Publications by authors named "Tamaki Kato"

37 Publications

Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia.

Clin Immunol 2021 Aug 9;229:108776. Epub 2021 Jun 9.

Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4 T-cells, CD8 T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor β-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.
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http://dx.doi.org/10.1016/j.clim.2021.108776DOI Listing
August 2021

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India.

Front Immunol 2020 8;11:619146. Epub 2021 Feb 8.

Institute of Child Health, Madras Medical College, Chennai, India.

Background: Severe Combined Immune Deficiency (SCID) is an inherited defect in lymphocyte development and function that results in life-threatening opportunistic infections in early infancy. Data on SCID from developing countries are scarce.

Objective: To describe clinical and laboratory features of SCID diagnosed at immunology centers across India.

Methods: A detailed case proforma in an Excel format was prepared by one of the authors (PV) and was sent to centers in India that care for patients with primary immunodeficiency diseases. We collated clinical, laboratory, and molecular details of patients with clinical profile suggestive of SCID and their outcomes. Twelve (12) centers provided necessary details which were then compiled and analyzed. Diagnosis of SCID/combined immune deficiency (CID) was based on 2018 European Society for Immunodeficiencies working definition for SCID.

Results: We obtained data on 277 children; 254 were categorized as SCID and 23 as CID. Male-female ratio was 196:81. Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively. Molecular diagnosis was obtained in 162 patients - (36), (26), (19), (17), (15), (13), (9), (3), (3), (2), (2), (2), (2), (2), (2), (2), (1), (1), (1), (1), (1), (1), and (1). Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%).

Conclusion: We document an exponential rise in number of cases diagnosed to have SCID over the last 10 years, probably as a result of increasing awareness and improvement in diagnostic facilities at various centers in India. We suspect that these numbers are just the tip of the iceberg. Majority of patients with SCID in India are probably not being recognized and diagnosed at present. Newborn screening for SCID is the need of the hour. Easy access to pediatric HSCT services would ensure that these patients are offered HSCT at an early age.
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http://dx.doi.org/10.3389/fimmu.2020.619146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897653PMC
June 2021

Axonal damage and behavioral deficits in rats with repetitive exposure of the brain to laser-induced shock waves: Effects of inter-exposure time.

Neurosci Lett 2021 04 13;749:135722. Epub 2021 Feb 13.

Division of Biomedical Information Sciences, National Defense Medical College Research Institute, Tokorozawa, Saitama, Japan. Electronic address:

Much attention has been given to effects of repeated exposure to a shock wave as a possible factor causing severe higher brain dysfunction and post-traumatic stress disorder (PTSD)-like symptoms in patients with mild to moderate blast-induced traumatic brain injury (bTBI). However, it is unclear how the repeated exposure and the inter-exposure time affect the brain. In this study, we topically applied low-impulse (∼54 Pa·s) laser-induced shock waves (LISWs; peak pressure, ∼75.7 MPa) to the rat brain once or twice with the different inter-exposure times (15 min, 1 h, 3 h, 24 h and 7 days) and examined anxiety-related behavior and motor dysfunction in the rats as well as expression of β-amyloid precursor protein (APP) as an axonal damage marker in the brains of the rats. The averaged APP expression scores for the rat brains doubly-exposed to LISWs with inter-exposure times from 15 min to 24 h were significantly higher than those for rats with a single exposure (P < 0.0001). The rats with double exposure to LISWs showed significantly more frequent anxiety-related behavior (P < 0.05) and poorer motor function (P < 0.01) than those of rats with a single exposure. When the inter-exposure time was extended to 7 days, however, the rats showed no significant differences either in axonal damage score or level of motor dysfunction. The results suggest that the cumulative effects of shock wave-related brain injury can be avoided with an appropriate inter-exposure time. However, clinical bTBI occurs in much more complex environments than those in our model. Further study considering other factors, such as the effects of acceleration, is needed to know the clinically-relevant, necessary inter-exposure time.
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http://dx.doi.org/10.1016/j.neulet.2021.135722DOI Listing
April 2021

DNA Ligase IV Deficiency Identified by Chance Following Vaccine-Derived Rubella Virus Infection.

