• Toxicological Research
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• v.28 no.4
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• pp.269-277
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• 2012

The purpose of this study was to understand the mechanism of cardiovascular disease (CVD) caused by exposure to hazardous chemicals. We investigated changes in the symptoms of metabolic syndrome, which is strongly related to CVD, and in levels of other CVD risk factors, with a special emphasis on the roles of catecholamines and oxidative stress. The results revealed that neither body mass index (BMI) nor waist and hip circumferences were associated with exposure to hazardous chemicals. Among metabolic syndrome criteria, only HDL-cholesterol level increased on exposure to hazardous chemicals. Levels of epinephrine (EP) and norepinephrine (NEP) were not influenced by exposure to hazardous chemicals; however, the total antioxidative capacity (TAC) reduced because of increased oxidative stress. Both hazardous chemical exposure level and metabolite excretion were related to EP, NEP, and the oxidative stress index (OSI). Logistic regression analysis with these factors as independent variables and metabolic syndrome criteria as dependent variables revealed that EP was associated with blood pressure, and NEP with metabolic syndrome in the chemical-exposed group. In conclusion, the results suggest that reactive oxygen species generated and oxidative stress due to exposure to hazardous chemicals act as mediators and cause changes in the physiological levels of EP and NEP to increase blood pressure. This ultimately leads to the development of CVD through increase in cholesterol, triglyceride, and blood glucose levels by lipid peroxidation.

• Biomolecules & Therapeutics
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• v.29 no.2
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• pp.127-134
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• 2021

Neuroinflammation―a common pathological feature of neurodegenerative disorders such as Alzheimer's disease―is mediated by microglial activation. Thus, inhibiting microglial activation is vital for treating various neurological disorders. 7,3',4'-Trihydroxyisoflavone (THIF)―a secondary metabolite of the soybean compound daidzein―possesses antioxidant and anticancer properties. However, the effects of 7,3',4'-THIF on microglial activation have not been explored. In this study, antineuroinflammatory effects of 7,3',4'-THIF in lipopolysaccharide (LPS)-stimulated BV2 microglial cells were examined. 7,3',4'-THIF significantly suppressed the production of the proinflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) as well as of the proinflammatory cytokine interleukin-6 (IL-6) in LPS-stimulated BV2 microglial cells. Moreover, 7,3',4'-THIF markedly inhibited reactive oxygen species (ROS) generation. Western blotting revealed that 7,3',4'-THIF diminished LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), glycogen synthase kinase-3β (GSK-3β), and nuclear factor kappa B (NF-κB). Overall, 7,3',4'-THIF exerts antineuroinflammatory effects against LPS-induced microglial activation by suppressing mitogen-activated protein kinase (MAPK) and NF-κB signaling, ultimately reducing proinflammatory responses. Therefore, these antineuroinflammatory effects of 7,3',4'-THIF suggest its potential as a therapeutic agent for neurodegenerative disorders.

• Journal of Ginseng Research
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• v.47 no.2
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• pp.311-318
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• 2023

Background: The beneficial effects of compound K (CK) on different chronic diseases have been shown to be at least related to antioxidant action. Nevertheless, since its antioxidant activity in human retinal pigment epithelial (RPE) cells is still unknown, here we investigated whether CK alleviates oxidative stress-stimulated damage in RPE ARPE-19 cells. Methods: The cytoprotective consequence of CK in hydrogen peroxide (H₂O₂)-treated cells was evaluated by cell viability, DNA damage, and apoptosis assays. Fluorescence analysis and immunoblotting were performed to investigate the inhibitory action of CK on reactive oxygen species (ROS) production and mitochondrial dysfunction. Results: H₂O₂-promoted cytotoxicity, oxidative stress, DNA damage, mitochondrial impairment, and apoptosis were significantly attenuated by CK in ARPE-19 cells. Furthermore, nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation level and its shuttling to the nucleus were increased, which was correlated with upregulated activation of heme oxygenase-1 (HO-1). However, zinc protoporphyrin, a blocker of HO-1, significantly abrogated the preventive action of CK in H₂O₂-treated ARPE-19 cells. Conclusion: This study indicates that activation of Nrf2/HO-1 signaling by CK plays an important role in rescuing ARPE-19 cells from oxidative cellular damage.

