Publications by authors named "Myung Sook Oh"

139 Publications

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

Reduced Levels of Intestinal Neuropeptides and Neurotrophins in Neurotoxin-Induced Parkinson Disease Mouse Models.

J Neuropathol Exp Neurol 2021 Jan;80(1):15-20

From the Neurobiota Research Center (NRC), Kyung Hee University, Seoul, South Korea.

Intestinal neuropeptides and neurotrophins as endocrine messengers play a key role in the bidirectional gut-brain interaction both in health and disease status. Their alterations in several neurological disorders have been reported, but whether a remarkable change occurs in Parkinson disease (PD) remains unexplored. In this study, we aimed to investigate the levels of 13 neuropeptides and 4 neurotrophins in the intestine of neurotoxin-induced PD mice. The PD mice were obtained by chronic injection of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) or MPTP/probenecid (MPTP/p). The levels of mRNA and protein expression in mouse intestines were measured by using real-time reverse transcription polymerase chain reaction and Western blotting, respectively. We found that the mRNA expression of 2 neuropeptides (cholecystokinin [CCK] and dynorphin A [Dyn A]) and 2 neurotrophins (brain-derived neurotrophic factor [BDNF] and neurotrophin-5) was significantly decreased in the colon of MPTP group compared to the vehicle-treated group. The protein levels of CCK, Dyn A, and BDNF were reduced in the colon of MPTP- or MPTP/p-treated mice compared to those of the vehicle-treated group. These data suggest that the intestinal expression of CCK, Dyn A, and BDNF was significantly reduced in PD animal models, and may play a role in the gut-brain axis in PD.
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http://dx.doi.org/10.1093/jnen/nlaa113DOI Listing
January 2021

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

Trans-Cinnamaldehyde Alleviates Amyloid-Beta Pathogenesis via the SIRT1-PGC1α-PPARγ Pathway in 5XFAD Transgenic Mice.

Int J Mol Sci 2020 Jun 24;21(12). Epub 2020 Jun 24.

Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Abnormal amyloid-β (Aβ) accumulation is the most significant feature of Alzheimer's disease (AD). Among the several secretases involved in the generation of Aβ, β-secretase (BACE1) is the first rate-limiting enzyme in Aβ production that can be utilized to prevent the development of Aβ-related pathologies. Cinnamon extract, used in traditional medicine, was shown to inhibit the aggregation of tau protein and Aβ aggregation. However, the effect of trans-cinnamaldehyde (TCA), the main component of cinnamon, on Aβ deposition is unknown. Five-month-old 5XFAD mice were treated with TCA for eight weeks. Seven-month-old 5XFAD mice were evaluated for cognitive and spatial memory function. Brain samples collected at the conclusion of the treatment were assessed by immunofluorescence and biochemical analyses. Additional in vivo experiments were conducted to elucidate the mechanisms underlying the effect of TCA in the role of Aβ deposition. TCA treatment led to improvements in cognitive impairment and reduced Aβ deposition in the brains of 5XFAD mice. Interestingly, the levels of BACE1 were decreased, whereas the mRNA and protein levels of three well-known regulators of BACE1, silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC1α), and PPARγ, were increased in TCA-treated 5XFAD mice. TCA led to an improvement in AD pathology by reducing BACE1 levels through the activation of the SIRT1-PGC1α-PPARγ pathway, suggesting that TCA might be a useful therapeutic approach in AD.
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http://dx.doi.org/10.3390/ijms21124492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352815PMC
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

Artemisiae Iwayomogii Herba Inhibits Growth, Motility, and the PI3K/AKT/mTOR Signaling Pathway in Hepatocellular Carcinoma Cells.

Planta Med 2020 Jul 19;86(10):717-727. Epub 2020 May 19.

Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea.

