• Journal of Ginseng Research
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• v.45 no.2
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• pp.264-272
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• 2021

Background: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ. Methods: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Results: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ. Conclusions: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.

• Journal of Environmental Analysis, Health and Toxicology
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• v.21 no.4
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• pp.281-291
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• 2018

Recently, long-range atmospheric transport (LRAT) from China is regarded as a major reason for elevated levels of particulate matter (PM) in Korea. However, local emissions also play an important role in PM pollution, especially in large-scale industrial cities. In this study, PM samples were collected at suburban, residential, and industrial sites in Ulsan, Korea. Polycyclic aromatic hydrocarbons (PAHs) and heavy metals were analyzed, and a potential human health risk assessment was conducted. The concentrations of PAHs and heavy metals in total suspended particles (TSP) increased during high $PM_{10}$ episodes, and backward trajectory analysis verified the influence of LRAT from China during the high episodes. Furthermore, the concentrations of PAHs and heavy metals in $PM_{2.5}$ and $PM_{10}$ at the industrial site were higher than those at the residential site. The risk assessment of PAHs and heavy metals in $PM_{2.5}$ suggested no significant health effects. The highest levels of PAHs were measured in the particle size of $0.32{\sim}0.56{\mu}m$ at the residential site, and those of heavy metals were detected in the particle size of 1.8~5.6 and $>18{\mu}m$, reflecting different major emissions sources for both groups. On the basis of this preliminary study, we are planning long-term monitoring and modeling studies to quantitatively evaluate the influence of industrial activities on the PM pollution in Ulsan.

• Journal of Environmental Analysis, Health and Toxicology
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• v.21 no.4
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• pp.292-303
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• 2018

The particle sizes and heavy metal concentrations (Pb, Zn, Cu, Cd, Hg, As, Cr, Ni, Li, Al) of surface sediments of the Yeongsan River were analyzed to assess the distribution and pollution level of heavy metals. The distribution of particle sizes was dominated by sand in the upstream sites (MS1-MS7) and by silt loam in the downstream sites (MS8-ML3), but MS3 and MS6, located slightly upstream of the two weirs, were found to be loamy sand and silt loam, respectively. The concentrations of Pb, Zn, Cu, Cd and Hg were higher at the upstream sites, while As, Cr, Ni and Li were higher at the downstream sites. The heavy metals of crustal origin (As, Cr, Ni and Li) were strongly correlated with particle size, while the other heavy metals (Pb, Zn, Cu, Cd and Hg) were weakly correlated with particle size. Considering their concentrations, most of heavy metals were evaluated as having almost no toxic effects on benthic organisms, at all sites. In addition, anthropogenic contamination by the $I_{geo}$, EF and CF were found to have no impact at most sites, with only low levels of pollution at the others. Using the PLI method, the MS2 and MS3 sites, located upstream, were assessed to be affected by anthropogenic contamination. Most importantly, Zn, Cu and Hg were found to be the elements responsible for most pollution, and they were highest at the upstream sites, implying pollution by domestic sewage and urban discharge.

• Journal of Environmental Analysis, Health and Toxicology
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• v.21 no.4
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• pp.252-263
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• 2018

Distributions of 15 PAHs and 82 PCBs were investigated in sediment and fish samples collected from the Suyoung Estuary of Busan, one of the most urbanized and newly contaminated areas in Busan. The concentrations of $S_{15}PAH$ in sediments ranged from 17.9 to 777 ng/g-dry and were mainly originated from combustion processes. The concentrations of $S_{82}PCB$ in sediments ranged from 0.55 to 12.5 ng/g-dry and were significantly correlated with those of 12 dioxin-like PCBs and 6 non-dioxin like PCBs. Higher concentrations of PAHs and PCBs were found in the upper river and the inner Suyoung Bay than in marina and the outer Suyoung Bay. No sites exceeded the ecotoxicological values of PAHs and PCBs in marine sediments. Benzo[a]-pyrene was not detected in fish samples and the concentrations of $S_4PAH$ (0.15~0.45 ng/g-wet) were lower than the maximum level set by EU. The levels of PCBs in fish samples were at less than 1% of the Korean maximum level and 2% of the EU maximum level. The concentrations of dioxin-like PCBs were $0.01{\sim}0.32pg-TEQ_{WHO-2005}/g-wet$, and the highest concentration was found in eels, which were at less than 5% of the EU maximum level. Dietary intakes of PAHs and PCBs through fish consumption were estimated, and their lifetime cancer risk and non-cancer risk were much lower.

