Publications by authors named "Young-Choon Lee"

194 Publications

Avenanthramide C Suppresses Matrix Metalloproteinase-9 Expression and Migration Through the MAPK/NF- κB Signaling Pathway in TNF-α-Activated HASMC Cells.

Front Pharmacol 2021 25;12:621854. Epub 2021 Mar 25.

Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon, South Korea.

In oat ingredients, flavonoids and phenolic acids are known to be the most important phenolic compounds. In phenolic compounds, wide-ranging biological responses, including antioxidative, anti-inflammatory, anti-allergic, and anti-cancer properties, were reported. Avenanthramide C (Avn C), a component of the phenolic compound of oats, has been reported to be highly antioxidant and anti-inflammatory, but its role in an anti-atherosclerosis response is unknown. The aim of this research was to assess the effect of Avn C on expression of MMP-9 on TNF-α-activated human arterial smooth-muscle cells (HASMC) and signaling involved in its anti-atherosclerosis activity. HASMC cells are known to produce inflammatory cytokines involving IL-6, IL-1β, and TNF-α during arteriosclerosis activity. Avn C specifically reduced IL-6 secretion in HASMC cells. Furthermore, we investigated whether Avn C could inhibit NF-κB nuclear protein translocation. Avn C suppressed nuclear protein translocation of NF-κB in TNF-α-stimulated HASMCs. The MMP-9 enzyme activity and expression are controlled through the MAPKs signaling path during the Avn C treatment. We confirmed that the levels of wound healing (-value = 0.013, * < 0.05) and migration (-value = 0.007, ** < 0.01) are inhibited by 100 ng/ml TNF-α and 100 μM Avn C co-treated. Accordingly, Avn C inhibited the expression of MMP-9 and cell migration through the MAPK/NF-κB signaling pathway in TNF-α-activated HASMC. Therefore, Avn C can be identified and serve as disease prevention material and remedy for atherosclerosis.
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http://dx.doi.org/10.3389/fphar.2021.621854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027239PMC
March 2021

REDD1 Is Involved in Amyloid β-Induced Synaptic Dysfunction and Memory Impairment.

Int J Mol Sci 2020 Dec 13;21(24). Epub 2020 Dec 13.

Department of Health Sciences, The Graduate School of Dong-A University, Dong-A University, Busan 49315, Korea.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid β (Aβ) in the brain. Although several studies reported possible mechanisms involved in Aβ pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aβ-responsive gene involved in Aβ cytotoxicity. However, we still do not know how Aβ increases the level of REDD1 and whether REDD1 mediates Aβ-induced synaptic dysfunction. To elucidate this, we examined the effect of Aβ on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aβ-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aβ-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aβ injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aβ-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aβ may increase REDD1 translation rather than transcription. Aβ activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aβ-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aβ blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aβ-induced synaptic deficits. REDD1 shRNA also blocked Aβ-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aβ pathology and could be a target for AD therapy.
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http://dx.doi.org/10.3390/ijms21249482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763153PMC
December 2020

4-O-methylascochlorin attenuates inflammatory responses induced by lipopolysaccharide in RAW 264.7 macrophages.

Int Immunopharmacol 2021 Jan 11;90:107184. Epub 2020 Dec 11.

Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, Seoburo 2066, Suwon City, Kyunggi-Do 16419, Republic of Korea; Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Seoul 06351, South Korea. Electronic address:

Inflammation is implicated in various diseases, such as inflammatory bowel disease and cancer. Ascochlorin (ASC) and its derivatives have been shown to modulate inflammatory responses in many previous studies. However, the effects of 4-O-methylascochlorin (MAC), one of the ASC derivatives, on inflammatory responses have yet to be reported. In addition, the consequences of chemical modification of ASC on protein signaling and immunity have yet to be fully understood. The fourth carbon in MAC is methylated, which may result in modulation of immune response differently compared with ASC. Hence, we have investigated the role of MAC in inflammatory response induced by lipopolysaccharide in murine macrophage cells. Here, we found that MAC treatment decreased the inflammatory response by murine macrophages. When murine macrophages were treated with MAC, the transcription and translation of various pro-inflammatory indicators such as iNOS and COX-2 decreased. In addition, the ELISA results showed that the expression of TNF-α, IL-6, and IL-1β, which are pro-inflammatory cytokines, was successfully decreased by MAC. Such effects of MAC appear to be mediated via downregulation of MAPK signaling and the transactivational activity of NF-κB. Lipopolysaccharide upregulates MAPK protein phosphorylation and NF-κB translocation, which in turn enhances the transactivation of genes related to NF-κB. Such results of lipopolysaccharide were attenuated by MAC. Collectively, our results indicate that MAC alleviated the inflammatory responses induced by lipopolysaccharide in murine macrophages successfully by modulating MAPK signaling pathway and NF-κB-related genes. This study shows that MAC, similar to other ASC derivatives, can potentially be used therapeutically to reduce the harmful damage induced by prolonged inflammation. In addition, the structural differences between ASC and its derivatives as well as their effect on intracellular signaling will also be discussed.
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http://dx.doi.org/10.1016/j.intimp.2020.107184DOI Listing
January 2021

Akt and calcium-permeable AMPA receptor are involved in the effect of pinoresinol on amyloid β-induced synaptic plasticity and memory deficits.

Biochem Pharmacol 2021 02 11;184:114366. Epub 2020 Dec 11.

Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Republic of Korea; Laboratory of Anti-viral Drug Discovery, Dong-A University, Busan, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan, Republic of Korea. Electronic address:

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by memory deficits. Although no drug has given promising results, synaptic dysfunction-modulating agents might be considered potential candidates for alleviating this disorder. Pinoresinol, a lignan found in Forsythia suspensa, is a memory-enhancing agent with excitatory synaptic activation. In the present study, we tested whether pinoresinol reduces learning and memory and excitatory synaptic deficits in an amyloid β (Aβ)-induced AD-like mouse model. Pinoresinol enhanced hippocampal long-term potentiation (LTP) through calcium-permeable AMPA receptor, which was mediated by Akt activation. Moreover, pinoresinol ameliorated LTP deficits in amyloid β (Aβ)-treated hippocampal slices via Akt signaling. Oral administration of pinoresinol ameliorated Aβ-induced memory deficits without sensory dysfunction. Moreover, AD-like pathology, including neuroinflammation and synaptic deficit, were ameliorated by pinoresinol administration. Collectively, pinoresinol may be a good candidate for AD therapy by modulating synaptic functions.
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http://dx.doi.org/10.1016/j.bcp.2020.114366DOI Listing
February 2021

Regulation of human β-galactoside α2,6-sialyltransferase (hST6Gal I) gene expression during differentiation of human osteoblastic MG-63 cells.

