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171.
Elizabeth A. Fry Pankaj Taneja Dejan Maglic Sinan Zhu Guangchao Sui Kazushi Inoue 《PloS one》2013,8(10)
Our recent study shows a pivotal role of Dmp1 in quenching hyperproliferative signals from HER2 to the Arf-p53 pathway as a safety mechanism to prevent breast carcinogenesis. To directly demonstrate the role of Dmp1 in preventing HER2/neu-driven oncogenic transformation, we established Flag-Dmp1α transgenic mice (MDTG) under the control of the mouse mammary tumor virus (MMTV) promoter. The mice were viable but exhibited poorly developed mammary glands with markedly reduced milk production; thus more than half of parous females were unable to support the lives of new born pups. The mammary glands of the MDTG mice had very low Ki-67 expression but high levels of Arf, Ink4a, p53, and p21Cip1, markers of senescence and accelerated aging. In all strains of generated MDTG;neu mice, tumor development was significantly delayed with decreased tumor weight. Tumors from MDTG;neu mice expressed Flag-Dmp1α and Ki-67 in a mutually exclusive fashion indicating that transgenic Dmp1α prevented tumor growth in vivo. Genomic DNA analyses showed that the Dmp1α transgene was partially lost in half of the MDTG;neu tumors, and Western blot analyses showed Dmp1α protein downregulation in 80% of the cases. Our data demonstrate critical roles of Dmp1 in preventing mammary tumorigenesis and raise the possibility of treating breast cancer by restoring Dmp1α expression. 相似文献
172.
173.
Kentaro Honda Takaomi Arai Nobuyuki Takahashi Kazushi Miyashita 《Ichthyological Research》2010,57(4):416-421
Microchemical analysis of the strontium (Sr) and calcium (Ca) ratios of otoliths was conducted to determine the life history
and migration of anadromous Sakhalin taimen, Hucho perryi. In 2008 and 2009, 10 specimens were sampled from Lake Akkeshi in eastern Hokkaido, Japan. Our results indicated that some
specimens migrated to brackish waters during their early life histories. Because the Sr:Ca ratios of the specimens in this
study were all less than those of specimens from Sakhalin Island during a previous study, specimens from Lake Akkeshi may
have migrated to brackish water, or may have remained in the ocean for only a short period. 相似文献
174.
Kazushi Tamura Takeomi Mizutani Hisashi Haga Kazushige Kawabata 《Histochemistry and cell biology》2010,133(1):59-67
In this study, we aimed at improving the temporal resolution of scanning probe microscopy (SPM) for observing living cells
by introducing soft cantilevers, low feedback-gain operations, and cantilever deflection imaging. We achieved visualization
of the mechanical architecture in leading lamellae of living fibroblasts at a temporal resolution of around 10 s, which is
higher than that of conventional contact-mode SPM. Time-lapse SPM could be used to monitor not only cytoskeletal dynamics
but also the dynamics of numerous microgranules. Statistical analysis of microgranular motion revealed that the microgranules
have superdiffusive behaviors and significant directional order of motion. We also found that the direction of their motion
is correlated with the direction of growing actin stress fibers. The combination of SPM with fluorescence microscopy showed
that vinculin, a component of cell-substratum adhesion sites, localizes at the microgranules. Our experimental data provides
a new insight into the intracellular mechanical architecture and its structural dynamics, suggesting that high-speed live-cell
SPM has great potential for investigating the structural origin of cellular dynamics. 相似文献
175.
Akihiro Furukawa Tsuyoshi Arita Susumu Satoh Kenji Wakabayashi Shinko Hayashi Yumi Matsui Kazushi Araki Masanori Kuroha Jun Ohsumi 《Bioorganic & medicinal chemistry letters》2010,20(7):2095-2098
In an investigation of (?)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARγ. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARγ modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARγ ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARγ full agonists are administrated. 相似文献
176.
Hiroaki Y Tani K Kamegawa A Gyobu N Nishikawa K Suzuki H Walz T Sasaki S Mitsuoka K Kimura K Mizoguchi A Fujiyoshi Y 《Journal of molecular biology》2006,355(4):628-639
Aquaporin-4 (AQP4) is the predominant water channel in the mammalian brain and an important drug target for treatment of cerebral edema, bipolar disorder and mesial temporal lobe epilepsy. We determined the AQP4 structure by electron crystallography of double-layered, two-dimensional (2D) crystals. The structure allows us to discuss how the expression ratio between the long and short AQP4 splicing variant can determine the size of in vivo orthogonal arrays. Furthermore, AQP4 contains a short 3(10) helix in an extracellular loop, which mediates weak but specific interactions between AQP4 molecules in adjoining membranes. This finding suggests a previously unexpected role for AQP4 in cell adhesion. This notion was corroborated by expression of AQP4 in L-cells, which resulted in clustering of the cells. Our AQP4 structure thus enables us to propose models for the size regulation of orthogonal arrays and channel-mediated cell adhesion. 相似文献
177.
