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1
Tian, Fang, Runzhe Liu, Chaoxin Fan, Yi Sun, Xi Huang, Zongxiu Nie, Xin Zhao, and Xiaoping Pu. "Effects of Thymoquinone on Small-Molecule Metabolites in a Rat Model of Cerebral Ischemia Reperfusion Injury Assessed using MALDI-MSI." Metabolites 10, no. 1 (January 7, 2020): 27. http://dx.doi.org/10.3390/metabo10010027.
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Thymoquinone is one of the main components present in Nigella sativa seeds and is known to have various biological functions in inflammation, oxidative stress, tumors, aging, and in lowering blood glucose levels. Few studies have focused on its neuroprotective effects and its regulation of small-molecule metabolites during cerebral ischemia reperfusion injury. In this study, transient middle cerebral occlusion (tMCAO) was used to establish the rat model of cerebral ischemia reperfusion injury. We investigated the effects of thymoquinone using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) in a model of ischemia reperfusion injury to explore the changes in small-molecule metabolites in the brain. We found that that thymoquinone significantly improved neurobehavioral scores, reduced the cerebral infarct area, alleviated brain edema, and increased the number of normal neurons following injury. MALDI-MSI revealed that thymoquinone reduced abnormal accumulations of glucose, citric acid, succinate and potassium ions. Thymoquinone also increased the amount of energy-related molecules such as ADP, AMP, GMP, and creatine, antioxidants such as glutathione, ascorbic acid, and taurine, and other metabolism-related molecules such as glutamate, glutamine, aspartate, N-acetyl-L-aspartate, and sodium ions in damaged areas of the brain following cerebral ischemia reperfusion injury. In summary, based on the neuroprotective effect of thymoquinone on cerebral ischemia reperfusion injury, this study revealed the regulation of thymoquinone on energy metabolism and small-molecule substance metabolism.
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Sandhu, G. S., A. C. Burrier, and D. R. Janero. "Adenosine deaminase inhibitors attenuate ischemic injury and preserve energy balance in isolated guinea pig heart." American Journal of Physiology-Heart and Circulatory Physiology 265, no. 4 (October 1, 1993): H1249—H1256. http://dx.doi.org/10.1152/ajpheart.1993.265.4.h1249.
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We investigated the effect of the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and coformycin on high-energy phosphate metabolism, tissue nucleotides and nucleosides, and recovery of contractile function in isolated, perfused guinea pig hearts. EHNA and coformycin (10 microM) improved postischemic recovery of contractile function approximately 85% and enhanced coronary flow rate in reperfused tissue approximately 40%. The protective effect of EHNA on recovery of contractile function was concentration dependent. Although adenosine (10 microM) increased coronary flow rate on reperfusion approximately twofold over vehicle, it failed to improve postischemic recovery of contractile function. EHNA and coformycin preserved cardiac ATP levels and increased endogenous tissue adenosine during ischemia. During reperfusion, these agents enhanced recovery of high-energy phosphates approximately twofold and potentiated adenosine release into the perfusate with concentration dependency. Furthermore, EHNA and coformycin reduced the extent of myocardial ischemia-reperfusion injury, as indicated by the approximately 55% reduction in creatine phosphokinase release. We conclude that inhibitors of adenosine deaminase attenuate myocardial ischemic injury and improve postischemic recovery of contractile function and metabolism through endogenous myocardial adenosine enhancement and ATP preservation.
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Spindler, Matthias, Klaus Meyer, Hinrik Strömer, Andrea Leupold, Ernest Boehm, Helga Wagner, and Stefan Neubauer. "Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 3 (September 2004): H1039—H1045. http://dx.doi.org/10.1152/ajpheart.01016.2003.
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The creatine kinase (CK) system is involved in the rapid transport of high-energy phosphates from the mitochondria to the sites of maximal energy requirements such as myofibrils and sarcolemmal ion pumps. Hearts of mice with a combined knockout of cytosolic M-CK and mitochondrial CK (M/Mito-CK−/−) show unchanged basal left ventricular (LV) performance but reduced myocardial high-energy phosphate concentrations. Moreover, skeletal muscle from M/Mito-CK−/− mice demonstrates altered Ca2+ homeostasis. Our hypothesis was that in CK-deficient hearts, a cardiac phenotype can be unmasked during acute stress conditions and that susceptibility to ischemia-reperfusion injury is increased because of altered Ca2+ homeostasis. We simultaneously studied LV performance and myocardial Ca2+ metabolism in isolated, perfused hearts of M/Mito-CK−/− ( n = 6) and wild-type (WT, n = 8) mice during baseline, 20 min of no-flow ischemia, and recovery. Whereas LV performance was not different during baseline conditions, LV contracture during ischemia developed significantly earlier (408 ± 72 vs. 678 ± 54 s) and to a greater extent (50 ± 2 vs. 36 ± 3 mmHg) in M/Mito-CK−/− mice. During reperfusion, recovery of diastolic function was impaired (LV end-diastolic pressure: 22 ± 3 vs. 10 ± 2 mmHg), whereas recovery of systolic performance was delayed, in M/Mito-CK−/− mice. In parallel, Ca2+ transients were similar during baseline conditions; however, M/Mito-CK−/− mice showed a greater increase in diastolic Ca2+ concentration ([Ca2+]) during ischemia (237 ± 54% vs. 167 ± 25% of basal [Ca2+]) compared with WT mice. In conclusion, CK-deficient hearts show an increased susceptibility of LV performance and Ca2+ homeostasis to ischemic injury, associated with a blunted postischemic recovery. This demonstrates a key function of an intact CK system for maintenance of Ca2+ homeostasis and LV mechanics under metabolic stress conditions.
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Ji, Lele, Feng Fu, Lihua Zhang, Wenchong Liu, Xiaoqing Cai, Lei Zhang, Qiangsun Zheng, Haifeng Zhang, and Feng Gao. "Insulin attenuates myocardial ischemia/reperfusion injury via reducing oxidative/nitrative stress." American Journal of Physiology-Endocrinology and Metabolism 298, no. 4 (April 2010): E871—E880. http://dx.doi.org/10.1152/ajpendo.00623.2009.
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It is well known that insulin possesses a cardioprotective effect and that insulin resistance is closely related to cardiovascular diseases. Peroxynitrite (ONOO−) formation may trigger oxidative/nitrative stress and represent a major cytotoxic effect in heart diseases. This study was designed to investigate whether insulin attenuates ONOO− generation and oxidative/nitrative stress in acute myocardial ischemia/reperfusion (MI/R). Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. Rats randomly received vehicle, insulin, or insulin plus wortmannin. Arterial blood pressure and left ventricular pressure were monitored throughout the experiment. Insulin significantly improved cardiac functions and reduced myocardial infarction, apoptotic cell death, and blood creatine kinase/lactate dehydrogenase levels following MI/R. Myocardial ONOO− formation was significantly attenuated after insulin treatment. Moreover, insulin resulted in a significant increase in Akt and endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, NO production, and antioxidant capacity in ischemic/reperfused myocardial tissue. On the other hand, insulin markedly reduced MI/R-induced inducible NOS (iNOS) and gp91phox expression in cardiac tissue. Inhibition of insulin signaling with wortmannin not only blocked the cardioprotection of insulin but also markedly attenuated insulin-induced antioxidative/antinitrative effect. Furthermore, the suppression on ONOO− formation by either insulin or an ONOO− scavenger uric acid reduced myocardial infarct size in rats subjected to MI/R. We concluded that insulin exerts a cardioprotective effect against MI/R injury by blocking ONOO− formation. Increased physiological NO production (via eNOS phosphorylation) and superoxide anion reduction contribute to the antioxidative/antinitrative effect of insulin, which can be reversed by inhibiting phosphatidylinositol 3′-kinase. These results provide important novel information on the mechanisms of cardiovascular actions of insulin.
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Yoshino, Takuya, Tomohisa Nagoshi, Ryuko Anzawa, Yusuke Kashiwagi, Keiichi Ito, Daisuke Katoh, Masami Fujisaki, et al. "Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts." Journal of Endocrinology 222, no. 2 (June 3, 2014): 289–99. http://dx.doi.org/10.1530/joe-14-0067.
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Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor (MR)-dependent pathways, the pathophysiological significance of aldosterone cascade activation in heart diseases has not yet been fully clarified. We herein examined the effects of short-term aldosterone stimulation at a physiological dose on cardiac function during ischemia–reperfusion injury (IRI). In order to study the effects of aldosterone preconditioning, male Wistar rat Langendorff hearts were perfused with 10−9 mol/l of aldosterone for 10 min before ischemia, and the response to IRI was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, preconditioning actions of aldosterone significantly improved the recovery in left ventricular contractility and left ventricular end-diastolic pressure associated with a reduced activity of creatine phosphokinase released into the perfusate after ischemia–reperfusion. Notably, the MR inhibitor eplerenone did not abrogate these beneficial effects. Biochemical analyses revealed that p38MAPK phosphorylation was significantly increased during aldosterone preconditioning before ischemia, whereas its phosphorylation was substantially attenuated during sustained ischemia–reperfusion, compared with the results for in the non-preconditioned control hearts. This dual regulation of p38MAPK was not affected by eplerenone. The phosphorylation levels of other MAPKs were not altered by aldosterone preconditioning. In conclusion, the temporal induction of the aldosterone cascade, at a physiological dose, has favorable effects on cardiac functional recovery and injury following ischemia–reperfusion in a MR-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.
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Yoshida, Shinichi, Raul Busto, Elena Martinez, Peritz Scheinberg, and Myron D. Ginsberg. "Regional Brain Energy Metabolism after Complete versus Incomplete Ischemia in the Rat in the Absence of Severe Lactic Acidosis." Journal of Cerebral Blood Flow & Metabolism 5, no. 4 (December 1985): 490–501. http://dx.doi.org/10.1038/jcbfm.1985.75.
