Nrf2: An all-rounder in depression

Zuo, Chengchao; Cao, Huấn; Song, Yu; Gu, Zhongya; Huang, Yaqi; Yang, Yuyan; Miao, Jinfeng; Zhu, Liudi; Chen, Jianguo; Jiang, Yongsheng; Wang, Furong

doi:10.1016/j.redox.2022.102522

Cited by 50 publications

(32 citation statements)

References 220 publications

(287 reference statements)

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“…In microglia cells, inflammatory signaling is to a large extent determined by the competition for CBP/p300-occupancy between the pro-inflammatory transcription factor NFκB (in particular the p65/RelA subunit) and the anti-inflammatory transcription factors, NRF2 and CREB [ 60 , 61 , 62 , 63 , 64 ]. As mentioned above, the balance between these pro- and anti-inflammatory pathways, which is essential for major depressive disorder [ 65 , 66 ], is influenced by the kinase activity of GSK3. Active GSK3 enhances the affinity of p65 for CBP and p300 [ 61 ] and, on the other hand, promotes the nuclear export of NRF2 [ 67 ], inhibits the nuclear import of CREB [ 60 ], and promotes the catabolism of CREB and NRF2 [ 68 ].…”

Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

“…Although GSK3 comes in two distinct isoforms, modulation of CREB and NRF2 seems to be mediated by the GSK3β isoform only [ 60 ]. NRF2 increases the transcription of genes involved in oxidant-defense [ 63 ] and factors that stimulate mitochondrial biosynthesis [ 66 , 69 ]. Downstream of CREB are anti-inflammatory mediators such as brain-derived neurotrophic factor (BDNF), IL1-receptor antagonist (IL1-RA), IL10, and DUSP1 [ 62 , 67 ].…”

Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

“…Notably, DUSP1 is an inhibitor of the pro-inflammatory kinase p38 [ 70 , 71 , 72 ]. Activation of NRF2 provides transcriptional repression of TNFα, IL1β, IL6, IL8, and CCL2 in microglia, monocytes, and macrophages [ 66 , 69 ]. For instance, activation of NRF2 reduced TLR4-induced IL1β, IL6, iNOS, and COX2 expression in primary mouse peritoneal macrophages [ 66 , 69 ].…”

Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

“…Activation of NRF2 provides transcriptional repression of TNFα, IL1β, IL6, IL8, and CCL2 in microglia, monocytes, and macrophages [ 66 , 69 ]. For instance, activation of NRF2 reduced TLR4-induced IL1β, IL6, iNOS, and COX2 expression in primary mouse peritoneal macrophages [ 66 , 69 ]. Stimulation of Toll-like receptors promotes the enzyme activity of GSK3β [ 14 ] (for review, see [ 73 ]), whereas active GSK3 inhibits the production of the anti-inflammatory cytokine IL10, of IL1-RA, BDNF, and DUSP1 [ 72 , 74 ].…”

Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

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Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles

Kalkman

2023

Biomedicines

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Depression is a major public health concern. Unfortunately, the present antidepressants often are insufficiently effective, whilst the discovery of more effective antidepressants has been extremely sluggish. The objective of this review was to combine the literature on depression with the pharmacology of antidepressant compounds, in order to formulate a conceivable pathophysiological process, allowing proposals how to accelerate the discovery process. Risk factors for depression initiate an infection-like inflammation in the brain that involves activation microglial Toll-like receptors and glycogen synthase kinase-3β (GSK3β). GSK3β activity alters the balance between two competing transcription factors, the pro-inflammatory/pro-oxidative transcription factor NFκB and the neuroprotective, anti-inflammatory and anti-oxidative transcription factor NRF2. The antidepressant activity of tricyclic antidepressants is assumed to involve activation of GS-coupled microglial receptors, raising intracellular cAMP levels and activation of protein kinase A (PKA). PKA and similar kinases inhibit the enzyme activity of GSK3β. Experimental antidepressant principles, including cannabinoid receptor-2 activation, opioid μ receptor agonists, 5HT2 agonists, valproate, ketamine and electrical stimulation of the Vagus nerve, all activate microglial pathways that result in GSK3β-inhibition. An in vitro screen for NRF2-activation in microglial cells with TLR-activated GSK3β activity, might therefore lead to the detection of totally novel antidepressant principles with, hopefully, an improved therapeutic efficacy.

