Ethanol Increases NADPH Oxidase-derived Oxidative Stress and Induces Apoptosis in Human Liver Adenocarcinoma Cells (SK-HEP-1)

Alcohol-induced liver injury is linked to oxidative stress and increased production of reactive oxygen species (ROS). Oxidative stress is an early event in the process of apoptosis. However, it is not completely understood how ethanol-induced oxidative stress induces apoptosis. In contrast, nicotinamide adenine dinucleotide phosphate oxidase (NOX) is known to generate ROS in hepatocytes. The purpose of the present study was to determine whether or not ethanol-induced ROS generation stimulates the death receptor or mitochondrial pathways of apoptosis in alcohol dehydrogenase containing human liver adenocarcinoma (SK-HEP-1) cells. Treatment with ethanol increased the generation of ROS and expression of NOX4 mRNA, and also induced mitochondrial dysfunction in SK-HEP-1 cells. Moreover, ethanol induced the activation of caspase-8 and -3 in hepatocytes. These activities were suppressed by pretreatment with N-acetyl-cysteine, an antioxidant, or apocynin, an inhibitor of NOX activity. These results suggested that ethanol induces an increase in NOX-derived ROS generation upstream of caspase-8 activation and in the mitochondria in SK-HEP-1 cells. In conclusion, this study demonstrated that ethanol increases the generation of ROS and subsequently induces apoptosis using a mechanism involving mitochondrial dysfunction and caspase activation in SK-HEP-1 cells

Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation

Protein phosphatase 4 catalytic subunit (PP4c) is a PP2A-related protein serine/threonine phosphatase with important functions in a variety of cellular processes, including microtubule (MT) growth/organization, apoptosis, and tumor necrosis factor signaling. In this study, we report that NDEL1 is a substrate of PP4c, and PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome. Targeted disruption of PP4c reveals disorganization of MTs and disorganized MT array. Loss of PP4c leads to an unscheduled activation of Cdk1 in interphase, which results in the abnormal phosphorylation of NDEL1. In addition, abnormal NDEL1 phosphorylation facilitates excessive recruitment of katanin p60 to the centrosome, suggesting that MT defects may be attributed to katanin p60 in excess. Inhibition of Cdk1, NDEL1, or katanin p60 rescues the defective MT organization caused by PP4 inhibition. Our work uncovers a unique regulatory mechanism of MT organization by PP4c through its targets Cdk1 and NDEL1 via regulation of katanin p60 distribution

切除不能進行胃癌に対する化学療法有効例の治癒形態の検討

大学院医学系研究

Supranormal orientation selectivity of visual neurons in orientation-restricted animals

Altered sensory experience in early life often leads to remarkable adaptations so that humans and animals can make the best use of the available information in a particular environment. By restricting visual input to a limited range of orientations in young animals, this investigation shows that stimulus selectivity, e.g., the sharpness of tuning of single neurons in the primary visual cortex, is modified to match a particular environment. Specifically, neurons tuned to an experienced orientation in orientation-restricted animals show sharper orientation tuning than neurons in normal animals, whereas the opposite was true for neurons tuned to non-experienced orientations. This sharpened tuning appears to be due to elongated receptive fields. Our results demonstrate that restricted sensory experiences can sculpt the supranormal functions of single neurons tailored for a particular environment. The above findings, in addition to the minimal population response to orientations close to the experienced one, agree with the predictions of a sparse coding hypothesis in which information is represented efficiently by a small number of activated neurons. This suggests that early brain areas adopt an efficient strategy for coding information even when animals are raised in a severely limited visual environment where sensory inputs have an unnatural statistical structure

Influence of Diabetes Mellitus on Left Ventricular Function in Patients Undergoing Coronary Artery Bypass Grafting

