• BMB Reports
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• 제49권11호
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• pp.617-622
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• 2016

Oxidative stress is closely associated with various diseases and is considered to be a major factor in ischemia. NAD(P)H: quinone oxidoreductase 1 (NQO1) protein is a known antioxidant protein that plays a protective role in various cells against oxidative stress. We therefore investigated the effects of cell permeable Tat-NQO1 protein on hippocampal HT-22 cells, and in an animal ischemia model. The Tat-NQO1 protein transduced into HT-22 cells, and significantly inhibited against hydrogen peroxide ($H_2O_2$)-induced cell death and cellular toxicities. Tat-NQO1 protein inhibited the Akt and mitogen activated protein kinases (MAPK) activation as well as caspase-3 expression levels, in $H_2O_2$ exposed HT-22 cells. Moreover, Tat-NQO1 protein transduced into the CA1 region of the hippocampus of the animal brain and drastically protected against ischemic injury. Our results indicate that Tat-NQO1 protein exerts protection against neuronal cell death induced by oxidative stress, suggesting that Tat-NQO1 protein may potentially provide a therapeutic agent for neuronal diseases.

• 동의생리병리학회지
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• 제22권4호
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• pp.835-840
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• 2008

Acupuncture has long been contended to be effective in an ischemic stroke. A real-time monitoring of glutamate, an excitotoxin in the process of ischemic neuronal damage, in the striatum is tried in a rat model of global ischemia. Global ischemia was induced by the 11 vessel occlusion method for 10 minutes, during which acupuncture stimulation on GB34 and GB39 points was executed. Glutamate release in the rat striatum was monitored 256 times per second using real-time amperometric biosensor. Real time measurement data of 10 minutes prior to the induction of ischemia served as baseline data. Data acquisition continued for 30 minutes after the initiation of reperfusion. Peak concentration of glutamate release along with incidentally measured EEG and cerebral blood flow was compared between cases with and without acupuncture stimulation. Peak concentration of glutamate lowered when acupuncture stimulation was executed. A real time monitoring system of 11 vessel-occlusion induced global ischemia model was successfully established. The effect by acupuncture on acute global ischemia was successfully observed in this real-time monitoring setting, which may be one of the neuroprotective mechanism of acupuncture.

• 대한한방내과학회지
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• 제31권4호
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• pp.763-774
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• 2010

Objectives : In condition of brain infarction, irreversible axon damage occurs in central nerve system(CNS), because gliosis becomes physical and mechanical barrier to axonal regeneration. Reactive gliosis induced by ischemic injury such as middle cerebral artery occlusion is involved with up-regulation of GFAP and CD81. The current study is to examine the effect of the Uncariae Ramulus et Uncus on CD81 and GFAP expression in the rat brain following middle cerebral artery occlusion. Methods : In order to study ischemic injuries on brain, infarction was induced by middle cerebral artery occlusion(MCAO) using insertion of a single nylon thread, through the internal carotid artery, into a middle cerebral artery. Cresyl violet staining, cerebral infarction size measurement, immunohistochemistry and microscopic examination were used to detect the expression of CD81 and GFAP and the effect on the infarct size and pyramidal cell death in the brain of the rat with cerebral infarction induced by MCAO. Results : The following results were obtained 1. Measuring the size of cerebral infartion induced by MCAO in the rat after injection of Uncariae Ramulus et Uncus showed the size was decreased. 2. Intravenous injection of Uncariae Ramulus et Uncus showed pyramidal cell death protection in the hippocampus in the MCAO rat. 3. Water extract injection of Uncariae Ramulus et Uncus decreased GFAP expression significantly in the MCAO rat. 4. Uncariae Ramulus et Uncus water extract decreased CD81 expression in the MCAO rat. 5. The administration of water extract of Uncariae Ramulus et Uncus induced up-regulation of c-Fos expression significantly compared with MCAO. 6. The admistration of water extract of Uncariae Ramulus et Uncus increased ERK expression significantly compared with MCAO. Conclusion : We observed that Uncariae Ramulus et Uncus could suppress the reactive gliosis, which disturbs the axonal regeneration in the brain of the rat with cerebral infaction after MCAO by controlling the expression of CD81 and GFAP. The effect may be modulated by the up-regulation of c-Fos and ERK. These results suggest that Uncariae Ramulus et Uncus can be a candidate to regenerate CNS injury.