• Korean Journal of Agricultural Science
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• v.50 no.4
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• pp.941-952
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• 2023

The metabolites of agrichemicals, such as organophosphorus pesticides, are known to be more hazardous than their parent pesticides. 3,5,6-trichloro-2-pyridinol (TCP) is a major degradation product of chlorpyrifos, one of the organophosphate insecticides widely used in agriculture. In vivo or in vitro exposure to chlorpyrifos has been known to interfere with male reproductive functions, leading to reduced fertility in mammals. Therefore, this study was performed to examine the changes in the fertilization competence of boar spermatozoa exposed to TCP. Sperm samples were subjected to varying concentrations of TCP (10, 50, 100, 200 µM) and different periods of incubation. Sperm motility, motion kinematics, viability, acrosome integrity, intracellular reactive oxygen species (ROS) production, and gene expression levels (ODf2, ZPBP2, AKAP3 and AKAP4) were evaluated after exposure of the sperm to TCP. A significant dose-dependent reduction in motility was observed in sperm samples incubated with TCP compared to the controls after both incubation periods. Sperm viability was significantly decreased in samples incubated with 50, 100, and 200 µM TCP in both incubation periods. A significantly lower percentage of normal acrosomes and gene expression levels were observed in sperm samples exposed to 50, 100, and 200 µM TCP after both incubation periods, compared to the controls. There was a significant increase in the ROS production in spermatozoa incubated with 100 - 200 µM TCP after both incubation periods. Consequently, the direct exposure of boar spermatozoa to TCP interferes with sperm functions and leads to decreased fertilization. In order to identify and address the various causes of reproductive decline, the impact of chemical metabolites needs to be discussed in depth.

• Journal of Pharmacopuncture
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• v.18 no.2
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• pp.7-18
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• 2015

Objectives: Lawsone (1,4 naphthoquinone) is a non redox cycling compound that can be catalyzed by DT diaphorase (DTD) into 1,2,4-trihydroxynaphthalene (THN), which can generate reactive oxygen species by auto oxidation. The purpose of this study was to evaluate the toxicity of the phytomarker 1,4 naphthoquinone and its metabolite THN by using the molecular docking program AutoDock 4. Methods: The 3D structure of ligands such as hydrogen peroxide ($H_2O_2$), nitric oxide synthase (NOS), catalase (CAT), glutathione (GSH), glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PDH) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) were drawn using hyperchem drawing tools and minimizing the energy of all pdb files with the help of hyperchem by $MM^+$ followed by a semi-empirical (PM3) method. The docking process was studied with ligand molecules to identify suitable dockings at protein binding sites through annealing and genetic simulation algorithms. The program auto dock tools (ADT) was released as an extension suite to the python molecular viewer used to prepare proteins and ligands. Grids centered on active sites were obtained with spacings of $54{\times}55{\times}56$, and a grid spacing of 0.503 was calculated. Comparisons of Global and Local Search Methods in Drug Docking were adopted to determine parameters; a maximum number of 250,000 energy evaluations, a maximum number of generations of 27,000, and mutation and crossover rates of 0.02 and 0.8 were used. The number of docking runs was set to 10. Results: Lawsone and THN can be considered to efficiently bind with NOS, CAT, GSH, GR, G6PDH and NADPH, which has been confirmed through hydrogen bond affinity with the respective amino acids. Conclusion: Naphthoquinone derivatives of lawsone, which can be metabolized into THN by a catalyst DTD, were examined. Lawsone and THN were found to be identically potent molecules for their affinities for selected proteins.

• Journal of Bio-Environment Control
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• v.29 no.4
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• pp.464-472
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• 2020

We suggest a hydroponic cultivation system combined with a plasma generator to investigate the changes in the growth and functional substance content of lettuces during the cultivation period. Lettuce seedlings of uniform size were planted in semi-DFT after seeding for 3 weeks, and the plasma-activated water was intermittently operated for 1 hour at an 8 hours cycle for 4 weeks. Lettuces grew with or without plasma-activated water with the nutrient solution in hydroponics culture systems. Among the reactive oxygen species generated during plasma-activated water treatment, brown spots and necrosis appeared in the individuals closer to the plasma generating device due to O₃, and there was no significant difference in the growth parameters. While the rutin and total phenolic content of the lettuce shoot grown in the nutrient solution were higher than that of the plasma-activated water, epicatechin contents in plasma-activated water were significantly greater than the nutrient solution. However, in the roots, all kinds of secondary metabolites measured in this work, rutin, epicatechin, quercetin, and total phenolic contents, were significantly higher in the plasma-activated water than the control. These results were indicated that the growth of lettuce was decreased due to the reactive oxygen species such as ozone in the plasma-activated water, but the secondary metabolites in the root zone increased significantly. It has needed to use this technology for the cultivation of root vegetables with the modified plasma-activated water systems to increase secondary metabolite in the roots.