Objectives. Left ventricular function was assessed by two-dimensional echocardiography before and one year after coronary artery bypass grafting CABG in a series of patients with severe coronary artery disease with diabetes mellitus DM and without DM non-DM . Methods. Twenty-three patients with DM and 50 patients without DM, all with no previous myocardial infarction, underwent two-dimensional echocardiography before CABG and one year after CABG, in a non-matched study. For a matched study, 31 patients without DM who had almost the same left ventricular function as DM patients at the baseline were selected to and compare the rate of improvement in left ventricular function between the DM group and the matched non-DM group. Results. In the non-matched study, patient characteristics were not significantly different between the 2 groups except for the incidence of congestive heart failure within one year before CABG, which was significantly higher in the DM group. Fractional shortening was significantly lower in the DM group at the baseline p 0.05 and also one year after CABG p 0.0001 . Significant improvement in fractional shortening was seen in the non-DM group p 0.001 , but not in the DM group. The left ventricular enddiastolic diameter LVDd was significantly larger in the DM group at the baseline p 0.01 , and was still significantly larger in the DM group at one year after CABG p 0.01 . No improvement in LVDd was seen in the DM group. In the matched study, fractional shortening of the non-DM group also showed significant improvement after CABG p 0.001 . Moreover, the rate of improvement in fractional shortening was higher in the non-DM group than in the DM group p 0.05 . LVDd tended to be larger in the DM group p NS . Conclusions. Left ventricular dysfunction and left ventricular impaired improvement were seen in the patients with DM, and CABG improved left ventricular function in the patients without DM with poor left ventricular function. These findings indicate that CABG therapy may be inadequate for improving left ventricular function in patients with DM and severe left ventricular dysfunction at the baseline.

Response of plasma toroidal flow to the transition between nested and stochastic magnetic field in LHD

Response of the plasma toroidal flow to the forward and backward transition between the nested and the stochastic magnetic field is studied using the charge exchange spectroscopy in the large helical device (LHD). Abrupt damping of toroidal flow associated with a transition from nested magnetic flux surface to a stochastic magnetic field is observed when the magnetic shear at the rational surface decreases to 0.5 after the exchange of the neutral beam injection (NBI) direction from co- to counter-direction in LHD. The stochastization of magnetic field occurs only in a narrow range of magnetic shear near 0.5 and spontaneousback-transition from stochastic to nested magnetic field (healing) is observed in the steady-state phase of magnetic shear. When the NBI direction is changed from counter- to co-direction, the healing of magnetic field occurs associated with the increase of magnetic shear

経頚静脈的管肝内門脈大循環短絡術による portal hypertensive gastropathy の変化

金沢大学医学系研究科荻野, 英

Poly ADP-ribose Polymerase (PARP) Staining for Immunohistological Investigation of Primary Breast Cancer

Given that clinical trials of poly ADP-ribose polymerase (PARP) 1 inhibitors are underway, in the present study we investigated the prevalence of triple-negative breast cancer and PARP1 expression in patients with primary invasive breast cancer. Immunohistological studies plus PARP staining were performed on samples from 206 primary breast cancer patients undergoing surgery at Showa University Hospital between January 2010 and May 2011. Fifteen patients (7.3%) were found to have triple-negative breast cancer. Hormone receptor-positive patients were significantly more likely to be PARP1 negative. There were no PARP1-negative patients in the triple-negative group. However, there was no significant difference in the rate of PARP1 negativity between patients with triple-negative breast cancer and those with other breast cancer subtypes. There were no PARP1-negative patients in the triple-negative breast cancer group. Given that the effectiveness of PARP inhibitors has not been sufficiently established in clinical trials, a more in-depth analysis is required to determine the factors contributing to effective treatment. Future studies should include more subjects with triple-negative breast cancer and those with BRCA mutations

Impurity emission characteristics of long pulse discharges in Large Helical Device

Line spectra from intrinsic impurity ions have been monitored during the three kinds of long-pulse discharges (ICH, ECH, NBI). Constant emission from the iron impurity shows no preferential accumulation of iron ion during the long-pulse operations. Stable Doppler ion temperature has been also measured from Fe XX, C V and C III spectra