() has been used in traditional medicine to cure various infectious diseases such as cholecystitis, hepatitis, and jaundice. In this study, the Artemisiae Iwayomogii Herba ethanol extract was investigated for the ability to inhibit growth of hepatocellular carcinoma and its underlying mechanism involved. The antiproliferative effect of Artemisiae Iwayomogii Herba ethanol extract was evaluated using cell viability and proliferation assays. The effect of Artemisiae Iwayomogii Herba ethanol extract on apoptosis was measured using western blotting, terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling staining, JC-1 staining, cytochrome release, immunohistochemistry, and immunofluorescence in mouse xenografts. Artemisiae Iwayomogii Herba ethanol extract inhibited hepatocellular carcinoma cell growth and proliferation in a dose-dependent manner. The apoptotic effect of Artemisiae Iwayomogii Herba ethanol extract was observed via increased levels of cleaved caspase-3 and cleaved PARP, as well as elevated numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling-positive apoptotic cells. Artemisiae Iwayomogii Herba ethanol extract also decreased XIAP and Mcl-1 expression via loss of mitochondrial membrane potential. Additionally, Artemisiae Iwayomogii Herba ethanol extract inhibited hepatocellular carcinoma cell invasion and migration. In the model, Artemisiae Iwayomogii Herba ethanol extract significantly inhibited tumor cell proliferation and increased the number of apoptotic cells with more activated cleaved caspase-3. A mechanistic study revealed that Artemisiae Iwayomogii Herba ethanol extract effectively suppressed the PI3K/AKT/mTOR signaling pathway in hepatocellular carcinoma cells. Our findings demonstrate that Artemisiae Iwayomogii Herba ethanol extract can efficiently induce apoptosis and inhibit the growth, migration, and invasion of human hepatocellular carcinoma cells, and simultaneously block PI3K/AKT/mTOR pathway. We therefore suggest Artemisiae Iwayomogii Herba ethanol extract as a novel natural agent for prevention and therapy of hepatocellular carcinoma.
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http://dx.doi.org/10.1055/a-1167-4284DOI Listing
July 2020

The Mixture of Gotu Kola, Cnidium Fruit, and Goji Berry Enhances Memory Functions by Inducing Nerve-Growth-Factor-Mediated Actions Both In Vitro and In Vivo.

Nutrients 2020 May 11;12(5). Epub 2020 May 11.

College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 191, Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Korea.

Nerve growth factor (NGF), a typical neurotrophin, has been characterized by the regulation of neuronal cell differentiation and survival involved in learning and memory functions. NGF has a main role in neurite extension and synapse formation by activating the cyclic adenosine monophosphate-response-element-binding protein (CREB) in the hippocampus. The purpose of this study was to determine whether a mixture of Gotu Kola, Cnidium fruit, and Goji berry (KYJ) enhances memory function by inducing NGF-mediated actions both in vitro and in vivo. The KYJ combination increased NGF concentration and neurite length in C6 glioma and N2a neuronal cells, respectively. Additionally, we discovered memory-enhancing effects of KYJ through increased NGF-mediated synapse maturation, CREB phosphorylation, and cell differentiation in the mouse hippocampus. These findings suggest that this combination may be a potential nootropic cognitive enhancer via the induction of NGF and NGF-dependent activities.
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http://dx.doi.org/10.3390/nu12051372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285178PMC
May 2020

DA-9801, a standardized Dioscorea extract, improves memory function via the activation of nerve growth factor-mediated signaling.

Nutr Neurosci 2020 Mar 27:1-12. Epub 2020 Mar 27.

