Acceleration of amyloidogenesis and memory impairment by estrogen deficiency through NF-κB dependent beta-secretase activation in presenilin 2 mutant mice.

Nearly 7-10 million people are living with Alzheimer's disease (AD) worldwide. Senile plaques composed of ß-amyloid (Aß) are a pathological hallmark of Alzheimer's disease. Presenilin 2 (PS2) mutations increase Aß generation in the brains of AD patients. The Aß is generated through the sequential cleavage of amyloid precursor protein by ß- and γ-secretases. Additionally, increasing evidences suggest that estrogen can reduce the development of AD via regulation of ß-secretases activity and beta-site APP-cleaving enzyme (BACE1) expression. But the underlying correlation mechanism of Aß generation by PS2 mutations and estrogen remains to be clarified. To investigate the anti-amyloidogenesis effect of estrogen in a PS2 mutative condition, we examined memory impairment in ovariectomized PS2 mutation (N141I) mice in which cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, Western blot analysis, immunostaining, immunofluorescence staining, ELISA and enzyme activity assays were used to examine the degree of Aß deposition in the brains. In the present study, Aß accumulated more in the ovariectomized PS2 mutant mice brain, and greatly worsened memory impairment and glial activation as well as neurogenic inflammation. In parallel with increased memory impairment, activity of ß-secretase and expression of the BACE1 increased inovariectomized PS2 mutant mice. Much higher activity of NF-κB was observed by EMSA in ovariectomized PS2 mutant mice. In addition, the Aß level was decreased by treatment of ß-estradiol through inhibiting BACE1 expression in PS2 transfacted PC12 cells. These results suggest that mutation of PS2 can lead to NF-κB mediate amyloidogensis, and this effect can be amplified by the absence of estrogen.

An apolipoprotein B100 mimotope prevents obesity in mice.

Although apolipoprotein B100 (ApoB100) plays a key role in peripheral fat deposition, it is not considered a suitable therapeutic target in obesity. In the present study we describe a novel ApoB100 mimotope, peptide pB1, and the use of pB1-based vaccine-like formulations (BVFs) against high-fat diet (HFD)-induced obesity. In HFD- compared with chow-fed adolescent mice, BVFs reduced the 3-month body-weight gains attributable to increased dietary fat by 44-65%, and prevented mesenteric fat accumulation and liver steatosis. The body-weight reductions paralleled the titres of pB1-reactive immunoglobulin G (IgG) antibodies, and pB1-reactive antibodies specifically recognized native ApoB100 and a synthetic peptide from the C-terminal half of ApoB100. In cultured 3T3L1 adipocytes, anti-pB1 antibodies increased lipolysis and inhibited low-density lipoprotein (LDL) uptake. In cultured RAW 264.7 macrophages, the same antibodies enhanced LDL uptake (without causing foam cell formation). These findings make ApoB100 a promising target for an immunization strategy against HFD-induced obesity.

Laparoscopic resection of small gastric submucosal tumors.

BACKGROUND: No consensus exists regarding the necessity of operative resection for patients with small, asymptomatic gastric submucosal tumors (SMTs). The purpose of this study is to evaluate clinical outcomes of resection by minimally invasive surgery. METHODS: The medical records of 20 consecutive patients who had undergone laparoscopic or robotic wedge resection for small (<5 cm) gastric SMTs between March 2008 and February 2009 were reviewed. Operative indications included all SMTs unquestionably visible by endoscopy, irrespective of symptoms. The operative procedures, clinicopathologic features, and operative results were assessed. RESULTS: Out of a total of 20 patients, 17 were asymptomatic, and 3 presented with vague abdominal discomfort. One patient had two tumors, therefore 21 total lesions were resected and evaluated (19 by laparoscopy and 2 by robotic procedures). There were 12 exogastric and 9 transgastric wedge resections. Mean operative time was 84 ± 28 min, and mean length of hospitalization was 4.7 ± 1.6 days. There were no major peri- or postoperative complications or mortalities. Mean tumor size was 2.4 ± 1.2 cm (range 0.6-4.8 cm). All lesions had microscopically negative resection margins. There were 16 gastrointestinal tumors (GISTs) and 5 other benign lesions. Fifteen of the GISTs had mitotic count (MC) <5 per 50 high-power fields (HPFs), and one lesion measuring 2.5 cm in size had MC of 38 per 50 HPFs. CONCLUSIONS: Small size cannot guarantee a specific malignant risk for gastric SMTs. Laparoscopic/robotic wedge resection is safe and effective in treating small, asymptomatic lesions. Therefore, an active surgical approach should be considered for management of patients with small gastric SMTs.