• Toxicological Research
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• v.31 no.4
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• pp.347-354
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• 2015

Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout ($Hfe^{-/-}$) and their control wild-type ($Hfe^{+/+}$) mice to $MnCl_2$ in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in $Hfe^{+/+}$ mice, but not in $Hfe^{-/-}$ mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed $Hfe^{+/+}$ compared with water-drinking $Hfe^{+/+}$ mice. However, Mn-exposed $Hfe^{-/-}$ mice spent more time to find the target hole than Mn-drinking $Hfe^{+/+}$ mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload disorders.

• Toxicological Research
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• v.31 no.1
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• pp.17-23
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• 2015

Excessive manganese (Mn) in the brain promotes a variety of abnormal behaviors, including memory deficits, decreased motor skills and psychotic behavior resembling Parkinson's disease. Hereditary hemochromatosis (HH) is a prevalent genetic iron overload disorder worldwide. Dysfunction in HFE gene is the major cause of HH. Our previous study has demonstrated that olfactory Mn uptake is altered by HFE deficiency, suggesting that loss of HFE function could alter manganese-associated neurotoxicity. To test this hypothesis, Hfe-knockout ($Hfe^{-/-}$) and wild-type ($Hfe^{+/+}$) mice were intranasally-instilled with manganese chloride ($MnCl_2$ 5 mg/kg) or water daily for 3 weeks and examined for memory function. Olfactory Mn diminished both short-term recognition and spatial memory in $Hfe^{+/+}$ mice, as examined by novel object recognition task and Barnes maze test, respectively. Interestingly, $Hfe^{-/-}$ mice did not show impaired recognition memory caused by Mn exposure, suggesting a potential protective effect of Hfe deficiency against Mn-induced memory deficits. Since many of the neurotoxic effects of manganese are thought to result from increased oxidative stress, we quantified activities of anti-oxidant enzymes in the prefrontal cortex (PFC). Mn instillation decreased superoxide dismutase 1 (SOD1) activity in $Hfe^{+/+}$ mice, but not in $Hfe^{-/-}$ mice. In addition, Hfe deficiency up-regulated SOD1 and glutathione peroxidase activities. These results suggest a beneficial role of Hfe deficiency in attenuating Mn-induced oxidative stress in the PFC. Furthermore, Mn exposure reduced nicotinic acetylcholine receptor levels in the PFC, indicating that blunted acetylcholine signaling could contribute to impaired memory associated with intranasal manganese. Together, our model suggests that disrupted cholinergic system in the brain is involved in airborne Mn-induced memory deficits and loss of HFE function could in part prevent memory loss via a potential up-regulation of anti-oxidant enzymes in the PFC.

• Nuclear Engineering and Technology
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• v.54 no.1
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• pp.110-116
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• 2022

Human failure event (HFE) dependency analysis is a part of human reliability analysis (HRA). For efficient HFE dependency analysis, a maximum number of minimal cut sets (MCSs) that have HFE combinations are generated from the fault trees for the probabilistic safety assessment (PSA) of nuclear power plants (NPPs). After collecting potential HFE combinations, dependency levels of subsequent HFEs on the preceding HFEs in each MCS are analyzed and assigned as conditional probabilities. Then, HFE recovery is performed to reflect these conditional probabilities in MCSs by modifying MCSs. Inappropriate HFE dependency analysis and HFE recovery might lead to an inaccurate core damage frequency (CDF). Using the above process, HFE recovery is performed on MCSs that are generated with a non-zero truncation limit, where many MCSs that have HFE combinations are truncated. As a result, the resultant CDF might be underestimated. In this paper, a new method is suggested to incorporate HFE recovery into the MCS generation stage. Compared to the current approach with a separate HFE recovery after MCS generation, this new method can (1) reduce the total time and burden for MCS generation and HFE recovery, (2) prevent the truncation of MCSs that have dependent HFEs, and (3) avoid CDF underestimation. This new method is a simple but very effective means of performing MCS generation and HFE recovery simultaneously and improving CDF accuracy. The effectiveness and strength of the new method are clearly demonstrated and discussed with fault trees and HFE combinations that have joint probabilities.

• Toxicological Research
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• v.30 no.4
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• pp.267-276
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• 2014

Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that these behavioral changes could be associated with altered dopaminergic neurotransmission, providing a therapeutic basis for psychiatric disorders caused by Pb toxicity.

