Nrf2: A promising therapeutic target in bone-related diseases

Che, Jingmin; Yang, Xiaoli; Jin, Zhankui; Xu, Cuixiang

doi:10.1016/j.biopha.2023.115748

Cited by 6 publications

(4 citation statements)

References 212 publications

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“…However, under oxidative stress, the cysteine residues that maintain the Keap1 association with Nrf2 are oxidized, modifying their shape and releasing Nrf2. Unbound Nrf2 translocated to the nucleus, modulating ARE-dependent gene expression and initiating the cytoprotective signaling cascade [19,20] (Figure 10).…”

Section: Discussionmentioning

confidence: 99%

“…Other studies explained that Nrf2 is indispensable for acquiring and maintaining bone mass even under various stress conditions. More studies show that Nrf2 overactivation inhibits bone formation, while its moderate activation promotes increased bone mass [18,19,23]. Earlier research reported that GCs induced osteoporosis through Nrf2/HO-1 signaling disruption [16,24].…”

Section: Introductionmentioning

confidence: 99%

“…Nrf2 plays an essential and controversial role in the defense against oxidative stress and regulation of bone homeostasis. Nrf2 inactive form is constitutively expressed in the cytoplasm, and its accumulation and activation in the nucleus are favored in oxidative injury [16,19]. Under oxidative stress, Nrf2 liberated from its inhibitory form and subsequently translocated to the nucleus and attached to the antioxidant-responsive element (ARE) regions in the promoter of different antioxidant genes, leading to increased expression of diverse detoxification and antioxidant enzymes as heme oxygenase-1 (HO-1) [20].…”

Section: Introductionmentioning

confidence: 99%

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The Therapeutic Potential of Two Egyptian Plant Extracts for Mitigating Dexamethasone-Induced Osteoporosis in Rats: Nrf2/HO-1 and RANK/RANKL/OPG Signals

Saleh,

El-Bessoumy

et al. 2024

Antioxidants

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The prolonged use of exogenous glucocorticoids, such as dexamethasone (Dex), is the most prevalent secondary cause of osteoporosis, known as glucocorticoid-induced osteoporosis (GIO). The current study examined the preventative and synergistic effect of aqueous chicory extract (ACE) and ethanolic purslane extract (EPE) on GIO compared with Alendronate (ALN). The phytochemical contents, elemental analysis, antioxidant scavenging activity, and ACE and EPE combination index were evaluated. Rats were randomly divided into control, ACE, EPE, and ACE/EPE MIX groups (100 mg/kg orally), Dex group (received 1.5 mg Dex/kg, Sc), and four treated groups received ACE, EPE, ACE/EPE MIX, and ALN with Dex. The bone mineral density and content, bone index, growth, turnover, and oxidative stress were measured. The molecular analysis of RANK/RANKL/OPG and Nrf2/HO-1 pathways were also evaluated. Dex causes osteoporosis by increasing oxidative stress, decreasing antioxidant markers, reducing bone growth markers (OPG and OCN), and increasing bone turnover and resorption markers (NFATc1, RANKL, ACP, ALP, IL-6, and TNF-α). In contrast, ACE, EPE, and ACE/EPE MIX showed a prophylactic effect against Dex-induced osteoporosis by modulating the measured parameters and the histopathological architecture. In conclusion, ACE/EPE MIX exerts a powerful synergistic effect against GIO by a mode of action different from ALN.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Therapeutic Potential of Two Egyptian Plant Extracts for Mitigating Dexamethasone-Induced Osteoporosis in Rats: Nrf2/HO-1 and RANK/RANKL/OPG Signals

Saleh,

El-Bessoumy

et al. 2024

Antioxidants

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“…Apart from the well-known action of the NRF2/KEAP1 signalling pathway as a regulator for antioxidative enzyme transcription providing cellular resistance to oxidative stress, the increase in the NRF2 signalling molecule inhibits RANKL and NF-κB expression to impede the efficacy of NFATc1 in osteoclast differentiation and formation. During osteoclastogenesis, NRF2 expression is lowered, compromising the antioxidant defence and augmenting the transcription activity of genes associated with osteoclastogenic differentiation [47]. Theoretically, active GSK3β negatively regulates NRF2 activity via phosphorylation and, subsequently, degradation of NRF2 [48].…”

Section: Nrf2/keap1 Signalling Pathwaymentioning

confidence: 99%

Glycogen Synthase Kinase-3 Beta (GSK3β) as a Potential Drug Target in Regulating Osteoclastogenesis: An Updated Review on Current Evidence

Wong

2024

Biomolecules

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Glycogen synthase kinase 3-beta (GSK3β) is a highly conserved protein kinase originally involved in glucose metabolism, insulin activity, and energy homeostasis. Recent scientific evidence demonstrated the significant role of GSK3β in regulating bone remodelling through involvement in multiple signalling networks. Specifically, the inhibition of GSK3β enhances the conversion of osteoclast progenitors into mature osteoclasts. GSK3β is recognised as a pivotal regulator for the receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), nuclear factor-kappa B (NF-κB), nuclear factor-erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1), canonical Wnt/beta (β)-catenin, and protein kinase C (PKC) signalling pathways during osteoclastogenesis. Conversely, the inhibition of GSK3β has been shown to prevent bone loss in animal models with complex physiology, suggesting that the role of GSK3β may be more significant in bone formation than bone resorption. Divergent findings have been reported regarding the efficacy of GSK3β inhibitors as bone-protecting agents. Some studies demonstrated that GSK3β inhibitors reduced osteoclast formation, while one study indicated an increase in osteoclast formation in RANKL-stimulated bone marrow macrophages (BMMs). Given the discrepancies observed in the accumulated evidence, further research is warranted, particularly regarding the use of GSK3β silencing or overexpression models. Such efforts will provide valuable insights into the direct impact of GSK3β on osteoclastogenesis and bone resorption.

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Protopine protects chondrocytes from undergoing ferroptosis by activating Nrf2 pathway

Chen,

Zhong,

Sang

et al. 2024

Biochemical and Biophysical Research Communications

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Nrf2: A promising therapeutic target in bone-related diseases

Cited by 6 publications

References 212 publications

The Therapeutic Potential of Two Egyptian Plant Extracts for Mitigating Dexamethasone-Induced Osteoporosis in Rats: Nrf2/HO-1 and RANK/RANKL/OPG Signals

The Therapeutic Potential of Two Egyptian Plant Extracts for Mitigating Dexamethasone-Induced Osteoporosis in Rats: Nrf2/HO-1 and RANK/RANKL/OPG Signals

Glycogen Synthase Kinase-3 Beta (GSK3β) as a Potential Drug Target in Regulating Osteoclastogenesis: An Updated Review on Current Evidence

Protopine protects chondrocytes from undergoing ferroptosis by activating Nrf2 pathway

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