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

Nerve growth factor (NGF) is a neurotrophin that plays a critical role in mammalian learning and memory functions. NGF also regulates neuronal cell differentiation and neurite outgrowth by activating ERK/CREB signaling. This present study examined the effects of a standardized Dioscorea extract (DA-9801), which is composed of Thunb and Makino on memory function via its NGF-potentiating activities using an and paradigm. Cells were incubated with or without different concentrations of DA-9801 (10, 25, and 50 μg/ml) extract for 24 h. The cultured conditioned medium from C6 glioma cells was used for NGF production assay, and neurite length in N2a cells was measured after every 2 h. Mice were orally treated with DA-9801 (10 and 100 mg/kg/day) once daily for 7 days. They were subjected to passive avoidance test to evaluate memory functions. The question of whether DA-9801 induced NGF synthesis was assessed by measuring the levels of NGF in the mouse cortical and hippocampal tissues. Hippocampal cell differentiation and NGF-mediated ERK/CREB signaling were evaluated by performing immunohistochemical analysis using BrdU, ki67, DCX, phosphorylated ERK and CREB in the mouse hippocampus. DA-9801 treatment increased the NGF contents and neurite length, respectively. Mice with DA-9801 administration showed memory enhancement in the passive avoidance test. DA-9801 also increased newborn cell differentiation, neurite length, NGF secretion, and ERK/CREB phosphorylation in the mouse hippocampus. These results suggest that DA-9801 treatment could improve memory function by inducing hippocampal NGF synthesis and ERK/CREB signaling.
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http://dx.doi.org/10.1080/1028415X.2020.1743916DOI Listing
March 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

Picrorhiza kurroa Prevents Memory Deficits by Inhibiting NLRP3 Inflammasome Activation and BACE1 Expression in 5xFAD Mice.

Neurotherapeutics 2020 01;17(1):189-199

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

One of the most significant pathologies of Alzheimer's disease (AD), an irreversible and progressive neurodegenerative disease that causes cognitive impairment, is the neuroinflammation facilitating the accumulation of amyloid-β (Aβ) peptide. Hence, the inhibition of abnormal neuroinflammatory response is considered a promising therapeutic approach for AD. Picrorhiza kurroa Bentham, Scrophulariae (PK) is a medicinal herb that has been traditionally used for the treatment of various diseases, including inflammation. This study aims to report the significance of PK treatment in markedly improving spatial learning memory and dramatically decreasing Aβ levels in Tg6799 mice, also known 5xFAD mice, which have five familial AD (FAD) mutations. Remarkably, these effects correlated with reversal of disease-related microglial neuroinflammation, as evidenced by shifting microglia phenotypes from the inflammatory form to the anti-inflammatory form and inhibiting the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 inflammasome activity. Moreover, PK administration induced silent information regulator type1/peroxisome proliferator-activated receptor-γ signaling, resulting in a decrease of β-secretase 1 (BACE1) expression, which involved in Aβ production. Overall, this study suggests that PK exhibits a neuroprotective effect by inducing alternative activation of microglia and downregulating the BACE1 expression, thereby ameliorating the disease pathophysiology and reversing the cognitive decline related to Aβ deposition in AD mice.
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http://dx.doi.org/10.1007/s13311-019-00792-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007473PMC
January 2020

Corrigendum to "6-Shogaol, an active constituent of ginger, attenuates neuroinflammation and cognitive deficits in animal models of dementia" [BBRC 449 (2014) 8-13].

Biochem Biophys Res Commun 2020 Jan 1;521(2):545. Epub 2019 Nov 1.

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

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http://dx.doi.org/10.1016/j.bbrc.2019.10.150DOI Listing
January 2020

Cuscutae Japonicae Semen Ameliorates Memory Dysfunction by Rescuing Synaptic Damage in Alzheimer's Disease Models.

Nutrients 2019 Oct 28;11(11). Epub 2019 Oct 28.

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

Alzheimer's disease (AD) is the most common type of dementia in the elderly. It is characterized by the accumulation of amyloid-beta (Aβ) and progressive cognitive impairment. To alleviate the symptoms of AD, functional foods and nutrients have been used for centuries. In this study, we investigated whether Cuscutae Japonicae Semen (CJS), a medicinal food traditionally used in East Asia, has effects on memory improvement and synapse protection in AD. We orally administered CJS to 5x familiar AD (5xFAD) transgenic mice and performed the Morris water maze test. The results showed that CJS treatment ameliorated the decline of memory function. Then, we demonstrated that CJS attenuated the degeneration of pre- and post-synaptic proteins in the hippocampi of 5xFAD mice. To demonstrate the effects of CJS in vitro, we treated Aβ in primary neuronal culture with CJS and observed that CJS rescued the loss of functional synapses. The protective effects of CJS on the synapse were due to the inhibition of activated caspase-3 expression. Additionally, CJS inhibited the phosphorylation of glycogen synthase kinase-3β and tau proteins, which contribute to synaptic dysfunction. Taken together, our results suggest that CJS is efficient in alleviating memory loss by rescuing caspase-3-mediated synaptic damage in AD treatment.
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http://dx.doi.org/10.3390/nu11112591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893468PMC
October 2019

