Publications by authors named "Tomoyuki Kimura"

31 Publications

Isolation of new derivatives of the 20-membered macrodiolide bispolide from Kitasatospora sp. MG372-hF19.

J Antibiot (Tokyo) 2021 Dec 6. Epub 2021 Dec 6.

Institute of Microbial Chemistry (BIKAKEN), Laboratory of Microbiology, Microbial Chemistry Research Foundation, Tokyo, Japan.

New three macrocyclic diolides, named bispolides C-E (1-3), were isolated from a fermentation broth of the actinomycete strain MG372-hF19, which produces an indole glycoside and leptomycins as we reported previously. The absolute structures of compounds 1-3 were elucidated by NMR and X-ray crystallography. Compounds 1-3 diverge from the known nine bispolides in their different alkylation patterns on the 20-membered macrocyclic diolide skeleton and the side chain in their planar structures. Furthermore, compounds 1-3 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci and cytotoxic activity against human cancer cell lines. Among them, compound 3 has the most potent biological activities against bacteria and tumor cells. Additionally, using a membrane-potential-sensitive fluorescence probe, we found that compounds 1-3 and elaiophylin have a similar effect on membrane potential in A549 human lung cancer cells.
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http://dx.doi.org/10.1038/s41429-021-00492-5DOI Listing
December 2021

Mepolizumab improved airway hyperresponsiveness in a patient with allergic bronchopulmonary aspergillosis.

Asian Pac J Allergy Immunol 2021 11 7. Epub 2021 Nov 7.

Showa University School of Medicine, Department of Medicine, Division of Respiratory Medicine and Allergology, Tokyo, Japan.

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a severe type of asthma characterized by hypersensitivity to Aspergillus fumigatus and lung infiltration with eosinophilia. The central pathogenesis of asthma is airway hyperresponsiveness (AHR), with eosinophils playing a critical role. Anti-interleukin (IL)-5 antibody therapy has been recently introduced to treat severe asthma, which reportedly inactivates and reduces eosinophil count. A recent case series highlighted the improvement in asthmatic symptoms associated with ABPA, but previous reports failed to demonstrate any improvement in AHR.

Objective: Herein, we aimed to elucidate the efficacy of mepolizumab in a patient with ABPA who showed improvement in AHR.

Methods: Case report.

Results: A 63-year-old Asian woman with ABPA showed improvement in asthmatic symptoms and AHR following mepolizumab therapy.

Conclusions: Our results suggest that IL-5 may serve in the pathogenesis of ABPA.
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http://dx.doi.org/10.12932/AP-030521-1125DOI Listing
November 2021

Extracorporeal Membrane Oxygenation for Secondary Organizing Pneumonia after Severe SARS-CoV-2 Infection: A Case Report.

Medicina (Kaunas) 2021 Sep 25;57(10). Epub 2021 Sep 25.

Department of Medicine, Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Tokyo 142-0064, Japan.

(Background) COVID-19 is caused by SARS-CoV-2 infection and may result in unfavorable outcomes. A recent large-scale study showed that treatment with dexamethasone leads to favorable outcomes in patients with severe COVID-19, and the use of extracorporeal membrane oxygenation (ECMO) has also been shown to improve outcomes. Recently, secondary organizing pneumonia (SOP) has been reported after SARS-CoV-2 infection, but the diagnostic and treatment strategies are still unclear. (Case presentation) Here, we report a patient with severe COVID-19 who developed SOP even after the use of dexamethasone, for whom the introduction of ECMO on the 19th day after hospitalization led to a favorable outcome. (Conclusions) Life-threatening SOP may evolve even after the use of dexamethasone, and the late-phase introduction of ECMO may save such patients with COVID-19.
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http://dx.doi.org/10.3390/medicina57101013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541682PMC
September 2021

Downregulation of type III interferons in patients with severe COVID-19.

J Med Virol 2021 07 13;93(7):4559-4563. Epub 2021 Apr 13.

Division of Respiratory Medicine and Allergology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Coronavirus disease 2019 (COVID-19) is globally rampant, and to curb the growing burden of this disease, in-depth knowledge about its pathophysiology is needed. This was an observational study conducted at a single center to investigate serum cytokine and chemokine levels of COVID-19 patients, based on disease severity. We included 72 consecutive COVID-19 patients admitted to our hospital from March 21 to August 31, 2020. Patients were divided into Mild-Moderate I (mild) and Moderate II-Severe (severe) groups based on the COVID-19 severity classification developed by the Ministry of Health, Labor and Welfare (MHLW) of Japan. We compared the patient characteristics as well as the serum cytokine and chemokine levels on the day of admission between the two groups. Our findings indicated that the severe group had significantly higher levels of serum fibrinogen, d-dimer, lactate dehydrogenase, C-reactive protein, ferritin, Krebs von den Lungen-6, surfactant protein (SP)-D, and SP-A than the mild group. Strikingly, the levels of interleukin (IL)-28A/interferon (IFN)-λ2 were significantly lower in the severe group than in the mild group. We believe that reduced levels of type III interferons (IFN-λs) and alterations in the levels of other cytokines and chemokines may impact the severity of the disease.
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http://dx.doi.org/10.1002/jmv.26993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250710PMC
July 2021

Saccharobipyrimicin, a new antibiotic from the leaf-litter actinomycete Saccharothrix sp. MM696L-181F4.

