures and might be more acceptable for cirrhotic patients.

The aim of this study was to investigate the potential mechanism and signaling pathway involved in chemotherapy-induced intestinal mucosal injury (CIMI), which is a common physiopathological problem in patients with cancer. For the in vivo experiment, mice received intraperitoneal injection of 5-fluorouracil (5-FU) at a dose of 75 mg/kg/day for 1, 3 or 5 days. Villus height and crypt depth of the small intestine, cell apoptosis and proliferation were then examined to determine the extent of CIMI. The expressions of Akt, p53, PUMA and p21 were evaluated both in vivo in mice models and in vitro in the IEC-6 and HCT116 cell lines. After 5-FU therapy both the intestinal villus height (275.93 μm vs 164.52 μm, P  < 0.001) and crypt depth (64.13 μm vs 42.48 μm, P  < 0.001) were decreased. The apoptotic index was greatly increased from 0.32% to 15.84% ( P  < 0.001) and proliferation was suppressed (63.58% vs 39.15%, P  < 0.001). Additionally, p53 expression was significantly increased in the intestinal crypt along with the expressions of PUMA and p21. Western blot showed that the administration of 5-FU induced p53/PUMA-mediated apoptosis and upregulated p21 expression to suppress cell proliferation. Chemotherapy might mediate intestinal injury via p53/PUMA-mediated apoptotic signaling and the suppression of proliferation in response to p21.

We aimed to investigate the safety of combined sedation with propofol plus fentanyl in patients with liver cirrhosis during screening esophagogastroduodenoscopy (SEGD) and a secondary prophylaxis for esophageal varices, endoscopic gastrointestinal ligation (EVL). A total of 309 patients with liver cirrhosis were enrolled and divided into the sedated SEGD group ( n  = 83), the sedated EVL group ( n  = 137) and the conscious EVL group ( n  = 89), respectively, and 100 participants with no liver diseases who underwent endoscopy for gastritis were regarded as the sedated control group. Patients in the sedated groups were administrated with propofol plus fentanyl during the endoscopic procedures and their minimal hepatic encephalopathy and sedation-related complications, including aspiration, hypoxia, hypotension and bradycardia, were evaluated and compared. The assessments of patient satisfaction and patient cooperation in the sedated and the conscious EVL groups were conducted. The incidences of complications during the endoscopic procedures were not significantly different among the sedated groups (20.5% in the sedated SEGD group, 22.6% in the sedated EVL group and 19.0% in the sedated control group). No minimal hepatic encephalopathy was induced in the sedated groups. More patients in the sedated EVL group were satisfactory with the procedure compared with the conscious EVL group, as evaluated by both endoscopists and the cirrhotic patients. A combined sedation with propofol plus fentanyl is safe for EVL as well as for SEGD in cirrhotic patients. Sedation might make it easier for endoscopists to perform procedures and might be more acceptable for cirrhotic patients.

Acquired vesico-rectal fistula is an uncommon complication of pelvic malignant tumors,surgical injury,inflammatory disorders such as tuberculosis infection,radiotherapy and less commonly diverticulum of the urinary tract.The fistula is often identified by urinary tract abnormalities such as dysuria,recurrent urinary tract infection,pneumaturia,and fecaluria.Here,we report an unusual case of a patient with a vesico-rectal fistula of tuberculous origin,presenting with severe acute diarrhea,metabolic acidosis,hyperchloremia and hypokalemia while with only mild urinary tract symptoms.The patient was cured by tuberculostatic therapy.

