• Journal of Chest Surgery
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• v.33 no.8
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• pp.605-612
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• 2000

Background: Ischemic preconditioning enhances the tolerance of myocardium against ischemia/reperfusion injury, with the enhancement of the recovery of post-ischemic myocardial function. This study was disigned to assess whether the protective effect of ischemic preconditioning could provide one additional hour of myocardial preservation in four hour myocardial ischemia in a rate heart. Material and method: Fourty four Spargue-Dawley rats, weighing 300~450gm, were divided into four groups. Group 1(n=7) and group 3(n=12) were subjected to 30 minutes of aerobic Langendorff perfusion without ischemic preconditioning and then preserved in saline solution at 2~4$^{\circ}C$ for 4 hours and 5 respectively. Group 2(n=7) and group 4(n=18) were perfused in the same way for 20 minutes, followed by 3 minutes of global mormothermic ischemia and 10 minutes of perfusion and then preserved in the same cold saline solution for 4 hours and 5 hours respectively. Heart rate, left ventricular developed pressure(LVDP), and coronary flow were measured at 15 minutes during perfusion as baseline. Spontaneous defibrillation time was measured after reperfusion. Heart rate, LVDP, and coronary flow were also recorded at 15 minutes, 30 minutes, and 45 minutes during reperfusion. Samples of the apical left ventricular wall were studied using a transmission electron microscope. Result: Time of spontaneous defibrillation(TSD) was significantly longer in group 4 than in group 1(p<0.001), and TSD in group 1 was significantly longer in comparision to that of group 2(p<0.05). Heart rate at 45 minutes was significantly higher in group 1 than in group 4(p<0.05). Heart rate at 15 min was significantly higher in group 2 than in group 1(p<0.001) and in group 4 than in group 3(p<0.05). Left ventricular developed pressure(LVDP) at 30 minutes and 45 minutes was higher in group 1 than in group 4(p<0.01), LVDP at 45 minutes was higher in group 4 than in group 3(p<0.05). Rate-pressure product(RPP) at 30 minutes and 45 minutes was higher in group 1 than in group 4(p<0.05). RPP at 15 minutes was higher in group 2 than in group 1(p<0.01). RPP at 30 minutes and 45 minutes was higher in group 4 than in group 3(p<0.05). Group 2 showed relatively less sarcoplasmic edema and less nuclear chromatin clearance than group 1. Group 4 showed less myocardial cell damage than group 3, group 4 showed less myocardial cell damage than group 3, group 4 showed more myocardial cell edema than group 1. Conclusion: Ischemic preconditioning enhanced the recovery of postischemic myocardial function after 4 hours and 5 hours preservation. However, it was not demonstrated that ischemic preconditioning could definitely provide one additional hour of myocardial preservation in four hour myocardial ischemia in a rat heart.

• Journal of Ginseng Research
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• v.31 no.1
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• pp.23-33
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• 2007

Ginsenosides are one of the most well-known traditional herbal medicines frequently used for the treatment of cardiovascular symptoms in korea. The anti-ischemic effects of the mixture of ginsenoside $Rg_3$, and CK on ischemia-induced isolated rat heart were investigated through analyses of changes in hemodynamics ; blood pressure, aortic flow, coronary flow, and cardiac output. The subjects in this study were divided into four groups: normal control, the mixture of ginsenoside $Rg_3$ and CK, an ischemia-induced group without any treatment, and an ischemia-induced group treated with the mixture of ginsenoside $Rg_3$ and CK. There were no significant differences in perfusion pressure, aortic flow, coronary flow and cardiac output between them before ischemia was induced. The supply of oxygen and buffer was stopped for five minutes to induce ischemia in isolated rat hearts, and the mixture of ginsenoside $Rg_3$ and CK was administered during ischemia induction. Treatments of the mixture of ginsenoside $Rg_3$ and CK significantly prevented decreases in perfusion pressure, aortic flow, coronary flow, and cardiac output under ischemic conditions. In addition, hemodynamics (except heart rate) of the group treated with the mixture of ginsenoside $Rg_3$ and CK significantly recovered 60 minutes after reperfusion compared to the control group (mixture+ischemia vs ischemia - average perfusion pressure: 74.4${\pm}$2.97% vs. 85.1${\pm}$3.01%, average aortic flow volume: 49.11${\pm}$2.72% vs. 59.97${\pm}$2.93%, average coronary flow volume: 58.50${\pm}$2.81% vs. 72.72${\pm}$2.99%, and average cardiac output: 52.47${\pm}$2.78% vs. 63.11${\pm}$2.76%, p<0.01, respectively). These results suggest that treatment of the mixture of ginsenoside $Rg_3$ and CK has distinct anti-ischemic effects in ex vivo model of ischemia-induced rat heart.

