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Volume 132, Issue 4
Displaying 1-19 of 19 articles from this issue
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Symposium Reviews
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Yuriko Higuchi, Hidetaka AkitaArticle type: Foreword
2012 Volume 132 Issue 4 Pages 395
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
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Yasuteru UranoArticle type: Review
2012 Volume 132 Issue 4 Pages 397-406
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSSeveral versatile and rational design strategies for novel fluorescence probes including those based on photoinduced electron transfer have been successfully established. Indeed, based on these design strategies, various novel fluorescence probes were successfully developed including those for reactive oxygen species and reporter enzymes. Furthermore, we have succeeded to visualize tiny tumors in living mice by using cancer-specific antibodies tagged with acidic-pH activatable fluorescence probes. Here, I will describe the details of probe design as well as some imaging results with living cells and animals by applying our novel fluorescence probes.
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Yuki Sudo, Michio HommaArticle type: Review
2012 Volume 132 Issue 4 Pages 407-416
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSLight is one of the most important energy sources and signals providing critical information to biological systems. The photoreceptor rhodopsin, which possesses retinal chromophore (vitamin A aldehyde) surrounded by seven transmembrane alpha-helices, is widely dispersed in prokaryotes and in eukaryotes. Although rhodopsin molecules work as distinctly different photoreceptors, they can be divided according to their two basic functions such as light-energy conversion and light-signal transduction. Thus rhodopsin molecules have great potential for controlling cellular activity by light. Indeed, a light-energy converter channel rhodopsin is used to control neural activity. From 2001, we have been working on various microbial sensory rhodopsins functioning as light-signal converters. In this review, we will introduce rhodopsin molecules from microbes, and will describe artificial and light-dependent protein expression system in Escherichia coli using Anabeana sensory rhodopsin (ASR). The newly developed tools would be widely useful for life scientists.
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Kazuya KabayamaArticle type: Review
2012 Volume 132 Issue 4 Pages 417-423
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSMembrane lateral heterogeneity is accepted as a requirement for the function of biological membranes, and the notion of the “raft/microdomain” gives specificity to this concept. Recently, fluorescence-based techniques such as fluorescence recovery after photobleaching (FRAP), single particle tracking (SPT), and fluorescence correlation spectroscopy (FCS) have shown promise for application to the dynamics of membrane molecules in microdomains. We previously revealed, by performing live-cell FRAP and SPT studies, a mechanism of insulin resistance in which dissociation of the insulin receptor (IR)-caveolin-1 (Cav1) complex was caused by an interaction between the IRβ subunit and the ganglioside GM3 cluster, a glycolipid-enriched membrane microdomain. We hoped to demonstrate that an alteration in the lipid component of microdomains affects lateral diffusion of membrane receptors. We therefore established an experimental system for monitoring the membrane organization of receptors by analyzing their lateral diffusion parameters in the plasma membranes of living cells using FRAP and SPT. In this study, measurement of the lateral diffusion of the IR was performed by fitting analysis to fluorescence recovery curves and trace analysis to individual fluorescent spots, which provided the diffusion constant. The results show how fast IR molecules diffuse before and after a change in membrane environment, such as stimulation by cholesterol depression or treatment with a glycosphingolipid (GSL) inhibitor. Using these techniques, we have established a method for determining the diffusion constant for the lateral movement of IR-EGFP, expressed in CHO-K1 cells. We will use these techniques for the lateral diffusion analysis of membrane receptors under other assay conditions, such as use of GSL-deficient cells or pathologic samples.
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Satoshi NishimuraArticle type: Review
2012 Volume 132 Issue 4 Pages 425-431
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSThe metabolic syndrome is a major risk factor of cardiovascular events, and obese visceral adipose tissue remodeling based on chronic inflammation plays a central role. To assess dynamic interplay between multiple cell types in obese adipose tissue, a visualization technique in vivo was developed. By this technique we identified inflammatory cell clusters associated with angiogenesis and adipogenesis in obese adipose tissue. We also found increased leukocyte-platelet-endothelial cell interactions in obese adipose tissue microcirculation, which were indicative of local chronic inflammation. Moreover, we found that large numbers of CD8+ effector T cells infiltrated into obese adipose tissue. Immunological and genetic depletion of CD8+ T cells reduced inflammatory (M1) macrophage infiltration and adipose tissue inflammation, and ameliorated systemic insulin resistance. Infiltration of CD8+ T cells is essential for inflammatory macrophage recruitment into obese adipose tissue, and the initiation and development of inflammation therein. Our results clearly demonstrate the power of our imaging technique to analyze complex cellular interplay in vivo, especially parenchymal and stromal cell crosstalk, and to evaluate new therapeutic interventions against conditions arising from these interactions.
