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  1. Article ; Online: Identification of 1β,2α-epoxytagitinin C as a Notch inhibitor, oxidative stress mechanism and its anti-leukemia activity

    Makita, Yoshinori / Saito, Shun / Tsuchiya, Anna / Ishibashi, Masami / Arai, Midori A.

    J Nat Med. 2022 Jan., v. 76, no. 1 p.234-243

    2022  

    Abstract: Notch signaling plays crucial roles in cell differentiation and proliferation, but aberrant activation of this signaling results in tumorigenesis and cancer progression. Notch signaling is thus a promising drug target for oncotherapy, and the development ...

    Abstract Notch signaling plays crucial roles in cell differentiation and proliferation, but aberrant activation of this signaling results in tumorigenesis and cancer progression. Notch signaling is thus a promising drug target for oncotherapy, and the development of Notch signaling inhibitors is eagerly awaited. Notch inhibitory activity-guided fractionation of a Spilanthes acmella extract led to the identification of five sesquiterpene lactones: tagitinin A (1), 1β,2α-epoxytagitinin C (2), tagitinin C (3), orizabin (4), and 2α-hydroxytirotundin (5). 1β,2α-Epoxytagitinin C (2) exhibited Notch signaling inhibition, with an IC₅₀ of 25.6 μM, and was further evaluated for its activity against HPB-ALL, a Notch-activated leukemia cell line. Compound 2 showed potent cytotoxicity against HPB-ALL (IC₅₀ 1.7 μM) and arrested the cell cycle at the G2/M phase, but did not induce apoptotic cell death. Notch inhibitory mechanism analysis suggested that compound 2 transcriptionally suppresses Notch1 mRNA. In addition, we found that oxidative stress induction is critical for Notch signaling inhibition and the cytotoxicity of compound 2. This is the first mechanism of small molecule Notch inhibition. Our results demonstrate that 1β,2α-epoxytagitinin C (2) is a potential anti-leukemia agent and further investigation of this compound is warranted.
    Keywords apoptosis ; carcinogenesis ; cell cycle ; cell differentiation ; cell lines ; cytotoxicity ; drugs ; fractionation ; neoplasm cells ; neoplasm progression ; oxidative stress ; sesquiterpenoid lactones ; transcription (genetics)
    Language English
    Dates of publication 2022-01
    Size p. 234-243.
    Publishing place Springer Singapore
    Document type Article ; Online
    ZDB-ID 1201350-x
    ISSN 1340-3443
    ISSN 1340-3443
    DOI 10.1007/s11418-021-01584-0
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2692: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Identification of 1β,2α-epoxytagitinin C as a Notch inhibitor, oxidative stress mechanism and its anti-leukemia activity.

    Makita, Yoshinori / Saito, Shun / Tsuchiya, Anna / Ishibashi, Masami / Arai, Midori A

    Journal of natural medicines

    2021  Volume 76, Issue 1, Page(s) 234–243

    Abstract: Notch signaling plays crucial roles in cell differentiation and proliferation, but aberrant activation of this signaling results in tumorigenesis and cancer progression. Notch signaling is thus a promising drug target for oncotherapy, and the development ...

    Abstract Notch signaling plays crucial roles in cell differentiation and proliferation, but aberrant activation of this signaling results in tumorigenesis and cancer progression. Notch signaling is thus a promising drug target for oncotherapy, and the development of Notch signaling inhibitors is eagerly awaited. Notch inhibitory activity-guided fractionation of a Spilanthes acmella extract led to the identification of five sesquiterpene lactones: tagitinin A (1), 1β,2α-epoxytagitinin C (2), tagitinin C (3), orizabin (4), and 2α-hydroxytirotundin (5). 1β,2α-Epoxytagitinin C (2) exhibited Notch signaling inhibition, with an IC
    MeSH term(s) Apoptosis ; Cell Line, Tumor ; Humans ; Leukemia/drug therapy ; Oxidative Stress ; Signal Transduction
    Language English
    Publishing date 2021-11-15
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 2227540-X
    ISSN 1861-0293 ; 1340-3443
    ISSN (online) 1861-0293
    ISSN 1340-3443
    DOI 10.1007/s11418-021-01584-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2692: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Evaluation of Naturally Occurring HIF-1 Inhibitors for Pulmonary Arterial Hypertension.

    Arai, Midori A / Sakuraba, Kota / Makita, Yoshinori / Hara, Yasumasa / Ishibashi, Masami

    Chembiochem : a European journal of chemical biology

    2021  Volume 22, Issue 18, Page(s) 2799–2804

    Abstract: Pulmonary arterial hypertension (PAH) is a rare and severe progressive disorder characterized by high pulmonary artery pressure. Chronic hypoxia causes a metabolic disorder and the Warburg effect in pulmonary arterial smooth muscle cells (PASMCs). ... ...

