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Sample records for ameliorates ischemia-reperfusion induced

  1. Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury.

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    Yung-Yang Liu

    Full Text Available Hypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs. However, the beneficial effects of hypoxic MSCs in ischemia/reperfusion (I/R lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels.I/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5×105 cells and high (1×106 cells dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined.I/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS, pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-κB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-κB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism.Hypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis.

  2. Britanin Ameliorates Cerebral Ischemia-Reperfusion Injury by Inducing the Nrf2 Protective Pathway.

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    Wu, Guozhen; Zhu, Lili; Yuan, Xing; Chen, Hao; Xiong, Rui; Zhang, Shoude; Cheng, Hao; Shen, Yunheng; An, Huazhang; Li, Tiejun; Li, Honglin; Zhang, Weidong

    2017-10-10

    Oxidative stress is considered the major cause of tissue injury after cerebral ischemia. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important defensive mechanisms against oxidative stresses and has been confirmed as a target for stroke treatment. Thus, we desired to find new Nrf2 activators and test their neuronal protective activity both in vivo and in vitro. The herb-derived compound, Britanin, is a potent inducer of the Nrf2 system. Britanin can induce the expression of protective enzymes and reverse oxygen-glucose deprivation, followed by reperfusion (OGD-R)-induced neuronal injury in primary cortical neurons in vitro. Furthermore, the administration of Britanin significantly ameliorated middle cerebral artery occlusion-reperfusion (MCAO-R) insult in vivo. We report here the crystal structure of the complex of Britanin and the BTB domain of Keap1. Britanin selectively binds to a conserved cysteine residue, cysteine 151, of Keap1 and inhibits Keap1-mediated ubiquitination of Nrf2, leading to induction of the Nrf2 pathway. Britanin is a potent inducer of Nrf2. The complex crystal structure of Britanin and the BTB domain of Keap1 help clarify the mechanism of Nrf2 induction. Britanin was proven to protect primary cortical neurons against OGD-R-induced injury in an Nrf2-dependant way. Additionally, Britanin had excellent cerebroprotective effect in an MCAO-R model. Our results demonstrate that the natural product Britanin with potent Nrf2-activating and neural protective activities both in vitro and in vivo could be developed into a cerebroprotective therapeutic agent. Antioxid. Redox Signal. 27, 754-768.

  3. Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage

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    Sun, Kai; Fan, Jingyu; Han, Jingyan

    2015-01-01

    Ischemic stroke and ischemia/reperfusion (I/R) injury induced by thrombolytic therapy are conditions with high mortality and serious long-term physical and cognitive disabilities. They have a major impact on global public health. These disorders are associated with multiple insults to the cerebral microcirculation, including reactive oxygen species (ROS) overproduction, leukocyte adhesion and infiltration, brain blood barrier (BBB) disruption, and capillary hypoperfusion, ultimately resulting in tissue edema, hemorrhage, brain injury and delayed neuron damage. Traditional Chinese medicine (TCM) has been used in China, Korea, Japan and other Asian countries for treatment of a wide range of diseases. In China, the usage of compound TCM preparation to treat cerebrovascular diseases dates back to the Han Dynasty. Even thousands of years earlier, the medical formulary recorded many classical prescriptions for treating cerebral I/R-related diseases. This review summarizes current information and underlying mechanisms regarding the ameliorating effects of compound TCM preparation, Chinese materia medica, and active components on I/R-induced cerebral microcirculatory disturbances, brain injury and neuron damage. PMID:26579420

  4. Microvesicles derived from human Wharton's Jelly mesenchymal stem cells ameliorate ischemia-reperfusion-induced renal fibrosis by releasing from G2/M cell cycle arrest.

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    Chen, Wenxia; Yan, Yongbin; Song, Chundong; Ding, Ying; Du, Tao

    2017-12-14

    Studies have demonstrated that microvesicles (MVs) derived from human Wharton's Jelly mesenchymal stromal cells (hWJMSCs) could ameliorate renal ischemia/reperfusion injury (IRI); however, the underlying mechanisms were not clear yet. Here, MVs were isolated and injected intravenously into rats immediately after ischemia of the left kidney, and Erk1/2 activator hepatocyte growth factor (HGF) or inhibitor U0126 was administrated. Tubular cell proliferation and apoptosis were identified by Ki67 or terminal-deoxynucleotidyl transferase-mediated nick end labeling immunostaining. Masson's tri-chrome straining and alpha-smooth muscle actin staining were used for assessing renal fibrosis. The mRNA or protein expression in the kidney was measured by quantitative reverse transcription-PCR or Western blot, respectively. The total collagen concentration was also determined. In vitro , NRK-52E cells that treated with MVs under hypoxia injury and with HGF or U0126 administration were used, and cell cycle analysis was performed. The effects of hWJMSC-MVs on enhancing the proliferation and mitigating the apoptosis of renal cells, abrogating IRI-induced fibrosis, improving renal function, decreasing collagen deposition, and altering the expression levels of epithelial-mesenchymal transition and cell cycle-related proteins in IRI rats were found. In vitro experiment showed that hWJMSC-MVs could induce G2/M cell cycle arrest and decrease the expression of collagen deposition-related proteins in NRK-52E cells after 24 or 48 h. However, U0126 treatment reversed these effects. In conclusion, MVs derived from hWJMSCs ameliorate IR-induced renal fibrosis by inducing G2/M cell cycle arrest via Erk1/2 signaling. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  5. Effect of Cuscuta chinensis on renal function in ischemia/reperfusion-induced acute renal failure rats.

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    Shin, Sun; Lee, Yun Jung; Kim, Eun Ju; Lee, An Sook; Kang, Dae Gill; Lee, Ho Sub

    2011-01-01

    The kidneys play a central role in regulating water, ion composition and excretion of metabolic waste products in the urine. Cuscuta chinensis has been known as an important traditional Oriental medicine for the treatment of liver and kidney disorders. Thus, we studied whether an aqueous extract of Cuscuta chinensis (ACC) seeds has an effect on renal function parameters in ischemia/reperfusion-induced acute renal failure (ARF) rats. Administration of 250 mg/kg/day ACC showed that renal functional parameters including urinary excretion rate, osmolality, Na(+), K(+), Cl(-), creatinine clearance, solute-free water reabsorption were significantly recovered in ischemia/reperfusion-induced ARF. Periodic acid Schiff staining showed that administration of ACC improved tubular damage in ischemia/reperfusion-induced ARF. In immunoblot and immunohistological examinations, ischemia/reperfusion-induced ARF decreased the expressions of water channel AQP 2, 3 and sodium potassium pump Na,K-ATPase in the renal medulla. However, administration of ACC markedly incremented AQP 2, 3 and Na,K-ATPase expressions. Therefore, these data indicate that administration of ACC ameliorates regulation of the urine concentration and renal functions in rats with ischemia/reperfusion-induced ARF.

  6. Anti-human tissue factor antibody ameliorated intestinal ischemia reperfusion-induced acute lung injury in human tissue factor knock-in mice.

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    Xiaolin He

    Full Text Available BACKGROUND: Interaction between the coagulation and inflammation systems plays an important role in the development of acute respiratory distress syndrome (ARDS. Anti-coagulation is an attractive option for ARDS treatment, and this has promoted development of new antibodies. However, preclinical trials for these antibodies are often limited by the high cost and availability of non-human primates. In the present study, we developed a novel alternative method to test the role of a humanized anti-tissue factor mAb in acute lung injury with transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: Human tissue factor knock-in (hTF-KI transgenic mice and a novel humanized anti-human tissue factor mAb (anti-hTF mAb, CNTO859 were developed. The hTF-KI mice showed a normal and functional expression of hTF. The anti-hTF mAb specifically blocked the pro-coagulation activity of brain extracts from the hTF-KI mice and human, but not from wild type mice. An extrapulmonary ARDS model was used by intestinal ischemia-reperfusion. Significant lung tissue damage in hTF-KI mice was observed after 2 h reperfusion. Administration of CNTO859 (5 mg/kg, i.v. attenuated the severity of lung tissue injury, decreased the total cell counts and protein concentration in bronchoalveolar lavage fluid, and reduced Evans blue leakage. In addition, the treatment significantly reduced alveolar fibrin deposition, and decreased tissue factor and plasminogen activator inhibitor-1 activity in the serum. This treatment also down-regulated cytokine expression and reduced cell death in the lung. CONCLUSIONS: This novel anti-hTF antibody showed beneficial effects on intestinal ischemia-reperfusion induced acute lung injury, which merits further investigation for clinical usage. In addition, the use of knock-in transgenic mice to test the efficacy of antibodies against human-specific proteins is a novel strategy for preclinical studies.

  7. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis.

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    Zhai, Mengen; Li, Buying; Duan, Weixun; Jing, Lin; Zhang, Bin; Zhang, Meng; Yu, Liming; Liu, Zhenhua; Yu, Bo; Ren, Kai; Gao, Erhe; Yang, Yang; Liang, Hongliang; Jin, Zhenxiao; Yu, Shiqiang

    2017-09-01

    Sirtuins are a family of highly evolutionarily conserved nicotinamide adenine nucleotide-dependent histone deacetylases. Sirtuin-3 (SIRT3) is a member of the sirtuin family that is localized primarily to the mitochondria and protects against oxidative stress-related diseases, including myocardial ischemia/reperfusion (MI/R) injury. Melatonin has a favorable effect in ameliorating MI/R injury. We hypothesized that melatonin protects against MI/R injury by activating the SIRT3 signaling pathway. In this study, mice were pretreated with or without a selective SIRT3 inhibitor and then subjected to MI/R operation. Melatonin was administered intraperitoneally (20 mg/kg) 10 minutes before reperfusion. Melatonin treatment improved postischemic cardiac contractile function, decreased infarct size, diminished lactate dehydrogenase release, reduced the apoptotic index, and ameliorated oxidative damage. Notably, MI/R induced a significant decrease in myocardial SIRT3 expression and activity, whereas the melatonin treatment upregulated SIRT3 expression and activity, and thus decreased the acetylation of superoxide dismutase 2 (SOD2). In addition, melatonin increased Bcl-2 expression and decreased Bax, Caspase-3, and cleaved Caspase-3 levels in response to MI/R. However, the cardioprotective effects of melatonin were largely abolished by the selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP), suggesting that SIRT3 plays an essential role in mediating the cardioprotective effects of melatonin. In vitro studies confirmed that melatonin also protected H9c2 cells against simulated ischemia/reperfusion injury (SIR) by attenuating oxidative stress and apoptosis, while SIRT3-targeted siRNA diminished these effects. Taken together, our results demonstrate for the first time that melatonin treatment ameliorates MI/R injury by reducing oxidative stress and apoptosis via activating the SIRT3 signaling pathway. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons

  8. Hyperglycemia Aggravates Hepatic Ischemia Reperfusion Injury by Inducing Chronic Oxidative Stress and Inflammation

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    Yihan Zhang

    2016-01-01

    Full Text Available Aim. To investigate whether hyperglycemia will aggravate hepatic ischemia reperfusion injury (HIRI and the underlying mechanisms. Methods. Control and streptozotocin-induced diabetic Sprague-Dawley rats were subjected to partial hepatic ischemia reperfusion. Liver histology, transferase, inflammatory cytokines, and oxidative stress were assessed accordingly. Similarly, BRL-3A hepatocytes were subjected to hypoxia/reoxygenation (H/R after high (25 mM or low (5.5 mM glucose culture. Cell viability, reactive oxygen species (ROS, and activation of nuclear factor-erythroid 2-related factor 2 (Nrf2 and nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB were determined. Results. Compared with control, diabetic rats presented more severe hepatic injury and increased hepatic inflammatory cytokines and oxidative stress. HIRI in diabetic rats could be ameliorated by pretreatment of N-acetyl-L-cysteine (NAC or apocynin. Excessive ROS generation and consequent Nrf2 and NF-κB translocation were determined after high glucose exposure. NF-κB translocation and its downstream cytokines were further increased in high glucose cultured group after H/R. While proper regulation of Nrf2 to its downstream antioxidases was observed in low glucose cultured group, no further induction of Nrf2 pathway by H/R after high glucose culture was identified. Conclusion. Hyperglycemia aggravates HIRI, which might be attributed to chronic oxidative stress and inflammation and potential malfunction of antioxidative system.

  9. Edaravone prevents lung injury induced by hepatic ischemia-reperfusion.

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    Uchiyama, Munehito; Tojo, Kentaro; Yazawa, Takuya; Ota, Shuhei; Goto, Takahisa; Kurahashi, Kiyoyasu

    2015-04-01

    Lung injury is a major clinical concern after hepatic ischemia-reperfusion (I/R), due to the production of reactive oxygen species in the reperfused liver. We investigated the efficacy of edaravone, a potent free-radical scavenger, for attenuating lung injury after hepatic I/R. Adult male Sprague-Dawley rats were assigned to sham + normal saline (NS), I/R + NS, or I/R + edaravone group. Rats in the I/R groups were subjected to 90 min of partial hepatic I/R. Five minutes before reperfusion, 3 mg/kg edaravone was administered to the I/R + edaravone group. After 6 h of reperfusion, we evaluated lung histopathology and wet-to-dry ratio. We also measured malondialdehyde (MDA), an indicator of oxidative stress, in the liver and the lung, as well as cytokine messenger RNA expressions in the reperfused liver and plasma cytokine concentrations. Histopathology revealed lung damages after 6 h reperfusion of partial ischemic liver. Moreover, a significant increase in lung wet-to-dry ratio was observed. MDA concentration increased in the reperfused liver, but not in the lungs. Edaravone administration attenuated the lung injury and the increase of MDA in the reperfused liver. Edaravone also suppressed the reperfusion-induced increase of interleukin-6 messenger RNA expressions in the liver and plasma interleukin-6 concentrations. Edaravone administration before reperfusion of the ischemic liver attenuates oxidative stress in the reperfused liver and the subsequent lung injury. Edaravone may be beneficial for preventing lung injury induced by hepatic I/R. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Obestatin Accelerates the Recovery in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

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    Jakub Bukowczan

    Full Text Available Several previous studies have shown that obestatin exhibits protective and regenerative effects in some organs including the stomach, kidney, and the brain. In the pancreas, pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis, and promotes survival of pancreatic beta cells and human islets. However, no studies investigated the effect of obestatin administration following the onset of experimental acute pancreatitis.The aim of this study was to evaluate the impact of obestatin therapy in the course of ischemia/reperfusion-induced pancreatitis. Moreover, we tested the influence of ischemia/reperfusion-induced acute pancreatitis and administration of obestatin on daily food intake and pancreatic exocrine secretion.Acute pancreatitis was induced by pancreatic ischemia followed by reperfusion of the pancreas. Obestatin (8 nmol/kg/dose was administered intraperitoneally twice a day, starting 24 hours after the beginning of reperfusion. The effect of obestatin in the course of necrotizing pancreatitis was assessed between 2 and 14 days, and included histological, functional, and biochemical analyses. Secretory studies were performed on the third day after sham-operation or induction of acute pancreatitis in conscious rats equipped with chronic pancreatic fistula.Treatment with obestatin ameliorated morphological signs of pancreatic damage including edema, vacuolization of acinar cells, hemorrhages, acinar necrosis, and leukocyte infiltration of the gland, and led to earlier pancreatic regeneration. Structural changes were accompanied by biochemical and functional improvements manifested by accelerated normalization of interleukin-1β level and activity of myeloperoxidase and lipase, attenuation of the decrease in pancreatic DNA synthesis, and by an improvement of pancreatic blood flow. Induction of acute pancreatitis by pancreatic ischemia followed by reperfusion significantly decreased daily food intake and

  11. Protective Effect of Ischemic Postconditioning against Ischemia Reperfusion-Induced Myocardium Oxidative Injury in IR Rats

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    Jiangwei Ma

    2012-03-01

    Full Text Available Brief episodes of myocardial ischemia-reperfusion (IR employed during reperfusion after a prolonged ischemic insult may attenuate the total ischemia-reperfusion injury. This phenomenon has been termed ischemic postconditioning. In the present study, we studied the possible effect of ischemic postconditioning on an ischemic reperfusion (IR-induced myocardium oxidative injury in rat model. Results showed that ischemic postconditioning could improve arrhythmia cordis, reduce myocardium infarction and serum creatin kinase (CK, lactate dehydrogenase (LDH and aspartate transaminase (AST activities in IR rats. In addition, ischemic postconditioning could still decrease myocardium malondialdehyde (MDA level, and increased myocardium Na+-K+-ATPase, Ca2+-Mg2+-ATPase, superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GSH-Px and glutathione reductase (GR activities. It can be concluded that ischemic postconditioning possesses strong protective effects against ischemia reperfusion-induced myocardium oxidative injury in IR rats.

  12. [The effect of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion in a rabbit model].

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    Wang, Ye; Yang, Jia-mei; Hou, Yuan-kai; Li, Dian-qi; Hu, Ming-hua; Liu, Peng

    2008-04-15

    To investigate the effect and mechanism of portal blood stasis on lung and renal injury induced by hepatic ischemia reperfusion. A rabbit hepatic ischemia reperfusion injury model was established by hepatic portal occlusion and in situ hypothermic irrigation for 30 min. Twenty-four New Zealand white rabbits were employed and randomly divided into 3 groups equally by different dosage of portal blood stasis removal: group A5 (5 ml blood removal), group A10 (10 ml blood removal),and group B (no blood removal). Eight rabbits were served as controls with no hepatic portal occlusion and hypothermic irrigation. After reperfusion 4 h serum endotoxin content, tumor necrosis factor-alpha (TNF-alpha), urea nitrogen (BUN), and creatinine (Cr) were examined respectively, meantime lung and kidney tissues were sampled to determine the content of malondialdehyde (MDA), superoxide dismutase (SOD), the pathology, and wet to dry weight ratio, broncho-alveolar lavage fluid protein content in lung tissues. Removing portal blood stasis ameliorated lung and renal injury as shown by decreasing the level of serum endotoxin, TNF-alpha, BUN, Cr, wet to dry weight ratio, broncho-alveolar lavage fluid protein content, MDA, SOD. TNF-alpha, Cr, broncho-alveolar lavage fluid protein content in lung tissues and MDA in kidney tissue in group A5 were significantly reduced compared with those in group B (P portal blood stasis before the resume of splanchnic circulation may ameliorate the lung and renal injury induced by hepatic ischemia reperfusion. The possible mechanism may be that portal blood stasis removal reduces endotoxin absorption, and further decreases production of serum TNF-alpha.

  13. Allopurinol Protects against Ischemia/Reperfusion-Induced Injury in Rat Urinary Bladders

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    Ju-Hyun Shin

    2015-01-01

    Full Text Available Bladder ischemia-reperfusion (I/R injury results in the generation of reactive oxygen species (ROS and markedly elevates the risk of lower urinary tract symptoms (LUTS. Allopurinol is an inhibitor of xanthine oxidase (XO and thus can serve as an antioxidant that reduces oxidative stress. Here, a rat model was used to assess the ability of allopurinol treatment to ameliorate the deleterious effects of urinary bladder I/R injury. I/R injury reduced the in vitro contractile responses of longitudinal bladder strips, elevated XO activity in the plasma and bladder tissue, increased the bladder levels of tumor necrosis factor-α (TNF-α, c-Jun N-terminal kinase (JNK, and p38 mitogen-activated protein kinase, reduced the bladder levels of extracellular regulated kinase (ERK, and decreased and increased the bladder levels of Bcl-2 and Bax, respectively. I/R injury also elevated lipid peroxidation in the bladder. Allopurinol treatment in the I/R injury was generated significantly ameliorating all I/R-induced changes. Moreover, an in situ fluorohistological approach also showed that allopurinol reduces the generation of intracellular superoxides enlarged by I/R injury. Together, the beneficial effects of allopurinol reducing ROS production may be mediated by normalizing the activity of the ERK, JNK, and Bax/Bcl-2 pathways and by controlling TNF-α expression.

  14. [Gene transfer-induced human heme oxygenase-1 over-expression protects kidney from ischemia-reperfusion injury in rats].

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    Lü, Jin-xing; Yan, Chun-yin; Pu, Jin-xian; Hou, Jian-quan; Yuan, He-xing; Ping, Ji-gen

    2010-12-14

    To study the protection of gene transfer-induced human heme oxygenase-1 over-expression against renal ischemia reperfusion injury in rats. The model of kidney ischemia-reperfusion injury was established with Sprague-Dawley rats. In the therapy group (n=18), the left kidney was perfused and preserved with Ad-hHO-1 at 2.5×10(9) pfu/1.0 ml after flushed with 0-4°C HC-A organ storage solution via donor renal aorta. The rats in control groups were perfused with 0.9% saline solution (n=12) or the vector carrying no interest gene Ad-EGFP 2.5×10(9) pfu/1.0 ml (n=18) instead of Ad-hHO-1. BUN and Cr in serum were measured by slide chemical methods. The kidney samples of rats were harvested for assay of histology, immunohistochemistry and quantification of HO enzymatic activity. Apoptosis cells in the kidney were measured by TUNEL. Ad-hHO-1 via donor renal aorta could transfect renal cells of rats effectively, enzymatic activity of HO in treated group [(1.62±0.07) nmol×mg(-1)×min(-1)] is higher than in control groups treated with saline solution team [(1.27±0.07) nmol×mg(-1)×min(-1)] and vector EGFP team [(1.22±0.06) nmol×mg(-1)×min(-1)] (PhHO-1 expressed hHO-1 in kidneys at a high level. Corresponding to this, the level of BUN and Cr, as well as the number of apoptosis cells, were decreased, and the damage in histology by HE staining was ameliorated. Over-expression of human HO-1 can protect the kidney from ischemia/reperfusion injury in rats.

  15. Geranylgeranylacetone ameliorates lung ischemia/reperfusion injury by HSP70 and thioredoxin redox system: NF-kB pathway involved.

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    Cao, Weijun; Li, Manhui; Li, Jianxiong; Li, Chengwei; Xu, Xin; Gu, Weiqing

    2015-06-01

    Geranylgeranylacetone (GGA) has been clinically used as an anti-ulcer drug. In the present study, we explored the protective effects of GGA on lung ischemia/reperfusion injury (IRI) and the underlying mechanism. The results demonstrated that GGA ameliorated the lung biochemical and histological alterations induced by IRI, which was reversed by HSP70 inhibition. To further explore the mechanism of GGA action, we focused on NF-kB and thioredoxin (Trx) redox system. It was shown that GGA induced the HSP70 and Trx-1 expression, NF-kB nuclear translocation and activated thioredoxin reductase (TrxR). The Trx-1 expression and TrxR activity was suppressed by HSP70 and NF-kB inhibition, while the nuclear NF-kB p65 expression was suppressed by HSP70 inhibitor. These results indicated that GGA may protect rat lung against IRI by HSP70 and Trx redox system, in which NF-kB pathway may be involved. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Role of TRPV1 channels in ischemia/reperfusion-induced acute kidney injury.

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    Lan Chen

    Full Text Available OBJECTIVES: Transient receptor potential vanilloid 1 (TRPV1 -positive sensory nerves are widely distributed in the kidney, suggesting that TRPV1-mediated action may participate in the regulation of renal function under pathophysiological conditions. Stimulation of TRPV1 channels protects against ischemia/reperfusion (I/R-induced acute kidney injury (AKI. However, it is unknown whether inhibition of these channels is detrimental in AKI or not. We tested the role of TRPV1 channels in I/R-induced AKI by modulating these channels with capsaicin (TRPV1 agonist, capsazepine (TRPV1 antagonist and using Trpv1-/- mice. METHODS AND RESULTS: Anesthetized C57BL/6 mice were subjected to 25 min of renal ischemia and 24 hrs of reperfusion. Mice were pretreated with capsaicin (0.3 mg/kg body weight or capsazepine (50 mg/kg body weight. Capsaicin ameliorated the outcome of AKI, as measured by serum creatinine levels, tubular damage,neutrophil gelatinase-associated lipocalin (NGAL abundance and Ly-6B.2 positive polymorphonuclear inflammatory cells in injured kidneys. Neither capsazepine nor deficiency of TRPV1 did deteriorate renal function or histology after AKI. Measurements of endovanilloids in kidney tissue indicate that 20-hydroxyeicosatetraeonic acid (20-HETE or epoxyeicosatrienoic acids (EETs are unlikely involved in the beneficial effects of capsaicin on I/R-induced AKI. CONCLUSIONS: Activation of TRPV1 channels ameliorates I/R-induced AKI, but inhibition of these channels does not affect the outcome of AKI. Our results may have clinical implications for long-term safety of renal denervation to treat resistant hypertension in man, with respect to the function of primary sensory nerves in the response of the kidney to ischemic stimuli.

  17. Ethyl Pyruvate Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Intrinsic Pathway of Apoptosis and Autophagy

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    Miao Shen

    2013-01-01

    Full Text Available Background. Hepatic ischemia-reperfusion (I/R injury is a pivotal clinical problem occurring in many clinical conditions such as transplantation, trauma, and hepatic failure after hemorrhagic shock. Apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. Ethyl pyruvate, a stable and simple lipophilic ester, has been shown to have anti-inflammatory properties. In this study, the purpose is to explore both the effect of ethyl pyruvate on hepatic I/R injury and regulation of intrinsic pathway of apoptosis and autophagy. Methods. Three doses of ethyl pyruvate (20 mg/kg, 40 mg/kg, and 80 mg/kg were administered 1 h before a model of segmental (70% hepatic warm ischemia was established in Balb/c mice. All serum and liver tissues were obtained at three different time points (4 h, 8 h, and 16 h. Results. Alanine aminotransferase (ALT, aspartate aminotransferase (AST, and pathological features were significantly ameliorated by ethyl pyruvate (80 mg/kg. The expression of Bcl-2, Bax, Beclin-1, and LC3, which play an important role in the regulation of intrinsic pathway of apoptosis and autophagy, was also obviously decreased by ethyl pyruvate (80 mg/kg. Furthermore, ethyl pyruvate inhibited the HMGB1/TLR4/ NF-κb axis and the release of cytokines (TNF-α and IL-6. Conclusion. Our results showed that ethyl pyruvate might attenuate to hepatic I/R injury by inhibiting intrinsic pathway of apoptosis and autophagy, mediated partly through downregulation of HMGB1/TLR4/ NF-κb axis and the competitive interaction with Beclin-1 of HMGB1.

  18. Pharmacological evaluation of tacrolimus (FK-506 on ischemia reperfusion induced vasculatic neuropathic pain in rats

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    Sood Shailja

    2010-06-01

    Full Text Available Abstract Background Ischemia reperfusion (I/R is common in various pathological conditions like diabetic complication, rheumatic arthritis, necrotizing vascular occlusive disease and trauma. Methods We have evaluated the effect of tacrolimus (1, 2 and 3 mg/kg, p.o. for 10 consecutive days on femoral arterial ischemic reperfusion (I/R induced neuropathic pain in rats. Behavioral parameters (i.e. hot plate, radiant heat, acetone drop, tail heat hyperalgesia, tail flick and tail cold allodynia tests were assessed at different time intervals (i.e. 0, 1, 4, 7, 10, 13 and 16th day and biochemical analysis in serum and tissue samples were also performed along with histopathological studies. Results Behavioral pain assessment revealed increase in the paw and tail withdrawal threshold in tacrolimus treated groups against hyperalgesic and allodynic stimuli as compared to the sham control group. We observed a decrease in the serum nitrate and thiobarbituric acid reactive substance (TBARS levels along with reduction in tissue myeloperoxidase (MPO and total calcium levels, whereas, rise in tissue reduced glutathione levels in tacrolimus treated groups. However, significant results were obtained in medium and high dose treated group as compared to sham control group. Histopathological study had revealed the increase in the neuronal edema and axonal degeneration in the I/R group whereas, tacrolimus ameliorate these effects. Conclusion Our results indicate the anti-oxidative, anti-inflammatory and calcium modulatory actions of tacrolimus. Therefore, it can be used as a therapeutic agent for the treatment of vascular inflammatory related neuropathic pain.

  19. Protective effects of persian honey, Apis Mellifera Meda Skorikov on side effects of chemotherapy and ischemia/reperfusion induced testicular injury.

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    Gholami, Mohammadreza; Abbaszadeh, Abolfazl; Baharvand, Parastoo; Hasanvand, Afshin; Hasanvand, Amin; Gharravi, Anneh Mohammad

    2018-05-23

    Introduction The aim of the present study was to survey the protective effect of pretreatment with Persian honey on amelioration of side effects of chemotherapy and ischemia/reperfusion induced testicular injury. Materials and methods Forty adult's male wistar rats were divided into four groups of ischemia-reperfusion (IR), honey + ischemia-reperfusion (HIR), Busulfan (B) and Busulfan intraperitoneally+ honey (BH). The seminiferous tubules were rated for their modified spermatogenesis index (SI) by Johnsons score. Detection of single- and double-stranded DNA breaks at the early stages of apoptosis was performed using the in-situ cell death detection kit. Total serum concentration of Follicle-stimulating hormone (FSH) , Luteinizing hormone (LH) and testosterone was measured using ELISA. All data were expressed as mean ± SD and significance was set at p≤0.05. Results Honey improved SI in the HIR and BH groups and serum levels of FSH and LH in the BH and HIR groups (phoney protect testis against chemotherapy and testicular IR injury, increase FSH and LH and testosterone and decrease the cellular damage and apoptosis. Honey can decrease the side effects of chemotherapy on reproductive system and prevent sterility.

  20. The Effect of PM 10 on Ischemia- Reperfusion Induced Arrhythmias in Rats

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    Esmat Radmanesh

    Full Text Available ABSTRACT Epidemiological studies show that particulate matter (PM is the principal instigator of some adverse clinical symptoms involving cardiovascular diseases. PM exposure can increase experimental infarct size and potentiate myocardial ischemia and arrhythmias in experimental MI models such as ischemia-reperfusion (I/R injury.The present study was aimed to evaluate the effects of particulate matter (PM10 on ischemia- reperfusion induced arrhythmias with emphasis on the protective role of VA as an antioxidant on them. Male Wistar rats were divided into 8 groups (n=10: Control, VAc, Sham, VA, PM1 (0.5 mg/kg, PM2 (2.5 mg/kg, PM3 group (5 mg/kg, PM3 + VA group. Within 48 hours, PM10 was instilled into trachea in two stages. Then the hearts were isolated, transferred to a Langendorff apparatus, and subjected to global ischemia (30 minutes followed by reperfusion (60 minutes. The ischemia- reperfusion induced ventricular arrhythmias were assessed according to the Lambeth conventions.In the present study,the number, incidence and duration of arrhythmiasduring30 minutes ischemia were demonstrated to be more than those in the reperfusion stage. PM exposure increased significantly the number, incidence and duration of arrhythmias in the ischemia and reperfusion duration. Vanillic acid reduced significantly the number, incidence and duration of arrhythmias during the ischemia and reperfusion period.In summary, the results of this study demonstrated that the protective and dysrhythmic effects of VA in the PM exposure rats in I/R model are probably related to its antioxidant properties.

  1. The effects of epidural bupivacaine on ischemia/reperfusion-induced liver injury.

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    Sarikus, Z; Bedirli, N; Yilmaz, G; Bagriacik, U; Bozkirli, F

    2016-01-01

    Several animal studies showed beneficial effects of thoracic epidural anesthesia (TEA) in hippocampal, mesenteric and myocardial IR injury (2-4). In this study, we investigated the effects of epidural bupivacaine on hepatic ischemia reperfusion injury in a rat model. Eighteen rats were randomly divided into three groups each containing 6 animals. The rats in Group C had sham laparotomy. The rats in the Group S were subjected to liver IR through laparotomy and 20 mcg/kg/h 0.9% NaCl was administered to these rats via an epidural catheter. The rats in the Group B were subjected to liver IR and were given 20 mcg/kg/h bupivacaine via an epidural catheter. Liver tissue was harvested for MDA analysis, apoptosis and histopathological examination after 60 minutes of ischemia followed by 360 minutes of reperfusion. Blood samples were also collected for TNF-α, IL-1β, AST and ALT analysis. The AST and ALT levels were higher in ischemia and reperfusion group, which received only normal saline via the thoracic epidural catheter, compared to the sham group. In the ischemia reperfusion group, which received bupivacaine via the epidural catheter, IL-1 levels were significantly higher than in the other groups. TNF-α levels were higher in the Groups S and B compared to the sham group. Bupivacaine administration induced apoptosis in all animals. These results showed that thoracic epidural bupivacaine was not a suitable agent for preventing inflammatory response and lipid peroxidation in experimental hepatic IR injury in rats. Moreover, epidural bupivacaine triggered apoptosis in hepatocytes. Further research is needed as there are no studies in literature investigate the effects of epidural bupivacaine on hepatic ischemia reperfusion injury (Tab. 3, Fig. 3, Ref. 34).

  2. Variable Ventilation Improved Respiratory System Mechanics and Ameliorated Pulmonary Damage in a Rat Model of Lung Ischemia-Reperfusion.

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    Soluri-Martins, André; Moraes, Lillian; Santos, Raquel S; Santos, Cintia L; Huhle, Robert; Capelozzi, Vera L; Pelosi, Paolo; Silva, Pedro L; de Abreu, Marcelo Gama; Rocco, Patricia R M

    2017-01-01

    Lung ischemia-reperfusion injury remains a major complication after lung transplantation. Variable ventilation (VV) has been shown to improve respiratory function and reduce pulmonary histological damage compared to protective volume-controlled ventilation (VCV) in different models of lung injury induced by endotoxin, surfactant depletion by saline lavage, and hydrochloric acid. However, no study has compared the biological impact of VV vs. VCV in lung ischemia-reperfusion injury, which has a complex pathophysiology different from that of other experimental models. Thirty-six animals were randomly assigned to one of two groups: (1) ischemia-reperfusion (IR), in which the left pulmonary hilum was completely occluded and released after 30 min; and (2) Sham, in which animals underwent the same surgical manipulation but without hilar clamping. Immediately after surgery, the left (IR-injured) and right (contralateral) lungs from 6 animals per group were removed, and served as non-ventilated group (NV) for molecular biology analysis. IR and Sham groups were further randomized to one of two ventilation strategies: VCV ( n = 6/group) [tidal volume (V T ) = 6 mL/kg, positive end-expiratory pressure (PEEP) = 2 cmH 2 O, fraction of inspired oxygen (FiO 2 ) = 0.4]; or VV, which was applied on a breath-to-breath basis as a sequence of randomly generated V T values ( n = 1200; mean V T = 6 mL/kg), with a 30% coefficient of variation. After 5 min of ventilation and at the end of a 2-h period (Final), respiratory system mechanics and arterial blood gases were measured. At Final, lungs were removed for histological and molecular biology analyses. Respiratory system elastance and alveolar collapse were lower in VCV than VV (mean ± SD, VCV 3.6 ± 1.3 cmH 2 0/ml and 2.0 ± 0.8 cmH 2 0/ml, p = 0.005; median [interquartile range], VCV 20.4% [7.9-33.1] and VV 5.4% [3.1-8.8], p = 0.04, respectively). In left lungs of IR animals, VCV increased the expression of interleukin-6 and

  3. Variable Ventilation Improved Respiratory System Mechanics and Ameliorated Pulmonary Damage in a Rat Model of Lung Ischemia-Reperfusion

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    Patricia R. M. Rocco

    2017-05-01

    Full Text Available Lung ischemia-reperfusion injury remains a major complication after lung transplantation. Variable ventilation (VV has been shown to improve respiratory function and reduce pulmonary histological damage compared to protective volume-controlled ventilation (VCV in different models of lung injury induced by endotoxin, surfactant depletion by saline lavage, and hydrochloric acid. However, no study has compared the biological impact of VV vs. VCV in lung ischemia-reperfusion injury, which has a complex pathophysiology different from that of other experimental models. Thirty-six animals were randomly assigned to one of two groups: (1 ischemia-reperfusion (IR, in which the left pulmonary hilum was completely occluded and released after 30 min; and (2 Sham, in which animals underwent the same surgical manipulation but without hilar clamping. Immediately after surgery, the left (IR-injured and right (contralateral lungs from 6 animals per group were removed, and served as non-ventilated group (NV for molecular biology analysis. IR and Sham groups were further randomized to one of two ventilation strategies: VCV (n = 6/group [tidal volume (VT = 6 mL/kg, positive end-expiratory pressure (PEEP = 2 cmH2O, fraction of inspired oxygen (FiO2 = 0.4]; or VV, which was applied on a breath-to-breath basis as a sequence of randomly generated VT values (n = 1200; mean VT = 6 mL/kg, with a 30% coefficient of variation. After 5 min of ventilation and at the end of a 2-h period (Final, respiratory system mechanics and arterial blood gases were measured. At Final, lungs were removed for histological and molecular biology analyses. Respiratory system elastance and alveolar collapse were lower in VCV than VV (mean ± SD, VCV 3.6 ± 1.3 cmH20/ml and 2.0 ± 0.8 cmH20/ml, p = 0.005; median [interquartile range], VCV 20.4% [7.9–33.1] and VV 5.4% [3.1–8.8], p = 0.04, respectively. In left lungs of IR animals, VCV increased the expression of interleukin-6 and intercellular

  4. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats

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    Wei-Chi Chou

    2015-01-01

    Full Text Available Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group, sham-operation (Sham, or sham plus caffeine (n=12 in each group. To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P<0.001 and P=0.008, resp.. Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2 and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P<0.05. These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs.