J Clin Immunol 2020 11 10;40(8):1187-1190. Epub 2020 Sep 10.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

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http://dx.doi.org/10.1007/s10875-020-00831-5DOI Listing
November 2020

A synonymous splice site mutation in IL2RG gene causes late-onset combined immunodeficiency.

Int J Hematol 2019 May 8;109(5):603-611. Epub 2019 Mar 8.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

X-Linked severe combined immunodeficiency (X-SCID) is a severe form of primary immunodeficiency characterized by absence of T cells and NK cells. X-SCID is caused by a loss-of-function mutation in the IL2RG gene that encodes common gamma chain (γc), which plays an essential role in lymphocyte development. We report the first case of hypomorphic X-SCID caused by a synonymous mutation in the IL2RG gene leading to a splice anomaly, in a family including two patients with diffuse cutaneous warts, recurrent molluscum contagiosum, and mild respiratory infections. The mutation caused aberrant splicing of IL2RG mRNA, subsequently resulted in reduced γc expression. The leaky production of normally spliced IL2RG mRNA produced undamaged protein; thus, T cells and NK cells were generated in the patients. Functional assays of the patients' T cells and NK cells revealed diminished cytokine response in the T cells and absent cytokine response in the NK cells. In addition, the TCR repertoire in these patients was limited. These data suggest that a fine balance between aberrant splicing and leaky production of normally spliced IL2RG mRNA resulted in late-onset combined immunodeficiency in these patients.
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http://dx.doi.org/10.1007/s12185-019-02619-9DOI Listing
May 2019

Clinical and Immunological Characterization of ICF Syndrome in Japan.

J Clin Immunol 2018 11 23;38(8):927-937. Epub 2018 Oct 23.

Department of Pediatrics, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-0042, Japan.

Objective: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive primary immunodeficiency. Hypogammaglobulinemia is a major manifestation of ICF syndrome, but immunoglobulin replacement therapy does not seem to be effective for some ICF patients. Therefore, we aimed to reassess the immunological characteristics of this syndrome.

Methods: Eleven Japanese patients with ICF syndrome were enrolled. We performed whole-exome sequencing in four cases and homozygosity mapping using SNP analysis in two. We evaluated their clinical manifestations and immunological status.

Results: We newly diagnosed six ICF patients who had tentatively been diagnosed with common variable immunodeficiency. We identified two novel mutations in the DNMT3B gene and one novel mutation in the ZBTB24 gene. All patients showed low serum IgG and/or IgG levels and were treated by periodic immunoglobulin replacement therapy. Three of the six patients showed worse results of the mitogen-induced lymphocyte proliferation test. Analyses of lymphocyte subpopulations revealed that CD19CD27 memory B cells were low in seven of nine patients, CD3 T cells were low in three patients, CD4/8 ratio was inverted in five patients, CD31 recent thymic emigrant cells were low in two patients, and CD19 B cells were low in four patients compared with those in the normal controls. ICF2 patients showed lower proportions of CD19 B cells and CD1656 NK cells and significantly higher proportions of CD3 T cells than ICF1 patients. T cell receptor excision circles were undetectable in two patients. Despite being treated by immunoglobulin replacement therapy, three patients died of influenza virus, fatal viral infection with persistent Epstein-Barr virus infection, or JC virus infection. One of three dead patients showed normal intelligence with mild facial anomaly. Two patients presented with autoimmune or inflammatory manifestations. Infectious episodes decreased in three patients who were started on trimethoprim-sulfamethoxazole and/or antifungal drugs in addition to immunoglobulin replacement therapy. These patients might have suffered from T cell immunodeficiency.

Conclusion: These results indicate that patients with ICF syndrome have a phenotype of combined immunodeficiency. Thus, to achieve a better prognosis, these patients should be treated as having combined immunodeficiency in addition to receiving immunoglobulin replacement therapy.
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http://dx.doi.org/10.1007/s10875-018-0559-yDOI Listing
November 2018

Transient Marked Increase of γδ T Cells in WHIM Syndrome After Successful HSCT.

J Clin Immunol 2018 07 4;38(5):553-555. Epub 2018 Jul 4.

Department of Pediatrics, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.

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http://dx.doi.org/10.1007/s10875-018-0529-4DOI Listing
July 2018

Dual emissive bispyrene peptide probes for highly sensitive measurements of trypsin activity and evaluation of trypsin inhibitors.

