Publications by authors named "Eugene Huh"

20 Publications

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Artemisiae Iwayomogii Herba inhibits lipopolysaccharide-induced neuroinflammation by regulating NF-κB and MAPK signaling pathways.

Phytomedicine 2021 Feb 10;84:153501. Epub 2021 Feb 10.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Background: Neuroinflammation plays a major role in the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The regulation of microglia is an efficient therapeutic approach to controlling neuroinflammation.

Purpose: In this study, we aimed to determine whether Artemisiae Iwayomogii Herba (AIH), which is herbal medicine traditionally used for inflammation-related disorders, controls neuroinflammatory responses by regulating the microglia-mediated signaling pathway.

Methods: BV-2 microglial cells were treated with AIH and lipopolysaccharides (LPS), then various pro-inflammatory mediators were analyzed using griess reaction, quantitative reverse-transcription polymerase chain reaction, or western blotting. C57BL/6 J mice were orally administered by AIH for 17 days and intraperitoneally injected with LPS for the last 14 days. The brains were collected and the microglial activation and nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) expression in the cortex and hippocampus were analyzed using immunohistochemistry or western blotting.

Results: In BV-2 microglial cells, we found that AIH inhibited nitric oxide (NO) production induced by LPS. AIH also suppressed the expressions of pro-inflammatory mediators, including inducible NO synthase, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-6. The study also revealed that the effects of AIH are related to the regulation of the nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, we found that AIH prevented the formation of NLRP3 inflammasomes. Consistent with the results of in vitro studies on the brains of LPS-injected mice, we observed that AIH suppressed microglial activation and NLRP3 expression.

Conclusion: Taken together, these results suggest that AIH attenuates neuroinflammation by regulating the NF-κB and MAPK pathways, and it may be used for treating neurological diseases.
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http://dx.doi.org/10.1016/j.phymed.2021.153501DOI Listing
February 2021

GC-TOF-MS-Based Metabolomic Analysis and Evaluation of the Effects of HX106, a Nutraceutical, on ADHD-Like Symptoms in Prenatal Alcohol Exposed Mice.

Nutrients 2020 Oct 2;12(10). Epub 2020 Oct 2.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Korea.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that occurs in children characterized by inattention and hyperactivity. Prenatal alcohol exposure (PAE) can disrupt fetal neuronal development and cause an ADHD-like hyperactive behavior in the offspring. In this study, we hypothesized that metabolic disturbance would involve in ADHD neuropathology and aimed to investigate the changes in metabolite profile in PAE-induced ADHD-like model and the effects of HX106, a nutraceutical, on ADHD-like pathophysiology and metabolite changes. To this end, we administered HX106 to the mouse offspring affected by PAE (OPAE) and assessed the hyperactivity using the open field test. We observed that HX106-treated OPAE showed less hyperactive behavior than vehicle-treated OPAE. The effects of HX106 were found to be related to the regulation of dopamine transporter and D2 dopamine receptor expression. Furthermore, using gas chromatography time-of-flight mass spectrometry-based metabolomics, we explored the metabolite changes among the experimental groups. The metabolite profile, particularly related with the amino acids, linoleic acid and amino sugar pathways, was altered by PAE and reversed by HX106 treatment partially similar to that observed in the control group. Overall, this study suggest that metabolite alteration would be involved in ADHD pathology and that HX106 can be an efficient supplement to overcome ADHD by regulating dopamine signaling-related protein expression and metabolite changes.
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http://dx.doi.org/10.3390/nu12103027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600704PMC
October 2020

Penta-fluorophenol: a Smiles rearrangement-inspired cysteine-selective fluorescent probe for imaging of human glioblastoma.

Chem Sci 2020 Jun 11;11(22):5658-5668. Epub 2020 May 11.

