Displaying all 13 publications

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  1. Lim CL, Nogawa T, Okano A, Futamura Y, Kawatani M, Takahashi S, et al.
    J Antibiot (Tokyo), 2016 06;69(6):456-8.
    PMID: 26648115 DOI: 10.1038/ja.2015.124
  2. Ooi LC, Watanabe N, Futamura Y, Sulaiman SF, Darah I, Osada H
    Cancer Sci, 2013 Nov;104(11):1461-7.
    PMID: 23910095 DOI: 10.1111/cas.12246
    Dysregulation of p27(Kip1) due to proteolysis that involves the ubiquitin ligase (SCF) complex with S-phase kinase-associated protein 2 (Skp2) as the substrate-recognition component (SCF(Skp2)) frequently results in tumorigenesis. In this report, we developed a high-throughput screening system to identify small-molecule inhibitors of p27(Kip1) degradation. This system was established by tagging Skp2 with fluorescent monomeric Azami Green (mAG) and CDK subunit 1 (Cks1) (mAGSkp2-Cks1) to bind to p27(Kip1) phosphopeptides. We identified two compounds that inhibited the interaction between mAGSkp2-Cks1 and p27(Kip1): linichlorin A and gentian violet. Further studies have shown that the compounds inhibit the ubiquitination of p27(Kip1) in vitro as well as p27(Kip1) degradation in HeLa cells. Notably, both compounds exhibited preferential antiproliferative activity against HeLa and tsFT210 cells compared with NIH3T3 cells and delayed the G1 phase progression in tsFT210 cells. Our approach indicates a potential strategy for restoring p27(Kip1) levels in human cancers.
  3. Osada H, Coelho de Amorim A, Velosa A, Wan WP, Lotrakul P, Hara H
    Int J Soc Psychiatry, 2013 Jun;59(4):398-400.
    PMID: 22408120 DOI: 10.1177/0020764012438477
    Compared with US or European countries, there are fewer mental health services for mothers of children with developmental disabilities in Latin American and/or Southeast Asian countries.
  4. Rawa MSA, Nogawa T, Okano A, Futamura Y, Nakamura T, Wahab HA, et al.
    Biosci Biotechnol Biochem, 2021 Jan 07;85(1):69-76.
    PMID: 33577647 DOI: 10.1093/bbb/zbaa051
    A new peptaibol, RK-026A (1) was isolated from a fungus, Trichoderma sp. RK10-F026, along with atroviridin B (2), alamethicin II (3), and polysporin B (4) as a cytotoxic compound, which was selected by principal component analysis of the MS data from 5 different culture conditions. The structure of 1 was determined as a new atroviridin B derivative containing Glu at the 18th residue instead of Gln by NMR and HR-MS analyses including the investigation of detailed MS/MS fragmentations. 1 showed cytotoxicity toward K562 leukemia cells at an IC50 value of 4.1 µm.
  5. Nogawa T, Okano A, Lim CL, Futamura Y, Shimizu T, Takahashi S, et al.
    J Antibiot (Tokyo), 2017 02;70(2):222-225.
    PMID: 27599762 DOI: 10.1038/ja.2016.113
  6. Kwong MMY, Lee JW, Samian MR, Watanabe N, Osada H, Ong EBB
    J Microbiol Methods, 2019 12;167:105743.
    PMID: 31629019 DOI: 10.1016/j.mimet.2019.105743
    This study compared the chronological life span and survival of Saccharomyces cerevisiae aged in a microplate or bottle, under different aeration and calorie restriction conditions. Our data shows that limited aeration in the microplate-aged culture contributed to slower outgrowth but extended yeast CLS compared to the bottle-aged culture.
  7. Rawa MSA, Nogawa T, Okano A, Futamura Y, Wahab HA, Osada H
    J Antibiot (Tokyo), 2021 08;74(8):485-495.
