Novel diterpenoid-type activators of the Keap1/Nrf2/ARE signaling pathway and their regulation of redox homeostasis

Li, Ailing; Shen, Tao; Wang, Tian; Zhou, Mingxing; Wang, Bin; Song, Jintong; Zhang, Peng-Liang; Wang, Xiaoling; Ren, Dongmei; Lou, Hongxiang; Wang, Xiaoning

doi:10.1016/j.freeradbiomed.2019.06.001

Cited by 23 publications

(14 citation statements)

References 44 publications

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“…The KEAP1/NRF2/ARE pathway is currently recognized as one most important cell defense systems to counteract oxidative injury and inflammation [ 31 ], thus its dysregulation is implicated in many human illnesses, particularly cancers [ 32 , 33 ]. Under unstressed conditions, Nrf2 is sequestered by Keap1 and anchored in the cytoplasm in the resting state [ 34 ]. While, under oxidative stress conditions, Nrf2 is activated and dissociated from Keap1 binding, then translocated into nuclei where it binds to the antioxidant response element (ARE) and promotes the expression of downstream antioxidative proteins, including NQO1 and HO1 [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Puerarin induces apoptosis in prostate cancer cells via inactivation of the Keap1/Nrf2/ARE signaling pathway

Luo

et al. 2021

Bioengineered

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In this study, we examined the antitumor effects of Puerarin (PEU) on androgen-independent (DU145 and PC-3) and androgen-dependent (LNCaP) prostate cancer cells, and explored its potential mechanisms. Supplement with PEU (2.5 μM, 5 μM, and 10 μM) exhibited a marked inhibitory effect against the growth of DU145 and PC-3 cells, especially beyond 24 h, whereas there is only slight growth inhibitory effect on LNCaP cells at the high concentration of 10 μM at 72 h. This loss of cell viability in DU145 and PC-3 cells by PEU was mediated by the induction of apoptosis via up-regulation of Bax and cleaved-caspase-3, but downregulation of Bcl-2. Moreover, more intracellular ROS and LDH production were observed in DU145 and PC-3 cells upon PEU treatment. Meanwhile, the amount of pro-inflammatory cytokines (IL-1β and IL-6) was increased, but the content of anti-inflammatory cytokines IL-10 was attenuated. Additionally, PEU pretreatment resulted in an increase of Keap1 protein expression, and a decline of Nrf2, HO-1 and NQO1 protein expression in DU145 and PC3 cells. The present findings indicated that PEU exerted its antitumor activities toward androgen-independent prostate cancer cells via inactivation of Keap1/ NrF2/ARE signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Puerarin induces apoptosis in prostate cancer cells via inactivation of the Keap1/Nrf2/ARE signaling pathway

Luo

et al. 2021

Bioengineered

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“…The reason for this may be that the levels of Nrf2 and HO-1, which is an ARE, can be activated in response to stress and inflammatory insults. Under oxidative or chemical stress, activated Nrf2 translocates into the nucleus and interacts with AREs (59). The expression of cytoprotective target genes, including phase II detoxifying enzymes, antioxidant proteins and molecular proteasomes/chaperones, is then transactivated in response to the stress (60).…”

Section: Discussionmentioning

confidence: 99%

Edaravone attenuates experimental asthma in mice through induction of HO‑1 and the Keap1/Nrf2 pathway