Protective effects of Belamcandae Rhizoma against skin damage by ameliorating ultraviolet-B-induced apoptosis and collagen degradation in keratinocytes.

Environ Toxicol 2019 Dec 21;34(12):1354-1362. Epub 2019 Aug 21.

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

Ultraviolet-B light (UV-B) is a major cause of skin photoaging, inducing cell death and extracellular matrix collapse by generating reactive oxygen species (ROS). Belamcandae Rhizoma (BR), the rhizome of Belamcanda chinensis Leman, exhibits antioxidant properties, but it remains unknown whether BR extract ameliorates UV-B-induced skin damage. In this study, we evaluated the effects of a standardized BR extract on UV-B-induced apoptosis and collagen degradation in HaCaT cells. BR was extracted using four different methods. We used radical-scavenging assays to compare the antioxidative activities of the four extracts. Cells were irradiated with UV-B and treated with BR boiled in 70% (vol/vol) ethanol (BBE). We measured cell viability, intracellular ROS levels, the expression levels of antioxidative enzymes, and apoptosis-related and collagen degradation-related proteins. The irisflorentin and tectorigenin levels were measured via high-performance liquid chromatography. BBE exhibited the best radical-scavenging and cell protective effects of the four BR extracts. BBE inhibited intracellular ROS generation and induced the synthesis of antioxidative enzymes such as catalase and glutathione. BBE attenuated apoptosis by reducing the level of caspase-3 and increasing the Bcl-2/Bax ratio. BBE reduced the level of matrix metalloproteinase-1 and increased that of type I collagen. The irisflorentin and tectorigenin contents were 0.23% and 0.015%, respectively. From these results, BBE ameliorated UV-B-induced apoptosis and collagen degradation by enhancing the expression of antioxidative enzymes. It may be a useful treatment for UV-B-induced skin damage.
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http://dx.doi.org/10.1002/tox.22836DOI Listing
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

Z-ligustilide and n-Butylidenephthalide Isolated from the Aerial Parts of Angelica tenuissima Inhibit Lipid Accumulation In Vitro and In Vivo.

Planta Med 2019 Jul 28;85(9-10):719-728. Epub 2019 May 28.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

Abnormal lipid metabolism, such as increased fatty acid uptake and esterification, is associated with nonalcoholic fatty liver disease (NAFLD). The aqueous extract of the aerial part of (ATX) inhibited high-fat diet-induced hepatic steatosis in mice as well as oleic acid-induced neutral lipid accumulation in HepG2 cells. ATX decreased the mRNA and protein levels of CD36 and diglyceride acyltransferase 2 (DGAT2), the maturation of sterol regulatory element-binding proteins (SREBP), and the expression of the lipogenic target genes and . The ATX components, Z-ligustilide and n-butylidenephthalide, inhibited the expression of FATP5 and DGAT2 and thus oleic acid-induced lipid accumulation in HepG2 cells. These results suggest that ATX and its active components Z-ligustilide and n-butylidenephthalide inhibit fatty acid uptake and esterification in mice and have potential as therapeutics for NAFLD.
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http://dx.doi.org/10.1055/a-0901-1307DOI Listing
July 2019

High Stability of a Donor-Acceptor Type Oxazepine-Containing Fluorophore and Its Applications in Cellular Imaging and Two-Photon Deep Tissue Imaging.

