• BMB Reports
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• 제43권10호
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• pp.704-709
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• 2010

The Swedish mutation (K595N/M596L) of amyloid precursor protein (APP-swe) has been known to increase abnormal cleavage of cellular APP by Beta-secretase (BACE), which causes tau protein hyperphosphorylation and early-onset Alzheimer's disease (AD). Here, we analyzed the effect of APP-swe in global gene expression using deep transcriptome sequencing technique. We found 283 genes were down-regulated and 348 genes were up-regulated in APP-swe expressing H4-swe cells compared to H4 wild-type cells from a total of approximately 74 million reads of 38 base pairs from each transcriptome. Two independent mechanisms such as kinase and phosphatase signaling cascades leading hyperphosphorylation of tau protein were regulated by the expression of APP-swe. Expressions of catalytic subunit as well as several regulatory subunits of protein phosphatases 2A were decreased. In contrast, expressions of tau-phosphorylating glycogen synthase kinase $3\beta$(GSK-3$\beta$), cyclin dependent kinase 5 (CDK5), and cAMP-dependent protein kinase A (PKA) catalytic subunit were increased. Moreover, the expression of AD-related Aquaporin 1 and presenilin 2 expression was regulated by APP-swe. Taken together, we propose that the expression of APP-swe modulates global gene expression directed to AD pathogenesis.

• Molecules and Cells
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• 제37권7호
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• pp.540-546
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• 2014

Several types of genetic and epigenetic regulation have been implicated in the development of drug resistance, one significant challenge for cancer therapy. Although changes in the expression of non-coding RNA are also responsible for drug resistance, the specific identities and roles of them remain to be elucidated. Long non-coding RNAs (lncRNAs) are a type of ncRNA (> 200 nt) that influence the regulation of gene expression in various ways. In this study, we aimed to identify differentially expressed lncRNAs in 5-fluorouracil-resistant colon cancer cells. Using two pairs of 5-FU-resistant cells derived from the human colon cancer cell lines SNU-C4 and SNU-C5, we analyzed the expression of 90 lncRNAs by qPCR-based profiling and found that 19 and 23 lncRNAs were differentially expressed in SNU-C4R and SNU-C5R cells, respectively. We confirmed that snaR and BACE1AS were down-regulated in resistant cells. To further investigate the effects of snaR on cell growth, cell viability and cell cycle were analyzed after transfection of siRNAs targeting snaR. Down-regulation of snaR decreased cell death after 5-FU treatment, which indicates that snaR loss decreases in vitro sensitivity to 5-FU. Our results provide an important insight into the involvement of lncRNAs in 5-FU resistance in colon cancer cells.

• 한국수산과학회지
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• 제55권3호
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• pp.310-318
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• 2022

Cnidium japonicum a biennial plant belonging to the family Umbelliferae, is a halophyte that grows in high-salinity areas of coastal sand dunes and sandy shores. This study was conducted to investigate the constituents, antioxidant activities, and physiological activities of C. japonicum. Mineral analyses revealed that potassium, sodium, calcium, and magnesium were the most prevalent minerals in C. japonicum. We used 80% ethanol, 80% methanol, and distilled water as solvents to prepare extracts from C. japonicum tissues, and the obtained extraction yields ranged between approximately 26% and 32%. Among the three extracts, the ethanol and methanol extracts had higher total polyphenol and flavonoid levels than the water extracts did. The antioxidant activities of methanol extracts were the highest among the various solvent extracts of C. japonicum as was the elastase/collagenase inhibitory activity. In contrast, the ethanol extract exhibited the highest tyrosinase inhibitory activity. Furthermore, the methanol extract possessed over 80% BACE1 (β-secretase) inhibitory activity at a final concentration of 20 ㎍/mL. Therefore, these results indicate that methanol and ethanol extracts of C. japonicum may be useful as antioxidant and functional substances in food and pharmaceutical material.

