High expression of death-associated protein 5 promotes glucose metabolism in gastric cancer cells and correlates with poor survival outcomes / 南方医科大学学报

OBJECTIVE@#To investigate the prognostic value of death-associated protein 5 (DAP5) in gastric cancer (GC) and its regulatory effect on aerobic glycolysis in GC cells.@*METHODS@#We analyzed DAP5 expression levels in GC and adjacent tissues and its association with survival outcomes of GC patients using public databases. We collected paired samples of GC and adjacent tissues from 102 patients undergoing radical resection of GC in our hospital from June, 2012 to July, 2017, and analyzed the correlation of DAP5 expression level detected immunohistochemically with the clinicopathological parameters of the patients. Cox regression analysis, Kaplan-Meier analysis, and ROC curves were used to explore the independent risk factors and the predictive value of DAP5 expression for 5-year survival of the patients. In the cell experiments, we observed the changes in aerobic glycolysis in MGC-803 cells following lentivirus-mediated DAP5 knockdown or overexpression by measuring glucose uptake and cellular lactate level and using qRT-PCR and Western blotting.@*RESULTS@#Analysis using the public databases showed that DAP5 was highly expressed in GC and correlated with tumor progression and poor survival outcomes of the patients (P < 0.05). In the clinical samples, DAP5 expression was significantly higher in GC than in the adjacent tissues (3.19±0.60 vs 1.00±0.12; t=36.863, P < 0.01), and a high expression of DAP5 was associated with a reduced 5-year survival rate of the patients (17.6% vs 72.5%; χ2=29.921, P < 0.05). A high DAP5 expression, T3-4, N2-3, and CEA≥5 ng/mL were identified as independent risk factors affecting 5-year survival outcomes of GC (P < 0.05), for which DAP5 expression showed a prediction sensitivity, specificity and accuracy of 73.2%, 80.4% and 79.0%, respectively. In MGC-803 cells, DAP5 knockdown significantly reduced glucose uptake, lactate level and the expressions of GLUT1, HK2 and LDHA, and DAP5 overexpression produced the opposite effects (P < 0.05).@*CONCLUSION@#A high expression of DAP5 in GC, which enhances cellular aerobic glycolysis to promote cancer progression, is correlated with a poor survival outcome and may serve as a biomarker for evaluating long-term prognosis of GC patients.

Pachymic acid protects against Crohn's disease-like intestinal barrier injury and colitis in miceby suppressingintestinal epithelial cell apoptosis via inhibiting PI3K/AKT signaling / 南方医科大学学报

OBJECTIVE@#To investigate the effect of pachymic acid (PA) against TNBS-induced Crohn's disease (CD)-like colitis in mice and explore the possible mechanism.@*METHODS@#Twenty-four C57BL/6J mice were randomized equally into control group, TNBS-induced colitis model group and PA treatment group. PA treatment was administered via intraperitoneal injection at the daily dose of 5 mg/kg for 7 days, and the mice in the control and model groups were treated with saline. After the treatments, the mice were euthanized for examination of the disease activity index (DAI) of colitis, body weight changes, colon length, intestinal inflammation, intestinal barrier function and apoptosis of intestinal epithelial cells, and the expressions of TNF-α, IL-6 and IL-1β in the colonic mucosa were detected using ELISA. The possible treatment targets of PA in CD were predicted by network pharmacology. String platform and Cytoscape 3.7.2 software were used to construct the protein-protein interaction (PPI) network. David database was used to analyze the GO function and KEGG pathway; The phosphorylation of PI3K/AKT in the colonic mucosal was detected with Western blotting.@*RESULTS@#PA significantly alleviated colitis in TNBS-treated mice as shown by improvements in the DAI, body weight loss, colon length, and histological inflammation score and lowered levels of TNF-α, IL-6 and IL-1β. PA treatment also significantly improved FITC-dextran permeability, serum I-FABP level and colonic transepithelial electrical resistance, and inhibited apoptosis of the intestinal epithelial cells in TNBS-treated mice. A total of 248 intersection targets were identified between PA and CD, and the core targets included EGFR, HRAS, SRC, MMP9, STAT3, AKT1, CASP3, ALB, HSP90AA1 and HIF1A. GO and KEGG analysis showed that PA negatively regulated apoptosis in close relation with PI3K/AKT signaling. Molecular docking showed that PA had a strong binding ability with AKT1, ALB, EGFR, HSP90AA1, SRC and STAT3. In TNBS-treated mice, PA significantly decreased p-PI3K and p-AKT expressions in the colonic mucosa.@*CONCLUSION@#PA ameliorates TNBS-induced intestinal barrier injury in mice by antagonizing apoptosis of intestinal epithelial cells possibly by inhibiting PI3K/AKT signaling.