• Journal of Environmental Analysis, Health and Toxicology
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• v.21 no.4
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• pp.220-228
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• 2018

$PM_{2.5}$-bound mercury (PBM) was monitored at weekly intervals for three years (from 2014 to 2016) at an urban (Seoul) and rural site (Baengnyeong) in South Korea. The average PBM concentrations in $PM_{2.5}$ samples over the entire sampling period were $12{\pm}11pg/m^3$ and $36{\pm}34pg/m^3$ for Baengnyeong and Seoul, respectively. Seasonal differences were pronounced, with concentrations being highest in winter due to local meteorological conditions (high gas-particle coefficient due to low temperature and low mixing layer height in winter) as well as seasonal factors, such as coal combustion for heating purposes in China. In Baengnyeong, the significant positive correlation of PBM with $PM_{2.5}$, air pollutants, and heavy metals suggested that coal combustion in China might be the most important source of ambient mercury in Korea. In winter, no correlation of PBM with $PM_{2.5}$, air pollutants, and heavy metals was seen in Seoul. Furthermore, Seoul showed higher $PBM/PM_{2.5}$ and $Pb/PM_{2.5}$ ratios in winter due to the strong atmospheric oxidation-reduction reaction conditions as well as local and regional PBM sources. We conclude that immediate attention must be given to addressing PBM levels in Korea, including considering it as a key component of future air quality monitoring activities and mitigation measures.

• Journal of Environmental Analysis, Health and Toxicology
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• v.21 no.4
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• pp.264-280
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• 2018

In this study, volatile organic compounds (VOCs) were measured using a proton transfer reaction-time of flight-mass spectrometer (PTR-ToF-MS) at the Seoul Metropolitan Area Intensive Monitoring Station (SIMS) in Korea during the summer season of 2018. The results revealed that oxygenated VOCs (OVOCs) contributed a large fraction (83.6%) of the total VOCs, with methanol being the most abundant constituent (38.6%). The VOCs measured at SIMS were strongly influenced by local conditions. Non-volatile organic compounds (NVOCs), such as pinene, increased due to northeasterly wind direction in the morning, and OVOCs and anthropogenic VOCS (AVOCs) increased with northwesterly wind direction during the daytime. This was the result of the eastward location of Bukhansan National Park and the westward location of urban area from the SIMS location. The VOCs included abundant oxidized forms of VOCs, which can affect the generation of fine dust through various response pathways in the atmosphere. The real-time measurement technique using PTR-ToF-MS suggested in this study is expected to contribute to an improved scientific understanding of high-concentration fine dust events because the high temporal resolution makes it possible to analyze the variations of VOCs reflected in dynamic events.

• Journal of Ginseng Research
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• v.45 no.3
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• pp.390-400
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• 2021

Background: We recently showed that gintonin, an active ginseng ingredient, exhibits antibrain neurodegenerative disease effects including multiple target mechanisms such as antioxidative stress and antiinflammation via the lysophosphatidic acid (LPA) receptors. Amyotrophic lateral sclerosis (ALS) is a spinal disease characterized by neurodegenerative changes in motor neurons with subsequent skeletal muscle paralysis and death. However, pathophysiological mechanisms of ALS are still elusive, and therapeutic drugs have not yet been developed. We investigate the putative alleviating effects of gintonin in ALS. Methods: The G93A-SOD1 transgenic mouse ALS model was used. Gintonin (50 or 100 mg/kg/day, p.o.) administration started from week seven. We performed histological analyses, immunoblot assays, and behavioral tests. Results: Gintonin extended mouse survival and relieved motor dysfunctions. Histological analyses of spinal cords revealed that gintonin increased the survival of motor neurons, expression of brain-derived neurotrophic factors, choline acetyltransferase, NeuN, and Nissl bodies compared with the vehicle control. Gintonin attenuated elevated spinal NAD(P) quinone oxidoreductase 1 expression and decreased oxidative stress-related ferritin, ionized calcium-binding adapter molecule 1-immunoreactive microglia, S100β-immunoreactive astrocyte, and Olig2-immunoreactive oligodendrocytes compared with the control vehicle. Interestingly, we found that the spinal LPA1 receptor level was decreased, whereas gintonin treatment restored decreased LPA1 receptor expression levels in the G93A-SOD1 transgenic mouse, thereby attenuating neurological symptoms and histological deficits. Conclusion: Gintonin-mediated symptomatic improvements of ALS might be associated with the attenuations of neuronal loss and oxidative stress via the spinal LPA1 receptor regulations. The present results suggest that the spinal LPA1 receptor is engaged in ALS, and gintonin may be useful for relieving ALS symptoms.

