• Journal of Ginseng Research
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• v.44 no.3
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• pp.386-398
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• 2020

Tissue fibrosis is an eventual pathologic change of numerous chronic illnesses, which is characterized by resident fibroblasts differentiation into myofibroblasts during inflammation, coupled with excessive extracellular matrix deposition in tissues, ultimately leading to failure of normal organ function. Now, there are many mechanistic insights into the pathogenesis of tissue fibrosis, which facilitate the discovery of effective antifibrotic drugs. Moreover, many chronic diseases remain a significant clinical unmet need. For the past five years, many research works have undoubtedly addressed the functional dependency of ginsenosides in different types of fibrosis and the successful remission in various animal models treated with ginsenosides. Caveolin-1, interleukin, thrombospondin-1 (TSP-1), liver X receptors (LXRs), Nrf2, microRNA-27b, PPARδ-STAT3, liver kinase B1 (LKB1)-AMPK, and TGF-β1/Smads are potential therapy targeting using ginsenosides. Ginsenosides can play a targeting role and suppress chronic inflammatory response, collagen deposition, and epitheliale-mesenchymal transition (EMT), as well as myofibroblast activation to attenuate fibrosis. In this report, our aim was to focus on the therapeutic prospects of ginsenosides in fibrosis-related human diseases making use of results acquired from various animal models. These findings should provide important therapeutic clues and strategies for the exploration of new drugs for fibrosis treatment.

• Journal of Life Science
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• v.23 no.8
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• pp.1057-1063
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• 2013

Citri Pericarpium is one of the most commonly used traditional herbal medicines in Korea, China, and Japan. Its extracts have many properties including the treatment of indigestion and inflammatory respiratory syndromes such as bronchitis and asthma. However, the underlying molecular mechanisms of anti-cancer activity and molecular targets are not fully understood. In this work, we investigated the anti-proliferative activity of Citri Pericapium (EMCP) methanol extract on reactive oxygen species (ROS) production and the association of these effects with apoptotic cell death using U937 human leukemia cells in vitro. EMCP treatment decreased cell proliferation in a dose-dependent manner following an increase of the sub-G1 phase, the down-regulation of Bax proteins, the activation of caspases, the degradation of poly (ADP-ribose) polymerase proteins (PARP), and the induction of ROS generation. However, the quenching of ROS generation by N-acetyl-L-cysteine administration, a scavenger of ROS, reversed the EMCP-induced apoptosis effects. In addition, heme oxygenase-1 expression also recovered by inhibiting the nuclear translocation of phosphorylated NF-E2-related factor 2. Taken together, our data indicate that ROS are involved as key mediators in the early molecular events in the EMCP-induced apoptotic pathway.

• The Korea Journal of Herbology
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• v.35 no.4
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• pp.25-36
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• 2020

Objective : Reflux esophagitis is a disease caused by the reflux of gastric acid and inflammation due to unstable gastroesophageal sphincter. The aim of the present study was to clarify the effect of Phellodendri Cortex (PC) on chronic reflux esophagitis (CRE) in rats. Methods : The anti-oxidant activity of PC was measured by total polyphenol, total flavonoid contents, 1, 1-diphenyl-2-picrylhydrazyl (DPPH), and 2, 2'-azinobis-3-ethyl-enzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity. A CRE was established surgically in SD rats. And then CRE rats were treated with water or PC 200 mg/kg body weight for 14 days. Besides, the anti-oxidant and inflammatory protein levels were evaluated using western blotting. Results : PC reduced esophagus tissues injury. The total polyphenol (36.05 ± 0.25 mg/g) and total flavonoid (72.90 ± 0.61 mg/g) of PC showed a high content. PC strongly reduced radical scavenging activities (DPPH IC₅₀ 43.58 ± 1.54 ㎍/㎖; ABTS IC₅₀ 36.75 ± 0.35 ㎍/㎖). Moreover, reactive oxygen species (ROS) and peroxynitrite (ONOO^-) levels in serum, the protein expression of inducible nitric oxide synthases (iNOS) were significantly reduced. In addition, the protein expression of NADPH oxidases related to oxidative stress were significantly reduced in PC compared to CRE control. PC effectively reduced inflammatory factors including, TNF-α, and IL-6 via NF-κBp65 inactivation through the inhibition of p-IκBα and increased anti-oxidant enzyme such as HO-1, SOD, catalase, and GPx-1/2 via Nrf2 activation. Conclusions : Taken together, these results show that PC can alleviate the esophageal mucosal ulcer though the inhibition of NF-κB inflammatory and the enhancement of Nrf2 anti-oxidant pathway.