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor associated with tumor initiation and progression. AhR expression is significantly increased in gastric cancer tissues and gastric cancer cell lines; however, the relationship between AhR and gastric cancer is still unclear. In the present study, we explored the effects of the inhibition of AhR expression by RNA interference on the biological behavior of gastric cancer cells (MKN45 and SGC7901), and elucidated the specific mechanisms of AhR action in the development of gastric cancer. Results showed that small interfering RNA (siRNA) against AhR effectively inhibited the expression of AhR, and decreased the expression of cytochrome P450 (CYP)1A1 and CYP1B1, which are classic target genes of the AhR pathway. Compared to the negative control group, AhR-siRNA-transfected cells showed decreased cellular growth, delayed G1-S cell cycle progression and increased apoptosis rate. Furthermore, inhibition of AhR expression by siRNA in SGC7901 cells led to decreased cell migratory and invasive ability, accompanied by downregulation of expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9. Our results, therefore, suggest that AhR promotes the growth and invasiveness of gastric cancer cells and AhR may serve as a promising therapeutic target for gastric cancer.

Abstract Background Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor associated with gastric carcinogenesis. 3,3'-Diindolylmethane (DIM) is a relatively non-toxic selective AhR modulator. This study was to detect the effects of DIM on gastric cancer cell growth. Methods Gastric cancer cell SGC7901 was treated with DIM at different concentrations (0,10,20,30,40,50 μmol/L) with or without an AhR antagonist, resveratrol. The expression of AhR and Cytochrome P4501A1 (CYP1A1), a classic target gene of AhR pathway, were detected by RT-PCR and Western blot; cell viability was measured by MTT assay, and the changes in cell cycle and apoptosis were analyzed by flow cytometry. Results RT-PCR and western-blot showed that with the increase of the concentration of DIM, AhR protein gradually decreased and CYP1A1 expression increased, suggesting that DIM activated the AhR pathway and caused the translocation of AhR from cytoplasm to nucleus. MTT assay indicated that the viability of SGC7901 cells was significantly decreased in a concentration- and time-dependent manner after DIM treatment and this could be partially reversed by resveratrol. Flow cytometry analysis showed that DIM arrested cell cycle in G1 phase and induced cell apoptosis. Conclusion Selective aryl hydrocarbon receptor modulator 3,3'-Diindolylmethane inhibits SGC7901 cell proliferation by inducing apoptosis and delaying cell cycle progression. AhR may be a potential therapeutic target for gastric cancer treatment.

Background/aims: Gastrokine-1 is a novel protein that plays an important role in the maintenance of the integrity of the gastric mucosa. However, whether Helicobacter pylori infection and non-steroidal anti-inflammatory drugs, which are known to cause gastric mucosal injuries, affect gastrokine-1 expression in the gastric mucosa is unknown. The aim of the present study was to determine gastric mucosal expression of gastrokine-1 in patients with Helicobacter pylori infection or long-term non-steroidal anti-inflammatory drug administration. Material and Methods: A total of 40 patients with functional dyspepsia (20 with Helicobacter pylori-negative chronic gastritis, and 20 with Helicobacter pylori-positive chronic gastritis), and 37 Helicobacter pylori-negative long-term non-steroidal anti-inflammatory drug users (26 with aspirin, 11 with selective cyclooxygenase-2 inhibitors) were selected. In addition, 20 Helicobacter pylori-negative healthy volunteers were recruited as controls. All subjects underwent endoscopies with biopsies taken from the antrum and the sites with lesions. Gastric mucosal changes were detected endoscopically and histologically, and gastrokine-1 protein expression in the antral mucosa was analyzed by immunohistochemistry. Results: Expression of gastrokine-1 protein was decreased in Helicobacter pylori-positive chronic gastritis compared with Helicobacter pylori-negative subjects and the healthy controls. Similarly, gastrokine-1 expression in non-steroidal anti-inflammatory drug users was also decreased, compared with the healthy controls, but there was no significant difference in gastrokine-1 expression between the aspirin group and selective cyclooxygenase-2 inhibitor group. Moreover, gastrokine-1 expression levels tended to be associated with the severity of chronic gastritis. Conclusions: Both Helicobacter pylori infection and long-term non-steroidal anti-inflammatory drug administration down-regulate gastrokine-1 expression in the gastric mucosa, which may contribute to the gastric mucosal injuries induced by these two factors.