J Antibiot (Tokyo) 2021 07 23;74(7):470-473. Epub 2021 Mar 23.

Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan.

In the course of screening for new antimicrobial compounds, a new antibiotic substance named saccharobipyrimicin was isolated from the leaf-litter actinomycete Saccharothrix sp. MM696L-181F4. The structure of saccharobipyrimicin was elucidated by various spectral methods, mainly single-crystal X-ray analysis and chemical degradation. It revealed that saccharobipyrimicin contained a 2,2'-bipyridine skeletal structure. Saccharobipyrimicin showed moderate and broad-spectrum antimicrobial activity. Two chemical derivatives of saccharobipyrimicin showed weaker antimicrobial activities than that of saccharobipyrimicin against most test microorganisms except two tolC mutants of Escherichia coli and Neisseria gonorrhoeae.
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http://dx.doi.org/10.1038/s41429-021-00418-1DOI Listing
July 2021

Utility of Basophil Activation Test in a Case of Daisaikoto- and Yokukansan-induced Lung Injury.

Intern Med 2021 May 22;60(10):1573-1576. Epub 2020 Dec 22.

Division of Respiratory Medicine and Allergology, Department of Medicine, Showa University School of Medicine, Japan.

Drug-induced lung injury is defined as a respiratory disorder. The usefulness of the basophil activation test (BAT) for drug allergy-related cases was recently reported. The patient was an 82-year-old woman who had been taking Daisaikoto and Yokukansan (herbal medicines) 3 months before developing dry cough. She was admitted to our hospital with an initial diagnosis of pneumonia with elevated serum LDH, KL-6, and IgE. Chest CT showed bilateral ground-glass opacities. Her bronchoalveolar lavage fluid showed increased eosinophils. Finally, a BAT was positive for both medications. Based on the findings, the patient was diagnosed with Daisaikoto- and Yokukansan-induced lung injury. The current case suggests that the BAT may be useful for the diagnosis of drug-induced lung injury.
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http://dx.doi.org/10.2169/internalmedicine.6296-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188028PMC
May 2021

[A CASE OF ANAPHYLAXIS DUE TO STINGING OF A Brachyponera chinensis].

Arerugi 2020 ;69(8):683-688

Department of Medicine, Division of Allergology and Respiratory medicine, School of Medicine, Showa University.

The case involved a man in his forties. While working at the restaurant that the patient runs, the patient experienced a stab-like pain on the left shoulder and developed systemic pruritic eruptions. He was diagnosed with anaphylaxis upon visiting our emergency department. Conjunctival hyperemia, lip swelling, cold sweats, and nausea presented later. A cap fluorescence enzyme immunoassay using the serum of the patient showed specific immunoglobulin E (IgE) positivity for wasps; therefore, we hypothesized that he had anaphylaxis caused by the insect's sting. Insects of the same species as that by which the patient had been stung were collected and finally identified as the Asian needle ant (Brachyponera chinensis). The freeze-dried insects' bodies were sonicated into powders and stored for following examinations. Next, a basophil activation test was performed using the patient's whole blood treated with the reagent above, which showed positivity. Furthermore, a skin prick test using the same reagent showed a positive result, and the reaction increased in a concentrationdependent manner. Based on these results, the patient was diagnosed with anaphylaxis after a sting by the ant. Based on the results of the allergen component specific IgE test, we speculated that the pathogens in this case was group5 allergen of the Asian needle ant. Anaphylaxis following insect stings by this ant has been reported frequently in South Korea. However, it is quite rare in Japan, although the ant is native to Japan. Clinicians should consider that this allergy can occur indoors, unlike allergies to other types of venom.
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http://dx.doi.org/10.15036/arerugi.69.683DOI Listing
November 2020

Correlation of Arterial CO and Respiratory Impedance Values among Subjects with COPD.

J Clin Med 2020 Aug 31;9(9). Epub 2020 Aug 31.

Department of Medicine, Division of Respiratory Medicine and Allergology, 1-5-8 Hatanodai, Shinagawa-ku, Showa University School of Medicine, Tokyo 142-0064, Japan.