Glycoconj J 2020 12 27;37(6):681-690. Epub 2020 Oct 27.

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, South Korea.

In this study, we found that gene expression of the human β-galactoside α2,6-sialyltransferase (hST6Gal I) was specifically increased during differentiation of human MG-63 osteoblastic cells by serum starvation (SS). In parallel, a distinct increase in binding to SNA, the α2,6-sialyl-specific lectin, was observed in serum-starved cells, as demonstrated by FACS analysis. 5'-Rapid amplification of cDNA ends analysis demonstrated that the increase of hST6Gal I transcript by SS is mediated by P1 promoter. To elucidate transcriptional regulation of hST6Gal I in SS-induced MG-63 cells, we functionally characterized the P1 promoter region of the hST6Gal I gene. The 5'-deletion analysis of P1 promoter region revealed that the 189 bp upstream region of transcription start site is critical for transcriptional activity of hST6Gal I gene in SS-induced MG-63 cells. This region contains the predicted binding sites for several transcription factors, including AREB6, FOXP1, SIX3, HNF1, YY2, and MOK2. The mutagenesis analysis for these sites and chromatin immunoprecipitation assay demonstrated that the YY2 binding site at -98 to -77 was essential for the SS-induced hST6Gal I gene expression during differentiation of MG-63 cells.
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http://dx.doi.org/10.1007/s10719-020-09959-3DOI Listing
December 2020

Rubrofusarin Attenuates Chronic Restraint Stress-Induced Depressive Symptoms.

Int J Mol Sci 2020 May 13;21(10). Epub 2020 May 13.

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 49315, Korea.

The aim of this study was to examine whether rubrofusarin, an active ingredient of the Cassia species, has an antidepressive effect in chronic restraint stress (CRS) mouse model. Although acute treatment using rubrofusarin failed, chronic treatment using rubrofusarin ameliorated CRS-induced depressive symptoms. Rubrofusarin treatment significantly reduced the number of Fluoro-Jade B-positive cells and caspase-3 activation within the hippocampus of CRS-treated mice. Moreover, rubrofusarin treatment significantly increased the number of newborn neurons in the hippocampus of CRS-treated mice. CRS induced activation of glycogen synthase kinase-3β and regulated development and DNA damage responses, and reductions in the extracellular-signal-regulated kinase pathway activity were also reversed by rubrofusarin treatment. Microglial activation and inflammasome markers, including nod-like receptor family pyrin domain containing 3 and adaptor protein apoptosis-associated speck-like protein containing CARD, which were induced by CRS, were ameliorated by rubrofusarin. Synaptic plasticity dysfunction within the hippocampus was also rescued by rubrofusarin treatment. Within in vitro experiments, rubrofusarin blocked corticosterone-induced long-term potentiation impairments. These were blocked by LY294002, which is an Akt inhibitor. Finally, we found that the antidepressant effects of rubrofusarin were blocked by an intracerebroventricular injection of LY294002. These results suggest that rubrofusarin ameliorated CRS-induced depressive symptoms through PI3K/Akt signaling.
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http://dx.doi.org/10.3390/ijms21103454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278964PMC
May 2020

3'-sialyllactose targets cell surface protein, SIGLEC-3, and induces megakaryocyte differentiation and apoptosis by lipid raft-dependent endocytosis.

Glycoconj J 2020 04 4;37(2):187-200. Epub 2020 Jan 4.

Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, 300 Chunchun-Dong, Jangan-Gu, Suwon City, Kyunggi-Do, 440-746, South Korea.

3'-sialyllactose is one of the abundant components in human milk oligosaccharides (HMOs) that protect infants from various viral infections in early stages of immune system development. 3SL is a combination of lactose and sialic acid. Most sialic acids are widely expressed in animal cells and they bind to siglec proteins. In this study, we demonstrate that 3SL specifically binds to CD33. It induces megakaryocyte differentiation and subsequent apoptosis by targeting cell surface protein siglec-3 (CD33) in human chronic myeloid leukemia K562 cells. The 3SL-bound CD33 was internalized to the cytosol via caveolae-dependent endocytosis. At the molecular level, 3SL-bound CD33 recruits the suppressor of cytokine signaling 3 (SOCS3) and SH2 domain-containing protein tyrosine phosphatase 1 (SHP1). SOCS3 is degraded with CD33 by proteasome degradation, while SHP-1 activates extracellular signal-regulated kinase (ERK) to induce megakaryocytic differentiation and subsequent apoptosis. The present study, therefore, suggests that 3SL is a potential anti-leukemia agent affecting differentiation and apoptosis.
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http://dx.doi.org/10.1007/s10719-019-09902-1DOI Listing
April 2020

Spinosin Attenuates Alzheimer's Disease-Associated Synaptic Dysfunction via Regulation of Plasmin Activity.

Biomol Ther (Seoul) 2020 Mar;28(2):131-136

Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 02447, Republic of Korea.

Hippocampal synaptic dysfunction is a hallmark of Alzheimer's disease (AD). Many agents regulating hippocampal synaptic plasticity show an ameliorative effect on AD pathology, making them potential candidates for AD therapy. In the present study, we investigated spinosin as a regulating agent of synaptic plasticity in AD. Spinosin attenuated amyloid β (Aβ)-induced long-term potentiation (LTP) impairment, and improved plasmin activity and protein level in the hippocampi of 5XFAD mice, a transgenic AD mouse model. Moreover, the effect of spinosin on hippocampal LTP in 5XFAD mice was prevented by 6-aminocaproic acid, a plasmin inhibitor. These results suggest that spinosin improves synaptic function in the AD hippocampus by regulating plasmin activity.
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http://dx.doi.org/10.4062/biomolther.2019.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059816PMC
March 2020

Cryptotanshinone enhances neurite outgrowth and memory via extracellular signal-regulated kinase 1/2 signaling.

Food Chem Toxicol 2020 Feb 30;136:111011. Epub 2019 Nov 30.

