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61.
The antiglutamine agent acivicin, l-(αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, inhibited the growth of hepatoma 3924A cells in culture. After 7 days of incubation with the drug, an lc50 of 1.4 μM was observed by determination of colony forming ability. A combination of cytidine (1 mM), deoxycytidine (10 μM) and guanosine (10 μM) completely protected the hepatoma cells against the cytotoxic action of acivicin, but each nucleoside by itself had no effect. Acivicin (0.1 mM) inhibited the incorporation of uridine and thymidine into macromolecules, but not that of leucine. Acivicin depressed the pools of CTP, GTP, dCTP, dGTP and dTTP to 46, 62, 40, 64 and 53%, respectively, but it increased UTP level to 152% of the values of untreated cancer cells. The activity of a highly purified CTP synthetase (EC 6.3.4.2) from rat liver and hepatoma 3924A was inhibited by acivicin. The inhibition was competitive with respect to l-glutamine, and the Ki values with liver and hepatoma enzymes, determined by Dixon and reciprocal plots, were 1.1 and 3.6 μM respectively. The hydroxy analog of acivicin was also a competitive inhibitor, but it was less effective than acivicin, with a Ki value of 1.8 mM for the hepatoma enzyme. Our observations on the impact of acivicin on the behavior of pools of ribonucleotides and deoxyribonucleotides and the competitive inhibition of purified CTP synthetase from hepatoma cells suggest that a major mechanism of action for this drug is the inhibition of CTP synthetase and GMP synthetase (EC 6.3.5.2). 相似文献
62.
Fujigaki Y Muranaka Y Sun D Goto T Zhou H Sakakima M Fukasawa H Yonemura K Yamamoto T Hishida A 《Virchows Archiv : an international journal of pathology》2005,446(2):164-176
To investigate the mechanisms of myofibroblast differentiation of interstitial fibroblastic cells (FCs) in rats with uranyl acetate-induced acute renal failure (ARF), we examined the relationship between the expression of -smooth muscle actin (-SMA), myofibroblast phenotype and tubular dilatation as well as cell shape and adhesion of FCs. Peritubular -SMA-positive myofibroblasts appeared after induction of ARF and extended along the damaged, dilated proximal tubules and then almost disappeared after proximal tubular recovery. The perimeter of proximal tubules correlated with fractional areas stained for -SMA (P<0.001). Most -SMA-positive cells did not incorporate [3H]-thymidine, indicating a low proliferative activity. Transmission electron microscopy showed that FCs increasingly attached to the tubular basement membrane by elongated cytoplasm-containing microfilament bundles, which formed abundant adherens and gap junctions from day 4 to day 7. Scanning electron microscopy showed hypertrophic FCs covering large areas of tubules after induction of ARF. Administration of chlorpromazine, which can inhibit cytoskeletal movement, after induction of ARF partially inhibited myofibroblast differentiation of FCs immunohistochemically and morphologically and resulted in more dilated proximal tubules in concert with aggravation of renal dysfunction and inhibition of regenerative repair at day 4 than vehicle-administered rats. Our results indicate that mechanical tension, judged by tubular dilatation, may contribute to the induction of -SMA phenotype with increased stress fiber formation and intercellular junctions in FCs to support damaged nephron structures by adjusting tensional homeostasis in rats with uranyl acetate-induced ARF. 相似文献
63.
