• Archives of Pharmacal Research
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• v.27 no.7
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• pp.751-756
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• 2004

Flavonoids have been demonstrated to exhibit a wide range of biological activities including anti-inflammatory and neuroprotective actions. Although a significant amount of flavonoids has been identified to be present as glycosides in medicinal plants, determinations of the biological activities of flavonoids were mainly carried out with aglycones of flavonoids. Therefore, the exact role of the glycosidation of flavonoid aglycones needs to be established. In an attempt to understand the possible role of glycosidation on the modulation of the biological activities of flavonoids, diverse glycosides of kaempferol, quercetin, and aromadendrin were examined in terms of their anti-inflammatory activity determined with the suppression of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV2 microglial cells. The results indicated that glycosidation of aglycones attenuated the suppressive activity of aglycones on LPS-induced NO production. Although attenuated, some of glycosides, depending on the position and degree of glycosidation, maintained the inhibitory capability of LPS-induced NO production. These findings suggest that glycosidation of flavonoid aglycones should be considered as an important modulator of the biological activities of flavonoids.

• 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 Ginseng Research
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• v.44 no.5
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• pp.704-716
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• 2020

Background: Ginsenoside Rh2 (GRh2) is a characterized component in red ginseng widely used in Korea and China. GRh2 exhibits a wide range of pharmacological activities, such as anti-inflammatory, antioxidant, and anticancer properties. However, its effects on Toxoplasma gondii (T. gondii) infection have not been clarified yet. Methods: The effect of GRh2 against T. gondii was assessed under in vitro and in vivo experiments. The BV2 cells were infected with tachyzoites of T. gondii RH strain, and the effects of GRh2 were evaluated by MTT assay, morphological observations, immunofluorescence staining, a trypan blue exclusion assay, reverse transcription PCR, and Western blot analyses. The in vivo experiment was conducted with BALB/c mice inoculated with lethal amounts of tachyzoites with or without GRh2 treatment. Results and conclusion: The GRh2 treatment significantly inhibited the proliferation of T. gondii under in vitro and in vivo studies. Furthermore, GRh2 blocked the activation of microglia and specifically decreased the release of inflammatory mediators in response to T. gondii infection through TLR4/NF-κB signaling pathway. In mice, GRh2 conferred modest protection from a lethal dose of T. gondii. After the treatment, the proliferation of tachyzoites in the peritoneal cavity of infected mice markedly decreased. Moreover, GRh2 also significantly decreased the T. gondii burden in mouse brain tissues. These findings indicate that GRh2 exhibits an antieT. gondii effect and inhibits the microglial activation through TLR4/NF-κB signaling pathway, providing the basic pharmacological basis for the development of new drugs to treat toxoplasmic encephalitis.

• Journal of Life Science
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• v.27 no.1
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• pp.8-14
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• 2017

Died Gardenia jasminoides fruit is used as a dye in the food and clothes industries in Asia. The present study investigated the anti-inflammatory effects of aqueous extract of G. jasminoides fruits (GJ) in BV-2 microglial cells. GJ inhibited lipopolysaccharide-induced nitric oxide (NO) secretion, inducible nitric oxide synthase (iNOS) expression, and reactive oxygen species production, without affecting cell viability. Furthermore, GJ increased the expression of heme oxygenase-1 (HO-1) in a dose-dependent manner. Moreover, the inhibitory effect of GJ on iNOS expression was abrogated by small interfering RNA-mediated knock-down of HO-1. In addition, GJ induced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates HO-1 expression. GJ-mediated expression of HO-1 was suppressed by LY294002, a phosphoinositide 3-kinase (PI-3K) inhibitor, and SB203580, a p38 kinase inhibitor, but not by the extracellular signal-regulated kinase (ERK) inhibitor PD98059 or c-Jun N-terminal kinase (JNK) inhibitor SP600125. GJ also enhanced the phosphorylation of Akt and p38. These results suggest that GJ suppresses the production of NO, a pro-inflammatory mediator, by inducing HO-1 expression via PI-3K/Akt/p38 signaling. These findings illustrate a novel molecular mechanism by which extract from G. jasminoides fruits inhibits neuroinflammation.