• The Journal of Internal Korean Medicine
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• v.42 no.1
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• pp.11-24
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• 2021

Objective: Chronic reflux esophagitis (CRE), characterized by esophageal mucosa ulcer, is caused by continuous backflow of gastric acid and consequent inflammation due to unstable gastroesophageal sphincter. The aim of the present study was to clarify the effect of an Arecae Semen and Coptidis Rhizoma mixture (AC-mix) on CRE. Methods: CRE was surgically induced in SD rats with three experimental groups used: normal; CRE control; and CRE treatment (200 mg/kg AC-mix). Blood and esophageal tissue were collected after two weeks of drug administration. The anti-oxidant activity of the AC-mix was measured by total polyphenol and total flavonoid contents as well as by radical scavenging activity with protein levels evaluated using western blotting. Results: CRE damage to the esophageal mucosa was significantly reduced in the AC-mix group as compared with the controls, and administration of the AC-mix was seen to inhibit NF-κBp65 activity. Consequently, the inactivation of NF-κBp65 significantly inhibited inflammatory mediators such as COX-2 and iNOS. Moreover, the anti-oxidant enzyme HO-1 significantly increased through activation of the Nrf2-Keap1 pathway. Matrix metalloproteinase-2 (MMP-2), which can break down collagen from the basement membrane and extracellular matrix, was decreased following AC-mix treatment, and elevated levels of MMP-2 were regulated by its tissue inhibitor. Conclusions: These results show that AC-mix can alleviate esophageal mucosa ulcer though inhibition of the NF-κBp65 inflammatory pathway and enhancement of the anti-oxidant Nrf2-Keap1 pathway.

• The Korea Journal of Herbology
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• v.30 no.4
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• pp.37-44
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• 2015

Objectives : The present study was designed to evaluate the anti-inflammatory and anti-oxidative stress activities through regulation of Nrf2-mediated genes by Rhei rhizoma and Glycyrrhiza rhizoma combined extract (RGE) in reflux esophagitis.Methods : The antioxidant activity of RGE in vitro was measured in terms of radical scavenging capacity such as DPPH and ABTS. RGE was administered at 350 mg/kg body weight prior to induction of reflux esophagitis. Reflux esophagitis was induced that tied the pylorus and the transitional junction between the forestomach and the corpus in Sprague-Dawley rats.Results : RGE scavenged DPPH and ABTS effectively and IC₅₀of RGE each were 4.9 μg/ml and 45.6 μg/ml. Our results show that RGE administration markedly ameliorated mucosal damage upon histological evaluation. In serum and esophagus tissue, RGE significantly suppressed the oxidative stress biomarkers. Reflux esophagitis induced rats exhibited down-regulation of antioxidant-related proteins in the esophagus; however, the levels with treatment of RGE were significantly higher than those of vehicle reflux esophagitis rats. RGE treatment caused significant reductions in activation of NF-κB transcription factor. Thus, RGE significantly exhibited potent anti-inflammatory activities by suppressing the protein expression levels of pro-inflammatory proteins such as COX-2 and iNOS and inflammatory cytokines such as TNF-αin the esophagus tissue.Conclusions : Reflux esophagitis caused considerable levels of oxidative stress in the esophageal mucosa and the administration of RGE reduced the esophageal mucosa damage through the regulation of Nrf2 and NF-κB pathways. Our findings can considered as supplementary therapy in the prevention or treatment of reflux esophagitis.

• Journal of Nutrition and Health
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• v.44 no.6
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• pp.488-497
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• 2011

Oxygen is necessary to sustain life, yet cellular oxygen metabolism creates destructive elements called free radicals. Free radicals are chemically unbalanced and carrying free electrons that can damage molecules, potentially damaging the cell itself. For this reason, many antioxidant products, including supplements and functional foods, are being developed. In particular, natural products are rich sources of pharmacologically active compounds. The purpose of this study was to investigate the antioxidant effects of target biomaterials in Korean traditional spices such as diallyl sulfide (DAS), capsaicin (CAP), and gingerol (GGR), and to investigate the response of the antioxidant defense system to oxidative stress by hydrogen peroxide ($H_2O_2$) compared to sulforaphane (SFN) in HepG2 cells. After the analysis of the cell viability using Cell Counting kit-8 (CCK-8) assay, we determined that the optimum levels were $200{\mu}M$ DAS, $25{\mu}M$ CAP, $50{\mu}M$ GGR, and $12.5{\mu}M$ SFN. Antioxidant enzymes were measured and protein expression was detected by Western blotting. All treatments showed a significant decrease in antioxidant enzyme activity such as superoxide dismutase, catalse, and glutathione peroxidase in HepG2 cells. Additionally, DAS, CAP, GGR and SFN increased the antioxidant system-related transcription factor Nrf2 which was found to be regulated by the activation of MAPK-JNK in this study. In conclusion, these results indicate the protective effects of DAS CAP, GGR, and SFN against $H_2O_2$-induced oxidative stress.

