Transcriptional activation of antioxidant gene expression by Nrf2 protects against mitochondrial dysfunction and neuronal death associated with acute and chronic neurodegeneration

Goodfellow, Molly J.; Borcar, Apurva; Proctor, Julie L.; Greco, Tiffany; Rosenthal, Robert; Fiskum, Gary

doi:10.1016/j.expneurol.2020.113247

Cited by 43 publications

(22 citation statements)

References 240 publications

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“…Upon exposure to stress, Nrf2 is isolated from Keap1, phosphorylated by protein kinase, and then translocated to the nucleus. Once in the nucleus, Nrf2 forms a heterodimer with small Maf proteins and binds to ARE, which promotes the expression of proteins involved in the response to redox homeostasis [ 49 , 50 ]. In addition, activated Nrf2 directly enhances PGC-1 α expression [ 14 , 17 ], and PGC-1 α or activated Nrf2 regulates NRF-1 expression by binding to the NRF-1 promoter region [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D‐Galactose‐Induced Aging Mice by Increasing Nrf2 and PGC‐1α through the cAMP‐CREB Pathway

Wang

Zhang

Zhao

et al. 2021

Oxidative Medicine and Cellular Longevity

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Aging is a complex phenomenon associated with oxidative stress and mitochondrial dysfunction. The objective of this study was to investigate the potential ameliorative effects of the phosphodiesterase inhibitor pentoxifylline (PTX) on the aging process and its underlying mechanisms. We treated D-galactose- (D-gal-) induced aging mice with PTX and measured the changes in behavior, degree of oxidative damage, and mitochondrial ultrastructure and content as well as the expression of nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated antioxidant genes and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha- (PGC-1α-) dependent mitochondrial biogenesis genes. The results demonstrated that PTX improved cognitive deficits, reduced oxidative damage, ameliorated abnormal mitochondrial ultrastructure, increased mitochondrial content and Nrf2 activation, and upregulated antioxidant and mitochondrial biogenesis gene expression in the hippocampus of wild-type aging mice. However, the above antiaging effects of PTX were obviously decreased in the brains of Nrf2-deficient D-gal-induced aging mice. Moreover, in hydrogen peroxide-treated SH-SY5Y cells, we found that cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and Nrf2/PGC-1α act in a linear way by CREB siRNA transfection. Thus, PTX administration improved the aging-related decline in brain function by enhancing antioxidative capability and promoting mitochondrial biogenesis, which might depend on increasing Nrf2 and PGC-1α by activating the cAMP-CREB pathway.

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Section: Discussionmentioning

confidence: 99%

Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D‐Galactose‐Induced Aging Mice by Increasing Nrf2 and PGC‐1α through the cAMP‐CREB Pathway

Wang

Zhang

Zhao

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Under physiological conditions, Keap1 combines with and inhibits Nrf2. Under the in uence of external oxidative stressors, Nrf2 is decoupled with Keap1 and combined with the antioxidant response element ARE to activate the Nrf2 signaling pathway, thereby increasing the expression of antioxidant proteins HO-1, SOD, NQO1, etc., and reducing oxidative damage and accumulation of toxicity metabolites [49,50] . In a study by Wang et al when the amygdala was rapidly ignited, the protein and gene levels of Nrf2, HO-1 and NQO1 increased signi cantly in the hippocampus, which con rmed that the Nrf2 signaling pathway plays an important role in the early stages of epileptic seizures [51] .…”

Section: Discussionmentioning

confidence: 99%

Genistein protects epilepsy-induced brain injury through regulating the JAK2/STAT3 and Keap1/Nrf2 signaling pathways in the developing rats

Yan

Peng

et al. 2021

European Journal of Pharmacology

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Section: Discussionmentioning

confidence: 99%

Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats

Huang

Feng

et al. 2021

Preprint

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Background: Epilepsy is a common chronic neurological disease caused by the over-synchronization of neurons that lead to brain dysfunction. Recurrent seizures or status epilepticus can cause irreversible brain damage. The JAK2-STAT3 signal transduction pathway is stimulated by cytokines and involved in various pathological processes including inflammation, apoptosis and immune regulation in central system diseases. Keap1/Nrf2 is an important anti-oxidative stress pathway, which can reduce the toxic effects of oxygen free radicals and endogenous toxins on neurons. Genistein (Gen) can modulate inflammation and neuronal apoptosis, and may thereby have antiepileptic effects. This study aimed to explore the regulation of Genistein on JAK2/STAT3 and Keap1/Nrf2 signaling pathway and the protective effects on brain injury after epilepsy. Methods: Pentylenetetrazole (PTZ) was used to induce epilepsy in developing rats and Genistein was used for pretreatment of epilepsy. The seizure latency, grade scores and duration of the first generalized tonic-clonic seizure (GTCs) were recorded. Hippocampus tissue was sampled at 24 hours post-epilepsy. Immunofluorescence staining was used to observe the number of mature neurons, activated microglia and astrocytes in the hippocampal CA1 region. Western blot and qRT-PCR were used to determine the protein and mRNA levels of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, Nrf2, HO-1, NQO1, caspase3, Bax and Bcl2 in the hippocampus. Results: Immunofluorescence showed that the number of neurons significantly decreased, and activated microglia and astrocytes significantly increased after epilepsy; Western blot and q-PCR showed that the expressions of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, caspase3 and Bax significantly increased, while Nrf2, HO-1, NQO1 and Bcl-2 were significantly reduced after epilepsy. These effects were reversed by Genistein treatment. Moreover, Genistein was found to prolong seizure latency and reduce seizure intensity score and duration of generalized tonic-clonic seizures(GTCs). Conclusions: Genistein can activate the Keap1/Nrf2 antioxidant stress pathway and attenuate the activation of microglia and astrocytes. Genistein also inhibits the JAK2-STAT3 inflammation pathway and expression of apoptotic proteins, and increases the number of surviving neurons, thus having a protective effect on epilepsy-induced brain damage.

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Transcriptional activation of antioxidant gene expression by Nrf2 protects against mitochondrial dysfunction and neuronal death associated with acute and chronic neurodegeneration

Cited by 43 publications

References 240 publications

Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D‐Galactose‐Induced Aging Mice by Increasing Nrf2 and PGC‐1α through the cAMP‐CREB Pathway

Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D‐Galactose‐Induced Aging Mice by Increasing Nrf2 and PGC‐1α through the cAMP‐CREB Pathway

Genistein protects epilepsy-induced brain injury through regulating the JAK2/STAT3 and Keap1/Nrf2 signaling pathways in the developing rats

Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats

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