High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance

David B. Lombard; William J. Kohler; Angela H. Guo; Christi Gendron; Melissa Han; Weiqiao Ding; Yang Lyu; Tsui Ting Ching; Feng Yung Wang; Tuhin S. Chakraborty; Zaneta Nikolovska-Coleska; Yuzhu Duan; Thomas Girke; Ao Lin Hsu; Scott D. Pletcher; Richard A. Miller

doi:10.1126/sciadv.aaz7628

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance

David B. Lombard^*, William J. Kohler, Angela H. Guo, Christi Gendron, Melissa Han, Weiqiao Ding, Yang Lyu, Tsui Ting Ching, Feng Yung Wang, Tuhin S. Chakraborty, Zaneta Nikolovska-Coleska, Yuzhu Duan, Thomas Girke, Ao Lin Hsu, Scott D. Pletcher, Richard A. Miller

^*此作品的通信作者

研究成果: Article › 同行評審

15 引文斯高帕斯（Scopus）

摘要

Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.

原文	English
文章編號	eaaz7628
期刊	Science Advances
卷	6
發行號	40
DOIs	https://doi.org/10.1126/sciadv.aaz7628
出版狀態	Published - 30 9月 2020

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10.1126/sciadv.aaz7628

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Lombard, D. B., Kohler, W. J., Guo, A. H., Gendron, C., Han, M., Ding, W., Lyu, Y., Ching, T. T., Wang, F. Y., Chakraborty, T. S., Nikolovska-Coleska, Z., Duan, Y., Girke, T., Hsu, A. L., Pletcher, S. D., & Miller, R. A. (2020). High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance. Science Advances, 6(40), 文章 eaaz7628. https://doi.org/10.1126/sciadv.aaz7628

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title = "High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance",

abstract = "Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.",

author = "Lombard, {David B.} and Kohler, {William J.} and Guo, {Angela H.} and Christi Gendron and Melissa Han and Weiqiao Ding and Yang Lyu and Ching, {Tsui Ting} and Wang, {Feng Yung} and Chakraborty, {Tuhin S.} and Zaneta Nikolovska-Coleska and Yuzhu Duan and Thomas Girke and Hsu, {Ao Lin} and Pletcher, {Scott D.} and Miller, {Richard A.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",

year = "2020",

month = sep,

day = "30",

doi = "10.1126/sciadv.aaz7628",

language = "English",

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Lombard, DB, Kohler, WJ, Guo, AH, Gendron, C, Han, M, Ding, W, Lyu, Y, Ching, TT, Wang, FY, Chakraborty, TS, Nikolovska-Coleska, Z, Duan, Y, Girke, T, Hsu, AL, Pletcher, SD & Miller, RA 2020, 'High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance', Science Advances, 卷 6, 編號 40, eaaz7628. https://doi.org/10.1126/sciadv.aaz7628

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T1 - High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance

AU - Lombard, David B.

AU - Kohler, William J.

AU - Guo, Angela H.

AU - Gendron, Christi

AU - Han, Melissa

AU - Ding, Weiqiao

AU - Lyu, Yang

AU - Ching, Tsui Ting

AU - Wang, Feng Yung

AU - Chakraborty, Tuhin S.

AU - Nikolovska-Coleska, Zaneta

AU - Duan, Yuzhu

AU - Girke, Thomas

AU - Hsu, Ao Lin

AU - Pletcher, Scott D.

AU - Miller, Richard A.

N1 - Publisher Copyright: © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2020/9/30

Y1 - 2020/9/30

N2 - Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.

AB - Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.

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SN - 2375-2548

VL - 6

JO - Science Advances

JF - Science Advances

IS - 40

M1 - eaaz7628

ER -

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance

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