• Journal of Ginseng Research
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• v.47 no.3
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• pp.408-419
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• 2023

Background: Ginsenoside compound K (CK), the main active metabolite in Panax ginseng, has shown good safety and bioavailability in clinical trials and exerts neuroprotective effects in cerebral ischemic stroke. However, its potential role in the prevention of cerebral ischemia/reperfusion (I/R) injury remains unclear. Our study aimed to investigate the molecular mechanism of ginsenoside CK against cerebral I/R injury. Methods: We used a combination of in vitro and in vivo models, including oxygen and glucose deprivation/reperfusion induced PC12 cell model and middle cerebral artery occlusion/reperfusion induced rat model, to mimic I/R injury. Intracellular oxygen consumption and extracellular acidification rate were analyzed by Seahorse multifunctional energy metabolism system; ATP production was detected by luciferase method. The number and size of mitochondria were analyzed by transmission electron microscopy and MitoTracker probe combined with confocal laser microscopy. The potential mechanisms of ginsenoside CK on mitochondrial dynamics and bioenergy were evaluated by RNA interference, pharmacological antagonism combined with co-immunoprecipitation analysis and phenotypic analysis. Results: Ginsenoside CK pretreatment could attenuate mitochondrial translocation of DRP1, mitophagy, mitochondrial apoptosis, and neuronal bioenergy imbalance against cerebral I/R injury in both in vitro and in vivo models. Our data also confirmed that ginsenoside CK administration could reduce the binding affinity of Mul1 and Mfn2 to inhibit the ubiquitination and degradation of Mfn2, thereby elevating the protein level of Mfn2 in cerebral I/R injury. Conclusion: These data provide evidence that ginsenoside CK may be a promising therapeutic agent against cerebral I/R injury via Mul1/Mfn2 mediated mitochondrial dynamics and bioenergy.

• Journal of Chest Surgery
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• v.35 no.1
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• pp.11-19
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• 2002

Background: Ischemia-reperfusion myocardial injury is an important factor to determine the early and the late mortality of transplanted patients. Recently, modulation of the cytosolic NADH/NAD+ ratio by Pyruvate and aspartate was tested to Protect the heart from ischemia-reperfusion injury. Material and Method: We added pyruvate and aspartate to the University of Wisconsin solution, and evaluated their effect on myocardial protection. We used 16 piglet(age 1 to 3 days) hearts. Eight hearts were arrested with and stored in the University of Wisconsin solution(UW solution) for 24 hours(control group), and the other eight hearts were arrested with and stored in the modified UW solution added pyruvate(3mmol/L) and aspartate(2 mmol/L)(test group). All hearts underwent modified reperfusion with blood cardioplegic solution followed by conversion to a left-sided working model with perfusion from a support pig. And then, we measured stroke work index(SWI), high-energy phosphate stores, and myocardial water content of the hearts. SWI was calculated at left ventricular end-diastolic pressures of 3, 6, 9, and 12 mmHg after 60 and 120 minutes reperfusion, respectively, Result: At 60 minutes and 120 minutes after reperfusion, SWI was higher in the test group than in the control group significantly. The levels of AMP, ADP, ATP of the test group were also higher. But, the creatine phosphate level and myocardial water content were similar in the two groups. Conclusion: From these results, we could Prove that pyruvate and aspartate enhance cardiac contractility and high-energy phosphate stores after ischemia.

• Journal of Chest Surgery
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• v.32 no.5
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• pp.413-421
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• 1999

Background: Ischemia reperfusion injury is known to contribute to the major causes of the early graft failure in lung transplantation. Triiodothyronine (T3) has been suggested to ameliorate ischemia reperfusion injury from both in vivo and in vitro experiments of various organs. Prospecting its beneficial effect for pulmonary allograft preservation, we made a new solution by adding T3 into the extracellular type dextran solution. Material and Method: Twelve adult mongrel dogs underwent left lung allotransplantation. Six donor dogs were flushed with the new solution(Group 1, n=6), and the remaining six were flushed with Euro-Collins solution to serve as controls(Group 2, n=6). Allografts were stored in each preservation solution for 20 hours at 4$^{\circ}C$. Left single lung transplantations were performed. The right pulmonary artery and the right main bronchus were clamped at 15 minutes after the reperfusion and maintained throughout the experiment to evaluate the transplanted left lung function. Result: Arterial carbon dioxide tension was better in group 1 than in group 2 throughout the experiment period and the difference was statistically significant at 2 hours after reperfusion(28.0${\pm}$3.0 mmHg and 53.1${\pm}$17.4 mmHg, p<0.05). The differences of arterial oxygen partial pressure, peak airway pressure and pulmonary vascular resistance showed no statistical significance. The malondialdehyde(MDA) level, measured from tissue obtained at 120 minutes after reperfusion showed no statistically significant difference. The tissue wet/dry ratio of group 1(649${\pm}$27 %) was significantly lower than that of group 2(686${\pm}$71 %, p<0.05). The microscopic examination revealed varying degrees of injury represented mainly by findings such as perivascular neutrophil infiltration, capillary hemorrhage and interstitial congestion. These findings were less severe in group 1 than those in group 2. Conclusion: The new solution demonstrated superior allograft preservation after 20 hour ischemia compared to Euro-Collins solution in canine single left lung transplantation model, these results suggest that T3 might be a promising agent for pulmonary allograft preservation.