Department of Biomedical Science , Graduate School , Kyung Hee University , Seoul 02447 , Korea . Email:

Two of the most critical factors for the survival of glioblastoma (GBM) patients are precision diagnosis and the tracking of treatment progress. At the moment, various sophisticated and specific diagnostic procedures are being used, but there are relatively few simple diagnosis methods. This work introduces a sensing probe based on a turn-on type fluorescence response that can measure the cysteine (Cys) level, which is recognized as a new biomarker of GBM, in human-derived cells and within on-site human clinical biopsy samples. The Cys-initiated chemical reactions of the probe cause a significant fluorescence response with high selectivity, high sensitivity, a fast response time, and a two-photon excitable excitation pathway, which allows the imaging of GBM in both mouse models and human tissue samples. The probe can distinguish the GBM cells and disease sites in clinical samples from individual patients. Besides, the probe has no short or long-term toxicity and immune response. The present findings hold promise for application of the probe to a relatively simple and straightforward following of GBM at clinical sites.
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http://dx.doi.org/10.1039/d0sc01085eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449700PMC
June 2020

A brain tumor-homing tetra-peptide delivers a nano-therapeutic for more effective treatment of a mouse model of glioblastoma.

Nanoscale Horiz 2020 07;5(8):1213-1225

Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.

Organ-specific cell-penetrating peptides (CPPs) are a class of molecules that can be highly effective at delivering therapeutic cargoes, and they are currently of great interest in cancer treatment strategies. Herein, we describe a new CPP (amino acid sequence serine-isoleucine-tyrosine-valine, or SIWV) that homes to glioblastoma multiforme (GBM) brain tumor tissues with remarkable specificity in vitro and in vivo. The SIWV sequence was identified from an isoform of annexin-A3 (AA3H), a membrane-interacting human protein. The mechanism of intracellular permeation is proposed to follow a caveolin-mediated endocytotic pathway, based on in vitro and in vivo receptor inhibition and genetic knockdown studies. Feasibility as a targeting agent for therapeutics is demonstrated in a GBM xenograft mouse model, where porous silicon nanoparticles (pSiNPs) containing the clinically relevant anticancer drug SN-38 are grafted with SIWV via a poly-(ethylene glycol) (PEG) linker. The formulation shows enhanced in vivo targeting ability relative to a formulation employing a scrambled control peptide, and significant (P < 0.05) therapeutic efficacy relative to free SN-38 in the GBM xenograft animal model.
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http://dx.doi.org/10.1039/d0nh00077aDOI Listing
July 2020

Stapf and Gypsum Attenuates Heat-Induced Hypothalamic Inflammation in Mice.

Toxins (Basel) 2019 12 30;12(1). Epub 2019 Dec 30.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Stapf (EH) exert toxic effects, such as excitability, cardiac arrhythmia, and others. On the contrary, in traditional herbal medicine, EH and gypsum (GF) are used most often to treat symptoms caused by external stressors. The hypothalamus plays a crucial role in thermal homeostasis. Inflammatory response in the hypothalamus by thermal stressors may affect thermal and energy homeostasis. This study investigates the effect of EH and GF against heat-induced mouse model. Mice were divided into four groups: saline, saline plus heat, EH plus heat, and GF plus heat treated groups. Heat stress was fixed at 43 °C for 15 min once daily for 3 days. Weight and ear and rectal temperature measurements were made after terminating heat stress. Hypothalamus tissue was collected to evaluate the HSP70, nuclear factor kappa-Β (NF-kB), and interleukin (IL)-1β protein expression levels. EH and GF treatment suppressed the increased body temperature. EH significantly ameliorated heat-induced body weight loss, compared to gypsum. Regulatory effects of EH and GF for body temperature and weight against heat stress were mediated by IL-1β reduction. EH showed significant HSP70 and NF-kB inhibition against heat stress. EH and GF contribute to the inhibition of heat-induced proinflammatory factors and the promotion of hypothalamic homeostasis.
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http://dx.doi.org/10.3390/toxins12010016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020418PMC
December 2019

High-throughput 16S rRNA gene sequencing reveals that 6-hydroxydopamine affects gut microbial environment.