  5. Neuroprotective effect of Feronia limonia on ischemia reperfusion induced brain injury in rats.

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    Rakhunde, Purushottam B; Saher, Sana; Ali, Syed Ayaz

    2014-01-01

    Brain stroke is a leading cause of death without effective treatment. Feronia limonia have potent antioxidant activity and can be proved as neuroprotective against ischemia-reperfusion induced brain injury. We studied the effect of methanolic extract of F. limonia fruit (250 mg/kg, 500 mg/kg body weight, p.o.) and Vitamin E as reference standard drug on 30 min induced ischemia, followed by reperfusion by testing the neurobehavioral tests such as neurodeficit score, rota rod test, hanging wire test, beam walk test and elevated plus maze. The biochemical parameters, which were measured in animals brain were catalase, superoxide dismutase (SOD), malondialdehyde and nitric oxide in control and treated rats. The methanolic extract of F. limonia fruit (250 mg/kg, 500 mg/kg body weight, p.o.) treated groups showed a statistically significant improvement in the neurobehavioral parameters such as motor performance (neurological status, significant increase in grasping ability, forelimb strength improvement in balance and co-ordination). The biochemical parameters in the brains of rats showed a significant reduction in the total nitrite (P < 0.01) and lipid peroxidation (P < 0.01), also a significant enhanced activity of enzymatic antioxidants such as catalase (P < 0.01) and SOD (P < 0.05). These observations suggest the neuroprotective and antioxidant activity of F. limonia and Vitamin E on ischemia reperfusion induced brain injury and may require further evaluation.

  6. Cardioprotection against ischemia/reperfusion injury by QiShenYiQi Pill® via ameliorate of multiple mitochondrial dysfunctions

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    Chen JR

    2015-06-01

    Full Text Available Jing Rui Chen,1–3 Jing Wei,1–3 Ling Yan Wang,1–3 Yan Zhu,1–3 Lan Li,1–3 Mary Akinyi Olunga,1–3 Xiu Mei Gao,1–3 Guan Wei Fan1–31Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, People’s Republic of China; 2Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Ministry of Education, 3Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of ChinaAim: To investigate the potential cardioprotective effects of QiShenYiQi Pill® (QSYQ on myocardial ischemia/reperfusion (I/R injury through antioxidative stress and mitochondrial protection.Methods and results: Sprague Dawley rats were pretreated with QSYQ or saline for 7 days and subjected to ischemia (30 minutes occlusion of the left anterior descending coronary artery and reperfusion (120 minutes. Cardiac functions were evaluated by echocardiogram and hemodynamics. Myocardial mitochondria were obtained to evaluate changes in mitochondrial structure and function, immediately after 120 minutes reperfusion. Pretreatment with QSYQ protected against I/R-induced myocardial structural injury and improved cardiac hemodynamics, as demonstrated by normalized serum creatine kinase and suppressed oxidative stress. Moreover, the impaired myocardial mitochondrial structure and function decreased level of ATP (accompanied by reduction of ATP5D and increase in the expression of cytochrome C. Myocardial fiber rupture, interstitial edema, and infiltrated leukocytes were all significantly ameliorated by pretreatment with QSYQ.Conclusion: Pretreatment of QSYQ in Sprague Dawley rats improves ventricular function and energy metabolism and reduces oxidative stress via ameliorating multiple mitochondrial dysfunctions during I/R injury.Keywords: QSYQ, ischemia/reperfusion injury, energy metabolism, mitochondria

  7. The novel guanylhydrazone CPSI-2364 ameliorates ischemia reperfusion injury after experimental small bowel transplantation.

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    Websky, Martin von; Fujishiro, Jun; Ohsawa, Ichiro; Praktiknjo, Michael; Wehner, Sven; Abu-Elmagd, Kareem; Kitamura, Koji; Kalff, Joerg C; Schaefer, Nico; Pech, Thomas

    2013-06-15

    Resident macrophages within the tunica muscularis are known to play a crucial role in initiating severe inflammation in response to ischemia reperfusion injury after intestinal transplantation contributing to graft dysmotility, bacterial translocation, and possibly, acute rejection. The p38 mitogen-activated protein kinase is a key player in the signaling of proinflammatory cytokine synthesis in macrophages. Therefore, we investigated the effects of CPSI-2364, an apparent macrophage-specific inhibitor of the p38 mitogen-activated protein kinase pathway in an isogenic intestinal rat transplantation model. Recipient and donor animals were treated perioperatively with CPSI-2364 (1 mg/kg, intravenously) or vehicle solution. Nontransplanted animals served as control. Animals were killed 30 min, 3 hr, and 18 hr after reperfusion. CPSI-2364 treatment resulted in significantly less leukocyte infiltration and significantly improved graft motor function (18 hr). Messenger RNA expression of proinflammatory cytokines (interleukin 6) and kinetic active mediators (NO) was reduced by CPSI-2364 in the early phase after transplantation. Histologic evaluation revealed the protective effects of CPSI-2364 treatment by a significantly less destruction of mucosal integrity at all time points. Perioperative treatment with CPSI-2364 improves graft motor function through impaired inflammatory responses to ischemia reperfusion injury by inhibition of proinflammatory cytokines and suppression of nitric oxide production in macrophages. CPSI-2364 presents as a promising complementary pharmacological approach preventing postoperative dysmotility for clinical intestinal transplantation.

  8. Atorvastatin protects against ischemia-reperfusion injury in fructose-induced insulin resistant rats.

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    Prakash, Prem; Khanna, Vivek; Singh, Vishal; Jyoti, Anupam; Jain, Manish; Keshari, Ravi Shankar; Barthwal, Manoj Kumar; Dikshit, Madhu

    2011-08-01

    High fructose (HFr) intake is known to cause insulin resistance syndrome (IRS), however its effect against acute coronary events remains elusive. The present study was undertaken to evaluate the effect of HFr (60%) diet on myocardial ischemia-reperfusion (MI-RP) injury and its modulation by atorvastatin treatment. Wistar rats kept on HFr/chow feeding for 10 weeks, received atorvastatin (30 mg/kg, per oral) or vehicle for two additional weeks followed by MI-RP injury. MI-RP injury was significantly augmented in HFr fed rats, as evident by the increase in infarct size (IS, 65 ± 5% vs. 43 ± 7%) and activities of cardiac injury biomarkers [serum lactate dehydrogenase (LDH, 698 ± 57 vs. 444 ± 26 U/L), creatinine kinase (CK-MB, 584 ± 58 vs. 435 ± 28 U/L) and tissue myeloperoxidase (MPO, 235 ± 15 vs. 101 ± 11 μM/min/100 mg tissue)]. Insulin resistance (plasma glucose, 64 ± 5 vs. 100 ± 5 mg/dl; AUC (0-120 min), p < 0.05), MI-RP injury (IS 20 ± 5%, LDH 292 ± 28 U/L, CK-MB 257 ± 13 U/L, MPO 95 ± 5 μM/min/100 mg tissue) and triglyceride (TG) level were significantly reduced, while myocardial Akt, p-Akt, eNOS, p-eNOS and iNOS protein expression were significantly enhanced following atorvastatin treatment in comparison to HFr fed rats. Oxidative stress marker, malondialdehyde and circulating levels of inflammatory cytokines (CRP, IL-6, IFN-γ and TNF) were significantly reduced, while total nitrite content in the tissue and plasma was significantly augmented in atorvastatin treated rats. Atorvastatin also ameliorated endothelial dysfunction and significantly enhanced aortic Akt and eNOS protein expression. Atorvastatin conferred significant protection against MI-RP injury and alleviated HFr induced IRS possibly by increasing NOS expression through Akt dependent pathway.

  9. 14S,21R-dihydroxy-docosahexaenoic acid treatment enhances mesenchymal stem cell amelioration of renal ischemia/reperfusion injury.

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    Tian, Haibin; Lu, Yan; Shah, Shraddha P; Wang, Quansheng; Hong, Song

    2012-05-01

    Bone marrow mesenchymal stem cells (MSCs) have shown potential to improve treatment of renal failure. The prohealing functions of MSCs have been found to be enhanced by treatment with the lipid mediator, 14S,21R-dihydroxy-docosa4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA). In this article, using a murine model of renal ischemia/reperfusion (I/R) injury, we found that treatment with 14S,21R-diHDHA enhanced MSC amelioration of renal I/R injury. Treated MSCs more efficiently inhibited I/R-induced elevation of serum creatinine levels, reduced renal tubular cell death, and inhibited infiltration of neutrophils, macrophages, and dendritic cells in kidneys. Conditioned medium from treated MSCs reduced the generation of tumor necrosis factor-α and reactive oxygen species by macrophages under I/R conditions. Infusion of treated MSCs more efficiently reduced I/R-damage to renal histological structures compared with untreated MSCs (injury score: 7.9±0.4 vs. 10.5±0.5). Treated MSCs were resistant to apoptosis in vivo when transplanted under capsules of I/R-injured kidneys (active caspase-3+ MSCs: 4.2%±2.8% vs. 11.7%±2.4% of control) and in vitro when cultured under I/R conditions. Treatment with 14S,21R-diHDHA promoted viability of MSCs through a mechanism involving activation of the phosphoinositide 3-kinase -Akt signaling pathway. Additionally, treatment of MSCs with 14S,21R-diHDHA promoted secretion of renotrophic hepatocyte growth factor and insulin growth factor-1. Similar results were obtained when 14S,21RdiHDHA was used to inhibit apoptosis of human MSCs (hMSCs) and to increase the generation of renotrophic cytokines from hMSCs. These findings provide a lead for new strategies in the treatment of acute kidney injury with MSCs.

  10. Effects and Mechanisms of Chinese Herbal Medicine in Ameliorating Myocardial Ischemia-Reperfusion Injury

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    Qing Liu

    2013-01-01

    Full Text Available Myocardial ischemia-reperfusion (MIR injury is a major contributor to the morbidity and mortality associated with coronary artery disease, which accounts for approximately 450,000 deaths a year in the United States alone. Chinese herbal medicine, especially combined herbal formulations, has been widely used in traditional Chinese medicine for the treatment of myocardial infarction for hundreds of years. While the efficacy of Chinese herbal medicine is well documented, the underlying molecular mechanisms remain elusive. In this review, we highlight recent studies which are focused on elucidating the cellular and molecular mechanisms using extracted compounds, single herbs, or herbal formulations in experimental settings. These studies represent recent efforts to bridge the gap between the enigma of ancient Chinese herbal medicine and the concepts of modern cell and molecular biology in the treatment of myocardial infarction.

  11. [Octanol preconditioning alleviates mouse cardiomyocyte swelling induced by simulated ischemia/reperfusion challenge in vitro].

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    Luo, Yukun; Fang, Jun; Fan, Lin; Lin, Chaogui; Chen, Zhaoyang; Chen, Lianglong

    2012-10-01

    To investigate the role of connexin 43-formed hemichannels in cell volume regulation induced by simulated ischemia/reperfusion (SI/R). Mouse cardiomyocytes isolated on a Langendorff apparatus with enzyme solution were aliquoted into control, SI/R and SI/R +octanol groups. Calcein-AM was used to stain the cells and the cell volume was measured with confocal microscope by stack scanning. Trypan blue was used to measure the cell viability after the treatments. Calcein-AM staining and cofocal microscopy yielded stable and reproducible results for cell volume measurement. Mouse cardiomyocytes subjected to simulated SI/R showed obvious cell swelling as compared with the control cells [(126∓6)% vs 100%, Poctanol preconditioning significantly attenuated the cell swelling [(113∓6)%, Poctanol preconditioning obviously reduced the viability of the cells with SI/R challenge [(31∓2)%, Poctanol can alleviate the cell swelling to enhance the viability of the cardiomyocytes following SI/R.

  12. Protective effect of nicotinamide adenine dinucleotide (NAD+) against spinal cord ischemia-reperfusion injury via reducing oxidative stress-induced neuronal apoptosis.

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    Xie, Lei; Wang, Zhenfei; Li, Changwei; Yang, Kai; Liang, Yu

    2017-02-01

    As previous studies demonstrate that oxidative stress and apoptosis play crucial roles in ischemic pathogenesis and nicotinamide adenine dinucleotide (NAD + ) treatment attenuates oxidative stress-induced cell death among primary neurons and astrocytes as well as significantly reduce cerebral ischemic injury in rats. We used a spinal cord ischemia injury (SCII) model in rats to verify our hypothesis that NAD + could ameliorate oxidative stress-induced neuronal apoptosis. Adult male rats were subjected to transient spinal cord ischemia for 60min, and different doses of NAD + were administered intraperitoneally immediately after the start of reperfusion. Neurological function was determined by Basso, Beattie, Bresnahan (BBB) scores. The oxidative stress level was assessed by superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. The degree of apoptosis was analyzed by deoxyuridinetriphosphate nick-end labeling (TUNEL) staining and protein levels of cleaved caspase-3 and AIF (apoptosis inducing factor). The results showed that NAD + at 50 or 100mg/kg significantly decreased the oxidative stress level and neuronal apoptosis in the spinal cord of ischemia-reperfusion rats compared with saline, as accompanied with the decreased oxidative stress, NAD + administration significantly restrained the neuronal apoptosis after ischemia injury while improved the neurological and motor function. These findings suggested that NAD + might protect against spinal cord ischemia-reperfusion via reducing oxidative stress-induced neuronal apoptosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. The effect of intermittent fasting and water restriction on myocardial ischemia/reperfusion-induced arrhythmia in rats

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    KAYA, Salih Tunç; BOZDOĞAN, Ömer

    2011-01-01

    To investigate the effect of intermittent fasting and water restriction on ischemia/reperfusion-induced arrhythmias. Materials and methods: Six minutes of ischemia followed by 6 min of reperfusion was produced by the ligation and then releasing of the left coronary artery. Intermittent fasting and water restriction were applied during 1 month for 12 h/day. The duration, type, and incidence of arrhythmias during reperfusion and the survival rate at the end of reperfusion were determined and c...

  14. The Effect of Recombinant Human MG53 Protein on Tourniquet-induced Ischemia Reperfusion Injury in Rat Muscle

    Science.gov (United States)

    2014-06-01

    blind to the treatment , and the prevalence of damaged fibers was quantitated from 10 10x images from each muscle . Approximately 800 fibers were counted...therapeutic cell membrane repair in treatment of muscular dystrophy . Sci Transl Med. 2012; 4(139):139ra185. 11. Weisleder N, Lin P, Zhao X, Orange M, Zhu H...The effect of recombinant human MG53 protein on tourniquet- induced ischemia reperfusion injury in rat muscle Benjamin T. Corona, Ph.D.1, Koyal Garg

  15. Maresin 1 Ameliorates Lung Ischemia/Reperfusion Injury by Suppressing Oxidative Stress via Activation of the Nrf-2-Mediated HO-1 Signaling Pathway

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    Quanchao Sun

    2017-01-01

    Full Text Available Lung ischemia/reperfusion (I/R injury occurs in various clinical conditions and heavily damaged lung function. Oxidative stress reaction and antioxidant enzymes play a pivotal role in the etiopathogenesis of lung I/R injury. In the current study, we investigated the impact of Maresin 1 on lung I/R injury and explored the possible mechanism involved in this process. MaR 1 ameliorated I/R-induced lung injury score, wet/dry weight ratio, myeloperoxidase, tumor necrosis factor, bronchoalveolar lavage fluid (BALF leukocyte count, BALF neutrophil ratio, and pulmonary permeability index levels in lung tissue. MaR 1 significantly reduced ROS, methane dicarboxylic aldehyde, and 15-F2t-isoprostane generation and restored antioxidative enzyme (superoxide dismutase, glutathione peroxidase, and catalase activities. Administration of MaR 1 improved the expression of nuclear Nrf-2 and cytosolic HO-1 in I/R-treated lung tissue. Furthermore, we also found that the protective effects of MaR 1 on lung tissue injury and oxidative stress were reversed by HO-1 activity inhibitor, Znpp-IX. Nrf-2 transcription factor inhibitor, brusatol, significantly decreased MaR 1-induced nuclear Nrf-2 and cytosolic HO-1 expression. In conclusion, these results indicate that MaR 1 protects against lung I/R injury through suppressing oxidative stress. The mechanism is partially explained by activation of the Nrf-2-mediated HO-1 signaling pathway.

  16. Roles of Endoplasmic Reticulum Stress in NECA-Induced Cardioprotection against Ischemia/Reperfusion Injury

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    Fengmei Xing

    2017-01-01

    Full Text Available Objective. This study aimed to investigate whether the nonselective A2 adenosine receptor agonist NECA induces cardioprotection against myocardial ischemia/reperfusion (I/R injury via glycogen synthase kinase 3β (GSK-3β and the mitochondrial permeability transition pore (mPTP through inhibition of endoplasmic reticulum stress (ERS. Methods and Results. H9c2 cells were exposed to H2O2 for 20 minutes. NECA significantly prevented H2O2-induced TMRE fluorescence reduction, indicating that NECA inhibited the mPTP opening. NECA blocked H2O2-induced GSK-3β phosphorylation and GRP94 expression. NECA increased GSK-3β phosphorylation and decreased GRP94 expression, which were prevented by both ERS inductor 2-DG and PKG inhibitor KT5823, suggesting that NECA may induce cardioprotection through GSK-3β and cGMP/PKG via ERS. In isolated rat hearts, both NECA and the ERS inhibitor TUDCA decreased myocardial infarction, increased GSK-3β phosphorylation, and reversed GRP94 expression at reperfusion, suggesting that NECA protected the heart by inhibiting GSK-3β and ERS. Transmission electron microscopy showed that NECA and TUDCA reduced mitochondrial swelling and endoplasmic reticulum expansion, further supporting that NECA protected the heart by preventing the mPTP opening and ERS. Conclusion. These data suggest that NECA prevents the mPTP opening through inactivation of GSK-3β via ERS inhibition. The cGMP/PKG signaling pathway is responsible for GSK-3β inactivation by NECA.

  17. Inhalation of water electrolysis-derived hydrogen ameliorates cerebral ischemia-reperfusion injury in rats - A possible new hydrogen resource for clinical use.

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    Cui, Jin; Chen, Xiao; Zhai, Xiao; Shi, Dongchen; Zhang, Rongjia; Zhi, Xin; Li, Xiaoqun; Gu, Zhengrong; Cao, Liehu; Weng, Weizong; Zhang, Jun; Wang, Liping; Sun, Xuejun; Ji, Fang; Hou, Jiong; Su, Jiacan

    2016-10-29

    Hydrogen is a kind of noble gas with the character to selectively neutralize reactive oxygen species. Former researches proved that low-concentration of hydrogen can be used to ameliorating cerebral ischemia/reperfusion injury. Hydrogen electrolyzed from water has a hydrogen concentration of 66.7%, which is much higher than that used in previous studies. And water electrolysis is a potential new hydrogen resource for regular clinical use. This study was designed and carried out for the determination of safety and neuroprotective effects of water electrolysis-derived hydrogen. Sprague-Dawley rats were used as experimental animals, and middle cerebral artery occlusion was used to make cerebral ischemia/reperfusion model. Pathologically, tissues from rats in hydrogen inhalation group showed no significant difference compared with the control group in HE staining pictures. The blood biochemical findings matched the HE staining result. TTC, Nissl, and TUNEL staining showed the significant improvement of infarction volume, neuron morphology, and neuron apoptosis in rat with hydrogen treatment. Biochemically, hydrogen inhalation decreased brain caspase-3, 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine-positive cells and inflammation factors concentration. Water electrolysis-derived hydrogen inhalation had neuroprotective effects on cerebral ischemia/reperfusion injury in rats with the effect of suppressing oxidative stress and inflammation, and it is a possible new hydrogen resource to electrolyze water at the bedside clinically. Copyright © 2016. Published by Elsevier Ltd.

  18. Exercise-induced circulating extracellular vesicles protect against cardiac ischemia-reperfusion injury.

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    Bei, Yihua; Xu, Tianzhao; Lv, Dongchao; Yu, Pujiao; Xu, Jiahong; Che, Lin; Das, Avash; Tigges, John; Toxavidis, Vassilios; Ghiran, Ionita; Shah, Ravi; Li, Yongqin; Zhang, Yuhui; Das, Saumya; Xiao, Junjie

    2017-07-01

    Extracellular vesicles (EVs) serve an important function as mediators of intercellular communication. Exercise is protective for the heart, although the signaling mechanisms that mediate this cardioprotection have not been fully elucidated. Here using nano-flow cytometry, we found a rapid increase in plasma EVs in human subjects undergoing exercise stress testing. We subsequently identified that serum EVs were increased by ~1.85-fold in mice after 3-week swimming. Intramyocardial injection of equivalent quantities of EVs from exercised mice and non-exercised controls provided similar protective effects against acute ischemia/reperfusion (I/R) injury in mice. However, injection of exercise-induced EVs in a quantity equivalent to the increase seen with exercise (1.85 swim group) significantly enhanced the protective effect. Similarly, treatment with exercise-induced increased EVs provided additional anti-apoptotic effect in H 2 O 2 -treated H9C2 cardiomyocytes mediated by the activation of ERK1/2 and HSP27 signaling. Finally, by treating H9C2 cells with insulin-like growth factor-1 to mimic exercise stimulus in vitro, we found an increased release of EVs from cardiomyocytes associated with ALIX and RAB35 activation. Collectively, our results show that exercise-induced increase in circulating EVs enhances the protective effects of endogenous EVs against cardiac I/R injury. Exercise-derived EVs might serve as a potent therapy for myocardial injury in the future.

  19. Combination Anti-Apoptotic Effect of Erythropoietin and Melatonin on Ischemia Reperfusion-Induced Renal Injury in Rats

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    Shokofeh Banaei

    2016-11-01

    Full Text Available Renal ischemia-reperfusion (IR contributes to the development of acute renal failure (ARF. Oxygen free radicals are considered to be principal components involved in the pathophysiological tissue alterations observed during renal IR. The purpose of this study was to investigate the combination effect of melatonin (MEL and erythropoietin (EPO, which are a potent antioxidant and anti-apoptotic agents, in IR-induced renal injury in rats. Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. MEL (10 mg/kg, i.p and EPO (5000 U/kg, i.p were administered prior to ischemia. After 24 h reperfusion, following decapitation, blood samples were collected for the determination of superoxide dismutase (SOD, glutathione peroxidase (GPx, and malondialdehyde (MDA levels. Also, renal samples were taken for histological evaluation and apoptosis assay. Ischemia-reperfusion increased SOD, GPx, MDA levels, and TUNEL positive cells. Histopathological findings of the IR group confirmed that there was renal impairment in the tubular epithelium. Treatment with EPO and MEL decreased SOD, GPx, and MDA levels, histopathological changes, and TUNEL positive cells. These results indicated that the combination of MEL and EPO could not exert more nephroprotective and anti-apoptotic effects than MEL treatment in renal ischemia-reperfusion injury.

  20. Hypercholesterolemic myocardium is vulnerable to ischemia-reperfusion injury and refractory to sevoflurane-induced protection.

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    Yong Xu

    Full Text Available Recent studies have demonstrated that volatile anesthetic postconditioning confers myocardial protection against ischemia-reperfusion (IR injury through activation of the reperfusion injury salvage kinase (RISK pathway. As RISK has been shown to be impaired in hypercholesterolemia. Therefore, we investigate whether anesthetic-induced cardiac protection was maintained in hypercholesterolemic rats. In the present study, normocholesteolemic or hypercholesterolemic rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Animals received 2.4% sevoflurane for 5 min or 3 cycles of 10-s ischemia/10-s reperfusion. The hemodynamic parameters, including left ventricular developed pressure, left ventricular end-diastolic pressure and heart rate, were continuously monitored. The infarct size, apoptosis, p-Akt, p-ERK1/2, p-GSK3β were determined. We found that both sevoflurane and ischemic postconditioning significantly improved heart pump function, reduced infarct size and increased the phosphorylation of Akt, ERK1/2 and their downstream target of GSK3β in the healthy rats. In the hypercholesterolemic rats, neither sevoflurane nor ischemic postconditioning improved left ventricular hemodynamics, reduced infarct size and increased the phosphorylated Akt, ERK1/2 and GSK3β. In contrast, GSK inhibitor SB216763 conferred cardioprotection against IR injury in healthy and hypercholesterolemic hearts. In conclusions, hyperchoesterolemia abrogated sevoflurane-induced cardioprotection against IR injury by alteration of upstream signaling of GSK3β and acute GSK inhibition may provide a novel therapeutic strategy to protect hypercholesterolemic hearts against IR injury.

  1. Administration of FTY720 during Tourniquet-Induced Limb Ischemia Reperfusion Injury Attenuates Systemic Inflammation

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    Anthony D. Foster

    2017-01-01

    Full Text Available Acute ischemia-reperfusion injury (IRI of the extremities leads to local and systemic inflammatory changes which can hinder limb function and can be life threatening. This study examined whether the administration of the T-cell sequestration agent, FTY720, following hind limb tourniquet-induced skeletal muscle IRI in a rat model would attenuate systemic inflammation and multiple end organ injury. Sprague-Dawley rats were subjected to 1 hr of ischemia via application of a rubber band tourniquet. Animals were randomized to receive an intravenous bolus of either vehicle control or FTY720 15 min after band placement. Rats (n=10/time point were euthanized at 6, 24, and 72 hr post-IRI. Peripheral blood as well as lung, liver, kidney, and ischemic muscle tissue was analyzed and compared between groups. FTY720 treatment markedly decreased the number of peripheral blood T cells (p<0.05 resulting in a decreased systemic inflammatory response and lower serum creatinine levels and had a modest but significant effect in decreasing the transcription of injury-associated target genes in multiple end organs. These findings suggest that early intervention with FTY720 may benefit the treatment of IRI of the limb. Further preclinical studies are necessary to characterize the short-term and long-term beneficial effects of FTY720 following tourniquet-induced IRI.

  2. Tramadol Alleviates Myocardial Injury Induced by Acute Hindlimb Ischemia Reperfusion in Rats

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    Takhtfooladi, Hamed Ashrafzadeh; Asl, Adel Haghighi Khiabanian [Department of Pathobiology, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Shahzamani, Mehran [Department of Cardiovascular Surgery, Isfahan University of Medical Sciences, Tehran (Iran, Islamic Republic of); Takhtfooladi, Mohammad Ashrafzadeh, E-mail: dr-ashrafzadeh@yahoo.com [Young Researchers and Elites Club, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Allahverdi, Amin [Department of Surgery, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Khansari, Mohammadreza [Department of Physiology, Science and Research Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of)

    2015-08-15

    Organ injury occurs not only during periods of ischemia but also during reperfusion. It is known that ischemia reperfusion (IR) causes both remote organ and local injuries. This study evaluated the effects of tramadol on the heart as a remote organ after acute hindlimb IR. Thirty healthy mature male Wistar rats were allocated randomly into three groups: Group I (sham), Group II (IR), and Group III (IR + tramadol). Ischemia was induced in anesthetized rats by left femoral artery clamping for 3 h, followed by 3 h of reperfusion. Tramadol (20 mg/kg, intravenous) was administered immediately prior to reperfusion. At the end of the reperfusion, animals were euthanized, and hearts were harvested for histological and biochemical examination. The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were higher in Groups I and III than those in Group II (p < 0.05). In comparison with other groups, tissue malondialdehyde (MDA) levels in Group II were significantly increased (p < 0.05), and this increase was prevented by tramadol. Histopathological changes, including microscopic bleeding, edema, neutrophil infiltration, and necrosis, were scored. The total injuryscore in Group III was significantly decreased (p < 0.05) compared with Group II. From the histological and biochemical perspectives, treatment with tramadol alleviated the myocardial injuries induced by skeletal muscle IR in this experimental model.

  3. Antiarrhythmic effect of tamoxifen on the vulnerability induced by hyperthyroidism to heart ischemia/reperfusion damage.

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    Pavón, Natalia; Hernández-Esquivel, Luz; Buelna-Chontal, Mabel; Chávez, Edmundo

    2014-09-01

    Hyperthyroidism, known to have deleterious effects on heart function, and is associated with an enhanced metabolic state, implying an increased production of reactive oxygen species. Tamoxifen is a selective antagonist of estrogen receptors. These receptors make the hyperthyroid heart more susceptible to ischemia/reperfusion. Tamoxifen is also well-known as an antioxidant. The aim of the present study was to explore the possible protective effect of tamoxifen on heart function in hyperthyroid rats. Rats were injected daily with 3,5,3'-triiodothyronine at 2mg/kg body weight during 5 days to induce hyperthyroidism. One group was treated with 10mg/kg tamoxifen and another was not. The protective effect of the drug on heart rhythm was analyzed after 5 min of coronary occlusion followed by 5 min reperfusion. In hyperthyroid rats not treated with tamoxifen, ECG tracings showed post-reperfusion arrhythmias, and heart mitochondria isolated from the ventricular free wall lost the ability to accumulate and retain matrix Ca(2+) and to form a high electric gradient. Both of these adverse effects were avoided with tamoxifen treatment. Hyperthyroidism-induced oxidative stress caused inhibition of cis-aconitase and disruption of mitochondrial DNA, effects which were also avoided by tamoxifen treatment. The current results support the idea that tamoxifen inhibits the hypersensitivity of hyperthyroid rat myocardium to reperfusion damage, probably because its antioxidant activity inhibits the mitochondrial permeability transition. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Is ursodeoxycholic acid crucial for ischemia/reperfusion-induced ovarian injury in rat ovary?

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    Akdemir, Ali; Sahin, Cagdas; Erbas, Oytun; Yeniel, Ahmet O; Sendag, Fatih

    2015-08-01

    Ursodeoxycholic acid is frequently used in cholestatic liver diseases. Also, it protects hepatocytes against oxidative stress induced by hydrophobic bile acids. We investigated the anti-oxidative effect of ursodeoxycholic acid on ischemia/reperfusion injury after ovarian de-torsion in rats. We designed five study groups. Group 1 (n = 6): Sham-operated group; group 2 (n = 6): torsion group; group 3 (n = 6): torsion and ursodeoxycholic acid, group 4 (n = 7): torsion/de-torsion group; and group 5 (n = 7): torsion/de-torsion and ursodeoxycholic acid. After that, ovarian samples were obtained and examined histologically and tissue levels of malondialdehyde were measured. Follicular degeneration, edema and inflammatory cells were significantly decreased in groups 3 and 5 in comparison with groups 2 and 4. Also, groups 4 and 5 were compared in terms of vascular congestion and hemorrhage and these were found to be significantly decreased in group 5. In addition, levels of malondialdehyde were significantly decreased in groups 3 and 5 in comparison with groups 2 and 4. We concluded that ursodeoxycholic acid might be useful to protect the ovary against ischemia and reperfusion injury.

  5. Curcumin inhibits endoplasmic reticulum stress induced by cerebral ischemia-reperfusion injury in rats

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    Zhu, Haiying; Fan, Yanxia; Sun, Hongyu; Chen, Liyan; Man, Xiao

    2017-01-01

    The aim of the present study was to observe the dynamic changes of the growth arrest and DNA damage-inducible 153 (GADD153) gene and caspase-12 in the brain tissue of rats with cerebral ischemia-reperfusion injury (CIRI) and the impact of curcumin pretreatment. A total of 60 rats were randomly divided into the normal group (N), the sham operation group (S), the dimethyl sulfoxide control group (D) and the curcumin treatment group (C). For group D and C, 12 (T1), 24 (T2) and 72 h (T3) of reperfusion were performed after 2 h ischemia. The expression levels of GADD153 and caspase-12 in the brain tissue were detected and compared among the groups by immunohistochemistry, immunofluorescence double staining and western blotting. The expression levels of GADD153 and caspase-12 were increased at T1compared with groups N and S, and the expression of caspase-12 peaked at T2 in group D, while GADD153 was increased until T3 in group D. Compared with group D, the expression levels of GADD153 and caspase-12 in group C at T2 and T3 were significantly decreased (P<0.05). Endoplasmic reticulum stress is involved in the pathological process of CIRI. Curcumin may decrease the expression levels of the above two factors, thus exhibiting protective effects against CIRI in rats. PMID:29067098

  6. Effect of Nigella sativa on ischemia-reperfusion induced rat kidney damage

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    Shahrzad Havakhah

    2015-12-01

    Full Text Available Objective(s:There are a few previously reported studies about the effect of Nigella sativa oil on renal ischemia-reperfusion injury (IRI. The aim of the present study was to test the hypothesis whether pre- or post-treatment with N. sativa hydroalcoholic extract (NSE would reduce tissue injury and oxidative damages in a clinically relevant rat model of renal IRI.    Materials and Methods: IRI was induced by clamping of bilateral renal arteries for 40 min fallowed by reperfusion for 180 min. NSE was prepared in a Soxhlet extractor and administrated with doses of 150 mg/kg or 300 mg/kg at 1 hr before ischemia induction (P-150 and 300 or at the beginning of reperfusion phase (T-150 and 300, via jugular catheter intravenously. The kidneys were then removed and subjected to biochemical analysis, comet assay or histopathological examination. Results: The kidneys of untreated IRI rats had a higher histopathological score (P

  7. Coronary arterial BK channel dysfunction exacerbates ischemia/reperfusion-induced myocardial injury in diabetic mice.

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    Lu, Tong; Jiang, Bin; Wang, Xiao-Li; Lee, Hon-Chi

    2016-09-01

    The large conductance Ca(2+)-activated K(+) (BK) channels, abundantly expressed in coronary artery smooth muscle cells (SMCs), play a pivotal role in regulating coronary circulation. A large body of evidence indicates that coronary arterial BK channel function is diminished in both type 1 and type 2 diabetes. However, the consequence of coronary BK channel dysfunction in diabetes is not clear. We hypothesized that impaired coronary BK channel function exacerbates myocardial ischemia/reperfusion (I/R) injury in streptozotocin-induced diabetic mice. Combining patch-clamp techniques and cellular biological approaches, we found that diabetes facilitated the colocalization of angiotensin II (Ang II) type 1 receptors and BK channel α-subunits (BK-α), but not BK channel β1-subunits (BK-β1), in the caveolae of coronary SMCs. This caveolar compartmentation in vascular SMCs not only enhanced Ang II-mediated inhibition of BK-α but also produced a physical disassociation between BK-α and BK-β1, leading to increased infarct size in diabetic hearts. Most importantly, genetic ablation of caveolae integrity or pharmacological activation of coronary BK channels protected the cardiac function of diabetic mice from experimental I/R injury in both in vivo and ex vivo preparations. Our results demonstrate a vascular ionic mechanism underlying the poor outcome of myocardial injury in diabetes. Hence, activation of coronary BK channels may serve as a therapeutic target for cardiovascular complications of diabetes.

