• Journal of Oriental Neuropsychiatry
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• v.19 no.3
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• pp.117-127
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• 2008

Objective: Bee venom (BV) has been used for the treatment of inflammatory diseases such as rheumatoid arthritis and relief of pain in Oriental medicine. The two main components of BV are melittin and phospholipase A2 (PLA2). Of these, melittin, the major active ingredient of BV, has been reported to induce apoptosis and to possess anti tumor effects. Several studies have established that the agents inducing apoptosis in target organs suppress tumorigenesis. As the other component, PLA2 has been reported to induce neurite outgrowth in PC12 cells. However, there was no report about proliferative effect of BV in neuronal cells. In order to examine the effect of BV on glioma cell, human glioma cell line, U87 was used. Methods: Analysis of proliferation was confirmed by MTT assay. BV increased cell number through dose and duration dependent manner and these effects are apparent at a concentration of 10 ug/ml. To observe which signaling molecules will be activated by BV, phosphorylation of Akt, MAPK, PYK2 or CREB were examined by Western blot analysis. To study the long term effect of BV in U87 cells, the image of cells treated with BV for 4 days were obtained. Results: The phosphorylation levels of PYK2 and Akt were increased at 5 min after addition of 10 ug/ml of BV and sustained to 2 hours. On the other hand, phosphorylation of MAPK and CREB were increased at 5 min, maximum at 10 min, and returned to 30 min. These imply that BV may activate two different signaling pathways, PYK2/Akt and MAPK/CREB. BV treated cells showed increased neurite number and length. Conclusion: These results propose that BV may induce differentiation as well as proliferation of U87 cells through the activation of PYK2/ Akt and MAPK/ CREB.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.109-114
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• 2018

Liquiritigenin (LQ) is a flavonoid that can be isolated from Glycyrrhiza radix. It is frequently used as a tranditional oriental medicine herbal treatment for swelling and injury and for detoxification. However, the effects of LQ on cognitive function have not been fully explored. In this study, we evaluated the memory-enhancing effects of LQ and the underlying mechanisms with a focus on the N-methyl-D-aspartic acid receptor (NMDAR) in mice. Learning and memory ability were evaluated with the Y-maze and passive avoidance tests following administration of LQ. In addition, the expression of NMDAR subunits 1, 2A, and 2B; postsynaptic density-95 (PSD-95); phosphorylation of $Ca^{2+}$/calmodulin-dependent protein kinase II (CaMKII); phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2); and phosphorylation of cAMP response element binding (CREB) proteins were examined by Western blot. In vivo, we found that treatment with LQ significantly improved memory performance in both behavioral tests. In vitro, LQ significantly increased NMDARs in the hippocampus. Furthermore, LQ significantly increased PSD-95 expression as well as CaMKII, ERK, and CREB phosphorylation in the hippocampus. Taken together, our results suggest that LQ has cognition enhancing activities and that these effects are mediated, in part, by activation of the NMDAR and CREB signaling pathways.

• Molecules and Cells
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• v.43 no.9
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• pp.821-830
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• 2020

Altered dendritic morphology is frequently observed in various neurological disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the cellular and molecular basis underlying these pathogenic dendritic abnormalities remains largely unclear. In this study, we investigated dendritic morphological defects caused by dipeptide repeat protein (DPR) toxicity associated with G4C2 expansion mutation of C9orf72 (the leading genetic cause of ALS and FTD) in Drosophila neurons and characterized the underlying pathogenic mechanisms. Among the five DPRs produced by repeat-associated non-ATG translation of G4C2 repeats, we found that arginine-rich DPRs (PR and GR) led to the most significant reduction in dendritic branches and plasma membrane (PM) supply in Class IV dendritic arborization (C4 da) neurons. Furthermore, expression of PR and GR reduced the number of Golgi outposts (GOPs) in dendrites. In Drosophila brains, expression of PR, but not GR, led to a significant reduction in the mRNA level of CrebA, a transcription factor regulating the formation of GOPs. Overexpressing CrebA in PR-expressing C4 da neurons mitigated PM supply defects and restored the number of GOPs, but the number of dendritic branches remained unchanged, suggesting that other molecules besides CrebA may be involved in dendritic branching. Taken together, our results provide valuable insight into the understanding of dendritic pathology associated with C9-ALS/FTD.

