Sagamihara, Japan
Sagamihara, Japan

Kitasato University is a renowned private university located in Minato, Tokyo, Japan.The head of the university is located in the Shirokane Campus, neighboring the Kitasato Institute. Its major educational facilities are located in the Sagamihara Campus, located 60 kilometers west of central Tokyo. The departments include the School of Medicine, School of Allied Health science, School of Pharmaceutical Studies, School of Veterinary Medicine and Animal science, School of Marine science, School of Nursing, and the School of Science.The school was named after Kitasato Shibasaburō. Wikipedia.

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Cane D.E.,Brown University | Ikeda H.,Kitasato University
Accounts of Chemical Research | Year: 2012

Tens of thousands of terpenoids are present in both terrestrial and marine plants, as well as fungi. In the last 5-10 years, however, it has become evident that terpenes are also produced by numerous bacteria, especially soil-dwelling Gram-positive organisms such as Streptomyces and other Actinomycetes. Although some microbial terpenes, such as geosmin, the degraded sesquiterpene responsible for the smell of moist soil, the characteristic odor of the earth itself, have been known for over 100 years, few terpenoids have been identified by classical structure- or activity-guided screening of bacterial culture extracts. In fact, the majority of cyclic terpenes from bacterial species have only recently been uncovered by the newly developed techniques of "genome mining". In this new paradigm for biochemical discovery, bacterial genome sequences are first analyzed with powerful bioinformatic tools, such as the BLASTP program or Profile Hidden Markov models, to screen for and identify conserved protein sequences harboring a characteristic set of universally conserved functional domains typical of all terpene synthases. Of particular importance is the presence of variants of two universally conserved domains, the aspartate-rich DDXX(D/E) motif and the NSE/DTE triad, (N/D)DXX(S/T)XX(K/R)(D/E). Both domains have been implicated in the binding of the essential divalent cation, typically Mg 2+, that is required for cyclization of the universal acyclic terpene precursors, such as farnesyl and geranyl diphosphate.The low level of overall sequence similarity among terpene synthases, however, has so far precluded any simple correlation of protein sequence with the structure of the cyclized terpene product. The actual biochemical function of a cryptic bacterial (or indeed any) terpene synthase must therefore be determined by direct experiment. Two common approaches are (i) incubation of the expressed recombinant protein with acyclic allylic diphosphate substrates and identification of the resultant terpene hydrocarbon or alcohol and (ii) in vivo expression in engineered bacterial hosts that can support the production of terpene metabolites. One of the most attractive features of the coordinated application of genome mining and biochemical characterization is that the discovery of natural products is directly coupled to the simultaneous discovery and exploitation of the responsible biosynthetic genes and enzymes.Bacterial genome mining has proved highly rewarding scientifically, already uncovering more than a dozen newly identified cyclic terpenes (many of them unique to bacteria), as well as several novel cyclization mechanisms. Moreover, bioinformatic analysis has identified more than 120 presumptive genes for bacterial terpene synthases that are now ripe for exploration. In this Account, we review a particularly rich vein we have mined in the genomes of two model Actinomycetes, Streptomyces coelicolor and Streptomyces avermitilis, from which the entire set of terpenoid biosynthetic genes and pathways have now been elucidated. In addition, studies of terpenoid biosynthetic gene clusters have revealed a wealth of previously unknown oxidative enzymes, including cytochromes P450, non-heme iron-dependent dioxygenases, and flavin monooxygenases. We have shown that these enzymes catalyze a variety of unusual biochemical reactions, including two-step ketonization of methylene groups, desaturation-epoxidation of secondary methyl groups, and pathway-specific Baeyer-Villiger oxidations of cyclic ketones. © 2011 American Chemical Society.

Mizuno Y.,Kitasato University | Kondo T.,Rehabilitation Hananoie Hospital
Movement Disorders | Year: 2013

Background: We evaluated the efficacy and safety of istradefylline, a selective adenosine A2A receptor antagonist administered as adjunctive treatment to levodopa for 12 weeks in a double-blind manner in Parkinson's disease patients with motor complications in Japan. Methods: A total of 373 subjects were randomized to receive placebo (n=126), istradefylline 20 mg/day (n=123), or istradefylline 40 mg/day (n=124). The primary efficacy variable was the change in daily OFF time. Other secondary variables were also evaluated. Results: The change in daily OFF time was significantly reduced in the istradefylline 20 mg/day (-0.99 hours, P = .003) and istradefylline 40 mg/day (-0.96 hours, P = .003) groups compared with the placebo group (-0.23 hours). The most common adverse event was dyskinesia (placebo, 4.0%; istradefylline 20 mg/day, 13.0%; istradefylline 40 mg/day, 12.1%). Conclusions: Istradefylline reduced daily OFF time and was well tolerated in Japanese PD patients with motor complications on levodopa treatment. © 2013 Movement Disorder Society.