    PMID: 34163024 DOI: 10.1038/s41429-021-00429-y
    Six new 11-mer peptaibols designed as zealpeptaibolins, A - F were isolated from the soil fungus, Trichoderma sp. RK10-F026, based on the principal component analysis of the MS data from five different culture compositions. Previously, 20-mer peptaibols from the same fungal strain were identified; 11-mer peptaibols in contrast were discovered from a different culture condition, signifying peptaibol production was culture condition-dependent. These peptaibols contained three Aib-Pro motifs in the sequence. The structures were established by NMR and HR-MS experiments including detailed MS/MS fragmentations. The absolute configurations were determined by Marfey's analysis. Zealpeptaibolin F exhibited the strongest cytotoxicity toward K562 leukemia cells with an IC50 value of 0.91 µM.
  8. A Abdelhakim I, Bin Mahmud F, Motoyama T, Futamura Y, Takahashi S, Osada H
    J Nat Prod, 2022 01 28;85(1):63-69.
    PMID: 34949088 DOI: 10.1021/acs.jnatprod.1c00677
    A recently discovered secondary metabolism regulator, NPD938, was used to alter the secondary metabolite profile in Fusarium sp. RK97-94. Three lucilactaene analogues were detected via UPLC-ESI-MS analysis in NPD938-treated culture. The three metabolites were successfully purified and identified as dihydroNG391 (1), dihydrolucilactaene (2), and 13α-hydroxylucilactaene (3) via extensive spectroscopic analyses. DihydroNG391 (1) exhibited weak in vitro antimalarial activity (IC50 = 62 μM). In contrast, dihydrolucilactaene (2) and 13α-hydroxylucilactaene (3) showed very potent antimalarial activity (IC50 = 0.0015 and 0.68 μM, respectively). These findings provide insight into the structure-activity relationship of lucilactaene and its analogues as antimalarial lead compounds.
  9. Lee JW, Ong TG, Samian MR, Teh AH, Watanabe N, Osada H, et al.
    Sci Rep, 2021 12 17;11(1):24148.
    PMID: 34921163 DOI: 10.1038/s41598-021-03490-7
    Ageing-related proteins play various roles such as regulating cellular ageing, countering oxidative stress, and modulating signal transduction pathways amongst many others. Hundreds of ageing-related proteins have been identified, however the functions of most of these ageing-related proteins are not known. Here, we report the identification of proteins that extended yeast chronological life span (CLS) from a screen of ageing-related proteins. Three of the CLS-extending proteins, Ptc4, Zwf1, and Sme1, contributed to an overall higher survival percentage and shorter doubling time of yeast growth compared to the control. The CLS-extending proteins contributed to thermal and oxidative stress responses differently, suggesting different mechanisms of actions. The overexpression of Ptc4 or Zwf1 also promoted rapid cell proliferation during yeast growth, suggesting their involvement in cell division or growth pathways.
  10. Tan FHP, Ting ACJ, Najimudin N, Watanabe N, Shamsuddin S, Zainuddin A, et al.
    J Gerontol A Biol Sci Med Sci, 2023 Oct 28;78(11):1944-1952.
    PMID: 37453137 DOI: 10.1093/gerona/glad169
    Alzheimer's disease (AD) is the most prevalent type of dementia globally. The accumulation of amyloid-beta (Aβ) extracellular senile plaques in the brain is one of the hallmark mechanisms found in AD. Aβ42 is the most damaging and aggressively aggregating Aβ isomer produced in the brain. Although Aβ42 has been extensively researched as a crucial peptide connected to the development of the characteristic amyloid fibrils in AD, the specifics of its pathophysiology are still unknown. Therefore, the main objective was to identify novel compounds that could potentially mitigate the negative effects of Aβ42. 3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carbonyl]amino]propanoic acid (THICAPA) was identified as a ligand for Aβ42 and for reducing fibrillary Aβ42 aggregation. THICAPA also improved cell viability when administered to PC12 neuronal cells that were exposed to Aβ42. Additionally, this compound diminished Aβ42 toxicity in the current AD Drosophila model by rescuing the rough eye phenotype, prolonging the life span, and enhancing motor functions. Through next-generation RNA-sequencing, immune response pathways were downregulated in response to THICAPA treatment. Thus, this study suggests THICAPA as a possible disease-modifying treatment for AD.