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan, 604-714, Republic of Korea. Electronic address:

Neurite outgrowth is important process in synaptic formation and neuronal development. Many previous studies reported that natural compounds as well as neurotrophins induce neurite outgrowth through various signaling pathways. In this study, we tested the effect of cryptotanshinone (CPT), a constituent of Salvia miltiorrhiza Bunge, on neurite outgrowth using neuro2a cell line, a mouse neuroblastoma cell line. And then, we examined the effect of CPT on learning and memory. We first found that CPT facilitated neurite outgrowth in a concentration-dependent manner. Although CPT induced MTT reduction, CPT did not induce LDH release. Moreover, CPT suppressed cell proliferation. CPT increased ERK1/2 phosphorylation and ERK1/2 inhibitor blocked CPT-facilitated neurite outgrowth. CPT also enhanced learning and memory without affecting basal sensory conditions and increased ERK1/2 phosphorylation in the hippocampus in a dose-dependent manner. These results demonstrate that CPT facilitates neurite outgrowth and enhances learning and memory, which may be mediated by facilitating ERK1/2 signal.
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http://dx.doi.org/10.1016/j.fct.2019.111011DOI Listing
February 2020

Mycobacterium tuberculosis-Secreted Protein, ESAT-6, Inhibits Lipopolysaccharide-Induced MMP-9 Expression and Inflammation Through NF-κB and MAPK Signaling in RAW 264.7 Macrophage Cells.

Inflammation 2020 Feb;43(1):54-65

Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, Sungkyunkwan University, Seoburo, Jangan-gu, 16419, Kyunggi-do, Republic of Korea.

-20pt?>Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium that causes contagious tuberculosis (TB). Recently, Mtb-secreted proteins have been considered virulence factors and candidates for drugs and vaccines. Among these proteins, 6-kDa early secreted antigenic target (ESAT-6) is known to be able to induce component of matrix metalloproteinase-9 (MMP-9) in epithelial cells, leading to recruitment of macrophages. However, detailed function of ESAT-6 during macrophage recruitment to inflammatory sites remains unknown. Thus, the objective of the present study was to elucidate such function of EAST-6 and mechanism(s) involved. In the present study, we have found that recombinant ESAT-6 purified in the form of ESAT-6 double-connected structure (2E6D) could inhibit lipopolysaccharide (LPS)-induced potential of cell migration and inflammation in murine macrophage cells. Interestingly, 2E6D suppressed LPS-induced MMP-9 expression at both protein and mRNA levels as well as its enzyme activity. Levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) enzymes as known upregulators of MMP-9 were significantly decreased when 2E6D has been treated. In addition, nitric oxide (NO) as a second messenger was also significantly decreased by treatment with the purified 2E6D. Furthermore, 2E6D inhibited LPS-induced phosphorylation of IκB and translocation of NF-κB. Moreover, 2E6D suppressed phosphorylation of MAPK signaling proteins. Taken together, these results suggest that ESAT-6 can suppress LPS-induced MMP-9 and inflammation by downregulating COX-2, iNOS, and NO through NF-κB and MAPK signaling.
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http://dx.doi.org/10.1007/s10753-019-01087-xDOI Listing
February 2020

The effect of coniferaldehyde on neurite outgrowth in neuroblastoma Neuro2a cells.

Neurochem Int 2019 12 12;131:104579. Epub 2019 Oct 12.

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan, 49315, Republic of Korea. Electronic address:

Neurite outgrowth is the differentiation process by which neurons establish synapses. In the dentate gyrus of the hippocampus, new neurons are constantly produced and undergo neurite outgrowth to form synapses, and this process is involved in cognitive ability. Therefore, if an agent could modulate neurite outgrowth, it could potentially be developed as a compound for modulating cognitive ability. In this study, we examined whether coniferaldehyde, a natural compound, regulates neurite outgrowth in Neuro2a cells. We ascertained morphological changes and measured the percentage of neurite-bearing cells and neurite lengths. Coniferaldehyde significantly increased the percentage of neurite-bearing cells, and the length of neurites in a concentration-dependent manner, without inducing cell death. We then have identified that, coniferaldehyde activates the extracellular signals-regulated Kinase 1 and 2 (ERK1/2), and further noted that, U0126, an ERK1/2 inhibitor, blocks coniferaldehyde-facilitated neurite outgrowth. Moreover, Subchronic administration of CA enhanced learning and memory, and increased neurite length of newborn neurons in the hippocampus. These results suggest that coniferaldehyde induces neurite outgrowth by a process possibly mediated by ERK1/2 signaling and enhances learning and memory.
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http://dx.doi.org/10.1016/j.neuint.2019.104579DOI Listing
December 2019

β-Amyrin Ameliorates Alzheimer's Disease-Like Aberrant Synaptic Plasticity in the Mouse Hippocampus.

Biomol Ther (Seoul) 2020 Jan;28(1):74-82

Department of Herbal Medicinal Pharmacology, College of Herbal Bio-industry, Daegu Haany University, Kyungsan 38610, Republic of Korea.

Alzheimer's disease (AD) is a progressive and most frequently diagnosed neurodegenerative disorder. However, there is still no drug preventing the progress of this disorder. β-Amyrin, an ingredient of the surface wax of tomato fruit and dandelion coffee, is previously reported to ameliorate memory impairment induced by cholinergic dysfunction. Therefore, we tested whether β-amyrin can prevent AD-like pathology. β-Amyrin blocked amyloid β (Aβ)-induced long-term potentiation (LTP) impairment in the hippocampal slices. Moreover, β-amyrin improved Aβ-induced suppression of phosphatidylinositol-3-kinase (PI3K)/Akt signaling. LY294002, a PI3K inhibitor, blocked the effect of β-amyrin on Aβ-induced LTP impairment. In experiments, we observed that β-amyrin ameliorated object recognition memory deficit in Aβ-injected AD mice model. Moreover, neurogenesis impairments induced by Aβ was improved by β-amyrin treatment. Taken together, β-amyrin might be a good candidate of treatment or supplement for AD patients.
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http://dx.doi.org/10.4062/biomolther.2019.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939697PMC
January 2020

The fruit of Crataegus pinnatifida ameliorates memory deficits in β-amyloid protein-induced Alzheimer's disease mouse model.

J Ethnopharmacol 2019 Oct 23;243:112107. Epub 2019 Jul 23.

Division of Bio-technology and Convergence, College of Bio-industry, Daegu Haany University, Kyungsan, 38578, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: The fruit of Crataegus pinnatifida is a traditional medicine widely used as digestive drug in East Asia. Although Chinese herbal medicine used it for mental health, scientific evidence does not exist, yet.

Aims Of Study: The aim of this study is to show that the ethanol extract of the fruit of Crataegus pinnatifida (CPE) has neuroprotective effect on Alzheimer' disease model mice.

