• 대한한의학회지
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• 제43권4호
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• pp.20-32
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• 2022

Objectives: Kyungok-go (KOG) is a traditional multi-herbal medicine commonly used for enforcing weakened immunity for long time. Recently, there are several reports that KOG has anti-inflammatory and immuno-stimulatory activities in many experimental models. However, the protective effects of KOG on neuronal inflammation are still undiscovered. Thus, we investigated the neuro-protective activity of KOG on lipopolysaccharide (LPS)-stimulated mouse microglia cells. To find out KOG's anti-neuroinflammatory effects on microglial cells, we examined the production of nitrite using griess assay, and mRNA expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α using real time RT-PCR. In addition, to examine the regulating mechanisms of KOG, we investigated the protein expression of mitogen-activated protein kinases (MAPKs) and Iκ-Bα by western blot. KOG inhibited the elevation of nitrite, iNOS and COX-2 on LPS-stimulated BV2 cells. Also, KOG significantly inhibited the pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α on LPS-stimulated BV2 microglial cells. Moreover, KOG inhibited the activation of c-Jun N-terminal kinase (JNK), P38 and degradation of Iκ-Bα but not the activation of extracellular signal regulated kinase (ERK) on LPS-stimulated BV2 microglial cells. These results showed KOG has the anti-inflammatory effects through the inhibition on nitrite, iNOS, COX-2, IL-1β, IL-6, and TNF-α via the deactivation of JNK, p38 and nuclear factor (NF)-κB on LPS-stimulated BV2 microglial cells. Thereby, KOG could offer the new and promising treatment for neurodegenerative disease related to neuroinflammation.

• 대한본초학회지
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• 제38권1호
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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.

• 정신신체의학
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• 제29권2호
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• pp.207-212
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• 2021

항-N-methyl-D-aspartate 수용체 뇌염(Anti-NMDAR encephalitis)은 NMDA 수용체에 대한 자가항체로 매개되는 신경 염증성 질환으로 초기에 뚜렷한 신경학 증상 없이 망상, 지각이상, 와해된 행동, 심한 불안, 인지기능저하 등의 정신증상이 두드러질 수 있다. 면역치료 혹은 종양제거와 같은 조기치료가 좋은 예후 인자이므로 질병초기에 정신질환과 구분하여 항-NMDAR 뇌염을 진단하는 것이 중요하다. 본 증례에서는 간질과 정신병적 증상을 보이는 26세 여성 A씨를 조기에 항-NMDAR 뇌염으로 확진한 뒤 양성 및 음성증상 척도(Positive and Negative Syndrome Scale, PANSS)를 사용하여 평가하였다. A씨의 항-NMDAR 뇌염 초기의 정신증상으로 PANSS에서 양성하위척도 보다 음성하위척도 점수가 더 높았다. 정신장애와 비교하여 항-NMDAR 뇌염 초기에 음성증상과 인지장애가 더욱 두드러질 가능성이 있다. A씨의 치료로는 rituximab과 난소 기형종의 제거가 효과적이었고 항정신병제로는 quetiapine을 사용하였다. 특히 젊은 여성에서 망상, 행동장애와 함께 음성증상, 인지장애, 긴장증, 의식수준의 변화, 운동이상증상 등이 관찰될 때 항-NMDAR 뇌염에 대한 평가를 고려해야 한다.

• Biomolecules & Therapeutics
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• 제25권5호
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• pp.519-527
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• 2017

Excessive activation of microglia causes the continuous production of neurotoxic mediators, which further causes neuron degeneration. Therefore, inhibition of microglial activation is a possible target for the treatment of neurodegenerative disorders. Balanophonin, a natural neolignoid from Firmiana simplex, has been reported to have anti-inflammatory and anti-cancer effects. In this study, we aimed to evaluate the anti-neuroinflammatory effects and mechanism of balanophonin in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. BV2 microglia cells were stimulated with LPS in the presence or absence of balanophonin. The results indicated that balanophonin reduced not only the LPS-mediated TLR4 activation but also the production of inflammatory mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), $Interleukin-1{\beta}$ ($IL-1{\beta}$), and tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), in BV2 cells. Balanophonin also inhibited LPS-induced inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2) protein expression and mitogen activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK. Interestingly, it also inhibited neuronal cell death resulting from LPS-activated microglia by regulating cleaved caspase-3 and poly ADP ribose polymerase (PARP) cleavage in N2a cells. In conclusion, our data indicated that balanophonin may delay the progression of neuronal cell death by inhibiting microglial activation.