• Molecules and Cells
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• v.42 no.10
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• pp.702-710
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• 2019

Neuroinflammation is an important contributor to the pathogenesis of neurodegenerative disorders including Parkinson's disease (PD). We previously reported that our novel synthetic compound KMS99220 has a good pharmacokinetic profile, enters the brain, exerts neuroprotective effect, and inhibits $NF{\kappa}B$ activation. To further assess the utility of KMS99220 as a potential therapeutic agent for PD, we tested whether KMS99220 exerts an anti-inflammatory effect in vivo and examined the molecular mechanism mediating this phenomenon. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, oral administration of KMS99220 attenuated microglial activation and decreased the levels of inducible nitric oxide synthase and interleukin 1 beta ($IL-1{\beta}$) in the nigrostriatal system. In lipopolysaccharide (LPS)-challenged BV-2 microglial cells, KMS99220 suppressed the production and expression of $IL-1{\beta}$. In the activated microglia, KMS99220 reduced the phosphorylation of $I{\kappa}B$ kinase, c-Jun N-terminal kinase, and p38 MAP kinase; this effect was mediated by heme oxygenase-1 (HO-1), as both gene silencing and pharmacological inhibition of HO-1 abolished the effect of KMS99220. KMS99220 induced nuclear translocation of the transcription factor Nrf2 and expression of the Nrf2 target genes including HO-1. Together with our earlier findings, our current results show that KMS99220 may be a potential therapeutic agent for neuroinflammation-related neurodegenerative diseases such as PD.

• Journal of Food Hygiene and Safety
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• v.38 no.6
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• pp.430-441
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• 2023

Velvet antler is widely used as a traditional medicine, and numerous studies have demonstrated its tremendous nutritional and medicinal values including immunity-enhancing effects. This study aimed to investigate different deer velvet extracts (Sample 1: raw extract, Sample 2: dried extract, and Sample 3: freeze-dried extract) for proximate composition, uronic acid, sulfated glycosaminoglycan, sialic acid, collagen levels, and chemical components using ultra-performance liquid chromatography-quadrupole-time-of-light mass spectrometry. In addition, we evaluated the cytotoxic effect of the deer velvet extracts on BV2 microglia, HT22 hippocampal cells, HaCaT keratinocytes, and RAW264.7 macrophages using the cell viability MTT assay. Furthermore, we evaluated acute toxicity of the deer velvet extracts at different doses (0, 500, 1000, and 2000 mg/kg) administered orally to both male and female ICR mice for 14 d (five mice per group). After treatment, we evaluated general toxicity, survival rate, body weight changes, mortality, clinical signs, and necropsy findings in the experimental mice based on OECD guidelines. The results suggested that in vitro treatment with the evaluated extracts had no cytotoxic effect in HaCaT keratinocytes cells, whereas Sample-2 had a cytotoxic effect at 500 and 1000 ㎍/mL on HT22 hippocampal cells and RAW264.7 macrophages. Sample 3 was also cytotoxic at concentrations of 500 and 1000 ㎍/mL to RAW264.7 and BV2 microglial cells. However, the mice treated in vivo with the velvet extracts at doses of 500-2000 mg/kg BW showed no clinical signs, mortality, or necropsy findings, indicating that the LD50 is higher than this dosage. These findings indicate that there were no toxicological abnormalities connected with the deer velvet extract treatment in mice. However, further human and animal studies are needed before sufficient safety information is available to justify its use in humans.

• Animal cells and systems
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• v.9 no.2
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• pp.101-105
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• 2005

[ ${\beta}ig-h3$ ] is a secretory protein that is induced by $TGF-{\beta}$ and implicated in various disease conditions including fibrosis. We have previously reported that ${\beta}ig-h3$ expression is implicated in astrocyte response to brain injury. In this study, we further investigated potential roles of ${\beta}ig-h3$ protein in the injured central nervous system (CNS). We specifically assessed whether the treatment of microglial cells with ${\beta}ig-h3$ can regulate microglial activity. Microglial cells are the prime effector cells in CNS immune and inflammatory responses. When activated, they produce a number of inflammatory mediators, which can promote neuronal injury. We prepared conditioned medium from the stable CHO cell line transfected with human ${\beta}ig-h3$ cDNA. We then examined the effects of the conditioned medium on the LPS- or $IFN-{\gamma}-mediated$ induction of proinflammatory molecules in microglial cells. Preincubation with the conditioned medium significantly attenuated LPS-mediated upregulation of $TNF-{\alpha},\;IL-1{\beta}$, iNOS and COX-2 mRNA expression in BV2 murine microglial cells. It also reduced $IFN-{\gamma}-mediated$ upregulation of $TNF-{\alpha}$ and COX-2 mRNA expression but not iNOS mRNA expression. Assays of nitric oxide release correlated with the mRNA data, which showed selective inhibition of LPS-mediated nitric oxide production. Although the regulatory mechanisms need to be further investigated, these results suggest that astrocyte-derived ${\beta}ig-h3$ may contribute to protection of the CNS from immune-mediated damage via controlling microglial inflammatory responses.