Tetsuya Takahashi MD Tetsuro Shishido MD PhD Ken Watanabe MD Takayuki Sugai MD Taku Toshima MD Daisuke Kinoshita MD PhD Miyuki Yokoyama MD PhD Harutoshi Tamura MD PhD Satoshi Nishiyama MD PhD Hiroki Takahashi MD PhD Takanori Arimoto MD PhD Takuya Miyamoto MD PhD Tetsu Watanabe MD PhD Yoko Shibata MD PhD Tsuneo Konta MD PhD Yoshiyuki Ueno MD PhD Takeo Kato MD PhD Takamasa Kayama MD PhD Isao Kubota MD PhD Masafumi Watanabe MD PhD 《Journal of clinical hypertension (Greenwich, Conn.)》2018,20(9):1319-1326
Pulse pressure (PP) is a risk factor for cardiovascular diseases and is associated with increased afterload and myocardial oxygen demand. Brain natriuretic peptide (BNP) and heart‐type fatty acid–binding protein (H‐FABP) are known as biomarkers indicating ventricular wall stress and silent myocardial damage. However, the association between PP and ventricular wall stress and silent myocardial damage in the general population is unclear. The authors enrolled 3504 patients who participated in a community‐based annual health check. Serum levels of BNP and H‐FABP were measured as markers of ventricular wall stress and silent myocardial damage. Patients were divided into four groups according to the quartiles of PP. Patients in the highest PP group showed higher serum BNP and H‐FABP levels than that of the other groups. Multivariate logistic analysis showed that high PP was independently associated with ventricular wall stress and silent myocardial damage on the basis of BNP and H‐FABP levels. Compared with systolic blood pressure, diastolic blood pressure, and mean blood pressure, PP was superior in predicting ventricular wall stress and silent myocardial damage evaluated according to BNP and H‐FABP levels, which was reflected by the receiver operating characteristic analysis. Screening of healthy patients revealed that high PP was related to high BNP and H‐FABP levels, suggesting that an asymptomatic general population with high PP may be exposed to ventricular wall stress and myocardial damage and might be susceptible to silent heart failure. 相似文献
64.
Noriyuki Shibata Akiyoshi Kakita Hitoshi Takahashi Yuetsu Ihara Keigo Nobukuni Harutoshi Fujimura Saburo Sakoda Makio Kobayashi 《Acta neuropathologica》2010,119(3):345-354
Compelling evidence identifies a link between cytotoxic effects of cytosolic phospholipase A2 (cPLA2) activity and neuron death in cell cultures. cPLA2 catalyzes the hydrolysis of membrane phospholipids to produce and release arachidonate, leading to plasma membrane injury,
inflammatory response and subsequent cell death. To assess a role for cPLA2 in the pathomechanism of amyotrophic lateral sclerosis (ALS), we performed immunohistochemical, immunoblot, and densitometric
analyses of cPLA2 and its active form phosphorylated at S505 (p-cPLA2) on spinal cords obtained at autopsy from ten sporadic ALS patients and ten age-matched controls. On sections, immunoreactivities
for cPLA2 and p-cPLA2 were distinct and localized in almost all of the motor neurons, reactive astrocytes, and activated microglia in the ALS cases,
while immunoreactivities were only weak or not at all observed in neurons and glia in the control cases. On immunoblots, both
the cPLA2/β-actin density ratio and the p-cPLA2/cPLA2 density ratio were significantly increased in the ALS group compared to the control group. There was no significant link
between the densitometric data and the clinical phenotypes, age at death or disease duration of the ALS patients. These results
provide in vivo evidence for increased expression and activation of cPLA2 in motor neurons, reactive astrocytes, and activated microglia in ALS, suggesting occurrence of arachidonate cascade-induced
motor neuron death via cell-autonomous and/or non-cell-autonomous mechanisms. 相似文献
65.
66.
Background
Peroral cholangioscopy-directed lithotripsy (PC-directed lithotripsy) has been successfully used for the treatment of difficult bile duct stones, including Mirizzi syndrome (MS). However, long-term outcome and risk factors for stone recurrence after PC-directed lithotripsy have not yet been elucidated. The aim of this study was to assess the outcomes of long-term follow-up after PC-directed lithotripsy and to clarify risk factors predicting stone recurrence. 相似文献67.
68.
