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991.
992.
Takanobu Jotatsu Shigehiro Yagishita Ken Tajima Fumiyuki Takahashi Kaoru Mogushi Moulid Hidayat Aditya Wirawan Ryo Ko Ryota Kanemaru Naoko Shimada Keiko Mitani Tsuyoshi Saito Kazuya Takamochi Kenji Suzuki Shinji Kohsaka Shinya Kojima Hiroshi Mukae Kazuhiro Yatera Kazuhisa Takahashi 《Biochemistry and Biophysics Reports》2017
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid progression. The mechanisms that lead to a shift from initial therapeutic sensitivity to ultimate therapeutic resistance are poorly understood. Although the SCLC genomic landscape led to the discovery of promising agents targeting genetic alterations that were already under investigation, results have been disappointing. Achievements in targeted therapeutics have not been observed for over 30 years. Therefore, the underlying disease biology and novel targets urgently require a better understanding. Epigenetic regulation is deeply involved in the cellular plasticity that could shift tumor cells to the malignant phenotype. We have focused on a histone modifier, LSD1, that is overexpressed in SCLC and is a potent therapeutic target. Interestingly, the LSD1 splice variant LSD1+8a, the expression of which has been reported to be restricted to neural tissue, was detected and was involved in the expression of neuroendocrine marker genes in SCLC cell lines. Cells with high expression of LSD1+8a were resistant to CDDP and LSD1 inhibitor. Moreover, suppression of LSD1+8a inhibited cell proliferation, indicating that LSD1+8a could play a critical role in SCLC. These findings suggest that LSD1+8a should be considered a novel therapeutic target in SCLC. 相似文献
993.
Kosuke Anan Moriyasu Masui Shinichiro Hara Miho Ohara Masaharu Kume Shoichi Yamamoto Shunji Shinohara Hiroki Tsuji Shinji Shimada Shigenori Yagi Nobuyoshi Hasebe Hiroyuki Kai 《Bioorganic & medicinal chemistry letters》2017,27(17):4194-4198
NR2B subunit containing N-methyl-d-aspartate (NMDA) receptor is an attractive target for chronic pain due to its involvement in disease states and its limited distribution in the central nervous system. Cyclohexanol-based leads 6a and 6c were identified as potent NR2B-selective NMDA antagonists utilizing a scaffold hopping approach. Further optimization of this series through replacement of the amide in the leads with an isoxazole and efforts to optimize the pharmacokinetic profiles led to the discovery of orally available brain penetrants 7k and 7l, which demonstrated analgesic activity in the mouse formalin test at early and late phases. 相似文献
994.
Isao Sakurada Toshiya Endo Katsuyoshi Hikita Tomokazu Hirabayashi Yoshitaka Hosaka Yutaka Kato Yoshitaka Maeda Shigeki Matsumoto Takashi Mizuno Hiroshi Nagasue Teruyuki Nishimura Shunsuke Shimada Mikihiko Shinozaki Keiko Taguchi Katsutoshi Takeuchi Tooru Yokoyama Alan Hruza Paul Reichert Shoji Furusako 《Bioorganic & medicinal chemistry letters》2017,27(11):2622-2628
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated. 相似文献
995.
Kentaro Ariyoshi Yohei Fujishima Tomisato Miura Yi Shang Shizuko Kakinuma Shimada Yoshiya Kosuke Kasai Akifumi Nakata Akira Tachibana Mitsuaki A. Yoshida 《In vitro cellular & developmental biology. Animal》2017,53(5):474-478
Primary hepatocyte culture is a crucial tool for investigations of liver function and for evaluating the toxic effects of drugs. In addition, chromosomal analysis of hepatocytes could also prove useful for understanding the mechanisms of hepatocarcinogenesis. However, cultivation of primary hepatocytes for chromosome analysis has been hampered by the specific equipment and skill required to perform the in situ perfusion step necessary for isolation of primary hepatocytes. In the present study, we aimed to establish a simple and efficient method of isolating hepatocytes suitable for chromosome analysis. We performed hepatocyte isolation without using collagenase perfusion, instead digesting liver tissues using collagenase in tubes. In addition, we examined hepatocyte and bone marrow cell (BMC) co-culture and cultivation of hepatocytes with medium containing BMC culture medium supernatants. We found that hepatocyte viability and attachment rate were significantly improved, both by co-culture with BMCs and medium containing BMC culture media supernatants, with the latter also significantly increasing the mitotic index. Using this simple method of isolation and cultivation, we could successfully perform chromosomal analysis of mouse primary hepatocytes. This method has the potential to help understand the mechanisms underlying chromosomal instability-mediated hepatocarcinogenesis. 相似文献
996.
Rodent population dynamics are predicted to respond positively to the masting of acorns, but diverging results have been published. This study tested the hypothesis that population responses to acorn masting vary depending on differences in the tolerance to tannins of different rodent species. The effects of acorn abundance on the rodent population densities were analyzed using a dataset obtained in Hokkaido, Japan. Specifically, population fluctuations of three rodent species (Apodemus speciosus, A. argenteus, and Myodes rufocanus) and the abundance of Quercus crispula acorns have been monitored since 1992. Acorn production in previous years had a positive effect on the annual population growth rates of A. speciosus; however, this trend was not clear in the other two species. Tannin tolerance, assessed by body weight changes in an acorn feeding experiment, exhibited clear differences among the rodent species; namely, the body weight of A. speciosus increased, whereas that of the other two species decreased. The observed responses to acorn masting of populations of the three sympatric rodent species reflected tannin tolerance. It suggests that only populations of species with high tannin tolerance positively respond to acorn masting. Previous studies tend to overlook species-specific abilities of coping with tannins in acorns. Our results emphasize the necessity of evaluating the tannin tolerance of rodents and the tannin content of acorns to understand how rodent population dynamics and acorn production are related. 相似文献
997.
