Chronic exposure of zearalenone inhibits antioxidant defense and results in aging-related defects associated with DAF-16/FOXO in Caenorhabditis elegans.

Zearalenone (ZEN), a mycotoxin with endocrine disruptive activity and oxidative stress generating ability, has been a worldwide environmental concern for its prevalence and persistency. However, the long-term effect of ZEN on aging process is not fully elucidated. Thus, the present study applied the Caenorhabditis elegans model to investigate the aging-related toxic effect and possible underlying mechanisms under prolonged and chronic ZEN exposure. Our results showed that locomotive behaviors significantly decreased in ZEN (0.3, 1.25, 5, 10, 50 µM) treated C. elegans. In addition, lifespan and aging markers including pharyngeal pumping and lipofuscin were also adversely affected by ZEN (50 µM). Furthermore, ZEN (50 µM) increased ROS level and downregulated antioxidant genes resulted from inhibition of nuclear DAF-16 translocation in aged C. elegans, which was further confirmed by more significant aging-related defects observed in ZEN treated daf-16 mutant. In conclusion, our findings suggest that the aging process and aging-related decline were induced by long-term exposure of ZEN in C. elegans, which is associated with oxidative stress, inhibition of antioxidant defense, and transcription factor DAF-16/FOXO.

The CBF1-independent Notch1 signal pathway activates human c-myc expression partially via transcription factor YY1.

Transcription factor Ying Yang 1 (YY1) indirectly regulates the C promoter-binding factor 1 (CBF1)-dependent Notch1 signaling via direct interaction with the Notch1 receptor intracellular domain (N1IC) on CBF1-response elements. To evaluate the possibility that the N1IC might modulate the gene expression of YY1 target genes through associating with YY1 on the YY1-response elements, we herein investigated the effect of Notch1 signaling on the expression of YY1 target genes. We found that the N1IC bound to the double-stranded oligonucleotides of YY1-response element to activate luciferase activity of the reporter gene with YY1-response elements through a CBF1-independent manner. Furthermore, the N1IC also bound to the promoter of human c-myc oncogene, a YY1 target gene, to elevate c-myc expression via a CBF1-independent pathway. The activation of reporter genes with YY1-response elements or human c-myc promoter by N1IC depended on the formation of N1IC-YY1-associated complex. To delineate the role of the Notch signal pathway in tumorigenesis, K562 cell lines expressing the N1IC were established. Compared with control cells, the proliferation and the tumor growth of N1IC-expressing K562 cells were suppressed. Taken together, these results suggest that the N1IC enhances the human c-myc promoter activity that is partially modulated by YY1 through a CBF1-independent pathway. However, the enhancement of c-myc expression by N1IC is insufficient to promote the tumor growth of K562 cells.

Abnormal gastroesophageal flap valve is highly associated with gastroesophageal reflux disease among subjects undergoing routine endoscopy in Taiwan.

OBJECTIVE: Gastroesophageal flap valve (GEFV) grade predicts severe gastroesophageal reflux disease in Caucasians, but its role in other populations is unclear. This study evaluated the significance of endoscopic grading of the GEFV in Taiwanese subjects. METHODS: Five hundred and six consecutive patients undergoing routine check-ups at the National Taiwan University Hospital were enrolled. Symptoms of upper gastrointestinal disease and endoscopic severity of esophageal mucosal injury were correlated to GEFV grades according to the Hill classification. RESULTS: The frequency of abnormal valves (Hill grades III or IV) was 27.3%. Of these, 42.7% had erosive esophagitis (EE). The majority of patients with EE were classified as Los Angeles grades A and B (79.7 and 16.9%, respectively). The prevalence of EE, hiatal hernia and, to a lesser degree, non-erosive reflux disease, increased with altered GEFV. Patients with abnormal valves were younger and more likely to be male, overweight, and to have atypical and extraesophageal symptoms. CONCLUSIONS: Taiwanese patients with abnormal GEFVs share similar characteristics and risk factors with the patients who have EE. Endoscopic grading of the GEFV is highly associated with GERD, and in particular EE, in subjects undergoing routine endoscopy.