• Journal of Microbiology and Biotechnology
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• 제31권8호
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• pp.1069-1078
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• 2021

Sevoflurane postconditioning (SPostC) has been proved effective in cardioprotection against myocardial ischemia/reperfusion injury. It was also reported that heat shock protein 70 (HSP70) could be induced by sevoflurane, which played a crucial role in hypoxic/reoxygenation (HR) injury of cardiomyocytes. However, the mechanism by which sevoflurane protects cardiomyocytes via HSP70 is still not understood. Here, we aimed to investigate the related mechanisms of SPostC inducing HSP70 expression to reduce the HR injury of cardiomyocytes. After the HR cardiomyocytes model was established, the cells transfected with siRNA for HSP70 (siHSP70) or not were treated with sevoflurane during reoxygenation. The lactate dehydrogenase (LDH) level was detected by colorimetry while cell viability and apoptosis were detected by MTT and flow cytometry. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to detect HSP70, apoptosis-, cell cycle-associated factors, iNOS, and Cox-2 expressions. Enzyme-linked immuno sorbent assay (ELISA) was used to measure malondialdehyde (MDA) and superoxide dismutase (SOD). SPostC decreased apoptosis, cell injury, oxidative stress and inflammation and increased viability of HR-induced cardiomyocytes. In addition, SPostC downregulated Bax and cleaved caspase-3 levels, while SPostC upregulated Bcl-2, CDK-4, Cyclin D1, and HSP70 levels. SiHSP70 had the opposite effect that SPostC had on HR-induced cardiomyocytes. Moreover, siHSP70 further reversed the effect of SPostC on apoptosis, cell injury, oxidative stress, inflammation, viability and the expressions of HSP70, apoptosis-, and cell cycle-associated factors in HR-induced cardiomyocytes. In conclusion, this study demonstrates that SPostC can reduce the HR injury of cardiomyocytes by inducing HSP70 expression.

• The Korean Journal of Physiology and Pharmacology
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• 제25권2호
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• pp.97-109
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• 2021

Neonatal hypoxia/ischemia (H/I), injures white matter, results in neuronal loss, disturbs myelin formation, and neural network development. Neuroinflammation and oxidative stress have been reported in neonatal hypoxic brain injuries. We investigated whether Paeoniflorin treatment reduced H/I-induced inflammation and oxidative stress and improved white matter integrity in a neonatal rodent model. Seven-day old Sprague-Dawley pups were exposed to H/I. Paeoniflorin (6.25, 12.5, or 25 mg/kg body weight) was administered every day via oral gavage from postpartum day 3 (P3) to P14, and an hour before induction of H/I. Pups were sacrificed 24 h (P8) and 72 h (P10) following H/I. Paeoniflorin reduced the apoptosis of neurons and attenuated cerebral infarct volume. Elevated expression of cleaved caspase-3 and Bad were regulated. Paeoniflorin decreased oxidative stress by lowering levels of malondialdehyde and reactive oxygen species generation and while, and it enhanced glutathione content. Microglial activation and the TLR4/NF-κB signaling were significantly down-regulated. The degree of inflammatory mediators (interleukin 1β and tumor necrosis factor-α) were reduced. Paeoniflorin markedly prevented white matter injury via improving expression of myelin binding protein and increasing O1-positive olidgodendrocyte and O4-positive oligodendrocyte counts. The present investigation demonstrates the potent protective efficiency of paeoniflorin supplementation against H/I-induced brain injury by effectually preventing neuronal loss, microglial activation, and white matter injury via reducing oxidative stress and inflammatory pathways.

• Journal of Chest Surgery
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• 제23권4호
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• pp.646-653
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• 1990