• Journal of Ginseng Research
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• v.45 no.3
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• pp.401-407
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• 2021

Background: Gintonin is an exogenous ginseng-derived G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. LPA induces in vitro morphological changes and migration through neuronal LPA1 receptor. Recently, we reported that systemic administration of gintonin increases blood-brain barrier (BBB) permeability via the paracellular pathway and its binding to brain neurons. However, little is known about the influences of gintonin on in vivo neuron morphology and migration in the brain. Materials and methods: We examined the effects of gintonin on in vitro migration and morphology using primary hippocampal neural precursor cells (hNPC) and in vivo effects of gintonin on adult brain neurons using real time microscopic analysis and immunohistochemical analysis to observe the morphological and locational changes induced by gintonin treatment. Results: We found that treating hNPCs with gintonin induced morphological changes with a cell rounding following cell aggregation and return to individual neurons with time relapses. However, the in vitro effects of gintonin on hNPCs were blocked by the LPA1/3 receptor antagonist, Ki16425, and Rho kinase inhibitor, Y27632. We also examined the in vivo effects of gintonin on the morphological changes and migration of neurons in adult mouse brains using anti-NeuN and -neurofilament H antibodies. We found that acute intravenous administration of gintonin induced morphological and migrational changes in brain neurons. Gintonin induced some migrations of neurons with shortened neurofilament H in the cortex. The in vivo effects of gintonin were also blocked by Ki16425. Conclusion: The present report raises the possibility that gintonin could enter the brain and exert its influences on the migration and morphology of adult mouse brain neurons and possibly explains the therapeutic effects of neurological diseases behind the gintonin administration.

• Nutrition Research and Practice
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• v.16 no.1
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• pp.60-73
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• 2022

BACKGROUND/OBJECTIVES: The extract from Dendropanax morbifera exhibited diverse therapeutic potentials. We aimed to evaluate the efficacy and safety of D. morbifera leaf extract for improving metabolic parameters in human. SUBJECTS/METHODS: A 12-week, double blind, placebo-controlled and randomized trial included a total of 74 adults, and they were assigned to the placebo group (n = 38) or 700 mg/day of D. morbifera group (n = 36). The efficacy endpoints were changes in glycemic, lipid, obesity, and blood pressure (BP) parameters, in addition to the prevalence of metabolic syndrome (MetS) and the numbers of MetS components. Safety was assessed by monitoring adverse events (AEs). RESULTS: After 12 weeks of treatment, the hemoglobin A1c (HbA1c) level significantly decreased in the D. morbifera group compared to that of the placebo group (difference: -0.13 ± 0.20% vs. 0.00 ± 0.28%, P = 0.031; % of change: -2.27 ± 3.63% vs. 0.10 ± 5.10%, P = 0.025). The homeostatic model assessment for insulin resistance level also decreased significantly from its baseline in the D. morbifera group. The systolic BP of D. morbifera group decreased significantly than that of placebo group (difference: -3.9 ± 9.8 mmHg vs. 3.3 ± 11.7 mmHg, P = 0.005; % of change: -2.8 ± 7.7% vs. 3.3 ± 10.2%, P = 0.005). However, the lipid parameters and body composition including body weight did not differ between the groups. The prevalence of MetS (36.8% vs. 13.9%, P = 0.022) and the incidence of MetS (10.5% vs. 13.9%, P = 0.027) at 12 weeks was significantly lower in the D. morbifera group than it was in the placebo group. No serious AEs occurred in either group. CONCLUSIONS: Supplementation with D. morbifera extracts over a 12-week period improved metabolic parameters such as HbA1c and BP and reduced the prevalence of MetS.

• Journal of Ginseng Research
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• v.46 no.3
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• pp.348-356
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• 2022

Background: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin exerts its neuronal and non-neuronal in vitro and in vivo effects through LPA receptor subtypes. However, it is unknown whether gintonin can bind to the plasma membrane of cells and can transactivate the epidermal growth factor (EGF) receptor. In the present study, we examined whether gintonin-biotin conjugates directly bound to LPA receptors and transactivated the EGF receptor. Methods: We designed gintonin-biotin conjugates through gintonin biotinylation and examined whether gintonin-biotin conjugate binding sites co-localized with the LPA receptor subtype binding sites. We further examined whether gintonin-biotin transactivated the EGF receptor via LPA receptor regulation via phosphor-EGF and cell migration assays. Results: Gintonin-biotin conjugates elicit [Ca²⁺]_i transient similar to that observed with unbiotinylated gintonin in cultured PC3 cells, suggesting that biotinylation does not affect physiological activity of gintonin. We proved that gintonin-biotin conjugate binding sites co-localized with the LPA1/6 receptor binding sites. Gintonin-biotin binding to the LPA1 receptor transactivates the epidermal growth factor (EGF) receptor through phosphorylation, while the LPA1/3 receptor antagonist, Ki16425, blocked phosphorylation of the EGF receptor. Additionally, an EGF receptor inhibitor AG1478 blocked gintonin-biotin conjugate-mediated cell migration. Conclusions: We observed the binding between ginseng-derived gintonin and the plasma membrane target proteins corresponding to the LPA1/6 receptor subtypes. Moreover, gintonin transactivated EGF receptors via LPA receptor regulation. Our results suggest that gintonin directly binds to the LPA receptor subtypes and transactivates the EGF receptor. It may explain the molecular basis of ginseng physiology/pharmacology in biological systems.