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Levels of energy metabolites were measured in forebrain regions in fasted rats subjected to 4-h recirculation after 1 h of either incomplete or complete ischemia. Both models of ischemia were produced by a procedure combining bilateral common carotid artery occlusion, systemic hypotension, and CSF pressure elevation; the degree of intracranial hypertension was varied to produce incomplete and complete ischemia. Levels of brain lactate at the end of ischemia ranged from 16 to 19 mmol/ kg in incomplete ischemia and from 11 to 13 mmol/kg in complete ischemia. Energy metabolism recovered evenly in the neocortical and subcortical regions with recirculation after incomplete ischemia. The metabolic recovery in the cerebral cortex after complete ischemia was similar to that observed after incomplete ischemia; however, recovery in the subcortical regions after complete ischemia was less extensive, NADH fluorescence remained high, and there was a fall in total creatine. Intracellular pH in the dorsal thalamus was more alkalotic after complete than incomplete ischemia. Thus, in the absence of profound tissue lactic acidosis, residual CBF during prolonged ischemia helps postischemic restitution of brain energy metabolism in subcortical regions. The pattern of poor recovery in these regions after complete ischemia suggests inadequate reperfusion. The decreased total creatine and the severe tissue alkalosis may be biochemical markers of advanced tissue injury during reflow.
7
Karu, Inga, Peeter Tähepöld, Toomas Andres Sulling, Margus Alver, Mihkel Zilmer, and Joel Starkopf. "Off-Pump Coronary Surgery causes Immediate Release of Myocardial Damage Markers." Asian Cardiovascular and Thoracic Annals 17, no. 5 (October 2009): 494–99. http://dx.doi.org/10.1177/0218492309348637.
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Off-pump coronary surgery does not eliminate the risks of ischemia-reperfusion injury. The main objective of this study was to describe the extent and time course of changes in myocardial metabolism and development of myocardial injury associated with revascularization. Coronary sinus and arterial blood samples for measurement of troponin I, creatine kinase MB, lactate, glutathione, and interleukin-6 were taken from 23 patients prior to grafting, after completion of each anastomosis, and up to the 1st postoperative morning. The results were evaluated together with parameters of cardiac function. Release of lactate, creatinine kinase MB, and troponin I into the coronary sinus was evident after completion of the 1st graft, and increased over time. During the procedure, only trace amounts of oxidized and reduced glutathione were detected in coronary sinus and arterial blood. Significant increases in interleukin-6 were found in coronary sinus samples after 5 and 20 min of reperfusion. Surgical trauma during off-pump coronary surgery is sufficient to activate an inflammatory response in the myocardium, together with unfavorable metabolic conditions to cause myocardial necrosis.
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Castillo, Oscar Arriagada, Gustavo Herrera, Carlos Manriquez, Andrea F. Rojas, and Daniel R. González. "Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion." Antioxidants 10, no. 4 (April 2, 2021): 555. http://dx.doi.org/10.3390/antiox10040555.
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The cardioprotective effects of nitric oxide (NO) have been described through S-nitrosylation of several important proteins in the mitochondria of the cardiomyocyte. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of S-nitrosothiols by producing denitrosylation, thus limiting the cardioprotective effect of NO. The effect of GSNOR inhibition on the damage by cardiac ischemia–reperfusion is still unclear. We tested the hypothesis that pharmacological inhibition of GSNOR promotes cardioprotection by increasing the levels of protein S-nitrosylation. In a model of ischemia–reperfusion in isolated rat heart, the effect of a GSNOR inhibitor, 5-chloro-3-(2-[4-ethoxyphenyl) (ethyl) amino]-2-oxoethyl)-1H-indole-2-carboxylic acid (C2), was investigated. Ventricular function and hemodynamics were determined, in addition to tissue damage and S-nitrosylation of mitochondrial proteins. Hearts treated with C2 showed a lower release of myocardial damage marker creatine kinase and a reduction in the infarcted area. It also improved post-ischemia ventricular function compared to controls. These results were associated with increasing protein S-nitrosylation, specifically of the mitochondrial complexes III and V. The pharmacological inhibition of GSNOR showed a concentration-dependent cardioprotective effect, being observed in functional parameters and myocardial damage, which was maximal at 1 µmol/L, associated with increased S-nitrosylation of mitochondrial proteins. These data suggest that GSNOR is an interesting pharmacological target for cardiac reperfusion injury.
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Aoyagi, Toshinori, Jason K. Higa, Hiroko Aoyagi, Naaiko Yorichika, Briana K. Shimada, and Takashi Matsui. "Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion." American Journal of Physiology-Heart and Circulatory Physiology 308, no. 12 (June 15, 2015): H1530—H1539. http://dx.doi.org/10.1152/ajpheart.00008.2015.
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Diet-induced obesity deteriorates the recovery of cardiac function after ischemia-reperfusion (I/R) injury. While mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, the effects of cardiac mTOR in ischemic injury under metabolic syndrome remains undefined. Using cardiac-specific transgenic mice overexpressing mTOR (mTOR-Tg mice), we studied the effect of mTOR on cardiac function in both ex vivo and in vivo models of I/R injury in high-fat diet (HFD)-induced obese mice. mTOR-Tg and wild-type (WT) mice were fed a HFD (60% fat by calories) for 12 wk. Glucose intolerance and insulin resistance induced by the HFD were comparable between WT HFD-fed and mTOR-Tg HFD-fed mice. Functional recovery after I/R in the ex vivo Langendorff perfusion model was significantly lower in HFD-fed mice than normal chow diet-fed mice. mTOR-Tg mice demonstrated better cardiac function recovery and had less of the necrotic markers creatine kinase and lactate dehydrogenase in both feeding conditions. Additionally, mTOR overexpression suppressed expression of proinflammatory cytokines, including IL-6 and TNF-α, in both feeding conditions after I/R injury. In vivo I/R models showed that at 1 wk after I/R, HFD-fed mice exhibited worse cardiac function and larger myocardial scarring along myofibers compared with normal chow diet-fed mice. In both feeding conditions, mTOR overexpression preserved cardiac function and prevented myocardial scarring. These findings suggest that cardiac mTOR overexpression is sufficient to prevent the detrimental effects of diet-induced obesity on the heart after I/R, by reducing cardiac dysfunction and myocardial scarring.
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Jiang, Miaomiao, Jingyu Ni, Yuanlin Cao, Xiaoxue Xing, Qian Wu, and Guanwei Fan. "Astragaloside IV Attenuates Myocardial Ischemia-Reperfusion Injury from Oxidative Stress by Regulating Succinate, Lysophospholipid Metabolism, and ROS Scavenging System." Oxidative Medicine and Cellular Longevity 2019 (June 24, 2019): 1–17. http://dx.doi.org/10.1155/2019/9137654.
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Astragaloside IV is one of the main active ingredients isolated from Astragalus membranaceus. Here we confirmed its protective effect against cardiac ischemia-reperfusion (I/R) injury and aimed to investigate the potential molecular mechanisms involved. Pretreatment of ex vivo and in vivo I/R-induced rat models by astragaloside IV significantly prevented the ratio of myocardium infarct size, systolic and diastolic dysfunction, and the production of creatine kinase and lactate dehydrogenase. Metabolic analyses showed that I/R injury caused a notable reduction of succinate and elevation of lysophospholipids, indicating excessive reactive oxygen species (ROS) generation driven by succinate’s rapid reoxidization and glycerophospholipid degradation. Molecular validation mechanistically revealed that astragaloside IV stimulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) released from Kelch-like ECH-associated protein 1 (Keap1) and translocated to the nucleus to combine with musculoaponeurotic fibrosarcoma (Maf) to initiate the transcription of antioxidative gene heme oxygenase-1 (HO-1), which performed a wide range of ROS scavenging processes against pathological oxidative stress in the hearts. As expected, increasing succinate and decreasing lysophospholipid levels were observed in the astragaloside IV-pretreated group compared with the I/R model group. These results suggested that astragaloside IV ameliorated myocardial I/R injury by modulating succinate and lysophospholipid metabolism and scavenging ROS via the Nrf2 signal pathway.
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Basireddy, Mahesh, T. Scott Isbell, Xinjun Teng, Rakesh P. Patel, and Anupam Agarwal. "Effects of sodium nitrite on ischemia-reperfusion injury in the rat kidney." American Journal of Physiology-Renal Physiology 290, no. 4 (April 2006): F779—F786. http://dx.doi.org/10.1152/ajprenal.00334.2005.
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Reactive oxygen and nitrogen species play a key role in the pathophysiology of renal ischemia-reperfusion (I/R) injury. Recent studies have shown that nitrite (NO2−) serves as an endogenous source of nitric oxide (NO), particularly in the presence of hypoxia and acidosis. Nanomolar concentrations of NO2− reduce injury following I/R in the liver and heart in vivo. The purpose of this study was to evaluate the role of NO2− in renal I/R injury. Male Sprague-Dawley rats underwent a unilateral nephrectomy followed by 45 min of ischemia of the contralateral kidney or sham surgery under isoflurane anesthesia. Animals received normal saline, sodium NO2−, or sodium nitrate (NO3−; 1.2 nmol/g body wt ip) at 22.5 min after induction of ischemia or 15 min before ischemia. A separate set of animals received saline, NO2−, or NO3− (0.12, 1.2, or 12 nmol/g body wt iv) 45 min before ischemia. Serum creatinine and blood urea nitrogen were increased following I/R injury but were not significantly different among treatment groups at 24 and 48 h after acute renal injury. Interestingly, NO3− administration appeared to worsen renal injury. Histological scoring for loss of brush border, tubular necrosis, and red blood cell extravasation showed no significant differences among the treatment groups. The results indicate that, contrary to the protective effects of NO2− in I/R injury of the liver and heart, NO2− does not provide protection in renal I/R injury and suggest a unique metabolism of NO2− in the kidney.