  8. Nebivolol and chrysin protect the liver against ischemia/reperfusion-induced injury in rats

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    Sayed M. Mizar

    2015-03-01

    Full Text Available Oxidative stress plays a key role in the pathogenesis of hepatic ischemia/reperfusion (I/R-induced injury, one of the leading causes of liver damage post-surgical intervention, trauma and transplantation. This study aimed to evaluate the protective effect of nebivolol and chrysin against I/R-induced liver injury via their vasodilator and antioxidant effects, respectively. Adult male Wister rats received nebivolol (5 mg/kg and/or chrysin (25 mg/kg by oral gavage daily for one week then subjected to ischemia via clamping the portal triad for 30 min then reperfusion for 30 min. Liver function enzymes, alanine transaminase (ALT and aspartate transaminase (AST, as well as hepatic Myeloperoxidase (MPO, total nitrate (NOx, glutathione (GSH and liver malondialdehyde (MDA were measured at the end of the experiment. Liver tissue damage was examined by histopathology. In addition, the expression levels of nitric oxide synthase (NOS subtypes, endothelial (eNOS and inducible (iNOS in liver samples were assessed by Western blotting and confirmed by immunohistochemical analysis. Both chrysin and nebivolol significantly counteracted I/R-induced oxidative stress and tissue damage biomarkers. The combination of these agents caused additive liver protective effect against I/R-induced damage via the up regulation of nitric oxide expression and the suppression of oxidative stress. Chrysin and nebivolol combination showed a promising protective effect against I/R-induced liver injury, at least in part, via decreasing oxidative stress and increasing nitric oxide levels.

  9. Inhaled nitric oxide pretreatment but not posttreatment attenuates ischemia-reperfusion-induced pulmonary microvascular leak.

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    Chetham, P M; Sefton, W D; Bridges, J P; Stevens, T; McMurtry, I F

    1997-04-01

    Ischemia-reperfusion (I/R) pulmonary edema probably reflects a leukocyte-dependent, oxidant-mediated mechanism. Nitric oxide (NO) attenuates leukocyte-endothelial cell interactions and I/R-induced microvascular leak. Cyclic adenosine monophosphate (cAMP) agonists reverse and prevent I/R-induced microvascular leak, but reversal by inhaled NO (INO) has not been tested. In addition, the role of soluble guanylyl cyclase (sGC) activation in the NO protection effect is unknown. Rat lungs perfused with salt solution were grouped as either I/R, I/R with INO (10 or 50 ppm) on reperfusion, or time control. Capillary filtration coefficients (Kfc) were estimated 25 min before ischemia (baseline) and after 30 and 75 min of reperfusion. Perfusate cell counts and lung homogenate myeloperoxidase activity were determined in selected groups. Additional groups were treated with either INO (50 ppm) or isoproterenol (ISO-10 microM) after 30 min of reperfusion. Guanylyl cyclase was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ-15 microM), and Kfc was estimated at baseline and after 30 min of reperfusion. (1) Inhaled NO attenuated I/R-induced increases in Kfc. (2) Cell counts were similar at baseline. After 75 min of reperfusion, lung neutrophil retention (myeloperoxidase activity) and decreased perfusate neutrophil counts were similar in all groups. (3) In contrast to ISO, INO did not reverse microvascular leak. (4) 8-bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP) prevented I/R-induced microvascular leak in ODQ-treated lungs, but INO was no longer effective. Inhaled NO attenuates I/R-induced pulmonary microvascular leak, which requires sGC activation and may involve a mechanism independent of inhibition of leukocyte-endothelial cell interactions. In addition, INO is ineffective in reversing I/R-induced microvascular leak.

  10. Carbonic anhydrase inhibitor attenuates ischemia-reperfusion induced acute lung injury.

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    Chou-Chin Lan

    Full Text Available Ischemia-reperfusion (IR-induced acute lung injury (ALI is implicated in several clinical conditions including lung transplantation, cardiopulmonary bypass surgery, re-expansion of collapsed lung from pneumothorax or pleural effusion and etc. IR-induced ALI remains a challenge in the current treatment. Carbonic anhydrase has important physiological function and influences on transport of CO2. Some investigators suggest that CO2 influences lung injury. Therefore, carbonic anhydrase should have the role in ALI. This study was undertaken to define the effect of a carbonic anhydrase inhibitor, acetazolamide (AZA, in IR-induced ALI, that was conducted in a rat model of isolated-perfused lung with 30 minutes of ischemia and 90 minutes of reperfusion. The animals were divided into six groups (n = 6 per group: sham, sham + AZA 200 mg/kg body weight (BW, IR, IR + AZA 100 mg/kg BW, IR + AZA 200 mg/kg BW and IR+ AZA 400 mg/kg BW. IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, pulmonary hypertension, neutrophilic sequestration, and an increase in the expression of pro-inflammatory cytokines. Increases in carbonic anhydrase expression and perfusate pCO2 levels were noted, while decreased Na-K-ATPase expression was noted after IR. Administration of 200mg/kg BW and 400mg/kg BW AZA significantly suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1, IL-6 and IL-17 and attenuated IR-induced lung injury, represented by decreases in pulmonary hyper-permeability, pulmonary edema, pulmonary hypertension and neutrophilic sequestration. AZA attenuated IR-induced lung injury, associated with decreases in carbonic anhydrase expression and pCO2 levels, as well as restoration of Na-K-ATPase expression.

  11. Does sucralfate prevent apoptosis occurring in the ischemia/reperfusion-induced intestinal injury?

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    Sencan, A; Yilmaz, O; Ozer, E; Günşar, C; Genç, K; Ulukuş, C; Taneli, C; Mir, E

    2003-08-01

    We have shown in a previous study that sucralfate is beneficial in the prophylaxis and treatment of hypoxia/reoxygenation-induced intestinal injury. The aim of this study is to investigate whether sucralfate has any effect on the prevention of apoptosis in the ischemia/reperfusion (I/R)-induced intestinal injury. Rats were randomized into three groups. Group 1 and 2 were subjected to I/R. Group 1 (treatment group) received sucralfate while group 2 (treatment control group) did not. Group 3 served as a normal control group (sham group). The terminal ileum was harvested for histopathologic investigation by light microscopy. The presence of apoptotic enterocytes (DNA fragmentation in cell nuclei) was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling (TUNEL) reaction. In treatment control group, 3 of 7 rats had severe inflammation. None of the sucralfate-treated rats showed severe inflammation, 6 of them only showed mild inflammatory changes (p < 0.05). The apoptotic percentage was found to be 37.1 +/- 9.4 in the sucralfate-treated group (group 1), whereas it was 45.4 +/- 3.9 in the untreated group (group 2) (p < 0.05). The sham group had a completely normal intestinal architecture. The present study shows that 1) the experimental model of I/R-induced intestinal injury induces enterocyte apoptosis; 2) sucralfate decreases enterocyte apoptosis in the experimental model of I/R-induced intestinal injury which may play a key role in the pathophysiological events leading to failure of the intrinsic gut barrier defense mechanisms.

  12. Arctigenin: A two-edged sword in ischemia/reperfusion induced acute kidney injury.

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    Han, Feng; Xia, Xin-Xin; Dou, Meng; Wang, Yu-Xiang; Xue, Wu-Jun; Ding, Xiao-Ming; Zheng, Jin; Ding, Chen-Guang; Tian, Pu-Xun

    2018-04-27

    Arctigenin (ATG) is one of the main active substances in fruit derived from Arctium lappa L. Previous studies have reported that ATG have antitumor, neuroprotective, antioxidant, antifibrosis and anti-inflammatory functions. However, the actions of ATG in kidney with acute injury following ischemia/ reperfusion (I/R) is still uncertain. In our study, mice were subjected to kidney I/R by having the kidney pedicles clamped and administered with vehicle or ATG (1, 3 or 9 mg/kg/d) via oral gavage for 7 consecutive days prior to I/R. Notably, ATG aggravated kidney I/R injury with the concentration increases. Multiple biochemical assays and histological examination showed ATG significantly alleviated the inflammatory response as reflected by a decreased expression of proinflammatory cytokine, TLR4/MyD88, and NF-κB, along with the infiltration of CD68 + macrophage and CD11b + Gr1 + neutrophil in the kidneys. Meanwhile, ATG alleviated I/R-induced oxidative stress proved by increasing kidney manganese superoxide dismutase and glutathione peroxidase activity but reducing levels of malonaldehyde and inducible nitric oxide synthase. On the contrary, apoptosis was significantly increased in kidneys of ATG-treated mice compared with vehicle-treated controls, especially in tubular cells. There were increased numbers of TUNEL positive cells and increased Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9 expression. The current study demonstrates that pretreatment of ATG aggravates I/R induced acute kidney injury by increasing apoptosis of tubular cells despite reducing infiltrating inflammatory cells and proinflammatory cytokine. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  13. Nitric oxide mediates lung injury induced by ischemia-reperfusion in rats.

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    Kao, Shang Jyh; Peng, Tai-Chu; Lee, Ru Ping; Hsu, Kang; Chen, Chao-Fuh; Hung, Yu-Kuen; Wang, David; Chen, Hsing I

    2003-01-01

    Nitric oxide (NO) has been reported to play a role in lung injury (LI) induced by ischemia-reperfusion (I/R). However, controversy exists as to the potential beneficial or detrimental effect of NO. In the present study, an in situ, perfused rat lung model was used to study the possible role of NO in the LI induced by I/R. The filtration coefficient (Kfc), lung weight gain (LWG), protein concentration in the bronchoalveolar lavage (PCBAL), and pulmonary arterial pressure (PAP) were measured to evaluate the degree of pulmonary hypertension and LI. I/R resulted in increased Kfc, LWG, and PCBAL. These changes were exacerbated by inhalation of NO (20-30 ppm) or 4 mM L-arginine, an NO precursor. The permeability increase and LI caused by I/R could be blocked by exposure to 5 mM N omega-nitro-L-arginine methyl ester (L-NAME; a nonspecific NO synthase inhibitor), and this protective effect of L-NAME was reversed with NO inhalation. Inhaled NO prevented the increase in PAP caused by I/R, while L-arginine had no such effect. L-NAME tended to diminish the I/R-induced elevation in PAP, but the suppression was not statistically significant when compared to the values in the I/R group. These results indicate that I/R increases Kfc and promotes alveolar edema by stimulating endogenous NO synthesis. Exogenous NO, either generated from L-arginine or delivered into the airway, is apparently also injurious to the lung following I/R. Copyright 2003 National Science Council, ROC and S. Karger AG, Basel

  14. Effects of FTY720 on Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats

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    Liangrong Wang

    2017-01-01

    Full Text Available Background. Sphingosine-1-phosphate (S1P is a biologically active lysophospholipid mediator involved in modulating inflammatory process. We investigated the effects of FTY720, a structural analogue of S1P after phosphorylation, on lung injury induced by hindlimb ischemia reperfusion (IR in rats. Methods. Fifty Sprague-Dawley rats were divided into groups SM, IR, F3, F5, and F10. Group SM received sham operation, and bilateral hindlimb IR was established in group IR. The rats in groups F3, F5, and F10 were pretreated with 3, 5, and 10 mg/kg/d FTY720 for 7 days before IR. S1P lyase (S1PL, sphingosine kinase (SphK 1, and SphK2 mRNA expressions, wet/dry weight (W/D, and polymorphonuclear/alveolus (P/A in lung tissues were detected, and the lung injury score was evaluated. Results. W/D, P/A, and mRNA expressions of S1PL, SphK1, and SphK2 were higher in group IR than in group SM, while these were decreased in both groups F5 and F10 as compared to IR (p<0.05. The lung tissue presented severe lesions in group IR, which were attenuated in groups F5 and F10 with lower lung injury scores than in group IR (p<0.05. Conclusions. FTY720 pretreatment could attenuate lung injury induced by hindlimb IR by modulating S1P metabolism and decreasing pulmonary neutrophil infiltration.

  15. Effects of Hydroalcoholic Extract of Cynodon Dactylon (L. Pers. on ISchemia/Reperfusion-Induced Arrhythmias

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    A Garjani

    2008-09-01

    Full Text Available Background and purpose of the study: Probable antiarrhythmic effects of Cynodon dactylon (L. pers. (family Poaceae against ischemia/reperfusion (I/R-induced arrhythmias were investigated in isolated rat heart. Methods: The hearts were subjected to 30min regional ischemia followed by 30min reperfusion and perfused with hydroalcoholic extract of rhizome of C. dactylon (25, 50, 100 and 200µg/ml. Results: During ischemia, the extract produced marked reduction in the number, duration and incidences of ventricular tachycardia (VT at 25 and 50µg/ml (p<0.001 and p<0.01, respectively. Total number of ischemic ventricular ectopic beats (VEBs were lowered by 25-100µg/ml (p<0.001, p<0.001 and p<0.05, respectively. At the reperfusion phase, C. dactylon (25 and 50µg/ml decreased incidence of VT from 100% (control to 13 and 33% (p<0.001 and p<0.05 respectively. Duration and number of VT and total VF incidence were also reduced at the same concentration (p<0.05 for all. Perfusion of the extract (25-100µg/ml was markedly lowered reversible VF duration from 218±99sec to 0 sec, 0 sec and 10±5sec (p<0.01, p<0.01 and p<0.05 respectively. Moreover, C. dactylon (25 and 50µg/ml decreased number of total VEBs from 349±73 to 35±17 (p<0.001 and 66±26 (p<0.01. In this study, it was also shown that perfusion of the extract produced a marked and concentration-dependent positive inotropic effect. Conclusion: The findings of this study indicate that C. dactylon produce protective effects against I/R-induced arrhythmias in isolated rat hearts probably by increase in the myocardial contractility and as a result by improvement of hemodynamic factors.

  16. Methimazole protects lungs during hepatic ischemia-reperfusion injury in rats: an effect not induced by hypothyroidism.

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    Tütüncü, Tanju; Demirci, Cagatay; Gözalan, Ugur; Yüksek, Yunus Nadi; Bilgihan, Ayse; Kama, Nuri Aydin

    2007-05-01

    Hepatic ischemia-reperfusion injury may lead to remote organ failure with mortal respiratory dysfunction. The aim of the present study was to analyze the possible protective effects of methimazole on lungs after hepatic ischemia-reperfusion injury. Forty male Wistar albino rats were randomized into five groups: a control group, in which bilateral pulmonary lobectomy was done; a hepatic ischemia-reperfusion group, in which bilateral pulmonary lobectomy was done after hepatic ischemia-reperfusion; a thyroidectomy-ischemia-reperfusion group (total thyroidectomy followed by, 7 days later, bilateral pulmonary lobectomy after hepatic ischemia-reperfusion); a methimazole-ischemia-reperfusion group (following methimazole administration for 7 days, bilateral pulmonary lobectomy was done after hepatic ischemia-reperfusion); and a methimazole +L-thyroxine-ischemia-reperfusion group (following methimazole and L-thyroxine administration for 7 days, bilateral pulmonary lobectomy was performed after hepatic ischemia-reperfusion). Pulmonary tissue specimens were evaluated histopathologically and for myeloperoxidase and malondialdehyde levels. All of the ischemia-reperfusion intervention groups had higher pulmonary injury scoring indices than the control group (P < 0.001). Pulmonary injury index of the ischemia-reperfusion group was higher than that of both the methimazole-supplemented hypothyroid and euthyroid groups (P = 0028; P = 0,038, respectively) and was similar to that of the thyroidectomized group. Pulmonary tissue myeloperoxidase and malondialdehyde levels in the ischemia-reperfusion group were similar with that in the thyroidectomized rats but were significantly higher than that in the control, and both the methimazole-supplemented hypothyroid and euthyroid groups. Methimazole exerts a protective role on lungs during hepatic ischemia-reperfusion injury, which can be attributed to its anti-inflammatory and anti-oxidant effects rather than hypothyroidism alone.

  17. Albumin infusion after reperfusion prevents gut ischemia-reperfusion-induced gut-associated lymphoid tissue atrophy.

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    Ikezawa, Fumie; Fukatsu, Kazuhiko; Moriya, Tomoyuki; Maeshima, Yoshinori; Okamoto, Koichi; Hara, Etsuko; Hiraide, Hoshio; Compher, Charlene W

    2006-01-01

    Our recent study clarified that gut ischemia-reperfusion (I/R) causes gut-associated lymphoid tissue (GALT) mass atrophy, a possible mechanism for increased morbidity of infectious complications after severe surgical insults. Because albumin administration reportedly reduces hemorrhagic shock-induced lung injury, we hypothesized that albumin treatment prevents GALT atrophy due to gut I/R. Male mice (n = 37) were randomized to albumin, normal saline, and sham groups. All groups underwent jugular vein catheter insertion. The albumin and normal saline groups underwent 75-minute occlusion of the superior mesenteric artery. During gut ischemia, all mice received normal saline infusions at 1.0 mL/h. The albumin group was given 5% bovine serum albumin in normal saline at 1.0 mL/h for 60 minutes after reperfusion, whereas the normal saline group received 0.9% sodium chloride at 1.0 mL/h. The sham group underwent laparotomy only. Mice were killed on day 1 or 7, and the entire small intestine was harvested. GALT lymphocytes were isolated and counted. Their phenotypes (alphabetaTCR, gammadeltaTCR, CD4, CD8, B220) were determined by flow cytometry. On day 1, the gut I/R groups showed significantly lower total lymphocyte and B cell numbers in Peyer's patches and the lamina propria than the sham group. However, the albumin infusion partially but significantly restored these cell numbers. On day 7, there were no significant differences in any of the parameters measured among the 3 groups. Albumin infusion after a gut ischemic insult may maintain gut immunity by preventing GALT atrophy.

  18. Isoflurane administration before ischemia and during reperfusion attenuates ischemia/reperfusion-induced injury of isolated rabbit lungs.

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    Liu, R; Ishibe, Y; Ueda, M; Hang, Y

    1999-09-01

    To investigate the effects of isoflurane on ischemia/ reperfusion (IR)-induced lung injury, we administered isoflurane before ischemia or during reperfusion. Isolated rabbit lungs were divided into the following groups: control (n = 6), perfused and ventilated for 120 min without ischemia; ISO-control (n = 6), 1 minimum alveolar anesthetic concentration (MAC) isoflurane was administered for 30 min before 120 min continuous perfusion; IR (n = 6), ischemia for 60 min, followed by 60 min reperfusion; IR-ISO1 and IR-ISO2, ischemia followed by reperfusion and 1 MAC (n = 6) or 2 MAC (n = 6) isoflurane for 60 min; ISO-IR (n = 6), 1 MAC isoflurane was administered for 30 min before ischemia, followed by IR. During these maneuvers, we measured total pulmonary vascular resistance (Rt), coefficient of filtration (Kfc), and lung wet to dry ratio (W/D). The results indicated that administration of isoflurane during reperfusion inhibited an IR-induced increase in Kfc and W/D ratio. Furthermore, isoflurane at 2 MAC, but not 1 MAC, significantly inhibited an IR-induced increase in Rt. The administration of isoflurane before ischemia significantly attenuated the increase in IR-induced Kfc, W/D, and Rt. Our results suggest that the administration of isoflurane before ischemia and during reperfusion protects against ischemia-reperfusion-induced injury in isolated rabbit lungs.

  19. Electroacupuncture ameliorates cognitive impairment through inhibition of NF-κB-mediated neuronal cell apoptosis in cerebral ischemia-reperfusion injured rats.

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    Feng, Xiaodong; Yang, Shanli; Liu, Jiao; Huang, Jia; Peng, Jun; Lin, Jiumao; Tao, Jing; Chen, Lidian

    2013-05-01

    Cognitive impairment is a serious mental deficit following stroke that severely affects the quality of life of stroke survivors. Nuclear factor‑κB (NF-κB)-mediated neuronal cell apoptosis is involved in the development of post-stroke cognitive impairment; therefore, it has become a promising target for the treatment of impaired cognition. Acupuncture at the Baihui (DU20) and Shenting (DU24) acupoints is commonly used in China to clinically treat post‑stroke cognitive impairment; however, the precise mechanism of its action is largely unknown. In the present study, we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment and investigated the underlying molecular mechanisms using a rat model of focal cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture at Baihui and Shenting was identified to significantly ameliorate neurological deficits and reduce cerebral infarct volume. Additionally, electroacupuncture improved learning and memory ability in cerebral I/R injured rats, demonstrating its therapeutic efficacy against post-stroke cognitive impairment. Furthermore, electroacupuncture significantly suppressed the I/R-induced activation of NF-κB signaling in ischemic cerebral tissues. The inhibitory effect of electroacupuncture on NF-κB activation led to the inhibition of cerebral cell apoptosis. Finally, electroacupuncture markedly downregulated the expression of pro-apoptotic Bax and Fas, two critical downstream target genes of the NF-κB pathway. Collectively, our findings suggest that inhibition of NF-κB‑mediated neuronal cell apoptosis may be one mechanism via which electroacupuncture at Baihui and Shenting exerts a therapeutic effect on post-stroke cognitive impairment.

  20. Dexamethasone Protects Against Tourniquet-Induced Acute Ischemia-Reperfusion Injury in Mouse Hindlimb

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    Ryan M. Corrick

    2018-03-01

    Full Text Available Extremity injuries with hemorrhage have been a significant cause of death in civilian medicine and on the battlefield. The use of a tourniquet as an intervention is necessary for treatment to an injured limb; however, the tourniquet and subsequent release results in serious acute ischemia-reperfusion (IR injury in the skeletal muscle and neuromuscular junction (NMJ. Much evidence demonstrates that inflammation is an important factor to cause acute IR injury. To find effective therapeutic interventions for tourniquet-induced acute IR injuries, our current study investigated effect of dexamethasone, an anti-inflammatory drug, on tourniquet-induced acute IR injury in mouse hindlimb. In C57/BL6 mice, a tourniquet was placed on unilateral hindlimb (left hindlimb at the hip joint for 3 h, and then released for 24 h to induce IR. Three hours of tourniquet and 24 h of release (24-h IR caused gastrocnemius muscle injuries including rupture of the muscle sarcolemma and necrosis (42.8 ± 2.3% for infarct size of the gastrocnemius muscle. In the NMJ, motor nerve terminals disappeared, and endplate potentials were undetectable in 24-h IR mice. There was no gastrocnemius muscle contraction in 24-h IR mice. Western blot data showed that inflammatory cytokines (TNFα and IL-1β were increased in the gastrocnemius muscle after 24-h IR. Treatment with dexamethasone at the beginning of reperfusion (1 mg/kg, i.p. significantly inhibited expression of TNFα and IL-1β, reduced rupture of the muscle sarcolemma and infarct size (24.8 ± 2.0%, and improved direct muscle stimulation-induced gastrocnemius muscle contraction in 24-h IR mice. However, this anti-inflammatory drug did not improve NMJ morphology and function, and sciatic nerve-stimulated skeletal muscle contraction in 24-h IR mice. The data suggest that one-time treatment with dexamethasone at the beginning of reperfusion only reduced structural and functional impairments of the skeletal muscle but not the

  1. Sepsis-induced myocardial dysfunction and myocardial protection from ischemia/reperfusion injury.

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    McDonough, Kathleen H; Virag, Jitka Ismail

    2006-01-01

    Sepsis, bacteremia and inflammation cause myocardial depression. The mechanism of the dysfunction is not clearly established partly because dysfunction can be elicited by many different mechanisms which can all manifest in disruption of myocardial mechanical function. In addition the models of sepsis and bacteremia and inflammation may vary drastically in the sequence of the coordinated immune response to the inflammatory or septic stimulus. Patterns of cytokine expression can vary as can other responses of the immune system. Patterns of neurohumoral activation in response to the stress of sepsis or bacteremia or inflammation can also vary in both magnitude of response and temporal sequence of response. Stress induced activation of the sympathetic nervous system and humoral responses to stress have a wide range of intensity that can be elicited. The fairly uniform response of the myocardium indicating cardiac dysfunction is surprisingly constant. Systolic performance, as measured by stroke volume or cardiac output and pressure work as estimated by ventricular pressure, are impaired when myocardial contraction is compromised. At times, diastolic function, assessed by ventricular relaxation and filling, is impaired. In addition to the dysfunction that occurs, there is a longer term response of the myocardium to sepsis, and this response is similar to that which is elicited in the heart by multiple brief ischemia/reperfusion episodes and by numerous pharmacological agents as well as heat stress and modified forms of lipopolysaccharide. The myocardium develops protection after an initial stress such that during a second stress, the myocardium does not exhibit as much damage as does a non-protected heart. Many agents can induce this protection which has been termed preconditioning. Both early preconditioning (protection that is measurable min to hours after the initial stimulus) and late preconditioning (protection that is measurable hours to days after the initial

  2. Antioxidant Action of Mangrove Polyphenols against Gastric Damage Induced by Absolute Ethanol and Ischemia-Reperfusion in the Rat

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    Felipe Meira de-Faria

    2012-01-01

    Full Text Available Rhizophora mangle, the red mangrove, has long been known as a traditional medicine. Its bark has been used as astringent, antiseptic, hemostatic, with antifungic and antiulcerogenic properties. In this paper, we aimed to evaluate the antioxidant properties of a buthanolic fraction of the R. mangle bark extract (RM against experimental gastric ulcer in rats. Unib-Wh rats received pretreatment of R. mangle after the induction of gastric injury with absolute ethanol and ischemia-reperfusion. Gastric tissues from both methods were prepared to the enzymatic assays, the levels of sulfhydril compounds (GSH, lipid peroxides (LPO, and the activities of glutathione reductase (GR, glutathione peroxidase (GPx, superoxide dismutase (SOD and myeloperoxidase (MPO were measured. The RM protected the gastric mucosa in both methods used, ethanol-induced gastric ulcer and ischemia-reperfusion, probably, by modulating the activities of the enzymes SOD, GPx, and GR and increasing or maintaining the levels of GSH; in adittion, LPO levels were reduced. The results suggest that the RM antioxidant activity leads to tissue protection; thus one of the antiulcer mechanisms present on the pharmacological effects of R. mangle is the antioxidant property.

  3. Prophylactic Ozone Administration Reduces Intestinal Mucosa Injury Induced by Intestinal Ischemia-Reperfusion in the Rat

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    Ozkan Onal

    2015-01-01

    Full Text Available Objectives. Intestinal ischemia-reperfusion injury is associated with mucosal damage and has a high rate of mortality. Various beneficial effects of ozone have been shown. The aim of the present study was to show the effects of ozone in ischemia reperfusion model in intestine. Material and Method. Twenty eight Wistar rats were randomized into four groups with seven rats in each group. Control group was administered serum physiologic (SF intraperitoneally (ip for five days. Ozone group was administered 1 mg/kg ozone ip for five days. Ischemia Reperfusion (IR group underwent superior mesenteric artery occlusion for one hour and then reperfusion for two hours. Ozone + IR group was administered 1 mg/kg ozone ip for five days and at sixth day IR model was applied. Rats were anesthetized with ketamine∖xyzlazine and their intracardiac blood was drawn completely and they were sacrificed. Intestinal tissue samples were examined under light microscope. Levels of superoxide dismutase (SOD, catalase (CAT, glutathioneperoxidase (GSH-Px, malondyaldehide (MDA, and protein carbonyl (PCO were analyzed in tissue samples. Total oxidant status (TOS, and total antioxidant capacity (TAC were analyzed in blood samples. Data were evaluated statistically by Kruskal Wallis test. Results. In the ozone administered group, degree of intestinal injury was not different from the control group. IR caused an increase in intestinal injury score. The intestinal epithelium maintained its integrity and decrease in intestinal injury score was detected in Ozone + IR group. SOD, GSH-Px, and CAT values were high in ozone group and low in IR. TOS parameter was highest in the IR group and the TAC parameter was highest in the ozone group and lowest in the IR group. Conclusion. In the present study, IR model caused an increase in intestinal injury.In the present study, ozone administration had an effect improving IR associated tissue injury. In the present study, ozone therapy

  4. Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia-reperfusion-induced hepatic injury in rats.

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    Abdel-Gaber, Seham A; Ibrahim, Mohamed A; Amin, Entesar F; Ibrahim, Salwa A; Mohammed, Rehab K; Abdelrahman, Aly M

    2015-08-01

    Ischemia-reperfusion (IR) injury represents an important pathological process of liver injury during major hepatic surgery. The role of cyclooxygenase (COX) enzymes in the pathogenesis of ischemia-reperfusion (IR)-induced liver injury is not clear. This study investigated the effect of a selective COX-2 inhibitor, celecoxib, versus non-selective, indomethacin, on hepatic IR injury in rats. Hepatic IR was induced in adult male rats. The animals were divided into 4 groups: normal control (sham group), IR non-treated group; IR-indomethacin-treated group; and IR-celecoxib-treated group. Liver injury was evaluated by serum alanine aminotransferase (ALT) and a histopathological examination of liver tissues. Hepatic tissue content of oxidative stress parameters glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, malondialdehyde (MDA), nitric oxide (NO) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α) were measured. Moreover, the immunohistochemical detection of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), and caspase-3 in the hepatic tissue was performed. Celecoxib, but not indomethacin, significantly attenuated hepatic IR injury as evidenced by reduction in serum ALT as well as by improvement in the histopathological scoring. Such effect was associated with attenuation in oxidative stress and TNF-α, along with modulation of immunohistochemical expression of eNOS, iNOS and caspase-3 in the hepatic tissue. The present study concluded that selective COX-2 inhibition (but not non-selective), is hepatoprotective against liver IR injury; indicating a differential role of COX-1 versus COX-2. Modulation of iNOS, eNOS and caspase-3 might participate in the protective effect of selective COX-2-inhibitors. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Effect of Γ-aminobutyric acid on kidney injury induced by renal ischemia-reperfusion in male and female rats: Gender-related difference.

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    Vafapour, Marzieh; Nematbakhsh, Mehdi; Monajemi, Ramesh; Mazaheri, Safoora; Talebi, Ardeshir; Talebi, Nahid; Shirdavani, Soheyla

    2015-01-01

    The most important cause of kidney injury is renal ischemia/reperfusion injury (IRI), which is gender-related. This study was designed to investigate the protective role of Γ-aminobutyric acid (GABA (against IRI in male and female rats. Thirty-six female and male wistar rats were assigned to six experimental groups. The IRI was induced by clamping renal vessels for 45 min then was performed reperfusion for 24 h. The group sex posed to IRI were pretreated with GABA and were compared with the control groups. Serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score increased in the IRI alone groups, (P GABA decreased these parameters in female significantly (P GABA. Testis weight did not alter in male rats. Serum level of nitrite and kidney level of malondialdehyde (MDA) had no significant change in both female and male rats. Kidney level of nitrite increased significantly in female rats experienced IRI and serum level of MDA increased significantly in males that were exposed to IRI (P GABA could ameliorate kidney injury induced by renal IRI in a gender dependent manner.

  6. Calreticulin Binds to Fas Ligand and Inhibits Neuronal Cell Apoptosis Induced by Ischemia-Reperfusion Injury

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    Beilei Chen

    2015-01-01

    Full Text Available Background. Calreticulin (CRT can bind to Fas ligand (FasL and inhibit Fas/FasL-mediated apoptosis of Jurkat T cells. However, its effect on neuronal cell apoptosis has not been investigated. Purpose. We aimed to evaluate the neuroprotective effect of CRT following ischemia-reperfusion injury (IRI. Methods. Mice underwent middle cerebral artery occlusion (MCAO and SH-SY5Y cells subjected to oxygen glucose deprivation (OGD were used as models for IRI. The CRT protein level was detected by Western blotting, and mRNA expression of CRT, caspase-3, and caspase-8 was measured by real-time PCR. Immunofluorescence was used to assess the localization of CRT and FasL. The interaction of CRT with FasL was verified by coimmunoprecipitation. SH-SY5Y cell viability was determined by MTT assay, and cell apoptosis was assessed by flow cytometry. The measurement of caspase-8 and caspase-3 activity was carried out using caspase activity assay kits. Results. After IRI, CRT was upregulated on the neuron surface and bound to FasL, leading to increased viability of OGD-exposed SH-SY5Y cells and decreased activity of caspase-8 and caspase-3. Conclusions. This study for the first time revealed that increased CRT inhibited Fas/FasL-mediated neuronal cell apoptosis during the early stage of ischemic stroke, suggesting it to be a potential protector activated soon after IRI.

  7. Role of lipoxygenases and the lipoxin A(4)/annexin 1 receptor in ischemia-reperfusion-induced gastric mucosal damage in rats.

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    Peskar, Brigitta M; Ehrlich, Karlheinz; Schuligoi, Rufina; Peskar, Bernhard A

    2009-01-01

    Rat gastric mucosal damage was induced by ischemia-reperfusion. The 5-lipoxygenase inhibitors MK886 and A63162, the 12-lipoxygenase inhibitor baicalein, the 15-lipoxygenase inhibitor PD146176 and the lipoxin (LX) A(4)/annexin 1 antagonist Boc1 increased mucosal damage in a dose-dependent manner. Low doses of these compounds, which have no effects on mucosal integrity, cause severe damage when combined with low doses of indomethacin, celecoxib or dexamethasone. 16,16-Dimethylprostaglandin (PG) E(2) and LXA(4) can replace each other in preventing mucosal injury induced by either cyclooxygenase or lipoxygenase inhibitors. The results suggest that not only cyclooxygenases, but also lipoxygenases have a role in limiting gastric mucosal damage during ischemia-reperfusion. Copyright 2009 S. Karger AG, Basel.

  8. MCPIP1-induced autophagy mediates ischemia/reperfusion injury in endothelial cells via HMGB1 and CaSR.

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    Xie, Xiaolong; Zhu, Tiebing; Chen, Lulu; Ding, Shuang; Chu, Han; Wang, Jing; Yao, Honghong; Chao, Jie

    2018-01-29

    Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) plays a important role in ischemia/reperfusion (I/R) injury. Autophagy is involved in activating endothelial cells in response to I/R. However, researchers have not clearly determined whether MCPIP1 mediates I/R injury in endothelial cells via autophagy, and its downstream mechanism remains unclear. Western blotting analyses and immunocytochemistry were applied to detect protein levels were detected in HUVECs. An in vitro scratch assay was used to detect cell migration. Cells were transfected with siRNAs to knockdown MCPIP1 and high mobility group box 1 (HMGB1) expression. The pharmacological activator of autophagy rapamycin and the specific calcium-sensing receptor (CaSR) inhibitor NPS-2143 were used to confirm the roles of autophagy and CaSR in I/R injury. I/R induced HMGB1 and CaSR expression, which subsequently upreguated the migration and apoptosis of HUVECs and coincided with the increase of autophagy. HMGB1 was involved in cell migration, whereas CaSR specifically participated in I/R-induced HUVEC apoptosis. Based on these findings, I/R-induced MCPIP1 expression regulates the migration and apoptosis of HUVECs via HMGB1 and CaSR, respectively, suggesting a new therapeutic targetof I/R injury.