• 한국수산과학회지
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• 제54권6호
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• pp.938-947
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• 2021

Messerschmidia sibirica is a halophyte that grows in high-salinity areas of coastal sand dunes and sandy shores. This study was conducted to investigate the constituents, antioxidant potency, and physiological activities of M. sibirica. Mineral analyses revealed that potassium, calcium, sodium, and magnesium were the most prevalent minerals in M. sibirica leaves and stems. We used 70% ethanol, 80% methanol, and distilled water as solvents to prepare extracts from M. sibirica tissues, with extraction yields of between approximately 19% and 27% being obtained. Among the six types of extract, the leaf ethanol extract (LEE) was characterized by the highest total polyphenol and flavonoid contents, and the antioxidant activities of the LEE were also the highest among the different solvent extracts. In addition, the leaf water extract was shown to have the highest tyrosinase and α-glucosidase inhibitory activities, whereas the leaf methanol extract was found to have the highest elastase inhibitory activity. Notably, all leaf extracts were established to have more than 75% β-secretase (BACE1) inhibitory activity at a final concentration of 0.5 mg/mL. These results indicate that leaf extracts of M. sibirica may have beneficial antioxidant properties, and could thus have potential application as functional supplements in food and pharmaceutical products.

• Journal of Ginseng Research
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• 제47권3호
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• pp.458-468
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• 2023

Background: As a complication of Type II Diabetes Mellitus (T2DM), the etiology, pathogenesis, and treatment of cognitive dysfunction are still undefined. Recent studies demonstrated that Ginsenoside Rg1 (Rg1) has promising neuroprotective properties, but the effect and mechanism in diabetes-associated cognitive dysfunction (DACD) deserve further investigation. Methods: After establishing the T2DM model with a high-fat diet and STZ intraperitoneal injection, Rg1 was given for 8 weeks. The behavior alterations and neuronal lesions were judged using the open field test (OFT) and Morris water maze (MWM), as well as HE and Nissl staining. The protein or mRNA changes of NOX2, p-PLC, TRPC6, CN, NFAT1, APP, BACE1, NCSTN, and Ab1-42 were investigated by immunoblot, immunofluorescence or qPCR. Commercial kits were used to evaluate the levels of IP3, DAG, and calcium ion (Ca²⁺) in brain tissues. Results: Rg1 therapy improved memory impairment and neuronal injury, decreased ROS, IP3, and DAG levels to revert Ca²⁺ overload, downregulated the expressions of p-PLC, TRPC6, CN, and NFAT1 nuclear translocation, and alleviated Aβ deposition in T2DM mice. In addition, Rg1 therapy elevated the expression of PSD95 and SYN in T2DM mice, which in turn improved synaptic dysfunction. Conclusions: Rg1 therapy may improve neuronal injury and DACD via mediating PLC-CN-NFAT1 signal pathway to reduce Aβ generation in T2DM mice.

• Biomolecules & Therapeutics
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• 제28권3호
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• pp.259-266
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• 2020

The present research work primarily investigated whether spinosin has the potential of improving the pathogenesis of Alzheimer's disease (AD) driven by β-amyloid (Aβ) overproduction through impacting the procession of amyloid precursor protein (APP). Wild type mouse Neuro-2a cells (N2a/WT) and N2a stably expressing human APP695 (N2a/APP695) cells were treated with spinosin for 24 h. The levels of APP protein and secreted enzymes closely related to APP procession were examined by western blot analysis. Oxidative stress related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were detected by immunofluorescence assay and western blot analysis, respectively. The intracellular reactive oxygen species (ROS) level was analyzed by flow cytometry, the levels of Aβ_1-42 were determined by ELISA kit, and Thioflavin T (ThT) assay was used to detect the effect of spinosin on Aβ_1-42 aggregation. The results showed that ROS induced the expression of ADAM10 and reduced the expression of BACE1, while spinosin inhibited ROS production by activating Nrf2 and up-regulating the expression of HO-1. Additionally, spinosin reduced Aβ_1-42 production by impacting the procession of APP. In addition, spinosin inhibited the aggregation of Aβ_1-42. In conclusion, spinosin reduced Aβ_1-42 production by activating the Nrf2/HO-1 pathway in N2a/WT and N2a/APP695 cells. Therefore, spinosin is expected to be a promising treatment of AD.