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Kosuru, Ramoji, Yin Cai, Vidya Kandula, Dan Yan, Chunyan Wang, Hong Zheng, Yalan Li, Michael G. Irwin, Sanjay Singh, and Zhengyuan Xia. "AMPK Contributes to Cardioprotective Effects of Pterostilbene Against Myocardial Ischemia- Reperfusion Injury in Diabetic Rats by Suppressing Cardiac Oxidative Stress and Apoptosis." Cellular Physiology and Biochemistry 46, no. 4 (2018): 1381–97. http://dx.doi.org/10.1159/000489154.
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Background/Aims: Pterostilbene (PT) exerts antidiabetic effects by decreasing blood glucose and modulating lipid metabolism and has been shown to attenuate myocardial ischemia-reperfusion (IR) injury in non-diabetic subjects. However, whether PT can protect against myocardial IR injury in diabetes is unknown. AMPK stimulation is indispensable in offering cardioprotection against myocardial IR injury in diabetes by limiting cardiac apoptosis. Thus, we hypothesized that PT may confer protection against myocardial IR injury in diabetes via AMPK activation. Methods: Sprague-Dawley rats at eight weeks of diabetes induction (induced by an intravenous dose of 65 mg/kg streptozotocin) were administered with vehicle or PT (20 and 40 mg/kg/day, p.o.) for four weeks (starting from week 9 to 12). At the end of week 12, myocardial IR injury was induced by subjecting the diabetic rats to 30 minutes of coronary artery ligation and followed by 2 hours of reperfusion. In in vitro studies, rat primary cardiomyocytes were incubated with low glucose (LG, 5.5 mM) or high glucose (HG, 30 mM) and exposed to 45 minutes hypoxia and 2 hours reoxygenation in the presence or absence of PT (0.5 µM) or the AMPK inhibitor compound C (CC, 5 µM). Results: PT significantly reduced post-ischemic cardiac infarct size, oxidative stress, plasma lactate dehydrogenase (LDH), creatine kinase-MB levels and apoptosis in diabetic rats. In cardiomyocytes, PT decreased hypoxia/ reoxygenation-induced oxidative stress, attenuated LDH and cleaved caspase3/caspase3 ratio and increased Bcl-2/Bax ratio and AMPK phosphorylation. However, CC administration blunted the cardioprotective effects of PT both in vivo and in vitro. Conclusion: Suppressing cardiac oxidative stress and apoptosis via AMPK stimulation may represent a primary mechanism whereby pterostilbene attenuates diabetic myocardial IR injury.
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Andrianova, Nadezda V., Vasily A. Popkov, Natalia S. Klimenko, Alexander V. Tyakht, Galina V. Baydakova, Olga Y. Frolova, Ljubava D. Zorova, Irina B. Pevzner, Dmitry B. Zorov, and Egor Y. Plotnikov. "Microbiome-Metabolome Signature of Acute Kidney Injury." Metabolites 10, no. 4 (April 4, 2020): 142. http://dx.doi.org/10.3390/metabo10040142.
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Intestinal microbiota play a considerable role in the host’s organism, broadly affecting its organs and tissues. The kidney can also be the target of the microbiome and its metabolites (especially short-chain fatty acids), which can influence renal tissue, both by direct action and through modulation of the immune response. This impact is crucial, especially during kidney injury, because the modulation of inflammation or reparative processes could affect the severity of the resulting damage or recovery of kidney function. In this study, we compared the composition of rat gut microbiota with its outcome, in experimental acute ischemic kidney injury and named the bacterial taxa that play putatively negative or positive roles in the progression of ischemic kidney injury. We investigated the link between serum creatinine, urea, and a number of metabolites (acylcarnitines and amino acids), and the relative abundance of various bacterial taxa in rat feces. Our analysis revealed an increase in levels of 32 acylcarnitines in serum, after renal ischemia/reperfusion and correlation with creatinine and urea, while levels of three amino acids (tyrosine, tryptophan, and proline) had decreased. We detected associations between bacterial abundance and metabolite levels, using a compositionality-aware approach—Rothia and Staphylococcus levels were positively associated with creatinine and urea levels, respectively. Our findings indicate that the gut microbial community contains specific members whose presence might ameliorate or, on the contrary, aggravate ischemic kidney injury. These bacterial taxa could present perspective targets for therapeutical interventions in kidney pathologies, including acute kidney injury.
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Neto, Joao Seda, Atsunori Nakao, Kei Kimizuka, Anna Jeanine Romanosky, Donna B. Stolz, Takashi Uchiyama, Michael A. Nalesnik, Leo E. Otterbein, and Noriko Murase. "Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide." American Journal of Physiology-Renal Physiology 287, no. 5 (November 2004): F979—F989. http://dx.doi.org/10.1152/ajprenal.00158.2004.
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Carbon monoxide (CO), a product of heme metabolism by heme oxygenases, is known to impart protection against oxidative stress. We hypothesized that CO would protect ischemia-reperfusion (I/R) injury of transplanted organs, and the efficacy of CO was studied in the rat kidney transplantation model. A Lewis rat kidney graft, preserved in University of Wisconsin solution at 4°C for 24 h, was orthotopically transplanted into syngeneic rats. Recipients were maintained in room air or exposed to CO (250 ppm) in air for 1 h before and 24 h after transplantation. Animals were killed 1, 3, 6, and 24 h after transplantation to assess efficacy of inhaled CO. Rapid upregulation of mRNA for IL-6, IL-1β, TNF-α, ICAM-1, heme oxygenase-1, and inducible nitric oxide synthase was observed within 3 h after transplantation in the control grafts of air-exposed recipients, associating with histopathological evidences of acute tubular necrosis, interstitial hemorrhage, and edema. In contrast, the increase of inflammatory mediators was markedly inhibited in kidney grafts of CO-treated recipients, which correlated with improved renal cortical blood flow. Further detailed morphological analyses revealed that CO preserved the glomerular vascular architecture and podocyte viability with less apoptosis of tubular epithelial cells and less ED1+ macrophage infiltration. CO inhalation resulted in improved serum creatinine levels and clearance, and animal survival was significantly improved with CO to 60.5 from 25 days in untreated controls. The study demonstrates that exposure of kidney graft recipients to CO at a low concentration can impart significant protective effects against renal I/R injury and improve function of renal grafts.
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Southworth, Richard, and Pamela B. Garlick. "Dobutamine responsiveness, PET mismatch, and lack of necrosis in low-flow ischemia: is this hibernation in the isolated rat heart?" American Journal of Physiology-Heart and Circulatory Physiology 285, no. 1 (July 2003): H316—H324. http://dx.doi.org/10.1152/ajpheart.00906.2002.
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The clinical hallmarks of hibernating myocardium include hypocontractility while retaining an inotropic reserve (using dobutamine echocardiography), having normal or increased [18F]fluoro-2-deoxyglucose-6-phosphate (18FDG6P) accumulation associated with decreased coronary flow [flow-metabolism mismatch by positron emission tomography (PET)], and recovering completely postrevascularization. In this study, we investigated an isolated rat heart model of hibernation using experimental equivalents of these clinical techniques. Rat hearts ( n = 5 hearts/group) were perfused with Krebs-Henseleit buffer for 40 min at 100% flow and 3 h at 10% flow and reperfused at 100% flow for 30 min (paced at 300 beats/min throughout). Left ventricular developed pressure fell to 30 ± 8% during 10% flow and recovered to 90 ± 7% after reperfusion. In an additional group, this recovery of function was found to be preserved over 2 h of reperfusion. Electron microscopic examination of hearts fixed at the end of the hibernation period demonstrated a lack of ischemic injury and an accumulation of glycogen granules, a phenomenon observed clinically. In a further group, hearts were challenged with dobutamine during the low-flow period. Hearts demonstrated an inotropic reserve at the expense of increased lactate leakage, with no appreciable creatine kinase release. PET studies used the same basic protocol in both dual- and globally perfused hearts (with 250MBq18FDG in Krebs buffer ± 0.4 mmol/l oleate). PET data showed flow-metabolism “mismatch;” whether regional or global,18FDG6P accumulation in ischemic tissue was the same as (glucose only) or significantly higher than (glucose + oleate) control tissue (0.023 ± 0.002 vs. 0.011 ± 0.002 normalized counts · s-1· g-1· min-1, P < 0.05) despite receiving 10% of the flow. This isolated rat heart model of acute hibernation exhibits many of the same characteristics demonstrated clinically in hibernating myocardium.
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Manju, L., and R. Renuka Nair. "Magnesium deficiency augments myocardial response to reactive oxygen species." Canadian Journal of Physiology and Pharmacology 84, no. 6 (June 2006): 617–24. http://dx.doi.org/10.1139/y06-017.
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Magnesium (Mg) deficiency and oxidative stress are independently implicated in the etiopathogenesis of various cardiovascular disorders. This study was undertaken to examine the hypothesis that Mg deficiency augments the myocardial response to oxidative stress. Electrically stimulated rat papillary muscle was used for recording the contractile variation. Biochemical variables of energy metabolism (adenosine triphosphate (ATP) and creatine phosphate) and markers of tissue injury (lactate dehydrogenase (LDH) release and lipidperoxidation), which can affect myocardial contractility, were assayed in Langendorff-perfused rat hearts. Hydrogen peroxide (100 µmol/L) was used as the source of reactive oxygen species. The negative inotropic response to H2O2 was significantly higher in Mg deficiency (0.48 mmol Mg/L) than in Mg sufficiency (1.2 mmol Mg/L). Low Mg levels did not affect ATP levels or tissue lipid peroxidation. However, H2O2 induced a decrease in ATP; enhanced lipid peroxidation and the release of LDH were augmented by Mg deficiency. Increased lipid peroxidation associated with a decrease in available energy might be responsible for the augmentation of the negative inotropic response to H2O2 in Mg deficiency. The observations from this study validate the hypothesis that myocardial response to oxidative stress is augmented by Mg deficiency. This observation has significance in ischemia–reperfusion injury, where Mg deficiency can have an additive effect on the debilitating consequences.