• The Journal of Korean Medicine
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• v.23 no.4
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• pp.161-168
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• 2002

Objectives: Hwangryunhaedok-tang (Huang-lian-jie-du-tang, HRHDT, 黃連解毒湯) is a traditional Korean herbal medicine that is formulated with Coptidis Rhizoma, Phellodendri Cortex, Scutellariae Radix and Gardeniae Fructus. HRHDT is cold (寒) and bitter (苦) in nature and has general properties of clearing heat and detoxifying (淸熱解毒), strengthening the stomach and settling the liver (健胃平肝), and reducing inflammation, fever and swelling. This formula can prevent and treat artherosclerosis, hyperplasia of the endothelium, cerebral fluid circulation, cerebral vascular deterioration through aging, impairment of neurotransmitters, or disruption of the functioning of the cerebral cortex following infection or trauma. The purpose of the study reported here was to determine the neuroprotective effect of HRHDT on global ischemia induced by 4-vessel occlusion in Wistar rats. Methods: HRHDT extract was lyophilized after extraction with 85% methanol and 100% water. Rats were induced to 10 minutes of forebrain ischemia by 4-vessel occlusion (4-VO) and reperfused again. HRHDT was administered with a dose of 100 mg/kg, and 500 mg/kg of 85% methanol extracts and 100 mg/kg of 100% water extracts, respectively, at 0 min and 90 min after 4-VO. Rats were killed at 7 days after ischemia and the number of CA1 pyramidal neurons was counted in hippocampal sections stained with cresyl violet. Results: Body temperature of animals showed no significant difference between saline-treated groups and HRHDT extracts-treated groups until 5 hours of reperfusion. This result indicated that neuroprotective effects of HRHDT extracts were not due to hypothermic effects. The administration of HRHDT showed a significant neuroprotective effect on hippocampal CA1 neurons at 7 days after ischemia compared to the saline-treated group (P<0.001). HRHDT methanol extracts of 100 mg/kg, 500 mg/kg and HRHDT water extracts of 100 mg/kg showed 88.5%, 98.3% and 95.1 % neuroprotection, respectively. Conclusions: The results of this study demonstrate that administration of HRHDT is highly effective in reducing neuronal damage in response to transient global cerebral ischemia. HRHDT may involve many mechanisms that might account for its high degree of efficacy. A number of factors including free radicals, glutamate, calcium overload, NO, and various cytokines have been proposed to have an important role in causing neuronal death after short periods of global ischemia. Further studies are needed to know the neuroprotective mechanisms of HRHDT.

• Archives of Plastic Surgery
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• v.46 no.2
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• pp.108-113
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• 2019

Background The aim of this study was to assess the safety of one-per-mil tumescent injections into viable skin flaps that had survived an ischemic insult, in order to assess the potential suitability of one-per-mil tumescent injections in future secondary reconstructive procedures such as flap revision and refinements after replantation. Methods Forty groin flaps harvested from 20 healthy Wistar rats weighing 220 to 270 g were subjected to acute ischemia by clamping the pedicle for 15 minutes. All flaps showing total survival on the 7th postoperative day were randomly divided into group A (one-per-mil tumescent infiltration; n=14), group B (normal saline infiltration; n=13), and group C (control, with no infiltration; n=13) before being re-elevated. Transcutaneous oxygen tension ($TcPO_2$) was measured before and after infiltration, and changes in $TcPO_2$ were statistically analyzed using analysis of variance, the paired t-test, and the independent t-test. The viability of flaps was also assessed using the Analyzing Digital Images software at 7 days after the second elevation. Results Thirty-nine flaps survived to the final assessment, with the sole exception of a flap from group A that did not survive the first elevation. $TcPO_2$ readings showed significant decreases (P<0.05) following both one-per-mil tumescent ($99.9{\pm}5.7mmHg$ vs. $37.2{\pm}6.3mmHg$) and normal saline ($103{\pm}8.5mmHg$ vs. $48.7{\pm}5.9mmHg$) infiltration. Moreover, all groin flaps survived with no signs of tissue necrosis. Conclusions One-per-mil tumescent infiltration into groin flap tissue that had survived ischemia did not result in tissue necrosis, although the flaps experienced a significant decrease of cutaneous oxygenation.