PLoS One 2019 12;14(8):e0217194. Epub 2019 Aug 12.

Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Dongdaemun-gu, Seoul, Republic of Korea.

Recently, there has been a rapid increase in studies on the relationship between brain diseases and gut microbiota, and clinical evidence on gut microbial changes in Parkinson's disease (PD) has accumulated. 6-Hydroxydopamine (6-OHDA) is a widely used neurotoxin that leads to PD pathogenesis, but whether 6-OHDA affects gut microbial environment has not been investigated. Here we performed the 16S rRNA gene sequencing to analyze the gut microbial community of mice. We found that there were no significant changes in species richness and its diversity in the 6-OHDA-lesioned mice. The relative abundance of Lactobacillus gasseri and L. reuteri probiotic species in feces of 6-OHDA-lesioned mice was significantly decreased compared with those of sham-operated mice, while the commensal bacterium Bacteroides acidifaciens in 6-OHDA-treated mice was remarkably higher than sham-operated mice. These results provide a baseline for understanding the microbial communities of 6-OHDA-induced PD model to investigate the role of gut microbiota in the pathogenesis of PD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217194PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690581PMC
March 2020

Protective effects of DA-9805 on dopaminergic neurons against 6-hydroxydopamine-induced neurotoxicity in the models of Parkinson's disease.

Biomed Pharmacother 2019 Sep 9;117:109184. Epub 2019 Jul 9.

Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea. Electronic address:

With the elderly population rapidly growing, the prevalence of Parkinson's disease (PD) is quickly increasing because neurodegenerative disorders are usually late-onset. Herbal medicines and formula are adjuvant therapies of conventional PD agents, which result in serious side effects with long-term use. This study evaluated the neuroprotective effects of DA-9805, a standardized herbal formula that consists of an ethanolic extract of Moutan Cortex Radix, Angelica Dahuricae Radix, and Bupleuri Radix against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in vitro and in vivo. In PC12 cells, DA-9805 at concentrations of 1 and 10 μg/mL ameliorated cell viability, which was reduced by 6-OHDA. In addition, DA-9805 activated the extracellular-regulated kinase-nuclear transcription factor-erythroid 2-related factor 2 pathway, subsequently stimulating antioxidative enzymes such as NAD(P)H:quinone oxidoreductase 1 and catalase and suppressing apoptosis. Furthermore, DA-9805 prevented 6-OHDA-induced movement impairment, as well as a decrease of dopaminergic neurons and dopamine transmission in rodents. Taken together, these results suggest that the mixed herbal formula DA-9805 may be a pharmaceutical agent for preventing or improving PD.
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http://dx.doi.org/10.1016/j.biopha.2019.109184DOI Listing
September 2019

An Integrative Approach to Treat Parkinson's Disease: Ukgansan Complements L-Dopa by Ameliorating Dopaminergic Neuronal Damage and L-Dopa-Induced Dyskinesia in Mice.

Front Aging Neurosci 2018 7;10:431. Epub 2019 Jan 7.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, South Korea.

Parkinson's disease (PD) is accompanied by motor impairments due to the loss of dopaminergic neurons in the nigrostriatal pathway. Levodopa (L-dopa) has been the gold standard therapy for PD since the 1960s; however, its neurotoxic features accelerate PD progression through auto-oxidation or the induction of dyskinetic movements. Ukgansan (UGS) is a well-known prescription for treating PD in traditional medicines of East Asia, and its anti-PD function has been experimentally evaluated. The present study investigated whether UGS attenuates (1) motor dysfunction and dopaminergic neuronal damage when co-treated with L-dopa and (2) L-dopa-induced dyskinesia (LID) in 6-hydroxydopamine (6-OHDA)-induced PD mice. Although L-dopa was found to reduce motor dysfunctions, it failed to decrease the dopaminergic neuronal damage and increased the expression of dopamine receptor 1 (D1R) and 2 (D2R) in the 6-OHDA-injected mouse striatum. Co-treatment with UGS resulted in normal striatal histology and ameliorated motor impairments. In addition, UGS suppressed the dyskinesia induced by chronic L-dopa treatment while restoring the dopaminergic neurons in the striatum. For the underlying mechanism, UGS reduced the overexpression of D1R-related signaling proteins, such as phosphorylated extracellular signal-regulated kinase, ΔFosB, and c-fos in the striatum. Overall, the results suggest that the effect of UGS could be complementary to L-dopa by ameliorating motor dysfunction, restoring the dopaminergic neurons, and suppressing the dyskinetic movements in PD.
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http://dx.doi.org/10.3389/fnagi.2018.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330324PMC
January 2019