Analysis on prognosis and influencing factors of postoperative low anterior resection syndrome for rectal cancer patients undergoing laparoscopic anus-preserving radical resection / 中华胃肠外科杂志

Objective@#To investigate the prognosis and influencing factors of postoperative low anterior resection syndrome (LARS) for rectal cancer patients undergoing laparoscopic sphincter-preserving radical resection.@*Methods@#A retrospective case-control study was used in this study. Clinical data of 268 rectal cancer patients undergoing laparoscopic sphincter-preserving radical resection at Department of Gastrointestinal Surgery of The First Affiliated Hospital of Bengbu Medical College from January 2016 to January 2018 were retrospectively collected. Inclusion criteria: (1) operation procedure was total mesorectal excision (TME) and sphincter-preserving radical resection; (2) rectal cancer was confirmed by postoperative pathology; (3) age of patient was ≥ 18 years old. Exclusion criteria: (1) patient who had history of pelvic surgery and pelvic fractures, which would affect the anorectal function; (2) patient who had history of preoperative chronic constipation and irritable bowel syndrome, which would affect defecation; (3) patient who developed postoperative complications, such as anastomotic leakage, which would affect defecation function; (4) patient who received long-term use of drugs, which would affect the function of gastrointestinal tract or anus; (5) patient suffered from mental illness, who was unable to communicate properly; (6) patient who was lack of clinical data or had incomplete clinical data. Patients were followed up at 3, 6 and 12 months postoperatively, and LARS was diagnosed and graded according to the LARS score scale. The LARS score ranged from 0 to 42 points, and 0 to 20 was difined as no LARS, 21 to 29 was mild LARS, and 30 to 42 was severe LARS. LARS score >20 points at any time point was defined as postoperative LARS. Severe LARS transferring into mild LARS and mild LARS transferring into no LARS was defined as symptom improvement. Incidence and outcomes of LARS were evaluated. The factors associated with LARS outcomes were analyzed using χ2 test and logistic regression model.@*Results@#A total of 268 patients were enrolled. The incidence of LARS was 42.9% (115/268), 32.5% (87/268) and 20.1% (54/268) at 3, 6, and 12 months postoperatively respectively, and no new case of LARS was found after 3 months postoperatively. The incidence of mild LARS was 25.7% (69/268), 17.2% (46/268) and 8.6% (23/268) at 3, 6, and 12 months postoperatively respectively, and mild LARS incidence at 6 months was significantly lower than that at 3 months (χ2=5.857, P=0.016), and was significantly higher than that at 12 months (χ2=8.799, P=0.003). The incidence of severe LARS was 17.2% (46/268), 15.3% (41/268) and 11.6% (31/268) at 3, 6, and 12 months postoperatively respectively, without significant difference among 3 time points (all P>0.05). The improvement rate within one year after surgery in patients with mild LARS diagnosed at 3 months was significantly higher than that in patients with severe LARS (88.4% vs. 32.6%, χ2=38.340, P<0.001). Univariate analysis showed that female, distance from anastomosis to anal verge < 5 cm and tumor diameter ≥ 5 cm were associated with unsatisfied LARS outcomes (all P<0.05). Logistic regression analysis showed that distance from anastomosis to anal verge <5 cm was an independent risk factor for LARS outcome (OR=3.589, 95% CI: 1.163 to 2.198, P<0.001).@*Conclusions@#The incidence of LARS after laparoscopic sphincter-preserving radical resection decreases with time. The improvement rate within postoperative 1-year of severe LARS is lower than that of mild LARS. Low anastomotic position may lead to impaired improvement of LARS.