Antinutritional effects of acorns and tannic acid on the Japanese wood mouse Apodemus speciosus were examined in the laboratory. The first feeding experiment was conducted for 15 days using three types of diet: control
diet (laboratory chow for mice), acorns of Quercus serrata (QS), and acorns of Q. mongolica var. grosseserrata (QM), which differ in tannin content (control, tannin free; QS, 2.7% tannic acid equivalent; QM, 8.5%). Six and one of eight
mice died in the QM and QS groups, respectively, whereas all mice survived in good health in the control group. Body weight
in the QM and QS groups decreased as much as 23.6% and 16.8% in the first 5 days, respectively, whereas that in the control
group did not change significantly. Dry matter intake in the QM group was 50.0% and 38.7% less than that in the control and
QS, respectively. Apparent dry matter digestibility was not different among the diets, but apparent nitrogen digestibility
did differ between the two acorn groups (QM, −17.5%; QS, 12.0%). The logistic regression analyses revealed that the survival
of mice was synergistically influenced by both dry matter intake and apparent nitrogen digestibility. In the second experiment,
wood mice fed the tannin-free formula diet, which is nutritionally matched to QS and QM acorns except for the tannin, did
not suffer antinutritional effects, whereas mice fed the tannin-supplemented formula diets suffered body weight loss and negative
nitrogen digestibility. These results indicate that the tannins in acorns could cause serious damage to the wood mouse, which
may rely on acorns as a usual diet. Plausible hypotheses explaining how the wood mice could overcome the deleterious effects
of the acorns are discussed.
Received: May 9, 2002 / Accepted: December 6, 2002 相似文献
998.
The role of an inositol 1,4,5‐trisphosphate (IP3)‐mediated transduction cascade in the response of taste receptor cells of the fleshfly Boettcherisca peregrina was investigated by using the following reagents: neomycin (an inhibitor of IP3 production), U73122 (an inhibitor of phospholipase C), adenophostin A (an agonist of the IP3‐gated channel), IP3, ruthenium red (a blocker of the IP3‐gated channel), and 2‐aminoethoxydiphenylborate (2‐APB; an antagonist of the IP3‐gated channel). For introduction into the receptor cell, the reagents were mixed with a detergent, deoxycholate (DOC). After treatment with neomycin + DOC or U73122 + DOC, the response of the sugar receptor cell to sugars was depressed compared with responses after treatment with DOC alone. During the treatment of adenophostin A + DOC, the response of the sugar receptor cell was elicited. After treatment with IP3 + DOC, the response of the sugar receptor cell to sugars and to amino acids was apparently enhanced. When taste stimuli were administered in the presence of ruthenium red or 2‐APB, the response of the sugar receptor cell to glucose were inhibited. The expression of genes for substances involved in the IP3 transduction cascade, such as G protein α subunit (dGqα), phospholipase C (norpA), and IP3 receptor (itpr), were examined in the taste receptor cell of the fruitfly Drosophila melanogaster by using the pox‐neuro70 mutant (poxn70), which lacks taste receptor cells. The expressed levels of dGqα and itpr in the tarsus of poxn70 mutant flies were reduced compared with those of wild‐type flies. These results suggest that the IP3 transduction cascade is involved in the response of the sugar receptor cell of the fly. © 2002 Wiley Periodicals, Inc. J Neurobiol 51: 66–83, 2002 相似文献
999.
Etsuko Watanabe Tomoo Shimada Miwa Kuroyanagi Mikio Nishimura Ikuko Hara-Nishimura 《The Journal of biological chemistry》2002,277(10):8708-8715
PV72, a type I membrane protein with three epidermal-growth factor (EGF)-like motifs, was found to be localized on the membranes of the precursor-accumulating (PAC) vesicles that accumulated precursors of various seed storage proteins. To clarify the function of PV72 as a sorting receptor, we expressed four modified PV72s and analyzed their ability to bind the internal propeptide (the 2S-I peptide) of pro2S albumin by affinity chromatography and surface plasmon resonance. The recombinant PV72 specifically bound to the 2S-I peptide with a K(D) value of 0.2 microm, which was low enough for it to function as a receptor. The EGF-like motifs modulated the Ca(2+)-dependent conformational change of PV72 to form a functional pocket for the ligand binding. The binding of Ca(2+) stabilizes the receptor-ligand complex even at pH 4.0. The association and dissociation of PV72 with the ligand is modulated by the Ca(2+) concentration (EC(50) value = 40 microm) rather than the environmental pH. Overall results suggest that Ca(2+) regulates the vacuolar sorting mechanism in higher plants. 相似文献
1000.
Choto-san is a formula used for the treatment of headache and vertigo. Recently it has often also been used for hypertension and dementia. One of the mechanisms involved is thought to be the improvement of blood circulation, but the details are still unclear. In this study, the effect of Chotosan was studied on nitric oxide (NO) function, hemorheological factors and endothelial function in stroke-prone spontaneously hypertensive rats (SHR-SP). Rats were given Choto-san in drinking water for eight weeks. Body weight, blood pressure, serum NO2-/NO3-, lipid peroxides, blood viscosity, erythrocyte deformability and endothelium-dependent/-independent relaxation were measured. The results indicated that Choto-san caused a decrease in blood pressure and an increase in erythrocyte deformability and NO function. Blood viscosity was not changed. Furthermore, endothelium-dependent relaxation by acetylcholine was significantly increased as compared to control. In this study, it was supposed that Choto-san had a protective effect on the endothelium. SHR-SP is a useful model for human brain stroke, and Choto-san showed a protective effect against cerebral vascular injury in the susceptible rat. 相似文献