Currently numerous methods are in use for myocardial protection from the ravages of ischemia and hypoxia. This study was designed to compare with FDP-GIK[Group II, n=8] and GIK cardioplegic solution[Group I, n=8] in ability of myocardial protection and was examined in the isolated working rat heart subjected to long period[120 min] of hypothermic[10 - 15K] ischemic arrest with multidose[every 30 min] cardioplegic infusion. During postischemic reperfusion period 20 min, hemodynamic functions[aortic flow, coronary flow, peak aortic pressure, cardiac output, heart rate], biochemical enzymatic & electrical activities were evaluated. The time from onset of reperfusion to the return of regular sinus rhythm was significantly reduced from 87$\pm$3 sec to 17$\pm$2 sec[P<0.05]. The postischemic recovery of aortic flow was better in the group II [95.1$\pm$3.3% of its preischemic control level] than in the Group I [75.4$\pm$6.8%] [P<0.05]. Cardiac output and stroke volume was also better in the group[91.3$\pm$1.6%, 89.4$\pm$2.6%, respectively] than in the Group I [79.1$\pm$3.7%, 77.0$\pm$4.8%, respectively] [P<0. 05]. Creatine kinase leakage was also significantly reduced from 33.8$\pm$4.9 IU /10 min / gm * dry weight to 15.4$\pm$3.6 IU /10 min /gm * dry weight[P<0.05]. It is suggested that adding FDP to GIK cardioplegic solution improves its ability to protect the heart against long period of hypoxic ischemia.

• The Korean Journal of Physiology and Pharmacology
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• 제25권3호
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• pp.239-249
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• 2021

The present study explored the therapeutic potential of hydrogen sulfide (H2S) in restoring aging-induced loss of cardioprotective effect of remote ischemic preconditioning (RIPC) along with the involvement of signaling pathways. The left hind limb was subjected to four short cycles of ischemia and reperfusion (IR) in young and aged male rats to induce RIPC. The hearts were subjected to IR injury on the Langendorff apparatus after 24 h of RIPC. The measurement of lactate dehydrogenase, creatine kinase and cardiac troponin served to assess the myocardial injury. The levels of H2S, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible factor (HIF-1α) were also measured. There was a decrease in cardioprotection in RIPC-subjected old rats in comparison to young rats along with a reduction in the myocardial levels of H2S, CBS, CSE, HIF-1α, and nuclear: cytoplasmic Nrf2 ratio. Supplementation with sodium hydrogen sulfide (NaHS, an H2S donor) and l-cysteine (H2S precursor) restored the cardioprotective actions of RIPC in old hearts. It increased the levels of H2S, HIF-1α, and Nrf2 ratio without affecting CBS and CSE. YC-1 (HIF-1α antagonist) abolished the effects of NaHS and l-cysteine in RIPC-subjected old rats by decreasing the Nrf2 ratio and HIF-1α levels, without altering H2S. The late phase of cardioprotection of RIPC involves an increase in the activity of H2S biosynthetic enzymes, which increases the levels of H2S to upregulate HIF-1α and Nrf2. H2S has the potential to restore aging-induced loss of cardioprotective effects of RIPC by upregulating HIF-1α/Nrf2 signaling.

• The Korean Journal of Physiology and Pharmacology
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• 제20권3호
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• pp.305-314
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• 2016

Inflammatory and fibrotic responses are accelerated during the reperfusion period, and excessive fibrosis and inflammation contribute to cardiac malfunction. NecroX compounds have been shown to protect the liver and heart from ischemia-reperfusion injury. The aim of this study was to further define the role and mechanism of action of NecroX-5 in regulating inflammation and fibrosis responses in a model of hypoxia/reoxygenation (HR). We utilized HR-treated rat hearts and lipopolysaccharide (LPS)-treated H9C2 culture cells in the presence or absence of NecroX-5 ($10{\mu}mol/L$) treatment as experimental models. Addition of NecroX-5 significantly increased decorin (Dcn) expression levels in HR-treated hearts. In contrast, expression of transforming growth factor beta 1 ($TGF{\beta}1$) and Smad2 phosphorylation (pSmad2) was strongly attenuated in NecroX-5-treated hearts. In addition, significantly increased production of tumor necrosis factor alpha ($TNF{\alpha}$), $TGF{\beta}1$, and pSmad2, and markedly decreased Dcn expression levels, were observed in LPS-stimulated H9C2 cells. Interestingly, NecroX-5 supplementation effectively attenuated the increased expression levels of $TNF{\alpha}$, $TGF{\beta}1$, and pSmad2, as well as the decreased expression of Dcn. Thus, our data demonstrate potential antiinflammatory and anti-fibrotic effects of NecroX-5 against cardiac HR injuries via modulation of the $TNF{\alpha}/Dcn/TGF{\beta}1/Smad2$ pathway.

