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Articles by A Watanabe
Total Records ( 19 ) for A Watanabe
  A Watanabe , M. A Sohail , D. A Gomes , A Hashmi , J Nagata , F. S Sutterwala , S Mahmood , M. N Jhandier , Y Shi , R. A Flavell and W. Z. Mehal
 

The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality. Monosodium urate (MSU) crystals (100 µg/ml) were used to experimentally induce inflammasome activation in LX-2 and primary mouse HSC. Twenty-four hours later primary mouse HSC were stained with -smooth muscle actin and visualized by confocal microscopy, and TGF-β and collagen1 mRNA expression was quantified. LX-2 cells were further cultured with or without MSU crystals for 24 h in a transwell chemotaxis assay with PDGF as the chemoattractant. We also examined inhibition of calcium (Ca2+) signaling in LX-2 cells treated with or without MSU crystals using caged inositol 1,4,5-triphosphate (IP3). Finally, we confirmed an important role of the inflammasome in experimental liver fibrosis by the injection of carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild-type mice and mice lacking components of the inflammasome. Components of the inflammasome are expressed in LX-2 cells and primary HSC. MSU crystals induced upregulation of TGF-β and collagen1 mRNA and actin reorganization in HSCs from wild-type mice but not mice lacking inflammasome components. MSU crystals inhibited the release of Ca2+ via IP3 in LX-2 cells and also inhibited PDGF-induced chemotaxis. Mice lacking the inflammasome-sensing and adaptor molecules, NLRP3 and apoptosis-associated speck-like protein containing CARD, had reduced CCl4 and TAA-induced liver fibrosis. We concluded that inflammasome components are present in HSC, can regulate a variety of HSC functions, and are required for the development of liver fibrosis.

  Y. C Lin , A Watanabe , W. C Chen , K. F Lee , I L Lee and W. H. Wang
 

Objectives  To determine the value of narrowband imaging (NBI) screening for the early detection of head and neck squamous cell carcinoma (HNSCC) in patients who have received treatment and to assess the impact of radiotherapy on detection rates.

Design  Cross-sectional study.

Setting  Tertiary referral center.

Patients  From July 1, 2007, through February 28, 2008, a total of 206 patients with HNSCC underwent rhinolarynx videoendoscopic screening performed using conventional white-light and NBI systems during their routine postoperative sessions.

Main Outcome Measure  The rate of detecting malignant tumors, depending on the anatomical site and stage of cancer and the history of radiotherapy after primary treatment.

Results  We identified 68 lesions by endoscopy in conventional white-light and/or NBI mode. Of these, 62 were histopathologically confirmed to be cancerous. The rates of detecting cancerous lesions by white-light and NBI modes were 100% and 97% for oral lesions, 69% and 100% for oropharyngeal lesions (P = .02), and 39% and 100% for hypopharyngeal lesions (P = .001), respectively. No difference was found between the 2 modes with regard to the detection of visible T1 to T4 tumors. However, NBI mode was significantly better than white-light mode for the detection of carcinoma in situ (P < .001).

Conclusion  We found that NBI-assisted endoscopy is highly useful for the detection of precancerous lesions in the oropharyngeal and hypopharyngeal mucosa and is not affected by a history of radiotherapy in patients with HNSCC.

  A. Y Lai , A Watanabe , T O`Brien and M. Kondo
 

Lymphoid and myeloid lineage segregation is a major developmental step during early hematopoiesis from hematopoietic stem cells. It is not clear, however, whether multipotent progenitors (MPPs) adopt a lymphoid or myeloid fate through stochastic mechanisms, or whether this process can be regulated by extracellular stimuli. In this study, we show that lymphoid lineage specification occurs in MPPs before lymphoid lineage priming, during which MPPs migrate from the proximal to the distal region relative to the endosteum of the bone marrow. Lymphoid-specified MPPs have low myeloid differentiation potential in vivo, but potently differentiate into myeloid cells in vitro. When treated with pertussis toxin, an inhibitor of G protein–coupled receptor signaling, lymphoid-specified MPPs regain in vivo myeloid potential, and their localization is dispersed in the bone marrow. These results clearly demonstrate that specific microenvironments that favorably support lymphoid or myeloid lineage development exist at structurally distinct regions in the bone marrow.