• Molecules and Cells
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• v.42 no.12
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• pp.893-905
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• 2019

Mitochondria are highly dynamic organelles that constantly undergo fission and fusion processes that closely related to their function. Disruption of mitochondrial dynamics has been demonstrated in acute kidney injury (AKI), which could eventually result in cell injury and death. Previously, we reported that augmenter of liver regeneration (ALR) alleviates renal tubular epithelial cell injury. Here, we gained further insights into whether the renoprotective roles of ALR are associated with mitochondrial dynamics. Changes in mitochondrial dynamics were examined in experimental models of renal ischemia-reperfusion (IR). In a model of hypoxia-reoxygenation (HR) injury in vitro, dynamin-related protein 1 (Drp1) and mitochondrial fission process protein 1 (MTFP1), two key proteins of mitochondrial fission, were downregulated in the Lv-ALR + HR group. ALR overexpression additionally had an impact on phosphorylation of Drp1 Ser637 during AKI. The inner membrane fusion protein, Optic Atrophy 1 (OPA1), was significantly increased whereas levels of outer membrane fusion proteins Mitofusin-1 and -2 (Mfn1, Mfn2) were not affected in the Lv-ALR + HR group, compared with the control group. Furthermore, the mTOR/4E-BP1 signaling pathway was highly activated in the Lv-ALR + HR group. ALR overexpression led to suppression of HR-induced apoptosis. Our collective findings indicate that ALR gene transfection alleviates mitochondrial injury, possibly through inhibiting fission and promoting fusion of the mitochondrial inner membrane, both of which contribute to reduction of HK-2 cell apoptosis. Additionally, fission processes are potentially mediated by promoting tubular cell survival through activating the mTOR/4E-BP1 signaling pathway.

• Biomedical Science Letters
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• v.10 no.4
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• pp.341-346
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• 2004

Tumor necrosis factor-α (TNF-α) or its mRNA expression are increased in acute nephrosis of various types including ischemia/reperfusion injury. This study was undertaken to determine whether pentoxifylline (PTX), an inhibitor of TNF-α production, provides a protective effect against hypoxia-induced cell injury in rabbit renal cortical slices. To induce hypoxia-induced cell injury, renal cortical slices were exposed to 100% N₂ atmosphere. Control slices were exposed to 100% O₂ atmosphere. The cell injury was estimated by measuring lactate dehydrogenase (LDH) release and p-aminohippurate (PAH) uptake. Exposure of slices to hypoxia increased the LDH release in a time-dependent manner. However, when slices were exposed to hypoxia in the presence of PTX, the LDH release was decreased. The protective effect of PTX was dose-dependent over the concentrations of 0.05∼1 mM. Hypoxia did not increase lipid peroxidation, whereas an organic hydroperoxide t-butylhydroperoxide (tBHP) resulted in a significant increase in lipid peroxidation. PTX did not affect tBHP-induced lipid peroxidation. Hypoxia decreased PAH uptake, which was significantly attenuated by PTX and glycine. tBHP-induced inhibition of PAH uptake was not altered by PTX, although it was prevented by antioxidant deferoxarnine. The PAH uptake by slices in rabbits with ischemic acute renal failure was prevented by PTX pretreatment. These results suggest that PTX may exert a protective effect against hypoxia-induced cell injury and its effect may due to inhibition of the TNF-α production, but not by its antioxidant action.

• Journal of Chest Surgery
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• v.29 no.10
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• pp.1076-1080
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• 1996

The results about the myocardial protection of recta of the nitric oxide precursor L-arginine upon reperrusion injury after ischemia are diverse. These diversities may be model dependent. Experiments were designed and performed to investigate myocardial protection effects according to the concentration of L-arginine. The Isolated rat hearts were subjected in a 30 minutes oi normothermic ischemia and reperfused for 30 minutes with reperfusate containing 0, 1, 2, 3, 4 moil L-arginine. After 30 minutes of reperfusion, group with 1 and 2 mM/L L-arginine showed a trend of better recovery in left ventricular systolic function(left ventricular developed pressure, positive maximum dpfdt), diastolic function(negative maximum dpfdt) and coronary flow compared to control group(reperfusate no L-arginine). Recovery was impaired with a higher concentration, and at 4 moil L-arginine r covery was worse than control(p (0, 05). These results suggest that optimal concentration of L-arginine Is Important or the recovery of myocardial and endothelial function after ischemia and reperfusion.