Chronic obstructive pulmonary disease (COPD) is a respiratory illness characterized by airflow limitation and chronic respiratory symptoms with a global prevalence estimated to be more than 10% in 2010 and still on the rise. Furthermore, hypercapnic subject COPD leads to an increased risk of mortality, morbidity, and poor QoL (quality of life) than normocapnic subjects. Series of studies showed the usefulness of the forced oscillation technique (FOT) to measure small airway closure. Traditional findings suggested that hypercapnia may not be the main treating targets, but recent findings suggested that blood stream CO may lead to a worse outcome. This study aimed to seek the relationship between CO and small airway closure by using FOT. Subjects with COPD ( = 124; hypercapnia 22 and normocapnia 102) were analyzed for all pulmonary function values, FOT values, and arterial blood gas analysis. Student's -test, Spearman rank correlation, and multi linear regression analysis were used to analyze the data. COPD subjects with hypercapnia showed a significant increase in R5, R20, Fres, and ALX values, and a greater decrease in X5 value than normocapnic patients. Also, multiple linear regression analysis showed R5 was associated with hypercapnia. Hypercapnia may account for airway closure among subjects with COPD and this result suggests treating hypercapnia may lead to better outcomes for such a subject group.
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http://dx.doi.org/10.3390/jcm9092819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564107PMC
August 2020

Combination treatment of short-course systemic corticosteroid and favipiravir in a successfully treated case of critically ill COVID-19 pneumonia with COPD.

Respir Med Case Rep 2020 27;31:101200. Epub 2020 Aug 27.

Division of Respiratory Medicine and Allergology, Department of Medicine, Showa University School of Medicine, Japan.

Use of systemic corticosteroids for the treatment for coronavirus disease 2019 (COVID-19) among chronic obstructive pulmonary disease (COPD) patients is not well described. A 58-year-old man with fever and progressive dyspnea was admitted to the Showa University Hospital, and showed severe respiratory failure which needed mechanical ventilation. His chest computed tomography scanning showed emphysema and bilateral ground-glass opacity caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. He received 30 mg prednisolone for five days with antiviral drug of favipiravir, and was successfully extubated on day five. A SARS-CoV-2 polymerase chain reaction (PCR) test became negative on day 15. He was discharged on day 21. Serum IgM and IgG antibodies against SARS-CoV-2 converted to positive on day 7 and they kept positive on day 54 for both IgM and IgG. Combination treatment of short-course systemic corticosteroid and favipiravir might improve the prognosis for critically ill COVID-19 pneumonia with COPD without negative influence on viral clearance or antibody production.
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http://dx.doi.org/10.1016/j.rmcr.2020.101200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450252PMC
August 2020

The Effect of Bronchoconstriction by Methacholine Inhalation in a Murine Model of Asthma.

Int Arch Allergy Immunol 2020 13;181(12):897-907. Epub 2020 Aug 13.

Department of Internal Medicine, Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Tokyo, Japan.

Introduction: Bronchoconstriction was recently shown to cause airway remodeling and induce allergic airway inflammation in asthma. However, the mechanisms how mechanical stress via bronchoconstriction could induce airway inflammation and remodeling remain unclear.

Objective: We investigated the effect of bronchoconstriction induced by methacholine inhalation in a murine model of asthma.

Methods: BALB/c female mice were sensitized and challenged with ovalbumin (OVA), followed by treatment with methacholine by a nebulizer twice a day for 7 days. Twenty-four hours after the last methacholine treatment, the bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The BALF was analyzed for total and differential cell counts and cytokine levels. The lung tissues were analyzed for goblet cell metaplasia, thickness of the smooth muscle, and lung fibrosis. The expression of cytokines in the lung was also examined.

Results: OVA sensitization and challenge induced infiltration of total cells, macrophages, and eosinophils in the BALF along with goblet cell metaplasia and increased airway smooth muscle hypertrophy. Seven days after the last OVA challenge, untreated mice achieved reduction in airway inflammation, while methacholine maintained the number of BALF total cells, macrophages, and eosinophils. The percentage of goblet cells and the thickness of airway smooth muscle were also maintained by methacholine. Moreover, the treatment of methacholine induced the expression of transforming growth factor (TGF)-β in the lung. This result indicates that the production of TGF-β is involved in induction of airway remodeling caused by bronchoconstriction with methacholine.

Conclusions: Repeated bronchoconstriction caused by methacholine inhalation elicited allergic airway inflammation and airway remodeling.
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http://dx.doi.org/10.1159/000509606DOI Listing
January 2021

Metacytofilin Is a Potent Therapeutic Drug Candidate for Toxoplasmosis.

J Infect Dis 2020 02;221(5):766-774

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido, Japan.

Background: Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-Toxoplasma compound.

Methods: Anti-Toxoplasma activities of MCF and its derivatives were evaluated in vitro and in vivo using nonpregnant and pregnant mice. To understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq.

Results: In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii-infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites.

Conclusions: With its potent anti-T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.
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http://dx.doi.org/10.1093/infdis/jiz501DOI Listing
February 2020

Synthesis and biological activity of analogs of CPZEN-45, a novel antituberculosis drug.

J Antibiot (Tokyo) 2019 12 30;72(12):970-980. Epub 2019 Aug 30.