• The Korean Journal of Physiology and Pharmacology
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• 제2권5호
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• pp.581-589
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• 1998

A regulating mechanism of the ATP-sensitive potassium channels $(K_{ATP}\;channels)$ is yet to fully explained. This study was carried out to investigate the effects of intracellular application of monocarboxylates (acetate, formate, lactate, and pyruvate) on $K_{ATP}$ channels in isolated rabbit ventricular myocytes. Single channel currents of $K_{ATP}$ channels were recorded using the excised inside-out or permeabilized attached (open-cell) patch-clamp technique at room temperature. Intracellular application of acetate, formate and pyruvate led to an inhibition of channel activity, whereas intracellular application of lactate increased channel activity. These effects were reversible upon washout. Analysis of single channel kinetics showed that monocarboxylates did not affect open-time constant and close-time constant. These results suggest that monocarboxylates participate in modulating $K_{ATP}$ channels activity in cardiac cells and that modulation of $K_{ATP}$ channels activity may resolve the discrepancy between the low $K_i$ in excised membrane patches and high levels of intracellular ATP concentration during myocardial ischemia or hypoxia.

• 대한임상독성학회지
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• 제13권1호
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• pp.46-49
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• 2015

Carbon monoxide (CO) intoxication is a leading cause of severe neuropsychological impairments. Peripheral nerve injury has rarely been reported. Following are brief statements describing the motor peripheral neuropathy involved bilateral lower extremities of a patient who recovered following acute carbon monoxide poisoning. After inhalation of smoke from a fire, a 60-year-old woman experienced bilateral leg weakness without edema or injury. Neurological examination showed diplegia and deep tendon areflexia in lower limbs. There was no sensory deficit in lower extremities, and no cognitive disturbances were detected. Creatine kinase was normal. Electroneuromyogram patterns were compatible with the diagnosis of bilateral axonal injury. Clinical course after normobaric oxygen and rehabilitation therapy was marked by complete recovery of neurological disorders. Peripheral neuropathy is an unusual complication of CO intoxication. Motor peripheral neuropathy involvement of bilateral lower extremities is exceptional. Various mechanisms have been implicated, including nerve compression secondary to rhabdomyolysis, nerve ischemia due to hypoxia, and direct nerve toxicity of carbon monoxide. Prognosis is commonly excellent without sequelae. Emergency physicians should understand the possible-neurologic presentations of CO intoxication and make a proper decision regarding treatment.

• 약학회지
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• 제32권5호
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• pp.343-350
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• 1988

Recent hypothesis suggested that intracellular accumulation of calcium is a common denominator of ischemic celullar damage. Flunarizine, a calcium entry blocker, posses vasodilating properties in cerebral vascular beds and clinically used in circulatory disorders. The present study was designed to evaluate the effect of flunarizine on ischemic and hypoxic brain damage. An ischemic model was made by bilateral carotid artery ligation (BCAL) in Wistar strain rat. Hypoxic model was made by intravenous injection(i.v.) of KCN to rats and mice. In mice, flunarizine not only reduced the mortality of KCN, but also delayed the onset time of convulsion. The contents of ATP, creatine phosphate and glucose, cerebral energy metabolite, decreased 30 minutes after BCAL and KCN i, v, while that of lactate increased. But these variations were suppressed by flunarizine. Furthermore, increase in the dosage of flunarizne generally promoted the recovery of cerebral energy metabolites in hypoxic animals. The results suggest that flunarizine had a protective effect against ischemic and hypoxic brain damage due to its ameliorating action on the cerebral energy metabolism.

• Journal of Ginseng Research
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• 제45권6호
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• pp.642-653
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• 2021

Background: Effective strategies are dramatically needed to prevent and improve the recovery from myocardial ischemia and reperfusion (I/R) injury. Direct interactions between the mitochondria and endoplasmic reticulum (ER) during heart diseases have been recently investigated. This study was designed to explore the cardioprotective effects of gypenoside XVII (GP-17) against I/R injury. The roles of ER stress, mitochondrial injury, and their crosstalk within I/R injury and in GP-17einduced cardioprotection are also explored. Methods: Cardiac contractility function was recorded in Langendorff-perfused rat hearts. The effects of GP-17 on mitochondrial function including mitochondrial permeability transition pore opening, reactive oxygen species production, and respiratory function were determined using fluorescence detection kits on mitochondria isolated from the rat hearts. H9c2 cardiomyocytes were used to explore the effects of GP-17 on hypoxia/reoxygenation. Results: We found that GP-17 inhibits myocardial apoptosis, reduces cardiac dysfunction, and improves contractile recovery in rat hearts. Our results also demonstrate that apoptosis induced by I/R is predominantly mediated by ER stress and associated with mitochondrial injury. Moreover, the cardioprotective effects of GP-17 are controlled by the PI3K/AKT and P38 signaling pathways. Conclusion: GP-17 inhibits I/R-induced mitochondrial injury by delaying the onset of ER stress through the PI3K/AKT and P38 signaling pathways.