  9. The extracellular matrix metalloproteinase inducer EMMPRIN is a target of nitric oxide in myocardial ischemia/reperfusion.

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    Tarin, Carlos; Lavin, Begoña; Gomez, Monica; Saura, Marta; Diez-Juan, Antonio; Zaragoza, Carlos

    2011-07-15

    Nitric oxide (NO) is an important defense against myocardial ischemia/reperfusion (I/R) injury. Although matrix metalloproteinase (MMP)-mediated necrosis of cardiac myocytes is well characterized, the role of inducible NO synthase (iNOS)-derived NO in this process is poorly understood. I/R injury was increased in iNOS-deficient mice and in mice treated with 1400 W (a pharmacological iNOS inhibitor) and was associated with significantly increased expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and EMMPRIN-associated MMPs. Transcriptional activity of an EMMPRIN luciferase promoter reporter expressed in cardiac myocytes was inhibited by NO in a cGMP-dependent manner, and this transcriptional inhibition was abolished by mutation of a putative E2F site. Consistent with these findings, EMMPRIN null mice, in which iNOS is normally induced, are partially protected against I/R injury. Pharmacological inhibition of iNOS in EMMPRIN null mice had no additional protective effect, suggesting that EMMPRIN is a downstream target of NO. Administration of anti-EMMPRIN neutralizing antibodies partly reduced the excess heart damage and MMP-9 expression induced by I/R in iNOS null mice, indicating that regulation of EMMPRIN is an important mechanism of NO-mediated cardioprotection. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Extract of grapefruit-seed reduces acute pancreatitis induced by ischemia/reperfusion in rats: possible implication of tissue antioxidants.

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    Dembinski, A; Warzecha, Z; Konturek, S J; Ceranowicz, P; Dembinski, M; Pawlik, W W; Kusnierz-Cabala, B; Naskalski, J W

    2004-12-01

    Grapefruit seed extract (GSE) has been shown to exert antibacterial, antifungal and antioxidant activity possibly due to the presence of naringenin, the flavonoid with cytoprotective action on the gastric mucosa. No study so far has been undertaken to determine whether this GSE is also capable of preventing acute pancreatic damage induced by ischemia/reperfusion (I/R), which is known to result from reduction of anti-oxidative capability of pancreatic tissue, and whether its possible preventive effect involves an antioxidative action of this biocomponent. In this study carried out on rats with acute hemorrhagic pancreatitis induced by 30 min partial pancreatic ischemia followed by 6 h of reperfusion, the GSE or vehicle (vegetable glycerin) was applied intragastrically in gradually increasing amounts (50-500 microl) 30 min before I/R. Pretreatment with GSE decreased the extent of pancreatitis with maximal protective effect of GSE at the dose 250 microl. GSE reduced the pancreatitis-evoked increase in serum lipase and poly-C specific ribonuclease activity, and attenuated the marked fall in pancreatic blood flow and pancreatic DNA synthesis. GSE administered alone increased significantly pancreatic tissue content of lipid peroxidation products, malondialdehyde and 4-hydroxyalkens, and when administered before I/R, GSE reduced the pancreatitis-induced lipid peroxidation. We conclude that GSE exerts protective activity against I/R-induced pancreatitis probably due to the activation of antioxidative mechanisms in the pancreas and the improvement of pancreatic blood flow.

  11. Protective Effect of Hesperetin and Naringenin against Apoptosis in Ischemia/Reperfusion-Induced Retinal Injury in Rats

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    Selcuk Kara

    2014-01-01

    Full Text Available Purpose. Hesperetin and naringenin are naturally common flavonoids reported to have antioxidative effects. This study was performed to investigate whether either hesperetin or naringenin has a protective effect against apoptosis on retinal ischemia/reperfusion (I/R injury. Methods. Retinal I/R was induced by increasing the intraocular pressure to 150 mmHg for 60 minutes. Thirty-three male Wistar albino rats were randomised into 5 groups named control, I/R + sham, I/R + solvent (DMSO, I/R + hesperetin, and I/R + naringenin. Animals were given either hesperetin, naringenin, or the solvent intraperitoneally immediately following reperfusion. Thickness of retinal layers and retinal cell apoptosis were detected by histological analysis, tunel assay, and immunohistochemistry assay. Results. Hesperetin and naringenin attenuated the I/R-induced apoptosis of retinal cells in the inner and outer nuclear cells of the rat retina. Retinal layer thickness of the naringenin treatment group was significantly thicker than that of the hesperetin, sham, and solvent groups (P<0.05. Conclusions. Hesperetin and naringenin can prevent harmful effects induced by I/R injury in the rat retina by inhibiting apoptosis of retinal cells, which suggests that those flavanones have a therapeutic potential for the protection of ocular ischemic diseases.

  12. Protective effect of edaravone for tourniquet-induced ischemia-reperfusion injury on skeletal muscle in murine hindlimb

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    2013-01-01

    Background Studies have shown that ischemia-reperfusion (I/R) produces free radicals leading to lipid peroxidation and damage to skeletal muscle. The purposes of this study were 1) to assess the histological findings of gastrocnemius muscle (GC) and tibialis anterior muscle (TA) in I/R injury model mice, 2) to histologically analyze whether a single pretreatment of edaravone inhibits I/R injury to skeletal muscle in murine models and 3) to evaluate the effect of oxidative stress on these muscles. Methods C57BL6 mice were divided in two groups, with one group receiving 3 mg/kg intraperitoneal injections of edaravone (I/R + Ed group) and the other group receiving an identical amount of saline (I/R group) 30 minutes before ischemia. Edaravone (3-methy-1-pheny1-2-pyrazolin-5-one) is a potent and novel synthetic scavenger of free radicals. This drug inhibits both nonenzymatic lipid peroxidation and the lipoxygenase pathway, in addition to having potent antioxidant effects against ischemia reperfusion. The duration of the ischemia was 1.5 hours, with reperfusion at either 24 or 72 hours (3 days). Specimens of gastrocnemius (GC) and anterior tibialis (TA) were removed for histological evaluation and biochemical analysis. Results This model of I/R injury was highly reproducible in histologic muscle damage. In the histologic damage score, the mean muscle fibers and inflammatory cell infiltration in the I/R + Ed group were significantly less than the corresponding values of observed in the I/R group. Thus, pretreatment with edaravone was observed to have a protective effect on muscle damage after a period of I/R in mice. In addition, the mean muscle injury score in the I/R + Ed group was also significantly less than the I/R group. In the I/R + Ed group, the mean malondialdehyde (MDA) level was lower than in the I/R group and western-blotting revealed that edaravone pretreatment decreased the level of inducible nitric oxide synthase (iNOS) expression. Conclusions Edaravone

  13. Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats

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    Zygmunt Warzecha

    2017-04-01

    Full Text Available Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

  14. Vagal modulation of high mobility group box-1 protein mediates electroacupuncture-induced cardioprotection in ischemia-reperfusion injury.

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    Zhang, Juan; Yong, Yue; Li, Xing; Hu, Yu; Wang, Jian; Wang, Yong-qiang; Song, Wei; Chen, Wen-ting; Xie, Jian; Chen, Xue-mei; Lv, Xin; Hou, Li-li; Wang, Ke; Zhou, Jia; Wang, Xiang-rui; Song, Jian-gang

    2015-10-26

    Excessive release of high mobility group box-1 (HMGB1) protein from ischemic cardiomyocytes activates inflammatory cascades and enhances myocardial injury after reperfusion. Here we report evidence that electroacupuncture of mice at Neiguan acupoints can inhibit the up-regulation of cardiac HMGB1 following myocardial ischemia and attenuate the associated inflammatory responses and myocardial injury during reperfusion. These benefits of electroacupuncture were partially reversed by administering recombinant HMGB1 to the mice, and further potentiated by administering anti-HMGB1 antibody. Electroacupuncture-induced inhibition of HMGB1 release was markedly reduced by unilateral vagotomy or administration of nicotinic receptor antagonist, but not by chemical sympathectomy. The cholinesterase inhibitor neostigmine mimicked the effects of electroacupuncture on HMGB1 release and myocardial ischemia reperfusion injury. Culture experiments with isolated neonatal cardiomyocytes showed that acetylcholine, but not noradrenaline, inhibited hypoxia-induced release of HMGB1 via a α7nAchR-dependent pathway. These results suggest that electroacupuncture acts via the vagal nerve and its nicotinic receptor-mediated signaling to inhibit HMGB1 release from ischemic cardiomyocytes. This helps attenuate pro-inflammatory responses and myocardial injury during reperfusion.

  15. Glucose supplementation does not interfere with fasting-induced protection against renal ischemia/reperfusion injury in mice.

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    Verweij, Mariëlle; van de Ven, Marieke; Mitchell, James R; van den Engel, Sandra; Hoeijmakers, Jan H J; Ijzermans, Jan N M; de Bruin, Ron W F

    2011-10-15

    Preoperative fasting induces robust protection against renal ischemia/reperfusion (I/R) injury in mice but is considered overcautious and possibly detrimental for postoperative recovery in humans. Furthermore, fasting seems to conflict with reported benefits of preoperative nutritional enhancement with carbohydrate-rich drinks. Here, we investigated whether preoperative ingestion of a glucose solution interferes with fasting-induced protection against renal I/R injury. Mice were randomized into the following groups: fasted for 3 days with access to water (fasted) or a glucose solution (fasted+glc) and fed ad libitum with water (fed) or a glucose solution (fed+glc). After induction of bilateral renal I/R injury, all animals had free access to food and water. Calorie intake, body weight, insulin sensitivity, kidney function, and animal survival were determined. Fed+glc mice had a comparable daily calorie intake as fed mice, but 50% of those calories were obtained from the glucose solution. Fasted+glc mice had a daily calorie intake of approximately 75% of the intake of both fed groups. This largely prevented the substantial body weight loss seen in fasted animals. Preoperative insulin sensitivity was significantly improved in fasted+glc mice versus fed mice. After I/R injury, kidney function and animal survival were superior in both fasted groups. The benefits of fasting and preoperative nutritional enhancement with carbohydrates are not mutually exclusive and may be a clinically feasible regimen to protect against renal I/R injury.

  16. Transient ureteral obstruction prevents against kidney ischemia/reperfusion injury via hypoxia-inducible factor (HIF-2α activation.

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    Shun Zhang

    Full Text Available Although the protective effect of transient ureteral obstruction (UO prior to ischemia on subsequent renal ischemia/reperfusion (I/R injury has been documented, the underlying molecular mechanism remains to be understood. We showed in the current study that 24 h of UO led to renal tubular hypoxia in the ipsilateral kidney in mice, with the accumulation of hypoxia-inducible factor (HIF-2α, which lasted for a week after the release of UO. To address the functions of HIF-2α in UO-mediated protection of renal IRI, we utilized the Mx-Cre/loxP recombination system to knock out target genes. Inactivation of HIF-2α, but not HIF-1α blunted the renal protective effects of UO, as demonstrated by much higher serum creatinine level and severer histological damage. UO failed to prevent postischemic neutrophil infiltration and apoptosis induction in HIF-2α knockout mice, which also diminished the postobstructive up-regulation of the protective molecule, heat shock protein (HSP-27. The renal protective effects of UO were associated with the improvement of the postischemic recovery of intra-renal microvascular blood flow, which was also dependent on the activation of HIF-2α. Our results demonstrated that UO protected the kidney via activation of HIF-2α, which reduced tubular damages via preservation of adequate renal microvascular perfusion after ischemia. Thus, preconditional HIF-2α activation might serve as a novel therapeutic strategy for the treatment of ischemic acute renal failure.

  17. Sirtuin 1 (SIRT1 activation mediates sildenafil induced delayed cardioprotection against ischemia-reperfusion injury in mice.

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    Mona Shalwala

    Full Text Available BACKGROUND: It has been well documented that phosphodiesterase-5 inhibitor, sildenafil (SIL protects against myocardial ischemia/reperfusion (I-R injury. SIRT1 is part of the class III Sirtuin family of histone deacetylases that deacetylates proteins involved in cellular stress response including those related to I-R injury. OBJECTIVE/HYPOTHESIS: We tested the hypothesis that SIL-induced cardioprotection may be mediated through activation of SIRT1. METHODS: Adult male ICR mice were treated with SIL (0.7 mg/kg, i.p., Resveratrol (RSV, 5 mg/kg, a putative activator of SIRT1 used as the positive control, or saline (0.2 mL. The hearts were harvested 24 hours later and homogenized for SIRT1 activity analysis. RESULTS: Both SIL- and RSV-treated mice had increased cardiac SIRT1 activity (P<0.001 as compared to the saline-treated controls 24 hours after drug treatment. In isolated ventricular cardiomyocytes, pretreatment with SIL (1 µM or RSV (1 µM for one hour in vitro also upregulated SIRT1 activity (P<0.05. We further examined the causative relationship between SIRT1 activation and SIL-induced late cardioprotection. Pretreatment with SIL (or RSV 24 hours prior to 30 min ischemia and 24 hours of reperfusion significantly reduced infarct size, which was associated with a significant increase in SIRT1 activity (P<0.05. Moreover, sirtinol (a SIRT1 inhibitor, 5 mg/kg, i.p. given 30 min before I-R blunted the infarct-limiting effect of SIL and RSV (P<0.001. CONCLUSION: Our study shows that activation of SIRT1 following SIL treatment plays an essential role in mediating the SIL-induced cardioprotection against I-R injury. This newly identified SIRT1-activating property of SIL may have enormous therapeutic implications.

  18. Manipulations of core temperatures in ischemia-reperfusion lung injury in rabbits.

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    Chang, Hung; Huang, Kun-Lun; Li, Min-Hui; Hsu, Ching-Wang; Tsai, Shih-Hung; Chu, Shi-Jye

    2008-01-01

    The present study was designed to determine the effect of various core temperatures on acute lung injury induced by ischemia-reperfusion (I/R) in our isolated rabbit lung model. Typical acute lung injury was successfully induced by 30 min of ischemia followed by 90 min of reperfusion observation. The I/R elicited a significant increase in pulmonary arterial pressure, microvascular permeability (measured by using the capillary filtration coefficient, Kfc), Delta Kfc ratio, lung weight gain and the protein concentration of the bronchoalveolar lavage fluid. Mild hypothermia significantly attenuated acute lung injury induced by I/R, all parameters having decreased significantly (p<0.05); conversely, mild hyperthermia did not further exacerbate acute lung injury. These experimental data suggest that mild hypothermia significantly ameliorated acute lung injury induced by ischemia-reperfusion in rabbits.

  19. Neuroprotective role of nanoencapsulated quercetin in combating ischemia-reperfusion induced neuronal damage in young and aged rats.

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    Aparajita Ghosh

    Full Text Available Cerebral stroke is the leading cause of death and permanent disability among elderly people. In both humans and animals, cerebral ischemia damages the nerve cells in vulnerable regions of the brain, viz., hippocampus, cerebral cortex, cerebellum, and hypothalamus. The present study was conducted to evaluate the therapeutic efficacy of nanoencapsulated quercetin (QC in combating ischemia-reperfusion-induced neuronal damage in young and aged Swiss Albino rats. Cerebral ischemia was induced by occlusion of the common carotid arteries of both young and aged rats followed by reperfusion. Nanoencapsulated quercetin (2.7 mg/kg b wt was administered to both groups of animals via oral gavage two hours prior to ischemic insults as well as post-operation till day 3. Cerebral ischemia and 30 min consecutive reperfusion caused a substantial increase in lipid peroxidation, decreased antioxidant enzyme activities and tissue osmolality in different brain regions of both groups of animals. It also decreased mitochondrial membrane microviscosity and increased reactive oxygen species (ROS generation in different brain regions of young and aged rats. Among the brain regions studied, the hippocampus appeared to be the worst affected region showing increased upregulation of iNOS and caspase-3 activity with decreased neuronal count in the CA1 and CA3 subfields of both young and aged rats. Furthermore, three days of continuous reperfusion after ischemia caused massive damage to neuronal cells. However, it was observed that oral treatment of nanoencapsulated quercetin (2.7 mg/kg b wt resulted in downregulation of iNOS and caspase-3 activities and improved neuronal count in the hippocampal subfields even 3 days after reperfusion. Moreover, the nanoformulation imparted a significant level of protection in the antioxidant status in different brain regions, thus contributing to a better understanding of the given pathophysiological processes causing ischemic neuronal damage.

  20. Ischemia postconditioning and mesenchymal stem cells engraftment synergistically attenuate ischemia reperfusion-induced lung injury in rats.

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    Chen, Shuchen; Chen, Liangwan; Wu, Xiaonan; Lin, Jiangbo; Fang, Jun; Chen, Xiangqi; Wei, Shijin; Xu, Jianxin; Gao, Qin; Kang, Mingqiang

    2012-11-01

    It has been reported that ischemic postconditioning (IPO) or mesenchymal stem cell (MSC) engraftment could protect organs from ischemia/reperfusion (I/R) injury. We investigated the synergetic effects of combined treatment on lung injury induced by I/R. Adult Sprague-Dawley rats were randomly assigned to one of the following groups: sham-operated control, I/R, IPO, MSC engraftment, and IPO plus MSC engraftment. Lung injury was assessed by arterial blood gas analysis, the wet/dry lung weight ratio, superoxide dismutase level, malondialdehyde content, myeloperoxidase activity, and tissue histologic changes. Cytokine expression was detected using real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. Cell apoptosis was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end assay and annexin V staining. MSC engraftment or IPO alone markedly attenuated the lung wet/dry weight ratio, malondialdehyde and myeloperoxidase production, and lung pathologic injury and enhanced arterial partial oxygen pressure, superoxide dismutase content, inhibited pro-inflammatory cytokine levels, and decreased cell apoptosis in lung tissue, compared with the I/R group. In contrast, IPO pretreatment enhanced the protective effects of MSC on I/R-induced lung injury compared with treatment alone. Moreover, in the combined treatment group, the number of MSC engraftments in the lung tissue was increased, associated with enhanced survival of MSCs compared with MSC treatment alone. Additional investigation showed that IPO treatment increased expression of vascular endothelial growth factor and stromal cell-derived factor-1 in I/R lung tissue. IPO might contribute to the homing and survival of transplanted MSCs and enhance their therapeutic effects through improvement of the microenvironment of I/R injury. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Nephroprotective Effect of Sonchus oleraceus Extract against Kidney Injury Induced by Ischemia-Reperfusion in Wistar Rats.

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    Torres-González, Liliana; Cienfuegos-Pecina, Eduardo; Perales-Quintana, Marlene M; Alarcon-Galvan, Gabriela; Muñoz-Espinosa, Linda E; Pérez-Rodríguez, Edelmiro; Cordero-Pérez, Paula

    2018-01-01

    Kidney ischemia-reperfusion (I/R) injury is the main cause of delayed graft function in solid organ transplantation. Sonchus oleraceus is a plant with well-known antioxidant and anti-inflammatory activities; however, its effects on renal I/R are unknown. To evaluate whether S. oleraceus extract (S.O.e.) has nephroprotective activity in an I/R model in Wistar rats. Animal groups ( n = 6): sham, I/R (45 min/15 h), S.O.e (300 mg/kg p.o.), and S.O.e + I/R (300 mg/kg, p.o.; 45 min/15 h). Renal function, proinflammatory cytokines, alanine aminotransferase, markers of oxidative stress, and histology were evaluated. None of the mediators evaluated differed significantly between the S.O.e and sham groups. Levels of blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and proinflammatory cytokines were higher, and superoxide dismutase (SOD) was lower in the I/R group than in the sham group. Histology showed tubular epithelial necrosis in the medulla and cortex in the I/R group. In the S.O.e + I/R group, S.O.e pretreatment attenuated the I/R-induced increases in BUN, creatinine, MDA, and proinflammatory cytokines induced, SOD was maintained, and histology showed discontinuous necrosis in the medulla but no necrosis in the cortex. S.O.e was neither hepatotoxic nor nephrotoxic. S.O.e. pretreatment showed a nephroprotective effect against I/R.

  2. Nephroprotective Effect of Sonchus oleraceus Extract against Kidney Injury Induced by Ischemia-Reperfusion in Wistar Rats

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    Liliana Torres-González

    2018-01-01

    Full Text Available Introduction. Kidney ischemia-reperfusion (I/R injury is the main cause of delayed graft function in solid organ transplantation. Sonchus oleraceus is a plant with well-known antioxidant and anti-inflammatory activities; however, its effects on renal I/R are unknown. Objective. To evaluate whether S. oleraceus extract (S.O.e. has nephroprotective activity in an I/R model in Wistar rats. Materials and Methods. Animal groups (n=6: sham, I/R (45 min/15 h, S.O.e (300 mg/kg p.o., and S.O.e + I/R (300 mg/kg, p.o.; 45 min/15 h. Renal function, proinflammatory cytokines, alanine aminotransferase, markers of oxidative stress, and histology were evaluated. Results. None of the mediators evaluated differed significantly between the S.O.e and sham groups. Levels of blood urea nitrogen (BUN, creatinine, malondialdehyde (MDA, and proinflammatory cytokines were higher, and superoxide dismutase (SOD was lower in the I/R group than in the sham group. Histology showed tubular epithelial necrosis in the medulla and cortex in the I/R group. In the S.O.e + I/R group, S.O.e pretreatment attenuated the I/R-induced increases in BUN, creatinine, MDA, and proinflammatory cytokines induced, SOD was maintained, and histology showed discontinuous necrosis in the medulla but no necrosis in the cortex. Conclusions. S.O.e was neither hepatotoxic nor nephrotoxic. S.O.e. pretreatment showed a nephroprotective effect against I/R.

  3. Edaravone, A Free Radical Scavenger, Ameliorates Early-Phase Ischemia/Reperfusion Injury and Increases Hepatocyte Proliferation in A Pig Hepatectomy Model

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    Mitsugi Shimoda

    2012-06-01

    Full Text Available Background: The effects of Edaravone (Edr on hepatic ischemia-reperfusion (I/R injury and liver regeneration were examined in a pig hepatectomy model. Methods: One hour of ischemia was induced by occluding the vessels and the bile duct of the right and median lobes. About a 40% left hepatectomy was performed after reperfusion. Six animals received Edr (3 mg/kg/h intravenously and six control animals received saline just before reperfusion. Remnant liver volume, hemodynamics, and levels of AST, ALT, LDH, and LA were compared between the groups. Expression of TGF-beta1 and IL-6 mRNA in hepatic tissues was examined using RT-PCR. Apoptosis and cell proliferation were demonstrated by TUNEL and Ki-67 staining, respectively. Results: Serum AST, LDH, and LA levels were significantly lower at 3 hours and 1 week after perfusion in animals that had received Edr. In the Edr group, hepatic tissues showed a greater tendency for the expression of TGF-beta1 mRNA to be inhibited at 1 week, although the difference was not significant. Also at 1 week in the Edr group, TUNEL-positive cells in the hepatic sinusoidal endothelium were significantly fewer, and Ki-67-positive cells were significantly more numerous. Conclusion: We conclude that Edr reduces hepatic injury and supports tissue regeneration after I/R injury in this pig model. [Arch Clin Exp Surg 2012; 1(3.000: 142-150

  4. A deficiency of apoptosis inducing factor (AIF in Harlequin mouse heart mitochondria paradoxically reduces ROS generation during ischemia-reperfusion

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    Qun eChen

    2014-07-01

    Full Text Available Background and Aims: AIF (apoptosis inducing factor is a flavin and NADH containing protein located within mitochondria required for optimal function of the respiratory chain. AIF may function as an antioxidant within mitochondria, yet when released from mitochondria it activates caspase-independent cell death. The Harlequin (Hq mouse has a markedly reduced content of AIF, providing an experimental model to query if the main role of AIF in the exacerbation of cell death is enhanced mitochondrial generation of reactive oxygen species (ROS or the activation of cell death programs. We asked if the ROS generation is altered in Hq heart mitochondria at baseline or following ischemia-reperfusion (IR.Methods: Buffer perfused mouse hearts underwent 30 min ischemia and 30 min reperfusion. Mitochondrial function including oxidative phosphorylation and H2O2 generation was measured. Immunoblotting was used to determine the contents of AIF and PAR [poly(ADP-ribose] in cell fractions.Results: There were no differences in the release of H2O2 between wild type (WT and Hq heart mitochondria at baseline. IR increased H2O2 generation from WT but not from Hq mitochondria compared to corresponding time controls. The complex I activity was decreased in WT but not in Hq mice following IR. The relocation of AIF from mitochondria to nucleus was increased in WT but not in Hq mice. IR activated PARP-1 only in WT mice. Cell injury was decreased in Hq mouse heart following in vitro IR.Conclusion: A deficiency of AIF within mitochondria does not increase ROS production during IR, indicating that AIF functions less as an antioxidant within mitochondria. The decreased cardiac injury in Hq mouse heart accompanied by less AIF translocation to the nucleus suggests that AIF relocation, rather than the AIF content within mitochondria, contributes to cardiac injury during IR.

  5. Role of Calcium Sensing Receptor in Streptozotocin-Induced Diabetic Rats Exposed to Renal Ischemia Reperfusion Injury

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    Bo Hu

    2018-02-01

    Full Text Available Background/Aims: Renal ischemia/reperfusion (I/R injury (RI/RI is a common complication of diabetes, and it may be involved in altering intracellular calcium concentrations at its onset, which can result in inflammation, abnormal lipid metabolism, the production of reactive oxygen species (ROS, and nitroso-redox imbalance. The calcium-sensing receptor (CaSR is a G-protein coupled receptor, however, the functional involvement of CaSR in diabetic RI/ RI remains unclear. The present study was intended to investigate the role of CaSR on RI/RI in diabetes mellitus (DM. Methods: The bilateral renal arteries and veins of streptozotocin (STZ-induced diabetic rats were subjected to 45-min ischemia followed by 2-h reperfusion with or without R-568 (agonist of CaSR and NPS-2143 (antagonist of CaSR at the beginning of I/R procedure. DM without renal I/R rats served as control group. The expressions of CaSR, calmodulin (CaM, and p47phox in the renal tissue were analyzed by qRT-PCR and Western blot. The renal pathomorphology, renal function, oxidative stress, inflammatory response, and calcium disorder were evaluated by detection of a series of indices by hematoxylin-eosin (HE staining, transmission electron microscope (TEM, commercial kits, enzyme-linked immunosorbent assay (ELISA, and spectrophotofluorometry, respectively. Results: Results showed that the expressions of CaSR, CaM, and p47phox in I/R group were significantly up-regulated as compared with those in DM group, which were accompanied by renal tissue injury, increased calcium, oxidative stress, inflammation, and nitroso-redox imbalance. Conclusion: These results suggest that activation of CaSR is involved in the induction of damage of renal tubular epithelial cell during diabetic RI/RI, resulting in lipid peroxidation, inflammatory response, nitroso-redox imbalance, and apoptosis.

  6. Diallyl trisulfide ameliorates myocardial ischemia-reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation.

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    Yu, Liming; Li, Shu; Tang, Xinlong; Li, Zhi; Zhang, Jian; Xue, Xiaodong; Han, Jinsong; Liu, Yu; Zhang, Yuji; Zhang, Yong; Xu, Yinli; Yang, Yang; Wang, Huishan

    2017-07-01

    Diallyl trisulfide (DATS) protects against apoptosis during myocardial ischemia-reperfusion (MI/R) injury in diabetic state, although the underlying mechanisms remain poorly defined. Previously, we and others demonstrated that silent information regulator 1 (SIRT1) activation inhibited oxidative stress and endoplasmic reticulum (ER) stress during MI/R injury. We hypothesize that DATS reduces diabetic MI/R injury by activating SIRT1 signaling. Streptozotocin (STZ)-induced type 1 diabetic rats were subjected to MI/R surgery with or without perioperative administration of DATS (40 mg/kg). We found that DATS treatment markedly improved left ventricular systolic pressure and the first derivative of left ventricular pressure, reduced myocardial infarct size as well as serum creatine kinase and lactate dehydrogenase activities. Furthermore, the myocardial apoptosis was also suppressed by DATS as evidenced by reduced apoptotic index and cleaved caspase-3 expression. However, these effects were abolished by EX527 (the inhibitor of SIRT1 signaling, 5 mg/kg). We further found that DATS effectively upregulated SIRT1 expression and its nuclear distribution. Additionally, PERK/eIF2α/ATF4/CHOP-mediated ER stress-induced apoptosis was suppressed by DATS treatment. Moreover, DATS significantly activated Nrf-2/HO-1 antioxidant signaling pathway, thus reducing Nox-2/4 expressions. However, the ameliorative effects of DATS on oxidative stress and ER stress-mediated myocardial apoptosis were inhibited by EX527 administration. Taken together, these data suggest that perioperative DATS treatment effectively ameliorates MI/R injury in type 1 diabetic setting by enhancing cardiac SIRT1 signaling. SIRT1 activation not only upregulated Nrf-2/HO-1-mediated antioxidant signaling pathway but also suppressed PERK/eIF2α/ATF4/CHOP-mediated ER stress level, thus reducing myocardial apoptosis and eventually preserving cardiac function.

  7. Different dose-dependent effects of hydrogen sulfide on ischemia-reperfusion induced acute kidney injury in rats

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    Fateme Azizi

    2017-12-01

    Conclusion: Our study demonstrates that different doses of Sodium hydrosulfide (NaHS can play diverse role in renal ischemia reperfusion injury. However, NaHS in the low-doses could protect the kidney from the RIR injury, in a higher dose NaHS exaggerated the renal function by increases plasma creatinine and BUN. Therefore, determining of the therapeutic doses of NaHS may be important in the protection of kidney from the RIR injury.

  8. The anti-inflammatory and anti-apoptotic effects of gallic acid against mucosal inflammation- and erosions-induced by gastric ischemia-reperfusion in rats.

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    Mard, Seyyed Ali; Mojadami, Shahnaz; Farbood, Yaghoob; Gharib Naseri, Mohammad Kazem

    2015-01-01

    The present study aimed to evaluate the protective effect of gallic acid on gastric mucosal lesions caused by ischemia-reperfusion (I/R) injury in rat. Forty male rats were randomly divided into sham, control (I/R injury) and three gallic acid-pretreated groups. To induce I/R lesions, the celiac artery was clamped for 30 min and then the clamp was removed to allow reperfusion for 6 hr. Pretreated rats received gallic acid (15, 30 or 60 mg kg(-1), intraperitoneally) 30 min prior to the induction of I/R injury. Macroscopic and microscopic evaluations of the areas of ulceration were compared. Samples of gastric mucosa were collected to evaluate the protein expression of pro-apoptotic factor, caspase-3, and pro-inflammatory enzyme, inducible nitric oxide synthase (iNOS) using western blot. Pretreatment with gallic acid decreased the total area of gastric lesions. Gallic acid at 30 mg kg(-1) decreased the levels of protein expression of caspase-3 and iNOS induced by I/R injury. Our findings showed the protective effect of gallic acid on gastric mucosa against ischemia-reperfusion injury. This effect of gallic acid was mainly mediated by reducing protein expression of iNOS and caspase-3.

  9. Total Flavonoids from Rosa laevigata Michx Fruit Ameliorates Hepatic Ischemia/Reperfusion Injury through Inhibition of Oxidative Stress and Inflammation in Rats

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    Xufeng Tao

    2016-07-01

    Full Text Available The effects of total flavonoids (TFs from Rosa laevigata Michx fruit against liver damage and cerebral ischemia/reperfusion (I/R injury have been reported, but its action on hepatic I/R injury remains unknown. In this work, the effects and possible mechanisms of TFs against hepatic I/R injury were examined using a 70% partial hepatic warm ischemia rat model. The results demonstrated TFs decreased serum aspartate transaminase (AST, alanine aminotransferase (ALT, myeloperoxidase (MPO, and lactate dehydrogenase (LDH activities, improved liver histopathology and ultrastructure through hematoxylin-eosin (HE staining and electron microscope observation. In addition, TFs significantly decreased malondialdehyde (MDA and increased the levels of superoxide dismutase (SOD and glutathione peroxidase (GSH-Px, which indicated that TFs alleviated oxidative stress caused by I/R injury. RT-PCR results proved that TFs downregulated the gene levels of inflammatory factors including interleukin-1 beta (IL-1β, interleukin-1 (IL-6, and tumor necrosis factor alpha (TNF-α. Further research indicated that TF-induced hepatoprotection was completed through inhibiting TLR4/MyD88 and activating Sirt1/Nrf2 signaling pathways. Blockade of the TLR4 pathway by TFs inhibited NF-κB and AP-1 transcriptional activities and inflammatory reaction. Activation of Sirt1/Nrf2 pathway by TFs increased the protein levels of HO-1 and GST to improve oxidative stress. Collectively, these findingsconfirmed the potent effects of TFs against hepatic I/R injury, which should be developed as a candidate for the prevention of this disease.

  10. Pressure Combined with Ischemia/Reperfusion Injury Induces Deep Tissue Injury via Endoplasmic Reticulum Stress in a Rat Pressure Ulcer Model

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    Fei-Fei Cui

    2016-02-01

    Full Text Available Pressure ulcer is a complex and significant health problem in long-term bedridden patients, and there is currently no effective treatment or efficient prevention method. Furthermore, the molecular mechanisms and pathogenesis contributing to the deep injury of pressure ulcers are unclear. The aim of the study was to explore the role of endoplasmic reticulum (ER stress and Akt/GSK3β signaling in pressure ulcers. A model of pressure-induced deep tissue injury in adult Sprague-Dawley rats was established. Rats were treated with 2-h compression and subsequent 0.5-h release for various cycles. After recovery, the tissue in the compressed regions was collected for further analysis. The compressed muscle tissues showed clear cellular degenerative features. First, the expression levels of ER stress proteins GRP78, CHOP, and caspase-12 were generally increased compared to those in the control. Phosphorylated Akt and phosphorylated GSK3β were upregulated in the beginning of muscle compression, and immediately significantly decreased at the initiation of ischemia-reperfusion injury in compressed muscles tissue. These data show that ER stress may be involved in the underlying mechanisms of cell degeneration after pressure ulcers and that the Akt/GSK3β signal pathway may play an important role in deep tissue injury induced by pressure and ischemia/reperfusion.

  11. Rapid reversal of human intestinal ischemia-reperfusion induced damage by shedding of injured enterocytes and reepithelialisation.