Bioorg Med Chem 2018 07 18;26(12):3468-3473. Epub 2018 May 18.

Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, 2-4 Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka 808-0196, Japan. Electronic address:

Peptide substrates were double labeled with pyrenes to prepare fluorescent probes for highly sensitive detection of protease activity and evaluation of protease inhibitors using pyrene monomer/excimer signals. Two proximate pyrene moieties formed excited state dimers in the probes, and these pyrene excimer formations were dissociated by tryptic digestion. The specificity constant of the optimum bispyrene peptide probe was 2.7 times higher than that of the conventional peptide-4-methylcoumarin amide. Moreover, our probe had high sensitivity with an estimated detection limit for trypsin of 4.11 pM. The half maximal inhibitory concentration and dissociation constant of the Bowman-Birk inhibitor were successfully estimated.
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http://dx.doi.org/10.1016/j.bmc.2018.05.021DOI Listing
July 2018

Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1.

J Allergy Clin Immunol 2019 01 18;143(1):266-275. Epub 2018 May 18.

Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan.

Background: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined.

Objective: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT.

Methods: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities.

Results: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT.

Conclusion: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.
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http://dx.doi.org/10.1016/j.jaci.2018.04.032DOI Listing
January 2019

Efficient near infrared fluorescence detection of elastase enzyme using peptide-bound unsymmetrical squaraine dye.

Bioorg Med Chem Lett 2017 09 22;27(17):4024-4029. Epub 2017 Jul 22.

Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, 2-4 Hibikino, Wakamatsu, Kitakyushu 808-0196, Japan. Electronic address:

Extended wavelength analyte-responsive fluorescent probes are highly desired for the imaging applications owing to their deep tissue penetration, and minimum interference from autofluorescence by biomolecules. Near infra-red (NIR) sensitive and self-quenching fluorescent probe based on the dye-peptide conjugate (SQ 1 PC) was designed and synthesized by facile and efficient one-pot synthetic route for the detection of Elastase activity. In the phosphate buffer solution, there was an efficient quenching of fluorescence of SQ 1 PC (86%) assisted by pronounced dye-dye interaction due to H-aggregate formation. Efficient and fast recovery of this quenched fluorescence of SQ 1 PC (> 50% in 30s) was observed on hydrolysis of this peptide-dye conjugate by elastase enzyme. Presently designed NIR sensitive self-quenching substrate offers the potential application for the detection of diseases related to proteases by efficient and fast detection of their activities.
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http://dx.doi.org/10.1016/j.bmcl.2017.07.057DOI Listing
September 2017

Novel fluorescent substrates for detection of trypsin activity and inhibitor screening by self-quenching.

Bioorg Med Chem Lett 2016 12 20;26(23):5736-5740. Epub 2016 Oct 20.

Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, 2-4 Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka 808-0196, Japan. Electronic address:

A group of self-quenching-based substrates with two fluorescent peptides for detection of trypsin activity was designed and synthesized. The substrates could be easily synthesized using simple solid-phase peptide synthesis techniques. Two fluorescent peptide substrates for trypsin were conjugated to the amino groups of lysine as a branched unit. The fluorescence of these substrates was self-quenched owing to the highly assembled fluorophores on the substrates. The release of these concentrated fluorophores by proteases allows for fluorescence recovery. Self-quenching reduced the fluorescence of the substrates by 64.1%, and the fluorescence intensity was recovered by the release of the fluorophores from the substrate peptides via tryptic cleavage. The kinetic assay revealed that the k/K values of the substrates were almost comparable to those of the standard fluorescent probe, peptide-MCA. The detection limit for trypsin was 111pM, and the calculation of IC and K values for the Bowman-Birk inhibitor was achieved using these substrates. These easily synthesizable self-quenching-based substrates have the potential to be useful for the detection of other disease-related protease activities.
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http://dx.doi.org/10.1016/j.bmcl.2016.10.053DOI Listing
December 2016

Widespread Molluscum Contagiosum with Atopic Dermatitis-like Skin Manifestations.

Acta Derm Venereol 2017 02;97(2):291-292

Department of Dermatology, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513, Saitama, Japan.

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http://dx.doi.org/10.2340/00015555-2511DOI Listing
February 2017

Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency.

