• Proceedings of the Korean Society of Applied Pharmacology
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• 2000.04a
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• pp.15-16
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• 2000

Transient forebrain ischemia results in delayed neuronal death in the CA1 region of the hippocampus after injury, which is, at least in part, a consequence of excessive generation of reactive oxygen species. Previous in vitro studies using cell cultures or brain slices have demonstrated that phospholipase D (PLD) in the nervous system is involved in the signaling mechanism in response to a variety of agonists. Several recent studies have shown that reactive oxygen species stimulate phospholipase D (PLD) activity in several kinds of cells. Therefore, this raises the possibility that PLD activity is enhanced in the ischemic brain. Meanwhile, osteopontin (OPN) was initially identified as a sialoglycoprotein in bone, but has since been found in various tissues. Although not much is known about its function, OPN seems to play an important role in inflammation and tissue repair. Recently, it was reported that OPN was upregulated in the activated microglia after focal brain ischemia, suggesting that OPN might play a role in wound healing after a focal stroke.

• The Korea Journal of Herbology
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• v.38 no.1
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• pp.11-19
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• 2023

Objectives : Neuroinflammation is a common pathological mechanism of neurodegenerative diseases, and the development of therapeutic agents is urgently needed. Red ginseng has been known to be good for the immune stimulation in Eastern Asia. Although the immuno-stimulatory activity of red ginseng are already known, the neuro-protective effects of cultivated red ginseng with fermented complex mushroom-cereal mycelium (RGFM) have not been conducted. Thus, in this study, we tried to investigate the anti-neuroinflammatory effect of RGFM water extract on lipopolysaccharide (LPS) stimulated BV2 cells. Methods : BV2 cells were pretreated with RGFM 1 h prior to LPS exposure. To determine the neuro-protective effects of RGFM water extract, we measured the expression of inflammatory mediators including inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and nitric oxide (NO) and pro-inflammatory cytokines such as interleukin (IL)-1𝛽, IL-6 and tumor necrosis factor (TNF)-𝛼 in LPS-stimulated BV2 cells. In addition, to find out the regulatory mechanism of RGFM water extract, we assessed the protein levels of mitogen-activated protein kinases (MAPKs) and inhibitory 𝜅B𝛼 (I𝜅B𝛼) by western blotting. Results : In our study, treatment of RGFM reduced the mRNA expression of iNOS and COX-2 and suppressed NO production in LPS-stimulated BV2 cells. Additionally, the secretion of IL-1𝛽 and TNF-𝛼 but not IL-6 was significantly inhibited by RGFM. Furthermore, RGFM water extract inhibited the phosphorylation of c-Jun N-terminal kinase (JNK). Conclusions : Taken together, these findings suggest that RGFM water extract has a protective effect on neuroinflammation through inhibition of JNK.

• Journal of Life Science
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• v.29 no.10
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• pp.1096-1103
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• 2019

Neuroinflammation is mediated by the activation of microglia and has been implicated in the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Therefore, the inhibition of neuroinflammation may be an effective solution to treat these brain disorders. Protaetia brevitarsis seulensis is an insect belonging to the order Coleoptera and inhabits Korea, China, Japan and Siberia. P. brevitarsis seulensis is an edible insect that can be consumed as a protein source for humans. It has been reported that P. brevitarsis seulensis contains useful bioactive substances for hepatoprotection and improving blood circulation, such as indole alkaloids. Microglia cells are the main source of proinflammatory cytokines and nitric oxide (NO) in the central nervous system, which Perform neuroimmune, inflammatory, and other neurobilogical functions. In this study, we investigated the anti-neuroinflammatory effects of P. brevitarsis seulensis ethanol extract (PBE) in activated microglia cells treated with lipopolysaccgarude (LPS, 100 ng/ml). As a result, PBE significantly inhibited NO production without cytotoxicity and decreased the expression levels of inducible NO synthase and cyclooxygenase-2. In addition, the production of inflammatory cytokine secreted by LPS was also reduced by PBE. These results suggest that PBE could be a good source of functional substances to prevent neuroinflammation and neurodegenerative diseases.

