• 한국독성학회:학술대회논문집
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• 한국독성학회 2006년도 추계학술대회
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• pp.55-64
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• 2006

The fetal central nervous system (CNS) is sensitive to diverse environmental factors, such as alcohol, heavy metals, irradiation, mycotoxins, neurotransmitters, and DNA damage, because a large number of processes occur during an extended period of development. Fetal neural damage is an important issue affecting the completion of normal CNS development. As many concepts about the brain development have been recently revealed, it is necessary to compare the mechanism of developmental abnormalities induced by extrinsic factors with the normal brain development. To clarify the mechanism of fetal CNS damage, we used one experimental model in which 5-azacytidine (5AZC), a DNA damaging and demethylating agent, was injected to the dams of rodents to damage the fetal brain. 5AzC induced cell death (apoptosis)and cell cycle arrest in the fetal brain, and it lead to microencephaly in the neonatal brain. We investigated the mechanism of apoptosis and cell cycle arrest in the neural progenitor cells in detail, and demonstrated that various cell cycle regulators were changed in response to DNA damage. p53, the guardian of genome, played a main role in these processes. Further, using DNA microarray analysis, tile signal cascades of cell cycle regulation were clearly shown. Our results indicate that neural progenitor cells have the potential to repair the DNA damages via cell cyclearrest and to exclude highly affected cells through the apoptotic process. If the stimulus and subsequent DNA damage are high, brain development proceeds abnormally and results in malformation in the neonatal brain. Although the mechanisms of fetal brain injury and features of brain malformation afterbirth have been well studied, the process between those stages is largely unknown. We hypothesized that the fetal CNS has the ability to repair itself post-injuring, and investigated the repair process after 5AZC-induced damage. Wefound that the damages were repaired by 60 h after the treatment and developmental processes continued. During the repair process, amoeboid microglial cells infiltrated in the brain tissue, some of which ingested apoptotic cells. The expressions of genes categorized to glial cells, inflammation, extracellular matrix, glycolysis, and neurogenesis were upregulated in the DNA microarray analysis. We show here that the developing brain has a capacity to repair the damage induced by the extrinsic stresses, including changing the expression of numerous genes and the induction of microglia to aid the repair process.

• 대한한의학회지
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• 제21권1호
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• pp.91-98
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• 2000

The water extract of Seongpungtang(SPT) has commonly been used for treatment of ischemic brain damage in Oriental traditional medicine. However, little is known about the mechanism by which the water extract of SPT rescues brain cells from ischemic damage. To elucidate the protective mechanism of ischemic induced cytotoxicity, the regulation of Lipopolysaccharide (LPS) and PMA (phobol-12-myristate-13-acetate) induced iNOS expression in microglial cells was investigated. LPS and PMA treatment for 48 hr in microglial cells markedly induced nitric oxide (NO), but treatment of the cells with the water extract of SPT decreased nitrite formation. In addition, LPS and PMA treatment for 48 hr induced severe cell death in microglial cells. However treatment of the cells with the water extract of SPT did not induce significant changes compared to the control cells. Furthermore, NO production was markedly decreased by treatment of nuclear factor kappa B(NF-kB) inhibitor, pyrrolidine dithiocarbamate(PDTC). According to the above results, it is suggested that the protective effects of the water extract of SPT against ischemic brain damage may be mediated by regulation of iNOS during ischemic condition.

• The Korean Journal of Physiology and Pharmacology
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• 제12권2호
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• pp.65-71
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• 2008

The present study examined the inhibitory effect of licorice compounds glycyrrhizin and a metabolite $18{\beta}$-glycyrrhetinic acid on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse and on the 1-methyl-4-phenylpyridinium ($MPP^+$)-induced cell death in differentiated PC12 cells. MPTP treatment increased the activities of total superoxide dismutase, catalase and glutathione peroxidase and the levels of malondialdehyde and carbonyls in the brain compared to control mouse brain. Co-administration of glycyrrhizin (16.8 mg/kg) attenuated the MPTP effect on the enzyme activities and formation of tissue peroxidation products. In vitro assay, licorice compounds attenuated the $MPP^+$-induced cell death and caspase-3 activation in PC12 cells. Glycyrrhizin up to $100{\mu}M$ significantly attenuated the toxicity of $MPP^+$. Meanwhile, $18{\beta}$-glycyrrhetinic acid showed a maximum inhibitory effect at $10{\mu}M$; beyond this concentration the inhibitory effect declined. Glycyrrhizin and $18{\beta}$-glycyrrhetinic acid attenuated the hydrogen peroxide- or nitrogen species-induced cell death. Results from this study indicate that glycyrrhizin may attenuate brain tissue damage in mice treated with MPTP through inhibitory effect on oxidative tissue damage. Glycyrrhizin and $18{\beta}$-glycyrrhetinic acid may reduce the $MPP^+$ toxicity in PC12 cells by suppressing caspase-3 activation. The effect seems to be ascribed to the antioxidant effect.