J Allergy Clin Immunol 2016 12 14;138(6):1672-1680.e10. Epub 2016 Jul 14.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.

Background: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6.

Objective: This study aimed to identify novel genes responsible for APDS.

Methods: Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays.

Results: We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway.

Conclusion: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.
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http://dx.doi.org/10.1016/j.jaci.2016.03.055DOI Listing
December 2016

Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism.

J Clin Immunol 2015 Oct 26;35(7):610-4. Epub 2015 Sep 26.

Department of Pediatrics, Graduate School of Medicine, University of Toyama, Toyama, Japan.

Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8(+) and CD56(+) cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients.
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http://dx.doi.org/10.1007/s10875-015-0202-0DOI Listing
October 2015

An efficient synthesis of SK-658 and its analogs as potent histone deacetylase inhibitors.

Bioorg Chem 2015 Apr 7;59:145-50. Epub 2015 Mar 7.

Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, Saitama 351-0198, Japan.

SK-658 is a potent histone deacetylase (HDAC) inhibitor that showed higher activity than SAHA due to the presence of extended hydrophobic group. We designed and synthesized thioester and SS-hybrid bearing SK-658 analogs as HDAC inhibitors. All the compounds were active in nano molar range and showed higher inhibitory activity than SAHA and SK-658. Among these, disulfide compounds showed the highest activity.
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http://dx.doi.org/10.1016/j.bioorg.2015.02.009DOI Listing
April 2015

RAG1 deficiency may present clinically as selective IgA deficiency.

J Clin Immunol 2015 Apr 6;35(3):280-8. Epub 2015 Mar 6.

Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan.

Background: Recombination-activating gene (RAG) 1 and 2 deficiency is seen in patients with severe combined immunodeficiency (SCID) and Omenn syndrome. However, the spectrum of the disease has recently expanded to include a milder phenotype.

Objective: We analyzed a 4-year-old boy who was initially given the diagnosis of selective immunoglobulin A deficiency (SIgAD) based on immunoglobulin serum levels without any opportunistic infections, rashes, hepatosplenomegaly, autoimmunity or granulomas. The patient was found to be infected with varicella zoster; however, the clinical course was not serious. He produced antiviral antibodies.

Methods: We performed lymphocyte phenotyping, quantification of T cell receptor excision circles (TRECs) and kappa deleting recombination excision circles (KRECs), an analysis of target sequences of RAG1 and 2, a whole-genome SNP array, an in vitro V(D)J recombination assay, a spectratype analysis of the CDR3 region and a flow cytometric analysis of the bone marrow.

Results: Lymphocyte phenotyping demonstrated that the ratio of CD4+ to CD8+ T cells was inverted and the majority of CD4+T cells expressed CD45RO antigens in addition to the almost complete lack of B cells. Furthermore, both TRECs and KRECs were absent. Targeted DNA sequencing and SNP array revealed that the patient carried a deletion of RAG1 and RAG2 genes on the paternally-derived chromosome 11, and two maternally-derived novel RAG1 missense mutations (E455K, R764H). In vitro analysis of recombination activity showed that both RAG1 mutant proteins had low, but residual function.

Conclusions: The current case further expands the phenotypic spectrum of mild presentations of RAG deficiency, and suggests that TRECs and KRECs are useful markers for detecting hidden severe, as well as mild, cases.
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http://dx.doi.org/10.1007/s10875-015-0146-4DOI Listing
April 2015

Bicyclic tetrapeptide histone deacetylase inhibitors with methoxymethyl ketone and boronic acid zinc-binding groups.

Bioorg Chem 2014 Dec 22;57:121-126. Epub 2014 Oct 22.

Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, Saitama 351-0198, Japan.

Histone deacetylase (HDAC) inhibitors are a class of potential therapeutics for the treatment of cancer. Bicyclic tetrapeptides equipped with methoxymethyl ketone and boronic acid as zinc-binding group were designed and synthesized. The inhibitory activities of these compounds were evaluated against HDAC enzymes. The cell-free and cell-based assay data showed that both potency and selectivity changed with the change in zinc-binding group. Boronic acid-based compound showed poor activity whereas methoxymethyl ketone-based compound displayed impressive activity in both cell-free and cell-based conditions.
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http://dx.doi.org/10.1016/j.bioorg.2014.10.003DOI Listing
December 2014

Design and synthesis of mono and bicyclic tetrapeptides thioester as potent inhibitor of histone deacetylases.