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Estrela, Gabriel Rufino, Leandro Ceotto Freitas-Lima, Alexandre Budu, Adriano Cleis de Arruda, Mauro Sergio Perilhão, Ricardo Ambrósio Fock, Jonatan Barrera-Chimal, and Ronaldo Carvalho Araújo. "Chronic Kidney Disease Induced by Cisplatin, Folic Acid and Renal Ischemia Reperfusion Induces Anemia and Promotes GATA-2 Activation in Mice." Biomedicines 9, no. 7 (July 2, 2021): 769. http://dx.doi.org/10.3390/biomedicines9070769.
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Anemia is a common feature of chronic kidney disease (CKD). It is a process related to erythropoietin deficiency, shortened erythrocyte survival, uremic erythropoiesis inhibitors, and disordered iron homeostasis. Animal models of CKD-induced anemia are missing and would be desirable in order to study anemia mechanisms and facilitate the development of novel therapeutic tools. We induced three different models of CKD in mice and evaluated the development of anemia characteristics. Mice were subjected to unilateral ischemia-reperfusion or received repeated low doses of cisplatin or folic acid to induce nephropathy. Renal function, kidney injury and fibrotic markers were measured to confirm CKD. Moreover, serum hemoglobin, ferritin and erythropoietin were analyzed. Renal mRNA levels of HIF-2α, erythropoietin, hepcidin, GATA-2, and GATA-2 target genes were also determined. All three CKD models presented increased levels of creatinine, urea, and proteinuria. Renal up-regulation of NGAL, KIM-1, and TNF-α mRNA levels was observed. Moreover, the three CKD models developed fibrosis and presented increased fibrotic markers and α-SMA protein levels. CKD induced decreased hemoglobin and ferritin levels and increased erythropoietin levels in the serum. Renal tissue showed decreased erythropoietin and HIF-2α mRNA levels, while an increase in the iron metabolism regulator hepcidin was observed. GATA-2 transcription factor (erythropoietin repressor) mRNA levels were increased in all CKD models, as well as its target genes. We established three models of CKD-induced anemia, regardless of the mechanism and severity of kidney injury.
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Hou, Jiangang, Songjie Cai, Yuya Kitajima, Masayuki Fujino, Hidenori Ito, Kiwamu Takahashi, Fuminori Abe, Tohru Tanaka, Qiang Ding, and Xiao-Kang Li. "5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury." American Journal of Physiology-Renal Physiology 305, no. 8 (October 15, 2013): F1149—F1157. http://dx.doi.org/10.1152/ajprenal.00275.2013.
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Renal ischemia reperfusion injury (IRI) is a major factor responsible for acute renal failure. An intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO), and iron (Fe2+), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe2+ 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe2+ increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe2+ treatments significantly decreased the tubular damage and number of apoptotic cells. IRI-induced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe2+ group. Furthermore, mRNA expression of HO-1, TNF-α, and interferon-γ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-α and interferon-γ were decreased in the 5-ALA/Fe2+-pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/Fe2+ can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO.
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Zhang, Yunfang, Haitham El-Sikhry, Ketul R. Chaudhary, Sri Nagarjun Batchu, Anooshirvan Shayeganpour, Taibeh Orujy Jukar, J. Alyce Bradbury, et al. "Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 1 (July 2009): H37—H46. http://dx.doi.org/10.1152/ajpheart.00983.2008.
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Human cytochrome P-450 (CYP)2J2 is abundant in heart and active in biosynthesis of epoxyeicosatrienoic acids (EETs). Recently, we demonstrated that these eicosanoid products protect myocardium from ischemia-reperfusion injury. The present study utilized transgenic (Tr) mice with cardiomyocyte-specific overexpression of human CYP2J2 to investigate protection toward toxicity resulting from acute (0, 5, or 15 mg/kg daily for 3 days, followed by 24-h recovery) or chronic (0, 1.5, or 3.0 mg/kg biweekly for 5 wk, followed by 2-wk recovery) doxorubicin (Dox) administration. Acute treatment resulted in marked elevations of serum lactate dehydrogenase and creatine kinase levels that were significantly greater in wild-type (WT) than CYP2J2 Tr mice. Acute treatment also resulted in less activation of stress response enzymes in CYP2J2 Tr mice (catalase 750% vs. 300% of baseline, caspase-3 235% vs. 165% of baseline in WT vs. CYP2J2 Tr mice). Moreover, CYP2J2 Tr hearts exhibited less Dox-induced cardiomyocytes apoptosis (measured by TUNEL) compared with WT hearts. After chronic treatment, comparable decreases in body weight were observed in WT and CYP2J2 Tr mice. However, cardiac function, assessed by measurement of fractional shortening with M-mode transthoracic echocardiography, was significantly higher in CYP2J2 Tr than WT hearts after chronic Dox treatment (WT 37 ± 2%, CYP2J2 Tr 47 ± 1%). WT mice also had larger increases in β-myosin heavy chain and cardiac ankryin repeat protein compared with CYP2J2 Tr mice. CYP2J2 Tr hearts had a significantly higher rate of Dox metabolism than WT hearts (2.2 ± 0.25 vs. 1.6 ± 0.50 ng·min−1·100 μg protein−1). In vitro data from H9c2 cells demonstrated that EETs attenuated Dox-induced mitochondrial damage. Together, these data suggest that cardiac-specific overexpression of CYP2J2 limited Dox-induced toxicity.
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Papachristoforou, Eleftheria, Vaia Lambadiari, Eirini Maratou, and Konstantinos Makrilakis. "Association of Glycemic Indices (Hyperglycemia, Glucose Variability, and Hypoglycemia) with Oxidative Stress and Diabetic Complications." Journal of Diabetes Research 2020 (October 12, 2020): 1–17. http://dx.doi.org/10.1155/2020/7489795.
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Oxidative stress (OS) is defined as a disturbance in the prooxidant-antioxidant balance of the cell, in favor of the former, which results in the antioxidant capacity of the cell to be overpowered. Excess reactive oxygen species (ROS) production is very harmful to cell constituents, especially proteins, lipids, and DNA, thus causing damage to the cell. Oxidative stress has been associated with a variety of pathologic conditions, including diabetes mellitus (DM), cancer, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and accelerated aging. Regarding DM specifically, previous experimental and clinical studies have pointed to the fact that oxidative stress probably plays a major role in the pathogenesis and development of diabetic complications. It is postulated that hyperglycemia induces free radicals and impairs endogenous antioxidant defense systems through several different mechanisms. In particular, hyperglycemia promotes the creation of advanced glycation end-products (AGEs), the activation of protein kinase C (PKC), and the hyperactivity of hexosamine and sorbitol pathways, leading to the development of insulin resistance, impaired insulin secretion, and endothelial dysfunction, by inducing excessive ROS production and OS. Furthermore, glucose variability has been associated with OS as well, and recent evidence suggests that also hypoglycemia may be playing an important role in favoring diabetic vascular complications through OS, inflammation, prothrombotic events, and endothelial dysfunction. The association of these diabetic parameters (i.e., hyperglycemia, glucose variability, and hypoglycemia) with oxidative stress will be reviewed here.
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Li, Dai, Ke Xia, Nian-Sheng Li, Dan Luo, Shan Wang, De-Jian Jiang, Han-Wu Deng, and Yuan-Jian Li. "Reduction of asymmetric dimethylarginine involved in the cardioprotective effect of losartan in spontaneously hypertensive rats." Canadian Journal of Physiology and Pharmacology 85, no. 8 (August 2007): 783–89. http://dx.doi.org/10.1139/y07-073.
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Previous studies have indicated that nitric oxide synthase (NOS) inhibitors can induce an increase of blood pressure and exacerbate myocardial injury induced by ischemia and reperfusion, whereas angiotensin II receptor antagonists protect the myocardium against injury induced by ischemia and reperfusion. Isolated hearts from male spontaneously hypertensive rats (SHR) or male Wistar-Kyoto rats (WKY) were subjected to 20 min global ischemia and 30 min reperfusion. Heart rate, coronary flow, left ventricular pressure, and its first derivatives (±dP/dtmax) were recorded, and serum concentrations of asymmetric dimethylarginine (ADMA) and NO and the release of creatine kinase in coronary effluent were measured. The level of ADMA was significantly increased and the concentration of NO was decreased in SHR. Ischemia and reperfusion significantly inhibited the recovery of cardiac function and increased the release of creatine kinase, and ischemia and reperfusion-induced myocardial injury in SHR was aggravated compared with WKY. Vasodilation responses to acetylcholine of aortic rings were decreased in SHR. Treatment with losartan (30 mg/kg) for 14 days significantly lowered blood pressure, elevated the plasma level of NO, and decreased the plasma concentration of ADMA in SHR. Treatment with losartan significantly improved endothelium-dependent relaxation and cardiac function during ischemia and reperfusion in SHR. Exogenous ADMA also aggravated myocardial injury induced by ischemia and reperfusion in isolated perfused heart of WKY, as shown by increasing creatine kinase release and decreasing cardiac function. The present results suggest that the protective effect of losartan on myocardial injury induced by ischemia and reperfusion is related to the reduction of ADMA levels.
