Inhibitory effect of ent-Sauchinone on amyloidogenesis via inhibition of STAT3-mediated NF-κB activation in cultured astrocytes and microglial BV-2 cells

Song, Seung-Ho; Jung, Yu Yeon; Hwang, Chul Ju; Lee, Hee Peom; Sok, Chang Hyun; Kim, Joo Hwan; Lee, Sang Min; Seo, Hyun Ok; Hyun, Byung Kook; Choi, Dong Young; Han, Sang Bae; Ham, Young Wan; Hwang, Bang Yeon; Hong, Jin Tae

doi:10.1186/1742-2094-11-118

Cited by 38 publications

(32 citation statements)

References 46 publications

(44 reference statements)

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“…Studies have also shown that lipopolysaccharide (LPS) can stimulate Aβ deposition [12][13][14], suggesting that neuroinflammation could be a causative contributor in the development and/or progression of AD.…”

Section: Introductionmentioning

confidence: 99%

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

et al. 2015

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Artemether, a lipid-soluble derivative of artemisinin has been reported to possess anti-inflammatory properties. In this study, we have investigated the molecular mechanisms involved in the inhibition of neuroinflammation by the drug. The effects of artemether on neuroinflammation-mediated HT22 neuronal toxicity were also investigated in a BV2 microglia/HT22 neuron co-culture. To investigate effects on neuroinflammation, we used LPS-stimulated BV2 microglia treated with artemether (5-40µM) for 24 hours. ELISAs and western blotting were used to detect pro-inflammatory cytokines, nitric oxide, PGE2, iNOS, COX-2 and mPGES-1. BACE-1 activity and Aβ levels were measured with ELISA kits. Protein levels of targets in NF-κB and p38 MAPK signalling, as well as HO-1, NQO1 and Nrf2 were also measured with western blot. NF-κB binding to the DNA was investigated using EMSA. MTT, DNA fragmentation and ROS assays in BV2-HT22 neuronal co-culture were used to evaluate the effects of artemether on neuroinflammation-induced neuronal death. The role of Nrf2 in the anti-inflammatory activity of artemether was investigated in BV2 cells transfected with Nrf2 siRNA. Artemether significantly suppressed pro-inflammatory mediators (NO/iNOS, PGE2/COX-2/mPGES-1, TNFα, and IL-6), Aβ and BACE-1 in BV2 cells following LPS stimulation. These effects of artemether were shown to be mediated through inhibition of NF-κB and p38MAPK signalling. Artemether produced increased levels of HO-1, NQO1 and GSH in BV2 microglia. The drug activated Nrf2 activity by increasing nuclear translocation of Nrf2 and its binding to antioxidant response elements in BV2 cells. Transfection of BV2 microglia with Nrf2 siRNA resulted in the loss of both anti-inflammatory and neuroprotective activities of artemether. We conclude that artemether induces Nrf2 expression and suggest that Nrf2 mediates the anti-inflammatory effect of artemether in BV2 microglia. Our results suggest that this drug has a therapeutic potential in neurodegenerative disorders. 3 KeywordsArtemether, neuroinflammation, BV2 microglia, HT22 hippocampal neurons, NF-κB, Nrf2 4 BackgroundIn the central nervous system (CNS), the microglia plays an important role in immune defence and tissue repair [1]. Under normal conditions, these cells provide surveillance whilst maintaining homeostasis in the brain [2]. In response to injury, harmful toxins, infection or inflammation, microglial cells become activated, secreting pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), reactive oxygen/nitrogen species and pro-inflammatory cytokines including IL-6 and TNFα [3,4]. These pro-inflammatory mediators are mainly regulated by the transcription factor NF-κB [5]. NF-κB binds to the DNA and its transcriptional activity regulates several genes, which promote neuroinflammation. The p38 mitogenactivated protein kinase (p38 MAPK) signalling pathway also plays an important role in the expression and activity of pro-inflammatory cytokines in microglial cells [6][7][8].Excessive production o...

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Section: Introductionmentioning

confidence: 99%

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

et al. 2015

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“…The STAT3 signaling has been reported to play a critical role in inflammatory responses in the CNS [ 37 ]. STAT3 is activated by phosphorylation at Tyr705, which induces STAT3 dimerization, nuclear translocation, and DNA binding, resulting in the transcription of genes encoding several inflammatory factors [ 37 – 40 ]. In our study, we observed that astrocytic p-STAT3 was up-regulated after MCAO in vivo and after OGD in vitro, and this effect was reversed by Sino treatment (Figs.…”

Section: Discussionmentioning

confidence: 99%

Sinomenine activates astrocytic dopamine D2 receptors and alleviates neuroinflammatory injury via the CRYAB/STAT3 pathway after ischemic stroke in mice