• 대한한의학회지
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• 제22권3호
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• pp.1-10
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• 2001

Objectives : The water extract of Nueihyuljunbang (NHJB) has long been used for treatment of ischemic brain damage in Oriental Medicine. However, little is known about the mechanism by which the water extract of NHJB recovers brain cens from ischemic damage. Methods : To elucidate the protective mechanism on ischemic induced cytotoxicity, we investigated the regulation of lipopolysaccharide (LPS) and phorbol-12-myristate-13-acetate (PMA)-induced inducible nitric oxide synthase (iNOS) expression in C6 glial cells. Results : LPS combined PMA treatment for 72 hours in C6 glial cells markedly induced nitric oxide (NO), but treatment of the cells with the water extract of NHJB decreased dose-dependently nitrite formation. In addition, LPS combined PMA treatment for 72 hours induced severe celt death and lactate dehydrogenase (LDH) release in C6 glial cells. However, treatment of the celts with the water extract of NHJB did not induce significant change compared to control cells. Furthermore, the protective effects of the water extract of NHJB were mimicked by the treatment of NGMMA, a specific inhibitor of NOS. LPS combined PMA induced iNOS activation in C6 glial cells caused chromosomal condensation and fragmentation of the nuclei by caspase activation. The treatment of C6 glial cells with the water extract of NHJB might suppress apoptosis via caspase inhibition by regulation of iNOS expression. Conclusions : From the results, we suggest that the protective effects of the water extract of NHJB against ischemic brain damage may be mediated by regulation of iNOS during ischemic condition.

• 대한한의학회지
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• 제21권4호
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• pp.84-92
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• 2000

Objectives : The water extract of Sebsaeng-eum(SheShengYin) has been used for treatment of ischemic brain damage in oriental medicine, However, little is known about the mechanism by which the water extract of Sebsaeng-eum(SheShengYin) rescues brain cells from ischemic damages. Methods : To elucidate the protective mechanism on ischemic induced cytotoxicity, We investigated the regulation of LPS and PMA induced iNOS expression in $C_{6}$ glial cells. Results : LPS and PMA treatment for 48 h in $C_{6}$ glial cells markedly induced NO, but treatment of the cells with the water extract of Sebsaeng-eum(SheShengYin) decreased nitrite formation. In addition, LPS and PMA treatment for 48 h induced severe cell death in $C_{6}$ glial cells. However treatment of the cells with the water extract of Sebsaeng-eum(SheSheng Yin) did not induce significant changes compared to the control. LPS and PMA induced iNOS activation in $C_{6}$ glial cells caused chromosomal condensation and fragmentation of nuclei. Conclusions : Taken together, We suggest that the protective effects of the water extract of Sebsaeng-eum(SheShengYin) against ischemic brain damages may be mediated by regulation of iNOS during ischemic condition.

• Journal of Ginseng Research
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• 제44권1호
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• pp.79-85
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• 2020

Background: Helicobacter pylori increases reactive oxygen species (ROS) and induces oxidative DNA damage and apoptosis in gastric epithelial cells. DNA damage activates DNA damage response (DDR) which includes ataxia-telangiectasia-mutated (ATM) activation. ATM increases alternative reading frame (ARF) but decreases mouse double minute 2 (Mdm2). Because p53 interacts with Mdm2, H. pylori-induced loss of Mdm2 stabilizes p53 and induces apoptosis. Previous study showed that Korean Red Ginseng extract (KRG) reduces ROS and prevents cell death in H. pylori-infected gastric epithelial cells. Methods: We determined whether KRG inhibits apoptosis by suppressing DDRs and apoptotic indices in H. pylori-infected gastric epithelial AGS cells. The infected cells were treated with or without KRG or an ATM kinase inhibitor KU-55933. ROS levels, apoptotic indices (cell death, DNA fragmentation, Bax/Bcl-2 ratio, caspase-3 activity) and DDRs (activation and levels of ATM, checkpoint kinase 2, Mdm2, ARF, and p53) were determined. Results: H. pylori induced apoptosis by increasing apoptotic indices and ROS levels. H. pylori activated DDRs (increased p-ATM, p-checkpoint kinase 2, ARF, p-p53, and p53, but decreased Mdm2) in gastric epithelial cells. KRG reduced ROS and inhibited increase in apoptotic indices and DDRs in H. pylori-infected gastric epithelial cells. KU-55933 suppressed DDRs and apoptosis in H. pylori-infected gastric epithelial cells, similar to KRG. Conclusion: KRG suppressed ATM-mediated DDRs and apoptosis by reducing ROS in H. pylori-infected gastric epithelial cells. Supplementation with KRG may prevent the oxidative stress-mediated gastric impairment associated with H. pylori infection.