  A Watanabe , T Fukami , M Nakajima , M Takamiya , Y Aoki and T. Yokoi
 

Flutamide, an antiandrogen drug, is widely used for the treatment of prostate cancer. The initial metabolic pathways of flutamide are hydroxylation and hydrolysis. It was recently reported that the hydrolyzed product, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1), is further metabolized to N-hydroxy FLU-1, an assumed hepatotoxicant. However, the esterase responsible for the flutamide hydrolysis has not been characterized. In the present study, we found that human arylacetamide deacetylase (AADAC) efficiently hydrolyzed flutamide using recombinant AADAC expressed in COS7 cells. In contrast, carboxylesterase1 (CES1) and CES2, which are responsible for the hydrolysis of many drugs, could not hydrolyze flutamide. AADAC is specifically expressed in the endoplasmic reticulum. Flutamide hydrolase activity was highly detected in human liver microsomes (Km, 794 ± 83 µM; Vmax, 1.1 ± 0.0 nmol/min/mg protein), whereas the activity was extremely low in human liver cytosol. The flutamide hydrolase activity in human liver microsomes was strongly inhibited by bis-(nonylphenyl)-phenylphosphate, diisopropylphosphorofluoride, and physostigmine sulfate (eserine) but moderately inhibited by sodium fluoride, phenylmethylsulfonyl fluoride, and disulfiram. The same inhibition pattern was obtained with the recombinant AADAC. Moreover, human liver and jejunum microsomes showing AADAC expression could hydrolyze flutamide, but human pulmonary and renal microsomes, which do not express AADAC, showed slight activity. In human liver microsomal samples (n = 50), the flutamide hydrolase activities were significantly correlated with the expression levels of AADAC protein (r = 0.66, p < 0.001). In conclusion, these results clearly showed that flutamide is exclusively hydrolyzed by AADAC. AADAC would be an important enzyme responsible for flutamide-induced hepatotoxicity.

  A Watanabe , T Fukami , M Nakajima , M Takamiya , Y Aoki and T. Yokoi
 

Flutamide, an antiandrogen drug, is widely used for the treatment of prostate cancer. The initial metabolic pathways of flutamide are hydroxylation and hydrolysis. It was recently reported that the hydrolyzed product, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1), is further metabolized to N-hydroxy FLU-1, an assumed hepatotoxicant. However, the esterase responsible for the flutamide hydrolysis has not been characterized. In the present study, we found that human arylacetamide deacetylase (AADAC) efficiently hydrolyzed flutamide using recombinant AADAC expressed in COS7 cells. In contrast, carboxylesterase1 (CES1) and CES2, which are responsible for the hydrolysis of many drugs, could not hydrolyze flutamide. AADAC is specifically expressed in the endoplasmic reticulum. Flutamide hydrolase activity was highly detected in human liver microsomes (Km, 794 ± 83 µM; Vmax, 1.1 ± 0.0 nmol/min/mg protein), whereas the activity was extremely low in human liver cytosol. The flutamide hydrolase activity in human liver microsomes was strongly inhibited by bis-(nonylphenyl)-phenylphosphate, diisopropylphosphorofluoride, and physostigmine sulfate (eserine) but moderately inhibited by sodium fluoride, phenylmethylsulfonyl fluoride, and disulfiram. The same inhibition pattern was obtained with the recombinant AADAC. Moreover, human liver and jejunum microsomes showing AADAC expression could hydrolyze flutamide, but human pulmonary and renal microsomes, which do not express AADAC, showed slight activity. In human liver microsomal samples (n = 50), the flutamide hydrolase activities were significantly correlated with the expression levels of AADAC protein (r = 0.66, p < 0.001). In conclusion, these results clearly showed that flutamide is exclusively hydrolyzed by AADAC. AADAC would be an important enzyme responsible for flutamide-induced hepatotoxicity.

  M. G Iwaizumi , M Takahashi , A Watanabe and M. Ubukata
 

When considering the genetic implications of immigrant gene flow, it is important to evaluate both the proportions of immigrant gametes and their genetic composition. We simultaneously investigated paternal and maternal gene flow in dispersed seeds in a natural population of Pinus densiflora located along a ridge. The paternity and maternity of a total of 454 dispersed seeds (in 2004 and 2005) were accurately and separately assigned to 454 candidate adult trees, by analyzing the nuclear DNA of both diploid biparentally derived embryos and haploid maternally derived megagametophytes of the seeds. The relative genetic diversities and differences between within-population and immigrant groups of both paternally and maternally derived gametes (4 groups) that formed the genotypes of the seeds were evaluated. Using 8 microsatellite markers, we found that 64.0–72.6% of paternally derived gametes, and 17.8–20.2% of maternally derived gametes, were from other populations. Principal coordinate analysis showed that the 4 gamete groups tended to be plotted at different locations on the scattergram, indicating that they each have different genetic compositions. Substantial paternal and maternal immigrant gene flow occurred in this population, and therefore, the overall genetic variation of dispersed seeds is enhanced by both paternally and maternally derived immigrant gametes.

 
 
 
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