Role of GABAA receptors in EEG activity and spatial recognition memory in aged APP and PS1 double transgenic mice.

Alzheimer's disease (AD) is a leading cause of dementia, with no effective treatment currently available. However, targeting the aging mechanism may improve outcomes and γ-aminobutyric acid (GABA) system alteration could have implications for treatment of cognitive decline in old age. We studied the effects of the GABA system on brain activity in aged APP and PS1 transgenic mice. Low dose (0.1 mg/kg i.p.) GABAA agonist muscimol and antagonist bicuculline were administered for moderate system activation and inhibition, respectively. EEGs from the hippocampus (Hip) and prefrontal cortex (PFC) were recorded under spontaneous state and during Y-maze performance. Basally, AD mice exhibited increased spontaneous EEG delta (2-4 Hz) and decreased spontaneous EEG alpha (8-12 Hz) activity in the Hip, and decreased Y-maze EEG theta (4-8 Hz) activity in the PFC. Interestingly, GABAA activation and inhibition in AD mice reduced EEG delta activity and increased EEG theta activity in the PFC, and behaviorally improved spatial recognition memory during Y-maze testing. Decreased spontaneous EEG delta activity was also observed in the PFC. Specifically, GABAA activation primarily affected low frequency EEG (2-12 Hz) activity in the PFC, whereas inhibition affected EEG activity across many frequencies in the PFC and Hip. These data provide evidence for slower brain activity in AD mice. Importantly, improved spatial memory after GABAA activation and inhibition may be explained by brain rhythm recovery in certain regions. Our study highlights the potential clinical use of GABAA drugs to improve cognitive disorders and restore neural network activity in AD.

Identification and verification of PRDX1 as an inflammation marker for colorectal cancer progression.

Chronic inflammation contributes to high risk of colorectal cancer (CRC) development. Thus, discovering inflammation biomarkers for monitoring of CRC progression is necessary. In this study, we performed isobaric tags for relative and absolute quantitation-based proteomic assay on CRC tissues and paired normal mucosal tissues to identify key components in CRC pathogenesis. A total of 115 altered protein expressions were found with over twofold difference as compared with normal controls, which were associated with various molecular functions and biological processes. Here, we found that peroxiredoxin 1 (PRDX1) expression was higher in CRC tissues than that of matched controls and was determined as a tumor biomarker by receiver operating characteristic curve. PRDX1 expression was significantly upregulated in NCM460 cells challenged by H2O2 in a dose-dependent manner. PRDX1 depletion in SW480 cells enhanced reactive oxygen species (ROS), NO, and ONOO(-) production and increased the mRNA and protein expressions of pro-inflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6] and chemokines (IL-8 and CXCL1), and partly activated nuclear factor-κB p65. Overall, our findings provide data on global alteration in the proteome of CRC tissues and reveal the potential of PRDX1 as an inflammation marker in CRC development, suggesting a novel therapy against inflammation-associated CRC.

A possible role of GDDR in the development of Helicobacter pylori-associated gastric cancer.

Helicobacter pylori (H. pylori) infection plays an important part in the development of gastric carcinoma. GDDR has been confirmed as a tumor suppressor gene in gastric tumorigenesis. However, the underlying mechanism of GDDR in H. pylori-induced carcinogenesis is not well known. The aim of this study is to investigate the clinicopathological significance and possible molecular mechanism of GDDR in gastric cancer associated with H. pylori. Western blot, real-time quantitative PCR (qRT-PCR), and immunohistochemistry were used to detect the expression level of GDDR with or without H. pylori infection. The function and possible related molecular mechanisms of GDDR were further explored in vitro and in vivo. The variability of GDDR expression appeared in the early stage of gastric carcinogenesis with positive H. pylori infection status. GDDR might inhibit the progression of normal gastric epithelial cells to cancer cells by suppressing NF-kappaB signaling pathway, which in turn could be regulated by H. pylori infection. Our results suggested, for the first time, that the gradual change in GDDR expression might not only be directly related to H. pylori infection but also be an early molecular event in the development of gastric carcinoma.

Human epidermal growth factor receptor 2 expression in mixed gastric carcinoma.