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Figueredo, Vincent M., Ivan Diamond, Hui-Zhong Zhou, and S. Albert Camacho. "Chronic dipyridamole therapy produces sustained protection against cardiac ischemia-reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 277, no. 5 (November 1, 1999): H2091—H2097. http://dx.doi.org/10.1152/ajpheart.1999.277.5.h2091.
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Sustained protection against ischemia-reperfusion injury is not available for patients at risk for myocardial infarction who may require emergent reperfusion therapy. Whereas ischemic preconditioning and adenosinergic agents reduce myocardial injury, they are only effective when given immediately before ischemia or reperfusion. We recently found chronic ethanol exposure, an adenosine uptake inhibitor, produced sustained cardioprotection against ischemia-reperfusion injury. We now ask whether chronic dipyridamole therapy, a clinically usable nucleoside transport inhibitor, induces similar cardioprotection. Perfused hearts from guinea pigs, given dipyridamole (4 mg ⋅ kg−1⋅ day−1) in their water for 2–6 wk ( n= 10 for each group), underwent ischemia-reperfusion. Injury was assessed by recovery of left ventricular developed (LVDP) and end-diastolic (LVEDP) pressures and creatine kinase release. During reperfusion, hearts from dipyridamole-treated animals (6 wk) had 74% higher LVDP, 28% lower LVEDP, and 61% lower creatine kinase release versus controls. Adenosine A1-receptor antagonism (8-cyclopentyl-1,3-dipropylxanthine; 200 nM) abolished the protection of dipyridamole but A2antagonism (3,7-dimethyl-1-propargylxanthine; 10 mM) did not. Dipyridamole therapy produces sustained protection against ischemia-reperfusion injury in guinea pigs. This cardioprotection requires adenosine A1receptor signaling at the time of ischemia.
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Obermaier, Robert, Oliver Drognitz, Stefan Benz, Ulrich T. Hopt, and Przemyslaw Pisarski. "Pancreatic Ischemia/Reperfusion Injury." Pancreas 37, no. 3 (October 2008): 328–32. http://dx.doi.org/10.1097/mpa.0b013e31816d9283.
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Lee, Warren H., John S. Gounarides, Eric S. Roos, and Michael S. Wolin. "Influence of peroxynitrite on energy metabolism and cardiac function in a rat ischemia-reperfusion model." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 4 (October 2003): H1385—H1395. http://dx.doi.org/10.1152/ajpheart.00808.2002.
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Ischemia-reperfusion generates peroxynitrite (ONOO–), which interacts with many of the systems altered by ischemia-reperfusion. This study examines the influence of endogenously produced ONOO– on cardiac metabolism and function. Nitro-l-arginine (an inhibitor of ONOO– biosynthesis) and urate (a scavenger of ONOO–) were utilized to investigate potential pathophysiological roles for ONOO– in a rat Langendorff heart model perfused with glucose-containing saline at constant pressure and exposed to 30 min of ischemia followed by 60 min of reperfusion. In this model, ischemia-reperfusion decreased contractile function (e.g., left ventricular developed pressure), cardiac work (rate-pressure product), efficiency of O2 utilization, membrane-bound creatine kinase activity, and NMR-detectable ATP and creatine phosphate without significantly altering the recovery of coronary flow, heart rate, lactate release, and muscle pH. Treatment with urate and nitro-l-arginine produced a substantial recovery of left ventricular developed pressure, rate-pressure product, efficiency of O2 utilization, creatine kinase activity, and NMR-detectable creatine phosphate and a partial recovery of ATP. The pattern of effects observed in this study and in previously published work with similar models suggests that ONOO– may alter key steps in the efficiency of mitochondrial high-energy phosphate generation.
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Almeida, Francine M., Angela S. Battochio, João P. Napoli, Katiusa A. Alves, Grace S. Balbin, Manoel Oliveira-Junior, Henrique T. Moriya, Paulo M. Pego-Fernandes, Rodolfo P. Vieira, and Rogerio Pazetti. "Creatine Supply Attenuates Ischemia-Reperfusion Injury in Lung Transplantation in Rats." Nutrients 12, no. 9 (September 10, 2020): 2765. http://dx.doi.org/10.3390/nu12092765.
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Ischemia-reperfusion injury (IRI) is one of the factors limiting the success of lung transplantation (LTx). IRI increases death risk after transplantation through innate immune system activation and inflammation induction. Some studies have shown that creatine (Cr) protects tissues from ischemic damage by its antioxidant action. We evaluated the effects of Cr supplementation on IRI after unilateral LTx in rats. Sixty-four rats were divided into four groups: water + 90 min of ischemia; Cr + 90 min of ischemia; water + 180 min of ischemia; and Cr + 180 min of ischemia. Donor animals received oral Cr supplementation (0.5 g/kg/day) or vehicle (water) for five days prior to LTx. The left lung was exposed to cold ischemia for 90 or 180 min, followed by reperfusion for 2 h. We evaluated the ventilatory mechanics and inflammatory responses of the graft. Cr-treated animals showed a significant decrease in exhaled nitric oxide levels and inflammatory cells in blood, bronchoalveolar lavage fluid and lung tissue. Moreover, edema, cell proliferation and apoptosis in lung parenchyma were reduced in Cr groups. Finally, TLR-4, IL-6 and CINC-1 levels were lower in Cr-treated animals. We concluded that Cr caused a significant decrease in the majority of inflammation parameters evaluated and had a protective effect on the IRI after LTx in rats.
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Kula-Alwar, Duvaraka, Hiran A. Prag, and Thomas Krieg. "Targeting Succinate Metabolism in Ischemia/Reperfusion Injury." Circulation 140, no. 24 (December 10, 2019): 1968–70. http://dx.doi.org/10.1161/circulationaha.119.042791.
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Mangino, M. J., C. B. Anderson, M. K. Murphy, E. Brunt, and J. Turk. "Mucosal arachidonate metabolism and intestinal ischemia-reperfusion injury." American Journal of Physiology-Gastrointestinal and Liver Physiology 257, no. 2 (August 1, 1989): G299—G307. http://dx.doi.org/10.1152/ajpgi.1989.257.2.g299.
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Mucosal arachidonic acid metabolism was examined after 3 h of ischemia and 1 h of reperfusion in isolated ileal segments in the dog. The cyclooxygenase products thromboxane B2, 6-ketoprostaglandin F1 alpha, and prostaglandin E2 increased by 365%, 97%, and 158%, respectively, after ischemia and reperfusion but were not altered after 3 h of ischemia alone. The potent chemotactic lipoxygenase product leukotriene B4 (LTB4) increased by 687% after ischemia and reperfusion and was not affected by ischemia without reperfusion. In addition, tissue production of the thiol ether leukotrienes (LTC4, LTD4, and LTE4) increased threefold after ischemia and reperfusion. Quantitation of regionally isomeric hydroxy acids produced from arachidonate revealed a 300% increase in 12-hydroxyeicosatetraenoate (12-HETE) after intestinal ischemia and reperfusion without a change in other isomers (15-HETE and 5-HETE). Stereochemical analysis of 12-HETE demonstrated exclusive synthesis of the S-enantiomer. A significant and time-dependent decrease in intestinal blood flow also occurred during reperfusion. Administration of the dual cyclooxygenase-lipoxygenase synthesis inhibitor BW755C (1 mg/kg ia) did not alter time-dependent decreases in blood flow and failed to inhibit eicosanoid synthesis. Histologic examinations of intestinal samples revealed significant mucosal damage associated with ischemia alone and ischemia after reperfusion. This study indicates that intestinal ischemia-reperfusion injury is associated with dramatic alterations in mucosal production of vasoactive eicosanoids and with changes in blood flow that occur during reperfusion but not during ischemia alone. These events may be involved in the pathology characteristic of this injury.
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Rubin, B. B., S. Liauw, J. Tittley, A. D. Romaschin, and P. M. Walker. "Prolonged adenine nucleotide resynthesis and reperfusion injury in postischemic skeletal muscle." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 5 (May 1, 1992): H1538—H1547. http://dx.doi.org/10.1152/ajpheart.1992.262.5.h1538.
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Skeletal muscle ischemia results in energy depletion and intracellular acidosis. Reperfusion is associated with impaired adenine nucleotide resynthesis, edema formation, and myocyte necrosis. The purpose of these studies was to define the time course of cellular injury and adenine nucleotide depletion and resynthesis in postischemic skeletal muscle during prolonged reperfusion in vivo. The isolated canine gracilis muscle model was used. After 5 h of ischemia, muscles were reperfused for either 1 or 48 h. Lactate and creatine phosphokinase (CPK) release during reperfusion was calculated from arteriovenous differences and blood flow. Adenine nucleotides, nucleosides, bases, and creatine phosphate were quantified by high-performance liquid chromatography, and muscle necrosis was assessed by nitroblue tetrazolium staining. Reperfusion resulted in a rapid release of lactate, which paralleled the increase in blood flow, and a delayed but prolonged release of CPK. Edema formation and muscle necrosis increased between 1 and 48 h of reperfusion (P less than 0.05). Recovery of energy stores during reperfusion was related to the extent of postischemic necrosis, which correlated with the extent of nucleotide dephosphorylation during ischemia (r = 0.88, P less than 0.001). These results suggest that both adenine nucleotide resynthesis and myocyte necrosis, which are protracted processes in reperfusing skeletal muscle, are related to the extent of nucleotide dephosphorylation during ischemia.
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Kang, Y. James, Guangqiu Li, and Jack T. Saari. "Metallothionein inhibits ischemia-reperfusion injury in mouse heart." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 3 (March 1, 1999): H993—H997. http://dx.doi.org/10.1152/ajpheart.1999.276.3.h993.
