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111.
Yano M Watanabe K Yamamoto T Ikeda K Senokuchi T Lu M Kadomatsu T Tsukano H Ikawa M Okabe M Yamaoka S Okazaki T Umehara H Gotoh T Song WJ Node K Taguchi R Yamagata K Oike Y 《The Journal of biological chemistry》2011,286(5):3992-4002
Sphingomyelin synthase 1 (SMS1) catalyzes the conversion of ceramide to sphingomyelin. Here, we generated and analyzed SMS1-null mice. SMS1-null mice exhibited moderate neonatal lethality, reduced body weight, and loss of fat tissues mass, suggesting that they might have metabolic abnormality. Indeed, analysis on glucose metabolism revealed that they showed severe deficiencies in insulin secretion. Isolated mutant islets exhibited severely impaired ability to release insulin, dependent on glucose stimuli. Further analysis indicated that mitochondria in mutant islet cells cannot up-regulate ATP production in response to glucose. We also observed additional mitochondrial abnormalities, such as hyperpolarized membrane potential and increased levels of reactive oxygen species (ROS) in mutant islets. Finally, when SMS1-null mice were treated with the anti-oxidant N-acetyl cysteine, we observed partial recovery of insulin secretion, indicating that ROS overproduction underlies pancreatic β-cell dysfunction in SMS1-null mice. Altogether, our data suggest that SMS1 is important for controlling ROS generation, and that SMS1 is required for normal mitochondrial function and insulin secretion in pancreatic β-cells. 相似文献
112.
Two types of mechanosensitive proprioceptor organ are present on the stinging apparatus of the honeybee: campaniform sensilla and mechanosensory hairplates. The campaniform sensilla are located on the surface of the tapering sting-shaft, which comprises an unpaired stylet and paired lancets. Each sensillum on the lancet differs from that on the stylet in terms of their topography and external morphology. The sensory afferents of the campaniform sensilla display slow-adapted firing responses to deformation of the cuticle that would be caused by the action of inserting the sting into a substrate, and their afferent signals induce and/or prolong the stinging response. By contrast, the mechanosensory hairplates are located at basal cuticular plates and on the posterior surface of the lancet valves. Two fields of hairplates on the second ramus at the ventral edge of the groove and on the antero-lateral edge of the oblong plate respond synchronously to protraction of the lancet. During the stinging response, these hairplates are likely to detect any sliding movement of the lancet and its position relative to the stylet. Afferent signals produced by them are likely to provide important information to the neuronal circuit for the generation and modulation of the stinging motor pattern. 相似文献
113.
Ohmine T Katsube T Tsuzaki Y Kazui M Kobayashi N Komai T Hagihara M Nishigaki T Iwamoto A Kimura T Kashiwase H Yamashita M 《Bioorganic & medicinal chemistry letters》2002,12(5):739-742
Anti-HIV-1 activities and pharmacokinetics of a series of novel arylpiperazinyl fluoroquinolones are reported. Modification at the C-8 position with a trifluoromethyl group was superior to that with a difluoromethoxy group to achieve higher anti-HIV-1 activity. Two compounds studied exhibited quite high anti-HIV-1 activities (IC(50)<50 nM) in vitro and high bioavailabilities (BA>90%) in monkeys. 相似文献
114.
This study aimed to reveal the soil seed accumulation processes for endozoochorous plants in the heavy-snowfall forests of Japan, where seed dispersal agents are few when compared to tropical forests. We assessed (1) primary seed dispersal by Japanese macaques (Macaca fuscata) by identifying dispersed seeds found in their feces, and (2) secondary seed dispersal by dung beetles by using beads (as seeds mimics) of different sizes, to quantify the frequency of seed burial and burial depths. We studied this diplochorous system in different forest types (undisturbed beech forest, conifer plantation, and secondary beech-oak forest) and during the spring and summer seasons. The key findings were as follows: (1) macaques dispersed the seeds of 11 and 14 plant species during spring and summer, respectively; (2) seeds dispersed by macaques in the spring were smaller and twice as abundant than those dispersed in the summer; (3) although no differences were observed in the amount of beads buried by beetles between seasons, all bead sizes tended to be buried in deeper soil layers in the spring than in the summer; and (4) the seed supply to the soil in undisturbed beech forest and conifer plantation was greater than the one in secondary beech-oak forest. Similar to what has been observed in tropical forests, seeds defecated by frugivorous mammals can be successfully incorporated into the underground soil seed bank through a diplochorous macaque-beetle system in temperate forests of deep snow regions. 相似文献
115.
Hiroto Izumi Asako McCloskey Kaori Shinmyozu Mutsuhito Ohno 《Nucleic acids research》2014,42(6):3998-4007
The assembly of spliceosomal U snRNPs in metazoans requires nuclear export of U snRNA precursors. Four factors, nuclear cap-binding complex (CBC), phosphorylated adaptor for RNA export (PHAX), the export receptor CRM1 and RanGTP, gather at the m7G-cap-proximal region and form the U snRNA export complex. Here we show that the multifunctional RNA-binding proteins p54nrb/NonO and PSF are U snRNA export stimulatory factors. These proteins, likely as a heterodimer, accelerate the recruitment of PHAX, and subsequently CRM1 and Ran onto the RNA substrates in vitro, which mediates efficient U snRNA export in vivo. Our results reveal a new layer of regulation for U snRNA export and, hence, spliceosomal U snRNP biogenesis. 相似文献
116.
