Caffeine-induced neurotoxicity mediated by Nrf2 pathway in PC12 cells and zebrafish larvae.

Caffeine is one of the most widely used psychostimulants in the world and possesses central excitative, anti-depressive, and neuroprotective properties. However, excessive ingestion or abuse of caffeine can lead to intoxication. Many toxic effects are attributed to oxidative damage, and nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical intracellular regulator of the oxidative stress response. Here, we investigated the neurotoxicity of caffeine in rat pheochromocytoma PC12 cells and zebrafish larvae. It was found that caffeine inhibited the viability of PC12 cells in a dose- and time-dependent manner. Furthermore, it induced PC12 cell apoptosis and elevated reactive oxygen species (ROS) production. Quantitative polymerase chain reaction (qPCR) and western blotting revealed that caffeine also inhibited the expression levels of Nrf2 mRNA and protein and its target genes (e.g., NADPH quinone oxidoreductase 1 [NQO1]). Furthermore, Nrf2 silencing attenuated the toxic effects of caffeine. In addition, zebrafish larvae were treated with different doses of caffeine. Behavioral experiments showed that a low dose of caffeine (0.05 to 0.3 mM) increased the average distance of movement and promoted excitation. Survivorship curves showed that caffeine (0.2 to 1.5 mM) caused lethality. Finally, qPCR revealed that a higher dose of caffeine inhibited mRNA levels in the Nrf2 pathway. Based on these results, this study identified for the first time that overuse of caffeine can induce neurotoxicity by inhibiting the Nrf2 pathway. These results will provide a new perspective for studies on caffeine toxicity.

Network analysis reveals crosstalk between autophagy genes and disease genes.

Autophagy is a protective and life-sustaining process in which cytoplasmic components are packaged into double-membrane vesicles and targeted to lysosomes for degradation. Accumulating evidence supports that autophagy is associated with several pathological conditions. However, research on the functional cross-links between autophagy and disease genes remains in its early stages. In this study, we constructed a disease-autophagy network (DAN) by integrating known disease genes, known autophagy genes and protein-protein interactions (PPI). Dissecting the topological properties of the DAN suggested that nodes that both autophagy and disease genes (inter-genes), are topologically important in the DAN structure. Next, a core network from the DAN was extracted to analyze the functional links between disease and autophagy genes. The genes in the core network were significantly enriched in multiple disease-related pathways, suggesting that autophagy genes may function in various disease processes. Of 17 disease classes, 11 significantly overlapped with autophagy genes, including cancer diseases, metabolic diseases and hematological diseases, a finding that is supported by the literatures. We also found that autophagy genes have a bridging role in the connections between pairs of disease classes. Altogether, our study provides a better understanding of the molecular mechanisms underlying human diseases and the autophagy process.

[Application of technetium-99m labelled sandostatin Somatostatin receptor imaging in the detection of lung cancer].

OBJECTIVE: To evaluate the clinical value of (99)Tc(m)-sandostatin receptors imaging ((99)Tc(m)-sandostatin) in detection of lung tumors in comparison with fludeoxyglucose F18 dual head coincidence imaging ((18)F-FDG DHC). METHODS: Fifty-six consecutive patients (40 men, 16 women; mean age: 62 years, range 35 - 80 years) with pulmonary neoplasm were referred for evaluation. All underwent sandostatin scintigraphy using hybrid SPECT/CT. (18)F-FDG DHC imaging was also performed in 23 patients using the same camera. The tumor uptake of (99)Tc(m)-sandostatin and (18)F-FDG DHC were measured respectively and expressed as the ratio of T/Nr and T/Nm. Final clinical diagnosis was confirmed by histopathological study. RESULTS: Out of 56 cases, 46 were confirmed to be malignant and 10 benign. The sensitivity, specificity and accuracy of (99)Tc(m)-sandostatin in diagnosis of lung cancer were 95.7%, 90.0%, 94.6%, respectively. The positive predictive value (PPR) was 97.8%, and the negative predictive value (NPR) was 81.8%. In the 23 patients underwent both methods, the sensitivity, specificity and accuracy of (18)F-FDG DHC were 100%, 60.0%, 82.6%, respectively; the PPR was 76.5%, and the NPR 100%. Out of 13 patients with malignant neoplasms, 6 patients had regional lymph node metastasis, and all of 10 abnormal lymph nodules showed high uptake of FDG, while (99)Tc(m)-sandostatin imaging only 2 regional metastasized lymph nodes in one patient. T/N(r) and T/N(m) were 3.15 +/- 1.30, and 10.61 +/- 4.35 respectively. There was no relationship between sandostatin uptake and glucose metabolism. CONCLUSION: (99)Tc(m)-sandostatin scintigraphy is a promising noninvasive imaging technique for detection of the primary tumor of lung cancer but of limited value in the detection of lymph node metastasis.