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Article: Methodology for awakening the potential secondary metabolic capacity in actinomycetes.

Saito, Shun / Arai, Midori A

2024 Volume 20, Page(s) 753–766

Abstract: Secondary metabolites produced by actinomycete strains undoubtedly have great potential for use in applied research areas such as drug discovery. However, it is becoming difficult to obtain novel compounds because of repeated isolation around the world. ... ...

Abstract	Secondary metabolites produced by actinomycete strains undoubtedly have great potential for use in applied research areas such as drug discovery. However, it is becoming difficult to obtain novel compounds because of repeated isolation around the world. Therefore, a new strategy for discovering novel secondary metabolites is needed. Many researchers believe that actinomycetes have as yet unanalyzed secondary metabolic activities, and the associated undiscovered secondary metabolite biosynthesis genes are called "silent" genes. This review outlines several approaches to further activate the metabolic potential of actinomycetes.
Language	English
Publishing date	2024-04-10
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2192461-2
ISSN	1860-5397
ISSN	1860-5397
DOI	10.3762/bjoc.20.69
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Target Protein-Oriented Isolations for Bioactive Natural Products.

Arai, Midori A

Chemical & pharmaceutical bulletin

2021 Volume 69, Issue 6, Page(s) 503–515

Abstract: Natural products are very attractive for development of medicine. Their structure and bioactivities are often beyond human knowledge and imagination. We have developed isolation methods for target protein-oriented natural products so as quickly to ... ...

Abstract	Natural products are very attractive for development of medicine. Their structure and bioactivities are often beyond human knowledge and imagination. We have developed isolation methods for target protein-oriented natural products so as quickly to discover bioactive compounds from natural resources. This review summarizes our recent results including protein beads methods for neural stem cells differentiation activators and new cancer drug candidates. Syntheses of isolated compounds are described. We also developed protein plate method for identification of protein-protein interaction inhibitors. Because protein binding ability is tightly related to bioactivity, protein-based natural products isolation is a powerful means to find new candidate medicines.
MeSH term(s)	Antineoplastic Agents, Phytogenic/chemical synthesis ; Antineoplastic Agents, Phytogenic/chemistry ; Antineoplastic Agents, Phytogenic/pharmacology ; Biological Products/chemical synthesis ; Biological Products/chemistry ; Biological Products/pharmacology ; Cell Differentiation/drug effects ; Humans ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/metabolism ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neural Stem Cells/drug effects ; Protein Binding/drug effects
Chemical Substances	Antineoplastic Agents, Phytogenic ; Biological Products ; Neoplasm Proteins
Language	English
Publishing date	2021-05-30
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	213307-6
ISSN	1347-5223 ; 0009-2363
ISSN (online)	1347-5223
ISSN	0009-2363
DOI	10.1248/cpb.c21-00040
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Article ; Online: 3-Hydroxy-3-(2-oxopropyl)indolin-2-one, a product of a human-derived Enterocloster strain, is an inhibitor of nitric oxide production.

Saito, Shun / Banno, Tomoya / Arai, Midori A

Bioscience, biotechnology, and biochemistry

2023 Volume 88, Issue 3, Page(s) 316–321

Abstract: When cultured anaerobically, Enterocloster sp. RD014215 was found to produce 1. Using nuclear magnetic resonance and mass spectroscopy, the planar structure of 1 was determined to be 3-hydroxy-3-(2-oxopropyl)indolin-2-one. The chirality of 1 was implied ... ...

Abstract	When cultured anaerobically, Enterocloster sp. RD014215 was found to produce 1. Using nuclear magnetic resonance and mass spectroscopy, the planar structure of 1 was determined to be 3-hydroxy-3-(2-oxopropyl)indolin-2-one. The chirality of 1 was implied as S by comparing the optical rotation value of 1 with literature reports of the synthesized compounds. To our knowledge, this work represents the first discovery of the metabolite produced by Enterocloster strain. 1 exhibited inhibition of nitric oxide (NO) production, demonstrating a 50% inhibitory activity (IC50) of 34 µm for NO production by murine macrophage cells subjected to lipopolysaccharide stimulation.
MeSH term(s)	Humans ; Mice ; Animals ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II ; Macrophages/metabolism ; Indoles/pharmacology ; Indoles/metabolism ; Lipopolysaccharides/pharmacology
Chemical Substances	Nitric Oxide (31C4KY9ESH) ; indolin-2-one ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Indoles ; Lipopolysaccharides
Language	English
Publishing date	2023-12-12
Publishing country	England
Document type	Journal Article
ZDB-ID	1106450-x
ISSN	1347-6947 ; 0916-8451
ISSN (online)	1347-6947
ISSN	0916-8451
DOI	10.1093/bbb/zbad172
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Article ; Online: Noaoxazole, a new heat shock metabolite produced by thermotolerant Streptomyces sp. HR41.