Institute of Microbial Chemistry (BIKAKEN), 3-14-23, Kamiosaki, Shinagawa-ku, Tokyo, Japan.

Analogs of CPZEN-45, which is expected to be a promising new antituberculosis drug that overcomes the shortcomings of caprazamycins, were synthesized and their biological activities were evaluated. The biological activity of analogs 1-3, which converted the anilide portion, and analogs 4 and 5, focusing on the seven-membered ring, were lower than that of CPZEN-45. These results suggest that the inhibitory activity of CPZEN-45 against TagO, an ortholog of WecA, has a strict structural limitation, and it was hoped for elucidation of the mode of action of CPZEN-45 using structural biology in the future.
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http://dx.doi.org/10.1038/s41429-019-0225-5DOI Listing
December 2019

Beneficial Effect of Early Intervention with Garenoxacin for Bacterial Infection-Induced Acute Exacerbation of Bronchial Asthma and Chronic Obstructive Pulmonary Disease.

Int Arch Allergy Immunol 2019;178(4):355-362. Epub 2019 Feb 13.

Division of Allergology and Respiratory Medicine, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.

Background: Chronic obstructive pulmonary disease (COPD) and asthma have similar clinical features and are both exacerbated by airway infection.

Objective: To determine whether garenoxacin mesylate hydrate (GRNX) added to the standard care for bacterial infection-induced acute exacerbation of asthma or COPD in adults has clinical benefits.

Method: This single-arm clinical trial was conducted from January 2015 to March 2016. Adults with a history of asthma or COPD for more than 12 months were recruited within 48 h of presentation with fever and acute deterioration of asthma or COPD requiring additional intervention. Participants were administered 400 mg GRNX daily for 7 days without additional systemic corticosteroids or other antibiotics. The primary outcome was efficacy of GRNX based on clinical symptoms and blood test results after 7 days of treatment. Secondary outcomes were: (1) comparison of the blood test results, radiograph findings, and bacterial culture surveillance before and after treatment; (2) effectiveness of GRNX after 3 days of administration; (3) analyzation of patient symptoms based on patient diary; and (4) continued effectiveness of GRNX on 14th day after the treatment (visit 3).

Results: The study included 44 febrile patients (34 asthma and 10 COPD). Frequently isolated bacteria included Moraxella catarrhalis (n = 6) and Klebsiella pneumoniae (n = 4). On visit 2, 40 patients responded, and no severe adverse events were observed. All secondary outcomes showed favorable results.

Conclusion: GRNX effectively treated asthma and COPD patients with acute bacterial infection without severe adverse events. Further research with a larger study population is needed.
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http://dx.doi.org/10.1159/000495761DOI Listing
May 2019

Flupyranochromene, a novel inhibitor of influenza virus cap-dependent endonuclease, from Penicillium sp. f28743.

J Antibiot (Tokyo) 2019 03 9;72(3):125-133. Epub 2019 Jan 9.

Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan.

Influenza virus RNA polymerase has cap-dependent endonuclease activity that produces capped RNA fragments for priming viral mRNA synthesis. This enzymatic activity is essential for viral propagation, but it is not present in any host cellular enzyme, making it an attractive target for the development of anti-influenza drugs. Here, we isolated a novel inhibitor of cap-dependent endonuclease, named flupyranochromene, from the fermentation broth of the fungus Penicillium sp. f28743. Structural analysis revealed that this compound bears a putative pharmacophore that chelates divalent metal ion(s) present in the endonuclease active site in the PA subunit of the polymerase. Consistently, in vitro endonuclease assays showed that flupyranochromene exerts its inhibitory effects by blocking endonucleolytic cleavage by the PA subunit of viral RNA polymerase complex.
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http://dx.doi.org/10.1038/s41429-018-0134-zDOI Listing
March 2019

Anti-influenza virus activity of a salcomine derivative mediated by inhibition of viral RNA synthesis.

Arch Virol 2018 Jun 1;163(6):1607-1614. Epub 2018 Mar 1.

Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan.

Influenza virus infection is a major threat to global health. Although vaccines and anti-influenza virus drugs are available, annual influenza virus epidemics result in severe illness, and an influenza pandemic occurs every 20-30 years. To identify candidate anti-influenza virus compounds, we screened approximately 5,000 compounds in an in-house library. We identified MZ7465, a salcomine derivative, as a potent inhibitor of influenza virus propagation. We analyzed the antiviral propagation mechanism of the hit compound by determining the amounts of viral proteins and RNA in infected cells treated with or without the hit compound. Treatment of infected cells with MZ7465 decreased both viral protein and RNA synthesis. In addition, an in vitro assay showed that viral RNA synthesis was directly inhibited by MZ7465. These results suggest that salcomine and its derivatives are potential candidates for the treatment of influenza virus infections.
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http://dx.doi.org/10.1007/s00705-018-3779-9DOI Listing
June 2018

Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by Amycolatopsis sp. ML1-hF4.