Qiu

Yan

Tao

et al. 2016

J Neuroinflammation

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BackgroundAstrocyte-mediated neuroinflammation plays a critical role in ischemic stroke-induced secondary cerebral injury. Previous studies have suggested that the dopamine D2 receptor (DRD2) acts as a key target in regulating the neuroinflammatory response. However, the underlying molecular mechanisms are still unknown, and effective DRD2 agonists are lacking. In the present study, we examined the anti-inflammatory and neuroprotective effects of sinomenine (Sino), a monomeric compound with potential immunoregulatory properties in nervous system.MethodsTTC staining, apoptosis assay, evaluation of brain edema, and neurological assessment were performed in the middle cerebral artery occlusion (MCAO) mouse model. Primary astrocytes exposed to oxygen glucose deprivation (OGD) were used in the in vitro experiments. Quantitative PCR was applied to assess the levels of inflammatory cytokines. Multi-labeling immunofluorescence, Western blot, co-immunoprecipitation, and electrophoretic mobility shift assay (EMSA) were also used to investigate the molecular mechanisms underlying the Sino-mediated anti-inflammatory effects in vivo and in vitro.ResultsSino remarkably attenuated the cerebral infarction and neuronal apoptosis, reduced the levels of inflammatory cytokines, and alleviated neurological deficiency in MCAO mice. Sino significantly inhibited astrocytic activation and STAT3 phosphorylation as well as increased DRD2 and αB-crystallin (CRYAB) expression after MCAO. In vitro, Sino blocked OGD-induced activation of STAT3 and generation of pro-inflammatory cytokines in primary astrocytes, and these effects were significantly abolished by either DRD2 or CRYAB knockdown. Additionally, Sino induced up-regulation and nuclear translocation of CRYAB in astrocytes and enhanced the interaction between CRYAB and STAT3, which further inhibited the activation and DNA-binding activity of STAT3.ConclusionsOur study demonstrates that Sino activates astrocytic DRD2 and thereby suppresses neuroinflammation via the CRYAB/STAT3 pathway, which sheds some light on a promising therapeutic strategy for ischemic stroke.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0739-8) contains supplementary material, which is available to authorized users.

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“…The prevalence of neurodegenerative disorders has increased nowadays and has become one of the most serious health issues worldwide. Neurodegenerative disorders are associated with a higher risk of neurodegenerative diseases, including Huntington's, Alzheimer's and Parkinson's (27,28). Abnormal microglia activation has a crucial role in the development of neurodegenerative disorders, although the exact mechanisms have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Petasites japonicus bakkenolide B inhibits lipopolysaccharide‑induced pro‑inflammatory cytokines via AMPK/Nrf2 induction in microglia

et al. 2017

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Abnormal neuroinflammatory responses have diverse roles in neuronal death, oxidative stress and neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Microglia regulate these responses via molecular signaling cascades that involve inflammatory cytokines and complement proteins. Bakkenolide B from Petasites japonicus exhibits significant anti‑inflammatory and anti‑allergic bioactivities. The present study investigated the anti‑neuroinflammatory effects and underlying molecular mechanisms of bakkenolide B on the lipopolysaccharide (LPS)‑mediated neuroinflammatory response in microglia. The results indicated that bakkenolide B pretreatment significantly reduced microglial production of interleukin (IL)‑1β, IL‑6, IL‑12, and tumor necrosis factor (TNF)‑α. Furthermore, this effect was associated with reduced production of reactive oxygen species. The role of bakkenolide B was then evaluated in the upregulation of nuclear factor erythroid 2‑related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathways. The results suggested that bakkenolide B significantly upregulated Nrf2/ARE pathway‑related downstream factors, such as NADPH dehydrogenase quinone‑1 (NQO‑1) and heme oxygenase‑1 (HO‑1). Silencing of Nrf2, HO‑1 and NQO‑1 diminished the anti‑neuroinflammatory properties of bakkenolide B. AMP‑activated protein kinase (AMPK) activates the Nrf2/ARE signaling pathway, and the results of the present study demonstrated that bakkenolide B increased AMPK phosphorylation in microglia. In addition, an AMPK inhibitor abolished the bakkenolide B‑induced increase in nuclear Nrf2, NQO‑1 and HO‑1 protein expression. Finally, an AMPK inhibitor diminished the bakkenolide B‑mediated inhibition of LPS‑stimulated TNF‑α production. Taken together, the present results demonstrate that bakkenolide B may be an effective and therapeutically relevant AMPK/Nrf2 pathway activator for suppressing abnormal neuro-inflammation in neurodegenerative diseases.

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Inhibitory effect of ent-Sauchinone on amyloidogenesis via inhibition of STAT3-mediated NF-κB activation in cultured astrocytes and microglial BV-2 cells

Cited by 38 publications

References 46 publications

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

Sinomenine activates astrocytic dopamine D2 receptors and alleviates neuroinflammatory injury via the CRYAB/STAT3 pathway after ischemic stroke in mice

Petasites japonicus bakkenolide B inhibits lipopolysaccharide‑induced pro‑inflammatory cytokines via AMPK/Nrf2 induction in microglia

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