Vitamin E: Curse or Benefit in Alzheimer's Disease? A Systematic Investigation of the Impact of α-, γ- and δ-Tocopherol on Aß Generation and Degradation in Neuroblastoma Cells.

OBJECTIVES: The E vitamins are a class of lipophilic compounds including tocopherols, which have high antioxidative properties. Because of the elevated lipid peroxidation and increased reactive oxidative species in Alzheimer's disease (AD) many attempts have been made to slow down the progression of AD by utilizing the antioxidative action of vitamin E. Beside the mixed results of these studies nothing is known about the impact of vitamin E on the mechanisms leading to amyloid-ß production and degradation being responsible for the plaque formation, one of the characteristic pathological hallmarks in AD. Here we systematically investigate the influence of different tocopherols on Aß production and degradation in neuronal cell lines. MEASUREMENTS: Beside amyloid-ß level the mechanisms leading to Aß production and degradation are examined. RESULTS: Surprisingly, all tocopherols have shown to increase Aß level by enhancing the Aß production and decreasing the Aß degradation. Aß production is enhanced by an elevated activity of the involved enzymes, the ß- and γ-secretase. These secretases are not directly affected, but tocopherols increase their protein level and expression. We could identify significant differences between the single tocopherols; whereas α-tocopherol had only minor effects on Aß production, δ-tocopherol showed the highest potency to increase Aß generation. Beside Aß production, Aß clearance was decreased by affecting IDE, one of the major Aß degrading enzymes. CONCLUSIONS: Our results suggest that beside the beneficial antioxidative effects of vitamin E, tocopherol has in respect to AD also a potency to increase the amyloid-ß level, which differ for the analysed tocopherols. We therefore recommend that further studies are needed to clarify the potential role of these various vitamin E species in respect to AD and to identify the form which comprises an antioxidative property without having an amyloidogenic potential.

[The prognostic importance of urinase type plasminogen activators (uPA) and plasminogen activator inhibitors (PAI-1) in the primary resection of oral squamous cell carcinoma]. / Prognostische Bedeutung des Plasminogenaktivators vom Urokinasetyp (uPA) und des Plasminogenaktivator-Inhibitors (PAI-1) beim primär resezierten Plattenepithelkarzinom der Mundhöhle.

This article examines the prognostic importance of urinase type plasminogen activators (uPA) and of plasminogen activator inhibitors (PAI-1) in cases of primary oral squamous cell carcinoma. Tissue samples were taken from the core of the tumour in 58 such primary surgical patients. The levels of uPA and PAI-1 were determined using ELISA. Statistical significance was calculated using the chi2- and log-rank tests. The mean follow-up (n=58) was 23 months. In order to determine prognostic value, the time before relapse was used. The mean time before relapse was 19 months. A total of 28 (40%) patients relapsed (local n=13, lymph node n=3, local and lymph node n=1, lymph node and skin n=1, other locations n=5). Such patients had significantly raised uPA (P<0.012) and PAI-1 (P<0.014) levels in the primary tumour. A optimal cutoff value for uPA (4.58 ng/mg) and PAI-1 (106.3 ng/mg) was determined using the multiple log-rank test. There was no significant correlation for patients with low or high levels (i.e. lower or higher than the cutoff value, respectively) with the usual clinical parameters such as localisation, N-stage, T-stage, differentiation and residual tumor status. Older patients (>58 years) had significantly higher levels of uPA and PAI-1 (P<0.017 and P<0.02, respectively). The likelihood of relapse was significantly higher in patients with high levels (uPA P<0.009, PAI-1 P<0.008). If the patients were divided into three groups depending on uPA and PAI-1 levels (group 1: uPA and PAI-1 low, n=35; group 2: uPA or PAI-1 high, n=12; group 3: uPA and PAI-1 high, n=11), relapses were more common in group 3 than in groups 1 or 2 (P<0.023). Patients with only surgical therapy (n=29) and those with postoperative radiotherapy (n=29) were used to evaluate postoperative follow-up. Cutoff levels were calculated for both groups. In the surgical therapy group this was uPA=5.63 ng/mg and PAI-1=106.3 ng/ml and in the surgical therapy plus radiotherapy group uPA=4.13 ng/mg and PAI-1=97.02 ng/mg. Kaplan-Meier curves showed a marked tendency for patients with higher levels to relapse more often. This is significant for surgical patients for PAI-1 (P<0.01) and for radiotherapy patients for uPA (P<0.04)

[Comparison of urokinase type plasminogen activators (uPA) and plasminogen activator inhibitors (PAI-1) in primary resection of oral squamous cell carcinoma]. / Vergleich des Plasminogenaktivators vom Urokinasetyp (uPA) und des Plasminogenaktivator-Inhibitors (PAI-1) mit klinischen Parametern beim resezierten Plattenepithelkarzinom der Mundhöhle.

This article examines the distribution and prognostic importance of urinase type plasminogen activators (uPA) and of plasminogen activator inhibitors (PAI-1) in cases of primary oral squamous cell carcinoma. Tissue from the primary tumor was taken from 79 patients. In order to make an intra-individual comparison, tissue from the healthy mucous membrane of the mouth was taken from 50 patients and metastatic tissue from lymph glands in the neck from 16 patients. The content of uPA and PAI-1 was determined using ELISA. After follow-up, 58 patients with primary surgical therapy were included. Statistical evaluation was carried out using the Kruskal-Wallis test, the Mann-Whitney U-test and the Wilcoxon test. Pearson's product moment correlation was used to determine the relationship between uPA and PAI-1 levels. The median uPA value was 3.43 ng/mg in primary tumor, and for PAI-1 47.1 ng/mg ( n=79). There was a significant correlation between uPA and PAI-1 both in the cancerous as well as the healthy tissue ( P<0.01). The intra-individual comparisons showed uPA and PAI-1 differed significantly between cancerous and healthy tissue ( P<0.0001) with the mean uPA and PAI-1 values being nine times higher in the cancerous tissue ( n=58). The correlation for between uPA and PAI-1 in tumors, healthy tissue and metastatic lymph node tissue ( n=16) showed highly significant values in the tumors ( P<0.001). The comparison between cancerous tissue in the primary tumor and the lymph nodes was not significant for PAI-1. For uPA, the values in the lymph nodes were significantly lower ( P<0.049). There were also significantly higher levels in metastatic lymph node tissue compared with healthy mucous membrane ( P=0.005 for uPA and P=0.003 for PAI-1). There was no significant correlation of PAI-1 and uPA ( n=79) with the patient's sex, size of the tumor (T stage), nodal status (N stage), differentiation (grade), or residual tumor status. If the patients were divided into two groups (< or =58 years and >58 years), the older patients had higher uPA ( P<0.017) and PAI-1 ( P<0.02) levels. The was no significant association between tumor localisation and uPA content in the tumor; for PAI-1 the association was significant ( P<0.02) in the individual areas of the mouth. A total of 23 (40%) patients relapsed (local n=13, lymph node n=3, local and lymph node n=1, lymph node and skin n=1, other locations n=5). Such patients had raised uPA ( P=0.012) and PAI-1 ( P=0.014) levels in the primary tumor. The high variability of the normal clinical parameters in tumors only has a limited prognostic value because it is not taken into account in individual cases. Thus determination of the PAI-1 level directly after surgery could provide an indication of the likelihood of a relapse and thus aid in determining the adjuvant therapy. This confirms a trend in that tumor associated proteases can also play a key role in oral squamous cell carcinoma as new, independent, prognostic factors. Whether or not uPA and PAI-1 will play such a role will be determined in additional multicentre clinical studies.