Amino Acids 2014 Oct 22;46(10):2435-44. Epub 2014 Jul 22.

Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400, Serdang, Malaysia,

Inhibitors of histone deacetylases (HDACs) are a promising class of anticancer agents that have an effect on gene regulation. The naturally occurring cyclic depsipeptide FK228 containing disulfide and Largazole possessing thioester functionalities act as pro-drugs and share the same HDAC inhibition mechanism in cell. Inspired from these facts, we have reported bicyclic tetrapeptide disulfide HDAC inhibitors resembling FK228 with potent activity and enhanced selectivity. In the present study, we report the design and synthesis of several mono and bicyclic tetrapeptide thioester HDAC inhibitors that share the inhibition mechanism similar to Largazole. Most of the compounds showed HDAC1 and HDAC4 inhibition and p21 promoting activity in nanomolar ranges. Among these the monocyclic peptides 1, 2 and bicyclic peptide, 4 are notable demanding more advanced research to be promising anticancer drug candidates.
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http://dx.doi.org/10.1007/s00726-014-1800-5DOI Listing
October 2014

Bicyclic tetrapeptides as potent HDAC inhibitors: effect of aliphatic loop position and hydrophobicity on inhibitory activity.

Bioorg Med Chem 2014 Aug 26;22(15):3862-70. Epub 2014 Jun 26.

Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, Saitama 351-0198, Japan.

Several histone deacetylase (HDAC) inhibiting bicyclic tetrapeptides have been designed and synthesized through intramolecular ring-closing metathesis (RCM) reaction and peptide cyclization. We designed bicyclic tetrapeptides based on CHAP31, trapoxin B and HC-toxin I. The HDAC inhibitory and p21 promoter assay results showed that the aliphatic loop position as well as the hydrophobicity plays an important role toward the activity of the bicyclic tetrapeptide HDAC inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2014.06.031DOI Listing
August 2014

Design and synthesis of CHAP31, trapoxin B and HC-toxin based bicyclic tetrapeptides disulfide as potent histone deacetylase inhibitors.

Bioorg Med Chem 2014 Aug 25;22(15):3850-5. Epub 2014 Jun 25.

Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, Saitama 351-0198, Japan.

The naturally occurring cyclic depsipeptide, FK228 inhibits histone deacetylase (HDAC) enzymes after reductive cleavage of intra-molecular disulfide bond. One of the sulfhydryl groups produced in the reduction interacts with zinc atom that involved in the catalytic mechanism of type 1 and 2 HDACs such as HDAC1, HDAC4, and HDAC6. In the present study, we describe the development of CHAP31, trapoxin B and HC-toxin based cyclic tetrapeptides with intra-molecular disulfide bond as HDAC inhibitors. The bicyclic tetrapeptides disulfide showed potent HDAC1 and HDAC4 inhibition and p21 promoting activity.
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http://dx.doi.org/10.1016/j.bmc.2014.06.029DOI Listing
August 2014

A convenient preparation of N (ε)-methyl-L-lysine derivatives and its application to the synthesis of histone tail peptides.

Amino Acids 2014 May 23;46(5):1305-11. Epub 2014 Feb 23.

Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Wakamatsu, Kitakyushu, 808-0196, Japan.

A convenient route is established for the preparation of N (α)-Fmoc-N (ε)-(Boc, methyl)-L-lysine and N (α)-Fmoc-N (ε)-dimethyl-L-lysine as building blocks to be used for the synthesis of methylated peptides. This methodology is based on the use of malonate derivatives and dibromobutane to produce key intermediates, L-2-amino-6-bromohexanoic acid derivatives, which could be modified to the required group at the ε-position. Fmoc-protection is accessible, so these compounds can be used in solution as well as in solid-phase peptide synthesis. Also the peptides containing these methylated lysines have been proved to resist the action of trypsin and lysyl endopeptidase. Thus, this new method could be considered as an improvement of the synthesis of N (ε)-methyl-L-lysine derivatives.
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http://dx.doi.org/10.1007/s00726-014-1690-6DOI Listing
May 2014

Design and synthesis of peptide-MCA substrates for a novel assay of histone methyltransferases and their inhibitors.

