• The Korean Journal of Physiology and Pharmacology
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• v.18 no.5
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• pp.397-402
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• 2014

Microglia are activated by inflammatory and pathophysiological stimuli in neurodegenerative diseases, and activated microglia induce neuronal damage by releasing cytotoxic factors like nitric oxide (NO). Activated microglia synthesize a significant amount of vitamin $D_3$ in the rat brain, and vitamin $D_3$ has an inhibitory effect on activated microglia. To investigate the possible role of vitamin $D_3$ as a negative regulator of activated microglia, we examined the effect of 25-hydroxyvitamin $D_3$ on NO production of lipopolysaccharide (LPS)-stimulated microglia. Treatment with LPS increased the production of NO in primary cultured and BV2 microglial cells. Treatment with 25-hydroxyvitamin $D_3$ inhibited the generation of NO in LPS-activated primary microglia and BV2 cells. In addition to NO production, expression of 1-${\alpha}$-hydroxylase and the vitamin D receptor (VDR) was also upregulated in LPS-stimulated primary and BV2 microglia. When BV2 cells were transfected with 1-${\alpha}$-hydroxylase siRNA or VDR siRNA, the inhibitory effect of 25-hydroxyvitamin $D_3$ on activated BV2 cells was suppressed. 25-Hydroxyvitamin $D_3$ also inhibited the increased phosphorylation of p38 seen in LPS-activated BV2 cells, and this inhibition was blocked by VDR siRNA. The present study shows that 25-hydroxyvitamin $D_3$ inhibits NO production in LPS-activated microglia through the mediation of LPS-induced 1-${\alpha}$-hydroxylase. This study also shows that the inhibitory effect of 25-hydroxyvitamin $D_3$ on NO production might be exerted by inhibiting LPS-induced phosphorylation of p38 through the mediation of VDR signaling. These results suggest that vitamin $D_3$ might have an important role in the negative regulation of microglial activation.

• Mass Spectrometry Letters
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• v.5 no.3
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• pp.70-78
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• 2014

Microglia are the confined immune cells of the central nervous system (CNS). In response to injury or infection, microglia readily become activated and release proinflammatory mediators that are believed to contribute to microglia-mediated neurodegeneration. In the present study, inflammation was induced in the immortalized murine microglial cell line BV-2 by lipopolysaccharide (LPS) treatment. We firstly performed phosphoproteomics analysis and phosphoinositide lipidomics analysis with LPS activated microglia in order to compare phosphorylation patterns in active and inactive microglia and to detect the pattern of changes in phosphoinositide regulation upon activation of microglia. Mass spectrometry analysis of the phosphoproteome of the LPS treatment group compared to that of the untreated control group revealed a notable increase in the diversity of cellular phosphorylation upon LPS treatment. Additionally, a lipidomics analysis detected significant increases in the amounts of phosphoinositide species in the LPS treatment. This investigation could provide an insight for understanding molecular mechanisms underlying microglia-mediated neurodegenerative diseases.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.6 no.2
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• pp.116-130
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• 2020

The aging society is globally one of biggest issue because it is related with various degenerative brain disease such as dementia, Parkinson's disease, Alzheimer's disease, multiple sclerosis, and cerebrovascular disease. These diseases are characterized by misfolded-protein aggregation; another pathological trait is "neuroinflammation". In physiological state, the resting microglia cells are activated and it removes abnormal synapses and cell membrane debris to maintain the homeostasis. In pathological state, however, microglia undergo morphological change form 'resting' to 'activated amoeboid phenotype' and the microglia cells are accumulated by neuronal damage, the inflammatory reactions induced nerve metamorphosis with a variety of neurotoxic factors including cytokines, chemokines, and reactive oxygen species. Thus, the activated microglia cell with various receptors (TSPO, COX, CR, P2XR, etc.) was perceived as important biomarkers for imaging the inflammatory progression. In this review, we would like to introduce the current status of the development of radiotracers that can image activated microglia.

• BMB Reports
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• v.46 no.8
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• pp.398-403
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• 2013

Inflammatory conditions mediated by activated microglia lead to chronic neuro-degenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. This study was conducted to determine the effect of floridoside isolated from marine red algae Laurencia undulata on LPS (100 ng/ml) activated inflammatory responses in BV-2 microglia cells. The results show that floridoside has the ability to suppress pro-inflammatory responses in microglia by markedly inhibiting the production of nitric oxide (NO) and reactive oxygen species (ROS). Moreover, floridoside down-regulated the protein and gene expression levels of iNOS and COX-2 by significantly blocking the phosphorylation of p38 and ERK in BV-2 cells. Collectively, these results indicate that floridoside has the potential to be developed as an active agent for the treatment of neuro-inflammation.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.138.1-138.1
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• 2003

Inflammatory responses from activated microglia are one of major causes of Alzheimer's disease (AD). Particularly, proinflammatory cytokines (PC), such as IL-l$\beta$ and TNF-$\alpha$, and nitric oxide (NO) are correlated with AD by inducing the chronic inflammation in the brain. In the present study, we found that microglia are activated by lipopolisaccharide (LPS) and Abeta42 (A$\beta$42), and those activated microglia produced such repertoires up to 72h with a turning point at 24h. However, no dose dependecy was found during the chasing time courses (6h to 72h). (omitted)

• Proceedings of the PSK Conference
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• 2003.10a
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• pp.106-107
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• 2003

tIn brain ischemic insult, inflammatory cells such as macrophages and lymphocytes are chemo-attracted into the brain lesion and release cytokines, resulting in an activation of microglia that are functionally equivalent to peripheral macrophages in the central nervous system. In cerebral ischemic insults, activated inflammatory cells such as microglia and macrophages may be implicated in the pattern and degree of ischemic injury by producing various bioactive mediators. (omitted)