• 대한한의학방제학회지
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• 제25권1호
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• pp.69-87
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• 2017

Objectives : Cheongnoemyeongsin-hwan (CNMSH) is a herb medicine to treat cognitive impairment. This study was investigated the effects of CNMSH on learning and memory impairment induced by cerebral hypoperfusion. Cerebral hypoperfusion was produced chronically by permanent bilateral common carotid artery occlusion (BCCAO) in rats. Methods : CNMSH was administered orally once a day (250 mg/kg) for 28 days starting at 4th week after the BCCAO. The acquisition of learning and the retention of memory were tested on 9th week after the BCCAO using the Morris water maze. In addition, effect of CNMSH on neuronal apoptosis and ${\beta}-amyloid$ accumulation in the hippocmapus was evaluated with immunohistochemistry and Western blotting. Results : 1. CNMSH and ChAL significantly shortened the escape latencies on the 2nd day of acquisition training trials. 2. ChAL significantly prolonged the swimming time spent in the target and peri-target zones and CNMSH also significantly prolonged the swimming time spent in the peri-target zone. 3. CNMSH and ChAL significantly increased the number of target heading in the retention test. 4. ChAL significantly shortened the time of the 1st target heading in the retention test, but CNMSH insignificantly shortened the time of that. 5. CNMSH and ChAL significantly increased the memory score in the retention test. 6. CNMSH and ChAL significantly attenuated the reduction of CA1 neurons, but insignificantly attenuated the reduction of CA1 thickness. 7. CNMSH and ChAL significantly attenuated the up-regulation of Bax expression in the CA1 of hippocampus. 8. CNMSH and ChAL significantly attenuated the up-regulation of cascapse-3 expression in the CA1 of hippocampus. 9. CNMSH and ChAL significantly attenuated the ${\beta}-amyloid$ accumulation in the CA1 of hippocampus. 10. CNMSH and ChAL significantly attenuated the up-regulation of APP expression in the CA1 of hippocampus. 11. CNMSH and ChAL significantly attenuated the up-regulation of BACE-1 expression in the CA1 of hippocampus. Conclusions : The results show that CNMSH attenuates neuronal apoptosis and ${\beta}-amyloid$ accumulation in the hippocampus and alleviates the impairment of learning and memory produced by chronic cerebral hypoperfusion. These results suggest that CNMSH may be a beneficial medicinal herb to treat cognitive impairment associated with neurodegenerative diseases.

• Biomolecules & Therapeutics
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• 제22권1호
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• pp.17-26
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• 2014

${\alpha}$-Asarone exhibits a number of pharmacological actions including neuroprotective, anti-oxidative, anticonvulsive, and cognitive enhancing action. The present study investigated the effects of ${\alpha}$-asarone on pro-inflammatory cytokines mRNA, microglial activation, and neuronal damage in the hippocampus and on learning and memory deficits in systemic lipopolysaccharide (LPS)-treated C57BL/6 mice. Varying doses of ${\alpha}$-asarone was orally administered (7.5, 15, or 30 mg/kg) once a day for 3 days before the LPS (3 mg/kg) injection. ${\alpha}$-Asarone significantly reduced TNF-${\alpha}$ and IL-$1{\beta}$ mRNA at 4 and 24 hours after the LPS injection at dose of 30 mg/kg. At 24 hours after the LPS injection, the loss of CA1 neurons, the increase of TUNEL-labeled cells, and the up-regulation of BACE1 expression in the hippocampus were attenuated by 30 mg/kg of ${\alpha}$-asarone treatment. ${\alpha}$-Asarone significantly reduced Iba1 protein expression in the hippocampal tissue at a dose of 30 mg/kg. ${\alpha}$-Asarone did not reduce the number of Iba1-expressing microglia on immunohistochemistry but the average cell size and percentage areas of Iba1-expressing microglia in the hippocampus were significantly decreased by 30 mg/kg of ${\alpha}$-asarone treatment. In the Morris water maze test, ${\alpha}$-asarone significantly prolonged the swimming time spent in the target and peri-target zones. ${\alpha}$-Asarone also significantly increased the number of target heading and memory score in the Morris water maze. The results suggest that inhibition of pro-inflammatory cytokines and microglial activation in the hippocampus by ${\alpha}$-asarone may be one of the mechanisms for the ${\alpha}$-asarone-mediated ameliorating effect on memory deficits.