Materials And Methods: Intracerebroventricular injection of Aβ was used to induce Alzheimer's disease-like pathology. Passive avoidance and Y-maze tasks were used to examine the effect of CPE on memory impairments by Aβ. Immunohistochemistry was used to examine the effect of CPE on glial activation. ThT assay was used to observe the effect of CPE on Aβ aggregation. MTT and LDH release assays were utilized to examine effects of CPE on Aβ-induced cytotoxicity.

Results: CPE prevented memory deficit in Aβ-induced memory impairment model. Moreover, CPE prevented glial activation in the hippocampus of Aβ-injected model. In in vitro test, CPE inhibited Aβ fibril formation in a concentration-dependent manner. CPE also caused disaggregation of Aβ fibrils. Along with this, CPE blocked neuronal cell death induced by Aβ.

Conclusions: Collectively, these experimental findings demonstrated that CPE could be a candidate for development of AD therapy.
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http://dx.doi.org/10.1016/j.jep.2019.112107DOI Listing
October 2019

Rubrofusarin inhibits Aβ aggregation and ameliorates memory loss in an Aβ-induced Alzheimer's disease-like mouse model.

Food Chem Toxicol 2019 Oct 23;132:110698. Epub 2019 Jul 23.

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan, 49315, Republic of Korea. Electronic address:

The misfolding and aggregation of amyloid β (Aβ) peptide is a common histopathologic characteristic in patients with Alzheimer's disease, so is considered to play an critical role. In the present study, we examined the effect of rubrofusarin, an ingredient of Cassiae semen, on Aβ aggregation and memory loss in an AD mouse model. Rubrofusarin inhibited Aβ aggregation in a concentration-dependent manner. Moreover, rubrofusarin dis-aggregated preformed Aβ fibrils in a concentration-dependent manner. Although aggregated Aβ induced memory loss, Aβ pre-incubated with rubrofusarin failed to induce memory loss. Moreover, rubrofusarin administration ameliorated Aβ aggregates-induced memory loss. Finally, rubrofusarin reduced glial fibrillary acidic protein or Iba-1-positive area, markers of neuroinflammation, in the hippocampus of Aβ-treated mice. These results suggest that rubrofusarin can decrease Aβ fibril formation and ameliorate memory loss in the AD mouse model.
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http://dx.doi.org/10.1016/j.fct.2019.110698DOI Listing
October 2019

Ascochlorin induces caspase-independent necroptosis in LPS-stimulated RAW 264.7 macrophages.

J Ethnopharmacol 2019 Jul 24;239:111898. Epub 2019 Apr 24.

Molecular and Cellular Glycobiology Laboratory, Department of Biological Science, SungKyunKwan University, Seoburo 2066, Suwon City, Kyunggi-Do, 16419, Republic of Korea; Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Seoul, 06351, South Korea. Electronic address:

Ethnopharmacological Relevance: Plant-specific fungus of natural compound of Ascochyta viciae has traditionally been used in the treatment of sleeping sickness and tumors. The anti-tumor activities of the compounds obtained from Pisum sativum L were evaluated in this study.

Aim Of The Study: In this study, during the prolonged incubation, treatment of the LPS-stimulated tumor-like macrophage RAW 264.7 cells with ASC exhibited the shift of anti-inflammatory behavior to a type of necroptotic cell death named necroptosis.

Materials And Methods: Ascochlorin (ASC) purified from plant-specific fungus Ascochyta viciae is a natural compound with the trimethyl oxocyclohexyl structure and an anti-cancer and antibiotic agent. The fungus contributes to the Ascochyta blight disease complex of pea (Pisum sativum L). RAW 264.7 cells have been stimulated with LPS and treated with ASC. Cell viability of the LPS-treated RAW 264.7 cells and bone marrow-derived macrophage (BMDM) cells were examined. Flow cytometry analysis with 7AAD and Annexin V was examined for the apoptotic or necroptosis/late-apoptosis. Cleaved caspase-3, -7 and -8 as well as cleaved PARP were assessed with a caspase inhibitor, z-VAD-fmk. LPS-responsible human leukemic U937 and colon cancer SW480 and HT-29 cells were also examined for the cell viabilities.

Results: Flow cytometry analysis after Annexin V and 7AAD double staining showed that ASC alone induces apoptosis in RAW 264.7 cells, while it induces necroptosis/late-apoptosis in LPS-treated RAW 264.7 cells. 7AAD and Annexin V positive populations were increased in the LPS-treated cells with ASC. Although viability of LPS-treated cells with ASC was decreased, the amounts of cleaved caspase-3, -7 and -8 as well as cleaved PARP were reduced when compared with ASC-treated cells. Upon ASC treatment, the cleaved caspase-8 level was not changed, however, cleaved caspase-3, -7, and PARP were reduced in LPS-stimulated RAW 264.7 cells treated with ASC, claiming a caspase-8 independent necroptosis of ASC. Furthermore, ASC and LPS-cotreated cells which a caspase inhibitor, z-VAD-fmk, was pretreated, showed the decreased cell viability compared with control cells without the inhibitor. Cell viability of RAW 264.7 cells co-treated with ASC and LPS when treated with z-VAD was decreased. In the LPS-responsible human leukemic U937 and colon cancer SW480 and HT-29 cells, cell viabilities were decreased by 10 μM ASC.

Conclusion: Prolonged stimulation of ASC with LPS induces the necroptosis in RAW cells. Activated immune cells may share the susceptibility of antitumor agents with the cancer cells.
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http://dx.doi.org/10.1016/j.jep.2019.111898DOI Listing
July 2019

4--Carboxymethylascochlorin Inhibits Expression Levels of on Inflammation-Related Cytokines and Matrix Metalloproteinase-9 Through NF-κB/MAPK/TLR4 Signaling Pathway in LPS-Activated RAW264.7 Cells.

Front Pharmacol 2019 27;10:304. Epub 2019 Mar 27.

Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea.