J Antibiot (Tokyo) 2017 Nov 15. Epub 2017 Nov 15.

Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan.

In the course of optimizing pargamicin A production in Amycolatopsis sp. ML1-hF4, we discovered novel cyclic depsipeptide compounds in the broth and designated them valgamicins A, C, T and V. The structures of these molecules were determined by spectroscopic studies, advanced Marfey's method and X-ray crystal structural analysis. Valgamicin C contains the extremely rare amino acid cleonine. To our knowledge, this is the first report of a cleonine-containing metabolite from a naturally isolated microorganism without any breeding or mutation treatment. None of the valgamicins showed potent antibacterial activity against either Gram-positive or -negative bacteria. Valgamicins A, C and T exhibited moderate cytotoxicity against human tumor cell lines.The Journal of Antibiotics advance online publication, 15 November 2017; doi:10.1038/ja.2017.135.
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http://dx.doi.org/10.1038/ja.2017.135DOI Listing
November 2017

Leptolyngbyolides, Cytotoxic Macrolides from the Marine Cyanobacterium Leptolyngbya sp.: Isolation, Biological Activity, and Catalytic Asymmetric Total Synthesis.

Chemistry 2017 Jun 31;23(35):8500-8509. Epub 2017 May 31.

Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo, 141-0021, Japan.

Four new macrolactones, leptolyngbyolides A-D, were isolated from the cyanobacterium Leptolyngbya sp. collected in Okinawa, Japan. The planar structures of leptolyngbyolides were determined by extensive NMR studies, although complete assignment of the absolute configuration awaited the catalytic asymmetric total synthesis of leptolyngbyolide C. The synthesis took advantage of the catalytic asymmetric thioamide-aldol reaction using copper(I) complexed with a chiral bidentate phosphine ligand to regulate two key stereochemistries of the molecule at the outset. The present total synthesis demonstrates the utility of this reaction for the construction of complex chemical entities. In addition to the total synthesis, this work reports that leptolyngbyolides depolymerize filamentous actin (F-actin) both in vitro and in cells. Detailed biological studies suggest the probable order of F-actin depolymerization and apoptosis caused by leptolyngbyolides.
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http://dx.doi.org/10.1002/chem.201701183DOI Listing
June 2017

New anti-cancer chemicals Ertredin and its derivatives, regulate oxidative phosphorylation and glycolysis and suppress sphere formation in vitro and tumor growth in EGFRvIII-transformed cells.

BMC Cancer 2016 07 19;16:496. Epub 2016 Jul 19.

Institute of Physiology and Medicine, Jobu University, Takasaki-shi, Gunma, Japan.

Background: EGFRvIII is a mutant form of the epidermal growth factor receptor gene (EGFR) that lacks exons 2-7. The resulting protein does not bind to ligands and is constitutively activated. The expression of EGFRvIII is likely confined to various types of cancer, particularly glioblastomas. Although an anti-EGFRvIII vaccine is of great interest, low-molecular-weight substances are needed to obtain better therapeutic efficacy. Thus, the purpose of this study is to identify low molecular weight substances that can suppress EGFRvIII-dependent transformation.

Methods: We constructed a new throughput screening system and searched for substances that decreased cell survival of NIH3T3/EGFRvIII spheres under 3-dimensional (3D)-culture conditions, but retained normal NIH3T3 cell growth under 2D-culture conditions. In vivo activity was examined using a mouse transplantation model, and derivatives were chemically synthesized. Functional characterization of the candidate molecules was investigated using an EGFR kinase assay, immunoprecipitation, western blotting, microarray analysis, quantitative polymerase chain reaction analysis, and measurement of lactate and ATP synthesis.

Results: In the course of screening 30,000 substances, a reagent, "Ertredin" was found to inhibit anchorage-independent 3D growth of sphere-forming cells transfected with EGFRvIII cDNA. Ertredin also inhibited sphere formation in cells expressing wild-type EGFR in the presence of EGF. However, it did not affect anchorage-dependent 2D growth of parental NIH3T3 cells. The 3D-growth-inhibitory activity of some derivatives, including those with new structures, was similar to Ertredin. Furthermore, we demonstrated that Ertredin suppressed tumor growth in an allograft transplantation mouse model injected with EGFRvIII- or wild-type EGFR-expressing cells; a clear toxicity to host animals was not observed. Functional characterization of Ertredin in cells expressing EGFRvIII indicated that it stimulated EGFRvIII ubiquitination, suppressed both oxidative phosphorylation and glycolysis under 3D conditions, and promoted cell apoptosis.

Conclusion: We developed a high throughput screening method based on anchorage-independent sphere formation induced by EGFRvIII-dependent transformation. In the course of screening, we identified Ertredin, which inhibited anchorage-independent 3D growth and tumor formation in nude mice. Functional analysis suggests that Ertredin suppresses both mitochondrial oxidative phosphorylation and cytosolic glycolysis in addition to promoting EGFRvIII degradation, and stimulates apoptosis in sphere-forming, EGFRvIII-overexpressing cells.
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http://dx.doi.org/10.1186/s12885-016-2521-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949881PMC
July 2016

Influence of Omalizumab on Allergen-Specific IgE in Patients with Adult Asthma.