• Biomolecules & Therapeutics
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• v.21 no.1
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• pp.21-28
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• 2013

Microglia play a role in maintaining and resolving brain tissue homeostasis. In pathological conditions, microglia release pro-inflammatory cytokines and cytotoxic factors, which aggravate the progression of neurodegenerative diseases. Autophagy pathway might be involved in the production of pro-inflammatory cytokines and cytotoxic factors in microglia, though details of the mechanism remain largely unknown. In the present study, we examined the role of the autophagy pathway in activated BV2 microglia cells. In BV2 cells, rapamycin treatment activated the formation of anti-LC3-labeled autophagosomes, whereas the ATG5 depletion using siRNA-ATG5 prevented the formation of LC3-labeled autophagosomes, indicating that BV2 cells exhibit an active classical autophagy system. When treated with LPS, BV2 cells expressed an increase of anti-LC3-labeled dots. The levels of LC3-labeled dots were not suppressed, instead tended to be enhanced, by the inhibition of the autophagy pathway with siRNA-ATG5 or wortmannin, suggesting that LPS-induced LC3-labeled dots in nature were distinct from the typical autophagosomes. The levels of LPS-induced expression of iNOS and IL6 were suppressed by treatment with rapamycin, and conversely, their expressions were enhanced by siRNA-ATG5 treatment. Moreover, the activation of the autophagy pathway using rapamycin inhibited cell death of LPS-stimulated microglia. These results suggest that although microglia possess a typical autophagy pathway, the glial cells express a non-typical autophagy pathway in response to LPS, and the activation of the autophagy pathway suppresses the expression of iNOS and IL6, and the cell death of LPS-stimulated microglia.

• The Korea Journal of Herbology
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• v.29 no.2
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• pp.33-38
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• 2014

Objectives : Inflammation is mediated by cellular components, such as leukocytes and microglia, and molecular components, including cytokines, extracellular proteases, and reactive oxygen species. Cnidium Rhizoma effects the anti-inflammatory, antioxidant, suppression of the microglia activation and protection of the nerve cell injury. For this reason, we investigated the anti-inflammatory effects of water extracts of Cnidium Rhizoma on intracerebral hemorrhage (ICH). Method : ICH was induced by the stereotaxic intracerebral injection of bacterial collagenase type IV (0.23 $U/{\mu}{\ell}$, 0.1 ${\mu}{\ell}/min$) in Sprague-Dawley rats. We orally administrated once 3 hours after ICH, then 2 times at 24-hour intervals the water extracts of Cnidium Rhizoma (500 mg/kg), myeloperoxidase (MPO) was observed by using immunofluorescense and expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and microglia were observed by using immunohistochemistry. Results : Infiltration of MPO expressing neutrophil, expression of iNOS and TNF-${\alpha}$ and activated microglia were significantly reduced in peri-hematoma of the rats fed with water extracts of Cnidium Rhizoma. Conclusion : These results demonstrated that water extracts of Cnidium Rhizoma suppressed an inflammatory reaction through inhibition of MPO, iNOS and TNF-${\alpha}$ positive cell and activated microglia number in peri-hematoma of ICH-induced rats.

• BMB Reports
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• v.42 no.6
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• pp.380-386
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• 2009

In neurodegenerative diseases, such as Alzheimer' and Parkinson', microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds. Prothrombin and kringle-2 increase levels of NO and the mRNA expression of iNOS, IL-1$\beta$, and TNF-$\alpha$ in microglial cells. In contrast, the human prothrombin kringle-2 derived peptide NSA9 inhibits NO release and the production of pro-inflammatory cytokines such as IL-1$\beta$, TNF-$\alpha$, and IL-6 in LPS-activated EOC2 microglia. In this study, we investigated the anti-inflammatory effects of NSA9 in human prothrombin- and kringle-2-stimulated EOC2 microglia. Treatment with 20-100 ${\mu}M$ of NSA9 attenuated both prothrombin- and kringle-2-induced microglial activation. NO production induced by MAPKs and NF-$\kappa$B was similarly reduced by inhibitors of ERK (PD98059), p38 (SB203580), NF-$\kappa$B (N-acetylcysteine), and NSA9. These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle-2.

• Korean Journal of Clinical Laboratory Science
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• v.52 no.4
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• pp.389-397
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• 2020

Microglial cells function as major immune cells in the brain, playing an important role in the protection and damage of neurons. BV2 microglia, activated by drug stimulation, secrete inflammatory cytokines by activating the nuclear factor kappa-light-chain-enhancer of the activated B cells pathway and are involved in neuroinflammatory and immune responses. The overactivation of microglia by stimuli can cause neuronal damage, leading to brain disease. Noni, a natural product, reduces the activity of microglia to prevent neuronal damage and is a potential natural medicine because it exerts excellent regeneration and anti-inflammatory effects on damaged cells. In this study, when noni was used to treat BV2 cells stimulated by the anti-cancer drug doxorubicin, it reduced the release of pro-inflammatory cytokines from BV2. On the other hand, neuronal damage is a side effect of doxorubicin. Therefore, the cytokines released from doxorubicin-stimulated BV2 cells treated with noni had a positive effect on the neuronal viability compared to those released from doxorubicin-stimulated BV2 cells not treated with Noni. Thus, Noni increases neuronal viability. These results suggest that noni inhibits the release of cytokines by regulating the nuclear factor kappa-light-chain-enhancer of the activated B cells pathway of BV2, thereby inhibiting neuronal damage.