Toll-like receptor 4 (TLR4) and matrix metalloproteinase-9 (MMP-9) are known to play important roles in inflammatory diseases such as arteriosclerosis and plaque instability. The purpose of this study was to perform the effect of 4--carboxymethylascochlorin (AS-6) on MMP-9 expression in lipopolysaccharide (LPS)-induced murine macrophages and signaling pathway involved in its anti-inflammatory effect. Effect of AS-6 on MAPK/NF-κB/TLR4 signaling pathway in LPS-activated murine macrophages was examined using ELISA, Western blotting, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence immunoassay. MMP-9 enzyme activity was examined by gelatin zymography. AS-6 significantly suppressed MMP-9 and MAPK/NF-κB expression levels in LPS-stimulated murine macrophages. Expression levels of inducible nitric oxide synthase (iNOS), COX2, MMP-9, JNK, ERK, p38 phosphorylation, and NF-κB stimulated by LPS were also decreased by AS-6. Moreover, AS-6 suppressed TLR4 expression and dysregulated LPS-induced activators of transcription signaling pathway. The results of this study showed that AS-6 can inhibit LPS-stimulated inflammatory response by suppressing TLR4/MAPK/NF-κB signals, suggesting that AS-6 can be used to induce the stability of atherosclerotic plaque and prevent inflammatory diseases in an model.
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http://dx.doi.org/10.3389/fphar.2019.00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445864PMC
March 2019

Intestine specific regulation of pig cytidine-5'-monophospho-N-acetylneuraminic acid hydroxylase gene for N-glycolylneuraminic acid biosynthesis.

Sci Rep 2019 03 12;9(1):4292. Epub 2019 Mar 12.

Molecular and Cellular Glycobiology Unit, Department of Biological Science, Sungkyunkwan University, Seoburo 2066, Jangan-Gu, Suwon, Gyunggi-Do, 16419, Korea.

N-glycolylneuraminic acid (Neu5Gc), a generic form of sialic acid, is enzymatically synthesized by cytidine-5'-monophospho-N-acetylneuraminic acid hydroxylase (CMAH). Although expression of pig CMAH gene pcmah encoding CMAH has been reported to be regulated by pathogenic infection and developmental processes, little is known about the mechanisms underlying the regulation of pcmah gene expression. The objective of this study was to determine mechanism(s) involved in intestine specific regulation of pcmah gene by identifying several cis-acting elements and nuclear transcription factors that could directly interact with these cis-acting elements. We identified intestine specific promoter region (Pi) of pcmah gene located at upstream regions of the 5'flanking region of exon 1a and found that the promoter region is responsible for the transcriptional regulation of 5'pcmah-1. Based on reporter assays using serially constructed luciferase genes with each deleted promoter, we demonstrated that the Pi promoter activity was more active in intestinal IPI-2I cells than that in kidney PK15 cells, corresponding to both mRNA expression patterns in the two cell lines. In addition, we found that Sp1 transcription factor was necessary for basal activity of Pi promoter and that Ets-1 contributed to intestine-specific activity of Pi promoter. This study helps us understand transcriptional regulation of pcmah in the intestine of pig tissues. It also allows us to consider potential roles of Neu5Gc in interaction with environmental factors present in the intestinal tissue during pathogenic infection and developmental process.
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http://dx.doi.org/10.1038/s41598-019-40522-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414617PMC
March 2019

The effects of pinoresinol on cholinergic dysfunction-induced memory impairments and synaptic plasticity in mice.

Food Chem Toxicol 2019 Mar 24;125:376-382. Epub 2019 Jan 24.

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan, 49315, Republic of Korea. Electronic address:

Dementia is a category of brain diseases that cause a decrease in cognitive functions. Alzheimer's disease (AD) is the most frequently mentioned neurodegenerative disease showing dementia. Although many useful drugs for dementia were developed, we still need better and safer drugs. Here, we tested pinoresinol, a lignan found in sesame seed and olive oil, whether it could be a candidate for this purpose. Pinoresinol (25 mg/kg, p.o.) ameliorated memory impairment in dementia model induced by cholinergic blockade in the passive avoidance test in a dose-dependent manner. Moreover, pinoresinol (50 μM) facilitated induction of hippocampal long-term potentiation, a cellular model of learning and memory. Pinoresinol blocked acetylcholinesterase (AchE), an acetylcholine-degrading enzyme, activity in a concentration-dependent manner. Moreover, pinoresinol (50 μM) facilitated calcium influx into neuro2a cell. These results suggest that pinoresinol improves memory impairment and facilitates hippocampal LTP induction and these results might be related to the effect of pinoresinol on AChE and calcium influx.
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http://dx.doi.org/10.1016/j.fct.2019.01.017DOI Listing
March 2019

Esculentoside B inhibits inflammatory response through JNK and downstream NF-κB signaling pathway in LPS-triggered murine macrophage RAW 264.7 cells.

Int Immunopharmacol 2019 Mar 9;68:156-163. Epub 2019 Jan 9.

Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, Sungkyunkwan University, Seoburo 2066, Jangan-Gu, Suwon, Gyunggi-Do 16419, Republic of Korea. Electronic address:

Natural compound esculentoside B (EsB), (2S,4aR,6aR,6aS,6bR,8aR,9R,10R,11S,12aR,14bS)-11-hydroxy-9-(hydroxymethyl)-2 methoxycarbonyl-2,6a,6b,9,12a-pentamethyl-10-[(2S,3R,4S,5R)-3,4,5-trihydroxyoxan-2-yl]oxy-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid with molecular weight of 664.833, isolated from roots of Phytolacca acinosa Roxb has been widely used as a constituent of traditional Chinese medicine (TCM). However, the anti-inflammatory capacity of EsB has not been reported yet. Therefore, the objective of this study was to investigate anti-inflammatory activities of EsB in LPS-treated macrophage RAW 264.7 cells. EsB could inhibit nitric oxide (NO) production. EsB also suppressed gene and protein expression levels of inducible isoform of NO synthase (NOS) and cyclooxygenase-2 in a dose-dependent manner. In addition, EsB decreased gene expression and protein secretion levels of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6. EsB remarkably suppressed nuclear translocation of nuclear factor kappa-B (NF-κB) from cytosolic space. Phosphorylation of IκB was also inhibited by EsB. Moreover, EsB specifically down-regulated phospho-c-Jun N-terminal kinase (p-JNK), but not p-p38 or phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2). Taken together, these results suggest that EsB has inhibitory effect on inflammatory response by inactivating NF-κB and p-JNK. It could be used as a new modulatory drug for effective treatment of inflammation-related diseases.
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http://dx.doi.org/10.1016/j.intimp.2019.01.003DOI Listing
March 2019

The ethanol extract of Zizyphus jujuba var. spinosa seeds ameliorates the memory deficits in Alzheimer's disease model mice.

J Ethnopharmacol 2019 Apr 31;233:73-79. Epub 2018 Dec 31.