• Journal of Yeungnam Medical Science
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• 제35권2호
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• pp.192-198
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• 2018

Background: Chronic inflammation can lower the seizure threshold and have influence on epileptogenesis. The components of red ginseng (RG) have anti-inflammatory effects. The abundance of peripherally derived immune cells in resected epileptic tissue suggests that the immune system is a potential target for anti-epileptogenic therapies. The present study used continuous electroencephalography (EEG) to evaluate the therapeutic efficacy of RG in intrahippocampal kainic acid (IHKA) animal model of temporal lobe epilepsy. Methods: Prolonged status epilepticus (SE) was induced in 7-week-old C57BL/6J mice via stereotaxic injection of kainic acid (KA, 150 nL; 1 mg/mL) into the right CA3/dorsal hippocampus. The animals were implanted electrodes and monitored for spontaneous seizures. Following the IHKA injections, one group received treatments of RG (250 mg/kg/day) for 4 weeks (RG group, n=7) while another group received valproic acid (VPA, 30 mg/kg/day) (VPA group, n=7). Laboratory findings and pathological results were assessed at D29 and continuous (24 h/week) EEG monitoring was used to evaluate high-voltage sharp waves on D7, D14, D21, and D28. Results: At D29, there were no differences between the groups in liver function test but RG group had higher blood urea nitrogen levels. Immunohistochemistry analyses revealed that RG reduced the infiltration of immune cells into the brain and EEG analyses showed that it had anticonvulsant effects. Conclusion: Repeated treatments with RG after IHKA-induced SE decreased immune cell infiltration into the brain and resulted in a marked decrease in electrographic seizures. RG had anticonvulsant effects that were similar to those of VPA without serious side effects.

• 대한임상검사과학회지
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• 제54권3호
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• pp.201-208
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• 2022

Neuroinflammation is defined as a neurological inflammation within the brain and the spinal cord. In neuroinflammation, microglia are the tissue-resident macrophages of the central nervous system, which act as the first line of defense against harmful pathogens. Dexmedetomidine (Dex) has an anti-inflammatory effect in many neurological conditions. Additionally, the microRNA-30a-5p (miR-30a-5p) mimic has been proven to be effective in macrophages in inflammatory conditions. This study aimed to investigate the synergistic anti-inflammatory effects of both miR-30a-5p and Dex in lipopolysaccharide (LPS)-induced BV2 cells. This study showed that miR-30a-5p and Dex decreased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation in LPS-induced BV2 cells. MiR-30a-5p and Dex alleviated tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), LPS-induced phosphorylation c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (ERK) and p38. Also, the expression of the NOD-like receptor pyrin domain containing 3 inflammasome (NLRP3), cleaved caspase-1, and ASC was inhibited. Furthermore, LPS-stimulated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression were attenuated by Dex and miR-30a-5p. Our results indicate that a combination of Dex and miR-30a-5p, attenuates NF-κB activation, the mitogen-activated protein kinase (MAPK) signaling pathway, and inflammatory mediators involved in LPS-induced inflammation and inhibits the activation of the NLRP3 inflammasome in LPS-activated BV2 cells.

• 생명과학회지
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• 제30권11호
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• pp.999-1006
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• 2020

최근 중추신경계에서 면역기능을 담당하는 미세아교세포(microglia)의 염증반응을 효율적으로 조절하는 것은 알츠하이머 병, 파킨슨 병 및 헌팅턴 병과 같은 퇴행성 뇌질환의 치료를 위한 중요한 타겟으로 인식되고 있다. 왕귀뚜라미(Teleogryllus emma)는 다양한 치료효능으로 인해 세계적으로 널리 이용되고 있으며, 본 연구팀에서는 최근 왕귀뚜라미의 전사체 분석을 통하여 항균활성을 가지는 다양한 종류의 새로운 항균 펩타이드(antimicrobial peptide; AMP) 후보들을 선별한 바 있다. 항균 펩타이드는 미생물에서부터 포유류까지 매우 다양한 종으로부터 발견되었으며, 현재는 항균활성뿐만 아니라 염증반응과 같은 다양한 질병의 치료제 개발을 위한 후보 물질로 관심을 받고 있다. 본 연구에서는 선행연구를 통하여 선별된 왕귀뚜라미 유래 항균 펩타이드들 중에서 Teleogryllusine(VKWKR-LNNNKVLQKIYFVKI-NH₂)으로 명명된 항균 펩타이드의 신경염증 억제 효능을 관찰하였다. Teleogryllusine의 신경염증 억제 효능을 관찰 하기 위하여 immortalized mouse microglia 세포주인 BV-2 세포에 Teleogryllusine을 1시간 전처리 한 후 LPS를 이용하여 BV-2 세포의 염증 반응을 유도하였다. 그 결과 Teleogryllusin은 최대 처리 농도인 80 ㎍/ml까지 세포독성 없이 nitric oxide (NO) 생성을 현저히 감소시킴을 확인할 수 있었다. 또한 염증반응 매개인자인 iNOS와 COX-2 및 cytokine (Il-6, TNF-α)의 발현을 유전자 수준과 단백질 수준에서 확인한 결과 Teleogryllusine 처리농도에 의존적으로 감소됨을 확인할 수 있었다. 또한 Teleogryllusine의 신경염증 억제작용 기작을 확인한 결과 mitogen activated protein kinases (MAPKs)와 IκB의 인산화 및 proteosome에 의한 IκB의 분해를 억제함으로서 BV-2 세포의 신경염증반응이 조절됨을 확인할 수 있었다. 이러한 결과로 보아 왕귀뚜라미 유래 Teleogryllusine 펩타이드는 신경염증반응에 의해 유도되는 퇴행성 뇌질환 치료 및 예방을 위한 의료용 소재로 사용될 수 있을 것으로 기대된다.