• 동의신경정신과학회지
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• 제19권1호
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• pp.125-146
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• 2008

Objectives : The purpose of this study is to suggest for the following experimental study of dementia by reviewing recent oriental medicine journals that have been published since 2000. Methods: We have investigated various types of studies in relation to dementia through 90 articles that have been published from 2000 to 2007 in recent oriental medicine journals were registered Korea research foundation. Results and Conclusions : 1. Since 2000, 88 articles in relation to dementia have been published and almost of them are herbal medicine-centered studies. Also they show a tendency to increase every year. The journal of oriental neuropsychiatry carries the highest number of studies in relation to dementia. 2. According to the experimental paper, there are 30 cases of using herb simplexes, 48 cases of herb-combined prescription, and 10 cases of other ways. Especially 7 cases of using herb-combined prescription relation to Sasang constitution are all for the Taeumin. 3. There are 85 cases of Animal and cellular experimental, 60 cases of using pathologic model induced cytotoxic activity, a case of using L-NAME, 3 cases of 192 saporin, 4 cases of ibotenic acid, 10 cases of focal cerebral ischemia, 3 cases of alcohol-administered, and one case of natural degradation. 4. Moms water maze, Radial arm maze Passive avoidance learning model were using for examining learning and memory of model animal 5. We propose that following studies of dementia are to he investigated of the applied method of using siRNA with tranceduced gene, sample preparation by water-soaking, oriental medical diagnosis, standardization of differentiating symptom and herb simplexes, building the database by classified prescriptions, and experiment model which are based on precise examining mechanism with cell line as like mouse H19-7 hippocampus, rat HT22 hippocampus, astrocyte, microglia, using the model of animals at APP, PS1, BACE, CT99/PS1, APOE4, Tau, APP/PSI/Tau

• 생약학회지
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• 제47권3호
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• pp.251-257
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• 2016

In this study, the radical scavenging activity and protective effect of ethanol extract from leaf of Engelhardtia chrysolepis HANCE (ECE) against oxidative stress were investigated under in vitro and cellular system. ECE showed strong radical scavenging activities in 1,1-diphenyl-2-picrylhydrazyl, hydroxyl(${\cdot}OH$) and nitric oxide(NO) radical as a concentration-dependent manner. Particularly, strong scavenging activity against the ${\cdot}OH$ and NO radical were observed with the $IC_{50}$ value of $1.30{\mu}g/ml$ and $12.61{\mu}g/ml$, respectively. Furthermore, the cellular oxidative stress was induced by amyloid beta($A{\beta}_{25-35}$) in C6 glial cells. The treatment of $A{\beta}_{25-35}$ to C6 glial cells generated high levels of reactive oxygen species(ROS) and declined cell viability. However, production of ROS was decreased by the treatment of ECE. In addition, the cell viability was significantly increased at each concentration(10, 25, $50{\mu}g/ml$) as dose-dependent manner. The Alzheimer's disease-related protein expressions in $A{\beta}_{25-35}$-treated C6 glial cells were analyzed. The ECE treatment inhibited expression of amyloid precursor protein(APP), C-terminal fragment-${\beta}(CTF-{\beta})$, ${\beta}$-site APP cleaving enzyme(BACE), phosphorylated tau(p-tau) proteins in C6 glial cells induced by $A{\beta}_{25-35}$. The present study indicated that ECE has strong radical scavenging activity and neuroprotective effect through attenuating oxidative stress.