PRSS23 knockdown inhibits gastric tumorigenesis through EIF2 signaling.

PRSS23 is a newly discovered serine protease that has been associated with tumor progression in various types of cancers. Our previous study showed PRSS23 is down-regulated obviously in Hedgehog pathway blocked gastric cancer cells. However, the correlation between PRSS23 and tumor progression of gastric cancer remains unclear. Here, the role and mechanism of PRSS23 in tumor progression of gastric cancer were determined. PRSS23 protein levels were significantly increased in gastric cancer tissues compared with the paired adjacent normal gastric mucosa tissues. The high expression of PRSS23 correlated strongly with both poor differentiated histology and cancer region of sinus ventriculi. Gastric cancer patients with low PRSS23 expression displayed a better prognosis. In gastric cancer cells, PRSS23 knockdown inhibited cell proliferation and induced apoptosis. In xenograft tumor model, PRSS23 knockdown led to dramatic decreases of the average tumor volume and the average tumor weight. In addition, PRSS23 knockdown suppressed gastric cancer growth through inhibiting EIF2 signaling using gene expression microarray analysis. Taken together, our results suggest PRSS23 is highly associated with human gastric tumorigenesis and progression. PRSS23 knockdown could suppress tumor growth of gastric cancer in vitro and in vivo through inhibiting EIF2 signaling, and EIF4E maybe a potential target of PRSS23. PRSS23 could serve as a potential target for gastric cancer therapy, and also a biomarker for the prediction of prognosis of gastric cancer.

Inhibition of ASM activity ameliorates DSS-induced colitis in mice.

Acid sphingomyelinase (ASM) is a membrane lipid hydrolase, acting to generate ceramide and regulate cell functions and inflammatory responses.The roles of ASM in mediating T cell functions are postulated whereas its function in regulation of macrophages remains uncertain. The study was performed to explore ASM activity in control of macrophage functions. RAW 264.7 cells were pretreated with desipramine, an ASM inhibitor, prior to LPS challenge in vitro. LPS initiated ASM activity in RAW 264.7 cells. Conversely, inhibition of ASM activity by desipramine diminished LPS induced ASM activities and TNF production of RAW 264.7 cells. The DSS colitis in mice was induced, and desipramine was administered to the mice two days post induction of colitis. Murine colitis was characterized by elevation of ASM activities in colon tissues. Desipramine administration overrode ASM activities in colon, and ameliorated DSS-induced colitis evidenced with the reduced disease activities and the decreased cytokine levels. Together, our data show a crucial role of ASM activity in regulation of macrophage functions and responses, and suggest that ASM represents a novel therapeutic approach for the management of immune diseases.

A nomogram based on the log odds of positive lymph nodes for predicting the prognosis of T1 stage rectal cancer.

Early detection and timely treatment is the key to improving the prognosis of rectal cancer. Lymph node metastasis is one of the reasons for the poor prognosis of rectal cancer, especially early-stage rectal cancer. In this study, we developed a nomogram based on log odds of positive lymph nodes (LODDS) to predict cancer-specific survival (CSS) in patients with T1 rectal cancer. We included 1934 patients from the Surveillance, Epidemiology, and End Results (SEER) database and divided them into a training cohort and an in-validation cohort. 140 patients from our hospital formed the ex-validation cohort. Multivariate Cox regression analysis indicated that age, sex, grade, and M stage were independent prognostic factors for CSS. LODDS showed better predictive ability than the N stage and PLNs (positive lymph nodes) and was further selected as an independent prognostic factor for the construction of the nomogram. The C-index of the nomogram was 0.743, 0.756, and 0.876 in the training, in-validation, and ex-validation cohorts, respectively. The AUC values of the three cohorts were 0.750, 0.703, and 0.958 at 3 years and 0.731, 0.678, and 0.783 at 5 years. The calibration curves and DCA demonstrated the nomogram's excellent performance. In conclusion, we developed and validated a new nomogram based on LODDS that can effectively predict CSS at 3 and 5 years for patients with T1 rectal cancer.

Molecular targeted treatment and drug delivery system for gastric cancer.