Int Arch Allergy Immunol 2015 21;168(3):165-72. Epub 2016 Jan 21.

Division of Respiratory Medicine and Allergology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Background: Omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody, inhibits the binding of circulating IgE to mast cells and basophils, resulting in fewer episodes of airway inflammation, asthma symptoms and exacerbations in patients with severe allergic asthma. Treatment of patients with asthma using omalizumab increases serum total IgE (tIgE) levels. However, little is known about the influence of omalizumab on allergen-specific IgE (sIgE).

Methods: tIgE and sIgE in 47 adult patients with severe asthma were measured with a fluorescent enzyme immunoassay (ImmunoCAP-FEIA) before and after omalizumab treatment.

Results: Treatment with omalizumab increased tIgE and sIgE levels. The increases in sIgE by class category after omalizumab treatment were positively correlated with baseline sIgE positivity before treatment. The mean changes in sIgE levels after omalizumab treatment were also correlated with baseline sIgE levels before treatment. The mean changes in tIgE levels were positively correlated with the mean changes in IgE levels against Dermatophagoides pteronyssinus, crude house dust, Japanese cedar and moth. Omalizumab markedly influenced the negative-to-positive seroconversion rate for IgE against Japanese cedar (30.8%), Candida (29.0%) and moth (28.0%). Finally, all patients with negative-to-positive seroconversion for Japanese cedar-specific IgE had cedar pollinosis before beginning omalizumab treatment.

Conclusions: The changes in sIgE levels after omalizumab treatment may be dependent on the baseline sIgE levels. Our data may indicate the presence of undetectable but functional sIgE.
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http://dx.doi.org/10.1159/000442668DOI Listing
June 2016

Association between specific IgE to Staphylococcus aureus enterotoxins A and B and asthma control.

Ann Allergy Asthma Immunol 2015 Sep 21;115(3):191-197.e2. Epub 2015 Jul 21.

Division of Respiratory Medicine and Allergology, Department of Medicine, Showa University, Tokyo, Japan.

Background: Recent studies have found that serum levels of Staphylococcus aureus enterotoxin (SE)-IgE are higher in patients with severe asthma compared with patients with nonsevere asthma. However, the association between SE-IgE and asthma control is not fully understood. Furthermore, SEA and SEB were the first reported SEs and subdivided into different groups. The influences of SEA-IgE and SEB-IgE on asthma control have not been elucidated.

Objective: To determine the relevance of SEA- and SEB-IgE in patients with adult asthma and to investigate the association of SEA-IgE, SEB-IgE, and asthma control, respectively.

Methods: The serum concentrations of SEA- and SEB-IgE in 172 adults with asthma were measured with a fluorescent enzyme immunoassay.

Results: The prevalence of SEA- and SEB-IgE was 16.2% and 22.1%, respectively. Total IgE levels and the prevalence of atopic dermatitis were higher in SEA-IgE- and SEB-IgE-positive patients than in SEA-IgE- and SEB-IgE-negative patients, respectively; more SEA-IgE- and SEB-IgE-positive patients owned pets. Sensitization to SEA was associated with a younger mean age and a younger mean age at asthma onset. Multiple regression analysis indicated an association between total IgE levels and SEB-IgE. The prevalence of poorly uncontrolled asthma was significantly higher in SEA-IgE-positive patients than in SEA-IgE-negative patients. In addition, fractional exhaled nitric oxide levels were higher in SEA-IgE-positive patients than in SEA-IgE-negative patients. Logistic regression analysis also identified an association between SEA-IgE and poor asthma control.

Conclusion: Our findings indicate that sensitization to SE, in particular SEA rather than SEB, is associated with poor asthma control in adults with asthma.
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http://dx.doi.org/10.1016/j.anai.2015.06.017DOI Listing
September 2015

An unusual terpene cyclization mechanism involving a carbon-carbon bond rearrangement.

Angew Chem Int Ed Engl 2015 Mar 16;54(14):4353-6. Epub 2015 Feb 16.

Biotechnology Research Center, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657 (Japan).

Terpene cyclization reactions are fascinating owing to the precise control of connectivity and stereochemistry during the catalytic process. Cyclooctat-9-en-7-ol synthase (CotB2) synthesizes an unusual 5-8-5 fused-ring structure with six chiral centers from the universal diterpene precursor, the achiral C20 geranylgeranyl diphosphate substrate. An unusual new mechanism for the exquisite CotB2-catalyzed cyclization that involves a carbon-carbon backbone rearrangement and three long-range hydride shifts is proposed, based on a powerful combination of in vivo studies using uniformly (13)C-labeled glucose and in vitro reactions of regiospecifically deuterium-substituted geranylgeranyl diphosphate substrates. This study shows that CotB2 elegantly demonstrates the synthetic virtuosity and stereochemical control that evolution has conferred on terpene synthases.
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http://dx.doi.org/10.1002/anie.201411923DOI Listing
March 2015

Identification of octenal-related dA and dC adducts formed by reactions with a hemin-ω-6-fat peroxidation model system.