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    Joep P M Derikx

    Full Text Available BACKGROUND: Intestinal ischemia-reperfusion (IR is a phenomenon related to physiological conditions (e.g. exercise, stress and to pathophysiological events (e.g. acute mesenteric ischemia, aortic surgery. Although intestinal IR has been studied extensively in animals, results remain inconclusive and data on human intestinal IR are scarce. Therefore, an experimental harmless model for human intestinal IR was developed, enabling us to clarify the sequelae of human intestinal IR for the first time. METHODS AND FINDINGS: In 30 patients undergoing pancreatico-duodenectomy we took advantage of the fact that in this procedure a variable length of jejunum is removed. Isolated jejunum (5 cm was subjected to 30 minutes ischemia followed by reperfusion. Intestinal Fatty Acid Binding Protein (I-FABP arteriovenous concentration differences across the bowel segment were measured before and after ischemia to assess epithelial cell damage. Tissue sections were collected after ischemia and at 25, 60 and 120 minutes reperfusion and stained with H&E, and for I-FABP and the apoptosis marker M30. Bonferroni's test was used to compare I-FABP differences. Mean (SEM arteriovenous concentration gradients of I-FABP across the jejunum revealed rapidly developing epithelial cell damage. I-FABP release significantly increased from 290 (46 pg/ml before ischemia towards 3,997 (554 pg/ml immediately after ischemia (p<0.001 and declined gradually to 1,143 (237 pg/ml within 1 hour reperfusion (p<0.001. Directly after ischemia the intestinal epithelial lining was microscopically normal, while subepithelial spaces appeared at the villus tip. However, after 25 minutes reperfusion, enterocyte M30 immunostaining was observed at the villus tip accompanied by shedding of mature enterocytes into the lumen and loss of I-FABP staining. Interestingly, within 60 minutes reperfusion the epithelial barrier resealed, while debris of apoptotic, shedded epithelial cells was observed in the lumen

  12. The Mechanism of Sevoflurane Preconditioning-Induced Protections against Small Intestinal Ischemia Reperfusion Injury Is Independent of Mast Cell in Rats

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    Xiaoliang Gan

    2013-01-01

    Full Text Available The study aimed to investigate whether sevoflurane preconditioning can protect against small intestinal ischemia reperfusion (IIR injury and to explore whether mast cell (MC is involved in the protections provided by sevoflurane preconditioning. Sprague-Dawley rats exposed to sevoflurane or treated with MC stabilizer cromolyn sodium (CS were subjected to 75-minute superior mesenteric artery occlusion followed by 2-hour reperfusion in the presence or absence of MC degranulator compound 48/80 (CP. Small intestinal ischemia reperfusion resulted in severe intestinal injury as demonstrated by significant elevations in intestinal injury scores and p47phox and gp91phox, ICAM-1 protein expressions and malondialdehyde and IL-6 contents, and MPO activities as well as significant reductions in SOD activities, accompanied with concomitant increases in mast cell degranulation evidenced by significant increases in MC counts, tryptase expression, and β-hexosaminidase concentrations, and those alterations were further upregulated in the presence of CP. Sevoflurane preconditioning dramatically attenuated the previous IIR-induced alterations except MC counts, tryptase, and β-hexosaminidase which were significantly reduced by CS treatment. Furthermore, CP exacerbated IIR injury was abrogated by CS but not by sevoflurane preconditioning. The data collectively indicate that sevoflurane preconditioning confers protections against IIR injury, and MC is not involved in the protective process.

  13. Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway.

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    Wang, Peng-Ran; Wang, Jun-Song; Zhang, Chao; Song, Xing-Fang; Tian, Na; Kong, Ling-Yi

    2013-08-26

    Huang-Lian-Jie-Du-Decotion (HLJDD, Hwangryun-Hae-Dok-Decotion in Japan), an ancient antipyretic and detoxifying traditional Chinese medicine formula, was reported to have protective effect on ischemic stroke. To investigate the therapeutic effect of HLJDD on ischemic stroke and explore its mode of action. A model of ischemic stroke in the rat was established after transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Rats were assigned randomly to groups of control, sham, transient ischemia/reperfusion (I/R), and three treatment groups by HLJDD at 2.5, 5.0, 10.0mg/kg. The neurological deficit, the cerebral infarct size, morphology abnormality, biochemical parameters were examined, and the levels of relevant proteins were determined by immunoblotting analysis to evaluate the protective effects of HLJDD on ischemic stroke and explore the underlying mechanism. Compared with I/R group, HLJDD significantly ameliorated neurological deficit and histopathology changes, decreased infarct area, and restored the levels of biochemical indicators including nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), total superoxide dismutase (T-SOD), Cu/Zn-SOD, Mn-SOD and glutathione peroxidase (GSH-PX). HLJDD also notably elevated the levels of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and other autophagy related genes (Atgs), promoted the activation of extracellular signal-regulated kinases (ERK), protein kinase B (Akt), 3-phosphoinositide-dependent kinase (PDK1), and inhibited the activation of mammalian target of rapamycin (mTOR), c-Jun N-terminal protein kinases (JNK), p38, phosphatase and tensin homolog (PTEN). HLJDD showed neuroprotective effects on ischemic stroke, at least in part to the induced protective autophagy via the regulation of mitogen-activated protein kinase (MAPK) signals. This Akt-independent protective autophagy is favorable in the treatment of stroke, avoiding unfavorable side

  14. Inhibition of P2X7 receptor ameliorates transient global cerebral ischemia/reperfusion injury via modulating inflammatory responses in the rat hippocampus

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    Chu Ketan

    2012-04-01

    Full Text Available Abstract Background Neuroinflammation plays an important role in cerebral ischemia/reperfusion (I/R injury. The P2X7 receptor (P2X7R has been reported to be involved in the inflammatory response of many central nervous system diseases. However, the role of P2X7Rs in transient global cerebral I/R injury remains unclear. The purpose of this study is to determine the effects of inhibiting the P2X7R in a rat model of transient global cerebral I/R injury, and then to explore the association between the P2X7R and neuroinflammation after transient global cerebral I/R injury. Methods Immediately after infusion with the P2X7R antagonists Brilliant blue G (BBG, adenosine 5′-triphosphate-2′,3′-dialdehyde (OxATP or A-438079, 20 minutes of transient global cerebral I/R was induced using the four-vessel occlusion (4-VO method in rats. Survival rate was calculated, neuronal death in the hippocampal CA1 region was observed using H & E staining, and DNA cleavage was observed by deoxynucleotidyl transferase-mediated UTP nick end labeling TUNEL. In addition, behavioral deficits were measured using the Morris water maze, and RT-PCR and immunohistochemical staining were performed to measure the expression of IL-1β, TNF-α and IL-6, and to identify activated microglia and astrocytes. Results The P2X7R antagonists protected against transient global cerebral I/R injury in a dosage-dependent manner. A high dosage of BBG (10 μg and A-0438079 (3 μg, and a low dosage of OxATP (1 μg significantly increased survival rates, reduced I/R-induced learning memory deficit, and reduced I/R-induced neuronal death, DNA cleavage, and glial activation and inflammatory cytokine overexpression in the hippocampus. Conclusions Our study indicates that inhibiting P2X7Rs protects against transient global cerebral I/R injury by reducing the I/R-induced inflammatory response, which suggests inhibition of P2X7Rs may be a promising therapeutic strategy for clinical treatment of

  15. Cardioprotection of CAPE-oNO2 against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-κB pathway in vivo and in vitro

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    Dejuan Li

    2018-05-01

    Full Text Available Caffeic acid phenethyl ester (CAPE could ameliorate myocardial ischemia/reperfusion injury (MIRI by various mechanisms, but there hadn’t been any reports on that CAPE could regulate silent information regulator 1 (SIRT1 and endothelial nitric oxide synthase (eNOS to exert cardioprotective effect. The present study aimed to investigate the cardioprotective potential of caffeic acid o-nitro phenethyl ester (CAPE-oNO2 on MIRI and the possible mechanism based on the positive control of CAPE. The SD rats were subjected to left coronary artery ischemia /reperfusion (IR and the H9c2 cell cultured in hypoxia/reoxygenation (HR to induce the MIRI model. Prior to the procedure, vehicle, CAPE or CAPE-oNO2 were treated in the absence or presence of a SIRT1 inhibitor nicotinamide (NAM and an eNOS inhibitor Nω-nitro-L-arginine methyl ester (L-NAME. In vivo, CAPE and CAPE-oNO2 conferred a cardioprotective effect as shown by reduced myocardial infarct size, cardiac marker enzymes and structural abnormalities. From immunohistochemical and sirius red staining, above two compounds ameliorated the TNF-α release and collagen deposition of IR rat hearts. They could agitate SIRT1 and eNOS expression, and consequently enhance NO release and suppress NF-κB signaling, to reduce the malondialdehyde content and cell necrosis. In vitro, they could inhibit HR-induced H9c2 cell apoptosis and ROS generation by activating SIRT1/eNOS pathway and inhabiting NF-κB expression. Emphatically, CAPE-oNO2 presented the stronger cardioprotection than CAPE both in vivo and in vitro. However, NAM and L-NAME eliminated the CAPE-oNO2-mediated cardioprotection by restraining SIRT1 and eNOS expression, respectively. It suggested that CAPE-oNO2 ameliorated MIRI by suppressing the oxidative stress, inflammatory response, fibrosis and necrocytosis via the SIRT1/eNOS/NF-κB pathway.

  16. Liver ischemia and ischemia-reperfusion induces and trafficks the multi-specific metal transporter Atp7b to bile duct canaliculi: possible preferential transport of iron into bile.

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    Goss, John A; Barshes, Neal R; Karpen, Saul J; Gao, Feng-Qin; Wyllie, Samuel

    2008-04-01

    Both Atp7b (Wilson disease gene) and Atp7a (Menkes disease gene) have been reported to be trafficked by copper. Atp7b is trafficked to the bile duct canaliculi and Atp7a to the plasma membrane. Whether or not liver ischemia or ischemia-reperfusion modulates Atp7b expression and trafficking has not been reported. In this study, we report for the first time that the multi-specific metal transporter Atp7b is significantly induced and trafficked by both liver ischemia alone and liver ischemia-reperfusion, as judged by immunohistochemistry and Western blot analyses. Although hepatocytes also stained for Atp7b, localized intense staining of Atp7b was found on bile duct canaliculi. Inductive coupled plasma-mass spectrometry analysis of bile copper, iron, zinc, and manganese found a corresponding significant increase in biliary iron. In our attempt to determine if the increased biliary iron transport observed may be a result of altered bile flow, lysosomal trafficking, or glutathione biliary transport, we measured bile flow, bile acid phosphatase activity, and glutathione content. No significant difference was found in bile flow, bile acid phosphatase activity, and glutathione, between control livers and livers subjected to ischemia-reperfusion. Thus, we conclude that liver ischemia and ischemia-reperfusion induction and trafficking Atp7b to the bile duct canaliculi may contribute to preferential iron transport into bile.

  17. Effects of babassu nut oil on ischemia/reperfusion-induced leukocyte adhesion and macromolecular leakage in the microcirculation: Observation in the hamster cheek pouch

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    Barbosa Maria do

    2012-11-01

    Full Text Available Abstract Background The babassu palm tree is native to Brazil and is most densely distributed in the Cocais region of the state of Maranhão, in northeastern Brazil. In addition to the industrial use of refined babassu oil, the milk, the unrefined oil and the nuts in natura are used by families from several communities of African descendants as one of the principal sources of food energy. The objective of this study was to evaluate the effects of babassu oil on microvascular permeability and leukocyte-endothelial interactions induced by ischemia/reperfusion using the hamster cheek pouch microcirculation as experimental model. Methods Twice a day for 14 days, male hamsters received unrefined babassu oil (0.02 ml/dose [BO-2 group], 0.06 ml/dose [BO-6 group], 0.18 ml/dose [BO-18 group] or mineral oil (0.18 ml/dose [MO group]. Observations were made in the cheek pouch and macromolecular permeability increase induced by ischemia/reperfusion (I/R or topical application of histamine, as well as leukocyte-endothelial interaction after I/R were evaluated. Results The mean value of I/R-induced microvascular leakage, determined during reperfusion, was significantly lower in the BO-6 and BO-18 groups than in the MO one (P Conclusions Our findings suggest that unrefined babassu oil reduced microvascular leakage and protected against histamine-induced effects in postcapillary venules and highlights that these almost unexploited nut and its oil might be secure sources of food energy.

  18. Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice.

    Science.gov (United States)

    Baumgardt, Shelley L; Paterson, Mark; Leucker, Thorsten M; Fang, Juan; Zhang, David X; Bosnjak, Zeljko J; Warltier, David C; Kersten, Judy R; Ge, Zhi-Dong

    2016-01-01

    Diabetic heart disease is associated with tetrahydrobiopterin oxidation and high arginase activity, leading to endothelial nitric oxide synthase dysfunction. Sepiapterin (SEP) is a tetrahydrobiopterin precursor, and L-citrulline (L-Cit) is converted to endothelial nitric oxide synthase substrate, L-arginine. Whether SEP and L-Cit are effective at reducing diabetic heart disease is not known. The present study examined the effects of SEP and L-Cit on diabetic cardiomyopathy and ischemia/reperfusion injury in obese type 2 diabetic mice. Db/db and C57BLKS/J mice at 6 to 8 weeks of age received vehicle, SEP, or L-Cit orally alone or in combination for 8 weeks. Cardiac function was evaluated with echocardiography. Db/db mice displayed hyperglycemia, obesity, and normal blood pressure and cardiac function compared with C57BLKS/J mice at 6 to 8 weeks of age. After vehicle treatment for 8 weeks, db/db mice had reduced ejection fraction, mitral E/A ratio, endothelium-dependent relaxation of coronary arteries, tetrahydrobiopterin concentrations, ratio of endothelial nitric oxide synthase dimers/monomers, and nitric oxide levels compared with vehicle-treated C57BLKS/J mice. These detrimental effects of diabetes mellitus were abrogated by co-administration of SEP and L-Cit. Myocardial infarct size was increased, and coronary flow rate and ± dP/dt were decreased during reperfusion in vehicle-treated db/db mice subjected to ischemia/reperfusion injury compared with control mice. Co-administration of SEP and L-Cit decreased infarct size and improved coronary flow rate and cardiac function in both C57BLKS/J and db/db mice. Co-administration of SEP and L-Cit limits diabetic cardiomyopathy and ischemia/reperfusion injury in db/db mice through a tetrahydrobiopterin/endothelial nitric oxide synthase/nitric oxide pathway. © 2016 American Heart Association, Inc.

  19. Ethanol extracts from Portulaca oleracea L. attenuated ischemia/reperfusion induced rat neural injury through inhibition of HMGB1 induced inflammation

    Science.gov (United States)

    Zheng, Chenggang; Liu, Chen; Wang, Wanyin; Tang, Gusheng; Dong, Liwei; Zhou, Juan; Zhong, Zhengrong

    2016-01-01

    It is well demonstrated that the high mobility group box 1 (HMGB1) mediated inflammation has been implicated as one of the important causes for brain damage induced by cerebral ischemia/reperfusion (I/R). In the present study, we assessed the neuro-protective and anti-inflammation effects of the ethanol extracts from Portulaca oleracea L. (EEPO) against cerebral I/R injury in the rat transient middle cerebral artery occlusion (tMCAO) model. Rats were administrated with their respective treatment for 7 days before the MCA occlusion. After that, rats were intraperitoneal injection with chloral hydrate and sacrificed by decapitation, then the serum and brain tissue were collected. The neurological deficit score, infarct size and brain edema were tested. The levels of serum cytokine as TNF-α, IL-1β, INF-γ, IL-6, and HMGB1 and LDH were detected. The protein level of tissue or nucleus HMGB1, IκB and p-p65 were tested, too. The results showed that pretreatment with EEPO significantly decreased the neurological deficit score, infarct size and brain edema. Moreover, EEPO decreased rat serum cytokine level and rat right cortices p-p65 and IκB protein level. In conclusion all these results suggested that pretreatment with EEFPO provided significant protection against cerebral I/R injury in rats might by virtue of its anti-inflammation property through inhibition of increase of neuleus HMGB1. PMID:27904702

  20. Hemodynamic changes in rat leg muscles during tourniquet-induced ischemia-reperfusion injury observed by near-infrared spectroscopy

    International Nuclear Information System (INIS)

    Kim, J G; Lee, J; Tromberg, B J; Brenner, M; Roe, J; Walters, T J

    2009-01-01

    In this study, we hypothesized that non-invasive continuous wave near-infrared spectroscopy (CWNIRS) can determine the severity or reversibility of muscle damage due to ischemia/reperfusion (I/R), and the results will be highly correlated with those from physical examination and histological analysis. To test this hypothesis, we performed CWNIRS measurements on two groups of male Sprague-Dawley rats (∼400 g) that underwent 2 h (n = 6) or 3 h (n = 7) of pneumatic tourniquet application (TKA). Tissue oxyhemoglobin [HbO 2 ] and deoxyhemoglobin [Hb] concentration changes were monitored during the 2 h or 3 h of 250 mmHg TKA and for an additional 2 h post-TKA. Rats were euthanized 24 h post-TKA and examined for injury, edema and viability of muscles. Contralateral muscles served as controls for each animal. In both groups, [HbO 2 ] dropped immediately, then gradually decreased further after TKA and then recovered once the tourniquet was released. However, releasing after 2 h of TKA caused [HbO 2 ] to overshoot above the baseline during reperfusion while the 3 h group continued to have lower [HbO 2 ] than baseline. We found a significant correlation between the elapsed time from tourniquet release to the first recovery peak of [HbO 2 ] and the muscle weight ratio between tourniquet and contralateral limb muscles (R = 0.86). Hemodynamic patterns from non-invasive CWNIRS demonstrated significant differences between 2 h and 3 h I/R. The results demonstrate that CWNIRS may be useful as a non-invasive prognostic tool for conditions involving vascular compromise such as extremity compartment syndrome

  1. Electroacupuncture ameliorates post-stroke learning and memory through minimizing ultrastructural brain damage and inhibiting the expression of MMP-2 and MMP-9 in cerebral ischemia-reperfusion injured rats.

    Science.gov (United States)

    Lin, Ruhui; Yu, Kunqiang; Li, Xiaojie; Tao, Jing; Lin, Yukun; Zhao, Congkuai; Li, Chunyan; Chen, Li-Dian

    2016-07-01

    The aim of the present study was to investigate the potential neuroprotective effects of electroacupuncture (EA) in the treatment of cerebral ischemia/reperfusion (I/R) injury, and to elucidate the association between this neuroprotective effect and brain ultrastructure and expression of matrix metalloproteinase (MMP)‑2 and 9. Rats underwent focal cerebral I/R injury by arterial ligation and received in vivo therapeutic EA at the Baihui (DU20) and Shenting (DU24) acupoints. The therapeutic efficacy was then evaluated following the surgery. The results of the current study demonstrated that EA treatment significantly ameliorated neurological deficits and reduced cerebral infarct volume compared with I/R injured rats. Furthermore, EA improved the learning and memory ability of rats following I/R injury, inhibited blood brain barrier breakdown and reduced neuronal damage in the ischemic penumbra. Furthermore, EA attenuated ultrastructural changes in the brain tissue following ischemia and inhibited MMP‑2/MMP‑9 expression in cerebral I/R injured rats. The results suggest that EA ameliorates anatomical deterioration, and learning and memory deficits in rats with cerebral I/R injury.

  2. Luteolin Inhibits Ischemia/Reperfusion-Induced Myocardial Injury in Rats via Downregulation of microRNA-208b-3p.

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    Chen Bian

    Full Text Available Luteolin (LUT, a kind of flavonoid which is extracted from a variety of diets, has been reported to convey protective effects of various diseases. Recent researches have suggested that LUT can carry out cardioprotective effects during ischemia/reperfusion (I/R. However, there have no reports on whether LUT can exert protective effects against myocardial I/R injury through the actions of specific microRNAs (miRs. The purpose of this study was to determine which miRs and target genes LUT exerted such function through.Expression of various miRs in perfused rat hearts was detected using a gene chip. Target genes were predicted with TargetScan, MiRDB and MiRanda. Anoxia/reoxygenation was used to simulate I/R. Cells were transfected by miR-208b-3p mimic, inhibitor and small interfering RNA of Ets1 (avian erythroblastosis virus E26 (v ets oncogene homolog 1. MiR-208b-3p and Ets1 mRNA were quantified by real-time quantitative polymerase chain reaction. The percentage of apoptotic cells was detected by annexin V-fluorescein isothiocyanate/propidium iodide dyeing and flow cytometry. The protein expression levels of cleaved caspase-3, Bcl-2, Bax, and Ets1 were examined by western blot analysis. A luciferase reporter assay was used to verify the combination between miR-208b-3p and the 3'-untranslated region of Ets1.LUT pretreatment reduced miR-208b-3p expression in myocardial tissue, as compared to the I/R group. And LUT decreased miR-208b-3p expression and apoptosis caused by I/R. However, overexpression of miR-208b-3p further aggravated the changes caused by I/R and blocked all the effects of LUT. Knockdown of miR-208b-3p expression also attenuated apoptosis, while knockdown of Ets1 promoted apoptosis. Further, the luciferase reporter assay showed that miR-208b-3p could inhibit Ets1 expression.LUT pretreatment conveys anti-apoptotic effects after myocardial I/R injury by decreasing miR-208b-3p and increasing Ets1 expression levels.

  3. The Protective Effect of γ-aminobutyric Acid on Kidney Injury Induced by Renal Ischemia-reperfusion in Ovariectomized Estradiol-treated Rats.

    Science.gov (United States)

    Talebi, Nahid; Nematbakhsh, Mehdi; Monajemi, Ramesh; Mazaheri, Safoora; Talebi, Ardeshir; Vafapour, Marzieh

    2016-01-01

    Renal ischemia-reperfusion injury (IRI) is one of the most important causes of kidney injury, which is possibly gender-related. This study was designed to investigate the role of γ-aminobutyric acid (GABA) against IRI in ovariectomized estradiol-treated rats. Thirty-five ovariectomized Wistar rats were used in six experimental groups. The first three groups did not subject to estradiol treatment and assigned as sham-operated, control, and GABA-treated groups. GABA (50 μmol/kg) and saline were injected in the treated and control groups 30 min before the surgery, respectively. The second three groups received the same treatments but received estradiol valerate (500 μg/kg, intramuscularly) 3 days prior to the surgery. The IRI was induced in the control and treated groups by clamping the renal artery for 45 min and then 24 h of reperfusion. All animals were sacrificed for the measurements. The serum levels of creatinine and blood urea nitrogen, kidney weight, and kidney tissue damage score significantly increased in the IRI rats (P GABA significantly decreased the aforementioned parameters (P levels of nitrite (nitric oxide metabolite) did not alter significantly. Serum level of malondialdehyde increased significantly in the ovariectomized rats exposed to IRI (P GABA improved IRI in ovariectomized rats. Estradiol was also nephroprotective against IRI. However, co-administration of estradiol and GABA could not protect the kidney against IRI.

  4. A novel bioactivity of andrographolide from Andrographis paniculata on cerebral ischemia/reperfusion-induced brain injury through induction of cerebral endothelial cell apoptosis.

    Science.gov (United States)

    Yen, Ting-Lin; Hsu, Wen-Hsien; Huang, Steven Kuan-Hua; Lu, Wan-Jung; Chang, Chao-Chien; Lien, Li-Ming; Hsiao, George; Sheu, Joen-Rong; Lin, Kuan-Hung

    2013-09-01

    Andrographolide, extracted from the leaves of Andrographis paniculata (Burm. f.) Nees (Acanthaceae), is a labdane diterpene lactone. It is widely reported to possess anti-inflammatory and antitumorigenic activities. Cerebral endothelial cells (CECs) play a crucial role in supporting the integrity and the function of the blood-brain barrier (BBB). However, no data are available concerning the effects of andrographolide in CECs. The aim of this study was to examine the detailed mechanisms of andrographolide on CECs. This study investigated a novel bioactivity of andrographolide on cerebral ischemia/reperfusion-induced brain injury. CECs were treated with andrographolide (20-100 µΜ) for the indicated times (0-24 h). After the reactions, cell survival rate and cytotoxicity were tested by the MTT assay and the lactate dehydrogenase (LDH) test, respectively. Western blotting was used to detect caspase-3 expression. In addition, analysis of cell cycle and apoptosis using PI staining and annexin V-FITC/PI labeling, respectively, was performed by flow cytometry. We also investigated the effect of andrographolide on middle cerebral artery occlusion (MCAO)/reperfusion-induced brain injury in a rat model. In the present study, we found that andrographolide (50-100 µΜ) markedly inhibited CEC growth according to an MTT assay and caused CEC damage according to a LDH test. Our data also revealed that andrographolide (50 µM) induced CEC apoptosis and caspase-3 activation as respectively detected by PI/annexin-V double staining and western blotting. Moreover, andrographolide arrested the CEC cell cycle at the G0/G1 phase by PI staining. In addition, andrographolide (5 mg/kg) caused deterioration of MCAO/reperfusion-induced brain injury in a rat model. These data suggest that andrographolide may disrupt BBB integrity, thereby deteriorating MCAO/reperfusion-induced brain injury, which are, in part, associated with its capacity to arrest cell-cycle and induce CEC

  5. Heme oxygenase-1 mediates the protective effects of ischemic preconditioning on mitigating lung injury induced by lower limb ischemia-reperfusion in rats.

    Science.gov (United States)

    Peng, Tsui-Chin; Jan, Woan-Ching; Tsai, Pei-Shan; Huang, Chun-Jen

    2011-05-15

    Lower limb ischemia-reperfusion (I/R) imposes oxidative stress, elicits inflammatory response, and subsequently induces acute lung injury. Ischemic preconditioning (IP), a process of transient I/R, mitigates the acute lung injury induced by I/R. We sought to elucidate whether the protective effects of IP involve heme oxygenase-1 (HO-1). Adult male rats were randomized to receive I/R, I/R plus IP, I/R plus IP plus the HO-1 inhibitor tin protoporphyrin (SnPP) (n = 12 in each group). Control groups were run simultaneously. I/R was induced by applying rubber band tourniquet high around each thigh for 3 h followed by reperfusion for 3 h. To achieve IP, three cycles of bilateral lower limb I/R (i.e., ischemia for 10 min followed by reperfusion for 10 min) were performed. IP was performed immediately before I/R. After sacrifice, degree of lung injury was determined. Histologic findings, together with assays of leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity) and lung water content (wet/dry weight ratio), confirmed that I/R induced acute lung injury. I/R also caused significant inflammatory response (increases in chemokine, cytokine, and prostaglandin E(2) concentrations), imposed significant oxidative stress (increases in nitric oxide and malondialdehyde concentrations), and up-regulated HO-1 expression in lung tissues. IP significantly enhanced HO-1 up-regulation and, in turn, mitigated oxidative stress, inflammatory response, and acute lung injury induced by I/R. In addition, the protective effects of IP were counteracted by SnPP. The protective effects of IP on mitigating acute lung injury induced by lower limb I/R are mediated by HO-1. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. A New Therapeutic Modality for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin Induces Cardioprotection from Ischemia-Reperfusion Injury via Activation of PI3K/Akt Pathway and Anti-Inflammation in a Rat Model.

    Directory of Open Access Journals (Sweden)

    Kazuhiro Nagaoka

    Full Text Available There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI, for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticle-mediated targeting of pitavastatin protects the heart from IR injury.In a rat IR model, poly(lactic acid/glycolic acid (PLGA nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11b-positive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3β, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium.Nanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.

  7. San-Huang-Xie-Xin-Tang Prevents Rat Hearts from Ischemia/Reperfusion-Induced Apoptosis through eNOS and MAPK Pathways

    Directory of Open Access Journals (Sweden)

    Shu-Fen Liou

    2011-01-01

    Full Text Available San-Huang-Xie-Xin-Tang (SHXT is a traditional Chinese medication consisting of three herbs, namely Coptidis rhizome, Scutellariae radix and Rhei rhizome. This study aimed to examine the cardioprotective effects of SHXT in a rat model of acute myocardial apoptosis induced by ischemia/reperfusion (I/R. Vehicle (intravenous saline or SHXT (intravenous or oral was administered prior to I/R (occlusion of left coronary artery for 45 min followed by reperfusion for 2 h. In the vehicle group, myocardial I/R caused myocardial infarction with increased plasma cardiac enzymes, severe arrhythmia and mortality. Myocardial apoptosis was induced by I/R as evidenced by DNA ladder and Bcl-2/Bax ratio. In the SHXT group, we found that SHXT significantly reduced plasma levels of cardiac enzymes, arrhythmia scores (from 5 ± 1 to 2 ± 1, P<.01 and mortality rate (from 53 to 0%, P<.01. In addition, pretreatment with intravenous SHXT reduced the infarct size dose-dependently when compared with the vehicle group (10 mg kg−1: 14.0 ± 0.2 versus 44.5 ± 5.0%, and 30 mg kg−1: 6.2 ± 1.2% versus 44.5 ± 5.0%, both P<.01. Similarly, oral administration of SHXT reduced the infarct size dose-dependently. Furthermore, SHXT markedly decreased the apoptosis induced by I/R with increased Bcl-2/Bax ratio. Finally, we found that SHXT counteracted the I/R-induced downstream signaling, resulting in increased myocardial eNOS expression and plasma nitrite, and decreased activation of ERK1/2, p38 and JNK. These data suggest that SHXT has cardioprotective effects against I/R-induced apoptosis, and that these effects are mediated, at least in part, by eNOS and MAPK pathways.

  8. Renoprotective effect of paricalcitol via a modulation of the TLR4-NF-κB pathway in ischemia/reperfusion-induced acute kidney injury

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae-Won, E-mail: maestro97@hanmail.net; Kim, Sun Chul, E-mail: linefe99@hanmail.net; Ko, Yoon Sook, E-mail: rainboweyes@hanmail.net; Lee, Hee Young, E-mail: cell1023@hanmail.net; Cho, Eunjung, E-mail: icdej@naver.com; Kim, Myung-Gyu, E-mail: gyu219@hanmail.net; Jo, Sang-Kyung, E-mail: sang-kyung@korea.ac.kr; Cho, Won Yong, E-mail: wonyong@korea.ac.kr; Kim, Hyoung Kyu, E-mail: hyoung@korea.ac.kr

    2014-02-07

    Highlights: • Paricalcitol. • Attenuation of renal inflammation. • Modulation of TLR4-NF-κB signaling. - Abstract: Background: The pathophysiology of ischemic acute kidney injury (AKI) is thought to include a complex interplay between vascular endothelial cell dysfunction, inflammation, and tubular cell damage. Several lines of evidence suggest a potential anti-inflammatory effect of vitamin D in various kidney injury models. In this study, we investigated the effect of paricalcitol, a synthetic vitamin D analog, on renal inflammation in a mouse model of ischemia/reperfusion (I/R) induced acute kidney injury (AKI). Methods: Paricalcitol was administered via intraperitoneal (IP) injection at 24 h before ischemia, and then I/R was performed through bilateral clamping of the renal pedicles. Twenty-four hours after I/R, mice were sacrificed for the evaluation of injury and inflammation. Additionally, an in vitro experiment using HK-2 cells was also performed to examine the direct effect of paricalcitol on tubular cells. Results: Pre-treatment with paricalcitol attenuated functional deterioration and histological damage in I/R induced AKI, and significantly decreased tissue neutrophil and macrophage infiltration and the levels of chemokines, the pro-inflammatory cytokine interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). It also decreased IR-induced upregulation of Toll-like receptor 4 (TLR4), and nuclear translocation of p65 subunit of NF-κB. Results from the in vitro study showed pre-treatment with paricalcitol suppressed the TNF-α-induced depletion of cytosolic IκB in HK-2 cells. Conclusion: These results demonstrate that pre-treatment with paricalcitol has a renoprotective effect in ischemic AKI, possibly by suppressing TLR4-NF-κB mediated inflammation.

  9. Effect of nuclear factor kappa B on intercellular adhesion molecule-1 expression and neutrophil infiltration in lung injury induced by intestinal ischemia/reperfusion in rats

    Science.gov (United States)

    Tian, Xiao-Feng; Yao, Ji-Hong; Li, Ying-Hua; Zhang, Xue-Song; Feng, Bing-An; Yang, Chun-Ming; Zheng, Shu-Sen

    2006-01-01

    AIM: To investigate the role of nuclear factor kappa B (NF-κB) in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion (I/R), and its effect on intercellular adhesion molecule-1 (ICAM-1) expression and neutrophil infiltration. METHODS: Twenty-four Wistar rats were divided randomly into control, I/R and pyrrolidine dithiocarbamate (PDTC) treatment groups, n = 8 in each. I/R group and PDTC treatment group received superior mysenteric artery (SMA) occluding for 1 h and reperfusion for 2 h. PDTC group was administrated with intraperitoneal injection of 2% 100 mg/kg PDTC 1 h before surgery. Lung histology and bronchia alveolus lung fluid (BALF) protein were assayed. Serum IL-6, lung malondialdehyde (MDA) and myeloperoxidase (MPO) as well as the expression level of NF-κB and ICAM-1 were measured. RESULTS: Lung injury induced by intestinal I/R, was characterized by edema, hemorrhage and neutrophil infiltration as well as by the significant rising of BALF protein. Compared to control group, the levels of serum IL-6 and lung MDA and MPO increased significantly in I/R group (P = 0.001). Strong positive expression of NF-κB p65 and ICAM-1 was observed. After the administration of PDTC, the level of serum IL-6, lung MDA and MPO as well as NF-κB and ICAM-1 decreased significantly (P < 0.05) when compared to I/R group. CONCLUSION: The activation of NF-κB plays an important role in the pathogenesis of lung injury induced by intestinal I/R through upregulating the neutrophil infiltration and lung ICAM-1 expression. PDTC as an inhibitor of NF-κB can prevent lung injury induced by intestinal I/R through inhibiting the activity of NF-κB. PMID:16489637

  10. Electroacupuncture prevents endothelial dysfunction induced by ischemia-reperfusion injury via a cyclooxygenase-2-dependent mechanism: A randomized controlled crossover trial.

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    Seung Min Kathy Lee

    Full Text Available Exploring clinically effective methods to reduce ischemia-reperfusion (IR injury in humans is critical. Several drugs have shown protective effects, but studies using other interventions have been rare. Electroacupuncture (EA has induced similar protection in several animal studies but no study has investigated how the effects could be translated and reproduced in humans. This study aimed to explore the potential effect and mechanisms of EA in IR-induced endothelial dysfunction in humans.This is a prospective, randomized, crossover, sham-controlled trial consisting of two protocols. Protocol 1 was a crossover study to investigate the effect of EA on IR-induced endothelial dysfunction. Twenty healthy volunteers were randomly assigned to EA or sham EA (sham. Flow mediated dilation (FMD of the brachial artery (BA, nitroglycerin-mediated endothelial independent dilation, blood pressure before and after IR were measured. In protocol 2, seven volunteers were administered COX-2 inhibitor celecoxib (200 mg orally twice daily for five days. After consumption, volunteers underwent FMD before and after IR identical to protocol 1.In protocol 1, baseline BA diameter, Pre-IR BA diameter and FMD were similar between the two groups (p = NS. After IR, sham group showed significantly blunted FMD (Pre-IR: 11.41 ± 3.10%, Post-IR: 4.49 ± 2.04%, p < 0.001. However, EA protected this blunted FMD (Pre-IR: 10.96 ± 5.30%, Post-IR: 9.47 ± 5.23%, p = NS, p < 0.05 compared with sham EA after IR. In protocol 2, this protective effect was completely abolished by pre-treatment with celecoxib (Pre-IR: 11.05 ± 3.27%; Post-IR: 4.20 ± 1.68%, p = 0.001.EA may prevent IR-induced endothelial dysfunction via a COX-2 dependent mechanism.

