著者

Tatsuhiro Akaishi Shohei Yamamoto Kazuho Abe

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.3, pp.301-308, 2022-03-01 (Released:2022-03-01)

参考文献数

45

被引用文献数

7

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Neuroinflammation induced by activated microglia is a key feature of neurodegenerative diseases such as Alzheimer’s disease. The natural flavonoid 3′,4′,7-trihydroxyflavone protects nerve cells from oxidative stress-mediated apoptosis and inhibits the aggregation of amyloid β protein in vitro. However, little is known about its effects on microglial activation. In this study, we investigated the effects of 3′,4′,7-trihydroxyflavone on lipopolysaccharide (LPS)- or interferon-γ (IFN-γ)-induced neuroinflammatory responses in MG6 microglial cells. 3′,4′,7-Trihydroxyflavone inhibited LPS- or IFN-γ-mediated nitric oxide (NO) generation and the upregulation of inducible NO synthase (iNOS) in MG6 cells. 3′,4′,7-Trihydroxyflavone also suppressed LPS- or IFN-γ-mediated phosphorylation of signal transducer and activator of transcription 1 (STAT1), which is crucial for iNOS expression. LPS stimulation induced rapid phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase (ERK) in MG6 cells. 3′,4′,7-Trihydroxyflavone significantly inhibited the LPS-mediated phosphorylation of JNK, but not that of ERK and p38 MAPK. The inhibitory effect of 3′,4′,7-trihydroxyflavone on NO generation was mimicked by pharmacological inhibition of the JNK signaling pathway with SP600125. Furthermore, SP600125 significantly inhibited LPS- or IFN-γ-mediated phosphorylation of STAT1 in MG6 cells. These results suggest that 3′,4′,7-trihydroxyflavone exerts anti-neuroinflammatory effects via inhibition of the JNK-STAT1 pathway in microglia.

著者

Hiroko Ushikubo Yui Tanimoto Kazuho Abe Tomohiro Asakawa Toshiyuki Kan Tatsuhiro Akaishi

出版者

公益社団法人日本薬学会

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.37, no.5, pp.748-754, 2014-05-01 (Released:2014-05-01)

参考文献数

26

被引用文献数

2 11

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Amyloid β protein (Aβ) self-assembles into insoluble fibrils, and forms the senile plaques associated with Alzheimer’s disease. 3,3′,4′,5′-Tetrahydroxyflavone, a synthetic analogue of the natural flavonoid fisetin, has been found to potently inhibit Aβ fibril formation. In the present study, we investigated how inhibition of Aβ fibril formation by this flavonoid affects Aβ conformation and neurotoxicity. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of Aβ1-42 (20 µM) incubated with or without 3,3′,4′,5′-tetrahydroxyflavone demonstrated that 3,3′,4′,5′-tetrahydroxyflavone (100 µM) rapidly caused formation of atypical Aβ conformers, which appeared as a very broad, smear-like band in the high molecular weight region and were distinguishable from soluble Aβ oligomers or mature Aβ fibrils. Transmission electron microscopy (TEM) revealed that large spherical Aβ aggregates were preferentially formed in the presence of 3,3′,4′,5′-tetrahydroxyflavone. The SDS-resistant, smear-like band on SDS-PAGE and the large spherical aggregates in TEM both disappeared after heat treatment (100°C, 10 min). Furthermore, a neurotoxicity assay with cultured rat hippocampal neurons demonstrated that Aβ incubated with 3,3′,4′,5′-tetrahydroxyflavone was significantly less toxic than Aβ incubated without the flavonoid. These results suggest that the newly synthesized fisetin analogue 3,3′,4′,5′-tetrahydroxyflavone directly produces atypical, large Aβ aggregates and reduces Aβ toxicity.

著者

Muneo Tsukiyama Tatsuhiro Akaishi Takuro Ueki Hidenobu Okumura Kazuho Abe

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.30, no.11, pp.2063-2068, 2007-11-01 (Released:2007-11-01)

参考文献数

20

被引用文献数

3 9

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Although the fruit of Nandina domestica THUNBERG (ND) has been used to treat respiratory disorders such as coughing and breathing difficulty in Japan for many years, very little is known about mechanisms underlying its action. In the present study, we investigated effects of the crude extract from ND (NDE) and one of its constituents, nantenine, on contractile responses in isolated guinea pig tracheal ring preparations. In normal experimental condition, guinea pig trachea remained tonically contracted during the resting state, and addition of NDE (1 mg/ml) caused a relaxation of tracheal smooth muscles, but had little effect on the responsiveness of trachea to acetylcholine. The basal, tonic contraction was abolished by the presence of atropine and indomethacin. In this condition, NDE at 0.1—1 mg/ml inhibited histamine-induced contraction in both competitive and non-competitive manners. NDE at 0.01—1 mg/ml inhibited serotonin-induced contraction in a competitive manner. Nantenine (2—20 μM) did not affect histamine-induced contraction, and slightly inhibited serotonin-induced contraction. These results suggest that NDE has inhibitory effects on tracheal smooth muscle contraction, and nantenine cannot account solely for this effect of NDE.