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.

[Differentiation of subtypes of renal cell carcinoma by double-phase helical computed tomography].

OBJECTIVE: To evaluate the imaging features of different subtypes of renal cell carcinoma (RCC) by double-phase helical computed tomography (CT) and to enhance its pre-operative diagnosis level. METHODS: A total of 460 RCC were reviewed retrospectively. Tumor size, enhancement degree, enhancement drop between corticomedullary (CMP), nephrographic (NP), enhancement pattern, and tumor density (homogeneity, degeneration or necrosis, calcification) were observed respectively. The clear cell, chromophobe and papillary types were analyzed for statistical analysis. RESULTS: They had difference in enhancement pattern and tumor density of clear cell, chromophobe (P < 0.05) and papillary types (P < 0.05). There were differences in enhancement degree, enhancement drop and combine degeneration or necrosis in all subtypes of RCC (P < 0.05). The clear cell type was of hypervascular tumor and showed a stronger enhancement (80.9%) than other types. The enhancement drop was also higher than other types and 57.9% of it was ≥ 30 HU. As for ≥ 30 HU, the clear cell type was diagnosed with a 57.9% sensitivity and a 91.9% specificity. Clear cell type tended to appear as peripheral and heterogeneous enhancement (66.3%, 94.6%); it was likely heterogeneous in density (91.6%) with frequent degeneration or necrosis (60.5%). The chromophobe type was of moderate vascular tumor and it exhibited middle-level enhancement (77.1%). The enhancement drop was low (< 30 HU, 80.0%). As for 0-30 HU, the chromophobe type was diagnosed with an 80.0% sensitivity and a 66.1% specificity. Its pattern ended to appear as homogeneous enhancement (65.7%); Homogeneous density, degeneration and necrosis were characteristic signs of chromophobe type. The papillary type was of hypovascular tumor and it exhibited slight or no enhancement (70.4%). The enhancement drop was low (< 30 HU, 92.6%) and the gradual enhancement (63.0%) was characteristic of this type. As for 0 Hu, the papillary type was diagnosed with a 63.0% sensitivity and a 91.8% specificity. It tended to appear as homogeneous density (63.0%). The unclassified type tended to appear as peripheral (9/12 cases) and stronger enhancement (7/12 cases) and heterogeneous density with degeneration or necrosis (9/12 cases). The multilocular cystic RCC appeared as complex cyst. And cystic wall enhancement was an important diagnostic point of cystic RCC. CONCLUSION: Double-phase helical CT plays an important role in the pre-operative differentiation of subtypes of RCC. Each type of RCC has its own features. A clinician may reach a correct pre-operative diagnosis.

[Value of CT scanning in the diagnosis of early cervical carcinoma].

OBJECTIVE: To investigate the value of CT scanning in preoperative diagnosis of early cervical carcinoma. METHODS: Abdominal and pelvic CT scans (MPR pictures for 50 patients) in 102 cervical carcinoma patients proven by biopsy pathology were retrospectively analyzed and compared with surgical pathologic findings. The pathological stages included > or = Ia in 39 patients, Ib 1 in 35, Ib 2 in 21, IIa in 6, IIb in 1. The tumor detection ability, thickness of cervical tumor invasion, T stage and lymph node stage showed by CT scan were evaluated. RESULTS: CT was not able to detect < or = Ia cervical carcinoma, however, CT was able to detect tumors in 71.4% of > or = Ib 1 stage (45/63) and 71.4% > or = Ib 2 (20/28), it also showed the depth of tumor invasion in 39.7% > or = Ib 1 (25/63). The overall accuracy of CT staging for tumor was 69.6% and the rate of metastatic lymph node detection 63.6% (7/11). With additional MPR pictures of spiral CT, the detection ability, vaginal involvement and objective shape of cervical tumor was improved. The cervical carcinoma in CT scan was found to be as homogeneous in 54.9% of patients (56/102), hypodense or heterogeneous in 42.2% (43/102), lower density nodual in 41.9% (18/43); occasionally as heterogeneous or hyperdensity noduals or irregular border of the cervix. The features of metastatic lymph nodes in CT scan were rounded or spheroid shape of soft tissue noduals with heterogeneous density caused by central necrosis and rim enhancement. CONCLUSION: CT scanning may be valuable in detection of > or = Ib 1 rather than < Ib 1 stage early cervical carcinoma. The additional MPR pictures of spiral CT is not only helpful in detecting tumor but also in determining the extension of cervical carcinoma.

[Peritoneal tuberculosis mimicking advanced ovarian carcinoma: distinction based on CT findings].

OBJECTIVE: To evaluate the computed tomography (CT) findings of peritoneal tuberculosis mimicking advanced ovarian carcinoma for better understanding of the CT manifestations and accurate preoperative diagnosis. METHODS: CT findings of 18 cases with tuberculous peritonitis clinically simulating advanced ovarian cancer but pathologically proved otherwise were retrospectively reviewed. RESULTS: 1. Masses with solid and cystic structures were found in 6 cases and tumor-like flakes were found in 7 cases in the adnexal regions. The solid components and tumor-like flakes were moderately to markedly enhanced with dynamic CT scanning. 2. The peritoneum was smooth and slightly thickened in 10 cases; irregular thickening was seen in 4 cases, and patches of calcification in 3 cases. Thickened peritoneum with pronounced enhancement was noted in 7 cases. 3. Omentum with flake-like thickening was noted in 11 cases, coarse reticulate thickening in 2 cases and omental cakes in 2 cases. The margin of the thickened omentum with enhancement was ill-defined. 4. Nodular and stripe-like thickening of the mesentery was noted in 16 cases. 5. Ascites was present in all of the 18 cases, being encapsulated in 14 of them. 6. Lymphadenopathy was seen in 9 cases, all at located in the diaphragmatic levels. Enhancement of the lymph nodes was marked in 8 of the 8 patients examined. They appeared as ring-like (> 1 cm in diameter) or uniform (