The purpose of this study was to improve the efficiency of the microbiological assays for biotin, niacin, and pantothenic acid by using lyophilized cells from Lactobacillus plantarum ATCC 8014. The use of lyophilized cells as an inoculum was assessed to avoid time-consuming processes like cell precultivation and washing. The authors also examined the effects of various protectants such as skim milk, sucrose, sorbitol, and trehalose on the assay. The viable cell counts of the lyophilized cells were found to be approximately equal for different protectants. The standard curves for biotin, niacin, and pantothenic acid concentrations obtained using lyophilized cells with sucrose and intact cells gave similar linear ranges. Furthermore, the measured vitamin concentrations of the standard reference material 3280 were in the range of the established values. Therefore, lyophilized cells with sucrose are potential alternative inocula for the turbidimetric method. This will increase the overall convenience associated with microbiological assays. 相似文献
69.
Fujigaki Y Muranaka Y Sakakima M Ohta I Sakao Y Fujikura T Sun Y Katafuchi R Joh K Hishida A 《Clinical and experimental nephrology》2008,12(6):432-439
BACKGROUND: Systemically podocytic infolding into the GBM which causes nonargyrophilic holes in the GBM in association with intra-GBM microstructures has been considered as a new pathological entity. However, its pathomechanisms are largely unknown. METHODS: We analyzed intra-GBM microstructures in an SLE patient with glomerulopathy associated with podocytic infolding by immunoelectron microscopy for vimentin (a marker for both podocyte and endothelium) and C5b-9 and by 3D reconstruction of transmission electron microscopy (TEM) images by computer tomography method. RESULTS: Immunofluorescent study showed immunoglobulin deposition in a diffuse, capillary pattern; however, electron-dense deposits like stage 3 membranous nephropathy could be found only in some capillary loops by TEM in spite of the systemic existence of podocytic infolding and the intra-GBM microstructures. Three-dimensional reconstructed images of the TEM images revealed that some of the intra-GBM microstructures made connections with the podocyte. The clustered microstructures underneath the podocyte and their surroundings looked as a whole like the degraded part of podocyte in 3D reconstructed images. Immunoelectron microscopy showed that vimentin was positive in most intra-GBM microstructures. C5b-9 was positive along the entire epithelial side of the GBM and in some microstructures, suggesting that the podocytes may be attacked by C5b-9 and that the microstructures may contain C5b-9 bound cellular membranes. CONCLUSION: Intra-GBM microstructures may be originated mainly from the podocyte. Podotyte and GBM injuries caused by C5b-9 attack to podocytes might contribute in part to podocytic infolding and intra-GBM microstructures in this case. 相似文献
70.
In patients with muscular dystrophy, such as Duchenne muscular dystrophy (DMD), microcirculation abnormalities and hypoxic ischemic conditions in muscle tissues are suspected to be induced by non-symptomatic coagulation fibrinolysis abnormalities and vascular dysfunction. Vascular endothelial growth factor (VEGF) is a critical regulating factor in angiogenesis that is known to be induced by hypoxic and/or ischemic conditions. To examine whether VEGF is associated with muscular dystrophy, we measured serum levels of VEGF in 52 patients with DMD, 15 with Becker muscular dystrophy (BMD), 20 with Fukuyama congenital muscular dystrophy (FCMD), eight with myotonic dystrophy (DM), and four with spinal muscular atrophy (SMA), as well as in 15 healthy and eight disease controls. The serum level of VEGF in the DMD patients was 267.7 ± 25.3 pg/ml (10.5–800.0), while it was 358.8 ± 96.3 pg/ml (0.2–1320.0) in the BMD patients, 261.4 ± 45.6 pg/ml (0.1–758.0) in the FCMD patients, 165.0 ± 63.4 pg/ml (2.6–479.0) in the DM patients, 96.0 ± 30.3 pg/ml (41.0–168.0) in the SMA patients, 148.3 ± 20.1 pg/ml (46.5–298.0) in the healthy controls, and 154.1 ± 54.0 pg/ml (7.2–343.0) in the disease controls. The level of VEGF in BMD was significantly elevated, as compared with DM, SMA, and control groups. Further, the level of VEGF in the bedridden sub-group of DMD patients was significantly elevated as compared with chair-bound DMD, DM, SMA, and control groups. We concluded that VEGF may reflect hypoxic and/or ischemic conditions in muscle tissue, and have a relationship with the process of disease progression in DMD and BMD patients. 相似文献