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Oxidative stress is believed to play a major role in ischemia-reperfusion injury to the heart. Metallothionein (MT), a potential free radical scavenger, may function in cardiac protection against ischemia-reperfusion damage. To test this hypothesis, a specific cardiac MT-overexpressing transgenic mouse model was used. The hearts isolated from these animals were subjected to 50 min of warm (37°C) zero-flow ischemia followed by 60- or 90-min reflow. Compared with the nontransgenic controls, the transgenic mouse hearts with MT concentrations ∼10-fold higher than normal showed significantly improved recovery of contractile force postischemia (69.2 ± 4.2 vs. 26.0 ± 6.0% at the end of 60-min reperfusion, P < 0.01). Efflux of creatine kinase from these transgenic hearts was reduced by more than 50% ( P < 0.01). In addition, the zone of infarction induced by ischemia-reperfusion at the end of 90-min reperfusion was suppressed by ∼40% ( P < 0.01) in the transgenic hearts. The results strongly indicate that MT provides protection against ischemia-reperfusion-induced heart injury.
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Trueblood, Nathan A., Ravichandran Ramasamy, Li Feng Wang, and Saul Schaefer. "Niacin protects the isolated heart from ischemia-reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 279, no. 2 (August 1, 2000): H764—H771. http://dx.doi.org/10.1152/ajpheart.2000.279.2.h764.
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Nicotinic acid (niacin) has been shown to decrease myocyte injury. Because interventions that lower the cytosolic NADH/NAD+ratio improve glycolysis and limit infarct size, we hypothesized that 1) niacin, as a precursor of NAD+, would lower the NADH/NAD+ratio, increase glycolysis, and limit ischemic injury and 2) these cardioprotective benefits of niacin would be limited in conditions that block lactate removal. Isolated rat hearts were perfused without (Ctl) or with 1 μM niacin (Nia) and subjected to 30 min of low-flow ischemia (10% of baseline flow, LF) and reperfusion. To examine the effects of limiting lactate efflux, experiments were performed with 1) Ctl and Nia groups subjected to zero-flow ischemia and 2) the Nia group treated with the lactate-H+cotransport inhibitor α-cyano-4-hydroxycinnamate under LF conditions. Measured variables included ATP, pH, cardiac function, tissue lactate-to-pyruvate ratio (reflecting NADH/NAD+), lactate efflux rate, and creatine kinase release. The lactate-to-pyruvate ratio was reduced by more than twofold in Nia-LF hearts during baseline and ischemic conditions ( P < 0.001 and P< 0.01, respectively), with concurrent lower creatine kinase release than Ctl hearts ( P < 0.05). Nia-LF hearts had significantly greater lactate release during ischemia ( P < 0.05 vs. Ctl hearts) as well as higher functional recovery and a relative preservation of high-energy phosphates. Inhibiting lactate efflux with α-cyano-4-hydroxycinnamate and blocking lactate washout with zero flow negated some of the beneficial effects of niacin. During LF, niacin lowered the cytosolic redox state and increased lactate efflux, consistent with redox regulation of glycolysis. Niacin significantly improved functional and metabolic parameters under these conditions, providing additional rationale for use of niacin as a therapeutic agent in patients with ischemic heart disease.
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Kong, Linghua, Martin Andrassy, Jong Sun Chang, Chun Huang, Tomohiro Asai, Matthias J. Szabolcs, Shunichi Homma, et al. "PKCβ modulates ischemia-reperfusion injury in the heart." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 4 (April 2008): H1862—H1870. http://dx.doi.org/10.1152/ajpheart.01346.2007.
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Protein kinase C-βII (PKCβII) is an important modulator of cellular stress responses. To test the hypothesis that PKCβII modulates the response to myocardial ischemia-reperfusion (I/R) injury, we subjected mice to occlusion and reperfusion of the left anterior descending coronary artery. Homozygous PKCβ-null (PKCβ−/−) and wild-type mice fed the PKCβ inhibitor ruboxistaurin displayed significantly decreased infarct size and enhanced recovery of left ventricular (LV) function and reduced markers of cellular necrosis and serum creatine phosphokinase and lactate dehydrogenase levels compared with wild-type or vehicle-treated animals after 30 min of ischemia followed by 48 h of reperfusion. Our studies revealed that membrane translocation of PKCβII in LV tissue was sustained after I/R and that gene deletion or pharmacological blockade of PKCβ protected ischemic myocardium. Homozygous deletion of PKCβ significantly diminished phosphorylation of c-Jun NH2-terminal mitogen-activated protein kinase and expression of activated caspase-3 in LV tissue of mice subjected to I/R. These data implicate PKCβ in I/R-mediated myocardial injury, at least in part via phosphorylation of JNK, and suggest that blockade of PKCβ may represent a potent strategy to protect the vulnerable myocardium.
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Han, Liping, Changqing Xu, Yimin Guo, Hongzhu Li, Chunming Jiang, and Yajun Zhao. "Polyamine metabolism in rat myocardial ischemia-reperfusion injury." International Journal of Cardiology 132, no. 1 (February 2009): 142–44. http://dx.doi.org/10.1016/j.ijcard.2007.07.163.
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Orsenigo, M. N., C. Porta, C. Sironi, U. Laforenza, G. Meyer, and M. Tosco. "Effects of creatine in a rat intestinal model of ischemia/reperfusion injury." European Journal of Nutrition 51, no. 3 (June 23, 2011): 375–84. http://dx.doi.org/10.1007/s00394-011-0222-3.
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Drognitz, Oliver, Robert Obermaier, Ernst von Dobschuetz, Przemyslaw Pisarski, and Hannes Neeff. "Pancreas Transplantation and Ischemia-Reperfusion Injury." Pancreas 38, no. 2 (March 2009): 226–27. http://dx.doi.org/10.1097/mpa.0b013e3181788e2b.
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Li, Tiegang, Nana Wang, and Min Zhao. "Neuroprotective Effect of Phosphocreatine on Focal Cerebral Ischemia-Reperfusion Injury." Journal of Biomedicine and Biotechnology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/168756.
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Phosphocreatine (PCr) is a natural compound, which can donate high-energy phosphate group to ADP to synthesize ATP, even in the absence of oxygen and glucose. At present, it is widely used in cardiac and renal ischemia-reperfusion (IR) disease. In this study, to examine the protective efficacy of PCr against cerebral IR, disodium creatine phosphate was injected intravenously into rats before focal cerebral IR. Intracranial pressure (ICP), neurological score, cerebral infarction volume, and apoptotic neurons were observed. Expression of caspase-3 and aquaporin-4 (AQP4) was analyzed. Compared with IR group, rats pretreated with PCr had better neurologic score, less infarction volume, fewer ultrastructural histopathologic changes, reduced apoptosis, and lower aquaporin-4 level. In conclusion, PCr is neuroprotective after transient focal cerebral IR injury. Such a protection might be associated with apoptosis regulating proteins.
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Li, G., Y. Chen, J. T. Saari, and Y. J. Kang. "Catalase-overexpressing transgenic mouse heart is resistant to ischemia-reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 273, no. 3 (September 1, 1997): H1090—H1095. http://dx.doi.org/10.1152/ajpheart.1997.273.3.h1090.
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Myocardial ischemia-reperfusion injury is at least partially mediated by oxygen-derived free radicals. Catalase is a major enzyme involved in the detoxification of hydrogen peroxide. The activity of catalase in the heart is very low, which may be a factor responsible for the high sensitivity of the heart to ischemia-reperfusion injury. The present study was undertaken to determine whether elevation of catalase specifically in the heart of transgenic mice can provide protection against ischemia-reperfusion injury. Hearts isolated from transgenic mice in which catalase in the heart was elevated approximately 60-fold higher than that in nontransgenic heart and from the non-transgenic littermates were subjected to 50 min of warm (37 degrees C) zero-flow ischemia followed by 90 min reflow. Compared with nontransgenic controls, transgenic hearts showed significantly improved recovery of contractile force (75 vs. 25% at the end of 90 min reperfusion, P < 0.01). Efflux of creatine kinase was reduced by approximately 50%, and the zone of myocardial infarction as demarcated by triphenyltetrazolium at the end of reperfusion was reduced by approximately 40% in transgenic hearts compared with nontransgenic controls. These findings support the view that hydrogen peroxide is an important cause of ischemia-reperfusion damage and suggest that protection may be provided by elevation of catalase activity.
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Zheng, Qun, Xiao-Yi Bao, Peng-Chong Zhu, Qiang Tong, Guo-Qing Zheng, and Yan Wang. "Ginsenoside Rb1 for Myocardial Ischemia/Reperfusion Injury: Preclinical Evidence and Possible Mechanisms." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/6313625.
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Ginseng is an important herbal drug that has been used worldwide for many years. Ginsenoside Rb1 (G-Rb1), the major pharmacological extract from ginseng, possesses a variety of biological activities in the cardiovascular systems. Here, we conducted a preclinical systematic review to investigate the efficacy of G-Rb1 for animal models of myocardial ischemia/reperfusion injury and its possible mechanisms. Ten studies involving 211 animals were identified by searching 6 databases from inception to May 2017. The methodological quality was assessed by using the CAMARADES 10-item checklist. All the data were analyzed using RevMan 5.3 software. As a result, the score of study quality ranged from 3 to 7 points. Meta-analyses showed that G-Rb1 can significantly decrease the myocardial infarct size and cardiac enzymes (including lactate dehydrogenase, creatine kinase, and creatine kinase-MB) when compared with control group (P<0.01). Significant decrease in cardiac troponin T and improvement in the degree of ST-segment depression were reported in one study (P<0.05). Additionally, the possible mechanisms of G-Rb1 for myocardial infarction are antioxidant, anti-inflammatory, antiapoptosis, promoting angiogenesis and improving the circulation. Thus, G-Rb1 is a potential cardioprotective candidate for further clinical trials of myocardial infarction.