• Herbal Formula Science
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• v.27 no.2
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• pp.121-136
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• 2019

Objective : To investigate the effect of sihogayonggolmoryeotang (SY) on Single Prolonged Stress(SPS)-induced Post Traumatic Stress Disorder(PTSD). Method : To confirm the effects of SY on SPS-induced PTSD, Changes in body weight, sucrose intake open field test(OFT) and forced swimming test(FST)were observed. After behavioral tests, the plasma corticosterone(CORT) from the abdominal aorta, serotonin(5-HT) from prefrontal cortex, hippocampus, amygdala and striatum, norepinephrine(NE) and dopamine(DA) from hippocampus was measured by ELISA. mRNA expression of brain-derived neurotrophic factor(BDNF) and cAMP response element-binding protein(CREB) in hippocampus was measured by RT-PCR. Result : Weight change and sucrose intakes of rats in 14th day after the administration of SY were significantly increased in the SPS + SY450 group compared to the SPS group (p<0.05). Numbers of crossing in the central zone in the OFT were significantly increased in the SPS + SY450 group (p<0.05) compared with the SPS group. The immobility time of FST was significantly decreased in SPS + SY450 group compared with SPS group (p<0.05). The change of plasma CORT concentration was significantly decreased in SPS + SY450 group compared with that in SPS group (p<0.05). The change of 5-HT concentration was significantly increased in the SPS + SY450 group at hippocampus and amygdala compared with the SPS group (p<0.05). The concentration of DA was significantly increased in the SPS + SY450 group compared with the SPS group (p<0.05). The expression of BDNF and CREB were significantly increased in SPS + SY450 group compared with the SPS group (p<0.05). Conclusion : SY administration lowered the increase of CORT caused by PTSD and increases the 5-HT concentration and reversed the decreased expression of NE and DA and BDNF and CREB by PTSD. It is postulated that SY is effective in treating PTSD by restoring cognitive function, memory impairment, unstable emotional disturbances.

• Journal of Ginseng Research
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• v.48 no.2
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• pp.163-170
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• 2024

Background: Mechanisms of synaptic plasticity in retinal ganglion cells (RGCs) are complex and the current knowledge cannot explain. Growth and regeneration of dendrites together with synaptic formation are the most important parameters for evaluating the cellular protective effects of various molecules. The effect of ginsenoside Rg1 (Rg1) on the growth of retinal ganglion cell processes has been poorly understood. Therefore, we investigated the effect of ginsenoside Rg1 on the neurite growth of RGCs. Methods: Expression of proteins and mRNA were detected by Western blot and qPCR. cAMP levels were determined by ELISA. In vivo effects of Rg1 on RGCs were evaluated by hematoxylin and eosin, and immunohistochemistry staining. Results: This study found that Rg1 promoted the growth and synaptic plasticity of RGCs neurite by activating the cAMP/PKA/CREB pathways. Meanwhile, Rg1 upregulated the expression of GAP43, Rac1 and PAX6, which are closely related to the growth of neurons. Meantime, H89, an antagonist of PKA, could block this effect of Rg1. In addition, we preliminarily explored the effect of Rg1 on enhancing the glycolysis of RGCs, which could be one of the mechanisms for its neuroprotective effects. Conclusion: Rg1 promoted neurite growth of RGCs through cAMP/PKA/CREB pathways. This study may lay a foundation for its clinical use of optic nerve diseases in the future.

• Journal of Ginseng Research
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• v.29 no.2
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• pp.86-93
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• 2005

This study was undertaken to determine the antagonism of the ginseng total saponin (GTS) on the development of nalbuphine-induced tolerance and physical dependence. GTS is blown to have antinarcotic action with a dose of 100mg/kg (i.p.) in rats. STS significantly inhibits the development of nalbuphine-induced physical dependence as well as the tolerance. The level of pCREB was elevated in the striatum by the chronic treatment with nalbuphine or GTS, how-ever, the elevation of pCREB was inhibited by the GTS co-treatment. It has been suggested that NMDA receptor and/or NO is involved in the penomena of opioid dependence and withdrawal. However, the level of nNOS and NR1 was not modulated by the treatment with nalbuphine or GTS on the cortex, hippocampus and striatum in the rat brain. These results suggest that the GTS could be used to ameliorate the nalbuphine tolerance and withdrawal symptoms.

