Background and Purpose
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no effective treatment. Fasudil hydrochloride (fasudil), a potent rho kinase (ROCK) inhibitor, is ...useful for the treatment of ischaemic diseases. In previous reports, fasudil improved pathology in mouse models of Alzheimer's disease and spinal muscular atrophy, but there is no evidence in that it can affect ALS. We therefore investigated its effects on experimental models of ALS.
Experimental Approach
In mice motor neuron (NSC34) cells, the neuroprotective effect of hydroxyfasudil (M3), an active metabolite of fasudil, and its mechanism were evaluated. Moreover, the effects of fasudil, 30 and 100 mg·kg−1, administered via drinking water to mutant superoxide dismutase 1 (SOD1G93A) mice were tested by measuring motor performance, survival time and histological changes, and its mechanism investigated.
Key Results
M3 prevented motor neuron cell death induced by SOD1G93A. Furthermore, M3 suppressed both the increase in ROCK activity and phosphorylated phosphatase and tensin homologue deleted on chromosome 10 (PTEN), and the reduction in phosphorylated Akt induced by SOD1G93A. These effects of M3 were attenuated by treatment with a PI3K inhibitor (LY294002). Moreover, fasudil slowed disease progression, increased survival time and reduced motor neuron loss, in SOD1G93A mice. Fasudil also attenuated the increase in ROCK activity and PTEN, and the reduction in Akt in SOD1G93A mice.
Conclusions and Implications
These findings indicate that fasudil may be effective at suppressing motor neuron degeneration and symptom progression in ALS. Hence, fasudil may have potential as a therapeutic agent for ALS treatment.
Abstract Hepatitis B infection remains the most common form of chronic hepatitis. Mother to child transmission occurs despite immunoprophylaxis with vaccination and immunoglobulin. In utero infection ...is suggested to account for most of the cases with immunoprophylaxis failure. Infants who suffer from hepatitis B infection at birth have a higher risk of becoming chronic carriers and may develop liver cirrhosis or hepatocellular carcinoma in the future. Infected germ cells, transplacental infection, invasive prenatal diagnostic tests and various perinatal factors are possible factors leading to in utero infection and subsequent immunoprophylaxis failure. Hepatitis B e antigen positive status and high viral load increase the risk of immunoprophylaxis failure. Recent evidence shows promising results regarding the use of antiviral treatment in late gestation to suppress viral load, so as to decrease the risk of vertical transmission. This review discusses the possible mechanisms of in utero infection and the use of antiviral treatment during pregnancy.
The proto-oncogene BMI1 and its product, Bmi1, is overexpressed in various types of tumors, particularly in aggressive tumors and tumors resistant to conventional chemotherapy. BMI1/Bmi1 is also ...crucially involved in cancer-initiating cell maintenance, and is recurrently upregulated in mantle cell lymphoma (MCL), especially aggressive variants. Recently, side population (SP) cells were shown to exhibit tumor-initiating characteristics in various types of tumors. In this study, we show that recurrent MCL cases significantly exhibit upregulation of BMI1/Bmi1. We further demonstrate that clonogenic MCL SP shows such tumor-initiating characteristics as high tumorigenicity and self-renewal capability, and that BMI1 was upregulated in the SP from recurrent MCL cases and MCL cell lines. On screening for upstream regulators of BMI1, we found that expression of microRNA-16 (miR-16) was downregulated in MCL SP cells by regulating Bmi1 in the SPs, leading to reductions in tumor size following lymphoma xenografts. Moreover, to investigate downstream targets of BMI1 in MCL, we performed cross-linking/chromatin immunoprecipitation assay against MCL cell lines and demonstrated that Bmi1 directly regulated pro-apoptotic genes such as BCL2L11/Bim and PMAIP1/Noxa, leading to enhance anti-apoptotic potential of MCL. Finally, we found that a proteasome inhibitor bortezomib, which has been recently used for relapsed MCL, effectively induced apoptosis among MCL cells while reducing expression of Bmi1 and increasing miR-16 in MCL SP. These results suggest that upregulation of BMI1 and downregulation of miR-16 in MCL SP has a key role in the disease's progression by reducing MCL cell apoptosis. Our results provide important new insight into the pathogenesis of MCL and strongly suggest that targeting BMI1/Bmi1 might be an effective approach to treating MCL, particularly refractory and recurrent cases.
Rock-surface temperatures were measured on a tor and a large block located below the timberline in the Kobugahara Highlands, an upland plateau composed of granodiorite in central Japan (36°N, E139°, ...1300
m a.s.l.). Many blocks in the region originate from core stones distributed on the plateau, and there are several block streams in the valley bottoms. The tor is situated at the upper end of one of these block streams. The large block appears to have detached from another tor. The mean air temperature of the coldest month is −
4
°C. Rock-surface temperatures were recorded continually every 30
min from December 1, 2002 through December 13, 2004 by thermistor probes connected to miniature data loggers. The diurnal and the annual freeze–thaw cycles and effective freeze–thaw cycles were recorded at each site. The freezing index of rock-surface temperature showed a marked variability from year to year. In addition, differences in local conditions at observation sites within a given area greatly affected the rock-surface temperature. These are important considerations in relation to local weathering below the timberline.
►The temperatures of the air and rock surface were measured on slopes below the timberline in a montane zone of central Japan (36° N, E139°, and 1300
m a.s.l.). ►It is clear that annual changes in the freezing index are large, and that there are large variations in the numbers of FTC and EFTC within the same area. ►These differences are primarily caused by differences in the depth of snow cover.
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