• Clinical and Experimental Pediatrics
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• 제52권1호
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• pp.105-110
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• 2009

목적 : 신생 백서의 저산소 허혈 뇌손상에 있어서의 erythropietin (Epo) 투여의 손상 예방 효과와 보호 기전에 철 대사가 관여하는지를 조사하고자 하였다. 방 법 : 신생 백서를 암수 구별 없이 생후 7일째에 편측 온목동맥 결찰 후 산소 농도 8%인 환경에 2시간 노출시켜 저산소 허혈을 유도하였으며 저산소 노출 직후 Epo 5,000 u/kg를 복강내 투여하였다. 이들은 저산소 허혈 유도 전 투여한 생리식염수, 철, deferoxamine 등에 따라 Epo군, Iron+Epo군, Def+Epo군, Iron+ Def+Epo군, 대조군으로 나누어 저산소 허혈 유도 후 7일에 뇌손상 정도를 비교하였다. 결 과 : Epo 투여시 뇌손상의 빈도와 정도는 대조군에 비해 감소하였다. 뇌손상의 빈도와 손상 점수로 뇌손상 정도를 비교한 결과 철 투여는 Epo의 뇌손상 예방 효과를 감소시키지 않았다. Deferoxamine 투여는 Epo 단독 투여군에 비해 뇌손상의 빈도와 정도가 경감하였으나 통계적 유의성은 없었다. 결 론 : Epo는 저산소 허혈 뇌손상에 있어 뇌손상 보호 효과를 보인다. 철 투여는 뇌손상을 악화시키지 않았으나 deferoxamine 동시 투여는 Epo 단독 투여에 비해 뇌손상의 빈도와 손상 점수가 감소하여 뇌손상 보호 효과에 철 대사가 관여할 가능성을 제시하였다.

• BMB Reports
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• 제49권7호
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• pp.382-387
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• 2016

Reactive oxygen species generated under oxidative stress are involved in neuronal diseases, including ischemia. Glutathione S-transferase pi (GSTpi) is a member of the GST family and is known to play important roles in cell survival. We investigated the effect of GSTpi against oxidative stress-induced hippocampal HT-22 cell death, and its effects in an animal model of ischemic injury, using a cell-permeable PEP-1-GSTpi protein. PEP-1-GSTpi was transduced into HT-22 cells and significantly protected against H2O2-treated cell death by reducing the intracellular toxicity and regulating the signal pathways, including MAPK, Akt, Bax, and Bcl-2. PEP-1-GSTpi transduced into the hippocampus in animal brains, and markedly protected against neuronal cell death in an ischemic injury animal model. These results indicate that PEP-1-GSTpi acts as a regulator or an antioxidant to protect against oxidative stress-induced cell death. Our study suggests that PEP-1-GSTpi may have potential as a therapeutic agent for the treatment of ischemia and a variety of oxidative stress-related neuronal diseases.

• Biomolecules & Therapeutics
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• 제9권3호
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• pp.167-175
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• 2001

Recent studies have shown that cytokines are capable of modulating cardiovascular function and that some drugs used in the treatment of heart failure variably modulate the production of cytokines. Hige- namine, a positive inotropic isoquinoline alkaloid, has been used traditionally as cardiac stimulant, and reported to reduce nitric oxide (NO) and inducible nitric oxide synthase (iNOS) expression in LPS- and/or cytokine-activated cells in vitro and in vivo. Therefore, we investigated whether higenamine modulates the production of proinflammatory cytokines in myocardial infarction. In addition, effects of higenamine on antioxidant action and antioxidant enzyme expression (MnSOD) were studied. Myocardial infarction (MI) was confirmed by measuring left ventricular (LV) pressure after occlusion of the left anterior descending coronary artery (LAD) for 5 weeks in rats. Treatment of higenamine (10 mg/kg/day) reduced infarct size about 35 %, which accompanied by reduction of production TNF-$\alpha$, IL-6, but not IFN-${\gamma}$ and IL-1$\beta$ in the myocardium. The expression of TNF-$\alpha$ mRNA in infracted myocardium was significantly reduced by higenamine. Although iNOS mRNA was not detected, nitrotyrosine staining was significantly increased in myocardium of Ml compared to higenamine-treated one, Indicating that peroxynitrite-induced damage is evident in MI. Cytochrome c oxidation by peroxynitrite was concentration-dependently reduced by higenamine, an effect which was almost compatible to glutathion. Higenamine treatment did not affect the expression of MnSOD mRNA in myocardial tissues in MI. Taken together, higenamine may be beneficial in oxidative stress conditions such as ischemic-reperfusion injury and MI due to antioxidant action as well as modulation of cytokines.