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

Ethnopharmacological Relevance: The seeds of Zizyphus jujuba var. spinosa (Bunge) Hu ex H.F. Chow (Rhamnaceae) have long been treated as hypnotic agent for sleep disturbances in traditional Chinese and Korean medicine and many previous studies have focused on its effect in central nervous system.

Aims Of Study: The present study aimed to provide evidence showing that the ethanol extract of Zizyphus jujuba var. spinosa seeds (EEZS), which may regulate plasmin activity, has the potential to serve as a therapeutic agent for AD.

Materials And Methods: Synaptic function was determined by measuring long-term potentiation (LTP) in Shaffer-collateral pathway of the hippocampus. Protein levels of plasmin or plasminogen were examined using western blotting. Plasmin activity was measured using ELISA. Cognitive functions were measured using passive avoidance and object recognition tests in the 5XFAD mice.

Results: Our in vitro analysis revealed that EEZS-treated hippocampal slices from 5XFAD mice, a mouse model of AD, showed significantly higher long-term potentiation levels than did vehicle-treated hippocampal slices from 5XFAD mice (P < 0.05). Additionally, EEZS significantly elevated the plasmin level and activity in the hippocampal slices from 5XFAD mice (P < 0.05). Co-treating the slices with EEZS and 6-aminocaproic acid, a plasmin inhibitor, blocked the ameliorating effects of EEZS on the synaptic deficits that were present in 5XFAD mice. Compatible with the in vitro study, the results of our in vivo investigation showed that administering EEZS orally to 5XFAD mice ameliorated their memory impairments. Orally administered EEZS also elevated the plasmin level and activity in the hippocampus of 5XFAD mice.

Conclusions: Collectively, our findings suggest that EEZS alleviates the AD-like symptoms in 5XFAD mice by regulating of plasmin activity and EEZS may be a suitable treatment for AD.
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http://dx.doi.org/10.1016/j.jep.2018.12.043DOI Listing
April 2019

Esculentoside H inhibits colon cancer cell migration and growth through suppression of MMP-9 gene expression via NF-kB signaling pathway.

J Cell Biochem 2019 06 7;120(6):9810-9819. Epub 2018 Dec 7.

Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Chunchun-Dong, Jangan-Gu, Suwon, Kyunggi-Do, Korea.

A water-soluble saponin, Esculentoside H (EsH), 3-O-(O-β-d-glucopyranosyl-(1→4)-β-d-xylopyranosyl)-28-β-d-glucopyranosylphytolaccagenin has been isolated and purified from the root extract of perennial plant Phytolacca esculenta. EsH is known to be an anticancer compound, having a capacity for TNF-α release. However, the effects of EsH on migration and growth in tumor cells have not yet been reported. In the current study, the suppressive effects of EsH on phorbol 12-myristate 13-acetate (PMA)-induced cell migration were examined in murine colon cancer CT26 cells and human colon cancer HCT116 cells. Interestingly, the transwell assay and wound healing show that EsH suppresses the PMA-induced migration and growth potential of HCT116 and CT26 colon cancer cells, respectively. EsH dose-dependently suppressed matrix metalloproteinases-9 (MMP-9) expression that was upregulated upon PMA treatment in messenger RNA levels and protein secretion. Since the expression of MMP-9 is correlated with nuclear factor-κB (NF-κB) signaling, it has been examined whether EsH inhibits PMA-induced IκB phosphorylation that leads to the suppression of NK-κB nuclear translocation. EsH repressed the phosphorylation level of JNK, but not extracellular signal-regulated kinase and p38 signaling when the cells were treated with PMA. Overall, these results demonstrated that EsH could suppress cancer migration through blockage of the JNK1/2 and NF-κB signaling-mediated MMP-9 expression.
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http://dx.doi.org/10.1002/jcb.28261DOI Listing
June 2019

Curcumin Downregulates Human GM3 Synthase (hST3Gal V) Gene Expression with Autophagy Induction in Human Colon Carcinoma HCT116 Cells.

Evid Based Complement Alternat Med 2018 11;2018:6746412. Epub 2018 Nov 11.

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 49315, Republic of Korea.

Our recent report showed that curcumin, polyphenolic compound isolated from the herb , upregulated the gene expression of human GD3 synthase (hST8Sia I) responsible for ganglioside GD3 synthesis with autophagy induction in human lung adenocarcinoma A549 cells. In this study, on the contrary to this finding, we demonstrated that curcumin downregulated the gene expression of human GM3 synthase (hST3Gal V) catalyzing ganglioside GM3 synthesis with autophagy induction in human colon carcinoma HCT116 cells. To clarify the mechanism leading to the downregulation of hST3Gal V gene expression in curcumin-treated HCT116 cells, we analyzed the curcumin-inducible promoter of the hST3Gal V gene by luciferase reporter assays. Promoter deletion analysis demonstrated that the -177 to -83 region, which includes putative binding sites for transcription factors NFY, CREB/ATF, SP1, EGR3, and MZF1, acts as the curcumin-responsive promoter of the hST3Gal V gene. Site-directed mutagenesis and chromatin immunoprecipitation analysis demonstrated that the CREB/ATF binding site at -143 is pivotal for curcumin-induced downregulation of hST3Gal V gene in HCT116 cells. The transcriptional activation of hST3Gal V in HCT116 cells was significantly repressed by an inhibitor of AMP-activated protein kinase (AMPK). These results suggest that AMPK signal pathway mediates hST3Gal V gene expression in HCT116 cells.
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http://dx.doi.org/10.1155/2018/6746412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252237PMC
November 2018

4-O-carboxymethylascochlorin protected against microglial-mediated neurotoxicity in SH-SY5Y and BV2 cocultured cells from LPS-induced neuroinflammation and death by inhibiting MAPK, NF-κB, and Akt pathways.

J Cell Biochem 2018 Oct 15. Epub 2018 Oct 15.

Department of Biological Sciences, Molecular and Cellular Glycobiology Unit, SungKyunKwan University, Suwon, Kyunggi-Do, Republic of Korea.

