A novel synthetic protoapigenone analogue, WYC02-9, induces DNA damage and apoptosis in DU145 prostate cancer cells through generation of reactive oxygen species.

The protoapigenone analogue WYC02-9, a novel synthetic flavonoid, has been shown to act against a variety of experimental tumors. However, its effects on prostate cancer and its mechanism of action are unknown. Thus, WYC02-9 was investigated for its cytotoxicity against DU145 prostate cancer cells, as was the underlying mechanisms by which WYC02-9 might induce DNA damage and apoptotic cell death through reactive oxygen species (ROS). WYC02-9 inhibited the cell growth of three prostate cancer cell lines, especially DU145 cells. In DU145 cells, WYC02-9 increased the generation of intracellular ROS, followed by induction of DNA damage and activation of the ATM-p53-H2A.X pathway and checkpoint-related signals Chk1/Chk2, which led to increased numbers of cells in the S and G2/M phases of the cell cycle. Furthermore, WYC02-9 induced apoptotic cell death through mitochondrial membrane potential decrease and activation of caspase-9, caspase-3, and PARP. The above effects were all prevented by the ROS scavenger N-acetylcysteine. Administration of WYC02-9 in a nude mouse DU145 xenograft model further identified the anti-cancer activity of WYC02-9. These findings therefore suggest that WYC02-9-induced DNA damage and mitochondria-dependent cell apoptosis in DU145 cells are mediated via ROS generation.

Early enteral 5% glucose infusion maintains the epidermal growth factor levels in the jejunal flap used for pharyngo-oesophageal reconstruction.

BACKGROUND: Free jejunal flap reconstruction is the main treatment for patients after pharyngo-oesophagectomy. Flaps are unavoidably subjected to ischaemia and reperfusion (I/R) during preparation. Enteral nutrition has been shown to improve the recovery of injured intestine, although the precise underlying mechanism remains unclear. This study was aimed to determine whether early enteral 5% glucose infusion is beneficial for the recovery of flap. Further, the possibility that enteral glucose infusion induces altered mucosal responses was evaluated. PATIENTS AND METHODS: Patients, who underwent free jejunal flap reconstructions after pharyngo-oesophagectomy, were enrolled. An externalised monitor loop was made to observe the viability of flap and to collect intestinal fluid. Control patients (n = 11) received peripheral parenteral nutrition for seven post-operation days. For early enteral-fed patients (n = 12), in addition to fluid infusion, administration of 5% glucose (25 ml h(-1)) via a jejunostomy tube was initiated 6h after surgery. Blood, flap fluid and mucosal specimens were harvested. Plasma and flap luminal levels of interleukin (IL)-6, IL-10, epidermal growth factor (EGF) and secretory immunoglobulin A (sIgA) were measured. Further, mucosal morphology was examined. RESULTS: There were no significant differences in either plasma or luminal concentrations of IL-6, IL-10 and sIgA at different time points between groups. The luminal EGF level in the control group reduced markedly from the 3rd postoperative day, contrasting with a well-maintained level in the early enteral-fed group. No significant difference in mucosal histology between groups was observed. CONCLUSION: Early enteral glucose infusion does not significantly benefit the ischaemia-reperfusion-injured flap; however, it does preserve EGF levels in the flap lumen.

Higher genetic susceptibility to inflammation in mild disease activity of systemic lupus erythematosus.

In order to test the hypothesis that stratification of Mexican Modification of the Systemic Lupus Erythematosus Disease Activity Index (MEX-SLEDAI) simplifies the genetic study of SLE, we evaluated the genetic susceptibility to inflammation and defects in clearance of immune complexes among SLE patients in Taiwan. SLE phenotypes were stratified according to the MEX-SLEDAI scores into two subgroups (10), and then according to renal disorder and neurological disorder, aiming to minimize any loss of power associated with disease heterogeneity. Upon stratification, IL1-beta polymorphism and LTA were significantly associated with SLE within the MEX-SLEDAI

Periodic alterations of jejunal mucosa morphology following free microvascular transfer for pharyngoesophageal reconstruction.

BACKGROUND: Free jejunal flap reconstruction is the treatment of choice for patients after pharyngoesophagectomy. It remains unclear as to how the transplanted jejunal mucosal damage proceeds after the warm ischaemia. The current study aims to assess the relationship between the duration of ischaemia and the damage of jejunal mucosa. PATIENTS AND METHODS: From May 2002 to February 2003, 15 free jejunal flaps in 15 patients were transplanted to the cervical area for the reconstruction after pharyngoesophagectomy. Biopsy specimens were taken from the monitor loop at the time of pedicle ligation, 10 min after reperfusion, every day for 10 days, 14th day, 28th day, and 40th day after operation. Mucosal injury was assessed based on an accepted three-point scale which evaluates oedema, inflammation, mucosal necrosis or exfoliation, shortening of villi, and increase of goblet cells. FINDINGS: All 15 jejunal flaps survived. The mean ischaemia time was 68.7+/-5.2 min (range: 37-116). Serious injury to the mucosa was observed at 10 min after reperfusion, and gradually recovered until the 8th day, when it became normal in all flaps. The degree of damage was not found to be correlated with the length of ischaemia (less than 116 min). Severe ischaemia/reperfusion-induced mucosal damage occurs immediately following reperfusion and gradually recovers with time. The severity of the damage is not related linearly to the ischaemia time within 2h. The mucosa recovers gradually from the 8th day and returns to normal at the 28th day.

Effects of oral arginine and glutamine on radiation-induced injury in the rat.

BACKGROUND: Exposure of the abdominal region to ionizing radiation is associated with serious untoward symptoms of intestinal dysfunction and some reports indicate that nutrient supplements may reduce these adverse effects. This study was designed to investigate the possible beneficial effects of oral arginine or glutamine supplementation on the radiation-induced tissue injury. MATERIALS AND METHODS: Rats were given one of three feeding regimens: standard diet and water (control group), diet and water containing 2% arginine (arginine group), diet and water containing 2% glutamine (glutamine group) for 3 days prior to radiation. All rats were then subjected to a single does of 1100 cGy to the abdomen. Several serum biochemical parameters and the histologic alterations in different segments of gastrointestinal tract and liver were measured 4 days after irradiation. RESULTS: All the arginine-fed rats developed diarrhea on Day 4 postirradiation, compared to 71% incidence in control rats and 86% in glutamine-fed rats. Serum levels of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in the arginine group were markedly higher than those in other groups. On histological examination, radiation caused more serious damage to various segments of intestine in the arginine-fed rats compared to rats on other feeding regimens. CONCLUSION: These observations seriously question the beneficial effects of arginine and glutamine supplementations on radiation-induced tissue injury.