Tectorigenin, a Flavonoid-Based Compound of Leopard Lily Rhizome, Attenuates UV-B-Induced Apoptosis and Collagen Degradation by Inhibiting Oxidative Stress in Human Keratinocytes.

Nutrients 2018 Dec 17;10(12). Epub 2018 Dec 17.

Department of Life and Nanopharmaceutical Sciences, Graduates School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Ultraviolet (UV) light, a major risk factor for external skin photoaging, induces oxidative stress in skin. UV causes a breakdown of skin homeostasis by impairing the extracellular matrix and inducing cell death. Tectorigenin, a constituent of leopard lily ( L.) rhizome, has been reported to possess antioxidant, hair-darkening, and anti-inflammatory activities; however, the effect of tectorigenin on UV-B-induced skin damage is unknown. Here, we investigated the anti-skin-damage effects of tectorigenin against UV-B-stimulated oxidative stress in human keratinocytes. We irradiated HaCaT cells with UV-B (25 mJ/cm²), followed by treatment with tectorigenin for 24 h. We found that tectorigenin decreased the levels of intracellular reactive oxygen species by increasing the expression of anti-oxidative enzymes, such as glutathione and catalase. Furthermore, tectorigenin inhibited apoptosis by reducing caspase-3- and Bcl-2-associated protein-X levels, and increasing Bcl-2 protein levels. Tectorigenin also decreased matrix metalloproteinase-1 levels and increased type 1 collagen levels, thus preventing collagen degradation. These data demonstrate that tectorigenin exerts anti-skin-damage effects in human keratinocytes by attenuating UV-B-induced hyper-oxidation, apoptosis, and collagen degradation.
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http://dx.doi.org/10.3390/nu10121998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316707PMC
December 2018

Ukgansan protects dopaminergic neurons from 6-hydroxydopamine neurotoxicity via activation of the nuclear factor (erythroid-derived 2)-like 2 factor signaling pathway.

Neurochem Int 2019 01 30;122:208-215. Epub 2018 Nov 30.

Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea. Electronic address:

The sustenance of redox homeostasis in brain is the crucial factor to treat Parkinson's disease (PD). Nuclear factor (erythroid-derived 2)-like 2 factor (Nrf2)-mediated antioxidant response is well known for the main cellular endogenous defense mechanisms against oxidative stress. This study investigated for the first time the effects and possible mechanisms of action of Ukgansan on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in both in vitro and in vivo models of PD. We investigated the protective effect of Ukgansan against 6-OHDA with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. In addition, we demonstrated that Ukgansan significantly increased the expression of antioxidant response elements (ARE) and pro-survival protein as Bcl2 and suppressed the expression of pro-apoptotic factors, such as Bax, cytochrome c, and caspase-3 using immunoblotting. For the in vivo study, we used a mouse model of PD involving stereotaxic injection of 6-OHDA into the striatum (ST). Ukgansan alleviated motor dysfunctions induced by 6-OHDA followed by pole, open-field, and rotation tests. Dopaminergic neuronal loss and Nrf2 activation were evaluated by immunohistochemistry in the mouse ST and substantia nigra pars compacta (SNpc) regions. Ukgansan significantly protected dopaminergic neurons from 6-OHDA toxicity in mouse ST and SNpc by activating Nrf2. These results indicate that Ukgansan inhibited 6-OHDA-induced dopaminergic neuronal cell damage via activation of Nrf2 and its related factors in 6-OHDA-induced dopaminergic loss in vitro and in vivo. Thus, Ukgansan might delay the progression of PD via maintenance of redox homeostasis.
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http://dx.doi.org/10.1016/j.neuint.2018.11.021DOI Listing
January 2019

Ginger and 6-shogaol protect intestinal tight junction and enteric dopaminergic neurons against 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine in mice.

