摘要:

Genistein is a plant isoflavonoid bearing potent tumor growth–regulating characteristics. This effect of genistein has been attributed partially to its tyrosine kinase–regulating properties, resulting in cell-cycle arrest and limited angiogenesis. Genistein has been used in chemotherapy-resistant cases of advanced leukemia with promising results. Here we demonstrate that genistein primarily affects nucleic acid synthesis and glucose oxidation in tumor cells using the [1,2-13C2]glucose isotope as the single tracer and gas chromatography/mass spectrometry to follow various intracellular glucose metabolites. The ribose fraction of RNA demonstrated a rapid 4.6%, 16.4%, and 46.3% decrease in isotope uptake through the nonoxidative branch of the pentose cycle and a sharp 4.8%, 24.6%, and 48% decrease in13CO2release from glucose after 2, 20, and 200 &mgr;mol/L genistein treatment, respectively. Fatty acid synthesis and the13C enrichment of acetyl units were not significantly affected by genistein treatment. De novo glycogen synthesis from media glucose was not detected in cultured MIA cells. It can be concluded from these studies that genistein controls tumor growth primarily through the regulation of glucose metabolism, specifically targeting glucose carbon incorporation into nucleic acid ribose through the nonoxidative steps of the pentose cycle, which represents a new paradigm for the antiproliferative action of a plant phytochemical.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Chronic pancreatitis is characterized by fibrosis. We reported an anti-inflammatory effect of the herbal medicine Saiko-keishi-to (TJ-10) on chronic pancreatitis. This study aimed to elucidate the antifibrotic effect of TJ-10. Four-week-old male WBN/Kob rats were fed a special pellet diet (MB-3) with or without TJ-10 (80 mg/100 g body weight) for 20 weeks. Pancreata were histopathologically examined at every 4 weeks, and the expression of fibrosis-related factors such as transforming growth factor &bgr;1(TGF-&bgr;1), fibronectin (FN), &agr;-smooth muscle actin (&agr;-SMA), and type III collagen was analyzed. In untreated WBN/Kob rats, chronic pancreatitis developed at 12 weeks and progressed with marked fibrosis at 16 weeks, and the expression of TGF-&bgr;1and FN peaked at 12 weeks. However, in the TJ-10–treated rats, the rate of pancreatic fibrosis and the expression of TGF-&bgr;1, FN, &agr;-SMA, and type III collagen at 12 and 16 weeks decreased significantly compared to those in the untreated rats. These results suggest that TJ-10 inhibits the pancreatic fibrosis by the suppression of TGF-&bgr;1expression.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Three-point mutations (R117H, N21I, A16V) within the cationic trypsinogen gene have been identified in patients with hereditary pancreatitis (HP). A genetic background has also been discussed for idiopathic juvenile chronic pancreatitis (IJCP), which closely mimicks the clinical pattern of HP, and alcoholic chronic pancreatitis because only a small number of heavy drinkers develop pancreatitis. This prompted us to screen 104 patients in our well-defined pancreatitis cohort for the currently known cationic trypsinogen gene mutations. The R117H mutation was detected in seven patients (six patients of two clinically classified HP families, one patient with clinically classified IJCP) and the A16V mutation in one IJCP patient. No cationic trypsinogen gene mutations were found in the remaining 96 patients with chronic and recurrent acute pancreatitis of various etiologies. Our results demonstrate the need for genetic testing to exclude HP, particularly in the presence of an atypical or unknown family history. In addition, cationic trypsinogen gene mutations are no predisposing factor in patients with chronic and recurrent acute pancreatitis of different etiologies.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Trypsinogen activation peptide (TAP) is a useful marker of severe acute pancreatitis. However, it is sometimes difficult to detect an elevation of plasma TAP in patients with acute pancreatitis because TAP is rapidly cleared from plasma. Therefore, urine TAP has been evaluated to provide an accurate prediction of the outcome of pancreatitis. In the present study, we examined the time course of plasma and urine TAP simultaneously after induction of taurocholate-induced pancreatitis in rats. Plasma TAP levels peaked at 1 hour after the induction of pancreatitis and then gradually decreased, but was still higher than prepancreatitis levels at 48 hours. Significant increases in urine TAP levels were seen at 0–6, 6–12, and 30–36 hours after induction of pancreatitis. The peak level of urine TAP output and TAP/creatinine ratio was observed at 6–12 and 30–36 hours, respectively. Urine TAP concentration showed a significant correlation with both urine TAP/creatinine ratio and TAP output in urine (p< 0.01). In conclusion, plasma TAP increased immediately after the induction of pancreatitis, but excretion of TAP into urine was delayed several hours in taurocholate-induced pancreatitis in rats. The measurement of urine TAP concentration alone sufficiently can reflect the amount of TAP liberated in the pancreas at initial stage of acute pancreatitis.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Severe acute pancreatitis is frequently complicated by local and systemic infections resulting in substantial morbidity, mortality, and health care costs. Antibiotic prophylaxis may prevent some infections. We searched for randomized, controlled trials comparing antibiotic prophylaxis with no prophylaxis in patients with acute necrotizing pancreatitis (ANP). Only trials that used antibiotics that reach minimum inhibitory concentration (MIC) in necrotic pancreatic tissue were included. We calculated relative risk reduction (RRR), absolute risk reduction (ARR), and number needed to treat (NNT) for individual trials and pooled data. Antibiotic prophylaxis significantly reduced sepsis by 21.1% (NNT = 5) and mortality by 12.3% (NNT = 8) compared with no prophylaxis. There was also a nonsignificant trend toward a decrease in local pancreatic infections (ARR = 12%; NNT = 8). Antibiotic prophylaxis decreases sepsis and mortality in patients with ANP. All patients with ANP should be given prophylaxis with an antibiotic with proven efficacy in necrotic pancreatic tissue.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