• Nutrition Research and Practice
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• v.13 no.6
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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.

• Molecules and Cells
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• v.42 no.4
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• pp.292-300
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• 2019

Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.

• Journal of Ginseng Research
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• v.44 no.3
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• pp.435-441
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• 2020

Background: As a process of aging, skeletal muscle mass and function gradually decrease. It is reported that ginsenoside Rb1 and Rb2 play a role as AMP-activated protein kinase activator, resulting in regulating glucose homeostasis, and Rb1 reduces oxidative stress in aged skeletal muscles through activating the phosphatidylinositol 3-kinase/Akt/Nrf2 pathway. We examined the effects of Rb1 and Rb2 on differentiation of the muscle stem cells and myotube formation. Methods: C2C12 myoblasts treated with Rb1 and/or Rb2 were differentiated and induced to myotube formation, followed by immunoblotting for myogenic marker proteins, such as myosin heavy chain, MyoD, and myogenin, or immunostaining for myosin heavy chain or immunoprecipitation analysis for heterodimerization of MyoD/E-proteins. Results: Rb1 and Rb2 enhanced myoblast differentiation through accelerating MyoD/E-protein heterodimerization and increased myotube hypertrophy, accompanied by activation of Akt/mammalian target of rapamycin signaling. In addition, Rb1 and Rb2 induced the MyoD-mediated transdifferentiation of the rhabdomyosarcoma cells into myoblasts. Furthermore, co-treatment with Rb1 and Rb2 had synergistically enhanced myoblast differentiation through Akt activation. Conclusion: Rb1 and Rb2 upregulate myotube growth and myogenic differentiation through activating Akt/mammalian target of rapamycin signaling and inducing myogenic conversion of fibroblasts. Thus, our first finding indicates that Rb1 and Rb2 have strong potential as a helpful remedy to prevent and treat muscle atrophy, such as age-related muscular dystrophy.

• Journal of Ginseng Research
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• v.47 no.3
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• pp.390-399
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• 2023

Background: Gintonin (GT), a Panax ginseng-derived lysophosphatidic acid receptor (LPAR) ligand, has positive effects in cultured or animal models for Parkinson's disease, Huntington's disease, and so on. However, the potential therapeutic value of GT in treating epilepsy has not yet been reported. Methods: Effects of GT on epileptic seizure (seizure) in kainic acid [KA, 55mg/kg, intraperitoneal (i.p.)]-induced model of mice, excitotoxic (hippocampal) cell death in KA [0.2 ㎍, intracerebroventricular (i.c.v.)]-induced model of mice, and levels of proinflammatory mediators in lipopolysaccharide (LPS)-induced BV2 cells were investigated. Results: An i.p. injection of KA into mice produced typical seizure. However, it was significantly alleviated by oral administration of GT in a dose-dependent manner. An i.c.v. injection of KA produced typical hippocampal cell death, whereas it was significantly ameliorated by administration of GT, which was related to reduced levels of neuroglial (microglia and astrocyte) activation and proinflammatory cytokines/enzymes expression as well as increased level of the Nrf2-antioxidant response via the upregulation of LPAR 1/3 in the hippocampus. However, these positive effects of GT were neutralized by an i.p. injection of Ki16425, an antagonist of LPA1-3. GT also reduced protein expression level of inducible nitric-oxide synthase, a representative proinflammatory enzyme, in LPS-induced BV2 cells. Treatment with conditioned medium clearly reduced cultured HT-22 cell death. Conclusion: Taken together, these results suggest that GT may suppress KA-induced seizures and excitotoxic events in the hippocampus through its anti-inflammatory and antioxidant activities by activating LPA signaling. Thus, GT has a therapeutic potential to treat epilepsy.