  11. Electroacupuncture prevents endothelial dysfunction induced by ischemia-reperfusion injury via a cyclooxygenase-2-dependent mechanism: A randomized controlled crossover trial

    Science.gov (United States)

    Park, Jimin; Woo, Jong Shin; Leem, Jungtae; Park, Jun Hyeong; Lee, Sanghoon; Chung, Hyemoon; Lee, Jung Myung; Kim, Jin-Bae; Kim, Woo-Shik; Kim, Kwon Sam; Kim, Weon

    2017-01-01

    Objective Exploring clinically effective methods to reduce ischemia-reperfusion (IR) injury in humans is critical. Several drugs have shown protective effects, but studies using other interventions have been rare. Electroacupuncture (EA) has induced similar protection in several animal studies but no study has investigated how the effects could be translated and reproduced in humans. This study aimed to explore the potential effect and mechanisms of EA in IR-induced endothelial dysfunction in humans. Methods This is a prospective, randomized, crossover, sham-controlled trial consisting of two protocols. Protocol 1 was a crossover study to investigate the effect of EA on IR-induced endothelial dysfunction. Twenty healthy volunteers were randomly assigned to EA or sham EA (sham). Flow mediated dilation (FMD) of the brachial artery (BA), nitroglycerin-mediated endothelial independent dilation, blood pressure before and after IR were measured. In protocol 2, seven volunteers were administered COX-2 inhibitor celecoxib (200 mg orally twice daily) for five days. After consumption, volunteers underwent FMD before and after IR identical to protocol 1. Results In protocol 1, baseline BA diameter, Pre-IR BA diameter and FMD were similar between the two groups (p = NS). After IR, sham group showed significantly blunted FMD (Pre-IR: 11.41 ± 3.10%, Post-IR: 4.49 ± 2.04%, p < 0.001). However, EA protected this blunted FMD (Pre-IR: 10.96 ± 5.30%, Post-IR: 9.47 ± 5.23%, p = NS, p < 0.05 compared with sham EA after IR). In protocol 2, this protective effect was completely abolished by pre-treatment with celecoxib (Pre-IR: 11.05 ± 3.27%; Post-IR: 4.20 ± 1.68%, p = 0.001). Conclusion EA may prevent IR-induced endothelial dysfunction via a COX-2 dependent mechanism. PMID:28591155

  12. Attenuation of ischemia/reperfusion-induced inhibition of the rapid component of delayed rectifier potassium current by Isosteviol through scavenging reactive oxygen species.

    Science.gov (United States)

    Yin, Chunxia; Chen, Yaoxu; Wu, Huanlin; Xu, Danping; Tan, Wen

    2017-12-01

    Isosteviol has been demonstrated to play a protective role during ischemia reperfusion (I/R) myocardial infarction. However, the underlying electrophysiological mechanisms of isosteviol are still unknown. Our previous study showed that the rapid component of the delayed rectifier potassium channel (I Kr ) plays an important role in the prolongation of I/R-induced QT interval-related arrhythmia. This study aimed to investigate whether isosteviol could attenuate I/R-induced prolongation of the action potential duration (APD) along with inhibition of I Kr , and we aimed to clarify the electrophysiological mechanism of isosteviol to determine its cardioprotective effects in guinea pigs. We observed that the APD 90 were 298.5±41.6ms in control, 528.6±56.7ms during I/R, and reduced to 327.8±40.5ms after 10μmol/L of isosteviol treatment. The I Kr currents were 1.44±0.06 pA·pF -1 in the control group, 0.50±0.07pA·pF -1 during I/R, and recovered to 1.20±0.12pA·pF -1 after 10μmol/L of isoteviol treatment. Moreover, isosteviol reduced the over-production of reactive oxygen species (ROS) during I/R. Importantly, isosteviol does not affect the I Kr and human ether-a-go-go-related gene currents of normal cardiomyocytes. It attenuated the I/R-induced inhibition of I Kr due to reduced over-production of ROS. Furthermore, isosteviol is safe and has no cardiotoxicity, and it might be beneficial for coronary reperfusion therapy. Copyright © 2017. Published by Elsevier B.V.

  13. [Study of neuron-protective effect and mechanism of neuregulin1β against cerebral ischemia reperfusion-induced injury in rats].

    Science.gov (United States)

    Ji, Y Q; Zhang, R; Teng, L; Li, H Y; Guo, Y L

    2017-07-18

    Objective: Thecurrent study is to explore the neuron-protective mechanism of neuregulin1β (NRG1β) in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) through inhibiting the c-Jun phosphorylation. Methods: After 24 h of MCAO/R (referring to Longa's method), neurobehavioral function was measured by modified neurological severity score (mNSS) test; the cerebral infarction volume was detected by triphenyltetrazolium chloride (TTC) staining; the blood brain barrier (BBB) permeability was measured by Evans Blue (EB); the neuron morphology of brain tissue was observed by Nissl stain; the ultra-structures of the neurons were observed by transmission electron microscopy (TEM); the apoptotic neurons were counted by in situ cell death detection kit colocalized with NeuN; the expressions of phospho-c-Jun was determined by immunofluorescent labeling and Western blot analysis. Results: Compared with the sham-operation rats, the rats receiving MCAO/R showed increased mNSS (9.7±1.2), cerebral infarction volume (41.4±3.0)%, permeability of BBB, deformation of neurons, ischemia-induced apoptosis (0.63±0.04), and enhanced expression of phospho-c-Jun protein (0.90±0.07) (all P <0.05). Our data indicated that NRG1β attenuated neurologic deficits (6.4±0.9), decreased the cerebral infarction volume (10.4±0.5), reduced EB extravasation (1.55±0.13) and the deformation of neurons, protected the ultra-structure of neurons, blocked ischemia-induced apoptosis (0.23±0.02), through down-regulated phospho-c-Jun expression (0.40±0.03) in MCAO/R rats ( P <0.05). Conclusion: NRG1β exerts neuron-protective effects against ischemia reperfusion-induced injury in rats through inhibiting the c-Jun phosphorylation.

  14. The antioxidant and antiapoptotic effects of crocin pretreatment on global cerebral ischemia reperfusion injury induced by four vessels occlusion in rats.

    Science.gov (United States)

    Oruc, Serdar; Gönül, Yücel; Tunay, Kamil; Oruc, Oya Akpinar; Bozkurt, Mehmet Fatih; Karavelioğlu, Ergün; Bağcıoğlu, Erman; Coşkun, Kerem Senol; Celik, Sefa

    2016-06-01

    Cerebral ischemia reperfusion (IR) injury is a process in which oxidative and apoptotic mechanisms play a part. Neuroprotective agents to be found could work out well for the efficient and safe minimization of cerebral IR injury. Crocin is a strong antioxidant agent; however the influence of this agent on the experimental cerebral ischemia model has not been studied extensively and thus it is not well-known. The objective of our study was to investigate the antioxidant, antiapoptotic and protective effects of crocin on the global cerebral IR induced by four-vessel occlusion. A total of 30 adult female Sprague-Dawley rats were equally and randomly separated into three groups as follows: sham, IR and IR+crocin (40mg/kg/day orally for 10days). 24h after electrocauterization of bilateral vertebral arteries, bilateral common carotid arteries were occluded for 30min and reperfused for 30min. Oxidative stress parameters (TAS, TOS, OSI), haematoxylin and eosin staining, caspase-3 and hypoxia-inducible factor-1 alpha (HIF-1α) expressions and TUNEL methods were investigated. There was a significant difference between the IR and sham groups by means of OSI level, histopathological scoring, caspase-3, HIF-1α and TUNEL-positive cell parameters. We have also observed that pre-treatment with crocin reduced these parameter levels back to the baseline. The data obtained from the present study suggest that crocin may exert antiapoptotic, antioxidant and protective effects in IR-mediated brain injury induced by four-vessel occlusion. To the best of our knowledge, this would be the first study to be conducted in this field. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Activation of the Nrf2/HO-1 Antioxidant Pathway Contributes to the Protective Effects of Lycium Barbarum Polysaccharides in the Rodent Retina after Ischemia-Reperfusion-Induced Damage

    Science.gov (United States)

    Chang, Raymond Chuen-Chung; So, Kwok-Fai; Brecha, Nicholas C.; Pu, Mingliang

    2014-01-01

    Lycium barbarum polysaccharides (LBP), extracts from the wolfberries, are protective to retina after ischemia-reperfusion (I/R). The antioxidant response element (ARE)–mediated antioxidant pathway plays an important role in maintaining the redox status of the retina. Heme oxygenase-1 (HO-1), combined with potent AREs in its promoter, is a highly effective therapeutic target for the protection against neurodegenerative diseases, including I/R-induced retinal damage. The aim of our present study was to investigate whether the protective effect of LBP after I/R damage was mediated via activation of the Nrf2/HO-1-antioxidant pathway in the retina. Retinal I/R was induced by an increase in intraocular pressure to 130 mm Hg for 60 minutes. Prior to the induction of ischemia, rats were orally treated with either vehicle (PBS) or LBP (1 mg/kg) once a day for 1 week. For specific experiments, zinc protoporphyrin (ZnPP, 20 mg/kg), an HO-1 inhibitor, was intraperitoneally administered at 24 h prior to ischemia. The protective effects of LBP were evaluated by quantifying ganglion cell and amacrine cell survival, and by measuring cell apoptosis in the retinal layers. In addition, HO-1 expression was examined using Western blotting and immunofluorescence analyses. Cytosolic and nuclear Nrf2 was measured using immunofluorescent staining. LBP treatment significantly increased Nrf2 nuclear accumulation and HO-1 expression in the retina after I/R injury. Increased apoptosis and a decrease in the number of viable cells were observed in the ganglion cell layer (GCL) and inner nuclear layer (INL) in the I/R retina, which were reversed by LBP treatment. The HO-1 inhibitor, ZnPP, diminished the LBP treatment-induced protective effects in the retina after I/R. Taken together, these results suggested that LBP partially exerted its beneficial neuroprotective effects via the activation of Nrf2 and an increase in HO-1 protein expression. PMID:24400114

  16. RP105 Protects Against Apoptosis in Ischemia/Reperfusion-Induced Myocardial Damage in Rats by Suppressing TLR4-Mediated Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Jun Yang

    2015-07-01

    Full Text Available Background: Myocardial apoptosis is heavily implicated in the myocardial damage caused by ischemia-reperfusion (I/R. Toll-like receptor 4 (TLR4 is a potent inducer of these apoptotic cascades. In contrast, the radioprotective 105 kDa protein (RP105 is a specific negative regulator of TLR4 signaling pathways. However, the precise mechanisms by which RP105 inhibits myocardium apoptosis via TLR4-associated pathways during I/R is not fully understood. Methods: We utilized a rat model of myocardial ischemic reperfusion injury (MIRI. Animals were pre-treated with Ad-EGFP adenovirus, Ad-EGFP-RP105 adenovirus, saline, or nothing (sham. After three days, rats underwent a 30min left anterior descending coronary artery occlusion and a 4h reperfusion. Mycardial tissue was assessed by immunohistochemistry, TUNEL-staining, Western blot, quantitative RT-PCR, and a morphometric assay. Results: RP105 overexpression resulted in a reduction in infarct size, fewer TUNEL-positive cardiomyocytes, and a reduction in mitochondrial-associated apoptosis cascade activity. Further, RP105 overexpression repressed I/R-induced myocardial injury by attenuating myocardial apoptosis. This was mediated by inhibiting TLR4 activation and the phosphorylation of P38MAPK and the downstream transcription factor AP-1. Conclusion: RP105 overexpression leads to the de-activation of TLR4, P38MAPK, and AP-1 signaling pathways, and subsequently represses apoptotic cascades and ensuing damage of myocardial ischemic reperfusion. These findings may become the basis of a novel therapeutic approach for reducing of cardiac damage caused by MIRI.

  17. Tetramethylpyrazine analogue CXC195 protects against cerebral ischemia/reperfusion-induced apoptosis through PI3K/Akt/GSK3β pathway in rats.

    Science.gov (United States)

    Chen, Lin; Wei, Xinbing; Hou, Yunfeng; Liu, Xiaoqian; Li, Senpeng; Sun, Baozhu; Liu, Xinyong; Liu, Huiqing

    2014-01-01

    CXC195 showed strongest protective effects among the ligustrazine derivatives in cells and prevented apoptosis induced by H2O2 injury. We recently demonstrated that CXC195 protected against cerebral ischemia/reperfusion (I/R) injury by its antioxidant activity. However, whether the anti-apoptotic action of CXC195 is involved in cerebral I/R injury is unknown. Here, we investigated the role of CXC195 in apoptotic processes induced by cerebral I/R and the possible signaling pathways. Male Wistar rats were submitted to transient middle cerebral artery occlusion for 2h, followed by 24h reperfusion. CXC195 was injected intraperitoneally at 2h and 12h after the onset of ischemia. The number of apoptotic cells was measured by TUNEL assay, apoptosis-related protein cleaved caspase-3, Bcl-2, Bax and the phosphorylation levels of Akt and GSK3β in ischemic penumbra were assayed by western blot. The results showed that administration of CXC195 at the doses of 3mg/kg and 10mg/kg significantly inhibited the apoptosis by decreasing the number of apoptotic cells, decreasing the level of cleaved caspase-3 and Bax, and increasing the level of Bcl-2 in rats subjected to I/R injury. Simultaneously, CXC195 treatment markedly increased the phosphorylation of Akt and GSK3β. Blockade of PI3K activity by wortmannin, dramatically abolished its anti-apoptotic effect and lowered both Akt and GSK3β phosphorylation levels. Our study firstly demonstrated that CXC195 protected against cerebral I/R injury by reducing apoptosis in vivo and PI3K/Akt/GSK3β pathway involved in the anti-apoptotic effect. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  18. Evaluation of the gender difference in the protective effects of ischemic postconditioning on ischemia-reperfusion-induced acute kidney injury in rats

    Directory of Open Access Journals (Sweden)

    Atefeh Mahmoudi

    2013-11-01

    Full Text Available Background: Several studies indicate that gender differences exist in tolerance of the kidney to ischemia reperfusion (IR injury. Recently, postconditioning (POC, induction of brief repetitive periods of IR, has been introduced to reduce the extent of the damage to the kidney. This method was shown to attenuate renal IR injury by modifying oxidative stress and reducing lipid peroxidation. Considering the gender effect on the results of several treatment methods, in this study, we investigated the impact of gender on the protective effect of POC on the rat kidney.Methods: In this study, after right nephrectomy, 48 male and female rats were randomly divided into 6 groups of 8 rats: In IR group, with the use of bulldog clamp, 45 minutes of left renal artery ischemia was induced followed by 24 hours of reperfusion. In the sham group, all of the above surgical procedures were applied except that IR was not induced. In the POC group, after the induction of 45 minutes ischemia, 4 cycles of 10 seconds of intermittent ischemia and reperfusion were applied before restoring of blood to the kidney. 24 hours later, serum and renal tissue samples were collected for renal functional monitoring and oxidative stress evaluation.Results: Postconditioning attenuated renal dysfunction considering the significant decrease in plasma creatinine and BUN compared with IR group only in male rats (P<0.05. Also, POC attenuated oxidative stress in male rats’ kidney tissues as demonstrated by a significantly reduced malondialdehyde (MDA level and increased superoxide dismutase (SOD activity (P<0.05. In female rats, there were no changes in functional markers and oxidative stress status in POC group compared to IR group. Conclusion: Considering gender difference, POC had protective effect against IR injury by attenuating functional and oxidative stress markers in male rat kidneys. This protective effect was not seen in female rats.

  19. Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on focal cerebral ischemia/reperfusion-induced inflammation, oxidative stress, and apoptosis in rats.

    Directory of Open Access Journals (Sweden)

    Gu Gong

    Full Text Available AIM: Glycyrrhizin (GL has been reported to protect against ischemia and reperfusion (I/R-induced injury by inhibiting the cytokine activity of high mobility group box 1 (HMGB1. In the present study, the protective effects of GL against I/R injury, as well as the related molecular mechanisms, were investigated in rat brains. METHODS: Focal cerebral I/R injury was induced by intraluminal filamentous occlusion of the middle cerebral artery (MCA in Male Sprague-Dawley rats. GL alone or GL and rHMGB1 were administered intravenously at the time of reperfusion. Serum levels of HMGB1 and inflammatory mediators were quantified via enzyme-linked immunosorbent assay (ELISA. Histopathological examination, immunofluorescence, RT-PCR and western blotting analyses were performed to investigate the protective and anti-apoptotic effects and related molecular mechanisms of GL against I/R injury in rat brains. RESULTS: Pre-treatment with GL significantly reduced infarct volume and improved the accompanying neurological deficits in locomotor function. The release of HMGB1 from the cerebral cortex into the serum was inhibited by GL administration. Moreover, pre-treatment with GL alleviated apoptotic injury resulting from cerebral I/R through the inhibition of cytochrome C release and caspase 3 activity. The expression levels of inflammation- and oxidative stress-related molecules including TNF-α, iNOS, IL-1β, and IL-6, which were over-expressed in I/R, were decreased by GL. P38 and P-JNK signalling were involved in this process. All of the protective effects of GL could be reversed by rHMGB1 administration. CONCLUSIONS: GL has a protective effect on ischemia-reperfusion injury in rat brains through the inhibition of inflammation, oxidative stress and apoptotic injury by antagonising the cytokine activity of HMGB1.

  20. Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide.

    Science.gov (United States)

    Toyoda, Tomomi; Tosaka, Shinya; Tosaka, Reiko; Maekawa, Takuji; Cho, Sungsam; Eguchi, Susumu; Nakashima, Masahiro; Sumikawa, Koji

    2014-01-01

    Ischemic postconditioning (PostC) protects the liver against ischemia-reperfusion (IR) injury. Milrinone, a phosphodiesterase 3 inhibitor, has been reported to exhibit preconditioning properties against hepatic IR injury; however, its PostC properties remain unknown. This study investigated whether milrinone has PostC properties against hepatic IR injury and the roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS). Male Wistar rats were separated into six groups: (1) group S: animals that underwent sham operation without ischemia, (2) group C: ischemia followed by reperfusion with no other intervention, (3) group M: milrinone administered immediately after reperfusion, (4) group MW: wortmannin, a PI3K inhibitor, injected before milrinone administration, (5) group MN: l-NAME, a NOS inhibitor, injected before milrinone administration, and (6) group MD, milrinone administered 30 min after reperfusion. Except for group S, all groups underwent 1 h of warm ischemia of median and left lateral lobes, followed by 5 h of reperfusion. Biochemical liver function analysis and histologic examination were performed. Serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, histologic damage scores, and apoptotic rate in group M were significantly lower than those in group C. The inhibition of PI3K or NOS prevented this protective effect. Milrinone administered 30 min after reperfusion did not show obvious protective effects. Milrinone-induced PostC protects against hepatic IR injury when it is administered immediately after reperfusion, and PI3K and NOS may play an important role in this protective effect. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Therapeutic hypothermia reduces intestinal ischemia/reperfusion ...

    African Journals Online (AJOL)

    The detached intestinal epithelial cells in hypothermia group showed ... of apoptosis than those in normothermia group at 4 h (17.30 ± 2.56 vs. ... intestinal ischemia/reperfusion (IR) injury, which could be attenuated by therapeutic hypothermia.

  2. Platelets Orchestrate Remote Tissue Damage After Mesenteric Ischemia-Reperfusion

    Science.gov (United States)

    2012-02-02

    Platelet Depletion Two days before I/R injury, mice received a single intraperitoneal injection of a titred affinity purified endotoxin-free rabbit...Egan R, Chen J, le Lucca JJ, Juang YT, Tsokos GC. IL-17 producing CD4 T cells mediate accelerated ischemia/reperfusion- induced injury in...activation in rheumatoid arthritis. Clin Rheumatol 26: 768–771, 2007. 77. Wang Y, Li Y, le Lucca SL, Simovic M, Tsokos GC, le Lucca JJ. Decay accelerating

  3. Attenuation of ischemia-reperfusion-induced alterations in intracellular Ca2+ in cardiomyocytes from hearts treated with N-acetylcysteine and N-mercaptopropionylglycine.

    Science.gov (United States)

    Saini-Chohan, Harjot K; Dhalla, Naranjan S

    2009-12-01

    This study was undertaken to test whether Ca(2+)-handling abnormalities in cardiomyocytes after ischemia-reperfusion (I/R) are prevented by antioxidants such as N-acetyl L-cysteine (NAC), which is known to reduce oxidative stress by increasing the glutathione redox status, and N-(2-mercaptopropionyl)-glycine (MPG), which scavenges both peroxynitrite and hydroxyl radicals. For this purpose, isolated rat hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion, and cardiomyocytes were prepared to monitor changes in the intracellular concentration of free Ca(2+) ([Ca(2+)](i)). Marked depression in the left ventricular developed pressure and elevation in the left ventricular end-diastolic pressure in I/R hearts were attenuated by treatment with NAC or MPG. Cardiomyocytes obtained from I/R hearts showed an increase in the basal level of [Ca(2+)](i) as well as augmentation of the low Na(+)-induced increase in [Ca(2+)](i), with no change in the KCl-induced increase in [Ca(2+)](i). These I/R-induced alterations in Ca(2+) handling by cardiomyocytes were attenuated by treatment of hearts with NAC or MPG. Furthermore, reduction in the isoproterenol-, ATP-, ouabain-, and caffeine-induced increases in [Ca(2+)](i) in cardiomyocytes from I/R hearts were limited by treatment with NAC or MPG. The increases in the basal [Ca(2+)](i), unlike the KCl-induced increase in [Ca(2+)](i), were fully or partially prevented by both NAC and MPG upon exposing cardiomyocytes to hypoxia-reoxygenation, H(2)O(2), or a mixture of xanthine and xanthine oxidase. These results suggest that improvement in cardiac function of I/R hearts treated with NAC or MPG was associated with attenuation of changes in Ca(2+) handling by cardiomyocytes, and the results support the view that oxidative stress due to oxyradical generation and peroxynitrite formation plays an important role in the development of intracellular Ca(2+) overload in cardiomyocytes as a consequence of I/R injury.

  4. Involvement of adenosine and standardization of aqueous extract of garlic (Allium sativum Linn.) on cardioprotective and cardiodepressant properties in ischemic preconditioning and myocardial ischemia-reperfusion induced cardiac injury

    Science.gov (United States)

    Sharma, Ashish Kumar; Munajjam, Arshee; Vaishnav, Bhawna; Sharma, Richa; Sharma, Ashok; Kishore, Kunal; Sharma, Akash; Sharma, Divya; Kumari, Rita; Tiwari, Ashish; Singh, Santosh Kumar; Gaur, Samir; Jatav, Vijay Singh; Srinivasan, Barthu Parthi; Agarwal, Shyam Sunder

    2012-01-01

    The present study investigated the effect of garlic (Allium sativum Linn.) aqueous extracts on ischemic preconditioning and ischemia-reperfusion induced cardiac injury, as well as adenosine involvement in ischemic preconditioning and garlic extract induced cardioprotection. A model of ischemia-reperfusion injury was established using Langendorff apparatus. Aqueous extract of garlic dose was standardized (0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.07%, 0.05%, 0.03%, 0.01%), and the 0.05% dose was found to be the most effective. Higher doses (more than 0.05%) were highly toxic, causing arrhythmia and cardiodepression, whereas the lower doses were ineffective. Garlic exaggerated the cardioprotective effect of ischemic preconditioning. The cardioprotective effect of ischemic preconditioning and garlic cardioprotection was significantly attenuated by theophylline (1,000 µmol/L) and 8-SPT (10 mg/kg, i.p.) and expressed by increased myocardial infarct size, increased LDH level, and reduced nitrite and adenosine levels. These findings suggest that adenosine is involved in the pharmacological and molecular mechanism of garlic induced cardioprotection and mediated by the modulation of nitric oxide. PMID:23554727

  5. Endothelin receptor mediated Ca(2+) signaling in coronary arteries after experimentally induced ischemia/reperfusion injury in rat

    DEFF Research Database (Denmark)

    Kristiansen, Sarah Brøgger; Haanes, Kristian A.; Sheykhzade, Majid

    2017-01-01

    a phenotypical shift, which includes increased evoked ETB induced contraction in the smooth muscle cell, and also a higher basal tone development which both are dependent on Ca(2+) influx through VGCCs. This is combined with alterations in the ETA calcium handling, which has a stronger dependence on Ca(2...

  6. Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents.

    Science.gov (United States)

    Bhattacharya, Pallab; Pandey, Anand Kumar; Paul, Sudip; Patnaik, Ranjana; Yavagal, Dileep R

    2013-01-01

    Aquaporin-4(AQP4) is an abundant water channel protein in brain that regulates water transport to maintain homeostasis. Cerebral edema resulting from AQP4 over expression is considered to be one of the major determinants for progressive neuronal insult during cerebral ischemia. Although, both upregulation and downregulation of AQP4 expression is associated with brain pathology, over expression of AQP4 is one of the chief contributors of water imbalance in brain during ischemic pathology. We have found that Piroxicam binds to AQP4 with optimal binding energy value. Thus, we hypothesized that Piroxicam is neuroprotective in the rodent cerebral ischemic model by mitigating cerebral edema via AQP4 regulation. Rats were treated with Piroxicam OR placebo at 30 min prior, 2 h post and 4 h post 60 minutes of MCAO followed by 24 hour reperfusion. Rats were evaluated for neurological deficits and motor function just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, RT-PCR and western blot experiments. Piroxicam pretreatment thirty minutes prior to ischemia and four hour post reperfusion afforded neuroprotection as evident through significant reduction in cerebral infarct volume, improvement in motor behavior, neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde were also found to be significantly reduced in ischemic brain regions in treated animals. This neuroprotection was found to be associated with inhibition of acid mediated rise in intracellular calcium levels and also downregulated AQP4 expression. Findings of the present study provide significant evidence that Piroxicam acts as a potent AQP4 regulator and renders neuroprotection in focal cerebral ischemia. Piroxicam could be clinically exploited for the treatment of brain stroke along with other anti-stroke therapeutics in future.

  7. Autophagy and Liver Ischemia-Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Raffaele Cursio

    2015-01-01

    Full Text Available Liver ischemia-reperfusion (I-R injury occurs during liver resection, liver transplantation, and hemorrhagic shock. The main mode of liver cell death after warm and/or cold liver I-R is necrosis, but other modes of cell death, as apoptosis and autophagy, are also involved. Autophagy is an intracellular self-digesting pathway responsible for removal of long-lived proteins, damaged organelles, and malformed proteins during biosynthesis by lysosomes. Autophagy is found in normal and diseased liver. Although depending on the type of ischemia, warm and/or cold, the dynamic process of liver I-R results mainly in adenosine triphosphate depletion and in production of reactive oxygen species (ROS, leads to both, a local ischemic insult and an acute inflammatory-mediated reperfusion injury, and results finally in cell death. This process can induce liver dysfunction and can increase patient morbidity and mortality after liver surgery and hemorrhagic shock. Whether autophagy protects from or promotes liver injury following warm and/or cold I-R remains to be elucidated. The present review aims to summarize the current knowledge in liver I-R injury focusing on both the beneficial and the detrimental effects of liver autophagy following warm and/or cold liver I-R.

  8. Exosomes from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells (hiPSC-MSCs) Protect Liver against Hepatic Ischemia/ Reperfusion Injury via Activating Sphingosine Kinase and Sphingosine-1-Phosphate Signaling Pathway.

    Science.gov (United States)

    Du, Yingdong; Li, Dawei; Han, Conghui; Wu, Haoyu; Xu, Longmei; Zhang, Ming; Zhang, Jianjun; Chen, Xiaosong

    2017-01-01

    This study aimed to evaluate the effects of exosomes produced by human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs-Exo) on hepatic ischemia-reperfusion (I/R) injury, as well as the underlying mechanisms. Exosomes derived from hiPSC-MSCs were isolated and characterized both biochemically and biophysically. hiPSC-MSCs-Exo were injected systemically into a murine ischemia/reperfusion injury model via the inferior vena cava, and then the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Primary hepatocytes and human hepatocyte cell line HL7702 were used to test whether exosomes could induce hepatocytes proliferation in vitro. In addition, the expression levels of proliferation markers (proliferation cell nuclear antigen, PCNA; Phosphohistone-H3, PHH3) were measured by immunohistochemistry and Western blot. Moreover, SK inhibitor (SKI-II) and S1P1 receptor antagonist (VPC23019) were used to investigate the role of sphingosine kinase and sphingosine-1-phosphate-dependent pathway in the effects of hiPSC-MSCs-Exo on hepatocytes. hiPSCs were efficiently induced into hiPSC-MSCs that had typical MSC characteristics. hiPSC-MSCs-Exo had diameters ranging from 100 to 200 nm and expressed exosome markers (Alix, CD63 and CD81). After hiPSC-MSCs-Exo administration, hepatocyte necrosis and sinusoidal congestion were markedly suppressed in the ischemia/reperfusion injury model, with lower histopathological scores. The levels of hepatocyte injury markers AST and ALT were significantly lower in the treatment group compared to control, and the expression levels of proliferation markers (PCNA and PHH3) were greatly induced after hiPSC-MSCs-Exo administration. Moreover, hiPSC-MSCs-Exo also induced primary hepatocytes and HL7702 cells proliferation in vitro in a dose-dependent manner. We found that hiPSC-MSCs-Exo could

  9. Amelioration of Ischemia/Reperfusion Injury During Resuscitation from Hemorrhage by Induction of Heme Oxygenase-1 (HO-1) in a Conscious Mouse Model of Uncontrolled Hemorrhage

    Science.gov (United States)

    2013-10-01

    against menadione -induced-oxidative stress, also induces HIF1a and this may explain their cytoprotective effect. KEY RESEARCH ACCOMPLISHMENTS: Due to...August 2010 - October 2011 : Compared CDDO-lm, CAPE, CAPA induced H0-1 mediated cytoprotection against menadione -induced-oxidative stress in HUVEC cells...Pharmaceutical Scientists (AAPS) 2013: Comparison of atmospheric oxygen versus physiological levels on cytotoxicity of menadione and cytoprotection by

  10. Renal ischemia reperfusion causes brain hippocampus oxidative ...

    African Journals Online (AJOL)

    Background: The acute kidney injury (AKI) may do damage to remote organs. Objective of the study is to investigate effect of seaweed extract (SE) on brain oxidative damage in kidney ischemia/reperfusion rats. Material and Methods: Animals were randomly divided into five groups. SE pre-fed to rats. Results: Kidney I/R ...

  11. Protective Effect of Extract of Folium Ginkgo on Repeated Cerebral Ischemia-Reperfusion Injury

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To study the protective effect of extract of Folium Ginkgo (FGE) on repeated cerebral ischemia-reperfusion injury. Methods: The model in waking mice induced by repeated cerebral ischemia-reperfusion were used in the experiment to observe the effect of FGE on behavior, oxygen free radical metabolism and prostaglandin E2 (PGE2) content by step-through experiment, diving stand and colorimetric method. Results: FGE could obviously improve the learning ability and memory of model animals, and could lower obviously the content of malonyldialdehyde, nitric oxide and PGE2, restore the lowered activity of superoxide dismutase and catalase in cerebral tissue. Conclusion: FGE has highly protective effect against repeated ischemia-reperfusion injury, the mechanism might be related with its action on anti-lipid oxidatin, improve the activity of antioxidase and inhibit the producing of PGE2.

  12. Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Oskar Kövamees

    Full Text Available Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes (NCT02009527.Male patients with CAD (n = 12 or CAD + type 2 diabetes (n = 12, were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nω-hydroxy-nor-L-arginine, 0.1 mg/min or saline.The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05. Nω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion. Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01. Endothelium-independent vasodilatation did not differ between the occasions.Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.

  13. Intratracheal Administration of Small Interfering RNA Targeting Fas Reduces Lung Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Del Sorbo, Lorenzo; Costamagna, Andrea; Muraca, Giuseppe; Rotondo, Giuseppe; Civiletti, Federica; Vizio, Barbara; Bosco, Ornella; Martin Conte, Erica L; Frati, Giacomo; Delsedime, Luisa; Lupia, Enrico; Fanelli, Vito; Ranieri, V Marco

    2016-08-01

    Lung ischemia-reperfusion injury is the main cause of primary graft dysfunction after lung transplantation and results in increased morbidity and mortality. Fas-mediated apoptosis is one of the pathologic mechanisms involved in the development of ischemia-reperfusion injury. We hypothesized that the inhibition of Fas gene expression in lungs by intratracheal administration of small interfering RNA could reduce lung ischemia-reperfusion injury in an ex vivo model reproducing the procedural sequence of lung transplantation. Prospective, randomized, controlled experimental study. University research laboratory. C57/BL6 mice weighing 28-30 g. Ischemia-reperfusion injury was induced in lungs isolated from mice, 48 hours after treatment with intratracheal small interfering RNA targeting Fas, control small interfering RNA, or vehicle. Isolated lungs were exposed to 6 hours of cold ischemia (4°C), followed by 2 hours of warm (37°C) reperfusion with a solution containing 10% of fresh whole blood and mechanical ventilation with constant low driving pressure. Fas gene expression was significantly silenced at the level of messenger RNA and protein after ischemia-reperfusion in lungs treated with small interfering RNA targeting Fas compared with lungs treated with control small interfering RNA or vehicle. Silencing of Fas gene expression resulted in reduced edema formation (bronchoalveolar lavage protein concentration and lung histology) and improvement in lung compliance. These effects were associated with a significant reduction of pulmonary cell apoptosis of lungs treated with small interfering RNA targeting Fas, which did not affect cytokine release and neutrophil infiltration. Fas expression silencing in the lung by small interfering RNA is effective against ischemia-reperfusion injury. This approach represents a potential innovative strategy of organ preservation before lung transplantation.

  14. The antiendotoxin agent taurolidine potentially reduces ischemia/reperfusion injury through its metabolite taurine.

    LENUS (Irish Health Repository)

    Doddakula, Kishore K

    2010-09-01

    Cardiopulmonary bypass results in ischemia\\/reperfusion (I\\/R)-induced endotoxemia. We conducted a prospective randomized trial to investigate the effect of taurolidine, an antiendotoxin agent with antioxidant and membrane-stabilizing properties, on patients undergoing coronary artery bypass grafting (CABG).

  15. Sphingosine-1-Phosphate reduces ischemia/reperfusion injury by phosphorylating the gap junction protein Connexin43

    DEFF Research Database (Denmark)

    Morel, Sandrine; Christoffersen, Christina; Axelsen, Lene N

    2016-01-01

    recruitment seems only indirectly affected. Importantly, short-term S1P treatment at the onset of reperfusion was sufficient to reduce ischemia/reperfusion injury in isolated perfused hearts. Mechanistic in vitro and ex vivo studies revealed that 5 min of S1P treatment induced phosphorylation of the gap...