• Nutrition Research and Practice
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• v.10 no.3
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• pp.265-273
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• 2016

BACKGROUND/OBJECTIVES: The inhibitory effect of Hijikia fusiforme (HF) extracts on degenerative osteoarthritis was examined in primary cultured rat cartilage cells and a monosodium iodoacetate (MIA)-induced osteoarthritis rat model. MATERIALS/METHODS: In vitro, cell survival and the expression of matrix metalloproteinases (MMPs), collagen type I, collagen type II, aggrecan, and tissue inhibitor of metalloproteinases (TIMPs) was measured after $H_2O_2$ ($800{\mu}M$, 2 hr) treatment in primary chondrocytes. In vivo animal study, osteoarthritis was induced by intra-articular injection of MIA into knee joints of rats, and then RH500, HFE250 and HFE500 were administered orally once a day for 28 days. To determine the anti-inflammatory effects of HFE, nitric oxide (NO), prostaglandin $E_2$ ($PGE_2$) expression were measured. In addition, real-time PCR was performed to measure the genetic expression of MMPs, collagen type I, collagen type II, aggrecan, and TIMPs. RESULTS: In the in vitro assay, cell survival after $H_2O_2$ treatment was increased by HFE extract (20% EtOH). In addition, anabolic factors (genetic expression of collagen type I, II, and aggrecan) were increased by HFE extract (20% EtOH). However, the genetic expression of MMP-3 and 7, known as catabolic factors were significantly inhibited by treatment with HFE extract (20% EtOH). In the in vivo assay, anabolic factors (genetic expression of collagen type I, II, aggrecan, and TIMPs) were increased by oral administration of HFE extract. However, the genetic expression of MMP-3 and 7, known as catabolic factors, and production of NO and $PGE_2$ were significantly inhibited by treatment with oral administration of HFE extract. CONCLUSION: HFE extract inhibited articular cartilage degeneration through preventing extracellular matrix degradation and chondrocyte injury.

• Clean Technology
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• v.14 no.3
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• pp.184-192
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• 2008

Fluoride-type cleaning agents such as 2,2,2-trifluoroethanol (TFEA) and hydrofluoroethers (HFEs) do not destroy ozone in the stratosphere and have low global warming potential compared to hydrofluorocarbons(HFCs) and hydrochlorofluorocarbons (HCFCs). Especially, HFEs which have no flash point are paid attention as next generation type of cleaning agents for chlorofluorocarbons (CFCs) since they are safe in handling and have excellent penetration ability compared to hydrocarbon cleaning agents with low flash point. Here, the physical properties and cleaning abilities of fluoride-type cleaning agents such as TFEA, HFE-7100, HFE-7200, HFE-476mec, HFE-449mec-f, AE-3000 and AE-3100E and silicide-type cleaning agents such as trifluoroetoxytrimethylsilane (TFES) and hexamethyldisilazane (HMDS) were measured and compared with those of ozone destruction substances such as CFC-113 and 1,1,1-trichloroethane. They were also compared with toxic methylene chloride (MC) and isopropyl alcohol (IPA) which are now being used as an alternative cleaning agents. As a result, TFEA and HFEs had lower cleaning ability for removal of various soils compared to chloride-type cleaning agents, but they showed excellent cleaning ability fur fluoride-type soils. TFES and HMDS also showed excellent cleaning ability for silicide-type soils.

• Clean Technology
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• v.16 no.3
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• pp.172-181
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• 2010

Hydrofluoroethers (HFEs) with fluoride molecules in their structure which are evaluated as the third generation replacement alternatives to chlorofluorocarbons (CFCs) are known to be excellent for removal of nanoparticles and fluoride-type soils due to their low surface tension and high wetting index. In addition, HFEs have good physical properties with no flash point and excellent drying characteristics. But, HFEs also have shortcomings in that they are not effective for removal of organic soils due to their poor solubility in soil. In this study, $C_5$ HFE-based cleaning agents were formulated through addition of solvents such as isopropyl alcohol (IPA), ethyleneglycol monoether (EG), propyleneglycol monoethylether (PM) to HFE-7100 [$CF_3CF_2CF_2CF_2OCH_3$] or HFE-mec-f [$CF_3CHF=CF_2OCH_2CF_3$] with its maximum amount, respectively, in order to have no flash point for the safety in the working environment. These solvents are known to be excellent for dissolving organics in soil. Their physical properties and cleaning abilities for fluxes, water-insoluble cutting oils, and fluoride-type oils were evaluated and compared with those of other cleaning agents with single components. The experimental results show that the HFE-based formulated cleaning agents have various good physical properties which are almost similar to those of a single type of HFE cleaner. They show excellent cleaning ability for fluxes, water-insoluble cutting oils, and fluoride-type oils. These results indicate that the HFE-based formulated cleaning agents can be applicable to various industrial cleaning fields because of their good physical properties and cleaning abilities for various soils.

• Proceedings of the Korean Nuclear Society Conference
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• 2004.10a
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• pp.599-600
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• 2004

• Proceedings of the Korean Nuclear Society Conference
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• 2005.05a
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• pp.1265-1266
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• 2005

• Journal of the Korean Chemical Society
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• v.34 no.6
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• pp.641-645
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• 1990

Ethanolic tetracarbonylhydridoferrate, HFe(CO)$_4^-$, combined with aqueous succinaldehyde is very efficient for the selective transformation of an amino group into a pyrrolidine ring. Phenylendiamines react with aqueous succinaldehyde in the presence of HFe(CO)$_4^-$, at room temperature under atmospheric pressure of carbon monoxide to give the corresponding pyrrolidines in moderate yields. In these reactions, the molar ratio of 1.0:1.0:1.0 of the ferrate-succinaldehydephenylenediamine system gave one pyrrolidine ring, and the case of 1.0:2.0:1.0 gave two pyrrolidine rings, selectively.