Tsuda K 《Obesity (Silver Spring, Md.)》2006,14(9):1505-1510
Objective: Abnormalities in physicochemical properties of the cell membranes may underlie the defects that are strongly linked to hypertension. Recent evidence indicates that adiponectin may have protective effects against cardiovascular diseases. The purpose of the present study was to assess the possible link between plasma adiponectin and membrane fluidity in normotensive (NT) and hypertensive (HT) men. Research Methods and Procedures: We measured the membrane fluidity (a reciprocal value of membrane microviscosity) of erythrocytes in NT and HT men by using an electron paramagnetic resonance and spin‐labeling method. Results: The order parameter (S) for the spin label agent (5‐nitroxide stearate) and the peak height ratio (h0/h?1) for 16‐nitroxide stearate in the electron paramagnetic resonance spectra of erythrocytes were significantly higher in HT men than in NT men, indicating that membrane fluidity of erythrocytes was decreased in HT men compared with NT men. Both of plasma adiponectin and nitric oxide (NO) metabolite levels were significantly lower in HT men than in NT men. The plasma adiponectin levels were correlated with plasma NO metabolites. The S and the h0/h?1 of erythrocytes were inversely correlated with the plasma adiponectin and NO metabolite levels, indicating that the decreased membrane fluidity of erythrocytes was associated with hypoadiponectinemia and reduced plasma NO metabolites. Discussion: The results of the present study demonstrated that plasma adiponectin levels were lower in HT men than in NT men and that hypoadiponectinemia was associated with decreased membrane fluidity of erythrocytes. The finding suggests that adiponectin may be linked to the rheologic behavior of the erythrocytes and the microcirculation in men, at least in part, by the NO‐dependent mechanism. 相似文献
178.
Matsudo Y Takamori Y Fujimura L Nishio S Sasagawa K Komuro I Tokuhisa T Hatano M 《Transgenic research》2006,15(5):573-581
Doxorubicin is one of the most effective drugs available for cancer chemotherapy. However, the clinical use of doxorubicin has been greatly limited because of severe side effects on cardiomyocytes. Since Nd1-L, a novel actin-binding protein, is expressed most abundantly in the heart of adult mice, we examined a role of Nd1-L in doxorubicin-induced cardiomyopathy. When doxorubicin (5 mg/kg × 4 times) was injected into adult mice at a 3-day-interval, approximately 50% of injected mice died within 4 weeks of the first injection. Nd1-L mRNA expression in the heart decreased within 3 weeks after the first injection and many cardiomyocytes of injected mice died by apoptosis. Overexpression of Nd1-L in the heart of transgenic mice protected the cardiomyocytes from apoptosis and improved survival rate after doxorubicin injection. Furthermore, activation of Erk1/2 was observed in cultured cells overexpressing Nd1-L. Thus, Nd1-L plays a critical role in protecting the heart from doxorubicin-induced cardiomyopathy. 相似文献
179.
Koizumi M Takagi-Sato M Okuyama R Araki K Sun W Nakai D Tsutsumi S Kawai K 《Oligonucleotides》2006,16(3):253-262
Protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity of the 2'-O-(2-methoxy)ethyl (2'- MOE)-modified gapmer antisense oligonucleotide, ISIS113715, was previously reported. This antisense oligonucleotide increases insulin sensitivity and normalizes plasma glucose levels in diabetic ob/ob and db/db mice. In the present study, the isosequential 2'-O,4'-C-ethylene-bridged nucleic acid (ENA)-modified oligonucleotide, ENA-1, was synthesized, and its ability to further improve the downregulation of PTP1B in db/db mice was examined. We demonstrated that, compared with ISIS113715, intraperitoneal and subcutaneous administration of ENA-1 more effectively decreased the plasma glucose levels in db/db mice. Moreover, ENA-1 decreased expression of PTP1B in the liver and fat of db/db mice more effectively than ISIS113715. We describe for the first time the functional comparison of 2'-MOE- and ENA-modified antisense oligonucleotides. Our data indicate that the enhancement of the efficacy of antisense oligonucleotides by ENA modifications is superior to that of second-generation 2'-MOE modifications in certain aspects. 相似文献
180.
Paget's disease (PD) of bone is a chronic focal skeletal disorder characterized by excessive bone resorption followed by abundant new bone formation. Enhanced levels of IL-6, RANKL, M-CSF, and endothelin-1 have been associated with PD. In the present study, we identified increased serum levels (2 to 5-fold) of inflammatory cytokine, kininogen (KNG) in patients with PD compared to normal subjects. Treatment of pagetic bone marrow derived stromal/preosteoblast cells with recombinant KNG (25 ng/ml) for 24 h period resulted in a 5-fold increase in the levels of phospho-HSP27 and a 3-fold increase in ERK1/2 phosphorylation in these cells. However, pagetic stromal cells stimulated with KNG in the presence of ERK activation inhibitor peptide did not significantly affect the levels of phospho-HSP27. KNG increased normal and pagetic marrow stromal cell proliferation at 1.4-fold and 2.5-fold, respectively. KNG in the presence of an ERK inhibitor peptide did not stimulate pagetic marrow stromal cell proliferation. Furthermore, siRNA suppression of HSP27 expression significantly decreased KNG inhibition of etoposide-induced caspase-3 activation and apoptosis in these cells. In summary, KNG modulate bone marrow derived stromal/preosteoblast cell proliferation and suppress etoposide-induced apoptosis through ERK and HSP27 activation, respectively. These results implicate a pathophysiologic role for KNG in patients with PD. 相似文献