  16. Ipsilateral common iliac artery plus femoral artery clamping for inducing sciatic nerve ischemia/reperfusion injury in rats: a reliable and simple method

    Directory of Open Access Journals (Sweden)

    Barzegar-Fallah Anita

    2008-12-01

    Full Text Available Abstract The aim of this study was to develop a practical model of sciatic ischemia reperfusion (I/R injury producing serious neurologic deficits and being technically feasible compared with the current time consuming or ineffective models. Thirty rats were divided into 6 groups (n = 5. Animal were anesthetized by using ketamine (50 mg/kg and xylazine (4 mg/kg. Experimental groups included a sham-operated group and five I/R groups with different reperfusion time intervals (0 h, 3 h, 1 d, 4 d, 7 d. In I/R groups, the right common iliac artery and the right femoral artery were clamped for 3 hrs. Sham-operated animals underwent only laparotomy without induction of ischemia. Just before euthanasia, behavioral scores (based on gait, grasp, paw position, and pinch sensitivity were obtained and then sciatic nerves were removed for light-microscopy studies (for ischemic fiber degeneration (IFD and edema. Behavioral score deteriorated among the ischemic groups compared with the control group (p

  17. Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment-Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats

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    Hai-Jing Sun

    2017-01-01

    Full Text Available Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA and 2-arachidonoylglycerol (2-AG detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS, malonaldehyde (MDA, and MPO (myeloperoxidase and increased superoxide dismutase (SOD production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.

  18. The effect of mitochondrial calcium uniporter on mitochondrial fission in hippocampus cells ischemia/reperfusion injury

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    Zhao, Lantao; Li, Shuhong; Wang, Shilei, E-mail: wshlei@aliyun.com; Yu, Ning; Liu, Jia

    2015-06-05

    The mitochondrial calcium uniporter (MCU) transports free Ca{sup 2+} into the mitochondrial matrix, maintaining Ca{sup 2+} homeostasis, thus regulates the mitochondrial morphology. Previous studies have indicated that there was closely crosstalk between MCU and mitochondrial fission during the process of ischemia/reperfusion injury. This study constructed a hypoxia reoxygenation model using primary hippocampus neurons to mimic the cerebral ischemia/reperfusion injury and aims to explore the exactly effect of MCU on the mitochondrial fission during the process of ischemia/reperfusion injury and so as the mechanisms. Our results found that the inhibitor of the MCU, Ru360, decreased mitochondrial Ca{sup 2+} concentration, suppressed the expression of mitochondrial fission protein Drp1, MIEF1 and Fis1, and thus improved mitochondrial morphology significantly. Whereas spermine, the agonist of the MCU, had no significant impact compared to the I/R group. This study demonstrated that the MCU regulates the process of mitochondrial fission by controlling the Ca{sup 2+} transport, directly upregulating mitochondrial fission proteins Drp1, Fis1 and indirectly reversing the MIEF1-induced mitochondrial fusion. It also provides new targets for brain protection during ischemia/reperfusion injury. - Highlights: • We study MCU with primary neuron culture. • MCU induces mitochondrial fission. • MCU reverses MIEF1 effect.

  19. Effects of Chronic and Acute Zinc Supplementation on Myocardial Ischemia-Reperfusion Injury in Rats.

    Science.gov (United States)

    Ozyıldırım, Serhan; Baltaci, Abdulkerim Kasim; Sahna, Engin; Mogulkoc, Rasim

    2017-07-01

    The present study aims to explore the effects of chronic and acute zinc sulfate supplementation on myocardial ischemia-reperfusion injury in rats. The study registered 50 adult male rats which were divided into five groups in equal numbers as follows: group 1, normal control; group 2, sham; group 3, myocardial ischemia reperfusion (My/IR): the group which was fed on a normal diet and in which myocardial I/R was induced; group 4, myocardial ischemia reperfusion + chronic zinc: (5 mg/kg i.p. zinc sulfate for 15 days); and group 5, myocardial ischemia reperfusion + acute zinc: the group which was administered 15 mg/kg i.p. zinc sulfate an hour before the operation and in which myocardial I/R was induced. The collected blood and cardiac tissue samples were analyzed using spectrophotometric method to determine levels of MDA, as an indicator of tissue injury, and GSH, as an indicator of antioxidant activity. The highest plasma and heart tissue MDA levels were measured in group 3 (p zinc administration and markedly by chronic zinc supplementation.

  20. Rapamycin protects kidney against ischemia reperfusion injury through recruitment of NKT cells.

    Science.gov (United States)

    Zhang, Chao; Zheng, Long; Li, Long; Wang, Lingyan; Li, Liping; Huang, Shang; Gu, Chenli; Zhang, Lexi; Yang, Cheng; Zhu, Tongyu; Rong, Ruiming

    2014-08-19

    NKT cells play a protective role in ischemia reperfusion (IR) injury, of which the trafficking in the body and recruitment in injured organs can be influenced by immunosuppressive therapy. Therefore, we investigated the effects of rapamycin on kidneys exposed to IR injury in early stage and on trafficking of NKT cells in a murine model. Balb/c mice were subjected to kidney 30 min ischemia followed by 24 h reperfusion. Rapamycin (2.5 ml/kg) was administered by gavage daily, starting 1 day before the operation. Renal function and histological changes were assessed. The proportion of NKT cells in peripheral blood, spleen and kidney was detected by flow cytometry. The chemokines and corresponding receptor involved in NKT cell trafficking were determined by RT-PCR and flow cytometry respectively. Rapamycin significantly improved renal function and ameliorated histological injury. In rapamycin-treated group, the proportion of NKT cells in spleen was significantly decreased but increased in peripheral blood and kidney. In addition, the CXCR3+ NKT cell in the kidney increased remarkably in the rapamycin-treated group. The chemokines, CXCL9 and CXCL10, as the ligands of CXCR3, were also increased in the rapamycin-treated kidney. Rapamycin may recruit NKT cells from spleen to the IR-induced kidney to ameliorate renal IR injury in the early stage.

  1. The effects of different anesthesia techniques on free radical production after tourniquet-induced ischemia-reperfusion injury at children's age

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    Budić Ivana

    2010-01-01

    Full Text Available Background/Aim. Reperfusion of previously ischemic tissue leads to injuries mediated by reactive oxygen species. The aim of the study was to investigate the effects of different anesthesia techniques on oxidative stress caused by tourniquetinduced ischemia-reperfusion (IR injury during extremity operations at children's age. Methods. The study included 45 patients American Society of Anesthesiologists (ASA classification I or II, 8 to 17 years of age, undergoing orthopedic procedures that required bloodless limb surgery. The children were randomized into three groups of 15 patients each: general inhalational anesthesia with sevoflurane (group S, total intravenous anesthesia with propofol (group T and regional anesthesia (group R. Venous blood samples were obtained at four time points: before peripheral nerve block and induction of general anesthesia (baseline, 1 min before tourniquet release (BTR, 5 and 20 min after tourniquet release (ATR. Postischemic reperfusion injury was estimated by measurement of concentration of malondialdehyde (MDA in plasma and erythrocytes as well as catalase (CAT activity. Results. Plasma MDA concentration in the group S was significantly higher at 20 min ATR in comparison with the groups T and R (6.78 ± 0.33 μmolL-1-1 vs 4.07 ± 1.53 and 3.22 ± 0.9. μmolL-1-1, respectively. There was a significant difference in MDA concentration in erytrocythes between the groups S and T after 5 min of reperfusion (5.88 ± 0.88 vs 4.27 ± 1.04 nmol/mlEr, p < 0.05. Although not statistically significant, CAT activity was slightly increased as compared to baseline in both groups S and R. In the group T, CAT activity decreased at all time points when compared with baseline, but the observed decrease was only statistically significant at BTR (34.70 ± 9.27 vs 39.69 ± 12.91 UL-1, p < 0.05. Conclusion. Continuous propofol infusion and regional anesthesia techniques attenuate lipid peroxidation and IR injury connected with tourniquet

  2. Rapamycin preconditioning attenuates transient focal cerebral ischemia/reperfusion injury in mice.

    Science.gov (United States)

    Yin, Lele; Ye, Shasha; Chen, Zhen; Zeng, Yaoying

    2012-12-01

    Rapamycin, an mTOR inhibitor and immunosuppressive agent in clinic, has protective effects on traumatic brain injury and neurodegenerative diseases. But, its effects on transient focal ischemia/reperfusion disease are not very clear. In this study, we examined the effects of rapamycin preconditioning on mice treated with middle cerebral artery occlusion/reperfusion operation (MCAO/R). We found that the rapamycin preconditioning by intrahippocampal injection 20 hr before MCAO/R significantly improved the survival rate and longevity of mice. It also decreased the neurological deficit score, infracted areas and brain edema. In addition, rapamycin preconditioning decreased the production of NF-κB, TNF-α, and Bax, but not Bcl-2, an antiapoptotic protein in the ischemic area. From these results, we may conclude that rapamycin preconditioning attenuate transient focal cerebral ischemia/reperfusion injury and inhibits apoptosis induced by MCAO/R in mice.

  3. Ethyl pyruvate protects colonic anastomosis from ischemia-reperfusion injury.

    Science.gov (United States)

    Unal, B; Karabeyoglu, M; Huner, T; Canbay, E; Eroglu, A; Yildirim, O; Dolapci, M; Bilgihan, A; Cengiz, O

    2009-03-01

    Ethyl pyruvate is a simple derivative in Ca(+2)- and K(+)-containing balanced salt solution of pyruvate to avoid the problems associated with the instability of pyruvate in solution. It has been shown to ameliorate the effects of ischemia-reperfusion (I/R) injury in many organs. It has also been shown that I/R injury delays the healing of colonic anastomosis. In this study, the effect of ethyl pyruvate on the healing of colon anastomosis and anastomotic strength after I/R injury was investigated. Anastomosis of the colon was performed in 32 adult male Wistar albino rats divided into 4 groups of 8 individuals: (1) sham-operated control group (group 1); (2) 30 minutes of intestinal I/R by superior mesenteric artery occlusion (group 2); (3) I/R+ ethyl pyruvate (group 3), ethyl pyruvate was administered as a 50-mg/kg/d single dose; and (4) I/R+ ethyl pyruvate (group 4), ethyl pyruvate administration was repeatedly (every 6 hours) at the same dose (50 mg/kg). On the fifth postoperative day, animals were killed. Perianastomotic tissue hydroxyproline contents and anastomotic bursting pressures were measured in all groups. When the anastomotic bursting pressures and tissue hydroxyproline contents were compared, it was found that they were decreased in group 2 when compared with groups 1, 3, and 4 (P .05). Ethyl pyruvate significantly prevents the delaying effect of I/R injury on anastomotic strength and healing independent from doses of administration.

  4. Noscapine protects OLN-93 oligodendrocytes from ischemia-reperfusion damage: Calcium and nitric oxide involvement.

    Science.gov (United States)

    Nadjafi, S; Ebrahimi, S-A; Rahbar-Roshandel, N

    2015-12-01

    This study was carried out to evaluate the effects of noscapine, a benzylisoquinoline alkaloid from opium poppy, on oligodendrocyte during ischemia/reperfusion-induced excitotoxic injury. Changes in intracellular calcium levels due to chemical ischemia and nitric oxide (NO) production during ischemia/reperfusion were evaluated as the hallmarks of ischemia-derived excitotoxic event. OLN-93 cell line (a permanent immature rat oligodendrocyte) was used as a model of oligodendrocyte. 30- or 60-minute-oxygen-glucose deprivation/24 hours reperfusion were used to induce excitotoxicity. MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay was used to evaluate cell viability. Ratiometric fluorescence microscopy using Ca(2+)-sensitive indicator Fura-2/AM was utilized to assess intracellular calcium levels. NO production was evaluated by Griess method. Noscapine (4 μM) significantly attenuated intracellular Ca(2+) elevation (P < 0.001). Also, noscapine significantly decreased NO production during a 30-minute oxygen-glucose deprivation/reperfusion (P < 0.01). The inhibitory effect of noscapine (4 μM) on intracellular Ca(2+) was greater than ionotropic glutamate receptors antagonists. Noscapine is protective against ischemia/reperfusion-induced excitotoxic injury in OLN-93 oligodendrocyte. This protective effect seems to be related to attenuation of intracellular Ca(2+) overload and NO production.

  5. Brief exposure to carbon monoxide preconditions cardiomyogenic cells against apoptosis in ischemia-reperfusion

    International Nuclear Information System (INIS)

    Kondo-Nakamura, Mihoko; Shintani-Ishida, Kaori; Uemura, Koichi; Yoshida, Ken-ichi

    2010-01-01

    We examined whether and how pretreatment with carbon monoxide (CO) prevents apoptosis of cardioblastic H9c2 cells in ischemia-reperfusion. Reperfusion (6 h) following brief ischemia (10 min) induced cytochrome c release, activation of caspase-9 and caspase-3, and apoptotic nuclear condensation. Brief CO pretreatment (10 min) or a caspase-9 inhibitor (Z-LEHD-FMK) attenuated these apoptotic changes. Ischemia-reperfusion increased phosphorylation of Akt at Ser472/473/474, and this was enhanced by CO pretreatment. A specific Akt inhibitor (API-2) blunted the anti-apoptotic effects of CO in reperfusion. In normoxic cells, CO enhanced O 2 - generation, which was inhibited by a mitochondrial complex III inhibitor (antimycin A) but not by a NADH oxidase inhibitor (apocynin). The CO-enhanced Akt phosphorylation was suppressed by an O 2 - scavenger (Tiron), catalase or a superoxide dismutase (SOD) inhibitor (DETC). These results suggest that CO pretreatment induces mitochondrial generation of O 2 - , which is then converted by SOD to H 2 O 2 , and subsequent Akt activation by H 2 O 2 attenuates apoptosis in ischemia-reperfusion.

  6. Brief exposure to carbon monoxide preconditions cardiomyogenic cells against apoptosis in ischemia-reperfusion

    Energy Technology Data Exchange (ETDEWEB)

    Kondo-Nakamura, Mihoko [Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Shintani-Ishida, Kaori, E-mail: kaori@m.u-tokyo.ac.jp [Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Uemura, Koichi; Yoshida, Ken-ichi [Department of Forensic Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)

    2010-03-12

    We examined whether and how pretreatment with carbon monoxide (CO) prevents apoptosis of cardioblastic H9c2 cells in ischemia-reperfusion. Reperfusion (6 h) following brief ischemia (10 min) induced cytochrome c release, activation of caspase-9 and caspase-3, and apoptotic nuclear condensation. Brief CO pretreatment (10 min) or a caspase-9 inhibitor (Z-LEHD-FMK) attenuated these apoptotic changes. Ischemia-reperfusion increased phosphorylation of Akt at Ser472/473/474, and this was enhanced by CO pretreatment. A specific Akt inhibitor (API-2) blunted the anti-apoptotic effects of CO in reperfusion. In normoxic cells, CO enhanced O{sub 2}{sup -} generation, which was inhibited by a mitochondrial complex III inhibitor (antimycin A) but not by a NADH oxidase inhibitor (apocynin). The CO-enhanced Akt phosphorylation was suppressed by an O{sub 2}{sup -} scavenger (Tiron), catalase or a superoxide dismutase (SOD) inhibitor (DETC). These results suggest that CO pretreatment induces mitochondrial generation of O{sub 2}{sup -}, which is then converted by SOD to H{sub 2}O{sub 2}, and subsequent Akt activation by H{sub 2}O{sub 2} attenuates apoptosis in ischemia-reperfusion.

  7. Hexokinase cellular trafficking in ischemia-reperfusion and ischemic preconditioning is altered in type I diabetic heart

    NARCIS (Netherlands)

    Gurel, Ebru; Ustunova, Savas; Kapucu, Aysegul; Yilmazer, Nadim; Eerbeek, Otto; Nederlof, Rianne; Hollmann, Markus W.; Demirci-Tansel, Cihan; Zuurbier, Coert J.

    2013-01-01

    Diabetes mellitus (DM) has been reported to alter the cardiac response to ischemia-reperfusion (IR). In addition, cardioprotection induced by ischemic preconditioning (IPC) is often impaired in diabetes. We have previously shown that the subcellular localisation of the glycolytic enzyme hexokinase

  8. Ischemia-reperfusion injury in rat fatty liver: role of nutritional status.

    Science.gov (United States)

    Caraceni, P; Nardo, B; Domenicali, M; Turi, P; Vici, M; Simoncini, M; De Maria, N; Trevisani, F; Van Thiel, D H; Derenzini, M; Cavallari, A; Bernardi, M

    1999-04-01

    Fatty livers are more sensitive to the deleterious effects of ischemia-reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia-reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers.

  9. Effect of olive leaf alcoholic extract on renal ischemia/reperfusion injury in adult male rats

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    mohammadreza nasirzade

    2014-05-01

    Full Text Available Ischemia-reperfusion (I/R is present at various degrees in kidney transplants. Several studies suggest that renal ischemia reperfusion (RIR can induce acute kidney injury.  Liver diseases and neurological disorders related to kidney injury is a common clinical problem. Olive leaf is a significant source of bioactive phenolic compounds. They have better antioxidant capacity, anti-inflammatory and radical scavenging. In this study 50 male rats were allocated randomly into 5 groups: control (intact animals, group-1(I/R 60min+olive leaf extract, group-2 (I/R 60min, group-3(I/R 120min+olive leaf extractand group-4(I/R 120min.The animals  received 100 mg/kg olive leaf extract in0.5 ml drinking water using gavage for 28 days. Other animals received 0.5 ml normal saline by gavages. At the end of the treatment, the level of antioxidant enzymes including TAC, MDA, SOD and GPX were determined in renal tissue. Administration of olive leaf extract can significantly increase activity of TAC, GPX and SOD in group1and 3compared with group2and4. Also, MDA level in renal tissue of treated groups was significantly lower than ischemia-reperfusion groups (p

  10. Neuroprotection of ebselen against ischemia/reperfusion injury involves GABA shunt enzymes.

    Science.gov (United States)

    Seo, Jeong Yeol; Lee, Choong Hyun; Cho, Jun Hwi; Choi, Jung Hoon; Yoo, Ki-Yeon; Kim, Dae Won; Park, Ok Kyu; Li, Hua; Choi, Soo Young; Hwang, In Koo; Won, Moo-Ho

    2009-10-15

    Seleno-organic compound, ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), is a substrate with radical-scavenging activity. In this study, we observed the neuroprotective effects of ebselen against ischemic damage and on GABA shunt enzymes such as glutamic acid decarboxylase 67 (GAD67), GABA transaminse (GABA-T) and succinic semialdehyde dehydrogenase (SSADH) in the hippocampal CA1 region after 5 min of transient forebrain ischemia in gerbils. For this, vehicle (physiological saline) or ebselen was administered 30 min before or after ischemia/reperfusion and sacrificed 4 days after ischemia/reperfusion. The administration of ebselen significantly reduced the neuronal death in the CA1 region induced by ischemia/reperfusion. In addition, treatment with ebselen markedly elevated GAD67, GABA-T and SSADH immunoreactivity and their protein levels compared to that in the vehicle-treated group, respectively. These results suggest that ebselen protects neurons from ischemic damage via control of the expressions of GABA shunt enzymes to enter the TCA cycle.

  11. Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy

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    Cheng Peng

    2018-05-01

    Full Text Available Background/Aims: Autophagy is essential for maintaining cellular homeostasis and the survival of terminally differentiated cells as neurons. In this study, we aim to investigate whether mitofusin 2, a mitochondrial fusion protein, mediates autophagy in cerebral ischemia/reperfusion (I/R injury. Methods: Primary cultured neurons were treated with oxygen-glucose deprivation/reperfusion to mimic cerebral I/R injury in vitro. Autophagosomes were visualized upon TEM. Autophagy-markers were then detected to monitor autophagy by western-blot and real-time PCR, and the autophagic flux was tracked with a mRFP-GFP-LC3 construct by fluorescence as well as autophagy inhibitors and agonists. The up- and downregulation of Mfn2 were through transfecting a lentivirusexpression vector respectively. And neuronal injury was detected by cell counting kit and TUNEL assay. Results: Results showed I/R increased autophagosome formation and inhibited autolysosome degradation. Furthermore, use of autophagy related agents demonstrated that I/R injury was caused by insufficient autophagy and aggravated by impaired autophagic degradation. The results also indicated that mitofusin 2 could ameliorate I/R injury through increasing autophagosome formation and promoting the fusion of autophagosomes and lysosomes. In contrast, downregulation of mitofusin 2 aggravated the I/R injury by inhibiting autophagosome formation and the fusion of autophagosomes and lysosomes. Additionly, mitofusin 2 overexpression did not lead to autolysosome accumulation induced by I/R. Conclusions: In summary, this study explicitly demonstrated that mitofusin 2 could ameliorate I/R injury mainly through promoting autophagy, which represented a potential novel strategy for neuroprotection against cerebral I/R damage.

  12. Blockade of Death Ligand TRAIL Inhibits Renal Ischemia Reperfusion Injury

    International Nuclear Information System (INIS)

    Adachi, Takaomi; Sugiyama, Noriyuki; Gondai, Tatsuro; Yagita, Hideo; Yokoyama, Takahiko

    2013-01-01

    Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). Many investigators have reported that cell death via apoptosis significantly contributed to the pathophysiology of renal IRI. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and induces apoptosis and inflammation. However, the role of TRAIL in renal IRI is unclear. Here, we investigated whether TRAIL contributes to renal IRI and whether TRAIL blockade could attenuate renal IRI. AKI was induced by unilateral clamping of the renal pedicle for 60 min in male FVB/N mice. We found that the expression of TRAIL and its receptors were highly upregulated in renal tubular cells in renal IRI. Neutralizing anti-TRAIL antibody or its control IgG was given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion. We found that TRAIL blockade inhibited tubular apoptosis and reduced the accumulation of neutrophils and macrophages. Furthermore, TRAIL blockade attenuated renal fibrosis and atrophy after IRI. In conclusion, our study suggests that TRAIL is a critical pathogenic factor in renal IRI, and that TRAIL could be a new therapeutic target for the prevention of renal IRI

  13. Prophylactic Treatment with Cerium Oxide Nanoparticles Attenuate Hepatic Ischemia Reperfusion Injury in Sprague Dawley Rats

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    Nandini D.P.K. Manne

    2017-07-01

    Full Text Available Background: Hepatic ischemia reperfusion is one the main causes for graft failure following transplantation. Although, the molecular events that lead to hepatic failure following ischemia reperfusion (IR are diverse and complex, previous studies have shown that excessive formation of reactive oxygen species (ROS are responsible for hepatic IR injury. Cerium oxide (CeO2 nanoparticles have been previously shown to act as an anti-oxidant and anti-inflammatory agent. Here, we evaluated the protective effects of CeO2 nanoparticles on hepatic ischemia reperfusion injury. Methods: Male Sprague Dawley rats were randomly assigned to one of the four groups: Control, CeO2 nanoparticle only, hepatic ischemia reperfusion (IR group and hepatic ischemia reperfusion (IR plus CeO2 nanoparticle group (IR+ CeO2. Partial warm hepatic ischemia was induced in left lateral and median lobes for 1h, followed by 6h of reperfusion. Animals were sacrificed after 6h of reperfusion and blood and tissue samples were collected and processed for various biochemical experiments. Results: Prophylactic treatment with CeO2 nanoparticles (0.5mg/kg i.v (IR+CeO2 group 1 hour prior to hepatic ischemia and subsequent reperfusion injury lead to a decrease in serum levels of alanine aminotransaminase and lactate dehydrogenase at 6 hours after reperfusion. These changes were accompanied by significant decrease in hepatocyte necrosis along with reduction in several serum inflammatory markers such as macrophage derived chemokine, macrophage inflammatory protein-2, KC/GRO, myoglobin and plasminogen activator inhibitor-1. However, immunoblotting demonstrated no significant changes in the levels of apoptosis related protein markers such as bax, bcl2 and caspase 3 in IR and IR+ CeO2 groups at 6 hours suggesting necrosis as the main pathway for hepatocyte death. Conclusion: Taken together, these data suggest that CeO2 nanoparticles attenuate IR induced cell death and can be used as a prophylactic

  14. Quantitative evaluation of 99mTc-GSA for fatty liver and ischemia-reperfusion injury in rats

    International Nuclear Information System (INIS)

    Kimoto, Mitsunori

    1996-01-01

    99m Tc-GSA (GSA) liver scintigraphy was performed in rats with fatty liver and ischemia-reperfusion injury to study the usefulness of GSA in evaluating these pathological processes. Fatty liver was produced by feeding rats a choline-deficient diet. The rats with fatty liver were divided into five groups according to the length of the diet (controls, two weeks, six weeks, 10 weeks, and 12 weeks). In the rats dieted for two weeks and six weeks, regional hepatic ischemia was also induced by clamping the left hepatic artery and the left portal vein for 10 minutes, then reperfusion was performed for 15 minutes. GSA was administered via the IVC. t 90 , or the time at which the liver time activity curve reached ninety percent of its peak value, was used as an index of GSA hepatic uptake, Ku and Kd, determined by two compartment analysis, were also used as indices. In rats of the fatty liver group, we confirmed microscopically that various degrees of fatty infiltration existed according to the diet period, and t 90 became significantly longer according to the severity of fatty infiltration. Ku and Kd also decreased according to the severity of fatty infiltration. In the rats with fatty infiltration and ischemia-reperfusion injury, t 90 also increased according to the severity of fatty infiltration, becoming longer than in the rats without ischemia-reperfusion injury. Quantitative analysis of GSA liver scintigraphy was useful for evaluating fatty liver and ischemia-reperfusion injury. (author)

  15. The effect of dexketoprofen on ischemia reperfusion injury.

    Science.gov (United States)

    Yildirim, Y; Karakaya, D; Kelsaka, E; Aksoy, A; Gülbahar, M Y; Bedir, A

    2014-01-01

    The purpose of this study was to demonstrate the effects of dexketoprofen on experimental ischemia/reperfusion injury induced in rat testicles. Twenty-four male Wistar albino-type rats were randomly separated into three groups. To develop testicular torsion, the right testicle was rotated 720° clockwise. After five hours of rotation, reperfusion was applied for 24 hours. The control group rats (Group C) had no procedures or treatments; basal numbers were used. Intraperitoneal 25 mg/kg dexketoprofen (1 cc) (Group D) or the same volume of serum physiologic (Group SP) were given to the Group D and Group SP rats 40 minutes before and 12 hours after detorsion. Twenty-four hours after detorsion, histopathological evaluation was performed by bilateral orchiectomy. Malondialdehyde (MDA) levels were detected in testicular tissue and in serum. Histopathologic changes in the spermatic cells of torsioned testicles in Group D were significantly less than those of Group SP (p dexketoprofen decreases I/R injury in both the torsion-formed testicle and the contralateral testicle. Thus, in patients who have urgent surgery for testicular detorsion, dexketoprofen can be preferred as an analgesic to reduce I/R injury. Further study is warranted to demonstrate this effect of dexketoprofen (Tab. 3, Fig. 1, Ref. 30).

  16. Protective Effects of Flavonoid Pomiferin on Heart Ischemia-Reperfusion

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    J. Nečas

    2007-01-01

    Full Text Available The objective of the present 15-day study was to evaluate the cardioprotective potential of flavonoid pomiferin isolated from the infructences of Maclura pomifera, Moraceae, against ischemia-reperfusion induced injury in rat hearts as a model of antioxidant-based composite therapy. Studies were performed with isolated, modifi ed Langendorff-perfused rat hearts and ischemia of heart was initiated by stopping the coronary flow for 30 min, followed by 60 min of reperfusion (14 ml min-1. Wistar rats were divided into three groups. The treated group received pomiferin (5 mg/kg/day in 0.5% Avicel; the placebo group received only 0.5% Avicel; the intact group was left without any applications. Biochemical indicators of oxidative damage, lipid peroxidation product malondialdehyde, antioxidant enzymes (superoxide dismutase, glutathione peroxidase, total antioxidant activity in serum and myocardium has been evaluated. We also examined the effect of pomiferin on cardiac function (left ventricular end-diastolic pressure, left ventricular pressure, peak positive +dP/dt (rate of pressure development after ischemia and reperfusion. Our results demonstrate that pomiferin attenuates the myocardial dysfunction provoked by ischemiareperfusion. This was confirmed by the increase in both the antioxidant enzyme values and the total antioxidant activity. The cardio-protection provided by pomiferin treatment results from the suppression of oxidative stress and correlates with the improved ventricular function.

  17. Bilirubin nanoparticle preconditioning protects against hepatic ischemia-reperfusion injury.

    Science.gov (United States)

    Kim, Jin Yong; Lee, Dong Yun; Kang, Sukmo; Miao, Wenjun; Kim, Hyungjun; Lee, Yonghyun; Jon, Sangyong

    2017-07-01

    Hepatic ischemia-reperfusion injury (IRI) remains a major concern in liver transplantation and resection, despite continuing efforts to prevent it. Accumulating evidence suggests that bilirubin possesses antioxidant, anti-inflammatory and anti-apoptotic properties. However, despite obvious potential health benefits of bilirubin, its clinical applications are limited by its poor solubility. We recently developed bilirubin nanoparticles (BRNPs) consisting of polyethylene glycol (PEG)-conjugated bilirubin. Here, we sought to investigate whether BRNPs protect against IRI in the liver by preventing oxidative stress. BRNPs exerted potent antioxidant and anti-apoptotic activity in primary hepatocytes exposed to hydrogen peroxide, a precursor of reactive oxygen species (ROS). In a model of hepatic IRI in mice, BRNP preconditioning exerted profound protective effects against hepatocellular injury by reducing oxidative stress, pro-inflammatory cytokine production, and recruitment of neutrophils. They also preferentially accumulated in IRI-induced inflammatory lesions. Collectively, our findings indicate that BRNP preconditioning provides a simple and safe approach that can be easily monitored in the blood like endogenous bilirubin, and could be a promising strategy to protect against IRI in a clinical setting. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Renoprotective effect of crocin following liver ischemia/ reperfusion injury in Wistar rats

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    Seyyed Ali Mard

    2017-10-01

    Full Text Available Objective(s: The objectives of the current study were to evaluate the effects of hepatic ‎ischemia/reperfusion (IR injury on the activity of antioxidant enzymes, biochemical factors, and ‎histopathological changes in rat kidney, and to investigate the effect of crocin on IR-‎related changes. Materials and Methods: Thirty-two male Wistar rats were randomly allocated into four groups (n=8. They were ‎sham-operated, IR, crocin pre-treatment, and crocin pretreatment+IR groups. Sham-operated ‎and Crocin pre-treatment groups received normal saline (N/S, 2 ml/day and crocin (200 mg/kg ‎for seven consecutive days intraperitoneally (IP, respectively, then rats underwent laparotomy, only. ‎IR and crocin pretreatment+IR groups received N/S and crocin with the same dose, time, and route, ‎respectively, then rats underwent partial (70% ischemia for 45 min that was followed by reperfusion ‎for 60 min. At the end of the experiment, kidney specimens were taken for histopathological and ‎antioxidant evaluations and also blood samples were obtained for biochemical analysis. Results: The results of the present study showed that crocin pre-treatment significantly increased ‎the activity of antioxidants, decreased the serum levels of liver enzymes and blood urea nitrogen ‎following IR-induced hepatic injury. Crocin also ameliorated kidney´s histopathological ‎disturbance beyond IR-induced hepatic injury. Conclusion: Crocin as an antioxidant agent protected renal insult following liver IR injury by ‎increasing the activity of antioxidant enzymes, reducing serum levels of liver enzymes, and ‎improving histopathological changes.‎

  19. Biological and Histopathological Investigations of Moclobemide on Injured Ovarian Tissue Following Induction of Ischemia-Reperfusion in Rats

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    Metin Ingec

    2012-01-01

    Full Text Available Background: The effects of moclobemide on damaged ovarian tissue induced by ischemia-reperfusion and damaged contralateral ovarian tissue were investigated in rats,biochemically and histologically.Materials and Methods: In this experimental study, 40 rats were equally divided intofour groups: 10 mg/kg moclobemide, 20 mg/kg moclobemide, ischemia/reperfusion control,and intact control groups. A 2-2.5-cm-long vertical incision was made in the lowerabdomen of each rat in order to reach the ovaries, after which a vascular clip was placedon the lower side of the right ovary of each animal in the two treatment groups and theischemia-reperfusion control group, but not in the healthy (intact control animal group.The purpose of this procedure was to create ischemia over the course of three hours, thenthe clips were unclamped to provide reperfusion for the next two hours. At the end ofthe two hours of reperfusion, all the animals were killed by high-dose anaesthesia andtheir ovaries were taken and subjected to histological and biochemical (malondialdehyde,nitric oxide, glutathione studies.Results: The obtained results showed that moclobemide suppressed nitric oxide andmalondialdehyde production in the ischemia - reperfusion damage area, and preventedthe decrease in endogenous antioxidant levels (glutathione in the rat ovariantissue. Moclobemide also prevented infiltration of leukocytes to the ovarian tissue.These results showed that moclobemide protected ovarian tissue against ischemiareperfusioninjury.Conclusion: This study shows that moclobemide represses malondialdehyde and nitricoxide production in the rat ovarian tissue subjected to ischemia-reperfusion injury andkeeps the endogenous antioxidant glutathione level from decreasing. Moclobemide alsoinhibits leukocytic migration into ovarian tissue following ischemia-reperfusion injury.From these results, it is suggested that moclobemide can be used in the treatment of ovarianischemia-reperfusion injury.

  20. EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages

    International Nuclear Information System (INIS)

    Gu, Da-min; Lu, Pei-Hua; Zhang, Ke; Wang, Xiang; Sun, Min; Chen, Guo-Qian; Wang, Qiong

    2015-01-01

    In this study, we tested the potential role of astragaloside IV (AS-IV) against oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damages in murine cortical neurons, and studied the associated signaling mechanisms. AS-IV exerted significant neuroprotective effects against OGD/R by reducing reactive oxygen species (ROS) accumulation, thereby attenuating oxidative stress and neuronal cell death. We found that AS-IV treatment in cortical neurons resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by Nrf2 Ser-40 phosphorylation, and its nuclear localization, as well as transcription of antioxidant-responsive element (ARE)-regulated genes: heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1) and sulphiredoxin 1 (SRXN-1). Knockdown of Nrf2 through lentiviral shRNAs prevented AS-IV-induced ARE genes transcription, and abolished its anti-oxidant and neuroprotective activities. Further, we discovered that AS-IV stimulated heparin-binding-epidermal growth factor (HB-EGF) release to trans-activate epidermal growth factor receptor (EGFR) in cortical neurons. Blockage or silencing EGFR prevented Nrf2 activation by AS-IV, thus inhibiting AS-IV-mediated anti-oxidant and neuroprotective activities against OGD/R. In summary, AS-IV protects cortical neurons against OGD/R damages through activating of EGFR-Nrf2 signaling. - Highlights: • Pre-treatment of astragaloside IV (AS-IV) protects murine cortical neurons from OGD/R. • AS-IV activates Nrf2-ARE signaling in murine cortical neurons. • Nrf2 is required for AS-IV-mediated anti-oxidant and neuroprotective activities. • AS-IV stimulates HB-EGF release to trans-activate EGFR in murine cortical neurons. • EGFR mediates AS-IV-induced Nrf2 activation and neuroprotection against OGD/R

  1. EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages

    Energy Technology Data Exchange (ETDEWEB)

    Gu, Da-min [Department of Anesthesiology, Affiliated Yixing People' s Hospital, Jiangsu University, Yixing (China); Lu, Pei-Hua, E-mail: lphty1_1@163.com [Department of Medical Oncology, Wuxi People' s Hospital Affiliated to Nanjing Medical University, Wuxi (China); Zhang, Ke; Wang, Xiang [Department of Anesthesiology, Affiliated Yixing People' s Hospital, Jiangsu University, Yixing (China); Sun, Min [Department of General Surgery, Affiliated Yixing People' s Hospital, Jiangsu University, Yixing (China); Chen, Guo-Qian [Department of Clinical Laboratory, Wuxi People' s Hospital Affiliated to Nanjing Medical University, Wuxi (China); Wang, Qiong, E-mail: WangQiongprof1@126.com [Department of Clinical Laboratory, Wuxi People' s Hospital Affiliated to Nanjing Medical University, Wuxi (China)

    2015-02-13

    In this study, we tested the potential role of astragaloside IV (AS-IV) against oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damages in murine cortical neurons, and studied the associated signaling mechanisms. AS-IV exerted significant neuroprotective effects against OGD/R by reducing reactive oxygen species (ROS) accumulation, thereby attenuating oxidative stress and neuronal cell death. We found that AS-IV treatment in cortical neurons resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by Nrf2 Ser-40 phosphorylation, and its nuclear localization, as well as transcription of antioxidant-responsive element (ARE)-regulated genes: heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1) and sulphiredoxin 1 (SRXN-1). Knockdown of Nrf2 through lentiviral shRNAs prevented AS-IV-induced ARE genes transcription, and abolished its anti-oxidant and neuroprotective activities. Further, we discovered that AS-IV stimulated heparin-binding-epidermal growth factor (HB-EGF) release to trans-activate epidermal growth factor receptor (EGFR) in cortical neurons. Blockage or silencing EGFR prevented Nrf2 activation by AS-IV, thus inhibiting AS-IV-mediated anti-oxidant and neuroprotective activities against OGD/R. In summary, AS-IV protects cortical neurons against OGD/R damages through activating of EGFR-Nrf2 signaling. - Highlights: • Pre-treatment of astragaloside IV (AS-IV) protects murine cortical neurons from OGD/R. • AS-IV activates Nrf2-ARE signaling in murine cortical neurons. • Nrf2 is required for AS-IV-mediated anti-oxidant and neuroprotective activities. • AS-IV stimulates HB-EGF release to trans-activate EGFR in murine cortical neurons. • EGFR mediates AS-IV-induced Nrf2 activation and neuroprotection against OGD/R.