• Journal of Chest Surgery
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• 제25권1호
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• pp.1-16
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• 1992

The quantitatively measured local myocardial perfusion rates with microspheres are used as an objective indicator of even distribution of cardioplegic solution, and the efficacy of the retrograde right atrial route of cardioplegia is evaluated in hearts with various levels of coronary arterial obstruction. After initial antegrade cardioplegia under the median sternotomy and aortic cannulation, 60 hearts from anesthetized New Zealand white rabbits are divided in random order as normal group [ligated left main coronary artery ; MA, MR] and diagonal group [ligated proximal diagonal artery ; LA, LR]. Half of each group [N=10] are perfused with antegrade cardioplegia[A] under the pressure of 100 cmH2O and the other half with retrograde right atrial route[R] under the pressure of 60 cmH2O[St. Thomas cardioplegic solution mixed with measured amount of microspheres]. The myocardium is subdivided into segments as A[atria], RV[right ventricle]. S[septum], LV[normally perfused left ventricular free wall], ROI[ischemic myocardium of left ventricular free wall]. LV and RQI are further divided into N[subendocardium] and P[subepicardium]. The resulting local myocardial perfusion rates and N /P of each group are compared with Wilcoxon rank sum test. The weight of the hearts is 5.94$\pm$0.66g, and there are no statistically significant dif-ferences[p>0.05, ANOVA] between six compared group. The mean flow rate[F: ml /g / min] of MR group is comparable with MA group[p>0.05], but in N and L group, there are significantly depressed F with right atrial route of cardioplegia, which means elevated perfusion resistance with this route. In spite of no significant differences in delivered doses of microsphere[DEL] between compared groups[p>0.05, ANOVA], there are significantly depressed REC and NF in hearts with right atrial cardioplegia which suggests increased requirement of cardioplegic solution with this route. The interventricular septum shows poor perfusion with right atrial route of cardioplegia without obstruction of supplying coronary arteries. But, with obstruction of coronary artery supplying septum as in M group, the flow rate is superior with right atrial route of infusion. The left ventricular free wall perfusion rates of every RQI with R route are superior to that of A route[p<0.05]. But, in LV segments, there are unfavorable effects of right atrial cardioplegia in L group, although the subendocardial perfusion is well maintained in N group. The LV free wall of left main group shows depressed perfusion rates with antegrade route as compared with RQI segments of diagonal group. But, by contraries, there are increased perfusion rates and superior N /P ratio with retrograde right atrial route. It implies more effective perfusion with right atrial route of cardioplegia in more proximal coronary arterial obstruction[i.e., M group as compared with L group]. As a conclusion, all region of ischemia have superior perfusion rates with right atrial car-dioplegia as compared with antegrade route, and especially excellent results can be obtained in hearts with more proximal obstruction of coronary arteries which would otherwise result in more severe ischemic damage. But, the depressed perfusion rates of the segments with normal coronary artery in hearts with coronary arterial obstruction may be a problem of concern with right atrial cardioplegia and needs solution.