• Journal of Chest Surgery
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• 제31권9호
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• pp.837-844
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• 1998

배경: 아데노신은 심근의 허혈상태에서 심근세포로부터 분비되어 부정맥과 심근허혈 및 수술후 재관류손상을 억제시키는 호르몬으로 알려져 있다. 아데노신의 심근보호 효과에 대한 연구는 주로 심정지액 속에 포함시킨 아데노신의 효과에 대하여 이루어 지고 있으나, 심정지액 속에 포함된 아데노신의 적정용량에 대해서는 보고가 다양하다. 저자들은 자체제작한 심폐체외순환 모델을 이용하여 단일용량의 아데노신(0.75 mg/Kg/min)이 우수한 심근보호효과를 나타낸 결과를 보고한 바 있으나 적절한 용량이었는지에 대한 확신은 없다. 따라서 본 연구의 목적은 심정지액 속에 포함된 아데노신의 적정용량을 알아보는데 있다. 대상 및 방법: 연구방법은 쥐를 이용하여 심정지시 심정지액(St. Thomas 심정지액)에 첨가한 아데노신의 용량에 따라 1군(0.5 mg/Kg/min), 2군(0.75 mg/Kg/min) 및 3군(1 mg/Kg/min) 으로 나누어 각각 10마리씩 실험하여 비교하였다. 마취 후 적출된 쥐심장의 대동맥과 좌심방에 도관을 삽관한 후에 심폐체외순환 모델에 연결하여 비작업성 순환과 작업성 순환을 시행하면서 혈역학적 수치를 측정하여 이를 대조값으로 이용하였다. 심정지액을 주입하여 심정지를 유도한 후에 90분간 허혈상태로 유지한 다음 비작업성 순환을 시행 후 작업성 순환으로 바꿔 10분, 30분 및 60분에 혈역학적 수치(심박동수, 수축기 대동맥압, 1분간 대동맥 박출량 및 관동맥관류량)를 측정하고, 생화학적 검사(CPK, Lactic Acid) 및 심장의 수분함유량도 측정하였다. 측정된 수치는 심정지 전 측정한 대조값에 대한 백분율로 환산하여 비교하였다. 결과: 실험 결과 심정지 전에 측정한 대조값 사이에는 세군 사이의 통계적인 유의성이 없었다. 심정지액의 주입 후 3군에서 가장 빨리 심정지가 일어났으며(p<0.05), 재관류 후 심박동이 돌아온 시간은 1군과 2군이 3군에 비하여 통계학적으로 유의하게 심박동이 빨리 돌아 왔다 (p<0.05). 그러나 1군과 2군 사이에는 유의성이 없었다. 심장의 재관류 후 측정한 심박동수의 회복률에서 10분에 측정한 값은 세군 사이에 유의성이 없었으나, 30분과 60분 에 측정한 값은 1군이 2군과 3군에 비하여 유의하게 높았으며(p<0.05), 2군도 3군에 비하여 유의하게 높았다(p<0.05). 수축기 대동맥압의 회복률, 1분 동안의 대동맥 박출량 및 심박출량(1분 동안의 대동맥 박출량과 관동맥관류량을 합산한 값)은 10분, 30분 및 60분에서 모두 2군이 1군과 3군에 비하여, 1군은 3군에 비하여 유의하게 높았다(p<0.05). 관동맥관류량의 회복률은 10분과 30분에 측정한 값은 2군이 1군과 3군에 비하여, 1군은 3군에 비하여 유의하게 높았으며(p<0.05), 60분에 측정한 값은 1군과 2군이 3군에 비하여 유의하게 높았다(p<0.05). 심근의 수분함유량과 관상동맥 관류량의 생화학적 검사결과 CPK와 Lactic Acid는 세군 사이에 유의성이 없었다. 결론 : 이상의 결과로 아데노신을 심정지용액에 첨가시 비교적 적정 용량은 0.75 mg/Kg/min 을 투여하는 것이 적절할 것으로 생각된다.