Org Lett 2019 06 16;21(11):3891-3894. Epub 2019 Apr 16.

Department of Chemistry, College of Natural Sciences , Seoul National University , Seoul 08826 , Republic of Korea.

A new donor (D)-acceptor (A) type naphthalene-based oxazepine-containing fluorophore, OXN-1, is reported, which shows unusually high stability in various environments. Its photophysical properties and structural stabilities under harsh conditions are thoroughly examined. The high stability of OXN-1 is explained by quantum chemical calculations. Its exceptional bioimaging capabilities for cells with low cytotoxicity are verified. In addition, its deep tissue imaging ability with two-photon microscopy (TPM) is evaluated.
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http://dx.doi.org/10.1021/acs.orglett.9b00784DOI Listing
June 2019

Anti-neuroinflammatory effect of Iresine celosia on lipopolysaccharide-stimulated microglial cells and mouse.

Biomed Pharmacother 2019 Mar 17;111:1359-1366. Epub 2019 Jan 17.

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, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Abnormal inflammatory response in the central nervous system plays a critical role in various neurological disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease. Therefore, modulation of abnormal neuroinflammation is thought to be a promising therapeutic strategy for these diseases. Based on this idea, we focused on finding a potential candidate material that would regulate excessive neuroinflammation. Iresine celosia has long been used as a traditional Mexican medicine to treat fever and oral disorders. In the present study, we evaluated the anti-neuroinflammatory effects of Iresine celosia extract (ICE) in lipopolysaccharide (LPS)-stimulated BV2 microglia cells and mice models. In BV2 microglia cells, ICE markedly inhibited production of nitric oxide and proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6 without causing cytotoxicity. ICE also ameliorated translocation of nuclear factor-κB from cytosol to nucleus by LPS. Moreover, ICE attenuated behavioral disturbances by inhibiting activation of microglia and astrocytes in LPS-treated mice. Collectively, these data indicate that ICE is a potential therapeutic agent for treating inflammation-related diseases.
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http://dx.doi.org/10.1016/j.biopha.2019.01.017DOI Listing
March 2019

Harnessing Intramolecular Rotation To Enhance Two-photon Imaging of Aβ Plaques through Minimizing Background Fluorescence.

Angew Chem Int Ed Engl 2019 04 20;58(17):5648-5652. Epub 2019 Mar 20.

Department of Chemistry, Korea University, Seoul, 02841, Korea.

The aggregation of amyloid beta (Aβ) proteins in senile plaques is a critical event during the development of Alzheimer's disease, and the postmortem detection of Aβ-rich proteinaceous deposits through fluorescent staining remains one of the most robust diagnostic tools. In animal models, fluorescence imaging can be employed to follow the progression of the disease, and among the different imaging methods, two-photon microscopy (TPM) has emerged as one of the most powerful. To date, several near-infrared-emissive two-photon dyes with a high affinity for Aβ fibrils have been developed, but there has often been a tradeoff between excellent two-photon cross-sections and large fluorescence signal-to-background ratios. In the current work, we introduced a twisted intramolecular charge state (TICT)-based de-excitation pathway, which results in a remarkable fluorescence increase of around 167-fold in the presence of Aβ fibrils, while maintaining an excellent two-photon cross section, thereby enabling high-contrast ex vivo and in vivo TPM imaging. Overall, the results suggest that adopting TICT de-excitation in two-photon fluorophores may represent a general method to overcome the tradeoff between probe brightness and signal-to-background ratio.
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http://dx.doi.org/10.1002/anie.201900549DOI Listing
April 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

Hydrazine Exposé: The Next-Generation Fluorescent Probe.

ACS Sens 2019 02 29;4(2):441-449. Epub 2019 Jan 29.

Department of Anatomy and Brain Korea 21 PLUS Project for Medical Science , Yonsei University, College of Medicine , Seoul 03722 , Republic of Korea.

