• The Korean Journal of Pain
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• 제34권1호
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• pp.35-46
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• 2021

Background: The present investigation explored the therapeutic actions of oleuropein along with the possible signaling pathway involved in attenuating neuropathic pain in chronic constriction injury (CCI) and vincristine-induced neuropathic pain in male rats. Methods: Four loose ligatures were placed around the sciatic nerve to induce CCI, and vincristine (50 ㎍/kg) was injected for 10 days to develop neuropathic pain. The development of cold allodynia, mechanical allodynia, and mechanical hyperalgesia was assessed using different pain-related behavioral tests. The levels of H2S, cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), orexin, and nuclear factor erythroid-2-related factor 2 (Nrf2) were measured in the sciatic nerve. Results: Treatment with oleuropein for 14 days led to significant amelioration of behavioral manifestations of neuropathic pain in two pain models. Moreover, oleuropein restored both CCI and vincristine-induced decreases in H2S, CSE, CBS, orexin, and Nrf2 levels. Co-administration of suvorexant, an orexin receptor antagonist, significantly counteracted the pain-attenuating actions of oleuropein and Nrf2 levels without modulating H2S, CSE and CBS. Conclusions: Oleuropein has therapeutic potential to attenuate the pain manifestations in CCI and vincristine-induced neuropathic pain, possibly by restoring the CSE, CBS, and H2S, which may subsequently increase the expression of orexin and Nrf2 to ameliorate behavioral manifestations of pain.

• 생약학회지
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• 제48권1호
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• pp.31-37
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• 2017

Glutamate-induced oxidative stress results in neuro-degenerative disorders in many central nervous system (CNS) such as Alzheimer's disease, ischemia, Huntington's disease, and Parkinson's disease. Our study was performed to investigate neuroprotective effects of Allium hookeri extracts (leaf, root, and whole) on glutamate-induced HT22 cells. In this study, ethanol extract of A. hookeri showed the outstanding neuroprotective effect in HT22 cells. In addition, we found that ethanol extract of A. hookeri root increased heme oxygenase (HO)-1 in HT22 cells. Moreover, ethanol extract of A. hookeri root also upregulated nuclear accumulation of nuclear factor E2-related factor 2 (Nrf2) in HT22 cells. These results demonstrate that ethanol extract of A. hookeri root contributes neuroprotective effects against glutamate-induced oxidative stress in HT22 cells, via Nrf2-mediated HO-1 expression. Our study suggests that ethanol extract of A. hookeri root could be the potential agent for the treatment of many neuro-degenerative diseases.

• 생약학회지
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• 제41권3호
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• pp.190-195
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• 2010

Glutamate-induced oxidative injury contributes to neuronal degeneration in many central nervous system (CNS) diseases, such as Parkinson's disease, Alzheimer's disease, epilepsy and ischemia. Inducible heme oxygenase (HO)-1 acts against oxidants that are thought to play a role in the pathogenesis of these diseases. NNMBS098, a composition comprising the water insoluble of the 70% EtOH extract of Zingiberis Rhizoma, showed the potent neuroprotective effects on glutamateinduced neurotoxicity by induced the expression of heme oxygenase (HO)-1 and increased HO activity in the mouse hippocampal HT22 cells. Furthermore, NNMBS098 caused the nuclear accumulation of nuclear factor E2-related factor 2 (Nrf2) in mouse hippocampal HT22 cells. In addition, we found that treatment with c-Jun N-terminal kinase (JNK) inhibitor (SP600125) reduced NNMBS098-induced HO-1 expression and NNMBS098 also increased JNK phosphorylation. Therefore, these results suggest that NNMBS098 increases cellular resistance to glutamate-induced oxidative injury in mouse hippocampal HT22 cells, presumably through JNK pathway-Nrf2-dependent HO-1 expression.

• Nutrition Research and Practice
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• 제13권6호
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• pp.473-479
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• 2019

BACKGROUND/OBJECTIVES: Anti-inflammatory and antioxidative activities of luteolin and luteolin-7-O-glucoside were compared in galactosamine (GalN)/lipopolysaccharide (LPS)-induced hepatitic ICR mice. MATERIALS/METHODS: Male ICR mice (6 weeks old) were divided into 4 groups: normal control, GalN/LPS, luteolin, and luteolin-7-O-glucoside groups. The latter two groups were administered luteolin or luteolin-7-O-glucoside (50 mg/kg BW) daily by gavage for 3 weeks after which hepatitis was induced by intraperitoneal injection of GalN and LPS (1 g/kg BW and $10{\mu}g/kg\;BW$, respectively). RESULTS: GalN/LPS produced acute hepatic injury by a sharp increase in serum AST, ALT, and $TNF-{\alpha}$ levels, increases that were ameliorated in the experimental groups. In addition, markedly increased expressions of cyclooxygenase (COX)-2 and its transcription factors, nuclear factor $(NF)-{\kappa}B$ and activator protein (AP)-1, were also significantly attenuated in the experimental groups. Compared to luteolin-7-O-glucoside, luteolin more potently ameliorated the levels of inflammatory mediators. Phase II enzymes levels and NF-E2 p45-related factor (Nrf)-2 activation that were decreased by GalN/LPS were increased by luteolin and luteolin-7-O-glucoside administration. In addition, compared to luteolin, luteolin-7-O-glucoside acted as a more potent inducer of changes in phase II enzymes. Liver histopathology results were consistent with the mediator and enzyme results. CONCLUSION: Luteolin and luteolin-7-O-glucoside protect against GalN/LPS-induced hepatotoxicity through the regulation of inflammatory mediators and phase II enzymes.