• Journal of Korean Neurosurgical Society
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• v.62 no.5
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• pp.545-550
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• 2019

Objective : Penumbra ACE68 reperfusion catheter is a new large bore aspiration catheter used for reperfusion of large vessel occlusion. The objective of this study was to investigate the efficacy of this catheter in comparison to that of previous Penumbra catheters in patients with acute ischemic stroke related to internal carotid artery (ICA) occlusion. Methods : Data of all eligible patients who received endovascular treatment (EVT) for ICA occlusion using Penumbra aspiration catheters between January 2015 and December 2018 were retrospectively reviewed. After dividing into two groups according to use of penumbra ACE68, baseline characteristics of patients, successful recanalization rate, puncture to recanalization time, and switch to stent base technique rate were assessed. Successful recanalization was defined by a thrombolysis in cerebral infarction (TICI) score ${\geq}2b$ and favorable functional outcome was defined according to modified Rankin scale (score, 0-2). Results : ACE68 reperfusion catheter was used in 29 of 75 eligible patients (39%). The puncture to recanalization time was significantly shorter ($26{\pm}18.2$ minutes vs. $40{\pm}24.9$ minutes, p=0.011) and the rate of switch to stent-based retrieval was significantly lower (3% vs. 20%, p=0.046) in ACE68 catheter group. Moreover, although not statistically significant, the successful recanalization rate was higher (83% vs. 76%, p=0.492) in ACE68 catheter group. Favorable functional outcome was observed in 48% of patients treated with ACE68 reperfusion catheter and in 30% of patients treated using other Penumbra systems (p=0.120). Baseline Alberta Stroke Program Early CT Scores ${\geq}8$ (odds ratio [OR], 9.74; 95% confidence interval [CI], 1.72-54.99; p=0.010) and successful recanalization (OR, 10.20; 95% CI, 1.13-92.46; p=0.039) were independent predictors of favorable outcome. Conclusion : EVT using ACE68 reperfusion catheter can be considered a first-line therapy in patients with acute ICA occlusion as it can achieve rapid recanalization and reduce the frequency of conversion to stent-retrieve therapy.

• Journal of Chest Surgery
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• v.31 no.10
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• pp.924-927
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• 1998

Background: Myocardial cell death after myocardial infarction or reperfusion is classified into necrosis and apoptosis. Bcl-2 protein is a cytoplasmic protein, which inhibits apoptosis and is expressed in acute stage of myocardial infarction but not in normal heart. This study was performed to investigate whether Bcl-2 protein was expressed respectively to the reperfusion time. Materials and methods: Thirty nine New Zealand white rabbits weighing 1.5-4.8 kg (mean, 2.9kg) were alloted into 7 groups (n=5 in each group) which underwent left anterior descending coronary artery(LAD) occlusion for 30 minutes, followed by reperfusion. The animals were sacrificed at 1, 4, 8, 12, 24 hours, and 3, 7 days after occlusion. Ventricle was excised immediately after intervention. Tissues were fixed in 10% buffured formalin and embedded in paraffin. Bcl-2 protein was detected by immunohistochemical stain with using monoclonal antibody against Bcl-2 protein. Results: The positive immunohistochemical reactivity for Bcl-2 protein was observed in 12, 24 hours, and 3 days reperfusion groups. Bcl-2 protein was detected in salvaged myocytes surrounding the infarcted area. Conclusions: Bcl-2 protein is expressed at the late acute stage of infarct. Therefore, the expression of Bcl-2 protein may not protect acute cell death, but may play a role in the prevention of late cell death after myocardial is chemia-reperfusion.