Nutr Neurosci 2020 Jun 19;23(6):455-464. Epub 2018 Sep 19.

Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.

Ginger and its compound, 6-shogaol, have been known for improving gastrointestinal (GI) function and reducing inflammatory responses in GI tract. Recently, the treatment of GI dysfunction has been recognized as an important part of the management of neurodegenerative diseases, especially for Parkinson's disease (PD). In this study, we investigated whether ginger and 6-shogaol attenuate disruptions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the intestinal barrier and the enteric dopaminergic neurons. C57BL/6J mice received MPTP (30 mg/kg) for 5 days to induce GI alterations. Ginger (30, 100, 300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 15 days including the period of MPTP injection. Ginger and 6-shogaol protected intestinal tight junction proteins disrupted by MPTP in mouse colon. In addition, ginger and 6-shogaol suppressed the increase of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α and IL-1β activated by macrophage. Moreover, ginger and 6-shogaol suppressed the MPTP-induced enteric dopaminergic neuronal damage via increasing the cell survival signaling pathway. These results indicate that ginger and 6-shogaol restore the disruption of intestinal integrity and enteric dopaminergic neurons in an MPTP-injected mouse PD model by inhibiting the processes of inflammation and apoptosis, suggesting that they may attenuate the GI dysfunction in PD patients.
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http://dx.doi.org/10.1080/1028415X.2018.1520477DOI Listing
June 2020

1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine/probenecid impairs intestinal motility and olfaction in the early stages of Parkinson's disease in mice.

J Neurol Sci 2018 09;392:77-82

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address:

Parkinson's disease (PD) is a progressive neurodegenerative disorder accompanied by movement deficits with selective degeneration of dopaminergic neurons in the substantia nigra (SN). Recent studies indicate that early diagnosis of PD has important implications for the disease-modifying strategy for PD showing not only some dopaminergic neuronal damage but also non-motor symptoms, which occur several years before the onset of motor symptoms. However, studies on the relationship between non-motor symptoms and its underlying mechanisms from the early to the late phase of PD are unknown. Here, we aimed to show alterations in the non-motor symptoms of PD, including colonic dysmotility and impaired olfaction, and the related factors by intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) plus probenecid (MPTP/p). A mouse model of the early stage of PD was developed by systemic administration of MPTP (25 mg/kg, i.p.) and probenecid (100 mg/kg, i.p.) at 3.5-day intervals for a total of 10 injections. We performed motor and non-motor behavioral tests after 3 (called asymptomatic) and 10 (called symptomatic) injections of MPTP/p compared with the untreated (called control) group. We found that there were motor disturbances at the symptomatic stage, while impairments in intestinal motility and olfaction were observed from the asymptomatic stage. We also found the reduction of dopaminergic neuronal cell numbers in the SN and striatal dopamine transporter levels starting from the asymptomatic stage. At both asymptomatic and symptomatic stages, we demonstrated alterations in the expression of several proteins that are associated with non-motor deficits in the mouse ileum or olfactory bulb compared with the control group. Our findings in chronic MPTP/p-induced mice suggest their potential use as an animal model for the early stage of PD as well as a significant correlation between changes in relevant factors and symptoms.
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http://dx.doi.org/10.1016/j.jns.2018.07.011DOI Listing
September 2018

Neuroprotection against 6-OHDA toxicity in PC12 cells and mice through the Nrf2 pathway by a sesquiterpenoid from Tussilago farfara.