AIM: To investigate human epidermal growth factor receptor 2 (HER2) amplification and protein expression in mixed gastric carcinoma. METHODS: Fluorescence in situ hybridization and immunohistochemistry were used to detect HER2 amplification and protein expression in 277 cases of mixed gastric carcinoma. Protein staining intensity was rate as 1+, 2+, or 3+. RESULTS: Of the 277 cases, 114 (41.2%) expressed HER2 protein. HER2 3+ staining was observed in 28/277 (10.1%) cases, 2+ in 37/277 (13.4%) cases, and 1+ in 49/277 (17.7%) cases. A HER2 amplification rate of 17% was detected, of which 25/28 (89.3%) were observed in the HER2 3+ staining group, 17/37 (45.9%) in 2+, and 5/49 (10.2%) in 1+. Of the 47 patients with HER2 amplification who received chemotherapy plus trastuzumab, 22 demonstrated median progression-free and overall survivals of 9.1 mo and 16.7 mo, respectively, which were significantly better than those achieved with chemotherapy alone (5.6 mo and 12.1 mo, respectively) in 19 previously treated patients (Ps < 0.05). CONCLUSION: HER2 detection in mixed gastric carcinoma displays high heterogeneity. Relatively quantitative parameters are needed for assessing the level of HER2 amplification and protein expression.

Identification of the up-regulation of TP-alpha, collagen alpha-1(VI) chain, and S100A9 in esophageal squamous cell carcinoma by a proteomic method.

Esophageal squamous cell carcinoma (ESCC) is one of the most common primary malignant tumor of digestive tract. However, the early diagnosis and molecular mechanisms that underlie tumor formation and progression have been progressed less. To identify new biomarkers for ESCC, we performed a comparative proteomic research. Isobaric tags for relative and absolute quantitation-based proteomic method was used to screen biomarkers between ESCC and normal. 802 non-redundant proteins were identified, 39 of which were differentially expressed with 1.5-fold difference (29 up-regulated and 10 down-regulated). Through Swiss-Prot and GO database, the location and function of differential proteins were analyzed, which are related to the biological processes of binding, cell structure, signal transduction, cell adhesion, etc. Among the differentially expressed proteins, TP-alpha, collagen alpha-1(VI) chain and S100A9 were verified to be upregulated in 77.19%, 75.44% and 59.65% of ESCC by immunohistochemistry and western-blot. Diagnostic value of these three proteins was validated. These results provide new insights into ESCC biology and potential diagnostic and therapeutic biomarkers, which suggest that TP-alpha, collagen alpha-1(VI) chain and S100A9 are potential biomarkers of ESCC, and may play an important role in tumorigenesis and development of ESCC.

Gastrointestinal tract specific gene GDDR inhibits the progression of gastric cancer in a TFF1 dependent manner.

The novel gene GDDR, also named trefoil factor interactions 1, is abundantly expressed in human gastric epithelial cells but significantly down-regulated in gastric cancer. In this study, we first demonstrated that GDDR was specifically expressed in the gastrointestinal tract epithelium, while suppressed in gastric cancer cells. Forced expression of GDDR suppressed the tumor growth as shown by MTT and xenograft assay. siRNA mediated TFF1 inhibition nearly blocked the growth inhibitory role of GDDR. In summary, our study suggested that gastrointestinal tract specific gene GDDR might inhibit gastric cancer growth in a TFF1 dependent manner.

[Isolation of a down-regulated novel gene with lower abundance in gastric cancer].

OBJECTIVE: To clone novel gene from suppression subtraction library established for screening down-regulated genes in gastric carcinoma, and the effects of novel gene on gastric tumorigenicity were analyzed. METHODS: Sequencing results of 860 positive colonies chosen randomly were compared by Blast program in GenBank. Novel gene fragment was amplified by rapid amplification of cDNA ends (RACE). The mRNA expression of novel gene was detected by Northern blot and semi-quantitative PCR in 25 cases of gastric carcinoma tissue and counterpart normal gastric mucosa. The structure and chromosomal location of novel gene were investigated by Bio-message technique. RESULTS: A 233 bp novel gene fragment was screened out from 860 clones and a 802 bp novel gene was obtained by RACE. The novel gene was named as GDDM, registered in the number of AF494508 by GenBank. The mRNA expression of GDDM in gastric carcinoma tissue (4.496+/-0.637) was significantly lower than that in the counterpart normal gastric mucosa (36.919+/-6.290)(P<0.01). Chromosomal location of GDDM gene was at 4q31. CONCLUSION: The cloned novel gene, GDDM, is down-regulated in gastric carcinoma, and it is likely to be involved in gastric tumorigenicity.