• 생명과학회지
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• 제30권7호
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• pp.651-659
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• 2020

허혈성 심혈관질환은 전 세계적으로 치사율이 높은 질병 중 하나이다. 이를 치료하기 위해 수술적 방법이 시행되고 있으나, 손상된 심근조직 회복의 어려움과 수술 후 부작용의 한계가 남아있다. 이러한 한계점을 극복하기 위해, 최근 줄기세포를 기반으로 한 심혈관질환의 세포치료제가 각광받고 있는데 그 중에서도 특히 혈관내피전구세포(EPC)는 높은 증식능과 분화능을 기반으로 손상된 혈관을 재생하고, 주변 조직의 재생을 돕는다는 장점이 있다. 또, EPC는 임상적으로 안전하며, 환자의 심근 기능을 회복시켜주기에 잠재적인 심혈관질환 치료제로서의 가능성이 대두되었다. 하지만, 환자 유래 EPC를 이용한 치료법은, 고령, 흡연 여부, 기저질환 등의 이유로 환자의 EPC 기능이 저하되어 있어, 그 치료 효능을 기대하기 어렵다. 따라서, 최근에는 세포 프라이밍 기법, 오가노이드 배양법과 같이 EPC의 생리학적 활성도를 올리는 체외 배양법의 개발과 3D 바이오프린팅 기법을 이용한 EPC의 이식 효율을 높여 치료 효능을 개선시킬 수 있는 새로운 접근법이 연구되고 있다. 본 연구에서는 EPC의 특징과 세포치료제로서의 임상적용 가능성에 대해 살펴보고자 한다.

• 대한임상검사과학회지
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• 제51권3호
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• pp.370-378
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• 2019

허혈 재관류 손상은 기관 이식, 외과적 혈관 재개통 및 출혈시에 발생하며 조직 및 기관 기능 장애를 유발한다. 최근 허혈 재관류 손상의 기전적 연구를 위해 간장 허혈 모델을 많이 이용하고 있다. 본 연구는 허혈 재관류 랫드 모델을 이용하여 항산화와 항염증 효과를 가진 것으로 알려진 Vanillin에 의한 간장 및 신장 손상에 대한 보호 효과를 알아보고 관련된 기전을 조사하기 위하여 실시하였다. 시험물질은 각각 100 mg/kg의 농도로 3일간 투여한 후, 60분동안 간을 결찰하여 허혈 재관류를 유도하여 관찰하였으며, 음성대조군, sham대조군 및 허혈재관류만 실시한 허혈 재관류대조군을 따로 두어, 약물투여군과 비교하였다. Vanillin 처치군에서는 AST, ALT 활성이 허혈 재관류대조군에 비해 유의하게 억제되었고, 조직병리학적 관찰에서도 염증 부분과 괴사부분이 현저하게 감소하였다. MDA와 SOD는 허혈 재관류군에 비해 유의적인 변화를 보였다. 이상의 결과를 종합하면 Vanillin은 간장 허혈 재관류에 의한 세포염증 및 세포괴사를 완화시켜 간세포 보호작용을 나타내었고, 신장의 사구체 및 원위세뇨관에 염증 변화를 완화 시키고 있어 세포 손상을 방어하는 것으로 생각되며, 이러한 방어효과는 항산화 기능에 의한 영향으로 사료된다.

• 대한한방내과학회지
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• 제23권2호
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• pp.181-190
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• 2002

The water extract of Omija-tang(OMJT) has been traditionally used for treatment of ischemic heart and brain damage in oriental medicine. However, little is known about the mechanism by which the water extract of OMJT protects cells from such damage. Therefore, this study was conducted to investigate the protective mechanisms of OMJT on $H_2O_2$-induced toxicity in H9c2 cardiomyoblast cells. Treatment of $H_2O_2$ markedly induced death of H9c2 cardiomyoblast cells in a dose-dependent manner. The characteristics of $H_2O_2$-induced death of H9c2 showed apparent apoptotic features, such as DNA fragmentation. However, OMJT significantly reduced both $H_2O_2$-induced cell death and chromatin fragmentation. The decrease of Bcl-XL expression by $H_2O_2$ was inhibited by OMJT. In addition, the increase of Bcl-XS and Bax expression were also inhibited by OMJT. In particular, Fas expression, which is generally recognized as cell death inducing signal by Fas/FasL interaction, was markedly increased by $H_2O_2$ in a time-dependent manner, whereas this increase was completely prevented by OMJT. The combined treatment of OMJT and $H_2O_2$ in H9c2 cells also reduced activation of caspase-9 and caspase-3 like protease. Taken together, this study indicates that the protective effects of the water extract of OMJT against oxidative damage may be mediated by the modulation of BcI-XL/S and Bax expression by way of the regulation of mitochondrial membrane potential and caspase cascades.