Gastric cancer is still a major cancer worldwide. The early diagnosis rate of gastric cancer in most high incidence countries is low. At present, the overall treatment effect of gastric cancer is poor, and the median overall survival remains low. Most of the patients with gastric cancer are in an advanced stage when diagnosed, and drug treatment has become the main means. Thus, new targeted drugs and therapeutic strategies are the hope of improving the therapeutic effect of gastric cancer. In this review, we summarize the new methods and advances of targeted therapy for gastric cancer, including novel molecular targeted therapeutic agents and drug delivery systems, with a major focus on the development of drug delivery systems (drug carriers and targeting peptides). Elaborating these new methods and advances will contribute to the management of gastric cancer.

Inhibition of NADPH oxidase activities ameliorates DSS-induced colitis.

NADPH oxidases (NOX) act to generate reactive oxygen species (ROS) and exhibit microbicidal bioactivity, whereas their roles in mediating immune responses of inflammation in intestine remain to be further elucidated. The study was performed to explore the effects of NOX activity on regulation of macrophage functions. Macrophage responses were induced by lipopolysaccharides (LPS) in RAW 264.7 cells (in vitro) or dextran sulfate sodium (DSS) in BALB/c mice (in vivo) respectively. LPS induced NOX2 expression and initiated NOX activities in RAW 264.7 cells. Conversely, inhibition of NOX activity by DPI and VAS2870 diminished LPS induced NOX activities and the downstream signaling in RAW 264.7 cells. Murine colitis was characterized by macrophage accumulation and elevation of NOX activities in colon tissues. DPI and VAS2870 administration overrode NOX activities and ROS productions in colon tissues, and ameliorated DSS-induced colitis evidenced with the reduced disease activities and the decreased cytokine levels. Intriguingly, NOX2 expression levels were elevated in colon tissues of patients with active inflammatory bowel disease. Together, our data show a crucial role of NOX activity in regulation of macrophage functions and responses, and suggest that NOX represents a novel therapeutic approach for the management of immune diseases.

Down-regulation of Gli transcription factor leads to the inhibition of migration and invasion of ovarian cancer cells via integrin ß4-mediated FAK signaling.

BACKGROUND: Recent evidence suggests that aberrant activation of Hedgehog (Hh) signaling by Gli transcription factors is characteristic of a variety of aggressive human carcinomas including ovarian cancer. Therefore, chemotherapeutic agents that inhibit activation of Gli transcription factors have emerged as promising novel therapeutic drugs for ovarian cancer. RESULTS: In this study, we show that activation of Hh signaling promoted cellular migration and invasion, whereas blockade of Hh signaling with GANT61 suppressed cellular migration and invasion in ovarian cancer cells. After treatment with GANT61, cDNA microarray analyses revealed changes in many genes such as Integrin ß4 subunit (ITGB4), focal adhesion kinase (FAK), etc. Furthermore, ITGB4 expression was up-regulated by Sonic Hedgehog (Shh) ligand and down-regulated by Hh signaling inhibitor. The Shh-mediated ovarian cell migration and invasion was blocked by neutralizing antibodies to ITGB4. In addition, phosphorylations of FAK were increased by Shh and decreased by Hh signaling inhibitor. Inhibition of Gli1 expression using siRNA mimicked the effects of GANT61 treatment, supporting the specificity of GANT61. Further investigations showed that activation of FAK was required for Shh-mediated cell migration and invasion. Finally, we found that down-regulation of Gli reduced the expression of ITGB4 and the phosphorylated FAK, resulting in the inhibition of tumor growth in vivo. CONCLUSIONS: The Hh signaling pathway induces cell migration and invasion through ITGB4-mediated activation of FAK in ovarian cancer. Our findings suggest that the diminishment of crosstalk between phosphorylated FAK and ITGB4 due to the down-regulation of Gli family transcription factors might play a pivotal role for inhibiting ovarian cancer progression.

Suppression of growth and migration by blocking the Hedgehog signaling pathway in gastric cancer cells.