• Journal of Chest Surgery
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• v.25 no.2
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• pp.131-136
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• 1992

The effect of temperature of cardioplegic solution on myocardial preservation was studied using isolated rat heart perfusion technique. Twenty Sprague-Dawley rats, weighing 120~140gm, were pretreated with intraperitoneal injection of heparin sodium[300u/kg] and then the hearts were excised after cervical herniation 30 minutes later. The hearts were perfused in isolated working heart apparatus with oxygenated modified Tyrode solution at 37oC. After 10 minutes of non working heart perfusion, the hearts were subjected to arrest for 30 minutes by administration of 5cc cardioplegic solution at the temperature of 4oC [Group I ], 15oC [Group II], 25oC [Group III], 37oC[Group IV]. At the same time, the topical cooling of heart was performed using ice saline. After arrest, the hearts were reperfused by non working heart perfusion for 1 hour with modified Tyrode solution at 37oC. The CPK, GOT and LDH in reperfusate were measured at 5,20,40,60 minutes after start of reperfusion. With the values of those, we compared the effect of temperature of cardioplegic solution on myocardial preservation. The results were as follows; 1. The enzyme values in reperfusate were highest at 5 minute and after then declined. 2. At 5 minutes after reperfusion, the enzyme values in Group I were lower than those in other Groups. These results suggest that the cardioplegic solutions using for cardiac arrest and myocardial protection can be working better at 4oC than at any other temperature.

• The Korean Journal of Physiology and Pharmacology
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• v.3 no.4
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• pp.405-414
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• 1999

The role of platelet-activating factor (PAF) was investigated in intestinal ischemia/reperfusion (I/R) induced acute lung injury associated with oxidative stress. To induce acute lung injury following intestinal I/R, superior mesenteric arteries were clamped with bulldog clamp for 60 min prior to the 120 min reperfusion in Sprague-Dawley rats. Acute lung injury by intestinal I/R was confirmed by the measurement of lung leak index and protein content in bronchoalveolar lavage (BAL) fluid. Lung leak and protein content in BAL fluid were increased after intestinal I/R, but decreased by WEB 2086, the PAF receptor antagonist. Furthermore, the pulmonary accumulation of neutrophils was evaluated by the measurement of lung myeloperoxidase (MPO) activity and the number of neutrophils in the BAL fluid. Lung MPO activity and the number of neutrophils were increased (p＜0.001) by intestinal I/R and decreased by WEB 2086 significantly. To confirm the oxidative stress induced by neutrophilic respiratory burst, gamma glutamyl transferase (GGT) activity was measured. Lung GGT activity was significantly elevated after intestinal I/R (p<0.001) but decreased to the control level by WEB 2086. On the basis of these experimental results, phospholipase $A_2\;(PLA_2),$ lysoPAF acetyltransferase activity and PAF contents were measured to verify whether PAF is the causative humoral factor to cause neutrophilic chemotaxis and oxidative stress in the lung following intestinal I/R. Intestinal I/R greatly elevated $PLA_2$ activity in the lung as well as intestine (p<0.001), whereas WEB 2086 decreased $PLA_2$ activity significantly (p<0.001) in both organs. LysoPAF acetyltransferase activity, the PAF remodelling enzyme, in the lung and intestine was increased significantly (p<0.05) also by intestinal I/R. Accordingly, the productions of PAF in the lung and intestine were increased (p<0.001) after intestinal I/R compared with sham rats. The level of PAF in plasma was also increased (p<0.05) following intestinal I/R. In cytochemical electron microscopy, the generation of hydrogen peroxide was increased after intestinal I/R in the lung and intestine, but decreased by treatment of WEB 2086 in the lung as well as intestine. Collectively, these experimental results indicate that PAF is the humoral mediator to cause acute inflammatory lung injury induced by intestinal I/R.

• Tuberculosis and Respiratory Diseases
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• v.54 no.5
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• pp.532-541
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• 2003

Background : Phospholipase $A_2$ ($PLA_2$) has been known to be involved in the pathogenesis of acute lung injury (ALI) including ARDS. Since doxycycline has the property of inhibiting secretory group II $PLA_2$, the therapeutic effect of doxycycline hyclate was investigated for gut ischemia/reperfusion (I/R)-induced ALI in Sprague-Dawley rats. Methods : ALI was induced in Sprague-Dawley rats by clamping of the superior mesenteric artery for 60 min, followed by 120 min of reperfusion. To confirm the pathogenetic mechanisms of this ALI associated with neutrophilic oxidative stress, we measured bronchoalveolar lavage (BAL) protein content and lung MPO, and performed cyto-chemical electron microscopy for detection of free radicals, assay of $PLA_2$ activity and cytochrome-c reduction assay. Results : In gut I/R-induced ALI rats, protein leakage, pulmonary neutrophil accumulation, free radical production and lung $PLA_2$ activity were all increased. These effects were reversed by doxycycline hyclate. Conclusion : Doxycycline appears to be effective in ameliorating the gut I/R-induced ALI by inhibiting $PLA_2$, thereby decreasing the production of free radicals from neutrophils.