Hydrazine (NH) is one of the most important pnictogen hydride chemicals, and is utilized within a wide spectrum of industries. As a result of its extensive use, hydrazine's monitoring methods have constantly come under fire due to its potential health risk and the subsequent environmental pollution. Fluorometric molecular sensing systems generally report with a major emphasis on the merit of fluorescence analysis. What we are proposing within this report is a next-generation fluorescent probe that allows hydrazine to become fully traceable, within multifarious environments that show fast and intuitional fluorescence transformation. A new sensing moiety, ortho-methoxy-methyl-ether ( o-OMOM) incorporated electron donor (D)-acceptor (A) type naphthaldehyde provides high selectivity and sensitivity amidst its superiority within practical applications for sensing hydrazine. The new probe overcomes most of the drawbacks of currently used fluorescent probes, and due to its successful demonstrations, such as real-time spray-based sensing, soil analysis, and two-photon tissue imaging, its potential for practical application is beyond reproach.
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http://dx.doi.org/10.1021/acssensors.8b01429DOI Listing
February 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

First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent.

Eur J Med Chem 2019 Jan 2;162:161-175. Epub 2018 Nov 2.

Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul, 02792, Republic of Korea. Electronic address:

Kinase irregularity has been correlated with several complex neurodegenerative tauopathies. Development of selective inhibitors of these kinases might afford promising anti-tauopathy therapies. While DAPK1 inhibitors halt the formation of tau aggregates and counteract neuronal death, CSF1R inhibitors could alleviate the tauopathies-associated neuroinflammation. Herein, we report the design, synthesis, biological evaluation, mechanistic study, and molecular docking study of novel CSF1R/DAPK1 dual inhibitors as multifunctional molecules inhibiting the formation of tau aggregates and neuroinflammation. Compound 3l, the most potent DAPK1 inhibitor in the in vitro kinase assay (IC = 1.25 μM) was the most effective tau aggregates formation inhibitor in the cellular assay (IC = 5.0 μM). Also, compound 3l elicited potent inhibition of CSF1R in the in vitro kinase assay (IC = 0.15 μM) and promising inhibition of nitric oxide production in LPS-induced BV-2 cells (55% inhibition at 10 μM concentration). Kinase profiling and hERG binding assay anticipated the absence of off-target toxicities while the PAMPA-BBB assay predicted potentially high BBB permeability. The mechanistic study and selectivity profile suggest compound 3l as a non-ATP-competitive DAPK1 inhibitor and an ATP-competitive CSF1R inhibitor while the in silico calculations illustrated binding of compound 3l to the substrate-binding site of DAPK1. Hence, compound 3l might act as a protein-protein interaction inhibitor by hindering DAPK1 kinase reaction through preventing the binding of DAPK1 substrates.
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http://dx.doi.org/10.1016/j.ejmech.2018.10.057DOI Listing
January 2019

Triple herbal extract DA-9805 exerts a neuroprotective effect via amelioration of mitochondrial damage in experimental models of Parkinson's disease.

Sci Rep 2018 10 29;8(1):15953. Epub 2018 Oct 29.

Department of Neuroscience, Graduate School, Kyung Hee University, Seoul, 02447, Korea.