• Journal of Chest Surgery
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• v.36 no.12
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• pp.894-903
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• 2003

Protection against ischemia-reperfusion injury is crucial for successful transplantation of the lung. It has been known that nitric oxide has many favorable effects on the donor lungs but at the same time, has some potential side effects of cytotoxicity. In this regards, we investigated whether the administration of nitroglycerin could decrease ischemia-reperfusion injury in isolated rat lung reperfusion model for the confirmation of the effect of nitroglycerin, a donor of nitric oxide, on lung transplantation. Material and Method: 35 Sprague-Dawley species male white rats were used for this experiment. For nitroglycerin group (n=18), nitroglycerin was administered intravenously followed by mixed in flushing solution for preservation. As a control group (n=17), we used the same amount of normal saline. To evaluate the effect of nitroglycerin on the lung, heart-lung block was obtained, weighed and stored in University of Wisconsin Solution at 1$0^{\circ}C$ for 24 hours. In each group of the isolated lungs, reperfusion was carried out with Krebs-Hensleit-diluted human blood for 60 minutes. As parameters of the state of the isolated lung, peak inspiratory and pulmonary arterial pressures were continuously recorded. Oxygen and carbon dioxide tension of reperfusing blood were measured before and after 30, 60 minutes of reperfusion. After sixty minutes of reperfusion, protein content in bronchoalveolar lavage fluid was measured also for the evaluation of the degree of alveolar flooding. Lung myeloperoxidase activity was determined to verify the accumulation of neutrophils. Results: Although statistically significant differences were not noted in peak inspiratory and pulmonary arterial pressure between control and nitroglycerin group, latter group showed lowering tendency of pulmonary arterial pressure during the entire reperfusion period. Oxygen tension was higher (p<0.05) in nitroglycerin group compared with that of the control group, in contrast, there were no differences in carbon dioxide tension, protein content in bronchoalveolar lavage fluid and myeloperoxidase activity between the groups. In the examination of ultrastructural changes, nitroglycerin denoted the protective effect on the pulmonary architecture compared with that of control group. Conclusion: Collectively, on the bases of these experimental results, prior treatment of donor lung with nitroglycerin could result in better preservation of the lung. Consequently, these nitroglycerin preserved lungs are thought to be more suitable for successful transplantation of the lung.

• Journal of Veterinary Clinics
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• v.26 no.2
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• pp.138-143
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• 2009

Ischemia/reperfusion injury(I/RI) is the major cause of acute renal failure and delayed graft function(DGF) unavoidable in renal transplantation. Enormous studies on ischemia damage playing a role in activating graft rejection factors, such as T cells or macrophages, are being reported. Present study was performed to determine whether ischemia time would play an important role in activating rejection-related factors or not in rat models of I/RI. Male Sprague-Dawley rats were submitted to 30, 45, and 60 minutes of warm renal ischemia with nephrectomy or control animals underwent sham operation(unilateral nephrectomy). Renal function and survival rates were evaluated on day 0, 1, 2, 3, 5 and 7. Immunofluorescence staining of dendritic cells(DCs), natural killer(NK) cells, macrophages, B cells, CD4+ and CD8+ T cells were measured on day 1 and 7 after renal I/RI. Survival rates dropped below 50% after day 3 in 45 minutes ischemia. Histologic analysis of ischemic kidneys revealed a significant loss of tubular architecture and infiltration of inflammatory cells. DCs, NK cells, macrophages, CD4+ and CD8+ T cells were infiltrated from a day after I/RI depending on ischemia time. Antigen presenting cells(DCs, NK cells or macrophages) and even T cells were infiltrated 24 hours post-I/RI, which is at the time of acute tubular necrosis. During the regeneration phase, not only these cells increased but B cells also appeared in more than 45 minutes ischemia. The numbers of the innate and the adaptive immune cells increased depending on ischemia as well as reperfusion time. These changes of infiltrating cells resulting from each I/RI model show that ischemic time plays a role in activating rejection related immune factors and have consequences on progression of renal disease in transplanted and native kidneys.

