Cheng Wei Tang

Preoperative growth inhibition of human gastric adenocarcinoma treated with a combination of celecoxib and octreotide

AbstractAim:To gain insight into the histopathological responses and molecular targets in the inhibition of growth of human gastric cancer treated with celecoxib (a cyclooxygenase [COX]-2 inhibitor) combined with octreotide.Methods:Seventy five patients with gastric cancer undergoing curative gastrectomy or extended resection were randomly divided into 3 groups. The apoptosis of tumor cells was measured by terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) assay. Gastric cancer microvessel density (MVD) and the expression of COX-2 were evaluated by immunohistochemical staining. The expression of somatostatin receptor (SSTR)-2 was detected with the biomolecular interaction analysis system. The transcription of non-steroidal anti-inflammatory drug-activated gene (NAG)-1 was measured by RT-PCR.Results:Compared with the control and celecoxib groups, more necrosis in the combination group was observed. The apoptotic rate in the combination group (7.06%±0.67%) was significantly higher than that in the control group (6.23%±1.29%, P<0.05). The MVD decreased considerably in the combination group. The upregulation of NAG-1 was displayed both in the celecoxib and combination groups. The positive rate of SSTR-2 in gastric cancers treated with celecoxib (48%) was significantly higher than that of control group (12%) after surgery (P<0.05).Conclusion:Celecoxib combined with octreotide significantly promoted necrosis in gastric adenocarci-noma through the induction of apoptosis and the reduction of MVD. NAG-1 and SSTR-2 might be the molecular targets for celecoxib or octreotide.

Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats.

Background Non-alcoholic fatty liver disease (NAFLD) caused by liver lipid dysregulation is linked to obesity. Somatostatin (SST) and its analogs have been used to treat pediatric hypothalamic obesity. However, the application of such drugs for the treatment of NAFLD has not been evaluated. Objective This study aimed to investigate the expression levels of important regulators of hepatic lipid metabolism and the possible effect of the SST analog octreotide on these regulators. Methods SD rats were assigned to a control group and a high-fat diet group. Obese rats from the high-fat diet group were further divided into the obese and octreotide-treated groups. The body weight, plasma SST, fasting plasma glucose (FPG), insulin, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) levels were measured. Hepatic steatosis was evaluated based on the liver TG content, HE staining and oil red O staining. The SREBP-1c, ACC1, FAS, MTP, apoB and ADRP expression levels in the liver were also determined by RT-PCR, qRT-PCR, western blot or ELISA. Results The obese rats induced by high-fat diet expressed more SREBP-1c, FAS and ADRP but less MTP protein in the liver than those of control rats, whereas octreotide intervention reversed these changes and increased the level of apoB protein. Compared to the control group, obese rats showed increased liver ACC1, SREBP-1c and apoB mRNA levels, whereas octreotide-treated rats showed decreased mRNA levels of apoB and SREBP-1c. This was accompanied by increased body weight, liver TG contents, FPG, TG, TC, LDL-C, FFA, insulin and derived homeostatic model assessment (HOMA) values. Octreotide intervention significantly decreased these parameters. Compared to the control group, the obese group showed a decreasing trend on plasma SST levels, which were significantly increased by the octreotide intervention. Conclusion Octreotide can ameliorate hepatic steatosis in obese rats, possibly by decreasing hepatic lipogenesis and increasing TG export from hepatocytes.

Octreotide promotes weight loss via suppression of intestinal MTP and apoB48 expression in diet-induced obesity rats

OBJECTIVEnThe goal of this study was to investigate the effect of octreotide on the expression of intestinal fat absorption-associated apolipoproteinB48 (apoB48), microsomal triglyceride transfer protein (MTP) and apolipoproteinAIV (apoAIV) in a high-fat diet-induced obesity rat model.nnnMETHODSnSprague-Dawley rats were placed into a control or high-fat diet group. Obese rats from the high-fat diet group were further divided into an obese group and an octreotide-treated group. Rats in the octreotide-treated group were subcutaneously injected with octreotide (40 μg/kg body weight) twice daily for 8 d. Body weight, fasting plasma glucose (FPG), fasting serum insulin, triglyceride (TG), total cholesterol (TC), and high density lipoprotein-cholesterol (HDL-C) were measured. Intestinal MTP, apoB48, and apoAIV expression levels were determined by real-time polymerase chain reaction, Western blot, or enzyme-linked immunosorbent assay analysis.nnnRESULTSnWe found high-fat diet-induced obesity rats express more apoB, MTP, and apoAIV mRNA as well as apoB48 and MTP protein in the intestine than normal chow-fed rats. This observation occurred along with increased body weight, FPG, TG, TC, fasting serum insulin, and Homeostatic Model Assessment value. Octreotide intervention significantly decreased body weight and blood parameters, and down-regulated expression of apoB mRNA and apoB48 protein, as well as MTP mRNA and proteins. However, apoAIV mRNA was not significantly different between obese and octreotide-treated rats although it was decreased by 47%.nnnCONCLUSIONnHigh-fat diet-induced obesity is associated with increased expression of apoB48, MTP, and apoAIV in the intestine. Octreotide intervention inhibited the overexpression of apoB48 and MTP, and consequently brought about reduced fat absorption and weight loss.

