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141.
Iwahashi M Naganawa A Kinoshita A Shimabukuro A Nishiyama T Ogawa S Matsunaga Y Tsukamoto K Okada Y Matsumoto R Nambu F Oumi R Odagaki Y Katagi J Yano K Tani K Nakai H Toda M 《Bioorganic & medicinal chemistry》2011,19(22):6935-6948
To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva. 相似文献
142.
Baba T Mori S Matsumura N Kariya M Murphy SK Kondoh E Kusakari T Kuroda H Mandai M Higuchi T Takakura K Fukuda MN Fujii S 《Biochemical and biophysical research communications》2007,360(2):363-369
Ovarian cancer is the leading cause of death in women with gynecological malignancies, with prognosis of advanced stage tumors determined by chemotherapeutic response and the success of tumor resection. Since aberrant RAS pathway activation is frequent in ovarian cancer, study of in vitro RAS-induced transformation and accompanying genomic expression changes in ovarian surface epithelial cells is imperative for development of new therapeutic modalities and for understanding tumorigenesis. cDNA microarray analysis revealed TROPHONIN (TRO), a homophilic adhesion molecule involved in blastocyst implantation, was among the genes most downregulated by RAS induction. TRO expression is higher in cisplatin-sensitive cancer cell lines and positively correlates with prognoses in ovarian cancers. TRO knockdown by RNA interference conferred cisplatin resistance and led to increased invasiveness of cultured ovarian cancer cells. These findings underscore the importance of TRO in tumorigenesis, and suggest that TRO may be a useful biomarker for cisplatin sensitivity and invasive potential. 相似文献
143.
Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice 总被引:3,自引:2,他引:1
Miyazawa K Kanaya T Tanaka S Takakura I Watanabe K Ohwada S Kitazawa H Rose MT Sakaguchi S Katamine S Yamaguchi T Aso H 《Histochemistry and cell biology》2007,127(3):291-301
The gastrointestinal tract is thought to be the main site of entry for the pathological isoform of the prion protein (PrPSc). Prion diseases are believed to result from a conformational change of the cellular prion protein (PrPc) to PrPSc. Therefore, PrPc expression is a prerequisite for the infection and spread of the disease to the central nervous system. However, the distribution
of PrPc in the gut is still a matter of controversy. We therefore investigated the localization of PrPc in the bovine and murine small intestine. In cattle, most PrPc positive epithelial cells were detected in the duodenum, while a few positive cells were found in the jejunum. PrPc was expressed in serotonin producing cells. In bovine Peyer’s patches, PrPc was distributed in extrafollicular areas, but not in the germinal centre of the jejunum and ileum. PrPc was expressed in myeloid lineage cells such as myeloid dendritic cells and macrophages. In mice, PrPc was expressed in some epithelial cells throughout the small intestine as well as in cells such as follicular dendritic cell
in the germinal centre of Peyer’s patches. In this study, we demonstrate that there are a number of differences in the localization
of PrPc between the murine and bovine small intestines. 相似文献
144.
145.
Norihito Shibata Nobumichi Ohoka Yusuke Sugaki Chiaki Onodera Mizuho Inoue Yoshiyuki Sakuraba Daisuke Takakura Noritaka Hashii Nana Kawasaki Yoichi Gondo Mikihiko Naito 《The Journal of biological chemistry》2015,290(47):28428-28437
During translation, stop codon read-through occasionally happens when the stop codon is misread, skipped, or mutated, resulting in the production of aberrant proteins with C-terminal extension. These extended proteins are potentially deleterious, but their regulation is poorly understood. Here we show in vitro and in vivo evidence that mouse cFLIP-L with a 46-amino acid extension encoded by a read-through mutant gene is rapidly degraded by the ubiquitin-proteasome system, causing hepatocyte apoptosis during embryogenesis. The extended peptide interacts with an E3 ubiquitin ligase, TRIM21, to induce ubiquitylation of the mutant protein. In humans, 20 read-through mutations are related to hereditary disorders, and extended peptides found in human PNPO and HSD3B2 similarly destabilize these proteins, involving TRIM21 for PNPO degradation. Our findings indicate that degradation of aberrant proteins with C-terminal extension encoded by read-through mutant genes is a mechanism for loss of function resulting in hereditary disorders. 相似文献
146.
Shigeo Koido Toshifumi Ohkusa Takayuki Kajiura Junko Shinozaki Manabu Suzuki Keisuke Saito Kazuki Takakura Shintaro Tsukinaga Shunichi Odahara Toyokazu Yukawa Jimi Mitobe Mikio Kajihara Kan Uchiyama Hiroshi Arakawa Hisao Tajiri 《PloS one》2014,9(1)
Previous work has demonstrated that intestinal bacteria, such as Fusobacterium varium (F. varium), contribute to the clinical activity in ulcerative colitis (UC); thus, an antibiotic combination therapy (amoxicillin, tetracycline, and metronidazole (ATM)) against F. varium can induce and maintain UC remission. Therefore, we investigated whether ATM therapy induces a long-term alteration of intestinal microbiota in patients with UC. Patients with UC were enrolled in a multicenter, randomized, double-blind, placebo-controlled study. Biopsy samples at the beginning of the trial and again at 3 months after treatment completion were randomly obtained from 20 patients. The terminal restriction fragment length polymorphism (T-RFLP) in mucosa-associated bacterial components was examined to assess the alteration of the intestinal microbiota. Profile changes of T-RFLP in mucosa-associated bacterial components were found in 10 of 12 patients in the treatment group and in none of 8 in the placebo group. Dice similarity coefficients using the unweighted pair group method with arithmetic averages (Dice-UPGMA) confirmed that the similarity of mucosal microbiota from the descending colon was significantly decreased after the ATM therapy, and this change was maintained for at least 3 months. Moreover, at 3 months after treatment completion, the F. varium/β-actin ratio, examined by real-time PCR using nested PCR products from biopsy samples, was reduced less than 40% in 8 of 12 treated patients, which was higher, but not significantly, than in 4 of 8 patients in the placebo group. Together, these results suggest that ATM therapy induces long-term alterations in the intestinal microbiota of patients with UC, which may be associated, at least in part, with clinical effects of the therapy. 相似文献
147.
