No abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) are widely used to reduce serum cholesterol in patients with hypercholesterolemia. Previous studies have shown that HRIs can induce apoptosis in colon cancer cells. In this study, we investigated the mechanisms underlying the apoptosis-inducing effect of HRIs in greater detail. The HRI lovastatin induced apoptosis in the human colon cancer cell line SW480 by blocking the cholesterol synthesis pathway. Immunoblot analysis of antiapoptotic molecules, including survivin, XIAP, cIAP-1, cIAP-2, Bcl-2, and Bcl-X L , revealed that only survivin expression was decreased by lovastatin. Survivin downregulation by RNA interference induced apoptosis, and survivin overexpression rendered the cells resistant to lovastatin-induced growth inhibition. These results indicate that survivin downregulation contributes substantially to the proapoptotic properties of lovastatin. Farnesyl pyrophosphate and geranylgeranyl pyrophosphate, two downstream intermediates in the cholesterol synthesis pathway, simultaneously reversed survivin down-regulation and the blocking of Ras isoprenylation by lovastatin. Ras isoprenylation is important for the activation of Ras-mediated signaling, including the activation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. The PI3-kinase inhibitor down-regulated survivin in SW480 cells. In addition, lovastatin blocked Ras activation and Akt phosphorylation. We conclude that survivin down-regulation is crucial in lovastatin-induced apoptosis in cancer cells and that lovastatin decreases survivin expression by inhibiting Ras-mediated PI3-kinase activation via the blocking of Ras isoprenylation.3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) 3 reductase inhibitors (HRIs) are widely used to reduce serum cholesterol and are well tolerated by patients with hypercholesterolemia (1). HRIs prevent the formation of mevalonate from HMG-CoA by inhibiting the enzyme HMG-CoA reductase, thereby inhibiting cholesterol synthesis (2). In large clinical trials designed to study the changes in coronary events in coronary heart disease patients receiving HRIs, the number of newly diagnosed colon cancer cases showed a reduction of between 43% (3) and 19% (4) during a 5-year follow-up period. It has been reported that HRIs could induce apoptosis in colon cancer cells (5-7). Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), two downstream intermediates in the cholesterol synthesis pathway, belong to a class of compounds named isoprenoids. They are bound to several cellular proteins, including small GTPases such as Ras, Rho, and Rac, by a posttranslational modification known as isoprenylation. This process involves the addition of a 15-carbon farnesyl chain in FPP (farnesylation) or a 20-carbon geranylgeranyl chain in GGPP (geranylgeranylation) to a cysteine sulfhydryl group near the carboxyl terminus. Isoprenylation of these proteins is crucial for membrane attachment (8, 9) and the subsequent acquisition of biological activity (10)...

To examine the effects of different solar irradiances on leaf characteristics at the leaf primordium and expansion stages, we shaded parts of branches in the upper canopies of two adult beech trees, Fagus crenata Blume and Fagus japonica Maxim., for 4 years. The treatments during the leaf primordium and leaf expansion stages, respectively, were: (1) high light and high light (H, control), (2) high light and low light (HL), (3) low light and low light (LL), and (4) low light and high light (LH). Both number of cell layers in palisade tissue and individual leaf area were affected by the previous-year irradiance, whereas cell length of palisade tissue was larger in LH leaves than in LL leaves, suggesting determination by current-year irradiance. Lamina chlorophyll/nitrogen ratio was higher in HL and LL leaves than in LH leaves, suggesting determination by current-year irradiance. Diurnal minimum values of leaf water potential measured under sunlit conditions were lower in H and LH leaves than in HL and LL leaves. Effective osmotic adjustment was found in H and LH leaves, suggesting that leaf water relations were affected by current-year irradiance. Net photosynthetic rate and stomatal conductance measured under sunlight conditions were higher in H and LH leaves than in HL and LL leaves. Thus, effects of current-year irradiance had a greater effect on leaf-area-based daily carbon gain than previous-year irradiance.

The chemical forms of carbon leaching from carbon-containing Zr and Fe-based metallic materials have been investigated to improve the estimation of the contribution of C-14 in the performance assessment of TRU waste disposal. Both organic and inorganic carbons were identified in the leached solution with carbon containing zirconium and steel, and the concentrations of total carbon (organic plus inorganic) in the leached solutions increased with time. The carbon concentrations in the leached solution for both metallic samples were higher at higher pH. With High Performance Liquid Chromatography (HPLC), organic carbons were identified to be low-molecular weight alcohols, carboxylic acids and aldehydes.To explore the chemical state of carbon in the matrix materials, the leaching experiments were carried out also for ZrC, Fe 3 C, the powder mixtures of carbon and zirconium, and of carbon and iron. The low-molecular weight organic carbons were detected only in the case of carbides (ZrC and Fe 3 C). The chemical forms of carbon in the zirconium alloy were suggested to be carbide or carbon by H.D.Smith [1]. The present result suggests that the chemical forms of carbon in zirconium or iron are mainly in the form of carbide.In the interest of performance assessment, the distribution coefficients of the organic carbon species identified in the leached solution for cement were obtained. As expected, some of them were shown to be larger than the values assumed in the performance assessment of Progress Report on Disposal Concept for TRU Waste in Japan [2].

I-129 is a very long-lived radionuclide that is released to an off-gas stream when spent fuels are dissolved at a reprocessing plant. An iodine filter can capture I-129 in the form of AgI. However, because AgI is unstable under the reducing conditions of a geological repository and I-129 has a very long half-life, I-129 can migrate to the biosphere. These characteristics make I-129 a key radionuclide for the safety assessment of a geological disposal of radioactive wastes generated from a reprocessing plant (TRU wastes). To improve disposal safety, several new waste forms have been developed to confine I-129 for a very long period in order to reduce the leaching of I-129 from radioactive wastes. These new waste forms have technical objectives of solidifying more than 95% of I-129 into the waste form and achieving a leaching rate of less than 10-5/y. Several iodine immobilization techniques have been examined. This paper presents experimental results concerning the treatment process, leaching behavior, modeling, and related elements of these immobilization techniques.