• 한방재활의학과학회지
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• 제32권1호
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• pp.1-19
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• 2022

Objectives This study aims to evaluate the wound healing effects of oral administered hot water extracts of Korean black ginseng (KBG). Methods 40 C57BL/6 mice were divided into five groups; normal, control, vitamin E 200 mg/kg, KBG 100 mg/kg, KBG 200 mg/kg, each n=8. Skin wounds were made in the back of all mice except normal group using biopsy punches. Wounds were observed on days 7 and 14 after injury. The anti-oxidant and inflammatory protein levels were evaluated using western blotting. Skin tissue was analyzed by hematoxylin & eosin and Masson's trichrome staining method. Results KBG significantly accelerated reducing wound area. KBG significantly decreased myeloperoxidase activity. KBG significantly decreased oxidative stress factors such as NADPH oxidase-4 and p22^phox and increased antioxidant enzymes including nuclear factor erythroid 2-related factor2, kelch-like ECH-associated protein-1, heme oxygenase-1, superoxide dismutase, catalase and glutathione peroxidase-1/2. Moreover, KBG significantly decreased inflammation factors including nuclear factor-κB, phosphorylated inhibitor of κBα, cyclooxygenase-2, inducible nitric oxide synthase, tumor necrosis factor-α and interleukin (IL)-6 and increased anti-inflammation cytokine such as IL-4 and IL-10. In addition, KBG significantly increased tight junction proteins including claudin-1, claudin-3, claudin-4. In histopathologic, KBG made the epithelium thin and uniform, and accelerated the remodeling of collagen. Conclusions The results suggest that KBG has healing effects on skin wound in mice by anti-inflammatory and antioxidant activity.

• IMMUNE NETWORK
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• 제9권1호
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• pp.12-19
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• 2009

Heme oxygenase (HO)-1 is an inducible enzyme that catalyzes the first and rate-limiting step in the oxidative degradation of free heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV), the latter being subsequently converted into bilirubin (BR). HO-1, once expressed during inflammation, forms high concentrations of its enzymatic by-products that can influence various biological events, and this expression is proven to be associated with the resolution of inflammation. The degradation of heme by HO-1 itself, the signaling actions of CO, the antioxidant properties of BV/BR, and the sequestration of ferrous iron by ferritin all concertedly contribute to the anti-inflammatory effects of HO-1. This review focuses on the anti-inflammatory mechanisms of HO-1 actions and its roles in inflammatory diseases.

• 생약학회지
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• 제42권3호
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• pp.276-281
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• 2011

Oxidative stress or the accumulation of reactive oxygen species (ROS) leads neuronal cellular death and dysfunction, and it contributes to neuronal degenerative disease such as Alzheimer's disease, Parkinson's disease and stroke. Glutamate-induced oxidative injury contributes to neuronal degeneration in many central nervous system (CNS) diseases, such as epilepsy and ischemia. Heme oxygenase-1 (HO-1) enzyme plays an important role of cellular antioxidant system against oxidant injury. The expression of HO-1 has cytoprotective effects in glutamate-induced oxidative cytotoxicity in HT22 cells. The induction of HO-1 is primarily regulated at the transcriptional level, and its induction by various inducers is related to the nuclear transcription factor-E2-related factor 2 (Nrf2). Nrf2 is a master regulator of the antioxidant response. NNMBS008, the water-insoluble fraction of the 70% EtOH extract of roots of Sophora flavescens, showed dominant neuroprotective effects on glutamate-induced neurotoxicity in mouse hippocampal HT22 cells by induced the expression of HO-1 and increased HO activity. In mouse hippocampal HT22 cells, NNMBS008 makes the nuclear accumulation of Nrf2 pathway. In conclusion, the waterinsoluble fraction of the 70% EtOH extract of roots of S. flavescens (NNMBS008) significantly protect glutamate-induced oxidative damage by induction of HO-1 via Nrf2 pathway in mouse hippocampal HT22 cells. These results suggest that these extracts could be the effective candidates for the treatment of ROS-related neurological diseases.