    Abstract Pulmonary arterial hypertension (PAH) is a rare and severe progressive disorder characterized by high pulmonary artery pressure. Chronic hypoxia causes a metabolic disorder and the Warburg effect in pulmonary arterial smooth muscle cells (PASMCs). Pyruvate dehydrogenase kinase 1 (PDK1) is a key enzyme in Warburg effect increased by hypoxia-inducible factor (HIF-1). We constructed a cell-based luciferase assay system for HIF-1 inhibitors. Using this system, six HIF-1 inhibitors were identified. Among these inhibitors, the effect of tagitinin C (1) on PASMC was investigated. Tagitinin C (1) clearly decreased the amount of HIF-1β and the HIF-1 target PDK1. This result indicates that HIF-1 inhibitors effectively decrease PDK1 activity, which is a cause of the metabolic disorder and Warburg effect observed in PASMCs. Identifying naturally occurring HIF-1 inhibitors could provide novel insights into the development of PAH medications.
    MeSH term(s) Biological Products/chemistry ; Biological Products/pharmacology ; Biological Products/therapeutic use ; Cell Line ; Cell Survival/drug effects ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Myocytes, Smooth Muscle/cytology ; Myocytes, Smooth Muscle/metabolism ; Pulmonary Arterial Hypertension/drug therapy ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/antagonists & inhibitors ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism ; Sesquiterpenes/chemistry ; Sesquiterpenes/pharmacology ; Sesquiterpenes/therapeutic use
    Chemical Substances Biological Products ; Hypoxia-Inducible Factor 1, alpha Subunit ; PDK1 protein, human ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase ; Sesquiterpenes ; tagitinin (59979-58-7)
    Language English
    Publishing date 2021-07-09
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2020469-3
    ISSN 1439-7633 ; 1439-4227
    ISSN (online) 1439-7633
    ISSN 1439-4227
    DOI 10.1002/cbic.202100223
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Isolation and evaluation of cardenolides from Lansium domesticum as Notch inhibitors

    Tsuchiya, Anna / Makita, Yoshinori / Koyano, Takashi / Kowithayakorn, Thaworn / Ishibashi, Masami / Arai, Midori A

    Natural medicines. 2020 Sept., v. 74, no. 4

    2020  

    Abstract: Since Notch signaling plays important roles in cell proliferation and differentiation, aberrant activation of this signaling contributes to cancer progression. In neural stem cells, Notch signaling inhibits differentiation by activating HES1 expression. ... ...

    Abstract Since Notch signaling plays important roles in cell proliferation and differentiation, aberrant activation of this signaling contributes to cancer progression. In neural stem cells, Notch signaling inhibits differentiation by activating HES1 expression. Therefore, Notch signaling inhibitors may be candidates for new anticancer drugs or have applications in neural regenerative medicine. In this study, six naturally occurring Notch inhibitors were isolated from the methanol (MeOH) extract of Lansium domesticum using our novel cell-based assay. Hongherin (2), a cardiac glycoside, demonstrated potent Notch inhibitory activity with an IC₅₀ of 0.62 μM and was found to be cytotoxic in HPB-ALL human T cell acute lymphoblastic leukemia cells. Hongherin (2) also induced the differentiation of C17.2 neural stem cells to neurons, causing a 65% increase in differentiation compared to the control. Mechanistically, hongherin (2) reduced the amount of Notch1 (full length) and mastermind-like protein (MAML). This indicates that hongherin (2) inhibits Notch signaling through a dual mechanism involving the reduction of both Notch1 and MAML protein levels.
    Keywords Lansium domesticum ; T-lymphocytes ; cardenolides ; cell proliferation ; cytotoxicity ; glycosides ; humans ; lymphocytic leukemia ; medicine ; methanol ; neoplasm progression
    Language English
    Dates of publication 2020-09
    Size p. 758-766.
    Publishing place Springer Singapore
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 1201350-x
    ISSN 1340-3443
    ISSN 1340-3443
    DOI 10.1007/s11418-020-01432-7
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2692: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Isolation of nocobactin NAs as Notch signal inhibitors from Nocardia farcinica, a possibility of invasive evolution.

    Arai, Midori A / Ebihara, Itsuki / Makita, Yoshinori / Hara, Yasumasa / Yaguchi, Takashi / Ishibashi, Masami

    The Journal of antibiotics

    2020  Volume 74, Issue 4, Page(s) 255–259

    Abstract: Notch signaling inhibitors with the potential of immune suppressor production by pathogenic bacteria for easy host infection were searched from extracts of Nocardia sp. Nocobactin NA-a (compound 1) and nocobactin NA-b (compound 2), which have been ... ...