We demonstrated that the dynamic aspects of cytokine production in rat acute pancreatitis, which was induced by cerulein and aggravated by subsequent lipopolysaccharide (LPS) injection. A priming effect by induction of mild pancreatitis with cerulein enhanced the subsequent cytokine production by LPS injection. Alternatively, after induction of severe pancreatitis with cerulein and LPS, cytokine production was markedly suppressed for ≥90 hours. Production of interleukin-2 (IL-2) by splenocytes decreased, and mortality rate after cecal ligation and puncture (CLP) increased significantly after induction of severe acute pancreatitis. These results suggest that the suppression of a cytokine response in severe acute pancreatitis may alter the defense system and, as a result, increase mortality after CLP.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Chemoactivation of the neutrophil (PMN) via the complement system has been observed in many inflammatory conditions and is thought to play a pathogenic role in acute pancreatitis. This study examined the effects of PMN depletion in experimental hemorrhagic pancreatitis and tested the role played by complement. Severe pancreatitis was induced by a choline-deficient, 0.5% ethionine–supplemented diet in female Institute of Cancer Research (ICR) mice weighing 11–13 g. Neutropenia was induced by an antibody injection. Total complement depletion was achieved by tail vein injections of cobra venom factor (CVF). Serum amylase levels and local pancreatic injury were not significantly modulated by either PMN or complement depletion at 72 hours. Systemic and remote organ injury, assessed by the formation of ascites, hematocrit, and serum alanine aminotransferase levels, was significantly reduced in neutropenic mice but failed to be moderated by complement depletion. In addition, liver and lung myeloperoxidase activity was independent of complement depletion. At 5 days, mortality was zero in PMN-depleted mice. There was no improvement in survival in the CVF-treated group. Neutrophils are important in the systemic injury and mortality of severe pancreatitis. PMN chemoactivation involves mechanisms other than complement.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Phospholipase C (PLC) isozymes are believed to play a role in regulating pancreatic exocrine and endocrine secretion. In an attempt to investigate the role of PLC, we examined the distribution patterns of PLC isozymes in the normal rat pancreas by Western blot analysis and immunohistochemistry. Western blot analysis was performed on pancreatic acinar tissues and the islet of Langerhans, which were separated from each other. PLC-&bgr; isozymes (&bgr;1, &bgr;2, &bgr;3, and &bgr;4), &dgr;1, and &dgr;2 were detected in both acinar and islet cells, whereas PLC-&ggr;1 and &ggr;2 were observed only in acinar tissues. On immunohistochemistry, the immunoreactivities of PLC isozymes except for PLC-&ggr;1 were observed as follows: PLC-&bgr;1, in both the exocrine and endocrine tissues; PLC-&bgr;2, mainly in the periphery of the islet and acinar cells; PLC-&bgr;3, in the periphery of the islet and in some ductal epithelium; PLC-&bgr;4, through the islet of Langerhans and ductal epithelium; PLC-&ggr;1, not detected in pancreatic tissue; PLC-&ggr;2, mainly in acinar cells; PLC-&dgr;1 and &dgr;2, in the islet and in ductal epithelium. These results suggest that the intrapancreatic site-specific existence of PLC isozymes may modulate pancreatic exocrine and endocrine functions through a PLC-mediated signal transduction.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The exact mechanisms of the development of pancreatic fibrosis are still unknown. To clarify the relationship between pancreatic fibrosis and free radicals, the effect of the administration of a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DDC), on pancreatic fibrosis in rats was studied. A single intraperitoneal injection of 500 mg/kg of DDC significantly reduced SOD activity and significantly increased lipid peroxidation products in the pancreas, showing no histologic changes of inflammation or necrosis. Repeated administration of 500 mg/kg DDC, twice a week, caused inter-and intralobular fibrosis with atrophy of acinar cells in the pancreas for at least 2 weeks without fibrosis of the liver and kidney. Administration of allopurinol showed preventive effects against DDC-induced pancreatic fibrosis. In conclusion, repeated administration of DDC, which caused pancreatic fibrosis, is a new experimental model of pancreatic fibrosis from the viewpoint of oxidative stress.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

We compared the effects of two incretin hormones, glucagon-like peptide-1 (7-36)amide (GLP-1) and cholecystokinin (CCK), on islet hormone secretion. GLP-1 strongly potentiated glucose-stimulated insulin secretion in the perfused rat pancreas and in vivo in mice (p< 0.001). In contrast, GLP-1 did not enhance arginine-induced insulin release under these experimental conditions. In the perfused rat pancreas, GLP-1 also potentiated glucose-stimulated somatostatin secretion but, again, had no effect on arginine-induced somatostatin release. However, GLP-1 promptly inhibited the arginine-induced glucagon release (p< 0.02). In contrast, CCK enhanced insulin release in response to arginine both in the perfused rat pancreas and in vivo in mice (p< 0.001). In conclusion, GLP-1, in contrast to CCK, failed to enhance arginine-induced insulin release both in vitro and in vivo. This suggests that a signal generated by nutrient metabolism is required for the potentiation of insulin secretion by GLP-1. Furthermore, GLP-1 directly inhibited arginine-induced glucagon release as no concurrent increase in insulin or somatostatin release was noted.

ISSN:0885-3177    

出版商:OVID    

年代:2001

数据来源: OVID