Saito, Shun / Suzuki, Shiina / Arai, Midori A

The Journal of antibiotics

2022 Volume 75, Issue 9, Page(s) 509–513

Abstract: The thermotolerant strain Streptomyces sp. HR41 was found to produce compound 1 only in a 45 °C culture, and not at the standard temperature. We previously designated this type of compound as a "heat shock metabolite" (HSM). NMR and MS analytical ... ...

Abstract	The thermotolerant strain Streptomyces sp. HR41 was found to produce compound 1 only in a 45 °C culture, and not at the standard temperature. We previously designated this type of compound as a "heat shock metabolite" (HSM). NMR and MS analytical techniques were used to determine that the chemical structure of 1 comprised a methylated-oxazole ring and a linear chain moiety modified with a terminal amide group. Thus, 1 was shown to be a new curromycin analog, which we have designated noaoxazole (1). Compound 1 weakly activated Notch signal reporter activity without exhibiting cytotoxicity against assay cells at the same concentration.
MeSH term(s)	Heat-Shock Response ; Oxazoles/metabolism ; Streptomyces/metabolism ; Thermotolerance
Chemical Substances	Oxazoles
Language	English
Publishing date	2022-08-02
Publishing country	England
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/s41429-022-00551-5
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Article ; Online: Corrrection to "Two Bioactive Compounds, Uniformides A and B, Isolated from a Culture of

Hara, Yasumasa / Watanabe, Keiichiro / Takaya, Akiko / Ebihara, Itsuki / Manome, Teruhisa / Arai, Midori A / Yaguchi, Takashi / Ishibashi, Masami

Organic letters

2022 Volume 24, Issue 31, Page(s) 5867

Language	English
Publishing date	2022-07-28
Publishing country	United States
Document type	Published Erratum
ISSN	1523-7052
ISSN (online)	1523-7052
DOI	10.1021/acs.orglett.2c02441
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Article ; Online: Notch activator cyclopiazonic acid induces apoptosis in HL-60 cells through calcineurin activation.

Suzuki, Shiina / Saito, Shun / Narushima, Yuki / Kodani, Shunta / Kagaya, Noritaka / Suenaga, Hikaru / Shin-Ya, Kazuo / Arai, Midori A

The Journal of antibiotics

2023 Volume 77, Issue 1, Page(s) 30–38

Abstract: We screened a library of microbial extracts and compounds library using our constructed assay cells and found pulicatins F (1) and G (2), and cyclopiazonic acid (CPA) (3) as Notch activators. Pulicatin F (1) and (±)-pulicatin G were synthesized and their ...

Abstract	We screened a library of microbial extracts and compounds library using our constructed assay cells and found pulicatins F (1) and G (2), and cyclopiazonic acid (CPA) (3) as Notch activators. Pulicatin F (1) and (±)-pulicatin G were synthesized and their activities were evaluated. Notch activation of CPA (3) was investigated using Western blot and RT-PCR. CPA (3) increased protein level of HES1 and mRNA expression of HES1. Also, the expression of FMS-like tyrosine kinase 3 (FLT3), which was known to inhibit apoptosis, was also inhibited by CPA (3) addition. The Notch activation by CPA (3) and cytotoxicity against HL-60 were clearly canceled by addition of FK506, which is an inhibitor of calcineurin (CaN). In addition, it was revealed that CPA (3) induced apoptosis in HL-60 cells.
MeSH term(s)	Humans ; HL-60 Cells ; Calcineurin ; Apoptosis ; Indoles/pharmacology
Chemical Substances	Calcineurin (EC 3.1.3.16) ; cyclopiazonic acid (X9TLY4580Z) ; Indoles
Language	English
Publishing date	2023-11-08
Publishing country	England
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/s41429-023-00673-4
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Article ; Online: Natural Compounds with BMI1 Promoter Inhibitory Activity from Mammea siamensis and Andrographis paniculata.