• Journal of the Korean Society of Food Culture
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• v.38 no.5
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• pp.365-372
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• 2023

Ipomoea aquatic is a leafy vegetable of the Convolvulaceae family, and is a tropical plant widely inhabiting southern China and Southeast Asia, and is widely known as Morning Glory in the West. In this study, the anti-inflammatory effects of ethyl acetate extract from Ipomoea aquatic extracts (IAE) were tested against lipopolysaccharide (LPS)-induced activation microglia BV2 cells. The production of nitric oxide (NO) and cell viability were measured using the Griess reagent and MTT assay, respectively. Inflammatory cytokine [interleukin (IL)-6, tumor necrosis factor (TNF)-α, and interleukin-1β (IL-1β)] were detected qPCR in LPS induced BV-2 cells. Subsequently, nuclear factor (NF)-κB, mitogen-activated protein kinases (MAPKs), and nuclear factor erythroid-2-related factor 2 (Nrf2) were analyzed through western blot analyses and immunofluorescence. Ipomoea aquatic down-regulated of inflammatory markers and up-regulated anti-inflammatory and anti-oxidants in BV2 cells.

• Journal of Life Science
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• v.29 no.11
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• pp.1258-1266
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• 2019

Yangkyuksanhwa-Tang (YKSH), consisting of nine different herbs, is commonly used in Soyangin-type individuals with stroke, based on the Sasang Constitution Theory in Korea. However, no evidence has yet confirmed a beneficial effect of YKSH in ischemic stroke treatment. In this study, we investigated the effects of YKSH on ischemic brain injury in a mouse model of cerebral ischemia. Focal cerebral ischemia in mice was induced by photothrombosis, and behavioral recovery was evaluated. Infarct volume, inflammation, and newly generated cells were evaluated by histology and immunochemistry. YKSH treatment resulted in a significant recovery from the motor impairments induced by focal cerebral ischemia, as determined with wire grip and rotarod tests. YKSH treatment also decreased the infarct volume and the number of cells positive for tumor necrosis factor-${\alpha}$ and myeloperoxidase when compared with a vehicle-treated control group. By contrast, YKSH treatment considerably increased the number of cells positive for glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1, as well as the number of cells doubly positive for Ki67/doublecortin when compared with the vehicle-treated group. These results suggest that YKSH treatment attenuated the infarct size by anti-inflammatory action, astrocyte and microglia activation, and neuronal proliferation, thereby facilitating neurofunctional recovery from a cerebral ischemic assault. YKSH could therefore be a potential treatment for neurofunctional restoration of the injured brains of patients with stroke.

• Molecular & Cellular Toxicology
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• v.4 no.2
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• pp.113-123
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• 2008

Microglia, which is the primary immune effector cells in the central nervous system, constitutes the first line of defense against infection and injury in the brain. The goal of this study was to determine the protective (anti-inflammation) mechanisms of forsythia suspense (FS) on LPS-induced activation of BV-2 microglial cells. The effects of FS on gene expression profiles in activated BV-2 microglial cells were evaluated using microarray analysis. BV-2 microglial cells were cultured in a 100mm dish $(1{\times}10^7/dish)$ for 24hr and then pretreated with $1{\mu}g/mL$ FS or left untreated for 30 min. Next, $1{\mu}g/mL$ LPS was added to the samples and the cells were reincubated at $37^{\circ}C$ for 30 min, 1hr, and 3hr. The gene expression profiles of the BV-2 microglial cells varied depending on the FS. The oligonucleotide microarray analysis revealed that MAPK pathway-related genes such as Mitogen activated protein kinase 1 (Mapk1), RAS protein activator like 2 (Rasal2), and G-protein coupled receptor 12 (Gpr12) and nitric oxide biosynthesis-related genes such as nitric oxide synthase 1 (neuronal) adaptor protein (Nos1ap), and dimethylarginine dimethylaminohydrolase 1 (Ddah1) were down regulated in FS-treated BV-2 microglial cells. FS can affect the MAPK pathway and nitric oxide biosynthesis in BV-2 microglial cells.

• Biomedical Science Letters
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• v.25 no.1
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• pp.92-98
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• 2019

Metformin is a drug used for the treatment of diabetes and is associated with anti-inflammatory reaction, but the underlying mechanism is unclear. In this study, we investigated the effect of metformin on the inflammatory response in BV-2 microglial cells induced by lipopolysaccharide (LPS) and S100 calcium-binding protein A8 (S100A8). The results revealed that metformin significantly attenuated several inflammatory responses in BV-2 microglial cells, including the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-${\alpha}$ and interleukin (IL)-6, involved in the activation of Beclin-1, a crucial regulator of autophagy. In addition, metformin inhibited the LPS-induced phosphorylation of ERK. Metformin also suppressed the activation of NOD-like receptor pyrin domain containing 3 inflammasomes composed of NLRP3, caspase-1, and apoptosis-associated speck like protein containing a caspase recruitment domain, which are involved in the innate immune response. Notably, metformin decreased the secretion of S100A8-induced IL-6 production. These findings suggest that metformin alleviates the neuroinflammatory response via autophagy activation.

