著者

Shuya Kasai Hiromi Yamazaki Kunikazu Tanji Máté János Engler Tomoh Matsumiya Ken Itoh

出版者

SOCIETY FOR FREE RADICAL RESEARCH JAPAN

雑誌

Journal of Clinical Biochemistry and Nutrition (ISSN:09120009)

巻号頁・発行日

vol.64, no.1, pp.1-12, 2019 (Released:2019-01-01)

参考文献数

109

被引用文献数

23 62

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Recent investigations have clarified the importance of mitochondria in various age-related degenerative diseases, including late-onset Alzheimer’s disease and Parkinson’s disease. Although mitochondrial disturbances can be involved in every step of disease progression, several observations have demonstrated that a subtle mitochondrial functional disturbance is observed preceding the actual appearance of pathophysiological alterations and can be the target of early therapeutic intervention. The signals from damaged mitochondria are transferred to the nucleus, leading to the altered expression of nuclear-encoded genes, which includes mitochondrial proteins (i.e., mitochondrial retrograde signaling). Mitochondrial retrograde signaling improves mitochondrial perturbation (i.e., mitohormesis) and is considered a homeostatic stress response against intrinsic (ex. aging or pathological mutations) and extrinsic (ex. chemicals and pathogens) stimuli. There are several branches of the mitochondrial retrograde signaling, including mitochondrial unfolded protein response (UPRMT), but recent observations increasingly show the importance of the ISR-ATF4 pathway in mitochondrial retrograde signaling. Furthermore, Nrf2, a master regulator of the oxidative stress response, interacts with ATF4 and cooperatively upregulates a battery of antioxidant and antiapoptotic genes while repressing the ATF4-mediated proapoptotic gene, CHOP. In this review article, we summarized the upstream and downstream mechanisms of ATF4 activation during mitochondrial stresses and disturbances and discuss therapeutic intervention against degenerative diseases by using Nrf2 activators.

著者

Syota SEINO Takeru KIMOTO Hidemi YOSHIDA Kunikazu TANJI Tomoh MATSUMIYA Ryo HAYAKARI Kazuhiko SEYA Shogo KAWAGUCHI Kazushi TSURUGA Hiroshi TANAKA Tadaatsu IMAIZUMI

出版者

Biomedical Research Press

雑誌

Biomedical Research (ISSN:03886107)

巻号頁・発行日

vol.39, no.3, pp.105-115, 2018-06-01 (Released:2018-06-12)

参考文献数

41

被引用文献数

10 15

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Accumulation and oligomerization of amyloid-beta (Aβ) peptides have been known to be a potent cause of neurodegenerative diseases such as Alzheimer’s disease (AD). To expand the possibilities of preventing AD, we investigated the effects of resveratrol dimers, gnetin C and ε-viniferin, on Aβ 1–42 (Aβ42) production and the reduced cell viability observed after Aβ42 treatment (monomers, 10 μM) in cultured SH-SY5Y human neuroblastoma cells. Among them, addition of gnetin C (20 μM) into the media reduced Aβ42 production most efficiently. Gnetin C suppressed the expression of β-site amyloid precursor protein-cleaving enzyme-1 (BACE1, β-secretase). Furthermore, gnetin C ameliorated the Aβ42-reduced cell viability most significantly. Concomitantly, gnetin C reduced intracellular Aβ oligomers (ca. 15 and 130 kDa) and elevated both levels of intracellular and extracellular Aβ monomers. Under the treatment with or without Aβ42, gnetin C upregulated the expression of matrix metalloproteinase-14 (MMP-14) which is assumed to be an Aβ-decomposing enzyme. Gnetin C may thereby prevent Aβ toxicity by suppressing BACE1 and enhancing MMP-14, together with reducing both internalization and oligomerization of exogenous Aβ monomers. The use of gnetin C may lead to the prevention of Aβ-mediated diseases, particularly AD.