Chem Res Toxicol 2013 Oct 1;26(10):1554-60. Epub 2013 Oct 1.

Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health , 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.

Deoxynucleosides were reacted in a lipid peroxidation model system, emulsified hemin-ethyl linoleate, and the adducts thus produced were analyzed by HPLC. Substantial amounts of stable adducts were detected in the dA- and dC-reaction mixtures. The structures of the major dA and dC adducts, other than the known 4-oxo-2-nonenal adducts, were determined to be etheno-type adducts, with a C₆ side chain bearing an α-hydroxyl-group. These results suggested that the substance involved in adduct formation is 2,3-epoxyoctanal. This compound showed mutagenicity in Salmonella strains TA 100 and TA 104 without the S-9 mix. In addition, based on the structure of a minor dC adduct, another possibly involved mutagen, 4-oxo-2-octenal, was proposed. These mutagens may be formed during storage and cooking of food, or during digestion, and may be involved in human cancers.
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http://dx.doi.org/10.1021/tx400245aDOI Listing
October 2013

Waldiomycin, a novel WalK-histidine kinase inhibitor from Streptomyces sp. MK844-mF10.

J Antibiot (Tokyo) 2013 Aug 1;66(8):459-64. Epub 2013 May 1.

Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan.

WalK, a histidine kinase, and WalR, a response regulator, make up a two-component signal transduction system that is indispensable for the cell-wall metabolism of low GC Gram-positive bacteria. WalK inhibitors are likely to show bactericidal effects against methicillin-resistant Staphylococcus aureus . We discovered a new WalK inhibitor, designated waldiomycin, by screening metabolites from actinomycetes. Waldiomycin belongs to the family of angucycline antibiotics and is structurally related to dioxamycin. Waldiomycin inhibits WalK from S. aureus and Bacillus subtilis at IC50s 8.8 and 10.2 μM, respectively, and shows antibacterial activity with MICs ranging from 4 to 8 μg ml(-1) against methicillin-resistant S. aureus and B. subtilis.
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http://dx.doi.org/10.1038/ja.2013.33DOI Listing
August 2013

Synthesis and assignment of the absolute configuration of indenotryptoline bisindole alkaloid BE-54017.

Org Lett 2012 Sep 23;14(17):4418-21. Epub 2012 Aug 23.

Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Tokyo 141-0021, Japan.

Synthesis of the indenotryptoline bisindole alkaloid, BE-54017, was accomplished using osmium-promoted cis-dihydroxylation of maleimide as a key step. After optical resolution, the absolute configuration of this molecule was determined by comparing its optical rotation and HPLC profile to those obtained for BE-54017 derived from enantiopure cladoniamide A, whose stereochemistry has been reported previously. BE-54017 with the correct absolute stereochemistry induced apoptosis of epidermal growth factor (EGF)-stimulated EGF receptor overexpressing A431 cells and inhibited vacuolar-type H(+)-ATPase (V-ATPase).
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http://dx.doi.org/10.1021/ol3019314DOI Listing
September 2012

Isolation and characterization of signermycin B, an antibiotic that targets the dimerization domain of histidine kinase WalK.

Antimicrob Agents Chemother 2012 Jul 23;56(7):3657-63. Epub 2012 Apr 23.

Department of Bioscience, Graduate School of Agriculture, Kinki University, Nara, Japan.

The WalK (histidine kinase)/WalR (response regulator) two-component signal transduction system is a master regulatory system for cell wall metabolism and growth. This system is conserved in low G+C Gram-positive bacteria, including Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis, and Streptococcus mutans. In this study, we found the first antibiotic that functions as a WalK inhibitor (signermycin B) by screening 10,000 Streptomyces extracts. The chemical structure (C(23)H(35)NO(4); molecular weight, 389.5) comprises a tetramic acid moiety and a decalin ring. Signermycin B exhibited antimicrobial activity, with MIC values ranging from 3.13 μg/ml (8 μM) to 6.25 μg/ml (16 μM) against Gram-positive bacteria that possess the WalK/WalR two-component signal transduction system, including the drug-resistant bacteria methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. The half-maximal inhibitory concentrations of signermycin B against WalK in these organisms ranged from 37 to 61 μM. To determine the mechanism of action of signermycin B, surface plasmon resonance response analysis with the two WalK domains of Bacillus subtilis and competition assay with ATP were performed. The results showed that signermycin B binds to the dimerization domain but not the ATP-binding domain of WalK. In the presence of the cross-linker glutaraldehyde, signermycin B did not cause protein aggregation but interfered with the cross-linking of WalK dimers. These results suggest that signermycin B targets the conserved dimerization domain of WalK to inhibit autophosphorylation. In Bacillus subtilis and Staphylococcus aureus, signermycin B preferentially controlled the WalR regulon, thereby inhibiting cell division. These phenotypes are consistent with those of cells starved for the WalK/WalR system.
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http://dx.doi.org/10.1128/AAC.06467-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393415PMC
July 2012

DNA modifications by the omega-3 lipid peroxidation-derived mutagen 4-oxo-2-hexenal in vitro and their analysis in mouse and human DNA.