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Yuriko HiguchiArticle type: Review
2012 Volume 132 Issue 4 Pages 433-439
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSFor successful development of cell-based therapy, both the disposition and differentiation of transplanted cells are directly related to therapeutic effects. In vivo imaging is an attractive tool to obtain real-time information on the disposition of target cells. In various types of imaging methods such as positron emission tomography(PET) and magnetic resonance imaging(MRI), fluorescence imaging is suitable for visualizing the disposition of cells because it can visualize single cells both in vitro and in vivo. For the trafficking of stem cells after transplantation, it is necessary to label living cells for long time periods without disturbing the function or differentiation of the labeled cells. Recently, we have developed quantum dots modified with polyamidoamine(PAMAM) dendrimers. These can more rapidly escape from endosomes and sustain their fluorescence intensity compared with unmodified quantum dots in primary cultured mesenchymal stem cells (MSCs). Fluorescence intensity was also sustained after intravenous injection of MSCs labeled with PAMAM dendrimer-modified quantum dots. To study the dynamics of MSCs in vivo, we constructed a piggyBack transposon vector that can integrate the target gene into the genome in mammalian cells, and established primary MSCs with long-term expression of EmGFP. In addition, we also developed a suction device stabilizing tissue for in vivo real time imaging. In this section, I present our recent findings on long-term fluorescent labeling of MSCs and in vivo visualizing of cell dynamics in a living mouse.
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Shiro Ueda, Takahiko OnoArticle type: Foreword
2012 Volume 132 Issue 4 Pages 441-442
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
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Kazunori KimuraArticle type: Review
2012 Volume 132 Issue 4 Pages 443-448
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSChronic kidney disease (CKD), defined as low glomerular filtration rates and/or the presence of albuminuria, is considered a risk factor for cardiovascular disease (CVD). In recent years, increasing emphasis has been placed on endothelial dysfunction as a key element underlying the relationship between CKD and CVD. Endothelial cells play a pivotal role in many aspects of vascular function by generating nitric oxide (NO). However, NO production is reduced in CKD patients, partially due to decreased endothelial NO production. One possible cause of NO deficiency is increased levels of endogenous NO synthase inhibitors, in particular asymmetric dimethylarginine (ADMA). Elevated plasma levels of ADMA are consequence of increased synthesis and reduced degradation. Accumulation of ADMA and inhibition of NO production might contribute to endothelial dysfunction, hypertension, initiation of atherosclerosis, and incidence of CVD. Clinical studies revealed that ADMA plasma concentration is increased in populations with renal disease, vascular diseases, and high cardiovascular risks. In this regard, ADMA is increasingly recognized as a biomarker of CKD and CVD. This review discusses ADMA-mediated endothelial dysfunction in CKD, especially focusing on the link between CKD and CVD.
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Takahiko OnoArticle type: Review
2012 Volume 132 Issue 4 Pages 449-453
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSConsidering that fibrin deposition is observed in glomerulonephritis as well as in diabetic nephropathy, we performed studies to clarify the roles of the coagulation pathway and the active type of coagulation factor X (factor Xa) in the development of chronic kidney disease (CKD) using animal models. Factor Xa activates various cell types through protease-activated receptor 2 (PAR2). Several in vitro studies have demonstrated that PAR2 can mediate factor Xa signaling, but not thrombin signaling. Coagulation processes proceed together with the extracellular matrix (ECM) accumulation through factor V expression in rat Thy-1 nephritis. DX-9065a, a factor Xa inhibitor, suppresses this type of glomerulonephritis. The factor Xa inhibitor danaparoid ameliorated proteinuria, cellular proliferation, and fibrin deposition in lipopolysaccharide (LPS)-triggered activation of High IgA (HIGA) strain of ddY mice. Another factor Xa inhibitor, fondaparinux, suppressed urinary protein, glomerular hypertrophy, and connective tissue growth factor (CTGF), and ECM protein deposition together with angiogenesis in diabetic db/db mice. Finally, in the model of peritoneal fibrosis, fondaparinux treatment decreased the thickness of submesothelial fibrotic tissue and angiogenesis. In consideration of the results to potential human therapy, factor Xa regulation may be promising for the treatment of the aggravation in glomerulonephritis and of the early phase of diabetic nephropathy. In the near future, novel factor Xa inhibitors with the characteristics of oral administration and biliary elimination may appear in the clinical use for treatment of cardiovascular diseases.
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Akira NishiyamaArticle type: Review
2012 Volume 132 Issue 4 Pages 455-459
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSIn recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. It has also been revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of chronic kidney disease (CKD). Indeed, most national guideline groups now recommend the use of RAS inhibitors in preference to other antihypertensive agents for hypertensive patients with CKD. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS. We will also discuss the impact of RAS inhibitors in preventing the progressive increases in the intrarenal RAS during the development of CKD.