    Abstract Notch signaling inhibitors with the potential of immune suppressor production by pathogenic bacteria for easy host infection were searched from extracts of Nocardia sp. Nocobactin NA-a (compound 1) and nocobactin NA-b (compound 2), which have been suggested as pathogenesis factors, were isolated from N. farcinica IFM 11523 isolated from the sputum of a Japanese patient with chronic bronchitis. Compounds 1 and 2 showed Notch inhibitory activities with IC
    MeSH term(s) Bronchitis, Chronic/microbiology ; Evolution, Molecular ; Host-Pathogen Interactions ; Humans ; Hydroxamic Acids/isolation & purification ; Hydroxamic Acids/pharmacology ; Magnetic Resonance Spectroscopy ; Nocardia/growth & development ; Nocardia/isolation & purification ; Nocardia/metabolism ; Nocardia/pathogenicity ; Nocardia Infections/microbiology ; Oxazoles/isolation & purification ; Oxazoles/metabolism ; Oxazoles/pharmacology ; Receptors, Notch/antagonists & inhibitors ; Receptors, Notch/metabolism ; Signal Transduction ; Sputum/microbiology ; Virulence Factors/metabolism ; Virulence Factors/pharmacology
    Chemical Substances Hydroxamic Acids ; Oxazoles ; Receptors, Notch ; Virulence Factors ; nocobactin NA-a ; nocobactin NA-b ; nocobactins (53571-21-4)
    Language English
    Publishing date 2020-12-14
    Publishing country Japan
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 390800-8
    ISSN 1881-1469 ; 0021-8820 ; 0368-3532
    ISSN (online) 1881-1469
    ISSN 0021-8820 ; 0368-3532
    DOI 10.1038/s41429-020-00393-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 207: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: Isolation and evaluation of cardenolides from Lansium domesticum as Notch inhibitors.

    Tsuchiya, Anna / Makita, Yoshinori / Koyano, Takashi / Kowithayakorn, Thaworn / Ishibashi, Masami / Arai, Midori A

    Journal of natural medicines

    2020  Volume 74, Issue 4, Page(s) 758–766

    Abstract: Since Notch signaling plays important roles in cell proliferation and differentiation, aberrant activation of this signaling contributes to cancer progression. In neural stem cells, Notch signaling inhibits differentiation by activating HES1 expression. ... ...

    Abstract Since Notch signaling plays important roles in cell proliferation and differentiation, aberrant activation of this signaling contributes to cancer progression. In neural stem cells, Notch signaling inhibits differentiation by activating HES1 expression. Therefore, Notch signaling inhibitors may be candidates for new anticancer drugs or have applications in neural regenerative medicine. In this study, six naturally occurring Notch inhibitors were isolated from the methanol (MeOH) extract of Lansium domesticum using our novel cell-based assay. Hongherin (2), a cardiac glycoside, demonstrated potent Notch inhibitory activity with an IC
    MeSH term(s) Cardenolides/chemistry ; Humans ; Plants/chemistry ; Receptors, Notch/antagonists & inhibitors ; Signal Transduction
    Chemical Substances Cardenolides ; Receptors, Notch
    Language English
    Publishing date 2020-07-09
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 2227540-X
    ISSN 1861-0293 ; 1340-3443
    ISSN (online) 1861-0293
    ISSN 1340-3443
    DOI 10.1007/s11418-020-01432-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 2692: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  7. Article ; Online: GLI1 Inhibitors Identified by Target Protein Oriented Natural Products Isolation (TPO-NAPI) with Hedgehog Inhibition.

    Arai, Midori A / Ochi, Fumie / Makita, Yoshinori / Chiba, Tetsuhiro / Higashi, Kyohei / Suganami, Akiko / Tamura, Yutaka / Toida, Toshihiko / Iwama, Atsushi / Sadhu, Samir K / Ahmed, Firoj / Ishibashi, Masami

    ACS chemical biology

    2018  Volume 13, Issue 9, Page(s) 2551–2559

    Abstract: This report describes the development of a target-protein-oriented natural-products-isolation (TPO-NAPI) method for Hedgehog inhibitors and the direct GLI1 inhibitor, 5'- O-methyl-3-hydroxyflemingin A (3), which inhibited hedgehog (Hh) signal ... ...

    Abstract This report describes the development of a target-protein-oriented natural-products-isolation (TPO-NAPI) method for Hedgehog inhibitors and the direct GLI1 inhibitor, 5'- O-methyl-3-hydroxyflemingin A (3), which inhibited hedgehog (Hh) signal transduction and diminished characteristics of cancer stem cells. Eight natural products (including three newly described products) that directly bind to GLI1 were rapidly obtained via the TPO-NAPI method developed using GLI1 protein-immobilized beads. 5'- O-Methyl-3-hydroxyflemingin A (3) inhibited Hh signaling (IC
    MeSH term(s) Antineoplastic Agents, Phytogenic/chemistry ; Antineoplastic Agents, Phytogenic/isolation & purification ; Antineoplastic Agents, Phytogenic/pharmacology ; Cell Line, Tumor ; Chalcones/chemistry ; Chalcones/isolation & purification ; Chalcones/pharmacology ; Fabaceae/chemistry ; Hedgehog Proteins/antagonists & inhibitors ; Hedgehog Proteins/metabolism ; Humans ; Molecular Docking Simulation ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Signal Transduction/drug effects ; Zinc Finger Protein GLI1/antagonists & inhibitors ; Zinc Finger Protein GLI1/metabolism
    Chemical Substances Antineoplastic Agents, Phytogenic ; Chalcones ; Hedgehog Proteins ; Zinc Finger Protein GLI1
    Language English
    Publishing date 2018-09-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.8b00492
    Database MEDical Literature Analysis and Retrieval System OnLINE

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