In our previous studies, structurally similar compounds of ascochlorin and ascofuranone exhibited anti-inflammatory activity. Neural inflammation plays a significant role in the commence and advancement of neurodegenerative diseases. It is not known whether 4-O-carboxymethylascochlorin (AS-6) regulates the initial stage of inflammatory responses at the cellular level in BV2 microglia cells. We here investigated the anti-inflammatory effects of AS-6 treatment in microglia cells with the microglial protection in neurons. We found that the lipopolysaccharide (LPS)-stimulated production of nitric oxide, a main regulator of inflammation, is suppressed by AS-6 in BV2 microglial cells. In addition, AS-6 dose-dependently suppressed the increase in COX-2 protein and messenger RNA levels in LPS-stimulated BV2 cells. Moreover, AS-6 inhibited the expression and secretion of proinflammatory cytokines in BV2 microglial cells. At the intracellular level, AS-6 inhibited LPS-activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in BV2 microglial cells. AS-6 negatively affected mitogen-activated protein kinases (MAPK) and Akt phosphorylation: Phosphorylated forms of ERK, JNK, p38, and Akt decreased. To check whether AS-6 protects against inflammatory inducer-mediated neurotoxicity, neuronal SH-SY5Y cells were coincubated with BV2 cells in conditioned medium. AS-6 exerted a neuroprotective effect by suppressing microglial activation by LPS or amyloid-β peptide. AS-6 is a promising suppressor of inflammatory responses in LPS-induced BV2 cells by attenuating NF-κB and MAPKs signaling. AS-6 protected against microglial-mediated neurotoxicity in SH-SY5Y and BV2 cocultured cells from LPS-induced neuroinflammation and death via inhibiting MAPK, NF-κB, and Akt pathways.
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http://dx.doi.org/10.1002/jcb.27464DOI Listing
October 2018

Comparison of endothelial cell attachment on surfaces of biodegradable polymer-coated magnesium alloys in a microfluidic environment.

PLoS One 2018 10;13(10):e0205611. Epub 2018 Oct 10.

National Science Foundation-Engineering Research Center for Revolutionizing Metallic Biomaterials, North Carolina Agricultural and Technical State University, Greensboro, North Carolina, United States of America.

Polymeric coatings can provide temporary stability to bioresorbable metallic stents at the initial stage of deployment by alleviating rapid degradation and providing better interaction with surrounding vasculature. To understand this interfacing biocompatibility, this study explored the endothelial-cytocompatibility of polymer-coated magnesium (Mg) alloys under static and dynamic conditions compared to that of non-coated Mg alloy surfaces. Poly (carbonate urethane) urea (PCUU) and poly (lactic-co-glycolic acid) (PLGA) were coated on Mg alloys (WE43, AZ31, ZWEKL, ZWEKC) and 316L stainless steel (316L SS, control sample), which were embedded into a microfluidic device to simulate a vascular environment with dynamic flow. The results from attachment and viability tests showed that more cells were attached on the polymer-coated Mg alloys than on non-coated Mg alloys in both static and dynamic conditions. In particular, the attachment and viability on PCUU-coated surfaces were significantly higher than that of PLGA-coated surfaces of WE43 and ZWEKC in both static and dynamic conditions, and of AZ31 in dynamic conditions (P<0.05). The elementary distribution map showed that there were relatively higher Carbon weight percentages and lower Mg weight percentages on PCUU-coated alloys than PLGA-coated alloys. Various levels of pittings were observed underneath the polymer coatings, and the pittings were more severe on the surface of Mg alloys that corroded rapidly. Polymer coatings are recommended to be applied on Mg alloys with relatively low corrosion rates, or after pre-stabilizing the substrate. PCUU-coating has more selective potential to enhance the biocompatibility and mitigate the endothelium damage of Mg alloy stenting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179289PMC
March 2019

Neuroprotective effect of the ethanol extract of Artemisia capillaris on transient forebrain ischemia in mice via nicotinic cholinergic receptor.

Chin J Nat Med 2018 Jun;16(6):428-435

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan 49315, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan 49315, Republic of Korea. Electronic address:

Artemisia capillaris Thunberg is a medicinal plant used as a traditional medicine in many cultures. It is an effective remedy for liver problems including hepatitis. Recent pharmacological reports have indicated that Artemisia species can exert various neurological effects. Previously, we reported a memory-enhancing effect of Artemisia species. However, the mechanisms underlying the neuroprotective effect of A. capillaris (AC) are still unknown. In the present study, we investigated the effect of an ethanol extract of AC on ischemic brain injury in a mouse model of transient forebrain ischemia. The mice were treated with AC for seven days, beginning one day before induction of transient forebrain ischemia. Behavioral deficits were investigated using the Y-maze. Nissl and Fluoro-jade B staining were used to indicate the site of injury. To determine the underlying mechanisms for the drug, we measured acetylcholinesterase activity. AC (200 mg·kg) treatment reduced transient forebrain ischemia-induced neuronal cell death in the hippocampal CA1 region. The AC-treated group also showed significant amelioration in the spontaneous alternation of the Y-maze test performance, compared to that in the untreated transient forebrain ischemia group. Moreover, AC treatment showed a concentration-dependent inhibitory effect on acetylcholinesterase activity in vitro. Finally, the effect of AC on forebrain ischemia was blocked by mecamylamine, a nonselective nicotinic acetylcholine receptor antagonist. Our results suggested that in a model of forebrain ischemia, AC protected against neuronal death through the activation of nicotinic acetylcholine receptors.
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http://dx.doi.org/10.1016/S1875-5364(18)30076-1DOI Listing
June 2018

Transcriptional Activation of Human GD3 Synthase (hST8Sia I) Gene in Curcumin-Induced Autophagy in A549 Human Lung Carcinoma Cells.

Int J Mol Sci 2018 Jul 2;19(7). Epub 2018 Jul 2.

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A university, Busan 604-714, Korea.

Curcumin, a natural polyphenolic compound isolated from the plant , is known to induce autophagy in various cancer cells, including lung cancer. In the present study, we also confirmed by LC3 immunofluorescence and immunoblotting analyses that curcumin triggers autophagy in the human lung adenocarcinoma A549 cell line. In parallel with autophagy induction, the gene expression of human GD3 synthase (hST8Sia I) responsible for ganglioside GD3 synthesis was markedly elevated in response to curcumin in the A549 cells. To investigate the transcriptional activation of hST8Sia I associated with the autophagy formation in curcumin-treated A549 cells, functional characterization of the 5'-flanking region of the hST8Sia I gene was carried out using the luciferase reporter assay system. Deletion analysis demonstrated that the -1146 to -646 region, which includes the putative c-Ets-1, CREB, AP-1, and NF-κB binding sites, functions as the curcumin-responsive promoter of hST8Sia I in A549 cells. The site-directed mutagenesis and chromatin immunoprecipitation assay demonstrated that the NF-κB binding site at -731 to -722 was indispensable for the curcumin-induced hST8Sia I gene expression in A549 cells. Moreover, the transcriptional activation of hST8Sia I by the curcumin A549 cells was strongly inhibited by compound C, an inhibitor of AMP-activated protein kinase (AMPK). These results suggest that curcumin controls hST8Sia I gene expression via AMPK signal pathway in A549 cells.
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http://dx.doi.org/10.3390/ijms19071943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073763PMC
July 2018

The enhancing effect of Aubang Gahl Soo on the hippocampal synaptic plasticity and memory through enhancing cholinergic system in mice.

