Magnolol attenuates depressive-like behaviors by polarizing microglia towards the M2 phenotype through the regulation of Nrf2/HO-1/NLRP3 signaling pathway

Tao, Weiwei; Hu, Yuwen; Chen, Zhaoyang; Dai, Yuxin; Hu, Yue; Qi, Mingming

doi:10.1016/j.phymed.2021.153692

Cited by 68 publications

(38 citation statements)

References 36 publications

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“…siRNA-induced silencing of Nrf2 expression blocked melatonin-induced upregulation of GPX4 and xCT expression in MC3T3 cells [68]. Moreover, the concentration of supernatant TNF-α was increased and that of supernatant IL-4 and IL-10 was decreased in Nrf2-silenced BV2 cells [69]. These findings are consistent with the observation that Nrf2 siRNA abrogated FA-mediated upregulation of GPX4, xCT, and FPN and NF-κB pathway inactivation.…”

Section: Discussionsupporting

confidence: 86%

Forsythoside A Mitigates Alzheimer's-like Pathology by Inhibiting Ferroptosis-mediated Neuroinflammation via Nrf2/GPX4 Axis Activation

et al. 2022

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Ferroptosis and neuroinflammation play crucial roles in Alzheimer's disease (AD) pathophysiology. Forsythoside A (FA), the main constituent of Forsythia suspensa (Thunb.) Vahl., possesses anti-inflammatory, antibacterial, antioxidant, and neuroprotective properties. The present study aimed to investigate the potential role of FA in AD neuropathology using male APP/PS1 double transgenic AD mice, Aβ1-42-exposed N2a cells, erastin-stimulated HT22 cells, and LPS-induced BV2 cells. FA treatment significantly improved mitochondrial function and inhibited lipid peroxidation in Aβ1-42-exposed N2a cells. In LPS-stimulated BV2 cells, FA treatment decreased the formation of the pro-inflammatory factors IL-6, IL-1β, and NO. In male APP/PS1 mice, FA treatment ameliorated memory and cognitive impairments and suppressed Aβ deposition and p-tau levels in the brain. Analyses using proteomics, immunohistochemistry, ELISA, and western blot revealed that FA treatment significantly augmented dopaminergic signaling, inhibited iron deposition and lipid peroxidation, prevented the activation of IKK/IκB/NF-κB signaling, reduced the secretion of pro-inflammatory factors, and promoted the production of anti-inflammatory factors in the brain. FA treatment exerted anti-ferroptosis and anti-neuroinflammatory effects in erastin-stimulated HT22 cells, and the Nrf2/GPX4 axis played a key role in these effects. Collectively, these results demonstrate the protective effects of FA and highlight its therapeutic potential as a drug component for AD treatment.

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Section: Discussionsupporting

confidence: 86%

Forsythoside A Mitigates Alzheimer's-like Pathology by Inhibiting Ferroptosis-mediated Neuroinflammation via Nrf2/GPX4 Axis Activation

et al. 2022

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“…The NLRP3 inflammasome is a cytoplasmic multiprotein complex of the innate immune system that can positively trigger a series of proinflammatory pathways. Mounting evidence has demonstrated that NLRP3 inflammasome is involved in microglia-induced inflammatory responses and microglial polarization ( 26 , 27 ). Chen et al.…”

Section: Discussionmentioning

confidence: 99%

“…Since PI cannot pass intact plasma membrane and can only be present in DNA of cells where the plasma membrane has been injured. During pyroptosis, pores can be formed in the cell membrane and can be detected by PI staining [26]. Therefore, PI staining is widely used as a detection for neuronal pyroptosis.…”

Section: Srt1720 Decreases Neuronal Pyroptosis and Apoptosis After Sah In Vitromentioning

confidence: 99%

“…The nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a key mediator of numerous vascular diseases through triggering a series of immune-inflammatory response ( 25 ). It has been demonstrated that the NLRP3 inflammasome is expressed in microglia and implicated in the modulation of inflammatory responses by switching microglia M1/M2 phenotypes ( 26 , 27 ). Intriguingly, emerging evidence indicates that SIRT1 could regulate NLRP3 inflammasome signaling in different research fields ( 3 , 28 , 29 ).…”

Section: Introductionmentioning

confidence: 99%

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SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage

et al. 2021

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Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling.

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“…A meroterpene from the seeds of Psoralea corylifolia , or bakuchiol, displayed similar effects by ameliorating cerebral ischemia-reperfusion injury via NLRP3/Nrf2 pathway ( 140 ). Tao et al indicated that magnalol, biphenolic neolignane found in the bark of Magnolia officinalis , stimulates microglia towards the M2 phenotype to heal depressive-like behaviors through regulating Nrf2/HO-1/NLRP3 axis ( 141 ). Bixin, an apocarotenoid in the seeds of the achiote tree, was proved to diminish neuroinflammation and demyelination in an experimental autoimmune encephalomyelitis mouse model via upregulating Nrf2 and suppressing TXNIP/NLRP3 Inflammasome ( 142 ).…”

Section: Preclinical Experience With Nrf2 Inducers Against Nlrp3 Infl...mentioning

confidence: 99%

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

2022

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The NLRP3 inflammasome is an intracellular multiprotein complex that plays an essential role in the innate immune system by identifying and eliminating a plethora of endogenous and exogenous threats to the host. Upon activation of the NLRP3 complex, pro-inflammatory cytokines are processed and released. Furthermore, activation of the NLRP3 inflammasome complex can induce pyroptotic cell death, thereby propagating the inflammatory response. The aberrant activity and detrimental effects of NLRP3 inflammasome activation have been associated with cardiovascular, neurodegenerative, metabolic, and inflammatory diseases. Therefore, clinical strategies targeting the inhibition of the self-propelled NLRP3 inflammasome activation are required. The transcription factor Nrf2 regulates cellular stress response, controlling the redox equilibrium, metabolic programming, and inflammation. The Nrf2 pathway participates in anti-oxidative, cytoprotective, and anti-inflammatory activities. This prominent regulator, through pharmacologic activation, could provide a therapeutic strategy for the diseases to the etiology and pathogenesis of which NLRP3 inflammasome contributes. In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.

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Magnolol attenuates depressive-like behaviors by polarizing microglia towards the M2 phenotype through the regulation of Nrf2/HO-1/NLRP3 signaling pathway

Cited by 68 publications

References 36 publications

Forsythoside A Mitigates Alzheimer's-like Pathology by Inhibiting Ferroptosis-mediated Neuroinflammation via Nrf2/GPX4 Axis Activation

Forsythoside A Mitigates Alzheimer's-like Pathology by Inhibiting Ferroptosis-mediated Neuroinflammation via Nrf2/GPX4 Axis Activation

SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

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