Fujii, Kazuki / Hara, Yasumasa / Arai, Midori A / Sadhu, Samir K / Ahmed, Firoj / Ishibashi, Masami

Chemical & pharmaceutical bulletin

2022 Volume 70, Issue 12, Page(s) 885–891

Abstract: A new coumarin derivative (1) and 30 known compounds were isolated from Mammea siamensis and Andrographis paniculata, guided by B cell-specific Moloney murine leukemia virus insertion region 1 (BMI1) promoter inhibitory activity. Among the isolated ... ...

Abstract	A new coumarin derivative (1) and 30 known compounds were isolated from Mammea siamensis and Andrographis paniculata, guided by B cell-specific Moloney murine leukemia virus insertion region 1 (BMI1) promoter inhibitory activity. Among the isolated compounds, 15 compounds showed BMI1 promoter inhibitory activity, and five compounds were found to be cytotoxic. 14-Deoxy-11,12-dehydroandrographolide (18) was highly cytotoxic to DU145 cells with an IC
MeSH term(s)	Animals ; Mice ; Andrographis paniculata ; Cell Line ; Mammea ; Polycomb Repressive Complex 1 ; Proto-Oncogene Proteins ; Triiodobenzoic Acids
Chemical Substances	Bmi1 protein, mouse ; compound 18 (31112-66-0) ; Polycomb Repressive Complex 1 (EC 2.3.2.27) ; Proto-Oncogene Proteins ; Triiodobenzoic Acids ; 14-Deoxy-11,12-dehydroandrographolide
Language	English
Publishing date	2022-11-14
Publishing country	Japan
Document type	Journal Article
ZDB-ID	213307-6
ISSN	1347-5223 ; 0009-2363
ISSN (online)	1347-5223
ISSN	0009-2363
DOI	10.1248/cpb.c22-00556
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Article: Successful management of acute graft-versus-host disease with ibrutinib during cord blood transplantation for germline

Uchimura, Ayana / Yasuda, Hajime / Onagi, Hiroko / Inano, Tadaaki / Shirane, Shuichi / Ishii, Midori / Azusawa, Yoko / Hamano, Yasuharu / Eguchi, Hidetaka / Arai, Masami / Ando, Jun / Ando, Miki

Heliyon

2024 Volume 10, Issue 2, Page(s) e24801

Abstract: Background: Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with significant morbidity and mortality, and efficacy of currently available therapeutics are limited. Acute ... ...

Abstract	Background: Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with significant morbidity and mortality, and efficacy of currently available therapeutics are limited. Acute and chronic GVHD are similar in that both are initiated by antigen presenting cells and activation of alloreactive B-cells and T-cells, subsequently leading to inflammation, tissue damage, and organ failure. One difference is that acute GVHD is mostly attributed to T-cell activation and cytokine release, whereas B-cells are the key players in chronic GVHD. Ibrutinib is an irreversible inhibitor of the Bruton's tyrosine kinase (BTK), which is part of B-cell receptor signaling. Ibrutinib is currently used for treating chronic GVHD, but its efficacy towards acute GVHD is unknown. Besides BTK, ibrutinib also inhibits interleukin-2 inducible T-cell kinase (ITK), which is predominantly expressed in T-cells and a crucial enzyme for activating the downstream pathway of TCR signaling. ITK activates PLCγ2 and facilitates signaling through NF-κB, NFAT, and MAPK, leading to activation and proliferation of T-cells and enhanced cytokine production. Therefore, the TCR signaling pathway is indispensable for development of acute GVHD, and ITK inhibition by ibrutinib would be a rational therapeutic approach. Case presentation: A 56-year-old male acute myeloid leukemia patient with Myeloid neoplasms with germline DEAD-box RNA helicase 41 ( Conclusion: Ibrutinib is a promising therapeutic for treating acute GVHD, and further studies are warranted.
Language	English
Publishing date	2024-01-17
Publishing country	England
Document type	Case Reports
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2024.e24801
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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
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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 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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