Protective effect of procyanidin B2 on intestinal barrier and against enteritis in a mouse model of trinitrobenzene sulphonic acid-induced colitis / 南方医科大学学报

OBJECTIVE@#To investigate the protective effect of procyanidin B2 (PCB2) on the intestinal barrier and against enteritis in mice with trinitrobenzene sulphonic acid (TNBS)-induced colitis and explore the possible mechanism.@*METHODS@#A mouse model of TNBS-induced colitis was established in male Balb/c mice aged 6-8 weeks. The successfully established mouse models were randomly divided into PCB2 treatment group (=10) and model group (=10) and were treated with daily intragastric administration of PCB2 (100 mg/kg, 0.2 mL) and 0.2 mL normal saline, respectively. After 4 weeks, the disease symptoms, intestinal inflammation, intestinal mucosal cell barrier function and the changes in PI3K/AKT signaling were evaluated using HE staining, immunofluorescence assay and Western blotting.@*RESULTS@#The disease activity index of the mice was significantly lower and the mean body weight was significantly greater in PCB2 group than in the model group in the 3rd and 4th weeks of intervention ( < 0.05). The levels of colonic inflammation and intestinal mucosal inflammatory mediators IL-1β and TNF-α were significantly lower while IL-10 was significantly higher in PCB2 group than in the model group ( < 0.05). Compared with those in the model group, the mice in PCB2 treatment group showed a significantly lower positive rate of bacterial translocation in the mesenteric lymph nodes and a lower thiocyanate-dextran permeability of the intestinal mucosa ( < 0.05). Western blotting showed that PCB2 treatment significantly increased the expressions of claudin-1 and ZO-1 ( < 0.05) and significantly lowered the expression levels of p-PI3K and p-AKT in the intestinal mucosa as compared with those in the model group ( < 0.05).@*CONCLUSIONS@#PCB2 suppresses intestinal inflammation and protects intestinal mucosal functions and structural integrity by inhibiting intestinal PI3K/AKT signaling pathway, suggesting the potential of PCB2 as a new drug for Crohn's disease.

Association of adenylate cyclase-associated protein 2 expression with histopathology and long-term prognosis of gastric cancer / 南方医科大学学报

OBJECTIVE@#To explore association of the expression levels of adenylate cyclase-associated protein 2 (CAP2) in gastric cancer tissues with the histopathology and long-term prognosis of the malignancy.@*METHODS@#This study was conducted among a total of 105 patients with gastric cancer undergoing radical gastrectomy in our hospital between January, 2010 and October, 2013. Immunohistochemistry was used to quantitatively assess the expression of CAP2 in gastric cancer tissues and the adjacent tissues. Based on the median relative expression level of CAP2 of 3.5, the patients were divided into low CAP2 expression group (=52) and high CAP2 expression group (=53). The Cox regression model was used to analyze the effect of CAP2 expression on the 5-year survival rate of the patients, and ROC curve analysis was used to assess the predictive value of CAP2 expression for the patients' long-term survival.@*RESULTS@#Immunohistochemical analysis showed that the expression levels of CAP2 ( < 0.01) and Ki67 ( < 0.01) were significantly higher in gastric cancer tissues than in the adjacent tissues, and the expression level of CAP2 was positively correlated with Ki67 ( < 0.01), peripheral blood CEA ( < 0.01) and CA19-9 ( < 0.01). The percentages of patients with CEA≥5 μg/L, CA19-9≥37 kU/L, pathological grade of G3-G4, T stage of 3-4, and N stage of 2-3 were significantly higher in patients with high CAP2 expression than in those with low CAP2 expression ( < 0.05). Kaplan- Meier survival analysis showed that the 5-year survival rate was significantly lower in patients with a high CAP2 expression ( < 0.01). A high expression level of CAP2, CEA≥5μg/L, CA19-9≥37 and pathological grades G3-G4 were all independent risk factors for shortened 5-year survival after radical gastrectomy ( < 0.01). With the relative expression level of 3.45 as the cut-off value, the sensitivity of CAP2 was 70.15% for predicting death 5 years after the surgery, with a specificity of 71.05% and an area under the curve of 0.779 ( < 0.01).@*CONCLUSIONS@#CAP2 is highly expressed in gastric cancer tissues in close relation with the tumor progression. CAP2 is an independent risk factor for 5-year survival rate after radical gastrectomy for gastric cancer and can be of clinical value in prognostic evaluation of the patients.