  11. Lim CL, Nogawa T, Uramoto M, Okano A, Hongo Y, Nakamura T, et al.
    J Antibiot (Tokyo), 2014 Apr;67(4):323-9.
    PMID: 24496142 DOI: 10.1038/ja.2013.144
    Two novel quinomycin derivatives, RK-1355A (1) and B (2), and one known quinomycin derivative, UK-63,598 (3), were isolated from a microbial metabolites fraction library of Streptomyces sp. RK88-1355 based on Natural Products Plot screening. The structural elucidation of 1 and 2 was established through two-dimensional NMR and mass spectrometric measurements. They belong to a class of quinomycin antibiotics family having 3-hydroxyquinaldic acid and a sulfoxide moiety. They are the first examples for natural products as a quinoline type quinomycin having a sulfoxide on the intramolecular cross-linkage. They showed potent antiproliferative activities against various cancer cell lines and they were also found to exhibit moderate antibacterial activity.
  12. Choi SB, Choong YS, Saito A, Wahab HA, Najimudin N, Watanabe N, et al.
    Mol Inform, 2014 Dec;33(11-12):742-8.
    PMID: 27485420 DOI: 10.1002/minf.201400080
    Present HIV antiviral therapy only targets structural proteins of HIV, but evidence shows that the targeting of accessory proteins will expand our options in combating HIV. HIV-1 Vpr, a multifunctional accessory protein involved in viral infection, replication and pathogenesis, is a potential target. Previously, we have shown that phenyl coumarin compounds can inhibit the growth arrest activity of Vpr in host cells and predicted that the inhibitors' binding site is a hydrophobic pocket on Vpr. To investigate our prediction of the inhibitors' binding site, we docked the coumarin inhibitors into the predicted hydrophobic binding pocket on a built model of Vpr and observed a linear trend between their calculated binding energies and prior experimentally determined potencies. Subsequently, to analyze the inhibitor-protein binding interactions in detail, we built homology models of Vpr mutants and performed docking studies on these models too. The results revealed that structural changes on the binding pocket that were caused by the mutations affected inhibitor binding. Overall, this study showed that the binding energies of the docked molecules are good indicators of the activity of the inhibitors. Thus, the model can be used in virtual screening to identify other Vpr inhibitors and for designing more potent inhibitors.
  13. Ong WD, Okubo-Kurihara E, Kurihara Y, Shimada S, Makita Y, Kawashima M, et al.
    Plant Cell Physiol, 2017 01 01;58(1):95-105.
    PMID: 28011868 DOI: 10.1093/pcp/pcw181
    Plants have a remarkable ability to perceive and respond to various wavelengths of light and initiate regulation of different cascades of light signaling and molecular components. While the perception of red light and the mechanisms of its signaling involving phytochromes are largely known, knowledge of the mechanisms of blue light signaling is still limited. Chemical genetics involves the use of diverse small active or synthetic molecules to evaluate biological processes. By combining chemicals and analyzing the effects they have on plant morphology, we identified a chemical, 3-bromo-7-nitroindazole (3B7N), that promotes hypocotyl elongation of wild-type Arabidopsis only under continuous blue light. Further evaluation with loss-of-function mutants confirmed that 3B7N inhibits photomorphogenesis through cryptochrome-mediated light signaling. Microarray analysis demonstrated that the effect of 3B7N treatment on gene expression in cry1cry2 is considerably smaller than that in the wild type, indicating that 3B7N specifically interrupts cryptochrome function in the control of seedling development in a light-dependent manner. We demonstrated that 3B7N directly binds to CRY1 protein using an in vitro binding assay. These results suggest that 3B7N is a novel chemical that directly inhibits plant cryptochrome function by physical binding. The application of 3B7N can be used on other plants to study further the blue light mechanism and the genetic control of cryptochromes in the growth and development of plant species.
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