Hasegawa M.,Kitasato University | Iyoda M.,Tokyo Metroplitan University
Chemical Society Reviews | Year: 2010

Recent progress in the study of electroconducting nanomaterials such as nanofibers, nanorods and other nanostructures based on the supramolecular self-assembly of hexabenzocoronenes, oligo(thiophene)s, tetrathiafulvalenes and perylene-3,4,9,10-tetracarboxylic diimides is described in this tutorial review. Conducting nanofibers and nanorods are constructed by doping π-donors or π-acceptors with oxidants or reductants before/after the formation of such nanostructures; however, some nanofibers show electric conductivity without any doping in the neutral state. Although cation radicals and anion radicals seem to be difficult to form nanofibers and nanorods, a limited number of cation radicals produce conducting nanofibers. For nanofibers and nanorods composed of weak π-donors and π-acceptors, their conductivities are measured by time-resolved microwave conductivity techniques. © 2010 The Royal Society of Chemistry.

The nonantibiotic small molecule cyslabdan, a labdan-type diterpene produced by Streptomyces sp. K04-0144, markedly potentiated the activity of the β-lactam drug imipenem against methicillin-resistant Staphylococcus aureus (MRSA). To study the mechanism of action of cyslabdan, the proteins that bind to cyslabdan were investigated in an MRSA lysate, which led to the identification of FemA, which is involved in the synthesis of the pentaglycine interpeptide bridge of the peptidoglycan of MRSA. Furthermore, binding assay of cyslabdan to FemB and FemX with the function similar to FemA revealed that cyslabdan had an affinity for FemB but not FemX. In an enzyme-based assay, cyslabdan inhibited FemA activity, where as did not affected FemX and FemB activities. Nonglycyl and monoglycyl murein monomers were accumulated by cyslabdan in the peptidoglycan of MRSA cell walls. These findings indicated that cyslabdan primarily inhibits FemA, thereby suppressing pentaglycine interpeptide bridge synthesis. This protein is a key factor in the determination of β-lactam resistance in MRSA, and our findings provide a new strategy for combating MRSA.

The organ-specific chronic inflammation-carcinoma sequence was summarized and proposed. As a typical model, the ulcerative colitis (UC)-UC-associated carcinoma sequence was selected, and the mechanism of development of UC and UC-associated carcinoma was reviewed, referring mainly to our data. Intestinal commensal bacteria, including Fusobacterium varium, obtained from the colonic mucosa of UC patients, can enter colonic epithelia and induce secretion of inflammatory cytokines, resulting in early inflammatory lesions consisting of cryptitis and crypt abscess. Inflammatory oxidative stress causes epithelial cell DNA-damage followed by p53 dependent G1 checkpoint activation and overloading, which causes p53 mutation. In long-standing UC, mucosal remodeling, including possible loss of crosstalk between epithelium and stroma may be critical for the development of UC-associated carcinoma, as well as accumulation of early p53 mutation at the crypt level and increase of other stem cell mutated crypts, telomere shortening, and genomic instability of epithelial and stromal cells, including subepithelial myofibroblasts (corresponding to colonic stellate cells or Ito cells) and interstitial cells. Thus, the stochastic (probabilistic) pathway to tumor development over time gains commonalty through chronic inflammation stimulation. For the prevention of cancer development, appropriate anti-inflammatory therapy is important with an accurate assessment of the inflammation status in the colorectum. © 2012 The Author. Pathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.

Human fibrinogen is a metal ion-binding protein, but its mechanism of binding with iron and heme has not been elucidated in detail. In this study, human fibrinogen was immobilized on CNBr-activated Sepharose 4B beads. The fibrinogen beads bound hemin (iron-protoporphyrin IX: PPIX) as well as iron ion released from ferrous ammonium sulfate (FAS) more efficiently than Sepharose 4B beads alone. Hemin bound to fibrinogen still exhibited pseudo-peroxidase activity. The affinity of fibrinogen binding to hemin, Sn-PPIX, Zn-PPIX and metal-free PPIX followed the order Sn-PPIX < metal-free PPIX < hemin < Zn-PPIX; PPIX bound more non-specifically to control beads. FAS significantly enhanced the binding of hemin to fibrinogen beads. These results suggest that human fibrinogen directly recognizes iron ion, the PPIX ring and metal ions complexed with the PPIX ring, and that the binding of hemin is augmented by iron ions. © 2013 Springer Science+Business Media New York.

Fujii H.,Kitasato University
Topics in Current Chemistry | Year: 2011

Twin and triplet drugs are defined as compounds that contain respectively two and three pharmacophore components exerting pharmacological effects in a molecule. The twin drug bearing the same pharmacophores is a "symmetrical twin drug", whereas that possessing different pharmacophores is a "nonsymmetrical twin drug." In general, the symmetrical twin drug is expected to produce more potent and/or selective pharmacological effects, whereas the nonsymmetrical twin drug is anticipated to show both pharmacological activities stemming from the individual pharmacophores (dual action). On the other hand, nonsymmetrical triplet drugs, which have two of the same pharmacophores and one different moiety, are expected to elicit both increased pharmacological action and dual action. The two identical portions could bind the same receptor sites simultaneously while the third portion could bind a different receptor site or enzyme. This review will mainly focus on the twin and triplet drugs with an evaluation of their in vivo pharmacological effects, and will also include a description of their pharmacology and synthesis. © 2010 Springer-Verlag Berlin Heidelberg.