Redox Biol 2018 09 1;18:6-15. Epub 2018 Jun 1.

Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, South Korea. Electronic address:

Oxidative stress plays a key role in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Therefore, the nuclear factor-E2-related factor 2 (Nrf2), a key regulator of the antioxidative response, is considered to be important as a therapeutic target for neurodegenerative diseases. We investigated the underlying mechanism of Nrf2-mediated neuroprotective effects against oxidative stress in the PC12 cell line by 7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), one of the sesquiterpenoids in Farfarae Flos. Pretreatment of PC12 cells with ECN had a protective effect against hydrogen peroxide (HO)- or 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. ECN upregulated the ARE-luciferase activity and induced the mRNA expression of Nrf2 and antioxidant enzyme heme oxygenase-1 (HO-1). Knockdown of Nrf2 by small, interfering RNA (siRNA) abrogated the upregulation of HO-1, indicating that ECN had induced HO-1 via the Nrf2 pathway. Pretreatment with the thiol reducing agents, N-acetylcysteine (NAC) or dithiothreitol (DTT), attenuated Nrf2 activation and HO-1 expression. However, the non-thiol reducing antioxidant, Trolox, failed to inhibit HO-1 induction by ECN. These results suggest that ECN may directly interact with Kelch-like ECH-associated protein 1 (Keap1) and modify critical cysteine thiols present in the proteins responsible for Nrf2-mediated upregulation of HO-1. In a 6-OHDA-induced mouse model of PD, administration of ECN ameliorated motor impairments and dopaminergic neuronal damage. Taken together, ECN exerts neuroprotective effects by activating the Nrf2/HO-1 signaling pathway in both PC12 cells and mice. Thus, ECN, as an Nrf2 activator, could be an attractive therapeutic candidate for the neuroprotection or treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.redox.2018.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041377PMC
September 2018

Development of a diagnostic method for Parkinson's disease by reverse-phase high-performance liquid chromatography coupled with integrated pulsed amperometric detection.

J Pharm Biomed Anal 2018 May 15;153:110-116. Epub 2018 Feb 15.

Department of Oriental Pharmaceutical Sciences, Graduate School, Kyung Hee University, 26 Kyungheeedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea; Department of Oriental Pharmaceutical Sciences, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheeedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea. Electronic address:

We developed a diagnostic method for Parkinson's disease by simultaneously analyzing biogenic amines and their metabolites using reverse-phase high-performance liquid chromatography coupled with integrated pulsed amperometric detection (RP-HPLC-IPAD) method. Dopamine (DA), 3, 4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), and homovanillic acid (HVA) were used as biomarkers to diagnose Parkinson's disease. All target components were detected with good sensitivity using sodium hydroxide (as a post-column eluent). The limit of detection (S/N = 3) and limit of quantification (S/N = 10) of the target components ranged from 0.020 to 2.400 ng and from 0.080 to 8.000 ng, respectively. The coefficients of linear regression ranged from 0.9996 to 1.0000, all inter-day and intra-day precision values were <3.43%, and the average recovery and RSD ranged from 97.55 to 103.60% and 0.22 to 4.79% for mice striatum samples. This method exhibited good selectivity, sensitivity, and reproducibility and can be used directly without any pretreatment steps. Our method will be useful as a tool to diagnose Parkinson's disease.
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http://dx.doi.org/10.1016/j.jpba.2018.02.025DOI Listing
May 2018

Ginger fermented with Schizosaccharomyces pombe alleviates memory impairment via protecting hippocampal neuronal cells in amyloid beta plaque injected mice.

Food Funct 2018 Jan;9(1):171-178

Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.