Background Gastrokine-1 (GKN1), a secreted protein, is specifically expressed in gastric mucosa to protect and maintain the integrity of gastric epithelium. The present study investigated differential expression of GKN1 in normal, precancerous, and cancerous gastric tissues, and explored the biological functions of GKN1 protein in gastric cancer cells. Methods RT-PCR, Western blot, and immunohistochemistry were performed to detect GKN1 expression in normal, precancerous, cancerous gastric tissues and seven gastric cancer cell lines. Gene transfection was used to restore GKN1 expression in gastric cancer AGS cells. Phenotypic changes (i.e., cell viability, apoptosis, cell cycle modulation, and sensitivity of gastric cancer cells to fluorouracil (5-FU)) were assayed in the transfected cells. DNA microarrays were used to analyze expression changes of apoptosis-related genes. Results Significant downregulation or absence of GKN1 expression in seven gastric cancer cell lines were detected and progressive decrease of GKN1 expression from normal mucosa, precancerous tissue, to cancer tissues was observed. Moreover, restoration of GKN1 expression suppressed gastric cancer cell viability and induced the cells to undergo apoptosis. GKN1 expression also enhanced tumor cell sensitivity to 5-FU treatment. Moreover, it was found that GKN1 expression in AGS cells modulated expression of 19 apoptosis-related genes. Conclusions Expression of GKN1 is progressively lost from normal mucosa, precancerous to cancerous gastric tissues, while restoration of GKN1 expression induces gastric cancer cells to undergo apoptosis, and enhances sensitivity of gastric cancer cells to 5-FU-induced apoptosis.

Trefoil factor 1 (TFF1) is a small cysteine-rich secreted protein which is principally expressed in the superficial cells of gastric mucosa. In gastric cancer, TFF1 is downregulated and plays an important role. Gastrokine 1 (GKN1) is a secreted protein with similar expression and biological functions to TFF1. This study aimed to determine the expression and biological functions of TFF1 and the relationships between TFF1 and GKN1 in gastric cancer. RT-PCR and immunohistochemistry were performed to detect TFF1 expression in gastric cancer cell lines and tissues. The transfected and co-transfected AGS cells which stably expressed TFF1 or both TFF1 and GKN1 were generated. Phenotypic changes such as cell viability, apoptosis and cell cycle modulation were assayed in the transfected cells. We found that TFF1 expression was significantly downregulated or lost in gastric cancer cell lines, gastric dysplasia and cancer. Restoration of TFF1 expression in AGS cells suppressed tumor cell viability and arrested AGS cells in the G1-S transition phase after olomoucine treatment. However, TFF1 was unable to induce cell apoptosis. In co-transfected cells, we found that TFF1 and GKN1 did not directly interact at the protein level. GKN1 was unable to cooperate with TFF1 on cell viability suppression, cell apoptosis and differentiation. Together, these results indicate that TFF1 expression is significantly downregulated in gastric cancer. TFF1 inhibited cell proliferation by delaying G1-S phase transition but not by inducing apoptosis. TFF1 may not interact or cooperate with GKN1 at the protein and functional level.

AIM:To determine the functional significance of aryl hydrocarbon receptor (AhR) in gastric carcinogenesis, and to explore the possible role of AhR in gastric cancer (GC) treatment.METHODS:RT-PCR, real-time PCR, and Western blotting were performed to detect AhR expression in 39 GC tissues and five GC cell lines. AhR protein was detected by immunohistochemistry (IHC) in 190 samples: 30 chronic superficial gastritis (CSG), 30 chronic atrophic gastritis (CAG), 30 intestinal metaplasia (IM), 30 atypical hyperplasia (AH), and 70 GC. The AhR agonist tetrachlorodibenzo-para-dioxin (TCDD) was used to treat AGS cells. MTT assay and flow cytometric analysis were performed to measure the viability, cell cycle and apoptosis of AGS cells.RESULTS:AhR expression was significantly increased in GC tissues and GC cell lines. IHC results indicated that the levels of AhR expression gradually increased, with the lowest levels in CSG, followed by CAG, IM, AH and GC. AhR expression and nuclear translocation were significantly higher in GC than in precancerous tissues. TCDD inhibited proliferation of AGS cells via induction of growth arrest at the G1-S phase.CONCLUSION:AhR plays an important role in gastric carcinogenesis. AhR may be a potential therapeutic target for GC treatment.