Kamiya K.,Kitasato University
Investigative ophthalmology & visual science | Year: 2012

We assessed the optical quality and intraocular scattering after posterior chamber phakic intraocular lens implantation. We examined prospectively 38 eyes of 19 consecutive patients undergoing implantable contact lens (ICL) implantation (mean age ± SD 36.3 ± 5.7 years), and 38 age-matched normal eyes of 19 healthy volunteers (mean age 36.4 ± 4.9 years). We assessed quantitatively the values of modulation transfer function (MTF) cutoff frequency, Strehl ratio, objective scattering index (OSI), and the Optical Quality Analysis System (OQAS) values (OVs). We compared these variables in eyes undergoing ICL implantation to those in healthy eyes. The mean MTF cutoff frequency, Strehl ratio, OSI, OV 100%, OV 20%, and OV 9% were 28.69 ± 8.59 cycles/degree, 0.17 ± 0.04, 1.06 ± 0.48, 0.96 ± 0.29, 0.83 ± 0.31, and 0.83 ± 0.32, respectively, 3 months after ICL implantation. We found no significant differences in the MTF cutoff frequency (Mann Whitney U test, P = 0.31), Strehl ratio (P = 0.46), OSI (P = 0.30), or OVs at contrasts of 100% (P = 0.51), 20% (P = 0.46), and 9% (P = 0.36), between the ICL and control groups. The optical quality parameters, such as the MTF cutoff frequency, Strehl ratio, OSI, or OVs in the ICL group, were not significantly different from those in the control group, suggesting that the optical quality and intraocular scattering of eyes undergoing ICL implantation essentially was equivalent to those of healthy eyes.

Matsuzawa R.,Kitasato University
Clinical journal of the American Society of Nephrology : CJASN | Year: 2012

The association between mortality and physical activity based on self-report questionnaire in hemodialysis patients has been reported previously. However, because self-report is a subjective assessment, evaluating true physical activity is difficult. This study investigated the prognostic significance of habitual physical activity on 7-year survival in a cohort of clinically stable and adequately dialyzed patients. A total of 202 Japanese outpatients who were undergoing maintenance hemodialysis three times per week at the hemodialysis center of Sagami Junkanki Clinic (Japan) from October 2002 to February 2012 were followed for up to 7 years. Physical activity was evaluated using an accelerometer at study entry and is expressed as the amount of time a patient engaged in physical activity on nondialysis days. Cox proportional hazard regression was used to assess the contribution of habitual physical activity to all-cause mortality. The median patient age was 64 (25th, 75th percentiles, 57, 72) years, 52.0% of the patients were women, and the median time on hemodialysis was 40.0 (25th, 75th percentiles, 16.8, 119.3) months at baseline. During a median follow-up of 45 months, 34 patients died. On multivariable analysis, the hazard ratio for all-cause mortality per 10 min/d increase in physical activity was 0.78 (95% confidence interval, 0.66-0.92; P=0.002). Engaging in habitual physical activity among outpatients undergoing maintenance hemodialysis was associated with decreased mortality risk.

Takahashi S.,Kitasato University
Anti-Cancer Agents in Medicinal Chemistry | Year: 2010

Arsenic trioxide (ATO) has shown great promise in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL). However, the risk/benefit ratios of ATO in hematologic malignancies other than APL are still unclear. In this review, the author attempts to provide current experimental and clinical challenges to gain more knowledge of the effects of ATO by examining combination therapies with other agents, especially for non-APL hematologic malignancies, such as acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphoid leukemia (CLL) and multiple myeloma (MM). The drugs combined with ATO can be roughly classified into (1) signaling inhibitors (imatinib, PD184352, LY294002, 17-Allylamino- 17-demethoxygeldanamycin: 17-AAG), (2) oxidative stress pathway modulators (ascorbic acid, 2-methoxyestradiol: 2-ME, dlbuthionine-[ S,R]-sulfoximine: BSO), (3) a chemotherapeutic drug (melphalan) and (4) others (bortezomib, ATRA). Some of these combination therapies have shown promising results in MM not only at the experimental level but also at the clinical level. However, studies are still ongoing for other non-APL hematologic malignancies. Since ATO is well tolerated and its toxicities are manageable and reversible, cell type-specific and efficient combination therapies with ATO are advantageous for non-APL hematological malignancies and should be developed in the near future. © 2010 Bentham Science Publishers Ltd.

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