Ginger, which has been widely used for dietary condiment, has been reported to improve memory dysfunction in an animal model of Alzheimer's disease (AD). Recently, a few trials have been carried out to enhance the effects of ginger by improving the bioavailability of its relevant components via fermentation. Some reports have suggested that the fermented ginger has the ability to affect the AD in vitro systems; however, its anti-amnesic effects on an in vivo model still remain to be investigated. In the present study, we aimed to investigate the neuroprotective effects of ginger fermented with Schizosaccharomyces pombe (FG) in the in vivo models of AD. The neuroprotective effects were investigated by employing behavioral, western blotting, and immunohistochemical assays. The administration of FG improved recognition memory, impaired by scopolamine injection, than that of non-fermented ginger. In addition, FG ameliorated memory impairment in amyloid beta (Aβ) plaque-injected mice via protecting neuronal cells in the CA3 area of the mouse hippocampus. Moreover, FG reinstated the pre- and postsynaptic protein levels decreased by Aβ plaque-toxicity. Overall, these data suggest that FG attenuates memory impairment in Aβ plaque-induced AD mice through inhibition of neuronal cell loss and synaptic disruption.
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http://dx.doi.org/10.1039/c7fo01149kDOI Listing
January 2018

Coptidis Rhizoma Prevents Heat Stress-Induced Brain Damage and Cognitive Impairment in Mice.

Nutrients 2017 Sep 23;9(10). Epub 2017 Sep 23.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Heat stress conditions lead to neuroinflammation, neuronal death, and memory loss in animals. Coptidis Rhizoma (CR) exhibits potent fever-reducing effects and has been used as an important traditional medicinal herb for treating fever. However, to date, the effects of antipyretic CR on heat-induced brain damages have not been investigated. In this study, CR significantly reduced the elevation of ear and rectal temperatures after exposure to heat in mice. Additionally, CR attenuated hyperthermia-induced stress responses, such as release of cortisol into the blood, and upregulation of heat shock protein and c-Fos in the hypothalamus and hippocampus of mice. The administration of CR inhibited gliosis and neuronal loss induced by thermal stress in the hippocampal CA3 region. Treatment with CR also reduced the heat stress-induced expression of nuclear factor kappa β, tumor necrosis factor-α, and interleukin-1β (IL-1β) in the hippocampus. Moreover, CR significantly decreased proinflammatory mediators such as IL-9 and IL-13 in the heat-stressed hypothalamus. Furthermore, CR attenuated cognitive dysfunction triggered by thermal stress. These results indicate that CR protects the brain against heat stress-mediated brain damage via amelioration of hyperthermia and neuroinflammation in mice, suggesting that fever-reducing CR can attenuate thermal stress-induced neuropathology.
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http://dx.doi.org/10.3390/nu9101057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691674PMC
September 2017

White Ginseng Protects Mouse Hippocampal Cells Against Amyloid-Beta Oligomer Toxicity.

Phytother Res 2017 Mar 23;31(3):497-506. Epub 2017 Jan 23.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Korea.

Amyloid-beta oligomer (AβO) is a soluble oligomer form of the Aβ peptide and the most potent amyloid-beta form that induces neuronal damage in Alzheimer's disease. We investigated the effect of dried white ginseng extract (WGE) on neuronal cell damage and memory impairment in intrahippocampal AβO (10 μM)-injected mice. Mice were treated with WGE (100 and 500 mg/kg/day, p.o.) for 12 days after surgery. WGE improved memory impairment by inhibiting hippocampal cell death caused by AβO. In addition, AβO-injected mice treated with WGE showed restoration of reduced synaptophysin and choline acetyltransferase intensity and lower levels of ionized calcium-binding adaptor molecule 1 in the hippocampus compared with those of vehicle-treated controls. These results suggest that WGE reverses memory impairment in Alzheimer's disease by attenuating neuronal damage and neuroinflammation in the AβO-injected mouse hippocampus. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/ptr.5776DOI Listing
March 2017

Protective effects of a herbal extract combination of Bupleurum falcatum, Paeonia suffruticosa, and Angelica dahurica against MPTP-induced neurotoxicity via regulation of nuclear receptor-related 1 protein.

Neuroscience 2017 01 19;340:166-175. Epub 2016 Oct 19.

Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address:

Parkinson's disease (PD) is one of the progressive neurodegenerative diseases of whose condition is characterized by dopaminergic neuronal cell loss and dysfunction in the substantia nigra pars compacta (SNpc) and the striatum. Recent studies have demonstrated that the nuclear receptor-related 1 protein (Nurr1) is critical of dopaminergic phenotype induction in mesencephalic dopaminergic neurons. Further, Nurr1 engages in synthesizing and storing dopamine through regulating levels of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). The aim of this study was to investigate the protective effects of a herbal extract combination, consisting of Bupleurum falcatum, Paeonia suffruticosa, and Angelica dahurica (MABH), on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like symptoms and to elucidate possible mechanisms of action focusing on Nurr1. In a subacute mouse model of MPTP-induced PD, MABH treatment resulted in recovery from movement impairments. MABH prevented dopamine depletion and protected against dopaminergic neuronal degradation induced by MPTP. Additionally, MABH increased Nurr1 expression in the SNpc of mice. To evaluate the effects of MABH on Nurr1 expression, we measured the protein levels of Nurr1 and its regulating factors using Western blot analysis in PC12 cells. MABH treatment induced the phosphorylation of extracellular signal-regulated kinase protein via increasing the protein expression levels of Nurr1 and ultimately the levels of TH, VMAT2, and DAT. These results indicate that MABH has protective effects on dopaminergic neurons in a mouse model of PD by regulating Nurr1.
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http://dx.doi.org/10.1016/j.neuroscience.2016.10.029DOI Listing
January 2017

A Comprehensive Review of Recent Studies on Herb-Drug Interaction: A Focus on Pharmacodynamic Interaction.

J Altern Complement Med 2016 Apr 22;22(4):262-79. Epub 2016 Mar 22.

1 Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University , Seoul, Korea.

Objectives: The concomitant use of herbal and conventional drugs accelerates the possibility of clinically significant herb-drug interactions (HDIs). This paper aims to analyze the current status of HDI studies worldwide and to review studies on HDI-induced pharmacodynamic (PD) interactions.

Methods: HDI studies published from 2000 to 2014 and indexed in PubMed were categorized according to publication year, area/country, study methods and objectives, and disease categories. The reviewed studies focused on HDI-induced PD; each PD interaction with concurrent use of approximately 100 herbal drugs and 70 conventional drugs was summarized. All PD-related articles were categorized according to four characteristics: herbal drugs, conventional drugs, types of PD interaction, and type of study. Among them, 17 well-designed clinical studies were evaluated by using the Jadad Quality Assessment Scale.

Results: The number of HDI reports has gradually increased since 2000, with a primary focus on neoplasms and diseases of the circulatory system. Most of these investigated pharmacokinetic reactions, such as cytochrome P450 enzyme metabolism, with fewer reports investigating PD. Most PD interaction studies investigated warfarin, ginkgo leaves, and St. John's wort. An evaluation of 17 studies revealed a generally positive view of PD effects involving synergism or reduced toxicity and a high average quality score (>3 points on a 0-5 scale).

Conclusions: These results demonstrate that most HDI studies so far have examined PK interactions and have been limited to very few conventional drugs and herbal drugs. This suggests that more studies focusing on PD are necessary to understand interactions between commonly used herbal and conventional drugs.
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http://dx.doi.org/10.1089/acm.2015.0235DOI Listing
April 2016

Houttuynia cordata Improves Cognitive Deficits in Cholinergic Dysfunction Alzheimer's Disease-Like Models.

Biomol Ther (Seoul) 2014 May;22(3):176-83

College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University ; Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, Seoul 130-701, Republic of Korea.

Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer's disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta (Aβ) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Aβ-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in Aβ-induced neurotoxicity. In mice with Aβ-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Aβ-induced neurotoxicity. Moreover, HCW, which had an IC50 value of 79.7 μg/ml for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD.
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http://dx.doi.org/10.4062/biomolther.2014.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060079PMC
May 2014