Bioorg Med Chem 2014 Feb 21;22(4):1268-75. Epub 2014 Jan 21.

Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.

Histone methyltransferases (HMTs) play an important role in controlling gene expression through site-specific methylation of lysines in core and linker histones within chromatin. As the typical HMTs, G9a and Set7/9 have been intensively studied that G9a is specific to the methylation at H3K9 and H3K27 and represses transcription, while Set7/9 methylates at H3K4. In this report we prepared various peptide-MCAs (4-methylcoumaryl-7-amides) related to histone tail and protein-substrates such as p53 and estrogen receptor-α. The fluorogenic substrates are applied for the assay of HMTs and an inhibitor, for example. The most sensitive and specific MCA-substrates to G9a and Set7/9 are discovered. The peptide-MCAs corresponding to the methylation sequences are promising for screening of HMT inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2014.01.011DOI Listing
February 2014

Maternal mosaicism of an ANKH mutation in a family with craniometaphyseal dysplasia.

Pediatr Int 2013 Apr;55(2):254-6

Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan.

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http://dx.doi.org/10.1111/ped.12067DOI Listing
April 2013

Purification and identification of an IgE suppressor from strawberry in an in vitro immunization system.

Cytotechnology 2012 May 11;64(3):309-14. Epub 2012 Feb 11.

Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, 2-4 Hibikino, Wakamatsu-ku, Kitakyushu, 808-0196, Fukuoka, Japan.

We purified and identified an IgE suppressor from the strawberry 'Toyonoka', based on the decrease of IgE production in in vitro immunization (IVI). Gel filtration experiment indicated that fractions in a 15-48 kDa range and <10 kDa have an IgE suppressive activity. Furthermore, the fraction in 15-48 kDa was subjected to chromatofocusing and found to have activities at isoelectric points, pI 6.0, 7.0, and 8.0-9.2. We focused on the active fractions of pI 8.0-9.2 and the purified a large amount of strawberry extracts by cation exchange resins in batch. A purified 39 kDa protein showed homology to plant glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in N-terminal amino acid sequence and had GAPDH enzymatic activity. Nucleotide sequence and deduced amino acid sequence of the obtained cDNA clone of the protein matched with the sequence of Fragaria x ananassa GAPDH in the GenBank with >98% identical nucleotides and >99% identical amino acids, respectively. The purified strawberry GAPDH suppressed total IgE production in IVI in a dose-dependent manner. From these results, we identified GAPDH as IgE suppressor in the strawberry. Our study may be applicable to the development of new methods to relieve allergic conditions using GAPDH and the screening of other functional factors for human health.
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http://dx.doi.org/10.1007/s10616-012-9432-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386393PMC
May 2012

Peptide-linked porphyrin sensitiser and colloidal Pt or Ir catalyst in the H2 formation reaction.

Photochem Photobiol Sci 2012 Feb 22;11(2):289-93. Epub 2011 Nov 22.

Faculty of Engineering, Kyushu Institute of Technology, Kitakyushu, 804-8550, Japan.

Porphyrins linking amphiphilic peptides were applied as photosensitisers, assuming that they would interact with the H(+) reduction catalyst, polymer-protected colloidal Pt or Ir. The close orientation of the porphyrin and metal catalyst may facilitate efficient electron transfer. The porphyrin linking a peptide containing glutamic acids (Glu), Ac-Cys(porph)-Glu-Val-Glu-Val-NH(2) (2), was an effective sensitiser for the H(2) generation reaction in the presence of N-benzyldihydronicotinamide and colloidal Pt or Ir in aqueous media under visible light illumination. At pH 5 and 7, 2 was a more efficient photosensitiser than tetrakis(p-carboxyphenyl)porphyrin (TCPP). The efficiency of H(+) reduction catalysts was in the order Ir-pGlu (polyglutamic acid) > Ir-PVP (polyvinylpyrrolidone) > Pt-PVP. Dynamic light scattering and scanning electron microscopy measurements showed that large particles formed when colloidal metal solutions were produced by microwave irradiation. Fluorescence quenching experiments suggested that electron transfer occurred from the photoexcited porphyrin to the colloidal Ir.
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http://dx.doi.org/10.1039/c1pp05250kDOI Listing
February 2012

Evaluation of functional groups on amino acids in cyclic tetrapeptides in histone deacetylase inhibition.