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Sumio HirataArticle type: Review
2012 Volume 132 Issue 4 Pages 461-470
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSThe kidney is the most important organ for the excretion of drugs. It was previously thought that appropriate dosages of these drugs could be easily estimated by evaluating the kidney function of patients and the excretion rate of the drug. However, the pharmacokinetic characteristics of patients with kidney disease are as follows: 1) Active metabolites with a higher polarity can accumulate, which can induce unpredictable adverse effects. For example, over sedation with morphine or the development of the fatal toxic syndrome in the case of allopulinol are due to the accumulation of active metabolites derived from these drugs. 2) Although the renal excretion rate of acetoaminophen is only less than 5%, the accumulation of its glucuronide conjugate during multiple dosing in patients with kidney failure may induce high serum acetoaminophen trough levels via the entero-hepatic circulation. 3) Although the renal excretion rate of the drugs are negligible, a remarkable increase in the serum levels of certain drugs were observed in patients with end stage kidney disease, suggesting a significant reduction in non-renal clearance probably by the accumulation of uremic toxins. For drugs that are likely to be administered to patients with kidney disease, even including drugs that are not excreted by the kidney, a full pharmacokinetic study should be conducted in patients and the results carefully assessed. Information on dosing adjustments for impaired kidney function based on estimated glomerular filtration rates should then be clearly stated in the package insert of the drugs.
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Shin-ichi TsunodaArticle type: Foreword
2012 Volume 132 Issue 4 Pages 471-472
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
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Haruhiko KamadaArticle type: Review
2012 Volume 132 Issue 4 Pages 473-477
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSA monoclonal antibody (Mab), due to its specific binding ability to a target protein, can potentially be one of the most useful tools for the functional analysis of proteins in recent proteomics-based research. However, the production of Mab is a very time-consuming and laborious process (i.e., preparation of recombinant antigens, immunization of animals, preparation of hybridomas), making it the rate-limiting step in using Mabs in high-throughput proteomics research, which heavily relies on comprehensive and rapid methods. Therefore, there is a great demand for new methods to efficiently generate Mabs against a group of proteins identified by proteome analysis. Here, we describe a useful method called “Antibody proteomic technique” for the rapid generations of Mabs to pharmaceutical target, which were identified by proteomic analyses of disease samples (ex. tumor tissue, etc.). We also introduce another method to find profitable targets on vasculature, which is called “Vascular proteomic technique”. Our results suggest that this method for the rapid generation of Mabs to proteins may be very useful in proteomics-based research as well as in clinical applications.
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Sumio OhtsukiArticle type: Review
2012 Volume 132 Issue 4 Pages 479-487
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSOmics analyses provided many candidates for drug targets and biomarkers. However, these analyses have not contributed to drug development efficiently because of top-down omics analyses. To solve this problem, we have recently developed quantitative targeted proteomics with multiplexed-multiple reaction monitoring (multiplexed-MRM) method, which enables us to perform bottom-up proteomics. In this method, the target proteins for quantification are selected prior to analysis based on the knowledge related to interesting phenomena. Target peptides for quantification are selected only from sequence information, so time-consuming procedures such as antibody preparation and protein purification are unnecessary. In this review, we introduce the technical features of multiplexed-MRM method as novel protein quantification method, and summarize its advantages with reference to recently reported results, including species differences, in vitro-to-in vivo reconstruction and personalized chemotherapy. This novel simultaneous protein quantification method overcomes problems of antibody-based quantification and would open new drug research based of protein as “Pharmacoproteomics”.
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Noritaka Hashii, Shiori Nakazawa, Nana KawasakiArticle type: Review
2012 Volume 132 Issue 4 Pages 489-497
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSGlycosylation of cells is known to alter with several biological events such as cell differentiations and proliferations as well as some diseases. “Glycomic approaches”, comprehensive qualitative and quantitative glycan analyses of the cells, have become increasingly important as a means of discovering biomarkers that have the potential of being used as disease diagnostic markers and molecular markers for cell characterizations. In this paper, we introduce a method of quantitative glycan profiling by liquid chromatography/mass spectrometry with a combination of an isotope tagging method. In addition, we demonstrate the potential of glycan profiling as a tool for the identification of differentiated human bone marrow mesenchymal stem cell (hMSC) and non-differentiated hMSC.
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Mitsutoshi SetouArticle type: Review
2012 Volume 132 Issue 4 Pages 499-506
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSMatrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS) enables the visualization of the distribution of a range of biomolecules that have varied structures in the cells and tissue sections. This emerging imaging technique was initially developed as a tool for protein imaging, but recently it is increasingly being used for the imaging of small organic molecules. IMS is an effective technique for the imaging of small metabolites, including endogenous metabolites such as lipids and exogenous drugs because of the following advantages: First, IMS does not require any specific labels or probes. Second, IMS is a non-targeted imaging method. Finally, the simultaneous imaging of many types of metabolite molecules is possible, and all these features are necessary for the assessment of metabolite localization. In this review, we discuss the capability of current IMS techniques for imaging small molecules, and introduce representative studies on imaging of endogenous and exogenous metabolites. In addition, the limitations and problems of the technique are also discussed, and reports of progress toward solving the problems with this technique are also introduced.