• Natural Product Sciences
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• v.25 no.2
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• pp.136-142
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• 2019

Ischemia/reperfusion-induced myocardial injury is the main cause of acute myocardial infarction. Dendropanax morbifera $L{\acute{e}}veille$ has been used in traditional medicines for the treatment of various diseases such as headache, infectious diseases, and general debility. However, the effect of extract from D. morbifera (EDM) on myocardial ischemic injury is still unknown. In this study, the effects of EDM on neonatal rat cardiomyocytes with hypoxia/reoxygenation (H/R) injury were investigated. The viability of cardiomyocytes with H (30 min)/R (1 h) decreased; however, treatment with EDM significantly inhibited H/R injury-induced cardiomyocyte death. Further, we observed that reactive oxygen species (ROS) generation and intracellular calcium concentration ($Ca^{2+}{_i}$) were significantly reduced in EDM-treated cardiomyocytes compared with that in H/R-injured positive control. In addition, western blotting results showed that EDM attenuated abnormal changes of RyR2 and SERCA2a genes in hypoxic cardiomyocytes. These results suggest that EDM ameliorates ROS generation and $Ca^{2+}{_i}$ homeostasis to prevent dysregulation of calcium regulatory proteins in the heart, thereby exerting cardioprotective effects and reducing hypoxia-induced cardiomyocyte damage, which verifies the potential use of EDM as a new therapeutic agent for the treatment of myocardial ischemic injury.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.5
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• pp.475-485
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• 2017

The present study aimed to explore the neuroprotective effect and possible mechanisms of rhGLP-1 (7-36) against transient ischemia/reperfusion injuries induced by middle cerebral artery occlusion (MCAO) in type 2 diabetic rats. First, diabetic rats were established by a combination of a high-fat diet and low-dose streptozotocin (STZ) (30 mg/kg, intraperitoneally). Second, they were subjected to MCAO for 2 h, then treated with rhGLP-1 (7-36) (10, 20, $40{\mu}g/kg$ i.p.) at the same time of reperfusion. In the following 3 days, they were injected with rhGLP-1 (7-36) at the same dose and route for three times each day. After 72 h, hypoglycemic effects were assessed by blood glucose changes, and neuroprotective effects were evaluated by neurological deficits, infarct volume and histomorphology. Mechanisms were investigated by detecting the distribution and expression of the nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) in ischemic brain tissue, the levels of phospho-PI3 kinase (PI3K)/PI3K ratio and heme-oxygenase-1 (HO-l), as well as the activities of superoxide dismutase (SOD) and the contents of malondialdehyde (MDA). Our results showed that rhGLP-1 (7-36) significantly reduced blood glucose and infarction volume, alleviated neurological deficits, enhanced the density of surviving neurons and vascular proliferation. The nuclear positive cells ratio and expression of Nrf2, the levels of P-PI3K/PI3K ratio and HO-l increased, the activities of SOD increased and the contents of MDA decreased. The current results indicated the protective effect of rhGLP-1 (7-36) in diabetic rats following MCAO/R that may be concerned with reducing blood glucose, up-regulating expression of Nrf2/HO-1 and increasing the activities of SOD.

• Journal of Ginseng Research
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• v.47 no.2
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• pp.199-209
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• 2023

Background: Due to the interrupted blood supply in cerebral ischemic stroke (CIS), ischemic and hypoxia results in neuronal depolarization, insufficient NAD+, excessive levels of ROS, mitochondrial damages, and energy metabolism disorders, which triggers the ischemic cascades. Currently, improvement of mitochondrial functions and energy metabolism is as a vital therapeutic target and clinical strategy. Hence, it is greatly crucial to look for neuroprotective natural agents with mitochondria protection actions and explore the mediated targets for treating CIS. In the previous study, notoginseng leaf triterpenes (PNGL) from Panax notoginseng stems and leaves was demonstrated to have neuroprotective effects against cerebral ischemia/reperfusion injury. However, the potential mechanisms have been not completely elaborate. Methods: The model of middle cerebral artery occlusion and reperfusion (MCAO/R) was adopted to verify the neuroprotective effects and potential pharmacology mechanisms of PNGL in vivo. Antioxidant markers were evaluated by kit detection. Mitochondrial function was evaluated by ATP content measurement, ATPase, NAD and NADH kits. And the transmission electron microscopy (TEM) and pathological staining (H&E and Nissl) were used to detect cerebral morphological changes and mitochondrial structural damages. Western blotting, ELISA and immunofluorescence assay were utilized to explore the mitochondrial protection effects and its related mechanisms in vivo. Results: In vivo, treatment with PNGL markedly reduced excessive oxidative stress, inhibited mitochondrial injury, alleviated energy metabolism dysfunction, decreased neuronal loss and apoptosis, and thus notedly raised neuronal survival under ischemia and hypoxia. Meanwhile, PNGL significantly increased the expression of nicotinamide phosphoribosyltransferase (NAMPT) in the ischemic regions, and regulated its related downstream SIRT1/2/3-MnSOD/PGC-1α pathways. Conclusion: The study finds that the mitochondrial protective effects of PNGL are associated with the NAMPT-SIRT1/2/3-MnSOD/PGC-1α signal pathways. PNGL, as a novel candidate drug, has great application prospects for preventing and treating ischemic stroke.