PURPOSE: Previous studies have indicated that Hedgehog signaling is essential for gastric cancer development, but its precise role is still unclear. The aim of this study was to clarify the role of Hedgehog signaling in gastric cancer development. METHODS: The expression of key Hedgehog signaling components in clinical samples of sequential gastric cancer stages was assessed by immunohistochemistry. The roles and regulatory mechanisms of Hedgehog signaling in human gastric cancer cells and normal gastric epithelial cells were investigated using multiple cell biological approaches and cDNA microarray analyses. RESULTS: Hedgehog signaling was found to be abnormally activated in a ligand-independent manner during gastric cancer development. Gli1 over-expression and reduced SuFu expression were found to be typical events in gastric cancer tissues. Gli1 over-expression was found to correlate with a poorly differentiated histology, advanced clinical stage, membrane serosa infiltration and lymph node metastasis in patients with gastric cancer. Data obtained from multiple cell biological assays showed that human gastric cancer cells require active Hedgehog signaling for survival, proliferation, migration and colony formation. N-Shh treatment significantly enhanced the migration, invasion and colony formation of gastric cancer cells. Moreover, the results of cDNA microarray analyses indicated that after treatment with cyclopamine or GANT61 (inhibitors of Hedgehog signaling), differentially expressed genes in gastric cancer cells were enriched in the apoptosis and MAPK pathways. Inhibitors of the Hedgehog pathway were found to suppress gastric cancer cell growth via apoptosis induction. CONCLUSIONS: Our findings indicate a vital role of the activated Hedgehog signaling pathway in promoting gastric initiation and progression. The Hedgehog signaling pathway may serve as a target for gastric cancer therapy.

Cytotoxicity and antibacterial activity of Lindera strychnifolia essential oils and extracts.

AIM OF THE STUDY: Lindera strychnifolia (LS) is widely used in traditional Chinese medicine. In the present study, we investigated cytotoxicity and antibacterial activity of essential oils and various fractions of ethanol extract of LS to explore the active components of LS and their pharmacological effects. MATERIALS AND METHODS: The in vitro cytotoxicities of essential oils and various solvent fractions of LS on three human cancer cell lines (A549, HeLa and Hep G2) and a non-cancerous cell line (HUVEC) were examined using a modified MTT assay. And by using agar disc diffusion and broth microdilution methods, the antibacterial activity of these samples was evaluated against 10 bacteria including 5 clinically isolated strains. The compositions of the essential oils from the leaves and roots of LS were also analyzed by GC and GC-MS. RESULTS: The leaf oil showed the strongest cytotoxicity on the cancer cell lines tested with the IC50 values ranged from 22 to 24 microg/ml after 24 h of treatment. The most sensitive microbial strain to all the samples was Staphylococcus aureus ATCC 25923. CONCLUSIONS: Our results showed that the essential oils of LS exhibited greater cytotoxicity and antibacterial activity than the solvent fractions of ethanol extract of LS.

Reactions of peroxynitrite and nitrite with organic molecules and hemoglobin.

In this work, the reactions of nitrite (NO2-) and peroxynitrite (ONOO-) with organic molecules as well as with hemoglobin (Hb) were examined and the potential interference with the detection of hydrogen peroxide and Hb was investigated. ONOO- at low concentrations (35-140 microM) induced a concentration-dependent oxidation of o-phenylenediamine and guaiacol, and this process can be improved by the addition of Hb in a concentration-dependent manner. This enhancing effect of Hb was possibly due to the formation of such highly reactive species as ferrylHb during the reaction of ONOO- and Hb. NO2- also oxidized the aromatic amine o-phenylenediamine, but its efficiency was much lower than that of ONOO-. A 300-fold excess of NO2- over hydrogen peroxide inhibited the oxidation of Pyrogallol Red mediated by hydrogen peroxide and Hb, which was due in part to the reaction of NO2- with Hb ferryl species compound I and compound II and the phenoxyl radical. These data suggest that ONOO- and NO2- can interfere with the detection of hydrogen peroxide. The overestimation or underestimation of the hydrogen peroxide detected is dependent upon the organic molecule utilized for detection and the relative rate of NO2-, superoxide, and ONOO- generation.