Effects of octreotide on glucose transporter type 2 expression in obese rat small intestine

AIMnTo investigate the effects of the somatostatin analogue, octreotide, on maltose and sucrase activities and expression of glucose transporter type 2 (GLUT2) in obese rat intestinal mucosa.nnnMETHODSnWe divided 49 Sprague-Dawley rats into a group of 31 high fat diet-induced obese rats and a group of 18 normal controls. The obese rats were separated into an octreotide treated group of 16 rats and an obese group of 15. The intervention group was injected with octreotide at 40 μg/kg body weight every 12 h for 8 d. Rat body weight was measured weekly to calculate Lees index. After euthanization, maltase and sucrase activities in the small intestine were measured by activity assays, and the fasting plasma glucose level was measured. The expression of GLUT2 in small intestinal mucosa was analyzed by immunohistochemistry, reverse transcriptase polymerase chain reaction and Western blotting assays.nnnRESULTSnBody weight, Lees index, fasting plasma glucose level, maltase activity in small intestinal mucosa, mucosa and apical GLUT2, GLUT2 mRNA and protein expression levels were all significantly higher in the obese group than in the normal control group (605.61 ± 141.00 vs 378.54 ± 111.75, 337.61 ± 10.82 vs 318.73 ± 20.10, 8.60 ± 1.38 vs 7.33 ± 0.70, 156.01 ± 58.81 vs 50.43 ± 30.49, 390 744.2 ± 62 469.21 vs 170 546.50 ± 50 646.14, 26 740.18 ± 3809.60 vs 354.98 ± 57.19, 0.26 ± 0.11 vs 0.07 ± 0.02, and 2.08 ± 0.59 vs 1.27 ± 0.38, respectively, all P < 0.01). Sucrase activity did not differ between the two groups. Octreotide intervention significantly decreased the body weight and fasting plasma glucose level of obese rats (508.27 ± 94.39 vs 605.61 ± 141.00, 7.58 ± 1.51 vs 8.60 ±1.38, respectively, all P < 0.05). The intestinal mucosa and apical GLUT2, expression of GLUT2 mRNA and protein were also significantly lower in the octreotide intervention group than in the obese group (269 975.2 ± 53 730.94 vs 390 744.2 ± 62 469.21, 3758.06 ±364.51 vs 26 740.18 ± 3809.60, 0.08 ± 0.02 vs 0.26 ±0.11, and 1.31 ± 0.27 vs 2.08 ± 0.59, respectively, all P < 0.01).nnnCONCLUSIONnHigh fat diet-induced obesity is associated with elevated intestinal maltase activity, GLUT2 expression, and permanent apical GLUT2 in the small intestinal mucosa of rats. Octreotide can inhibit these effects.

Transcatheter arterial embolization followed by octreotide and celecoxib synergistically prolongs survival of rabbits with hepatic VX2 allografts

To validate the efficacy of an innovative multimodality therapy with transcatheter arterial embolization (TAE) plus octreotide and celecoxib in reducing neoangiogenesis and prolonging the survival of rabbits with hepatocellular carcinoma.

Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats

Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)–hypoxia-inducible factor-1α (HIF-1α)–vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK–HIF-1α–VEGF signaling pathway.

Pancreatic panniculitis in acute pancreatitis

Subcutaneous manifestations of acute pancreatitis (AP), including ecchymosis and pancreatic panniculitis, are seldomly seen in clinical settings. Compared with ecchymosis such as Cullen’s sign and Grey Turner’s sign, pancreatic panniculitis (subcutaneous fat necrosis) is much rarer. Clinicians, especially those with less experiences, may be unable to identify pancreatic panniculitis because few photographs of the subcutaneous manifestations are available under this condition. Pancreatic panniculitis is usually confirmed by subcutaneous biopsy. If the typical subcutaneous manifestations are consistently related to subcutaneous fat necrosis, it would be possible for patients to avoid an invasive biopsy. In this study, we presented a case of pancreatic panniculitis with subcutaneous manifestations at the early and late stage of severe acute pancreatitis (SAP). Previous case reports on pancreatic panniculitis were also reviewed.

Expression of cyclooxygenase-2 is correlated with lncRNA-COX-2 in cirrhotic mice induced by carbon tetrachloride

Multiple long non-coding RNAs (lncRNAs) have been demonstrated to be involved in liver disease. Increased cyclooxygenase-2 (COX-2) levels have also been reported to be involved in the progression of liver cirrhosis. In the present study, the correlations between lncRNA-COX-2 RNA expression levels, COX-2 mRNA expression levels and liver fibrosis were examined. Liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl4) in mice for 2 months (CCl4-2M) or 3 months (CCl4-3M). Liver histopathological evaluation was conducted using hematoxylin and eosin and Masson trichrome staining. Hepatic expression of COX-2 and lncRNA-COX-2 was evaluated by reverse transcription-quantitative polymerase chain reaction and immunohistochemical staining. Compared with the control group, fibrotic areas were increased four and nine times in the CCl4-2M group and the CCl4-3M group, respectively. LncRNA-COX-2 and COX-2 upregulation were observed in the cirrhotic liver. COX-2 mRNA expression levels and lncRNA-COX-2 RNA expression levels were significantly positively correlated with the fibrotic area. In addition, COX-2 mRNA expression was significantly positively correlated with lncRNA-COX-2 expression. These results suggest that expression of COX-2 and lncRNA-COX-2 increased with the progression of liver fibrosis. LncRNA-COX-2 may potentially be considered as a novel therapeutic target for liver fibrosis.

Inhibition of cyclooxygenase-2 alleviates liver cirrhosis via improvement of the dysfunctional gut-liver axis in rats

Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis.

Etiology, clinical features and management of acute recurrent pancreatitis.

To study the etiology and clinical features of acute recurrent pancreatitis (ARP) and to determine its optimal management and outcomes.