Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Shih, Andy Y.; Johnson, Dale G.; Wong, Gloria; Kraft, Andrew D.; Jiang, Lei; Erb, Heidi; Johnson, Jeffrey A.; Murphy, Timothy H.

doi:10.1523/jneurosci.23-08-03394.2003

Cited by 700 publications

(704 citation statements)

References 84 publications

Supporting

Mentioning

674

Contrasting

Unclassified

Order By: Relevance

“…Activation of the Keap1-Nrf2-ARE pathway by small molecules in astrocytes accelerates the resistance of neurons to the non-excitotoxic glutamate toxicity (Kraft et al 2004). Protection against the ROS in co-culture neuron culture is conferred by the precise astrocyte stimulation of Nrf2 (Shih et al 2003). In the animal model of HD, astrocyte-specific activation of Nrf2 reduces the disease pathogenesis (Calkins et al 2005).…”

Section: Huntington's Diseasementioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

View full text Add to dashboard Cite

The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

show abstract

Section: Huntington's Diseasementioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Hence, the Nrf2‐ARE pathway is considered a high‐value therapeutic target (de Vries et al, 2008; Johnson and Johnson, 2015; van Muiswinkel and Kuiperij, 2005). It is preferentially activated in astrocytes while neurons largely depend on astrocytes for the antioxidant defense (Kraft, Johnson, & Johnson, 2004; Lee, Calkins, Chan, Kan, & Johnson, 2003; Shih et al, 2003). Therefore, unsurprisingly, many studies report that activation of the Nrf2 pathway in astrocytes is neuroprotective (Calkins, Vargas, Johnson, & Johnson, 2010; Chen et al, 2009; Gan, Vargas, Johnson, & Johnson, 2012; Vargas, Johnson, Sirkis, Messing, & Johnson, 2008).…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

View full text Add to dashboard Cite

Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

show abstract

“…15 Nrf2 has also been shown to protect against oxidative stressinduced cell death by upregulation of enzymes involved in GSH biosynthesis, use, and export. 16 High intracellular GSH levels have been associated with apoptotic resistant phenotypes in several models of apoptosis, 17,18 and GSH depletion by itself has been observed to either induce or stimulate apoptosis. 17,19 For example, buthionine sulfoximine (BSO)-induced GSH depletion does not trigger apoptosis, but potentiates death receptor-induced apoptosis in T cells.…”

Section: Figure 1 Apoptotic Signaling Pathways (See Text For Furthermentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

View full text Add to dashboard Cite

Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms. Apoptosis or programmed cell death is a ubiquitous homeostatic process involved in numerous biological systems. Under physiological conditions it is critical not only in the turnover of cells in tissues but also during normal development and senescence. Moreover, its deregulation has been widely observed to occur as either a cause or consequence of distinct pathologies including cancer, autoimmune, and neurodegenerative diseases. Apoptosis is a highly organized program induced by a myriad of stimuli that are characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations in individual cells without involving an inflammatory response. Early stages of apoptosis are characterized by initiator caspase activation, cell shrinkage, loss of plasma membrane lipid asymmetry, and chromatin condensation. The execution phase of apoptosis is characterized by activation of executioner caspases and endonucleases, apoptotic body formation, and cell fragmentation 1 (Figure 1). Interestingly, recent studies have shown that changes in the intracellular milieu of the cells, such as alterations in the redox environment, are important regulators of the progression to apoptosis. 2 These discoveries have lead to the concept of a permissive apoptotic environment necessary for the activation of the proper signaling pathways regulating apoptosis. Glutathione (GSH) depletion is an early hallmark in the progression of cell death in response to a variety of apoptotic stimuli in numerous cell types 3,4 (Figure 2), although the exact role of GSH depletion in apoptosis is still controversial. We review recent data that show new insights into the understanding of the causes and consequences that alterations in the redox environment of the cell have on apoptosis.The Role of GSH in the Regulation of Apoptosis GSH synthesis, depletion, and apopt...

show abstract

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Cited by 700 publications

References 84 publications

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Apoptosis and glutathione: beyond an antioxidant

Contact Info

Product

Resources

About