J Ethnopharmacol 2018 Oct 26;224:91-99. Epub 2018 May 26.

Division of Bio-technology and Convergence, College of Bio-industry, Daegu Haany University, Kyungsan 38578, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Aubang Gahl Soo (AGS) is a Korean traditional drink manufactured from medicinal plants and fruits using sugar or honey. Although traditional old book stated its effects on body, there is no scientific evidence yet. Therefore, in the present study, we tested AGS on brain functions.

Aim Of This Study: In this study, we tried to uncover the effect of on brain functions. To do this we examined the action of AGS on the hippocampal synaptic function and memory in mice.

Materials And Methods: To examine the effect of AGS on synaptic plasticity, we observed input-output curves (I/O curve), paired-pulse facilitation (PPF), and long-term potentiation (LTP) using mouse hippocampal slices. Moreover, to investigate the functional relevance of the effect of AGS on synaptic plasticity, we conducted passive avoidance, Y-maze and Morris water maze tests. To examine relevant mechanism, acetylcholinesterase (AChE) activity and acetylcholine (ACh) level assay were also conducted.

Results: In the basal synaptic transmission study, we found that AGS did not affect I/O curves and PPF. However, AGS facilitated hippocampal LTP in a concentration-dependent manner. Moreover, AGS blocked AChE activity (IC = 485 μg/ml). Moreover, ACh level was increased by AGS (100 μg/ml) treatment. Along with this, facilitating effect of AGS on hippocampal LTP also blocked by scopolamine, a muscarinic acetylcholine receptor antagonist. Moreover, AGS also ameliorated memory impairments induced by scopolamine in passive avoidance, Y-maze, and Morris water maze tests.

Conclusions: These results suggest that AGS facilitates hippocampal LTP through activating cholinergic system and ameliorates cholinergic dysfunction-induced memory deficit.
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http://dx.doi.org/10.1016/j.jep.2018.05.017DOI Listing
October 2018

Fluoxetine Inhibits Natural Decay of Long-Term Memory via Akt/GSK-3β Signaling.

Mol Neurobiol 2018 Sep 9;55(9):7453-7462. Epub 2018 Feb 9.

Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.

Understanding the mechanisms underlying the natural decay of long-term memory can help us find means of extending the duration of long-term memory. However, the neurobiological processes involved in the decay of long-term memory are poorly understood. In the present study, we examined the effect of acute and chronic treatment of fluoxetine on natural decay of long-term memory and the possible mechanism. Late administration of fluoxetine prolonged the persistence of long-term memory in mice, as demonstrated by object location recognition and Barnes maze tests. Fluoxetine altered Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling in the hippocampus. Late short- and long-term pharmacological inhibition of GSK-3β mimicked the effect of fluoxetine on memory persistence. Pharmacological inhibition of Akt blocked the effect of fluoxetine on memory persistence. Finally, late infusion of fluoxetine increased hippocampal long-term potentiation (LTP) and pharmacological inhibition of GSK-3β blocked the natural decline in LTP. These results demonstrate that GSK-3β might be a key molecule in memory decay process, and fluoxetine extends the period of long-term memory maintenance via Akt/GSK-3β signaling.
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http://dx.doi.org/10.1007/s12035-018-0919-xDOI Listing
September 2018

The Seed of Zizyphus jujuba var. spinosa Attenuates Alzheimer's Disease-Associated Hippocampal Synaptic Deficits through BDNF/TrkB Signaling.

Biol Pharm Bull 2017 ;40(12):2096-2104

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University.

Ziziphus jujuba is a plant, which bears fruits and seeds that are used for medicinal purposes in Traditional oriental medicine. The seed of Zizyphus jujuba var. spinosa (EZJ) has been also traditionally used for psychiatric disorders in Chinese and Korean medicines. Recent findings have indicated that EZJ improves memory impairment, a common symptom of various neurological diseases. However, the effects of EZJ on amyloid β (Aβ) toxicity, which is a main cause of Alzheimer's disease (AD), remain to be elucidated. To illuminate the potential anti-AD effect and mechanism in the mouse hippocampal tissue, we examined the effect of standardized EZJ on Aβ-induced synaptic long-term potentiation (LTP) deficit in the hippocampal tissue. EZJ blocked Aβ-induced LTP deficits in a concentration-dependent manner. Moreover, EZJ increased brain-derived neurotrophic factor (BDNF) level in naïve hippocampal slices. The finding that the blockade of BDNF receptor reduced the effect of EZJ suggests that EZJ ameliorates the Aβ-induced LTP deficit through BDNF/topomyosin receptor kinase B (TrkB) signaling. However, transcription or translation inhibitors failed to block the effect of EZJ, suggesting that BDNF synthesis is not required for the action of EZJ on LTP. Finally, we found that EZJ stimulates plasmin activity. In contrast, plasmin inhibitor blocked the effect of EZJ on the Aβ-induced LTP deficit. Our findings indicate that EZJ ameliorates Aβ-induced LTP deficits through BDNF/TrkB signaling. This phenomenon is induced by a regulatory effect of EZJ on the post-translation modification of BDNF.
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http://dx.doi.org/10.1248/bpb.b17-00378DOI Listing
July 2018

Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity.

Neuropharmacology 2018 Jan 25;128:282-292. Epub 2017 Oct 25.

Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, Republic of Korea; Institute of Convergence Bio-Health, Dong-A University, Busan, Republic of Korea. Electronic address:

Amyloid β (Aβ) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of Aβ is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD-associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus-dependent memory impairments using Aβ-injected as well as 5XFAD AD model mice. Oligomeric Aβ injections into the 3rd ventricle caused concentration-dependent and time-dependent impairments in learning/memory and synaptic plasticity. Moreover, Aβ aberrantly regulated caspase-3, GSK-3β, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3β inhibitor ameliorated memory impairments and synaptic deficits in Aβ-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both Aβ-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD.
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http://dx.doi.org/10.1016/j.neuropharm.2017.10.028DOI Listing
January 2018