• Natural Product Sciences
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• 제28권3호
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• pp.153-160
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• 2022

Neuroinflammation is known to be associated with brain injury in Alzheimer's disease (AD), and the inhibition of microglial activation, a key player in inflammatory response, is considerd as important target for AD. In this study, the ethanol extract of aerial parts of Forsythia velutina Nakai, a Korean native species, significantly inhibited nitric oxide (NO) production in LPS-stimulated BV2 microglial cells. Thus, the active principles in F. velutina aerial parts were isolated based on activity-guided isolation method. As a result, six compounds were isolated and their structures were elucidated based on NMR data and the comparison with the relevant references as arctigenin (1), matairesinol (2), rengyolone (3), ursolic acid (4), secoisolariciresinol (5), and arctiin (6). Among them, four compounds including arctigenin (1), matairesinol (2), secoisolariciresinol (5), and arctiin (6) significantly inhibited NO production in a dose-dependent manner. In particular, matairesinol (2) and secoisolariciresinol (5) reduced 60% of NO production compared to LPS-treated group. This inhibitory effects of matairesinol (2) and secoisolariciresinol (5) were accompanied with the reduced expression levels of iNOS and COX-2. These results suggest that the extract of F. velutina and its active compounds could be beneficial for neuroinflammatory diseases including AD.

• IMMUNE NETWORK
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• 제22권1호
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• pp.9.1-9.23
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• 2022

In the past few decades, biological drugs and small molecule inhibitors targeting inflammatory cytokines, immune cells, and intracellular kinases have become the standard-of-care to treat autoimmune diseases. Inhibition of TNF, IL-6, IL-17, and IL-23 has revolutionized the treatment of autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. B cell depletion therapy using anti-CD20 mAbs has shown promising results in patients with neuroinflammatory diseases, and inhibition of B cell survival factors is approved for treatment of systemic lupus erythematosus. Targeting co-stimulatory molecules expressed on Ag-presenting cells and T cells is also expected to have therapeutic potential in autoimmune diseases by modulating T cell function. Recently, small molecule kinase inhibitors targeting the JAK family, which is responsible for signal transduction from multiple receptors, have garnered great interest in the field of autoimmune and hematologic diseases. However, there are still unmet medical needs in terms of therapeutic efficacy and safety profiles. Emerging therapies aim to induce immune tolerance without compromising immune function, using advanced molecular engineering techniques.

• 생약학회지
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• 제48권4호
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• pp.261-267
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• 2017

As part of the search for bioactive constituents of Korean medicinal plants, twelve steroids (1-12) were isolated from the rhizomes of Dioscorea nipponica. The isolated compounds were identified as diosgenin ($3{\beta}$, 25R)-spirost-5-en-3-ol (1), 25(R)-dracaenoside E (2), dioscin (3), gracillin (4), prosapogenin B (5), 25(R)-dracaenoside G (6), diosgenin 3-O-${\beta}$-D-glucopyranosyl($1{\rightarrow}3$)-${\beta}$-D-glucopyranoside (7), ophipogonin C′ (8), 7-oxodioscin (9), protodioscin (10), hypoglaucin F (11), and protoneogracillin (12). Their structures were characterized by spectroscopic data and identified by comparing these data with those in the literatures. All the isolates (1-12) were evaluated for their neuroprotective effects through induction of nerve growth factor in C6 glioma cells and effects on nitric oxide (NO) production in murine microglia cell line BV-2. Compounds 7 and 12 were found to induce upregulation of NGF secretion without causing significant cell toxicity and compound 4 exhibited potent anti-neuroinflammatory activity.