Pan

Feng

et al. 2019

Exp Ther Med

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Asthma is a chronic disease that threatens public health worldwide. Multiple studies have shown that oxidative stress plays an important role in the pathogenesis of asthma. Edaravone (Eda), a free radical scavenger, has been found to have a protective effect against lung injury due to its ability to eliminate reactive oxygen species. The present study aimed to investigate the effect of Eda on asthma and the mechanism underlying its actions. An experimental asthma model was induced in mice, before they were treated with different doses of Eda. Measurements of airway responsiveness to methacholine (Mch), cell counts and cytokine levels in bronchoalveolar lavage fluid (BALF) and of the oxidative products and antioxidant enzymes in lung tissue were taken in these asthma model mice and compared with control mice. Protein levels of kelch-like ECH-associated protein-1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were determined in the lung tissue of normal mice and Nrf2 and HO-1-deficient mice subject to the asthma model to investigate the mechanisms underlying Eda action. The results indicated that Eda effectively reduced airway responsiveness to Mch. The total number of cells and the numbers of eosinophils, lymphocytes and neutrophils in BALF of asthma model mice were also significantly reduced by Eda treatment when compared with normal saline treatment. Eda treatment significantly alleviated perivascular edema, peribronchial inflammation and macrophage infiltration in the alveolar space and decreased the levels of inflammatory cytokines released in BALF compared with control. Eda also significantly reduced the levels of oxidative stress markers in BALF and restored the levels of antioxidative enzyme, superoxide dismutase, when compared with control. The Keap1/Nrf2 ratio was significantly decreased with Eda compared with control due to an increase in Nrf2 and a decrease in Keap1 expression. HO-1 expression was increased by Eda. The airway responsiveness of Nrf2-/mice or HO-1-/mice to Mch was significantly higher compared with normal mice treated with Eda. Taken together, the results of the present study show that Eda exerts anti-inflammatory and antioxidative effects, which suggests a potential use for Eda in reduction of asthma severity. The activated Keap1/Nrf2 pathway and HO-1 may be involved in the anti-asthmatic effect of Eda.

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“…The activation of HO-1 is directly regulated by the transcription factor Nrf2. Activated Nrf2 is transferred into the nucleus, which is complex with antioxidant response elements and increases the activation of HO-1 (Li et al, 2019). The NF-κB is a classic transcription factor that refers to many inflammation-associated physiologic events, such as innate and adaptive immunity, autoimmune diseases, and cancer (Mitchell & Carmody, 2018).…”

Section: Ionmentioning

confidence: 99%

Oral administration ofLactobacillus plantarumCQPC11 attenuated the airway inflammation in an ovalbumin (OVA)‐induced Balb/c mouse model of asthma

Lan

Gui

Zeng

et al. 2022

Journal of Food Biochemistry

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This study investigated the antiasthmatic and anti-inflammatory effects of Lactobacillus plantarum-CQPC11 (LP-CQPC11) on ovalbumin (OVA)-induced asthmatic Balb/c mice. Administration of different doses of LP-CQPC11 (10 5 , 10 7 , and 10 9 colony-forming unit [CFU]/mouse) effectively reduced airway hyperresponsiveness (AHR) and the lung W/D ratio in asthmatic mice. LP-CQPC11 treatment reduced the accumulation of inflammatory cells in the BALF and attenuated histologic edema in asthmatic mice. Administration of LP-CQPC11 decreased the serum levels of OVA-specific IgE, IgE, and OVA-specific IgG1. LP-CQPC11 treatment decreased the levels of inflammatory cytokines (TNFα, IL-4, IL-13, IL-5, and IL-6) in the BALF of asthmatic mice. In addition, LP-CQPC11 also elevated the mRNA levels of Foxp3 and T-bet and decreased the mRNA levels of Gata3 and RORγt in asthmatic mice lungs. Administration of LP-CQPC11 also reduced OVA-induced oxidative stress by improving the activities of GSH-Px, SOD, and catalase in the lungs. Finally, LP-CQPC11 treatment also significantly decreased the activation of the NF-κB pathway to modulate the inflammatory reaction in the lungs of asthmatic mice. The results from this study clearly demonstrated that oral administration of LP-CQPC11 exhibited outstanding activity in attenuating OVA-induced asthma in a mouse model. Furthermore, LP-CQPC11 may be an effective microecologic agent in preventing allergic asthma in the future.

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Novel diterpenoid-type activators of the Keap1/Nrf2/ARE signaling pathway and their regulation of redox homeostasis

Cited by 23 publications

References 44 publications

Puerarin induces apoptosis in prostate cancer cells via inactivation of the Keap1/Nrf2/ARE signaling pathway

Puerarin induces apoptosis in prostate cancer cells via inactivation of the Keap1/Nrf2/ARE signaling pathway

Edaravone attenuates experimental asthma in mice through induction of HO‑1 and the Keap1/Nrf2 pathway

Oral administration ofLactobacillus plantarumCQPC11 attenuated the airway inflammation in an ovalbumin (OVA)‐induced Balb/c mouse model of asthma

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