The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

O’Connell, Maria A.; Hayes, John D.

doi:10.1042/bst20150069

Cited by 145 publications

(113 citation statements)

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“…In addition, SFN also possibly ameliorated the memory impairment in diabetic model through anti-inflammation [25]. Recent studies have demonstrated that Nrf2-ARE signaling is also involved in attenuating inflammation-associated pathogenesis [26]. However, these potential reasons still require further verifications.…”

Section: Discussionmentioning

confidence: 97%

Sulforaphane Prevents Neuronal Apoptosis and Memory Impairment in Diabetic Rats

Wang

Fang

Zhen

et al. 2016

Cell Physiol Biochem

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Background/Aims: To explore the effects of sulforaphane (SFN) on neuronal apoptosis in hippocampus and memory impairment in diabetic rats. Methods: Thirty male rats were randomly divided into normal control, diabetic model and SFN treatment groups (N = 10 in each group). Streptozotocin (STZ) was applied to establish diabetic model. Water Morris maze task was applied to test learning and memory. Tunel assaying was used to detect apoptosis in hippocampus. The expressions of Caspase-3 and myeloid cell leukemia 1(MCL-1) were detected by western blotting. Neurotrophic factor levels and AKT/GSK3β pathway were also detected. Results: Compared with normal control, learning and memory were apparently impaired, with up-regulation of Caspase-3 and down-regulation of MCL-1 in diabetic rats. Apoptotic neurons were also found in CA1 region after diabetic modeling. By contrast, SFN treatment prevented the memory impairment, decreased the apoptosis of hippocampal neurons. SFN also attenuated the abnormal expression of Caspase-3 and MCL-1 in diabetic model. Mechanically, SFN treatment reversed diabetic modeling-induced decrease of p-Akt, p-GSK3β, NGF and BDNF expressions. Conclusion: SFN could prevent the memory impairment and apoptosis of hippocampal neurons in diabetic rat. The possible mechanism was related to the regulation of neurotropic factors and Akt/GSK3β pathway.

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Section: Discussionmentioning

confidence: 97%

Sulforaphane Prevents Neuronal Apoptosis and Memory Impairment in Diabetic Rats

Wang

Fang

Zhen

et al. 2016

Cell Physiol Biochem

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“…Previous in silico analysis predicted 85 NRF2-miRNA interactions, with 63 miRNAs that can regulate NRF2 directly or indirectly [34]. Nfe2l2 proved to be a critical player in homeostasis and several organs in mammals, such as brain, liver and kidney [35].…”

Section: Discussionmentioning

confidence: 99%

The Differentially Expressed Circular RNAs in the Substantia Nigra and Corpus Striatum of Nrf2-Knockout Mice

Yang¹,

Zhang²,

Lin³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway plays a protective role in both acute neuronal damage and chronic neurodegeneration-related oxidative stress. Circular RNAs (circRNAs) are involved with various diseases in the central nervous system (CNS). This study aimed to identify the key circRNAs involved in Nrf2-neuroprotection against oxidative stress. Methods: The differentially expressed circRNAs (DEcircRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice were identified by microarray analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was then used to validate the expression of selected DEcircRNAs in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice. Based on our previous microarray analysis of the differentially expressed mRNAs (DEmRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice, the DEcircRNA-miRNA-DEmRNA interaction network was constructed. Functional annotation of DEmRNAs that shared the same binding miRNAs with DEcircRNAs was performed using gene ontology (GO) and pathway analyses. Results: A total of 65 and 150 significant DEcircRNAs were obtained in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, respectively, and seventeen shared DEcircRNAs were found in both these two tissues. The qRT-PCR results were generally consistent with the microarray results. The DEcircRNA-miRNA-DEmRNA interaction network and pathway analysis indicated that mmu_circRNA_34132, mmu_circRNA_017077 and mmu-circRNA-015216 might be involved with Nrf2-mediated neuroprotection against oxidative stress. Mmu_circRNA_015216 and mmu_circRNA_017077 might play roles in the Nrf2-related transcriptional misregulation and Nrf2-mediated processes of rheumatoid arthritis, respectively. In addition to these two processes, mmu_circRNA_34132 may be a potential regulator of Nrf2-mediated protection for diabetes mellitus and Nrf2-mediated defence against ROS in hearts. Conclusion: In conclusion, our study identified the key DEcircRNAs in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, which might provide new clues for further exploring the mechanism of Nrf2-mediated neuroprotection against oxidative stress and other Nrf2-mediated processes.

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“…Linking our findings, impaired Nrf-2/HO-1 signaling is responsible for the increased responsiveness to IL-1β, as shown by the increased IL-6 and PGE 2 release and ROS production by chondrocytes. The Nrf-2/HO-1 axis is a crucial cell survival mechanism that counteracts oxidative stress and inflammation (24,40). Deficiencies in this axis have been identified in some systemic diabetic complications, such as retinopathy or cardiopathy (33)(34)(35)41).…”

Section: Discussionmentioning

confidence: 99%

The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes–associated osteoarthritis

Vaamonde‐García

Pigenet

Laiguillon

et al. 2017

Journal of Biological Chemistry

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Epidemiological findings support the hypothesis that type 2 diabetes mellitus (T2DM) is a risk factor for osteoarthritis (OA). Moreover, OA cartilage from patients with T2DM exhibits a greater response to inflammatory stress, but the molecular mechanism is unclear. To investigate whether the antioxidant defense system participates in this response, we examined here the expression of nuclear factor-erythroid 2-related factor (Nrf-2), a master antioxidant transcription factor, and of heme oxygenase-1 (HO-1), one of its main target genes, in OA cartilage from T2DM and non-T2DM patients as well as in murine chondrocytes exposed to high glucose (HG). Ex vivo experiments indicated that Nrf-2 and HO-1 expression is reduced in T2DM versus non-T2DM OA cartilage (0.57-fold Nrf-2 and 0.34-fold HO-1), and prostaglandin E 2 (PGE 2 ) release was increased in samples with low HO-1 expression. HG-exposed, IL-1β-stimulated chondrocytes had lower Nrf-2 levels in vitro, particularly in the nuclear fraction, than chondrocytes exposed to normal glucose (NG). Accordingly, HO-1 levels were also decreased (0.49-fold) in these cells. The HO-1 inducer cobalt protoporphyrin IX more efficiently attenuated PGE 2 and IL-6 release in HG+IL-1β-treated cells than in NG+IL-1β-treated cells. Greater reductions in HO-1 expression and increase in PGE 2 /IL-6 production were observed in HG+IL-1β-stimulated chondrocytes from Nrf-2 −/− mice than in chondrocytes from wild-type mice. We conclude that the Nrf-2/HO-1 axis is a critical pathway in the hyperglucidic-mediated dysregulation of chondrocytes. Impairments in this antioxidant system may explain the greater inflammatory responsiveness of OA cartilage from T2DM patients and may inform treatments of such patients.

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The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

Cited by 145 publications

References 14 publications

Sulforaphane Prevents Neuronal Apoptosis and Memory Impairment in Diabetic Rats

Sulforaphane Prevents Neuronal Apoptosis and Memory Impairment in Diabetic Rats

The Differentially Expressed Circular RNAs in the Substantia Nigra and Corpus Striatum of Nrf2-Knockout Mice

The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes–associated osteoarthritis

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