Chem Res Toxicol 2010 Mar;23(3):630-6

Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.

4-Oxo-2-hexenal (4-OHE), which forms a 2'-deoxyguanosine (dG) adduct in a model lipid peroxidation system, is mutagenic in the Ames test. It is generated by the oxidation of omega-3 fatty acids and is commonly found in dietary fats, such as fish oil, perilla oil, rapeseed oil, and soybean oil. 4-OHE also forms adducts with 2'-deoxyadenosine (dA), 2'-deoxycytidine (dC), and 5-methyl-2'-deoxycytidine (5-Me-dC) in DNA. In this study, we characterized the structures of these adducts in detail. We measured the amounts of 4-OHE-DNA adducts in mouse organs by LC/MS/MS, after 4-OHE was orally administered to mice. The 4-OHE-dA, 4-OHE-dC, 4-OHE-dG, and 4-OHE-5-Me-dC adducts were detected in stomach and intestinal DNA in the range of 0.25-43.71/10(8) bases. After the 4-OHE administration, the amounts of these DNA adducts decreased gradually over 7 days. We also detected 4-OHE-dC in human lung DNA, in the range of 2.6-5.9/10(9) bases. No difference in the 4-OHE adduct levels was detected between smokers and nonsmokers. Our results suggest that 4-OHE-DNA adducts are formed by endogenous as well as environmental lipid peroxides.
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http://dx.doi.org/10.1021/tx9003819DOI Listing
March 2010

Endocyclic extension of porphyrin pi-system by interior functionalization of N-confused porphyrins.

Chemistry 2008 ;14(34):10585-94

Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, 744 Moto-oka, Nishi-ku, Fukuoka 819-0395, Japan.

Internally alkynylated or cyanated N-confused porphyrins have been prepared, and these have been characterized by NMR, UV/Vis/NIR absorption, and X-ray analysis. The desired porphyrins have been synthesized by interconversion between an N-confused porphyrin and an N-fused porphyrin. In the case of terminal alkyne derivatives, intramolecular addition of a pyrrolic NH moiety to the triple bond occurred at ambient temperature to give etheno-bridged N-confused porphyrins. Significant bathochromic shifts in the absorbances of these compounds may be reasonably explained in terms of an increase in their HOMO energy levels due to effective overlap of the porphyrin pi-orbital and the bridged alkene pi-orbital. The corresponding rhodium(I) complexes have also been prepared, and these have been characterized by NMR and X-ray analysis.
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http://dx.doi.org/10.1002/chem.200801156DOI Listing
December 2008

Doubly N-fused porphyrin.

Angew Chem Int Ed Engl 2008 ;47(46):8913-6

Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, Fukuoka 819-0395, Japan.

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http://dx.doi.org/10.1002/anie.200803670DOI Listing
December 2008

Endocyclic extension of porphyrin pi-system in etheno-bridged N-confused tetraphenylporphyrin.

Chem Commun (Camb) 2008 Jan(1):102-4

Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.

Etheno-bridged N-confused tetraphenylporphyrin was synthesized through flipping of the confused pyrrole ring and endocyclic extension of [18]annulenic pi-conjugated system was exemplified by the absorption spectra as well as the calculated Kohn-Sham orbitals.
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http://dx.doi.org/10.1039/b713845hDOI Listing
January 2008

Ferritization treatment of copper in soil by electrokinetic remediation.

J Hazard Mater 2007 May 9;143(3):662-7. Epub 2007 Jan 9.

Division of Material Science, Hokkaido University, N10 W5, Kita-Ku, Sapporo 060-0810, Japan.

The usefulness of the combined use of the electrokinetic (EK) remediation and a ferrite treatment zone (FTZ) was demonstrated for a treatment of the contaminated soil with heavy metal ions. Copper ions in contaminated soil were transferred into the FTZ by the EK technology and were ferritized in this system. The distribution of copper in a migration chamber after EK treatment with FTZ for 48h showed the large difference in the total and eluted concentration of copper. This indicated that copper ions transferred by EK into the FTZ were ferritized there with ferrite reagent in soil alkalified by EK process. The copper-ferrite compound, which was not dissolved with diluted acid, was retained in the FTZ and accumulated there. The ratio of the ferritized amount of copper against total copper was 92% in the EK process with FTZ after 48 h.
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http://dx.doi.org/10.1016/j.jhazmat.2007.01.010DOI Listing
May 2007
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