• Journal of the Korean Society of Food Science and Nutrition
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• v.45 no.8
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• pp.1208-1213
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• 2016

Advanced glycation end product (AGE) formation and reactive oxygen species are potential therapeutic targets for the prevention of diabetic nephropathy and other pathogenic complications. Activity-guided isolation of an ethylacetate-soluble portion of 80% methanolic extract from fruits of Sorbus commixta of the Ulleung Island origin using AGE formation inhibition assay led to the isolation and identification of three caffeoylquinic acid derivatives of a previously known structure, 3-O-caffeoylquinic acid (neochlorogenic acid; 1), 4-O-caffeoylquinic acid (cryptochlorogenic acid; 2), and 5-O-caffeoylquinic acid (chlorogenic acid; 3). The structures of these compounds were confirmed by interpretation of nuclear magnetic resonance and mass spectrometry data. Among the isolates, the major metabolite, neochlorogenic acid (1) showed the most potent inhibitory effect against AGE formation with an $IC_{50}$ value of $167.5{\pm}3.5{\mu}M$. Furthermore, all isolated chlorogenic acid isomers were evaluated for their radical scavenging activity against peroxynitrite, and structurally related isomers 1, 2, and 3 exhibited potent inhibitory effects in this radical scavenging assay. This result suggests that the monocaffeoyl quinic acid derivatives isolated from S. commixta might be beneficial for the regulation of diabetic complications and related diseases.

• Journal of Life Science
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• v.29 no.2
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• pp.191-197
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• 2019

Parkinson's disease (PD) is a progressive neurodegenerative disease that mainly affects motor system with clinical features such as bradykinesia, rigidity, tremor and abnormal posture. PD is characterized by the death of dopaminergic neurons in the substantia nigra pars compacta, which is associated with accumulation of oxidative stress and dysregulation of intracellular signaling pathway. Quercetin-3-O-glucuronide (Q3GA), a major metabolite of quercetin, has been reported to have neuroprotective effects. In this study, we examined the neuroprotective effect of Q3GA against 1-methyl-4-phenyl pyridinium ($MPP^+$)-induced neurotoxicity of PD and the underlying molecular mechanisms in SH-SY5Y cells. MTT and LDH assay showed that Q3GA significantly decreased $MPP^+$-induced cell death, which is accompanied by a reduction in poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, it attenuated $MPP^+$-induced intracellular reactive oxygen species (ROS) with the reduction of Bax/ Bcl-2 ratio. Moreover, Q3GA significantly increased the phosphorylation of Akt and cAMP response element binding protein (CREB), but it has no effects on the phosphorylation of extracellular signal-regulated kinase (ERK). Taken together, these results demonstrate that Q3GA significantly attenuates $MPP^+$-induced neurotoxicity through ROS reduction and Akt/CREB signaling pathway in SH-SY5Y cells. Our findings suggest that Q3GA might be one of the potential candidates for the prevention and/or treatment of PD.

• Tuberculosis and Respiratory Diseases
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• v.41 no.3
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• pp.222-230
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• 1994

Background: Paraquat, a widely used herbicide, is extremely toxic, causing multiple organ failure in humans. Paraquat especially leads to irreversible progressive pulmonary fibrosis, which is related to oxygen free radicals. However, its biochemical mechanism is not clear. Natural mechanisms that prevent damage from oxygen free radicals include changes in glutathione level, G6PDH, superoxide dismutase(SOD), catalase, and glutathione peroxidase. The authors think catalase is closely related to paraquat toxicity in the lungs Method: The effects of 3-amino-1,2,4-triazole(aminotriazole), a catalase inhibitor, on mice administered with paraquat were investigated. We studied the effects of aminotriazole on the survival of mice administered with paraquat, by comparing life spans between the group to which paraquat had been administered and the group to which a combination of paraquat and aminotriazole had been administered. We measured glutathion level, glucose 6-phosphate dehydrogenase(G6PDH), superoxide dismutase(SOD), catalase, and glutathione peroxidase(GPx) in the lung tissue of 4 groups of mice: the control group, group A(aminotriazole injected), group B(paraquat administered), group C(paraquat and aminotriazole administered). Results: The mortality of mice administered with paraquat which were treated with aminotriazole was significantly increased compared with those of mice not treated with aminotriazole. Glutathione level in group B was decreased by 20%, a significant decrease compared with the control group. However, this level was not changed by the administration of aminotriazole(group C). The activity of G6PDH in all groups was not significantly changed compared with the control group. The activities of SOD, catalase, and glutathione peroxidase(GPx) in the lung tissue were significantly decreased by paraquat administration(group B); catalase showed the largest decrease. Catalase and GPX were significantly decreased by aminotriazole treatment in mice administered with paraquat but change in SOD activity was not significant(group C). Conclusion: Decrease in catalase activity by paraquat suggests that paraquat toxicity in the lungs is closely related to catalase activity. Paraquat toxicity in mice is enhanced by aminotriazole administration, and its result is related to the decrease of catalase activity rather than glutathione level in the lungs. Production of hydroxyl radicals, the most reactive oxygen metabolite, is accelerated due to increased hydrogen peroxide by catalase inhibition and the lung damage probably results from nonspecific tissue injury of hydroxyl radicals.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2007.11a
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• pp.79-92
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• 2007