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Hoehn, Richard S., Aaron P. Seitz, Peter L. Jernigan, Erich Gulbins, and Michael J. Edwards. "Ischemia/Reperfusion Injury Alters Sphingolipid Metabolism in the Gut." Cellular Physiology and Biochemistry 39, no. 4 (2016): 1262–70. http://dx.doi.org/10.1159/000447831.
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Background: Intestinal ischemia/reperfusion injury (I/R) is a significant cause of morbidity and mortality in surgical patients. Ceramide is a mediator of apoptosis and has been implicated as increasing bacterial infection susceptibility. The metabolite of ceramide, sphingosine, was recently shown to play an important role in the cell-autonomous, innate immune response of the upper respiratory tract by killing bacterial pathogens. The role of ceramide and/or sphingosine after mesenteric I/R is unknown. We investigated the specific effects of intestinal I/R on tissue ceramide and sphingosine concentration and resulting susceptibility to bacterial invasion. Methods: To simulate intestinal I/R, C57BL/6 mice underwent 30 minutes of vascular clamp-induced occlusion of the superior mesenteric artery followed by variable reperfusion times. Jejunum segments and intraluminal contents were analyzed for ceramide, sphingosine and bacteria using immunohistochemistry. Jejunum samples were also homogenized and cultured to quantify bacterial presence in the proximal intestine. Results: We hypothesized that I/R induces an increase of ceramide in the intestine resulting in increased permeability, while a concomitant decrease of sphingosine may permit bacterial overgrowth. Control mice had no measurable bacteria in their proximal jejunum as measured by tissue culture and immunohistochemistry. After I/R, bacterial counts in the jejunum increased in a time-dependent manner, reaching a peak at 12 hours after reperfusion. Immunohistochemical analysis revealed a marked increase in ceramide in the vasculature of jejunal villi. In contrast, while ceramide concentrations in the epithelial cells decreased after I/R, sphingosine levels appeared to remain unchanged. Surprisingly, bacteria present in the jejunal lumen following I/R contained a ceramide coat. Conclusion: These data indicate that intestinal I/R leads to small intestine bacterial overgrowth as well as ceramide formation in the jejunal vasculature, which may contribute to the gut permeability associated with this injury. Moreover, our novel finding of ceramide in bacterial membranes represents a new opportunity to investigate the dynamic pathogenicity of the gut microbiome. The hypothesis that a decrease of sphingosine after I/R permits bacterial overgrowth in the intestine was not confirmed.
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Caswell, John E., Micah B. Strange, David M. Rimmer, Michael F. Gibson, Phillip Cole, and David J. Lefer. "A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 4 (April 2005): H1796—H1801. http://dx.doi.org/10.1152/ajpheart.00905.2004.
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HBOC-201 (Biopure; Cambridge, MA) is a glutaraldehyde-polymerized bovine hemoglobin (Hb) solution that is stroma free, has lower viscosity than blood, and promotes O2unloading. We investigated the effects of HBOC-201 in a canine model of myocardial ischemia-reperfusion injury. Dogs were anesthetized and subjected to 90 min of regional myocardial ischemia and 270 min of reperfusion. HBOC-201 or 0.9% saline vehicle equivalent to 10% total blood volume was infused 30 min before myocardial ischemia. Hemodynamic data and peripheral blood samples were taken at baseline, 1 h of myocardial ischemia, and 1, 2, and 4 h of reperfusion. At 270 min of reperfusion, the area at risk (AAR) per left ventricle and the area of infarction (Inf) per AAR were determined. The myocardial AARs in the two study groups were similar. In addition, myocardial blood flow (as measured by radioactive microspheres) in the ischemic zone was similar between the vehicle and HBOC-201 groups. HBOC-201-infused dogs demonstrated a significant ( P < 0.01) 56% reduction in Inf/AAR. Analysis of blood samples taken at 4 h of reperfusion showed a significant ( P < 0.05) reduction in creatine kinase MB isoform for the HBOC-201 group. Histological analysis of the myocardium demonstrated significant ( P < 0.01) reductions in neutrophil infiltration in the HBOC-201 group. These data indicate that treatment with HBOC-201 before myocardial ischemia-reperfusion reduces the extent of myocardial inflammation and ischemia-reperfusion injury in the canine myocardium.
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Pye, Joseph, Farhad Ardeshirpour, Arlene McCain, Dwight A. Bellinger, Elizabeth Merricks, Julian Adams, Peter J. Elliott, et al. "Proteasome inhibition ablates activation of NF-κB in myocardial reperfusion and reduces reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 3 (March 1, 2003): H919—H926. http://dx.doi.org/10.1152/ajpheart.00851.2002.
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Both acute coronary occlusion and reperfusion of an infarct-related artery lead to significant myocardial cell death. Recent evidence has been presented that activation of the transcription factor nuclear factor-κB (NF-κB) plays a critical role in reperfusion injury. NF-κB is usually bound to its inhibitor, IκB, and classic activation of NF-κB occurs when the 20S proteasome degrades IκB that has been phosphorylated and ubiquitinated. In this study, activation of NF-κB was inhibited by systemic administration of a 20S proteasome inhibitor (PS-519) in a porcine model of myocardial reperfusion injury. The experimental protocol induced myocardial ischemia in the distribution of the left anterior descending coronary artery for 1 h with subsequent reperfusion for 3 h. A single systemic treatment with PS-519 reduced 20S proteasome activity; blocked activation of NF-κB induced by reperfusion; reduced creatine kinase, creatine kinase-muscle-brain fraction, and troponin I release from the myocardium; preserved regional myocardial function measured by segmental shortening; significantly reduced the size of myocardial infarction; and exhibited no acute toxicity. These data show that myocardial reperfusion injury can be inhibited by using proteasome inhibitors, which likely function through the inhibition of NF-κB activation.
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Almeida, Francine Maria, Manoel Carneiro Oliveira-Junior, Renato Aparecido Souza, Ricardo Costa Petroni, Sonia Fatima Soto, Francisco Garcia Soriano, Paulo Tarso Camillo de Carvalho, et al. "Creatine supplementation attenuates pulmonary and systemic effects of lung ischemia and reperfusion injury." Journal of Heart and Lung Transplantation 35, no. 2 (February 2016): 242–50. http://dx.doi.org/10.1016/j.healun.2015.06.012.
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Fu, Ying, Cai Zhao, Rengui Saxu, Chaoran Yao, Lianbo Zhao, Weida Zheng, Peng Yu, and Yuou Teng. "Anastatin Derivatives Alleviate Myocardial Ischemia-Reperfusion Injury via Antioxidative Properties." Molecules 26, no. 16 (August 6, 2021): 4779. http://dx.doi.org/10.3390/molecules26164779.
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(±)-Anastatins A and B are flavonoids isolated from Anastatica hierochuntica. In a previous study, twenty-four di- and tri-substituted novel derivatives of anastatins were designed and their preliminary antioxidant activities were evaluated. In the present study, the protective effect of myocardial ischemia-reperfusion (I/R) and the systematic antioxidant capacity of 24 derivatives were further studied. Compound 13 was the most potent among all the compounds studied, which increased the survival of H9c2 cells to 80.82%. The antioxidant capability of compound 13 was evaluated in ferric reducing antioxidant power, 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging, and 2,2-diphenyl-1-picrylhydrazyl assays. It was observed that compound 13 significantly reduced infarcted areas and improved histopathological and electrocardiogram changes in rats with myocardial I/R injury. Moreover, compound 13 decreased the leakage rates of serum lactate dehydrogenase, creatine kinase, and malonyldialdehyde from rat myocardial tissues and increased the level of glutathione and superoxide dismutase activities following myocardial I/R injury in rats. Taken together, we concluded that compound 13 had potent cardioprotective effects against myocardial I/R injury both in vitro and in vivo owing to its extensive antioxidant activities.
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Thourani, Vinod H., Sukhdev S. Brar, Thomas P. Kennedy, Lisa R. Thornton, John A. Watts, Russell S. Ronson, Zhi-Qing Zhao, Anne L. Sturrock, John R. Hoidal, and Jakob Vinten-Johansen. "Nonanticoagulant heparin inhibits NF-κB activation and attenuates myocardial reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 6 (June 1, 2000): H2084—H2093. http://dx.doi.org/10.1152/ajpheart.2000.278.6.h2084.
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Heparin reduces ischemia-reperfusion injury to myocardium. This effect has been attributed to complement inhibition, but heparin also has other activities that might diminish ischemia-reperfusion. To further probe these mechanisms, we compared heparin or an o-desulfated nonanticoagulant heparin with greatly reduced anticomplement activity. When given at the time of coronary artery reperfusion in a canine model of myocardial infarction, heparin or o-desulfated heparin equally reduced neutrophil adherence to ischemic-reperfused coronary artery endothelium, influx of neutrophils into ischemic-reperfused myocardium, myocardial necrosis, and release of creatine kinase into plasma. Heparin or o-desulfated heparin also prevented dysfunction of endothelial-dependent coronary relaxation following ischemic injury. In addition, heparin and o-desulfated heparin inhibited translocation of the transcription nuclear factor-κB (NF-κB) from the cytoplasm to the nucleus in human endothelial cells and decreased NF-κB DNA binding in human endothelium and ischemic-reperfused rat myocardium. Thus heparin and nonanticoagulant heparin decrease ischemia-reperfusion injury by disrupting multiple levels of the inflammatory cascade, including the novel observation that heparins inhibit activation of the proinflammatory transcription factor NF-κB.
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Prathapasinghe, Gamika A., Yaw L. Siow, and Karmin O. "Detrimental role of homocysteine in renal ischemia-reperfusion injury." American Journal of Physiology-Renal Physiology 292, no. 5 (May 2007): F1354—F1363. http://dx.doi.org/10.1152/ajprenal.00301.2006.