BACKGROUND:Abberant aryl hydrocarbon receptor (AhR) expression and AhR pathway activation are involved in gastric carcinogenesis. However, the relationship between AhR pathway activation and gastric cancer progression is still unclear. In present study, we used 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD), a classic and most potent ligand of AhR, to activate AhR pathway and investigated the effect of AhR pathway activation on human gastric cancer AGS cell invasion and explored the corresponding mechanism.RESULTS:To determine whether AhR pathway can be activated in AGS cells, we examined the expression of CYP1A1, a classic target gene of AhR pathway, following TCDD exposure. RT-PCR and western blot analysis showed that both CYP1A1 mRNA and protein expression were increased in a dose-dependent manner following TCDD treatment and AhR antagonist resveratrol (RSV) could reverse this TCDD-induced CYP1A1 expression. To determine whether TCDD treatment of AGS cells results in an induction of MMP-9 expression, we detected MMP-9 mRNA using RT-PCR and detected MMP-9 enzymatic activity using gelatin zymography. The results showed that both MMP-9 mRNA expression and enzymatic activity were gradually increased with the concentration increase of TCDD in media and these changes could be reversed by RSV treatment in a dose-dependent manner. To examine whether AhR activation-induced MMP-9 expression and activity in AGS cells results in increased migration and invasion, we performed wound healing migration assay and transwell migration and invasion assay. After TCDD treatment, the migration distance and the migration and invasion abilities of AGS cells were increased with a dose-dependent manner. To demonstrate AhR activation-induced MMP-9 expression is mediated by c-Jun, siRNA transfection was performed to silence c-Jun mRNA in AGS cells. The results showed that MMP-9 mRNA expression and activity in untreated control AGS cells were very weak; After TCDD (10 nmol/L) treatment, MMP-9 mRNA expression and activity were significant increased; This TCDD-induced MMP-9 expression and activity increase could be abolished by c-Jun siRNA transfection.CONCLUSION:AhR pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of MMP-9. Our results provide insight into the mechanism and function of the AhR pathway and its impact on gastric cancer progression.

Objective To assess the accuracy of four clinical diagnostic criteria systems[Ranson,Glasgow,APACHEⅡ and Balthazar CT severity index(CTSI)] in the prediction of severity acute pancreatitis. Methods Two hundreds and thirty eight patients with acute pancreatitis were retrospectively studied with these four criteria systems.Clinical criteria of four systems together with the duration of fasting and hospitalization were analyzed.The sensitivity and specificity of severe acute pancreatitis of these four systems were assessed.Using receiver operating characteristic(ROC) curves. Results Among 238 patients,mild pancreatitis was identified in 189 patients,and severe pancreatitis in 49 patients.The mean scores of Ranson,Glasgow,APACHEⅡ,CTSI between mild pancreatitis and severe pancreatitis were statistical and significant difference(p0.01).The scores of the four systems were correlated significantly with days of fasting and hospitalization.The sensitivity of CTSI system was the highest(83.67%) and largest AUC(0.91) in predicting acute pancreatitis outcomes.APACHEⅡ(48h) system had the highest specificity. Conclusion CDSI is more useful in predicting acute pancreatitis and comprehensive assessment can improve the accuracy in predicting the severity of the disease.