Oxidative stress have known to be a risk factor for the degenerative processes and closely related to a lot of diseases. It is well established that antioxidants are good in protection and therapeutic means against oxidative damage. There is increasing interest in natural antioxidants and many natural antioxidants have been found and utilized as the possible protection for various diseases and skin aging. We have screened natural antioxidant agents for cosmeceuticals, nutraceuticals, and drugs as therapeutic and preventive means against oxidative stress, and have developed a number of novel antioxidants from various natural sources. A novel melanin synthesis inhibitor, Melanocin A, isolated from the metabolite of a fungal strain Eupenicillium shearii F80695 inhibited mushroom tyrosinase and melanin biosynthesis of B16 melanoma cells with $IC_{50}$ value of 9.0 nM and MIC value of $0.9\;{\mu}M$, respectively. Melanocin A also exhibited potent antioxidant activity by scavenging of DPPH and superoxide anion radicals. UV was found to increase the level of hydrogen peroxides and other reactive oxygen species (ROS) in skin tissues. This increase in ROS may not only alter the structure and function of many genes and proteins directly but may also modulate their expressions through signal transduction pathways and, ultimately, lead to skin damage. We investigated the effect of Melanocin A on UV-induced premature skin aging. Firstly, the effect of Melanocin A on UV-induced matrix metalloproteinase (MMP)-9 expression in an immortalized human keratinocyte cell line, HaCaT in vitro was investigated. Acute UV irradiation induced MMP-9 expression at both the mRNA and protein levels and Melanocin A suppressed this expression in a dose-dependent manner. We then investigated UV-induced skin changes in hairless mice in vivo by Melanocin A. Chronic exposure of hairless mouse dorsal skin to UV increased skin thickness and induced wrinkle formation and the gelatinase activities of MMP-2 and MMP-9. Moreover, Melanocin A significantly suppressed UV-induced morphologic skin changes and MMP-2 and MMP-9 expression. These results show that Melanocin A can prevent the harmful effects of UV that lead to skin aging. Therefore, we suggest that Melanocin A should be viewed as a potential therapeutic agent for preventing and/or treating premature skin aging. Terrein is a bioactive fungal metabolite isolated from Penicillium species. Terrein has a relatively simple structure and can be easily synthesized. However, the biologic effects of terrein are comparatively unknown. We found for the first time that terrein potently inhibit melanin production in melanocytes and has a strong hypopigmentary effect in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Treatment of Mel-Ab cells with terrein (10-100 mM) for 4 days significantly reduced melanin levels in a dose-dependent manner. In addition, terrein at the same concentration also reduced tyrosinase activity. We then investigated whether terrein influences the extracellular signal-regulated protein kinase (ERK) pathway and the expression of microphthalmia-associated transcription factor (MITF), which is required for tyrosinase expression. Terrein was found to induce sustained ERK activation and MITF down-regulation, and luciferase assays showed that terrein inhibits MITF promoter activity in a dose-dependent manner. To elucidate the correlation between ERK pathway activation and a decreased MITF transcriptional level, PD98059, a specific inhibitor of the ERK pathway, was applied before terrain treatment and found to abrogate the terrein-induced MITF attenuation. Terrein also reduced the tyrosinase protein level for at least 72 h. These results suggest that terrain reduces melanin synthesis by reducing tyrosinase production via ERK activation, and that this is followed by MITF down-regulation.