• Biomedical Science Letters
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• v.25 no.3
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• pp.227-236
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• 2019

In this study, the anti-oxidant, anti-inflammatory, and anti-obesity activities of an ethanol extracts of Ulmus divididiana var. japonica (UDE) were investigated in vitro and in vivo. UDE anti-oxidant activity was evaluated with an Electron Spin Resonance (ESR) spectrometer, which measured 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging activity. Cell viabilities were estimated using 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay. LPS-stimulated BV-2 microglia were used to study the production of nitric oxide (NO). Cells stimulated with LPS produce more NO than normal control cells. However, cells treated with the UDE decreased this production in a concentration dependent manner (100, 250, 500, $1,000{\mu}g/mL$). Also, we investigated the anti-obese activity of UDE in SD rats. The SD rats were randomly divided into five groups: 10% low fat diet (N), 45% high fat diet (H), 45% high fat diet + garcinia extracts 200 mg/kg/day (HG200), high fat diet + UDE 200 mg/kg/day (HU200), high fat diet + UDE 400 mg/kg/day (HU400). UDE was found to lower whole body and abdominal and epididymal adipose tissue weights and lowered plasma levels of triglyceride (TG), compared to those in H group. Histological analyses of the liver and fat tissues of rat treated with UDE revealed significantly decreased number of lipid droplets and decreased size of adipocytes compared to the H group. These results suggest that UDE might be used to develop potent anti-oxidant, anti-inflammatory, and anti-obesity agents, and may be useful as ingredients for related new functional raw materials.

• BMB Reports
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• v.54 no.11
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• pp.557-562
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• 2021

Microglial activation is closely associated with neuroinflammatory pathologies. The nucleotide-binding and oligomerization domain-like receptor containing a pyrin domain 3 (NLRP3) inflammasomes are highly organized intracellular sensors of neuronal alarm signaling. NLRP3 inflammasomes activate nuclear factor kappa-B (NF-κB) and reactive oxygen species (ROS), which induce inflammatory responses. Moreover, NLRP3 dysfunction is a common feature of chronic inflammatory diseases. The present study investigated the effect of a novel thiazol derivative, N-cyclooctyl-5-methylthiazol-2-amine hydrobromide (KHG26700), on inflammatory responses in lipopolysaccharide (LPS)-treated BV-2 microglial cells. KHG26700 significantly attenuated the expression of several pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, in these cells, as well as the LPS-induced increases in NLRP3, NF-κB, and phospho-IkBα levels. KHG26700 also suppressed the LPS-induced increases in protein levels of autophagy protein 5 (ATG5), microtubule-associated protein 1 light chain 3 (LC3), and beclin-1, as well as downregulating the LPS-enhanced levels of ROS, lipid peroxidation, and nitric oxide. These results suggest that the anti-inflammatory effects of KHG26700 may be due, at least in part, to the regulation of the NLRP3-mediated signaling pathway during microglial activation.

• Journal of Life Science
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• v.25 no.6
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• pp.656-662
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• 2015

Natural products and natural product structures play a general and highly significant role in drug discovery and development process because it has various merits and potentials for new drug source that have extensive clinical experience, development time contraction, excellent stability and safety. In several neurological disorders, neuronal death and excessive activation of microglia (neuro-inflammation) are observed. A number of drug discovery-related neuronal cell death and neuro-inflammation was studied from natural products, respectively. However, until now, it has not been possible to study dual-protection molecules recorded in the Natural Product library. In the present study, using the natural product-derived library of the Institute for Korea Traditional Medical Industry, we investigated dual-protective molecules against glutamate (a classical excitatory neurotransmitter)-induced oxidative stress mediated neuronal cell death and LPS-induced excessive activated microglial cells (immune cells of the brain). Chrysophanol, extracted from Rheum palmatum, had dual-protective effects against both glutamate-induced neuronal cell death and LPS-induced NO production, triggering proinflammatory cytokines and microglia activation and resulting in neuroinflammation. Flow-cytometry analysis revealed that chrysophanol had a scavenger effect, scavenging glutamate- and LPS-induced reactive oxygen species (ROS) produced by neuronal and microglial cells, respectively. Based on the present study, chrysophanol may have an important protective role against neuronal cell death and neuroinflammation in the brain. The results may be helpful for studying drug development candidates for treating central nervous system disorders.