The emerging role of redox-sensitive Nrf2–Keap1 pathway in diabetes

Bhakkiyalakshmi, Elango; Sireesh, Dornadula; Rajaguru, P.; Paulmurugan, Ramasamy; Ramkumar, Kunka Mohanram

doi:10.1016/j.phrs.2014.10.004

Cited by 133 publications

(99 citation statements)

References 145 publications

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“…After exposure of mouse oocyte to 200 nM brusatol for up to 14 h, these genes show time-dependent decreases in the mRNA levels, as described in mitotic cells[19]. Based on the literature [24–26], we postulated that ROS and/or mitochondria function are likely to be the targets of Nrf2 on spindle/chromosomes in oocytes. Although Nrf2-mediated signaling pathway was inhibited as described in mitotic cells, we unexpectedly discovered that Brusatol treatment had little effects on ROS production and mitochondria function in oocytes.…”

Section: Discussionmentioning

confidence: 77%

The toxic effects and possible mechanisms of Brusatol on mouse oocytes

Ma¹,

Li²,

Zhang³

et al. 2017

PLoS ONE

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Brusatol is a natural quassinoid that shows a potential therapeutic use in cancer models by the inhibition of Nuclear factor erythroid 2-related factor 2 (Nrf2) and is capable of inducing a variety of biological effects. The effects of Brusatol on oocyte meiosis has not been addressed. In this study, we investigated the impact of Brusatol treatment on mouse oocyte maturation and its possible mechanism. Our data demonstrated that Brusatol treatment disrupted oocyte maturation and spindle/chromosome organization by modulating Nrf2-Cyclin B1 pathway, as the influence of Brusatol was compensated by the addition of Nrf2 activation plasmid, and the mRNA and protein levels of Cyclin B1 were severely reduced in oocytes following Nrf2 decline. In summary, our data support a model that Brusatol, through the inhibition of Nrf2, modulate Cyclin B1 levels, consequently disturbing proper spindle assembly and chromosome condensation in meiotic oocytes.

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Section: Discussionmentioning

confidence: 77%

The toxic effects and possible mechanisms of Brusatol on mouse oocytes

Ma¹,

Li²,

Zhang³

et al. 2017

PLoS ONE

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“…PERK has been proposed as an Nrf2 activator in the context of ER stress and oxidative stress 24 . During the UPR and oxidative stress, PERK signaling activates Nrf2, the PERK substrate, to dissociate from its negative regulator Keap1 to induce the expression of a set of phase II detoxifying enzymes including hemeoxygenase 1 (HO-1), γ-glutamylcysteine synthetase (γ-GCS), glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 (NQO1) 38 . Keap1/Nrf2 dependent antioxidant protection system is considered one of the most important cellular defence mechanisms in scavenging ROS to combat oxidative stress and ER stress 39, 40 .…”

Section: Discussionmentioning

confidence: 99%

Tangluoning, a traditional Chinese medicine, attenuates in vivo and in vitro diabetic peripheral neuropathy through modulation of PERK/Nrf2 pathway

Yang

Yao

Liu

et al. 2017

Sci Rep

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Prolonged hyperglycemia-induced oxidative stress and endoplasmic reticulum stress have been demonstrated to play a key role in progression of diabetic peripheral neuropathy (DPN). PERK/ Nrf2 pathway plays a predominant role in oxidative and endoplasmic reticulum (ER) stress which is associated with cell survival. This study examined the modulation of the PERK/Nrf2 pathway and apoptosis by a traditional Chinese medicine Tangluoning (TLN) in streptozotocin-induced DPN rat models and the effects of serum TLN on the PERK/Nrf2 pathway, apoptosis, intracellular reactive oxygen species and mitochondrial membrane potential in Schwann cells cultured in 150 mM glucose. It is found that TLN attenuated oxidative and ER stress and apoptosis through the PERK/Nrf2 pathway by upregulating p-PERK, Nrf2/ARE pathways and downregulating the CHOP-related apoptosis pathways in the experimental DPN models both in vivo and in vitro.

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“…Sulforaphane is known to activate Nrf-2 by interacting with the cysteine residues of Keap1, which is responsible for Nrf-2 ubiquitination (Hu, Eggler, Mesecar, & van Breemen, 2011;Li, Paonessa, & Zhang, 2012). Multiple studies have shown that sulforaphane has remarkable health benefits, including cancer chemoprevention (Tortorella, Royce, Licciardi, & Karagiannis, 2015), avoidance of ischaemia/reperfusion injury (Pan et al, 2014), diabetes (Bhakkiyalakshmi, Sireesh, Rajaguru, Paulmurugan, & Ramkumar, 2015), neurotoxicity (Lee, Jeong, & Park, 2014) and hepatotoxicity (Li et al, 2014). Although a few reports show the effect of sulforaphane mediated activation of Nrf-2 pathway on T cell responses (Geisel et al, 2014), the underlying mechanisms are not completely worked out.…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane, a naturally occurring isothiocyanate, exhibits anti-inflammatory effects by targeting GSK3β/Nrf-2 and NF-κB pathways in T cells

Checker

Gambhir

Thoh

et al. 2015

Journal of Functional Foods

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A B S T R A C TA potent Nrf-2 activator sulforaphane (SF), which is currently under clinical trials for cancer therapy, was employed to elucidate the role of Keap1/Nrf-2/ARE signalling pathway in T-cell responses. SF suppressed mitogen induced T-cell and B-cell proliferation. It also inhibited mitogen induced upregulation of T-cell (CD25 and CD69) and B-cell (CD80 and CD86) activation markers and suppressed secretion of cytokines (IL-2, IL-4, IL-6 and IFN-γ). SF induced oxidative stress and its anti-inflammatory effects were abrogated by thiol antioxidants. SF activated PI3K/AKT, leading to phosphorylation mediated suppression of GSK3β resulting in Nrf-2 activation. We also show for the first time that SF can prevent direct interaction between NF-κB and its consensus sequence by modulating thiol groups. It also suppressed homeostatic proliferation of T-cells and suppressed lipopolysaccharide induced proinflammatory mediators in macrophages. Our study shows that the potent anti-inflammatory effects of SF are mediated via modulation of PI3K/AKT/GSK3β/Nrf-2 and NF-κB pathway in T-cells.

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The emerging role of redox-sensitive Nrf2–Keap1 pathway in diabetes

Cited by 133 publications

References 145 publications

The toxic effects and possible mechanisms of Brusatol on mouse oocytes

The toxic effects and possible mechanisms of Brusatol on mouse oocytes

Tangluoning, a traditional Chinese medicine, attenuates in vivo and in vitro diabetic peripheral neuropathy through modulation of PERK/Nrf2 pathway

Sulforaphane, a naturally occurring isothiocyanate, exhibits anti-inflammatory effects by targeting GSK3β/Nrf-2 and NF-κB pathways in T cells

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