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

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

doi:10.1126/sciadv.aaz7628

Cited by 19 publications

(3 citation statements)

References 57 publications

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“…Although excess ROS reduce lifespan by causing extensive cellular dysfunction and damage, birds are remarkably long-lived. Generally, cellular stress resistance is an evolutionarily conserved feature of longevity [ 47 ]. The KEAP1-NRF2 system is one of the major mechanisms that enhances cellular stress resistance.…”

Section: Longevity and The Keap1-nrf2 Systemmentioning

confidence: 99%

The KEAP1-NRF2 System in Healthy Aging and Longevity

Matsumaru

Motohashi

2021

Antioxidants

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Aging is inevitable, but the inherently and genetically programmed aging process is markedly influenced by environmental factors. All organisms are constantly exposed to various stresses, either exogenous or endogenous, throughout their lives, and the quality and quantity of the stresses generate diverse impacts on the organismal aging process. In the current oxygenic atmosphere on earth, oxidative stress caused by reactive oxygen species is one of the most common and critical environmental factors for life. The Kelch-like ECH-associated protein 1-NFE2-related factor 2 (KEAP1-NRF2) system is a critical defense mechanism of cells and organisms in response to redox perturbations. In the presence of oxidative and electrophilic insults, the thiol moieties of cysteine in KEAP1 are modified, and consequently NRF2 activates its target genes for detoxification and cytoprotection. A number of studies have clarified the contributions of the KEAP1-NRF2 system to the prevention and attenuation of physiological aging and aging-related diseases. Accumulating knowledge to control stress-induced damage may provide a clue for extending healthspan and treating aging-related diseases. In this review, we focus on the relationships between oxidative stress and aging-related alterations in the sensory, glandular, muscular, and central nervous systems and the roles of the KEAP1-NRF2 system in aging processes.

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Section: Longevity and The Keap1-nrf2 Systemmentioning

confidence: 99%

The KEAP1-NRF2 System in Healthy Aging and Longevity

Matsumaru

Motohashi

2021

Antioxidants

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“…Следует отметить, что кофе без кофеина и табак без никотина, как сообщается, обеспечивают нейропротекцию с помощью Nrf2-зависимого механизма [39] в модели болезни Паркинсона на дрозофиле. В недавнем скрининге соединений, вызывающих устойчивость к химическим стрессорам, в качестве вторичного скрининга использовали C. elegans и дрозофилу для идентификации двух активаторов Nrf2 [40].…”

Section: Drosophila Melanogaster и Htsunclassified

High Throughput Screening in Drug Discovery: Problems And Solutions

Hushpulian,

Gaisina,

Nikulin

et al. 2024

Lomonosov Chemistry Journal

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World-wide introduction of high throughput screening (HTS) methods in drug discovery research did not result in the increased number of novel medications on the market. We discuss novel trends in drug discovery that came from the understanding that majority of diseases are multifactorial and that one enzyme has many protein substrates. Hence, new approaches are focused on development of drugs, which (1) trigger survival pathways to return the organism to homeostatic balance, and (2) inhibit enzymes modifying histones or transcription factors not at the active site, but by displacement of protein substrates from the enzyme complexes. A good example for both approaches comes from the development of activators of antioxidant defense. We analyze and illustrate problems of commonly used in vitro HTS assays, and briefl y discuss advantages and limitations of small animal models. The novel approaches are complementary to the standard HTS and do not substitute for testing in mammals. Development of transgenic reporter mice to monitor drug effects by means of in vivo imaging is extremely promising to select proper dosage and administration regimes for full-range PK studies.

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“…11 Nuclear factor erythroid-2-related factor 2 (Nrf2) is one of the critical regulators of the cellular response to defend against oxidative stress. 12 Under oxidative stress conditions, Nrf2 is isolated from Kelch-like ECH-associated protein 1 (Keap1) and translocate into the nucleus from the cytoplasm. 13 Upon entering the nucleus, Nrf2 regulates the expressions of downstream antioxidant enzymes by binding to the antioxidant response element (ARE).…”

Section: Introductionmentioning

confidence: 99%

Ginseng Saponin Rb1 Attenuates Cigarette Smoke Exposure-Induced Inflammation, Apoptosis and Oxidative Stress via Activating Nrf2 and Inhibiting NF-κB Signaling Pathways

Li,

et al. 2023

COPD

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Cigarette smoke exposure is one of the major risk factors for the development of chronic obstructive pulmonary disease (COPD). Ginseng saponin Rb1 (Rb1) is a natural extract from ginseng root with anti-inflammatory and anti-oxidant effects. However, the underlying mechanism of the Rb1 in COPD remains unknown. Therefore, we sought to explore the role of Rb1 in cigarette smokeinduced damage and to reveal the potential mechanism. Methods: The cell viability and lactose dehydrogenase (LDH) activity were analyzed using cell counting kit-8 (CCK-8) and LDH release assays. We further investigated the inflammation, apoptosis and oxidative stress markers and analyzed the nuclear factor-kappa B (NF-κB) and nuclear factor erythroid-2-related factor 2 (Nrf2) pathways in BEAS-2B cells and COPD rat model following cigarette smoke extract (CSE) exposure. Results: Our results showed that CSE promoted inflammation, apoptosis and oxidative stress in BEAS-2B cells. Rb1 suppressed the inflammatory response by inhibiting expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β and inhibiting the NF-κB signaling pathway. Rb1 possessed the ability to hinder cell apoptosis induced by CSE. In addition, Rb1 concurrently reduced CSE-induced oxidative reactions and promoted Nrf2 translocation to nucleus. For in vivo study, Rb1 treatment alleviated CSE-induced lung injury, apoptosis, reactive oxygen species (ROS) release and inflammatory reactions. Also, Rb1 treatment activated Nrf2 signaling and inactivated NF-κB signaling in COPD rats. Conclusion: Rb1 attenuates CSE-induced inflammation, apoptosis and oxidative stress by suppressing NF-κB and activating Nrf2 signaling pathways, which provides novel insights into the mechanism underlying CSE-induced COPD.

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

Cited by 19 publications

References 57 publications

The KEAP1-NRF2 System in Healthy Aging and Longevity

The KEAP1-NRF2 System in Healthy Aging and Longevity

High Throughput Screening in Drug Discovery: Problems And Solutions

Ginseng Saponin Rb1 Attenuates Cigarette Smoke Exposure-Induced Inflammation, Apoptosis and Oxidative Stress via Activating Nrf2 and Inhibiting NF-κB Signaling Pathways

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