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Regular Articles
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Makiko Ishizaki, Hatsuo Maeda, Ikuko OkamotoArticle type: Regular Article
2012 Volume 132 Issue 4 Pages 507-515
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSIn Japan, pharmacists as well as patients often have problems distinguishing one ethical tablet from another because they can be very similar in color. In an attempt to solve this problem, we hypothesized using a background sheet of dark gray identified by N3.5 on the Munsell color system (Munsell CS). The colors of 369 and 656 ethical tablets in Japan and the USA, respectively, were measured. On the Munsell CS, the Japanese tablets were localized mostly in the range of hues between 10R∼10Y with values ≧8 and chroma ≦4, while the colors of the American tablets were scattered over the hue spectrum with a variety of values and chroma. Based on these findings, we examined the effects of background colors on discrimination between 5 tablets classified into yellow, yellow red, red, or mixed groups that represented typical domestic Japanese tablets. Background colors of light, medium, and dark gray, purple, blue, and blue green were selected based on a general concept on color discrimination. The influence of white 10 mm-ruled squares on background sheets was examined as well. Under JIS Z8723 conditions, 42 volunteers used a 4-point scale to evaluate how clearly they could discriminate between each set of tablets on each of the background sheets. Variance analysis of the obtained data with SPSS® demonstrated that with healthy vision, use of a dark gray background sheet with or without ruled squares enabled the sharpest and most feasible discrimination between all sets of tablets. A similar test with dark gray and white clearly demonstrated that the former works as a practical background color for discrimination among different domestic Japanese tablets.
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Fumi Suzuki, Kazuhiko Hanada, Mariko Motoki, Hiroyasu OgataArticle type: Regular Article
2012 Volume 132 Issue 4 Pages 517-523
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSThe aim of this study was to elucidate the factors affecting dialysis clearance and the need for additional doses of drugs during and after continuous hemofiltration (CHF) and hemodiafiltration (CHDF). We performed a literature search of MEDLINE using the terms hemofiltration OR hemodiafiltration AND pharmacokinetics to obtain the clearances of CHF and CHDF in a clinical setting. The relationships between molecular weight, the unbound fraction (fuB), ultrafiltration flow rate (UFR) and dialysis flow rate were analyzed. The need for additional doses of certain drugs was also discussed based on the ratio of dialysis and systemic clearances. The clearance of CHF for 32 reported drugs was significantly correlated with the product of fuB×UFR (r=0.841, p<0.001), and furthermore the plots obtained lay on a line of y=x. The clearance of CHDF also showed good correlation with the product of fuB×UFR (r=0.795, p<0.001), but the plots were higher than the line for y=x, suggesting that additional clearance by dialysis was not negligible. The elimination by both forms of dialysis for drugs excreted mainly via the kidneys, and with a higher fuB, was considerable. The extent of drug clearance by both CHF and CHDF is determined mainly by fuB and UFR. The ratio of dialysis clearance to systemic clearance should be estimated to determine the contribution of CHF and CHDF.
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Note
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Hirofumi Tamaki, Hiroki Satoh, Satoko Hori, Yasufumi SawadaArticle type: Note
2012 Volume 132 Issue 4 Pages 525-529
Published: April 01, 2012
Released on J-STAGE: April 01, 2012
JOURNAL FREE ACCESSConfusion of drug names is one of the most common causes of drug-related medical errors. A similarity measure of drug names, “vwhtfrag”, was developed to discriminate whether drug name pairs are likely to cause confusion errors, and to provide information that would be helpful to avoid errors. The aim of the present study was to evaluate and improve vwhtfrag. Firstly, we evaluated the correlation of vwhtfrag with subjective similarity or error rate of drug name pairs in psychological experiments. Vwhtfrag showed a higher correlation to subjective similarity (college students: r=0.84) or error rate than did other conventional similarity measures (htco, cos1, edit). Moreover, name pairs that showed coincidences of the initial character strings had a higher subjective similarity than those which had coincidences of the end character strings and had the same vwhtfrag. Therefore, we developed a new similarity measure (vwhtfrag+), in which coincidence of initial character strings in name pairs is weighted by 1.53 times over coincidence of end character strings. Vwhtfrag+ showed a higher correlation to subjective similarity than did unmodified vwhtfrag. Further studies appear warranted to examine in detail whether vwhtfrag+ has superior ability to discriminate drug name pairs likely to cause confusion errors.
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