Emiko Yoda Kohmi Rai Mai Ogawa Yuki Takakura Hiroshi Kuwata Hidenori Suzuki Yoshihito Nakatani Makoto Murakami Shuntaro Hara 《PloS one》2014,9(10)
In platelets, group IVA cytosolic phospholipase A2 (cPLA2α) has been implicated as a key regulator in the hydrolysis of platelet membrane phospholipids, leading to pro-thrombotic thromboxane A2 and anti-thrombotic 12-(S)-hydroxyeicosatetranoic acid production. However, studies using cPLA2α-deficient mice have indicated that other PLA2(s) may also be involved in the hydrolysis of platelet glycerophospholipids. In this study, we found that group VIB Ca2+-independent PLA2 (iPLA2γ)-deficient platelets showed decreases in adenosine diphosphate (ADP)-dependent aggregation and ADP- or collagen-dependent thromboxane A2 production. Electrospray ionization mass spectrometry analysis of platelet phospholipids revealed that fatty acyl compositions of ethanolamine plasmalogen and phosphatidylglycerol were altered in platelets from iPLA2γ-null mice. Furthermore, mice lacking iPLA2γ displayed prolonged bleeding times and were protected against pulmonary thromboembolism. These results suggest that iPLA2γ is an additional, long-sought-after PLA2 that hydrolyzes platelet membranes and facilitates platelet aggregation in response to ADP. 相似文献
148.
Sezaki T Inada K Sogabe T Kakuda K Tomiyama L Matsuno Y Ichikawa T Matsuo M Ueda K Kioka N 《PloS one》2012,7(4):e35519
Discs large homolog 5 (Dlg5) is a member of the membrane-associated guanylate kinase adaptor family of proteins, some of which are involved in the regulation of epithelial-to-mesenchymal transition (EMT). Dlg5 has been described as a susceptibility gene for Crohn's disease; however, the physiological function of Dlg5 is unknown. We show here that transforming growth factor-β (TGF-β)-induced EMT suppresses Dlg5 expression in LLc-PK1 cells. Depletion of Dlg5 expression by knockdown promoted the expression of the mesenchymal marker proteins, fibronectin and α-smooth muscle actin, and suppressed the expression of E-cadherin. In addition, activation of JNK and p38, which are stimulated by TGF-β, was enhanced by Dlg5 depletion. Furthermore, inhibition of the TGF-β receptor suppressed the effects of Dlg5 depletion. These observations suggest that Dlg5 is involved in the regulation of TGF-βreceptor-dependent signals and EMT. 相似文献
149.
Furuichi Y Sugiura T Kato Y Takakura H Hanai Y Hashimoto T Masuda K 《Biochemical and biophysical research communications》2012,418(4):774-779
Since carnitine plays an important role in fat oxidation, influx of carnitine could be crucial for muscle metabolism. OCTN2 (SLC22A5), a sodium-dependent solute carrier, is assumed to transport carnitine into skeletal muscle cells. Acute regulation of OCTN2 activity in rat hindlimb muscles was investigated in response to electrically induced contractile activity. The tissue uptake clearance (CL(uptake)) of l-[(3)H]carnitine during muscle contraction was examined in vivo using integration plot analysis. The CL(uptake) of [(14)C]iodoantipyrine (IAP) was also determined as an index of tissue blood flow. To test the hypothesis that increased carnitine uptake involves the translocation of OCTN2, contraction-induced alteration in the subcellular localization of OCTN2 was examined. The CL(uptake) of l-[(3)H]carnitine in the contracting muscles increased 1.4-1.7-fold as compared to that in the contralateral resting muscles (p<0.05). The CL(uptake) of [(14)C]IAP was much higher than that of l-[(3)H]carnitine, but no association between the increase in carnitine uptake and blood flow was obtained. Co-immunostaining of OCTN2 and dystrophin (a muscle plasma membrane marker) showed an increase in OCTN2 signal in the plasma membrane after muscle contraction. Western blotting showed that the level of sarcolemmal OCTN2 was greater in contracting muscles than in resting muscles (p<0.05). The present study showed that muscle contraction facilitated carnitine uptake in skeletal muscles, possibly via the contraction-induced translocation of its specific transporter OCTN2 to the plasma membrane. 相似文献
150.
The blast fungus Magnaporthe oryzae, one of the most devastating rice pathogens in the world, shows biotin-dependent growth. We have developed a strategy for
creating disease resistance to M. oryzae whereby intercellular production of tamavidin 1, a biotin-binding protein from Pleurotus cornucopiae occurs in transgenic rice plants. The gene that encodes tamavidin 1, fused to the sequence for a secretion signal peptide
derived from rice chitinase gene, was connected to the Cauliflower mosaic virus 35S promoter, and the resultant construct
was introduced into rice. The tamavidin 1 was accumulated at levels of 0.1–0.2% of total soluble leaf proteins in the transgenic
rice and it was localized in the intercellular space of rice leaves. The tamavidin 1 purified from the transgenic rice was
active, it bound to biotin and inhibited in vitro growth of M. oryzae by causing biotin deficiency. The transgenic rice plants showed a significant resistance to M. oryzae. This study shows the possibility of a new strategy to engineer disease resistance in higher plants by taking advantage of
a pathogen’s auxotrophy. 相似文献