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Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

Section: Activation Of Microglia Cells By Risk Factors For Depressionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles

Kalkman

2023

Biomedicines

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“…Inflammation and oxidative stress were found to enhance each other, thus establishing a pathological state [ 1 ], which may be found in various psychiatric disorders. The variety of external stimuli to which organisms are subjected triggers adaptive responses, which are designed to restore homoeostasis through a fine balance between oxidation and antioxidant activity [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

The Nrf2 Pathway in Depressive Disorders: A Systematic Review of Animal and Human Studies

et al. 2023

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There is increasing interest in the involvement of antioxidative systems in protecting from depression. Among these, Nrf2 occupies a central place. We aimed to review the role of Nrf2 in depression. For this reason, we conducted a PubMed search using as search strategy (psychiatr*[ti] OR schizo*[ti] OR psychot*[ti] OR psychos*[ti] OR depress*[ti] OR MDD[ti] OR BD[ti] OR bipolar[ti] OR Anxiety[ti] OR antidepress*[ti] OR panic[ti] OR obsess*[ti] OR compulsio*[ti] OR “mood disord*”[ti] OR phobi*[ti] OR agoraphob*[ti] OR anorex*[ti] OR anorect*[ti] OR bulimi*[ti] OR “eating disorder*”[ti] OR neurodevelopm*[ti] OR retardation[ti] OR autism[ti] OR autistic[ti] OR ASM[ti] OR adhd[ti] OR “attention-deficit”[ti]) AND nrf2, which on the 9th of March produced 208 results of which 89 were eligible for our purposes. Eligible articles were studies reporting data of Nrf2 manipulations or content by any treatment in human patients or animals with any animal model of depression. Most studies were on mice only (N = 58), 20 on rats only, and three on both rats and mice. There were two studies on cell lines (in vitro) and one each on nematodes and fish. Only four studies were conducted in humans, one of which was post mortem. Most studies were conducted on male animals; however, human studies were carried out on both men and women. The results indicate that Nrf2 is lower in depression and that antidepressant methods (drugs or other methods) increase it. Antioxidant systems and plasticity-promoting molecules, such as those in the Nrf2–HO-1, BDNF–TrkB, and cyclic AMP–CREB pathways, could protect from depression, while glycogen synthase kinase-3β and nuclear factor κB oppose these actions, thus increasing depressive-like behaviours. Since Nrf2 is also endowed with tumorigenic and atherogenic potential, the balance between benefits and harms must be taken into account in designing novel drugs aiming at increasing the intracellular content of Nrf2.

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A Novel ⋅OH‐Monitor ER‐Targeted Probe to Expose the Function of Sorafenib

Kong,

Zhao,

Zhu

et al. 2024

Chemistry An Asian Journal

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The hydroxyl radical (·OH), widely recognized as the most potent free radical, plays a crucial role in numerous physiological and pathological pathways due to its strong oxidizability. Ferroptosis, as a novel mode of cell death, is initiated by the accumulation of iron‐dependent lipid peroxidation. Among them, ·OH as the original reactive oxygen species (ROSs) is mass‐produced due to Fenton reaction in vivo and closely related to cancer treatment. Besides, endoplasmic reticulum (ER) as a membrane‐rich structure organelle, is a crucial organelle in all eukaryotes where excessive expression of ROSs, including ·OH can trigger ER stress which was reported that was closely related to ferroptosis. So developing a new probe for their interrelationship research is important. In this paper, we constructed a 1,8‐naphthalimide‐based ER‐targeted fluorescence probe named M‐1 to monitor ·OH variation in vitro and vivo. What’s more, we achieved the monitor of ·OH during ER stress and ferroptosis processes in cancer cells, and further explored the important role of ER stress and ferroptosis processes in SF (sorafenib) involved cancer cells.

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Nrf2: An all-rounder in depression

Cited by 50 publications

References 220 publications

Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles

Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles

The Nrf2 Pathway in Depressive Disorders: A Systematic Review of Animal and Human Studies

A Novel ⋅OH‐Monitor ER‐Targeted Probe to Expose the Function of Sorafenib

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