• Biomolecules & Therapeutics
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• 제20권2호
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• pp.144-151
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• 2012

The molecular mechanisms by which a variety of naturally-occurring dietary compounds exert chemopreventive effects have been a subject of intense scientific investigations. Induction of phase II detoxification and anti-oxidant enzymes through activation of Nrf2/ARE-dependent gene is recognized as one of the major cellular defense mechanisms against oxidative or xenobiotic stresses and currently represents a critical chemopreventive mechanism of action. In the present review, the functional significance of Keap1/Nrf2 protein module in regulating ARE-dependent phase II detoxification and anti-oxidant gene expression is discussed. The biochemical mechanisms underlying the phosphorylation and expression of Keap1/Nrf2 proteins that are controlled by the intracellular signaling kinases and ubiquitin-mediated E3 ligase system as well as control of nucleocytoplasmic translocation of Nrf2 by its innate nuclear export signal (NES) are described.

• 대한본초학회지
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• 제30권1호
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• pp.85-93
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• 2015

Objectives : Bilobalide (BIL) is a predominant sesquiterpene trilactone constituent that accounts for a partial portion of the standardized Ginkgonis Folium extract, which has been widely used to treat a variety of neurological disorders involving cerebral ischemia and neurodegeneration. In this study, it was tested whether BIL exhibits anti-inflammatory activities on inflammation response, or not. Methods : To elucidate the molecular mechanisms of BIL on pharmacological and biochemical actions in inflammation, we examined the effect of BIL on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated macrophages. The investigation was focused on how BIL affect on inflammation-related mediators including various signals such as nitric oxide (NO), prostaglandin $E_2$ ($PGE_2$), inducible NO synthase(iNOS), cyclooxygenase-2(COX-2), interleukin-6(IL-6), tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), mitogen-activated protein kinases(MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells ($NF-{\kappa}B$) in LPS-stimulated RAW 264.7 cells. Results : We found that BIL inhibited LPS-induced NO, $PGE_2$, IL-6 and $TNF-{\alpha}$ productions as well as the expressions of iNOS and COX-2. Furthermore, BIL suppressed the LPS-induced phosphorylation for MAPK activation. Conclusions : These results suggest that BIL has inhibitory effects on LPS-induced $PGE_2$, NO, IL-6 and $TNF-{\alpha}$ production, as well as the expressions of iNOS and COX-2 in the murine macrophage. It seems that these inhibitory effects occur by blocking the phosphorylation of MAPKs for activation. Then, BIL suppressed the activation of nuclear factor $NF-{\kappa}B$ in nucleus. These observations suggest that BIL has anti-inflammatory effect by inhibiting.

• 생명과학회지
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• 제29권4호
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• pp.402-409
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• 2019

생삼을 쪄서 건조시킨 홍삼은 전통적으로 사용되고 있는 약재로서 면역, 내분비 및 중추신경계 작용을 증진시키며 염증을 억제하는 효과가 있는 것으로 알려져 있다. 본 연구에서는 그람 양성균의 세포벽 성분인 lipoteichoic acid (LTA)에 의한 염증반응에 홍삼추출액(RGE)이 항염증 효과를 가지는지 관찰하고 그 작용 기전을 연구하였다. BV-2 소교세포에서 RGE는 세포에 독성을 유도하지 않으면서 LTA로 인한 nitric oxide (NO)의 생성과 inducible nitric oxide synthase (iNOS) 발현을 억제하였으며, NF-kB p65의 핵으로의 이동과 IkB-a의 분해 또한 억제하였다. 한편, RGE는 농도의존적으로 heme oxygenase-1 (HO-1)의 발현을 유도하였으며, HO-1 siRNA를 처리했을 때는 RGE가 iNOS의 발현을 억제하지 못하였다. RGE는 HO-1의 발현에 관여하는 전사인자인 nuclear factor E2-related factor 2 (Nrf2)를 핵으로 이동을 촉진시켰다. 또한 RGE에 의한 HO-1의 발현은 phosphatidylinositol-3-kinase(PI-3K) 및 MAPK 억제제에 의해 감소되었으며, RGE가 Akt와 ERK, p38, JNK의 인산화를 유도하였다. 이상의 결과를 종합해보면, RGE는 PI-3K/Akt 및 ERK, p38, JNK 신호전달과정을 통해 HO-1의 발현을 유도함으로써 NO와 같은 염증매개물질의 생성을 억제한다는 것을 알 수 있다. 그러므로 홍삼추출액은 그람 양성균에 의한 신경염증과 염증관련 신경계 질환의 치료제로서 사용될 수 있을 것이라 사료된다.