Moutan cortex, Angelica Dahurica root, and Bupleurum root are traditional herbal medicines used in Asian countries to treat various diseases caused by oxidative stress or inflammation. Parkinson's disease (PD) has been associated with mitochondrial dysfunction, but no effective treatment for mitochondrial dysfunction has yet been identified. In this study we investigated the neuroprotective effects of the triple herbal extract DA-9805 in experimental models of PD. DA-9805 was prepared by extracting three dried plant materials (Moutan cortex, Angelica Dahurica root, and Bupleurum root in a 1:1:1 mixture) with 90% ethanol on a stirring plate for 24 h at room temperature and fingerprinted using high-performance liquid chromatography. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP), which both exert neurotoxic effects on dopaminergic neurons by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) complex I, were used to make experimental models of PD. In MPP-treated SH-SY5Y cells, DA-9805 ameliorated the suppression of tyrosine hydroxylase expression and mitochondrial damage on OXPHOS complex 1 activity, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and oxygen consumption rate. In the MPTP-induced subacute PD model mice, oral administration of DA-9805 recovered dopamine content as well as bradykinesia, as determined by the rotarod test. DA-9805 protected against neuronal damage in the substantia nigra pars compacta (SNpc) and striatum. In both in vitro and in vivo models of PD, DA-9805 normalized the phosphorylation of AKT at S473 and T308 on the insulin signaling pathway and the expression of mitochondria-related genes. These results demonstrate that the triple herbal extract DA-9805 showed neuroprotective effects via alleviating mitochondria damage in experimental models of PD. We propose that DA-9805 may be a suitable candidate for disease-modifying therapeutics for PD.
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http://dx.doi.org/10.1038/s41598-018-34240-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206089PMC
October 2018

A Novel and Selective p38 Mitogen-Activated Protein Kinase Inhibitor Attenuates LPS-Induced Neuroinflammation in BV2 Microglia and a Mouse Model.

Neurochem Res 2018 Dec 16;43(12):2362-2371. Epub 2018 Oct 16.

Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, South Korea.

Neuroinflammation is an important pathological feature in neurodegenerative diseases. Accumulating evidence has suggested that neuroinflammation is mainly aggravated by activated microglia, which are macrophage like cells in the central nervous system. Therefore, the inhibition of microglial activation may be considered for treating neuroinflammatory diseases. p38 mitogen-activated protein kinase (MAPK) has been identified as a crucial enzyme with inflammatory roles in several immune cells, and its activation also relates to neuroinflammation. Considering the proinflammatory roles of p38 MAPK, its inhibitors can be potential therapeutic agents for neurodegenerative diseases relating to neuroinflammation initiated by microglia activation. This study was designed to evaluate whether NJK14047, a recently identified novel and selective p38 MAPK inhibitor, could modulate microglia-mediated neuroinflammation by utilizing lipopolysaccharide (LPS)-stimulated BV2 cells and an LPS-injected mice model. Our results showed that NJK14047 markedly reduced the production of nitric oxide and prostaglandin E by downregulating the expression of various proinflammatory mediators such as nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α and interleukin-1β in LPS-induced BV2 microglia. Moreover, NJK14047 significantly reduced microglial activation in the brains of LPS-injected mice. Overall, these results suggest that NJK14047 significantly reduces neuroinflammation in cellular/vivo model and would be a therapeutic candidate for various neuroinflammatory diseases.
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http://dx.doi.org/10.1007/s11064-018-2661-1DOI Listing
December 2018

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

Peucedani Japonici Radix ameliorates lipopolysaccharide-induced neuroinflammation by regulating microglial responses.

Neurosci Lett 2018 11 10;686:161-167. Epub 2018 Sep 10.

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:

Neuroinflammation is an inflammatory process within the central nervous system that is mediated by microglial activation, which releases pro-inflammatory mediators leading to neurodegeneration. In this study, we investigated the effects of Peucedani Japonici Radix (PJR), a medicinal herb traditionally used in East Asia to treat neuroinflammation both in vitro and in vivo. First, we examined the effects of PJR on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. The results showed that PJR suppressed the LPS-induced increase of several inflammatory factors, such as nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, prostaglandin E2, interleukin-1β, and tumor necrosis factor-α. We also revealed that PJR inhibited the nuclear factor kappa B (NF-κB) pathway, which is the upstream modulator of inflammatory processes. Furthermore, to confirm the regulatory effects of PJR on microglia in vivo, we measured the number of ionized calcium-binding adapter molecule 1-positive cells in mouse brains and found that PJR treatment reduced microglial activation. Taken together, these results suggest that PJR inhibits microglia-mediated neuroinflammation through the modulation of NF-κB signaling and has the therapeutic potential to prevent inflammation-related neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.neulet.2018.09.010DOI Listing
November 2018

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