Daidzein attenuates abdominal aortic aneurysm through NF-κB, p38MAPK and TGF-ß1 pathways.

The current study focuses on the protection of daidzein on nerves, as daidzein was demonstrated to have a protective effect on neurons of the central nervous system in a glutamate excitotoxicity and oxygen/glucose deprivation model. However, the effect of daidzein on the abdominal aortic aneurysm (AAA) remains unclear. The angiotensin II-induced AAA mouse model was utilized in the present study to determine the effect of daidzein on AAA. The results demonstrated that daidzein significantly attenuated incidence of AAA, max aortic aneurysm and mortality in the angiotensin II­induced AAA mice. Daidzein had an anti­inflammatory effect by inhibiting tumor necrosis factor α (TNF-α), interleukin 1ß (IL­1ß) and nuclear factor κB (NF­κB) protein expression. In addition, daidzein strongly suppressed the gene expression of cyclooxygenase (COX)­2, matrix metalloproteinase 2 (MMP­2), tissue inhibitor of metalloproteinase 1 (TIMP-1), transforming growth factor ß1 (TGF­ß1), and inhibited inducible nitric oxide synthase (iNOS) protein expression in angiotensin II­induced AAA mice. It also inhibited phosphorylation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. These results demonstrate, to the best of our knowledge for the first time, that the anti­inflammatory effects and inhibitory mechanism of daidzein attenuates AAA in angiotensin II­induced mice. Daidzein contains strong anti­inflammatory activity and affects various mechanism pathways including the NF­κB, p38MAPK and TGF-ß1 pathway.

[Clinical analysis of 29 cases with neuroendocrine neoplasm in the digestive system].

OBJECTIVE: To investigate the diagnosis and treatment of neuroendocrine neoplasm (NEN) in the digestive system. METHODS: Clinical data of 29 patients with NEN from January 2000 to December 2012 in The First Affiliated Hospital of Dalian Medical University were analyzed retrospectively and the prognosis was evaluated according to the new WHO classification. RESULTS: There were 19 males and 10 females and the average age was 46.5 years. All the patients had no clinical manifestations of carcinoid syndrome, and they all received surgical treatment. Two cases were gastric neuroendocrine carcinoma(NEC), who received radical total gastrectomy and distal gastric resection respectively. Three cases had neoplasm in the duodenum, including 2 NEC and 1 neuroendocrine tumor(NET), and they all underwent Whipple's procedure. Two cases were small intestine NEC, who received partial small intestine resection. Three cases had neoplasm in the appendix, including 1 NEC treated with right hemicolectomy and 2 NET with appendectomy. One case was ascending colon NEC, who received right hemicolectomy. Eighteen cases had neoplasm in the rectum, including 4 NEC treated with low anterior resection and abdominoperineal resection respectively, and 14 cases of NET underwent low anterior resection, local resection, and endoscopic resection respectively. The 1- and 3- year survival rates of 13 NEC cases were 38.4% and 7.7% respectively. The 5-year survival rate of 16 NET cases was 81.3%. CONCLUSIONS: NEN of digestive system is located mainly in the rectum and the clinical symptom is unspecific. Radical resection of NEN is the preferred treatment. The prognosis of NEC is poor, and that of NET is better.

Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma.

SOX2, a SRY-related HMG box protein, is thought to be an important transcription factor during organogenesis, including the stomach although the expression and function are unclear. We investigated SOX2 protein expression to clarify its roles in differentiation and carcinogenesis of the stomach. Using polyclonal SOX2 antibodies, expression of SOX2 in gastric normal mucosae, intestinal metaplasia and carcinomas from 68 gastric carcinoma patients was studied by immuohistochemistry. SOX2 was strongly and moderately expressed in the nuclei of the foveolar epithelium and intestinal metaplasia, respectively, the expression being much higher than that in carcinomas (p<0.0001). Using antibodies to MUC5AC, MUC2 and CD10, the 68 gastric carcinomas were classified into gastric type, intestinal type, mixed gastric and intestinal type, and null type. A significant difference in SOX2 expression was observed between the gastric and intestinal types (p<0.05), with a higher expression in the former than in the latter. Moreover, over-expression of SOX2 induced the mRNA expression of endogenous MUC5AC, a specific mucin marker for the gastric type, in COS-7 cells. Our findings indicate that SOX2 may play a role in differentiation of the human gastric epithelium, and that SOX2 may be involved in gastric carcinogenesis, particularly in the gastric type.

CDX2, a homeobox transcription factor, upregulates transcription of the p21/WAF1/CIP1 gene.

The CDX2 homeobox transcription factor plays key roles in intestinal development and homeostasis. CDX2 is downregulated during colorectal carcinogenesis, whereas overexpression of CDX2 results in growth inhibition and differentiation of colon carcinoma and intestinal cells. However, the means by which CDX2 functions remain poorly understood. p21/WAF1/CIP1 is one of the cyclin-dependent kinase inhibitors. In addition to its role in cell cycle control, p21 plays critical roles in differentiation and tumor suppression. The overlapping in both the expression and function of CDX2 and p21 in the small intestine and colon strongly suggests a link between these two genes. By means of luciferase reporter and electrophoretic mobility shift assays, we show here that CDX2 transactivated and physically interacted with the promoter of p21 in a p53-independent manner. Moreover, overexpression of CDX2 increased the mRNA expression of p21 in HT-29 colon carcinoma cells, as demonstrated by reverse transcription-polymerase chain reaction. These data suggest that p21 is a transcriptional target of CDX2. Our results may thus provide a new mechanism underlying the functions of CDX2.

Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression.

Intestinal mucin gene MUC2 is abundantly expressed in goblet cells. To identify the transcriptional activator that regulates goblet-specific expression of MUC2, we analyzed the interaction between the MUC2 promoter and homeodomain proteins CDX1/2, which are involved in the regulation of intestinal development and differentiation. COS-7 cells were transiently transfected with a CDX1 or CDX2 expression construct and then used for the luciferase assay, reverse transcription-polymerase chain reaction, and electrophoretic mobility shift assay (EMSA). The CDX2 expression construct activated the MUC2 promoter and increased the endogenous MUC2 mRNA level, while the CDX1 one did not. EMSA revealed that CDX2 bound to the MUC2 gene cis element, MUC2-WT. These results suggest that CDX2, but not CDX1, interacts with the MUC2 promoter and activates MUC2 transcription, and plays an important role in the differentiation of goblet cells.

Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach.

The roles of CDX2 and CDX1 homeobox genes during gastric carcinogenesis remain poorly defined. We have studied the expression of CDX2/1 in gastric cancers and intestinal metaplasia (IM) of 69 gastric carcinoma patients by immunohistochemistry. CDX2/1 were shown to be ectopically overexpressed in IM in 41 (85%) of 48, and 47 (90%) of 52 cases, respectively. The expression of CDX2/1 was detected in 38 (55%) and 51 (74%) of the 69 gastric carcinomas, respectively. The histological type of the gastric carcinomas was independently associated with CDX2 expression, but not with that of CDX1, with higher CDX2 expression in intestinal type (differentiated type) than in diffuse type (undifferentiated type) gastric carcinomas. Our results thus suggest that CDX2 and CDX1 may play a role during IM formation and gastric carcinogenesis.