Amino Acids 2012 Jun 3;42(6):2103-10. Epub 2011 Jun 3.

Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Wakamatsu, Kitakyushu, 808-0196, Japan.

The naturally occurring cyclic tetrapeptide, chlamydocin, originally isolated from fungus Diheterospora chlamydosphoria, consists of α-aminoisobutyric acid, L-phenylalanine, D-proline and an unusual amino acid (S)-2-amino-8-((S)-oxiran-2-yl)-8-oxooctanoic acid (Aoe) and inhibits the histone deacetylases (HDACs), a class of regulatory enzymes. The epoxyketone moiety of Aoe is the key functional group for inhibition. The cyclic tetrapeptide scaffold is supposed to play important role for effective binding to the surface of enzymes. In place of the epoxyketone group, hydroxamic acid and sulfhydryl group have been applied to design inhibitor ligands to zinc atom in catalytic site of HDACs. In the research for more potent HDAC inhibitors, we replaced the epoxyketone moiety of Aoe with different functional groups and synthesized a series of chlamydocin analogs as HDAC inhibitors. Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid. On the contrary, we confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition.
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http://dx.doi.org/10.1007/s00726-011-0947-6DOI Listing
June 2012

Bicyclic peptides as potent inhibitors of histone deacetylases: optimization of alkyl loop length.

Bioorg Med Chem Lett 2010 Feb 21;20(3):997-9. Epub 2009 Dec 21.

Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu 808-0196, Japan.

Bicyclic tetrapeptide hydroxamic acids were prepared as histone deacetylase (HDAC) inhibitors, and the evaluated inhibitory activity shows that they are potent against HDAC1 and HDAC4. The in vivo activity depends on alkyl loop length.
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http://dx.doi.org/10.1016/j.bmcl.2009.12.054DOI Listing
February 2010

Smart Immobilization of oligopeptides through electrochemical deposition onto surface.

Anal Chim Acta 2007 Nov 26;604(1):76-80. Epub 2007 May 26.

Department of Biological Functions and Engineering, Kyushu Institute of Technology, Kitakyushu Science and Research Park, Fukuoka 808-0196, Japan.

A novel method for electrochemical molecular immobilization has been developed. Molecular immobilization on an electroconductive material surface is achieved by genetic and chemical introduction of a tag. The immobilization reaction is based on the remarkable phenomenon of neutral metal complex formation on a redox interface. For electrochemical immobilization, a metal coordinative peptide (EC tag) is introduced to the target molecule and is coordinated with a divalent metal ion. In the electrochemical immobilization process, the coordinated metal in the oligopeptide is reduced to the zero-valent metal state and is deposited on the electroconductive substrate. In the present study, we exploit our previous findings to carry out electrochemical peptide immobilization. This immobilization process can be modulated by an applied potential. Although the immobilized peptide is tightly attached the substrate, it can be removed by oxidation of deposited metal though application of an oxidation potential. The method can be employed for the immobilization of various molecules, e.g. proteins, peptides, and nano-materials, on electroconductive solid surfaces. The unique advantages of the present molecular immobilization method are the ease of application and the novel molecular modulations that are achievable.
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http://dx.doi.org/10.1016/j.aca.2007.05.033DOI Listing
November 2007

Interaction of aliphatic cap group in inhibition of histone deacetylases by cyclic tetrapeptides.

Bioorg Med Chem 2008 Jan 15;16(1):437-45. Epub 2007 Sep 15.

Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu 808-0196, Japan.

Inhibitors of histone deacetylases (HDACs) are a promising class of anticancer agents that effect gene regulation. To know the interaction of aliphatic cap groups with HDACs, cyclic tetrapeptide and bicyclic peptide disulfide hybrids were synthesized without aromatic ring in their macrocyclic framework. Benzene ring of l-Phe in chlamydocin was replaced with several aliphatic amino acids and also a fused bicyclic tetrapeptide was synthesized by ring closing metathesis using Grubb's first generation catalyst. The inhibitory activities of the cyclic peptides against histone deacetylase enzymes were evaluated, which demonstrated most of them are interesting candidates as anticancer agents.
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http://dx.doi.org/10.1016/j.bmc.2007.09.021DOI Listing
January 2008
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