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Ischemia followed by reperfusion is a major cause for renal injury in both native kidney and renal allografts. Hyperhomocysteinemia, a condition of elevated plasma homocysteine (Hcy) level, is associated with cardiovascular diseases. Recent evidence suggests that Hcy, at higher levels, may be harmful to other organs such as the kidney. In this study, we investigated the role of Hcy in ischemia-reperfusion-induced renal injury. The left kidney of a Sprague-Dawley rat was subjected to either 30-min or 1-h ischemia followed by 1- or 24-h reperfusion. Ischemia-reperfusion caused a significant increase in peroxynitrite formation and lipid peroxidation in kidneys, which reflected oxidative stress. The number of apoptotic cells in those kidneys was also markedly increased. Hcy levels were elevated 2.9- and 1.5-fold in kidneys subjected to ischemia alone or ischemia-reperfusion, respectively. Further investigation revealed that elevation of Hcy level in the kidney upon ischemia-reperfusion was due to reduced activity of cystathionine-β-synthase, a key enzyme in Hcy metabolism. Administration of anti-Hcy antibodies into the kidney not only abolished ischemia-reperfusion-induced oxidative stress and cell death in the kidneys but also restored renal function after 1 h of reperfusion. However, such a protective effect was not sustained after 24 h of reperfusion. In conclusion, ischemia-reperfusion impairs Hcy metabolism in the kidney. Hcy, at elevated levels, is capable of inducing oxidative stress and renal injury. Neutralization of Hcy with antibodies offers transient functional benefit against ischemia-reperfusion-induced oxidative stress and renal injury. These results suggest that Hcy may play a detrimental role in the kidney during ischemia-reperfusion.
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Leipala, J. A., R. Bhatnagar, E. Pineda, S. Najibi, K. Massoumi, and L. Packer. "Protection of the reperfused heart by L-propionylcarnitine." Journal of Applied Physiology 71, no. 4 (October 1, 1991): 1518–22. http://dx.doi.org/10.1152/jappl.1991.71.4.1518.
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The effects of L-propionylcarnitine on mechanical function, creatine phosphate and ATP content, and lactate dehydrogenase leakage were studied in isolated perfused rat hearts exposed to global no-flow ischemia for 30 min followed by reperfusion for 20 min. Five and 10 mM L-propionylcarnitine resulted in a 100% recovery of left ventricular-developed pressure, whereas the recovery was only 40% in the hearts perfused without this agent. Ischemia-reperfusion caused a 85% loss of creatine phosphate and a 77% loss of ATP, which was prevented by 10 mM L-propionylcarnitine. Five millimolar L-propionylcarnitine protected the heart from the loss of creatine phosphate but not from the loss of ATP. Ten millimolar L-propionylcarnitine failed to improve the postischemic left ventricular-developed pressure, when it was added to the perfusate only after ischemia. L-propionylcarnitine alleviated the decrease of coronary flow in the reperfused hearts. Lactate dehydrogenase leakage was aggravated in the beginning of the reperfusion period by 10 mM L-propionylcarnitine. This adverse effect was, however, transient. L-Propionylcarnitine provides protection for the postischemic reperfused heart in a dose-dependent manner. The optimal time for administration is before the ischemic insult. High doses of this compound may perturb cell membrane integrity. Moreover, the present data point to an intracellular, metabolic, and perhaps anaplerotic mechanism of action of L-propionylcarnitine in cardiac ischemia-reperfusion injury.
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Obermaier, Robert, Oliver Drognitz, Andrea Grub, Ernst von Dobschuetz, Wolfgang Schareck, Ullrich Theodor Hopt, and Stefan Benz. "Endotoxin Preconditioning in Pancreatic Ischemia/Reperfusion Injury." Pancreas 27, no. 3 (October 2003): e51-e56. http://dx.doi.org/10.1097/00006676-200310000-00020.
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Bianca-Liana, Grigorescu, Fodor Raluca Ştefania, Scridon Alina, Perian Marcel, Badea Iudita, Cioc Adrian Dan, Cotoi Ovidiu Simion, Copotoiu Sanda-Maria, and Azamfirei Leonard. "The Assessment of Reperfusion Inflammatory Injury in Ischemic Preconditioned Diabetic Rats." Acta Medica Marisiensis 61, no. 4 (December 1, 2015): 282–86. http://dx.doi.org/10.1515/amma-2015-0087.
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AbstractObjective: The assessment of systemic reperfusion injury and the contractile force of the peripheral muscles post-acute ischemia of the hind limbs in healthy versus diabetic ischemic preconditioned rats.Method: The study included 16 Wistar rats divided into two groups: the control group and the diabetic ischemic preconditioned group. Acute ischemia was induced, followed by reperfusion. The assessment of reperfusion injury used biochemical, histopathological and functional determinations (peak tetanic tension-PTT, specific tension-ST).Results: Ischemia-reperfusion injury was more severe in control group regarding creatine-kinase (CK) (CK1=470.13 IU/L versus CK2=230.88 IU/L, p=0.0001) and myoglobin (390.25 ng/mL versus 47.99 ng/mL, p=0.025). Cytolysis enzymes were significantly increased in diabetic preconditioned rats (Alanine aminotransferase ALAT1=46 IU/L, ALAT2=167.8 IU/L, p=0.02; Aspartate aminotransferase ASAT1=106 IU/L, ASAT2=237.5 IU/L, p=0.016). Functional assessment (PTT and ST) highlighted roughly equal values. A paradoxical response occurred in diabetic rats (the contractile force increased during the period of the stimulation). Histopathological findings showed that rhabdomyolysis was more severe in the control group, while inflammatory systemic response due to reperfusion injury was less expressed in diabetic ischemic preconditioned rats.Conclusions: Ischemic preconditioning reduces the severity of reperfusion injury and allows the preservation of contractile muscle function in diabetic rats.
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Maksimovich, N. Ye, I. K. Dremza, E. I. Troyan, Ya N. Maksimovich, and A. N. Borodinskii. "The correcting effects of dihydroquercetin in cerebral ischemia-reperfusion injury." Biomeditsinskaya Khimiya 60, no. 6 (2014): 643–50. http://dx.doi.org/10.18097/pbmc20146006643.
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The dynamics of changes in the mitochondrial respiratory function, changes in the parameters of carbohydrate metabolism and some parameters of oxidative stress in the brain tissue have been investigated under conditions of ischemia-reperfusion and administration of dihydroquercetin. Dihydroquercetin (65 mg/kg) was administered per os 1 h before modeling of ischemia-reperfusion. Studies were carried 1 h after reperfusion. It was found that administration of dihydroquercetin caused a corrective effect to impairments of the respiratory function of mitochondria, indicators of carbohydrate metabolism and parameters of oxidative stress induced by ischemia-reperfusion.
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Hochhauser, Edith, Shaye Kivity, Daniel Offen, Nilanjana Maulik, Hajime Otani, Yael Barhum, Hannah Pannet, et al. "Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 6 (June 1, 2003): H2351—H2359. http://dx.doi.org/10.1152/ajpheart.00783.2002.
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The role of the proapototic Bax gene in ischemia-reperfusion (I/R) injury was studied in three groups of mice: homozygotic knockout mice lacking the Bax gene (Bax−/−), heterozygotic mice (Bax+/−), and wild-type mice (Bax+/+). Isolated hearts were subjected to ischemia (30 min, 37°C) and then to 120 min of reperfusion. The left ventricular developed force of Bax-deficient vs. Bax+/+ hearts at stabilization and at 120 min of reperfusion was 1,411 ± 177 vs. 1,161 ± 137 mg and 485 ± 69 vs. 306 ± 68 mg, respectively. Superior cardiac function of Bax−/− hearts after I/R was accompanied by a decrease in creatine kinase release, caspase 3 activity, irreversible ischemic injury, and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. Electron microscopic evaluation revealed reduced damage to mitochondria and the nuclear chromatin structure in Bax-deficient mice. In the Bax+/− hearts, the damage markers were moderate. The superior tolerance of Bax knockout hearts to I/R injury recommends this gene as a potential target for therapeutic intervention in patients with severe and intractable myocardial ischemia.
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Tosaki, Arpad, Nilanjana Maulik, Gerald Cordis, Ovidiu C. Trifan, Laurentiu M. Popescu, and Dipak K. Das. "Ischemic preconditioning triggers phospholipase D signaling in rat heart." American Journal of Physiology-Heart and Circulatory Physiology 273, no. 4 (October 1, 1997): H1860—H1866. http://dx.doi.org/10.1152/ajpheart.1997.273.4.h1860.
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Recent studies have indicated that repeated brief episodes of ischemia and reperfusion render the myocardium more tolerant to subsequent lethal ischemic injury. In view of the previous observations that ischemia-reperfusion potentiates phospholipase D signaling and that such signaling is beneficial for the heart, we investigated whether a similar phospholipase D signaling is responsible for the beneficial effects associated with repeated ischemia and reperfusion. Using an isolated perfused working rat heart model, we demonstrated that four brief episodes of 5 min of ischemia and 10 min of reperfusion reduced the incidence of ventricular arrhythmias, enhanced the postischemic ventricular performance, and decreased the release of creatine kinase from the reperfused heart, with simultaneous activation of phospholipase D generating the second messengers diacylglycerol and phosphatidic acid and leading to the translocation and activation of protein kinase C. The specific antiphospholipase D antibody blocked the activation of phospholipase D and attenuated the generation of diacylglycerol and phosphatidic acid and activation of protein kinase C. In concert, phospholipase D inhibition increased the incidence of ventricular arrhythmias, blocked the beneficial effects of preconditioning on the ventricular performance, and increased the amount of creatine kinase release from the coronary effluent. The results of this study indicate that repeated brief episodes of ischemia and reperfusion exert beneficial effects on the intact rat heart by triggering the activation of a phospholipase D signaling mechanism.