• 대한임상검사과학회지
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• 제52권4호
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• pp.389-397
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• 2020

Microglial cells function as major immune cells in the brain, playing an important role in the protection and damage of neurons. BV2 microglia, activated by drug stimulation, secrete inflammatory cytokines by activating the nuclear factor kappa-light-chain-enhancer of the activated B cells pathway and are involved in neuroinflammatory and immune responses. The overactivation of microglia by stimuli can cause neuronal damage, leading to brain disease. Noni, a natural product, reduces the activity of microglia to prevent neuronal damage and is a potential natural medicine because it exerts excellent regeneration and anti-inflammatory effects on damaged cells. In this study, when noni was used to treat BV2 cells stimulated by the anti-cancer drug doxorubicin, it reduced the release of pro-inflammatory cytokines from BV2. On the other hand, neuronal damage is a side effect of doxorubicin. Therefore, the cytokines released from doxorubicin-stimulated BV2 cells treated with noni had a positive effect on the neuronal viability compared to those released from doxorubicin-stimulated BV2 cells not treated with Noni. Thus, Noni increases neuronal viability. These results suggest that noni inhibits the release of cytokines by regulating the nuclear factor kappa-light-chain-enhancer of the activated B cells pathway of BV2, thereby inhibiting neuronal damage.

• 한국수의병리학회지
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• 제3권2호
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• pp.73-76
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• 1999

The tissue distribution and cellular localization of viral antigen in the brain of aborted fetus with bovine viral diarrhea virus(BVDV) infection was studied; BVDV antigens was detected in spleen, kidney, lung, eyelid as well as brain. In the brain, the virus was recognized in neurons and non-neuronal cells in the cerebellum and cerebrum. Many cells in the superficial layer and occasional Purkinje cells had BVDV antigens. As well, BVDV was also found in the perivascular cells, vascular endothelial cells and smooth muscle cells in the vessels and neuroglial cells in the white matter. This finding suggests that BVD virus favors infect progenitor cells in the brain, notably in the superficial layer of cerebellum, and damage normal development of cerebellum, which leads to cerebellar hypoplasia.

• 혜화의학회지
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• 제8권1호
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• pp.425-449
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• 1999

For the evaluation of the effect on SWS, experiments were made on hyperlipidemia induced by hypercholesterol diet, inhibitory reaction to human platelet aggregation, Pulmonary thrombosis induced by collagen and epinephrine, global cerebral ischemia induced by KCN, brain ischemia induced by MCA occlusion, cytotoxicity of PC12 cells induced by amyloid ${\beta}$ protein(25-35), and NO production in RAW cells stimulated by lipopolysaccharide. The results were obtained as follows : 1. In the experiment on hyperlipidemia, the level of serum total cholesterol, phospholipid, and LDL-cholesterol were significantly decreased while the level of triglyceride, VLDL-cholesterol, and HDL-cholesterol had no significant change. 2. In the experiment on inhibitory reaction to platelet aggregation, SWS inhibited platelet aggregation induced by ADP(36.05%), by collagen(20.4%), and by thrombin(0.6%). 3. In the experiment on pulmonary thrombosis induced by collagen and epinephrine, the protective effect was found(37%). 4. In the experiment on global cerebral ischemia, coma duration induced by KCN changed insignificantly. 5. In the experiment on MCA occlusion, the change of neurologic grades on hind limb was significant only after the operation. Besides brain ischemic area and edema ratio were significantly decreased. 6. In the experiment on cytotoxicity of PC 12 cells induced by amyloid ${\beta}$ protein, the significant protective effect was found as concentration increases. 7. In the experiment on NO production in RAW cells stimulated by lipopolysaccharide, NO was significantly decreased. According to the results, it is expected that SWS might be effective on hyperlipidemia and brain damage.

• Clinical and Experimental Pediatrics
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• 제56권7호
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• pp.271-274
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• 2013

Brain insults, including neurotrauma, infection, and perinatal injuries such as hypoxic ischemic encephalopathy, generate inflammation in the brain. These inflammatory cascades induce a wide spectrum of cytokines, which can cause neuron degeneration, have neurotoxic effects on brain tissue, and lead to the development of seizures, even if they are subclinical and occur at birth. Cytokines are secreted by the glial cells of the central nervous system and they function as immune system mediators. Cytokines can be proinflammatory or anti-inflammatory. Interleukin (IL)-$1{\beta}$ and IL-8 are proinflammatory cytokines that activate additional cytokine cascades and increase seizure susceptibility and organ damage, whereas IL-1 receptor antagonist and IL-10 act as anti-inflammatory cytokines that have protective and anticonvulsant effects. Therefore, the immune system and its associated inflammatory reactions appear to play an important role in brain damage. Whether cytokine release is relevant for the processes of epileptogenesis and antiepileptogenesis, and whether epileptogenesis could be prevented by immunomodulatory treatment should be addressed in future clinical studies. Furthermore, early detection of brain damage and early intervention are essential for the prevention of disease progression and further neurological complications. Therefore, cytokines might be useful as biomarkers for earlier detection of brain damage in high-risk infants.