Mana Iizuka Yuhya Wakasa Hiroto Tsuboi Hiromitsu Asashima Tomoya Hirota Yuya Kondo Isao Matsumoto Fumio Takaiwa Takayuki Sumida 《Plant biotechnology journal》2014,12(8):1143-1152
Rheumatoid arthritis (RA) is an autoimmune disease associated with the recognition of self proteins secluded in arthritic joints. We previously reported that altered peptide ligands (APLs) of type II collagen (CII256‐271) suppress the development of collagen‐induced arthritis (CIA). In this study, we generated transgenic rice expressing CII256‐271 and APL6 contained in fusion proteins with the rice storage protein glutelin in the seed endosperm. These transgene products successfully and stably accumulated at high levels (7–24 mg/g seeds) in protein storage vacuoles (PB‐II) of mature seeds. We examined the efficacy of these transgenic rice seeds by performing oral administration of the seeds to CIA model mice that had been immunized with CII. Treatment with APL6 transgenic rice for 14 days significantly inhibited the development of arthritis (based on clinical score) and delayed disease onset during the early phase of arthritis. These effects were mediated by the induction of IL‐10 from CD4+ CD25? T cells against CII antigen in splenocytes and inguinal lymph nodes (iLNs), and treatment of APL had no effect on the production of IFN‐γ, IL‐17, IL‐2 or Foxp3+ Treg cells. These findings suggest that abnormal immune suppressive mechanisms are involved in the therapeutic effect of rice‐based oral vaccine expressing high levels of APLs of type II collagen on the autoimmune disease CIA, suggesting that the seed‐based mucosal vaccine against CIA functions via a unique mechanism. 相似文献
117.
Seiya Yokoyama Sho Kitamoto Michiyo Higashi Yuko Goto Taro Hara Dai Ikebe Taketo Yamaguchi Yoshifumi Arisaka Toru Niihara Hiroto Nishimata Sadao Tanaka Kyoichi Takaori Surinder K. Batra Suguru Yonezawa 《PloS one》2014,9(4)
Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs). Our immunohistochemistry (IHC) studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type); MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type); High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4) expression in cancer cell line was regulated by DNA methylation. We have developed a novel ‘methylation-specific electrophoresis (MSE)’ method to analyze the DNA methylation status of mucin genes by high sensitivity and resolution. By using the MSE method, we evaluated pancreatic juice samples from 45 patients with various pancreatic lesions. The results were compared with final diagnosis of the pancreatic lesions including IHC of mucin expression in the paired pancreatic tissues. The results indicated that the DNA methylation status of MUC1, MUC2 and MUC4 in pancreatic juice matched with the mucin expression in tissue. Analyses of the DNA methylation status of MUC1, MUC2 and MUC4 were useful for differential diagnosis of human pancreatic neoplasms, with specificity and sensitivity of 87% and 80% for PDAC; 100% and 88% for intestinal-type IPMN; and 88% and 77% for gastric-type IPMN, respectively. In conclusion, MSE analysis of human pancreatic juice may provide useful information for selection of treatment for pancreatic neoplasms. 相似文献
118.
Hiroshi Saga Akira Ohhata Akio Hayashi Makoto Katoh Tatsuo Maeda Hirotaka Mizuno Yuka Takada Yuka Komichi Hiroto Ota Naoya Matsumura Masami Shibaya Tetsuya Sugiyama Shinji Nakade Katsuya Kishikawa 《PloS one》2014,9(4)
Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation.The IC50 values of ONO-8540506 for lysophospholipase D activity were 6.4–19 nM for recombinant autotaxin/ENPP2 proteins and 4.7–11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration.Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia. 相似文献
119.
Hiroto Kuwabara Stephen J. Heishman James R. Brasic Carlo Contoreggi Nicola Cascella Kristen M. Mackowick Richard Taylor Olivier Rousset William Willis Marilyn A. Huestis Marta Concheiro Gary Wand Dean F. Wong Nora D. Volkow 《PloS one》2014,9(12)
The rewarding effects of nicotine are associated with activation of nicotine receptors. However, there is increasing evidence that the endogenous opioid system is involved in nicotine''s rewarding effects. We employed PET imaging with [11C]carfentanil to test the hypotheses that acute cigarette smoking increases release of endogenous opioids in the human brain and that smokers have an upregulation of mu opioid receptors (MORs) when compared to nonsmokers. We found no significant changes in binding potential (BPND) of [11C]carfentanil between the placebo and the active cigarette sessions, nor did we observe differences in MOR binding between smokers and nonsmokers. Interestingly, we showed that in smokers MOR availability in bilateral superior temporal cortices during the placebo condition was negatively correlated with scores on the Fagerström Test for Nicotine Dependence (FTND). Also in smokers, smoking-induced decreases in [11C]carfentanil binding in frontal cortical regions were associated with self-reports of cigarette liking and wanting. Although we did not show differences between smokers and nonsmokers, the negative correlation with FTND corroborates the role of MORs in superior temporal cortices in nicotine addiction and provides preliminary evidence of a role of endogenous opioid signaling in frontal cortex in nicotine reward. 相似文献