• International Journal of Oral Biology
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• v.47 no.2
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• pp.25-31
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• 2022

Lysophosphatidic acid (LPA) is a bioactive lipid messenger involved in the pathogenesis of chronic inflammation and various diseases. Recent studies have shown an association between periodontitis and neuroinflammatory diseases such as Alzheimer's disease, stroke, and multiple sclerosis. However, the mechanistic relationship between periodontitis and neuroinflammatory diseases remains unclear. The current study found that lysophosphatidic acid receptors 1 (LPAR1) and 6 (LPAR6) exhibited increased expression in primary microglia and astrocytes. The primary astrocytes were then treated using medium conditioned to mimic periodontitis through addition of Porphyromonas gingivalis lipopolysaccharides, and an increased nitric oxide (NO) production was observed. Application of conditioned medium from human periodontal ligament stem cells with or without LPAR1 knockdown showed a decrease in the production of NO and expression of inducible nitric oxide synthase and interleukin 1 beta. These findings may contribute to our understanding of the mechanistic link between periodontitis and neuroinflammatory diseases.

• International Journal of Stem Cells
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• v.16 no.4
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• pp.415-424
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• 2023

Therapeutic efficacy of mesenchymal stem cells (MSCs) is determined by biodistribution and engraftment in vivo. Compared to intravenous infusion, biodistribution of locally transplanted MSCs are partially understood. Here, we performed a pharmacokinetics (PK) study of MSCs after local transplantation. We grafted human MSCs into the brains of immune-compromised nude mice. Then we extracted genomic DNA from brains, lungs, and livers after transplantation over a month. Using quantitative polymerase chain reaction with human Alu-specific primers, we analyzed biodistribution of the transplanted cells. To evaluate the role of residual immune response in the brain, MSCs expressing a cytosine deaminase (MSCs/CD) were used to ablate resident immune cells at the injection site. The majority of the Alu signals mostly remained at the injection site and decreased over a week, finally becoming undetectable after one month. Negligible signals were transiently detected in the lung and liver during the first week. Suppression of Iba1-positive microglia in the vicinity of the injection site using MSCs/CD prolonged the presence of the Alu signals. After local transplantation in xenograft animal models, human MSCs remain predominantly near the injection site for limited time without disseminating to other organs. Transplantation of human MSCs can locally elicit an immune response in immune compromised animals, and suppressing resident immune cells can prolong the presence of transplanted cells. Our study provides valuable insights into the in vivo fate of locally transplanted stem cells and a local delivery is effective to achieve desired dosages for neurological diseases.

• Journal of Oriental Neuropsychiatry
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• v.9 no.1
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• pp.73-82
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• 1998

Substantial evidence has accumulated that Alzheimer's disease is associated with a local inflammatory reaction in senile plaques which may be immunemediated, and includes extensive Brain Neuroglial invasion, lymphocytic infiltration, cytokine deposition. Tumor necrosis factor a (TNF-a) is a cytokine which plays an important immunoenhancing role in the local acute and chronic inflammatory response in response to a variety of stimuli. The neuropeptide, substance P, can stimulate secretion of TNF-a from Brain Neuroglial cells. Neuroglia have substance P receptors in the central nervous system. WQ investigated whether RADIX ASPARAGI inhibits secretion of TNF-a from primary cultures of Brain Neuroglial cells containing both astrocyte (∼90%) and microglia (∼10%). RADIX ASPARAGI dose-dependently inhibited the TNF-a secretion induced by substance P plus lipopolysaccharide (LPS). In cultures enriched for micoglia (>95% pure). LPS stimulated the secretion of TNF-a but substance P caused no enhancement. Because there was no synergism between substance P and LPS in the microglial cultures it is resonable to substance P madiated enhancement of TNF-a secretion. IL-1 is a modulator of TNF-a secretion in the immune system. Also IL-1 has been shown to elevate TNF- a secretion from LPS-stimulated Brain Neuroglial cells while having no effect on Brain Neuroglial cells in the absence of LPS. We therfore investigated whether IL-1 mediates the RADIX ASPARAGI inhibition of TNF-a secretion form primary Brain Neuroglial cells. Treatment of RADIX ASPARAGI to mixed cultures stimulated with both substance P and LPS decreased TNF-a secretion to the level observed with LPS alone. These results indicate that RADIX ASPARAGI possess strong antiinflammatory activity in the cental nervous system by inhibition of inflammatory cytokines secretion from Brain Neuroglial cells.