• Natural Product Sciences
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• v.20 no.4
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• pp.296-300
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• 2014

The present study investigated the effects of (-)-sesamin on dopamine biosynthesis in PC12 cells. Treatment with (-)-sesamin (25 and $50{\mu}M$) increased intracellular dopamine levels and enhanced L-DOPA-induced increase in dopamine levels in PC12 cells. (-)-Sesamin (25 and $50{\mu}M$) also induced the phosphorylation of cyclic AMP-dependent kinase A (PKA), cyclic AMP-response element binding protein (CREB) and tyrosine hydroxylase (TH) in PC12 cells. These results suggest that (-)-sesamin induces dopamine biosynthesis via the PKA-CREB-TH pathways in PC12 cells. (-)-Sesamin needs to be studied further to serve as an adjuvant phytonutrient in neurodegenerative disease.

• Natural Product Sciences
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• v.24 no.2
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• pp.99-102
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• 2018

This study investigated the effects of ombuoside, a flavonol glycoside, on dopamine biosynthesis in PC12 cells. Ombuoside at concentrations of 1, 5, and $10{\mu}M$ increased intracellular dopamine levels at 1 - 24 h. Ombuoside (1, 5, and $10{\mu}M$) also significantly increased the phosphorylation of tyrosine hydroxylase (TH) (Ser40) and cyclic AMP-response element binding protein (CREB) (Ser133) at 0.5 - 6 h. In addition, ombuoside (1, 5, and $10{\mu}M$) combined with L-DOPA (20, 100, and $200{\mu}M$) further increased intracellular dopamine levels for 24 h compared to L-DOPA alone. These results suggest that ombuoside regulates dopamine biosynthesis by modulating TH and CREB activation in PC12 cells.

• BMB Reports
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• v.46 no.12
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• pp.567-574
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• 2013

Liver plays a major role in maintaining glucose homeostasis in mammals. Under fasting conditions, hepatic glucose production is critical as a source of fuel to maintain the basic functions in other tissues, including skeletal muscle, red blood cells, and the brain. Fasting hormones glucagon and cortisol play major roles during the process, in part by activating the transcription of key enzyme genes in the gluconeogenesis such as phosphoenol pyruvate carboxykinase (PEPCK) and glucose 6 phosphatase catalytic subunit (G6Pase). Conversely, gluconeogenic transcription is repressed by pancreatic insulin under feeding conditions, which effectively inhibits transcriptional activator complexes by either promoting post-translational modifications or activating transcriptional inhibitors in the liver, resulting in the reduction of hepatic glucose output. The transcriptional regulatory machineries have been highlighted as targets for type 2 diabetes drugs to control glycemia, so understanding of the complex regulatory mechanisms for transcription circuits for hepatic gluconeogenesis is critical in the potential development of therapeutic tools for the treatment of this disease. In this review, the current understanding regarding the roles of two key transcriptional activators, CREB and FoxO1, in the regulation of hepatic gluconeogenic program is discussed.

• Biomolecules & Therapeutics
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• v.21 no.3
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• pp.229-233
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• 2013

This study was aimed at investigating the possible effects of phytoceramide (Pcer) on learning and memory and their underlying mechanisms. Phytoceramide was orally administered to ICR mice for 7 days. Memory performances were assessed using the passive avoidance test and Y-maze task. The expressions of phosphorylated cAMP response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF) were measured with immunoblot. The incorporation of 5-bromo-2-deoxyuridine (BrdU) in hippocampal regions was investigated by using immunohistochemical methods. Treatment of Pcer enhanced cognitive performances in the passive avoidance test and Y-maze task. Immunoblotting studies revealed that the phosphorylated CREB and BDNF were significantly increased on hippocampus in the Pcer-treated mice. Immunohistochemical studies showed that the number of immunopositive cells to BrdU was significantly increased in the hippocampal dentate gyrus regions after Pcer-treatment for 7 days. These results suggest that Pcer contribute to enhancing memory and BDNF expression and it could be secondary to the elevation of neurogenesis.