  2. Effect Of Ischemia-Reperfusion On Healing In Intestinal Anastomosis ...

    African Journals Online (AJOL)

    The effect of reperfusion injury on the healing of intestinal anastomotic wound directly subjected to ischemia-reperfusion stress was investigated in dogs. Three groups of dogs were utilized for the study. In group A (Control) cranial mesenteric artery and collateral blood supply were isolated but not occluded. In groups B and ...

  3. Mechanism of Mitochondrial Connexin43′s Protection of the Neurovascular Unit under Acute Cerebral Ischemia-Reperfusion Injury

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    Shuai Hou

    2016-05-01

    Full Text Available We observed mitochondrial connexin43 (mtCx43 expression under cerebral ischemia-reperfusion (I/R injury, analyzed its regulation, and explored its protective mechanisms. Wistar rats were divided into groups based on injections received before middle cerebral artery occlusion (MCAO. Cerebral infarction volume was detected by 2,3,5-triphenyltetrazolim chloride staining, and cell apoptosis was observed by transferase dUTP nick end labeling. We used transmission electron microscopy to observe mitochondrial morphology and determined superoxide dismutase (SOD activity and malondialdehyde (MDA content. MtCx43, p-mtCx43, protein kinase C (PKC, and p-PKC expression were detected by Western blot. Compared with those in the IR group, cerebral infarction volumes in the carbenoxolone (CBX and diazoxide (DZX groups were obviously smaller, and the apoptosis indices were down-regulated. Mitochondrial morphology was damaged after I/R, especially in the IR and 5-hydroxydecanoic acid (5-HD groups. Similarly, decreased SOD activity and increased MDA were observed after MCAO; CBX, DZX, and phorbol-12-myristate-13-acetate (PMA reduced mitochondrial functional injury. Expression of mtCx43 and p-mtCx43 and the p-Cx43/Cx43 ratio were significantly lower in the IR group than in the sham group. These abnormalities were ameliorated by CBX, DZX, and PMA. MtCx43 may protect the neurovascular unit from acute cerebral IR injury via PKC activation induced by mitoKATP channel agonists.

  4. Effectiveness of sugammadex for cerebral ischemia/reperfusion injury.

    Science.gov (United States)

    Ozbilgin, Sule; Yılmaz, Osman; Ergur, Bekir Ugur; Hancı, Volkan; Ozbal, Seda; Yurtlu, Serhan; Gunenc, Sakize Ferim; Kuvaki, Bahar; Kucuk, Burcu Ataseven; Sisman, Ali Rıza

    2016-06-01

    Cerebral ischemia may cause permanent brain damage and behavioral dysfunction. The efficacy and mechanisms of pharmacological treatments administered immediately after cerebral damage are not fully known. Sugammadex is a licensed medication. As other cyclodextrins have not passed the necessary phase tests, trade preparations are not available, whereas sugammadex is frequently used in clinical anesthetic practice. Previous studies have not clearly described the effects of the cyclodextrin family on cerebral ischemia/reperfusion (I/R) damage. The aim of this study was to determine whether sugammadex had a neuroprotective effect against transient global cerebral ischemia. Animals were assigned to control, sham-operated, S 16 and S 100 groups. Transient global cerebral ischemia was induced by 10-minute occlusion of the bilateral common carotid artery, followed by 24-hour reperfusion. At the end of the experiment, neurological behavior scoring was performed on the rats, followed by evaluation of histomorphological and biochemical measurements. Sugammadex 16 mg/kg and 100 mg/kg improved neurological outcome, which was associated with reductions in both histological and neurological scores. The hippocampus TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and caspase results in the S 16 and S 100 treatment groups were significantly lower than those of the I/R group. Neurological scores in the treated groups were significantly higher than those of the I/R group. The study showed that treatment with 16 mg/kg and 100 mg/kg sugammadex had a neuroprotective effect in a transient global cerebral I/R rat model. However, 100 mg/kg sugammadex was more neuroprotective in rats. Copyright © 2016. Published by Elsevier Taiwan.

  5. Effectiveness of sugammadex for cerebral ischemia/reperfusion injury

    Directory of Open Access Journals (Sweden)

    Sule Ozbilgin

    2016-06-01

    Full Text Available Cerebral ischemia may cause permanent brain damage and behavioral dysfunction. The efficacy and mechanisms of pharmacological treatments administered immediately after cerebral damage are not fully known. Sugammadex is a licensed medication. As other cyclodextrins have not passed the necessary phase tests, trade preparations are not available, whereas sugammadex is frequently used in clinical anesthetic practice. Previous studies have not clearly described the effects of the cyclodextrin family on cerebral ischemia/reperfusion (I/R damage. The aim of this study was to determine whether sugammadex had a neuroprotective effect against transient global cerebral ischemia. Animals were assigned to control, sham-operated, S 16 and S 100 groups. Transient global cerebral ischemia was induced by 10-minute occlusion of the bilateral common carotid artery, followed by 24-hour reperfusion. At the end of the experiment, neurological behavior scoring was performed on the rats, followed by evaluation of histomorphological and biochemical measurements. Sugammadex 16 mg/kg and 100 mg/kg improved neurological outcome, which was associated with reductions in both histological and neurological scores. The hippocampus TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling and caspase results in the S 16 and S 100 treatment groups were significantly lower than those of the I/R group. Neurological scores in the treated groups were significantly higher than those of the I/R group. The study showed that treatment with 16 mg/kg and 100 mg/kg sugammadex had a neuroprotective effect in a transient global cerebral I/R rat model. However, 100 mg/kg sugammadex was more neuroprotective in rats.

  6. Melatonin Protective Effects against Liver Ischemia/Reperfusion Injury

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    Abbas Khonakdar-Tarsi

    2016-02-01

    Full Text Available Hepatic ischemia-reperfusion (I/R is a common phenomenon during liver surgery, transplantation, infection and trauma which results in damage and necrosis of the hepatic tissue through different pathways. Mechanisms involved in I/R damage are very intricate and cover several aspects. Several factors are involved in I/R-induced damages; briefly, decrease in sinusoidal perfusion and ATP generation because of low or no O2 supply, increase in production of reactive oxygen species (ROS and inflammatory factors and destruction of parenchymal cells resulted by these molecules are of the main causes of liver tissue injury during reperfusion. Melatonin’s antioxidant effect, and regulatory roles in the expression of different genes in the I/R insulted liver have been investigated by several studies. Melatonin and its metabolites are of the powerful direct scavengers of free radicals and ROS, so it can directly protect liver cell impairment from oxidative stress following I/R. In addition, this bioactive molecule up-regulates anti-oxidant enzyme genes like superoxide dismutase (SOD, glutathione peroxidase (GSH-Px and catalase (CAT. Tumor necrosis factors (TNF-α and interleukin-1 (IL-1, as potent pro-inflammatory factors, are generated in huge amounts during reperfusion. Melatonin is able to alleviate TNF-α generation and has hepatoprotective effect during I/R. It reduces the production of pro-inflammatory cytokines and chemokines via reducing the binding of NF-κB to DNA. Imbalance between vasodilators (nitric oxide, NO and vasoconstrictors (endothelin, ET during I/R was shown to be the primary cause of liver microcirculation disturbance. Melatonin helps maintaining the stability of liver circulation and reduces hepatic injury during I/R through preventing alteration of the normal balance between ET and NO. The aim of this review was to explore the mechanisms of liver I/R injuries and the protective effects of melatonin against them.

  7. Pomegranate extract protects against cerebral ischemia/reperfusion injury and preserves brain DNA integrity in rats.

    Science.gov (United States)

    Ahmed, Maha A E; El Morsy, Engy M; Ahmed, Amany A E

    2014-08-21

    Interruption to blood flow causes ischemia and infarction of brain tissues with consequent neuronal damage and brain dysfunction. Pomegranate extract is well tolerated, and safely consumed all over the world. Interestingly, pomegranate extract has shown remarkable antioxidant and anti-inflammatory effects in experimental models. Many investigators consider natural extracts as novel therapies for neurodegenerative disorders. Therefore, this study was carried out to investigate the protective effects of standardized pomegranate extract against cerebral ischemia/reperfusion-induced brain injury in rats. Adult male albino rats were randomly divided into sham-operated control group, ischemia/reperfusion (I/R) group, and two other groups that received standardized pomegranate extract at two dose levels (250, 500 mg/kg) for 15 days prior to ischemia/reperfusion (PMG250+I/R, and PMG500+I/R groups). After I/R or sham operation, all rats were sacrificed and brains were harvested for subsequent biochemical analysis. Results showed reduction in brain contents of MDA (malondialdehyde), and NO (nitric oxide), in addition to enhancement of SOD (superoxide dismutase), GPX (glutathione peroxidase), and GRD (glutathione reductase) activities in rats treated with pomegranate extract prior to cerebral I/R. Moreover, pomegranate extract decreased brain levels of NF-κB p65 (nuclear factor kappa B p65), TNF-α (tumor necrosis factor-alpha), caspase-3 and increased brain levels of IL-10 (interleukin-10), and cerebral ATP (adenosine triphosphate) production. Comet assay showed less brain DNA (deoxyribonucleic acid) damage in rats protected with pomegranate extract. The present study showed, for the first time, that pre-administration of pomegranate extract to rats, can offer a significant dose-dependent neuroprotective activity against cerebral I/R brain injury and DNA damage via antioxidant, anti-inflammatory, anti-apoptotic and ATP-replenishing effects. Copyright © 2014 Elsevier Inc

  8. A vigilant, hypoxia-regulated heme oxygenase-1 gene vector in the heart limits cardiac injury after ischemia-reperfusion in vivo.

    Science.gov (United States)

    Tang, Yao Liang; Qian, Keping; Zhang, Y Clare; Shen, Leping; Phillips, M Ian

    2005-12-01

    The effect of a cardiac specific, hypoxia-regulated, human heme oxygenase-1 (hHO-1) vector to provide cardioprotection from ischemia-reperfusion injury was assessed. When myocardial ischemia and reperfusion is asymptomatic, the damaging effects are cumulative and patients miss timely treatment. A gene therapy approach that expresses therapeutic genes only when ischemia is experienced is a desirable strategy. We have developed a cardiac-specific, hypoxia-regulated gene therapy "vigilant vector'' system that amplifies cardioprotective gene expression. Vigilant hHO-1 plasmids, LacZ plasmids, or saline (n = 40 per group) were injected into mouse heart 2 days in advance of ischemia-reperfusion injury. Animals were exposed to 60 minutes of ischemia followed by 24 hours of reperfusion. For that term (24 hours) effects, the protein levels of HO-1, inflammatory responses, apoptosis, and infarct size were determined. For long-term (3 week) effects, the left ventricular remodeling and recovery of cardiac function were assessed. Ischemia-reperfusion resulted in a timely overexpression of HO-1 protein. Infarct size at 24 hours after ischemia-reperfusion was significantly reduced in the HO-1-treated animals compared with the LacZ-treated group or saline-treated group (P < .001). The reduction of infarct size was accompanied by a decrease in lipid peroxidant activity, inflammatory cell infiltration, and proapoptotic protein level in ischemia-reperfusion-injured myocardium. The long-term study demonstrated that timely, hypoxia-induced HO-1 overexpression is beneficial in conserving cardiac function and attenuating left ventricle remodelling. The vigilant HO-1 vector provides a protective therapy in the heart for reducing cellular damage during ischemia-reperfusion injury and preserving heart function.

  9. The role of calcium in modulating the reactivity of the smooth muscle cells during ischemia/reperfusion. Part 2

    Directory of Open Access Journals (Sweden)

    Katarzyna Szadujkis-Szadurska

    2010-04-01

    Full Text Available Background:Damage of transplanted organs during reperfusion is still a problem that prompts the search for new drugs able to diminish the risk of graft rejection. The aim of this study was to examine the influence of antioxidant system on the contraction of arteries induced by angiotensin II during ischemia/reperfusion and to determine the role of intracellular and extracellular calcium ions under these conditions.Material/Methods:The experiments were performed on male Wistar rats’ tail arteries. The effects of angiotensin II on vascular tone were examined after ischemia/reperfusion in the presence of catalase or aminotriazole. To determine the role of intracellular and extracellular Ca[sup]2 [/sup], the experiments were performed in Ca[sup]2 [/sup]-free PSS and PSS.Results:Angiotensin II increased perfusion pressure in both Ca[sup]2 [/sup]-free PSS and PSS. After ischemia, the reactions induced by angiotensin II were lower, while after reperfusion they were higher. In the presence of catalase the effects induced by angiotensin II were lower and in the presence of aminotriazole higher.Conclusions:Ischemia inhibits and reperfusion augments the perfusion pressure induced by angiotensin II. The results confirm the vasoprotective effect of catalase and the destructive influence of aminotriazole in modulating the reactions of vascular smooth muscle cells to ANG II after ischemia/reperfusion. These results suggest that the antioxidant system plays a role in modulating the reactions induced by angiotensin II after ischemia/reperfusion and that reperfusion disturbs the balance between antioxidants and the production of reactive oxygen species.

  10. Cardioprotective Effects of Quercetin in Cardiomyocyte under Ischemia/Reperfusion Injury

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    Yi-Wen Chen

    2013-01-01

    Full Text Available Quercetin, a polyphenolic compound existing in many vegetables, fruits, has antiinflammatory, antiproliferation, and antioxidant effect on mammalian cells. Quercetin was evaluated for protecting cardiomyocytes from ischemia/reperfusion injury, but its protective mechanism remains unclear in the current study. The cardioprotective effects of quercetin are achieved by reducing the activity of Src kinase, signal transducer and activator of transcription 3 (STAT3, caspase 9, Bax, intracellular reactive oxygen species production, and inflammatory factor and inducible MnSOD expression. Fluorescence two-dimensional differential gel electrophoresis (2D-DIGE and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS can reveal the differentially expressed proteins of H9C2 cells treated with H2O2 or quercetin. Although 17 identified proteins were altered in H2O2-induced cells, these proteins such as alpha-soluble NSF attachment protein (α-SNAP, Ena/VASP-like protein (Evl, and isopentenyl-diphosphate delta-isomerase 1 (Idi-1 were reverted by pretreatment with quercetin, which correlates with kinase activation, DNA repair, lipid, and protein metabolism. Quercetin dephosphorylates Src kinase in H2O2-induced H9C2 cells and likely blocks the H2O2-induced inflammatory response through STAT3 kinase modulation. This probably contributes to prevent ischemia/reperfusion injury in cardiomyocytes.

  11. The calcium-binding protein complex S100A8/A9 has a crucial role in controlling macrophage-mediated renal repair following ischemia/reperfusion

    NARCIS (Netherlands)

    Dessing, Mark C.; Tammaro, Alessandra; Pulskens, Wilco P.; Teske, Gwendoline J.; Butter, Loes M.; Claessen, Nike; van Eijk, Marco; van der Poll, Tom; Vogl, Thomas; Roth, Johannes; Florquin, Sandrine; Leemans, Jaklien C.

    2015-01-01

    Upon ischemia/reperfusion (I/R)-induced injury, several damage-associated molecular patterns are expressed including the calcium-binding protein S100A8/A9 complex. S100A8/A9 can be recognized by Toll-like receptor-4 and its activation is known to deleteriously contribute to renal I/R-induced injury.

  12. Roles for C-X-C chemokines and C5a in lung injury after hindlimb ischemia-reperfusion

    DEFF Research Database (Denmark)

    Bless, N M; Warner, R L; Padgaonkar, V A

    1999-01-01

    We evaluated the roles of the C-X-C chemokines cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) as well as the complement activation product C5a in development of lung injury after hindlimb ischemia-reperfusion in rats. During reperfusion, CD11b...... and CD18, but not CD11a, were upregulated on neutrophils [bronchoalveolar lavage (BAL) and blood] and lung macrophages. BAL levels of CINC and MIP-2 were increased during the ischemic and reperfusion periods. Treatment with either anti-CINC or anti-MIP-2 IgG significantly reduced lung vascular......, 58, and 23%, respectively (P MIP-2 as well as the complement activation product C5a are required for lung neutrophil recruitment and full induction of lung injury after hindlimb ischemia-reperfusion in rats....

  13. Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury.

    Science.gov (United States)

    Godar, Rebecca J; Ma, Xiucui; Liu, Haiyan; Murphy, John T; Weinheimer, Carla J; Kovacs, Attila; Crosby, Seth D; Saftig, Paul; Diwan, Abhinav

    2015-01-01

    Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from in-vivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEB-mediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fasting-induced autophagy in myocardial ischemia-reperfusion injury.

  14. Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

    Science.gov (United States)

    Godar, Rebecca J; Ma, Xiucui; Liu, Haiyan; Murphy, John T; Weinheimer, Carla J; Kovacs, Attila; Crosby, Seth D; Saftig, Paul; Diwan, Abhinav

    2015-01-01

    Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from in-vivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEB-mediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fasting-induced autophagy in myocardial ischemia-reperfusion injury. PMID:26103523

  15. Bicarbonate modulates oxidative and functional damage in ischemia-reperfusion.

    Science.gov (United States)

    Queliconi, Bruno B; Marazzi, Thire B M; Vaz, Sandra M; Brookes, Paul S; Nehrke, Keith; Augusto, Ohara; Kowaltowski, Alicia J

    2013-02-01

    The carbon dioxide/bicarbonate (CO(2)/HCO(3)(-)) pair is the main biological pH buffer. However, its influence on biological processes, and in particular redox processes, is still poorly explored. Here we study the effect of CO(2)/HCO(3)(-) on ischemic injury in three distinct models (cardiac HL-1 cells, perfused rat heart, and Caenorhabditis elegans). We found that, although various concentrations of CO(2)/HCO(3)(-) do not affect function under basal conditions, ischemia-reperfusion or similar insults in the presence of higher CO(2)/HCO(3)(-) resulted in greater functional loss associated with higher oxidative damage in all models. Because the effect of CO(2)/HCO(3)(-) was observed in all models tested, we believe this buffer is an important determinant of oxidative damage after ischemia-reperfusion. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Hypercholesterolemia aggravates myocardial ischemia reperfusion injury via activating endoplasmic reticulum stress-mediated apoptosis.

    Science.gov (United States)

    Wu, Nan; Zhang, Xiaowen; Jia, Pengyu; Jia, Dalin

    2015-12-01

    The effect of hypercholesterolemia on myocardial ischemia reperfusion injury (MIRI) is in controversy and the underlying mechanism is still not well understood. In the present study, we firstly detected the effects of hypercholesterolemia on MIRI and the role of endoplasmic reticulum (ER) stress-mediated apoptosis pathway in this process. The infarct size was determined by TTC staining, and apoptosis was measured by the TUNEL method. The marker proteins of ER stress response and ER stress-mediated apoptosis pathway were detected by Western blot. The results showed that high cholesterol diet-induced hypercholesterolemia significantly increased the myocardial infarct size, the release of myocardium enzyme and the ratio of apoptosis, but did not affect the recovery of cardiac function. Moreover, hypercholesterolemia also remarkably up-regulated the expressions of ER stress markers (glucose-regulated protein 78 and calreticulin) and critical molecules in ER stress-mediated apoptosis pathway (CHOP, caspase 12, phospho-JNK). In conclusion, our study demonstrated that hypercholesterolemia enhanced myocardial vulnerability/sensitivity to ischemia reperfusion injury involved in aggravation the ER stress and activation of ER stress-mediated apoptosis pathway and it gave us a new insight into the underlying mechanisms associated with hypercholesterolemia-induced exaggerated MIRI and also provided a novel target for preventing MIRI in the presence of hypercholesterolemia. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Loss of PINK1 increases the heart's vulnerability to ischemia-reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Hilary K Siddall

    Full Text Available Mutations in PTEN inducible kinase-1 (PINK1 induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson's disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI by preventing mitochondrial dysfunction.Over-expressing PINK1 in HL-1 cardiac cells reduced cell death following simulated IRI (29.2±5.2% PINK1 versus 49.0±2.4% control; N = 320 cells/group P5 animals/group; P<0.05. Cardiomyocytes isolated from PINK1-/- hearts had a lower resting mitochondrial membrane potential, had inhibited mitochondrial respiration, generated more oxidative stress during simulated IRI, and underwent rigor contracture more rapidly in response to an uncoupler when compared to PINK1+/+ cells suggesting mitochondrial dysfunction in hearts deficient in PINK1.We show that the loss of PINK1 increases the heart's vulnerability to ischemia-reperfusion injury. This may be due, in part, to increased mitochondrial dysfunction. These findings implicate PINK1 as a novel target for cardioprotection.

  18. The protective effects of tadalafil on renal damage following ischemia reperfusion injury in rats

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    Bulent Erol

    2015-09-01

    Full Text Available Ischemia-reperfusion injury can cause renal damage, and phosphodiesterase inhibitors are reported to regulate antioxidant activity. We investigated the prevention of renal damage using tadalafil after renal ischemia reperfusion (I/R injury in rats. A total of 21 adult male Wistar albino rats were randomly divided into three groups of seven, including Group 1-control, Group 2-I/R, and Group 3-tadalafil + I/R group (I/R-T group received tadalafil intraperitoneally at 30 minutes before ischemia. Inducible nitric oxide synthase, endothelial nitric oxide synthase, malondialdehyde, and total antioxidant capacity levels were evaluated, and histopathological changes and apoptosis in the groups were examined. Tadalafil decreased malondialdehyde levels in the I/R group and increased the total antioxidant capacity level. Histopathological and immunohistochemical findings revealed that tadalafil decreased renal injury scores and the ratios of injured cells, as measured through apoptotic protease activating factor 1, inducible nitric oxide synthase, and endothelial nitric oxide synthase levels. We suggest that tadalafil has protective effects against I/R-related renal tissue injury.

  19. Protective Effect of SGK1 in Rat Hippocampal Neurons Subjected to Ischemia Reperfusion

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    Wei Zhang

    2014-07-01

    Full Text Available Background/Aims: To investigate the protective effect of SGK1 (serum- and glucocorticoid-inducible protein kinase 1 in rat hippocampal neurons in vitro and in vivo following ischemia reperfusion (I/R. Methods: Isolated rat hippocampal neurons were subjected to 2 h of oxygen and glucose deprivation (OGD then returned to normoxic conditions for 10, 30 or 60 min. Cell apoptosis and protein expression of SGK1 were analyzed. To examine SGK1 function, we overexpressed SGK1 in rat hippocampal neurons. Finally we examined the involvement of PI3K/Akt/GSK3β signaling by treating the cells (untransfected or transfected with expression vector encoding SGK1 with the PI3K inhibitor LY294002. Findings were confirmed in vivo in a rat model of middle cerebral artery occlusion. Results: I/R caused a time-dependent increase in apoptosis, both in vitro and in vivo. SGK1 protein levels decreased significantly under the same conditions. Overexpression of SGK1 reduced apoptosis following OGD or I/R compared to cells transfected with empty vector and subjected to the same treatment, or sham-operated animals. Addition of LY294002 revealed that the action of SGK1 in suppressing apoptosis was mediated by the PI3K/Akt/GSK3β pathway. Conclusion: SGK1 plays a protective role in ischemia reperfusion in rat hippocampal neurons, exerting its effects via the PI3K/Akt/GSK3β pathway.

  20. Comparison of the Protective Effects of Erythropoietin and Melatonin on Renal Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Banaei, Shokofeh; Ahmadiasl, Nasser; Alihemmati, Alireza

    2016-07-01

    Renal ischemia-reperfusion (IR) contributes to the development of acute renal failure (ARF). Oxygen free radicals are considered to be the principal components involved in the pathophysiological tissue alterations observed during renal IR. In this study, we compared the effects of melatonin (MEL) and erythropoietin (EPO), both known antioxidant and anti-inflammatory agents, on IR-induced renal injury in rats. Wistar albino rats were unilaterally nephrectomized and then subjected to 45 minutes of renal pedicle occlusion followed by 24 hours of reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to the onset of ischemia. After 24 hours of reperfusion and following decapitation, blood samples were collected for the determination of the hemoglobin (Hb) and hematocrit (Hct) levels. Additionally, renal samples were taken for histological evaluation. Ischemia-reperfusion significantly decreased the observed Hb and Hct values. The histopathological findings in the IR group confirmed that there was an increase in the hyaline cast and thickening of the Bowman capsule basement membrane. Treatment with EPO or MEL significantly increased the Hb and Hct values. In the MEL + IR group, the histopathological changes were lower than those found in the EPO + IR group. Treatment with EPO and MEL had a beneficial effect on renal IR injury. The results may also indicate that MEL protects against morphological damage better than EPO in renal IR injury.

  1. Curcumin and dexmedetomidine prevents oxidative stress and renal injury in hind limb ischemia/reperfusion injury in a rat model.

    Science.gov (United States)

    Karahan, M A; Yalcin, S; Aydogan, H; Büyükfirat, E; Kücük, A; Kocarslan, S; Yüce, H H; Taskın, A; Aksoy, N

    2016-06-01

    Curcumin and dexmedetomidine have been shown to have protective effects in ischemia-reperfusion injury on various organs. However, their protective effects on kidney tissue against ischemia-reperfusion injury remain unclear. We aimed to determine whether curcumin or dexmedetomidine prevents renal tissue from injury that was induced by hind limb ischemia-reperfusion in rats. Fifty rats were divided into five groups: sham, control, curcumin (CUR) group (200 mg/kg curcumin, n = 10), dexmedetomidine (DEX) group (25 μg/kg dexmedetomidine, n = 10), and curcumin-dexmedetomidine (CUR-DEX) group (200 mg/kg curcumin and 25 μg/kg dexmedetomidine). Curcumin and dexmedetomidine were administered intraperitoneally immediately after the end of 4 h ischemia, just 5 min before reperfusion. The extremity re-perfused for 2 h and then blood samples were taken and total antioxidant capacity (TAC), total oxidative status (TOS) levels, and oxidative stress index (OSI) were measured, and renal tissue samples were histopathologically examined. The TAC activity levels in blood samples were significantly lower in the control than the other groups (p OSI were found to be significantly increased in the control group compared to others groups (p model.

  2. Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy

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    Ming-Shuo Sun

    2018-01-01

    Full Text Available Acute ischemic stroke is a common cause of morbidity and mortality worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes. Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury has been found to play a key role in the process. Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death. Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier. In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage. This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage.

  3. Repetitive postprandial hyperglycemia increases cardiac ischemia/reperfusion injury: prevention by the alpha-glucosidase inhibitor acarbose.

    Science.gov (United States)

    Frantz, Stefan; Calvillo, Laura; Tillmanns, Jochen; Elbing, Inka; Dienesch, Charlotte; Bischoff, Hilmar; Ertl, Georg; Bauersachs, Johann

    2005-04-01

    Protective effects of the alpha-glucosidase inhibitor acarbose have been reported for various diabetic complications. In the STOP-NIDDM study, even patients without overt diabetes, but with impaired glucose tolerance, had a reduction in cardiovascular events when treated with acarbose. Therefore, we investigated the effect of repetitive postprandial hyperglycemia on the cardiac ischemia/reperfusion injury in vivo. Mice were treated daily by single applications of placebo, sucrose (4 g/kg body weight), or sucrose + acarbose (10 mg/kg body weight) by gavage for 7 days. Acarbose treatment significantly reduced the sucrose-induced increase in plasma glucose concentration. Subsequently, animals underwent 30 min of ischemia by coronary artery ligation and 24 h of reperfusion in vivo. In the sucrose group, ischemia/reperfusion damage was significantly increased (infarct/area at risk, placebo vs. sucrose, 38.8+/-7.5% vs. 62.2+/-4.8%, P<0.05). This was prevented by acarbose treatment (infarct/area at risk 30.7+/-7.2%). While myocardial inflammation was similar in all groups, oxidative stress as indicated by a significant increase in lipid peroxides was enhanced in the sucrose, but not in the sucrose + acarbose group. In summary, repetitive postprandial hyperglycemia increases ischemia/reperfusion damage. This effect can be prevented by treatment with the alpha-glucosidase inhibitor acarbose.

  4. Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

    2017-09-01

    A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

  5. The Protective Effect of Curcumin versus Sodium Nitroprusside on Intestinal Ischemia/Reperfusion Injury

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    Dalia M Saleh

    2014-04-01

    Full Text Available Objective: Intestinal ischemia/reperfusion (I/R injury is a signi and #64257;cant complication in abdominal vascular surgery. Various treatment modalities have been applied, however, the role of nitric oxide (NO in this type of injury is still controversial. Aim of the work: To compare the protective effect of curcumin vs sodium nitroprusside (SNP, NO donor on intestine and remote organs following intestinal I/R injury. Methods: Rats were divided into 4 groups (sham-control, I/R, curcumin+I/R, SNP+I/R. I/R was induced by 30 min clamping the superior mesenteric artery (SMA then 60 min reperfusion. Rats were pretreated with either curcumin (80 mg/kg/day with food for one week or SNP (5 mg/kg, i.p prior to I/R. Intestinal levels of malondialdehyde (MDA, Nitrite/nitrate, superoxide dismutase (SOD and reduced glutathione (GSH were measured. The sections from jejunum, lungs and liver were stained with hematoxylin and eosin (H and E for histopathological examination. Immunohistochemical stains for eNOS expression in the jejunum and cleaved caspase-3 for apoptosis in the lungs and liver were done. Results: I/R resulted in both local and remote organs in and #64258;ammation associated with signi and #64257;cant increase in MDA and nitrate/nitrite and significant decrease in SOD and GSH levels. These histological and biochemical changes were improved by pretreatment with curcumin and to less extent by SNP. Immunohistochemical examination showed significant decrease in eNOS activity in the I/R group which was improved by curcumin pretreatment not by SNP. Liver apoptosis was improved by curcumin while lung apoptosis was improved by SNP. Conclusion: Curcumin ameliorates I/R-induced local and remote organs damage through its anti-inflammatory and antiapoptotic effect. SNP may be beneficial in I/R injury but not as significant as curcumin. [J Interdiscipl Histopathol 2014; 2(2.000: 74-87

  6. Endotoxin tolerance does not limit mild ischemia-reperfusion injury in humans in vivo.

    NARCIS (Netherlands)

    Draisma, A.; Goeij, M. de; Wouters, C.W.; Riksen, N.P.; Oyen, W.J.G.; Rongen, G.A.P.J.M.; Boerman, O.C.; Deuren, M. van; Hoeven, J.G. van der; Pickkers, P.

    2009-01-01

    Animal studies have shown that previous exposure to lipopolysaccharide (LPS) can limit ischemia-reperfusion injury. We tested whether pretreatment with LPS also protects against ischemia-reperfusion injury in humans in vivo. Fourteen volunteers received bolus injections of incremental dosages of LPS

  7. Effect of baicalin on toll-like receptor 4-mediated ischemia/reperfusion inflammatory responses in alcoholic fatty liver condition

    International Nuclear Information System (INIS)

    Kim, Seok-Joo; Lee, Sun-Mee

    2012-01-01

    Alcoholic fatty liver is susceptible to secondary stresses such as ischemia/reperfusion (I/R). Baicalin is an active component extracted from Scutellaria baicalensis, which is widely used in herbal preparations for treatment of hepatic diseases and inflammatory disorders. This study evaluated the potential beneficial effect of baicalin on I/R injury in alcoholic fatty liver. Rats were fed an alcohol liquid diet or a control isocaloric diet for 5 weeks, and then subjected to 60 min of hepatic ischemia and 5 h of reperfusion. Baicalin (200 mg/kg) was intraperitoneally administered 24 and 1 h before ischemia. After reperfusion, baicalin attenuated the increases in serum alanine aminotransferase activity, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels in alcoholic fatty liver. The increased levels of TNF-α and IL-6 mRNA expression and inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expressions increased after reperfusion, which were higher in ethanol-fed animals, were attenuated by baicalin. In ethanol-fed animals, baicalin attenuated the increases in toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 protein expressions and the nuclear translocation of NF-κB after reperfusion. In conclusion, our findings suggest that baicalin ameliorates I/R-induced hepatocellular damage by suppressing TLR4-mediated inflammatory responses in alcoholic fatty liver. -- Highlights: ► Baicalin attenuates hepatic I/R-induced inflammation in alcoholic fatty liver. ► Baicalin downregulates TLR4, MyD88 expression during I/R in alcoholic fatty liver. ► Baicalin attenuates NF-κB nuclear translocation during I/R in alcoholic fatty liver.

  8. Experimental chronic kidney disease attenuates ischemia-reperfusion injury in an ex vivo rat lung model.

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    Chung-Kan Peng

    Full Text Available Lung ischemia reperfusion injury (LIRI is one of important complications following lung transplant and cardiopulmonary bypass. Although patients on hemodialysis are still excluded as lung transplant donors because of the possible effects of renal failure on the lungs, increased organ demand has led us to evaluate the influence of chronic kidney disease (CKD on LIRI. A CKD model was induced by feeding Sprague-Dawley rats an adenine-rich (0.75% diet for 2, 4 and 6 weeks, and an isolated rat lung in situ model was used to evaluate ischemia reperfusion (IR-induced acute lung injury. The clinicopathological parameters of LIRI, including pulmonary edema, lipid peroxidation, histopathological changes, immunohistochemistry changes, chemokine CXCL1, inducible nitric oxide synthase (iNOS, proinflammatory and anti-inflammatory cytokines, heat shock protein expression, and nuclear factor-κB (NF-κB activation were determined. Our results indicated that adenine-fed rats developed CKD as characterized by increased blood urea nitrogen and creatinine levels and the deposition of crystals in the renal tubules and interstitium. IR induced a significant increase in the pulmonary arterial pressure, lung edema, lung injury scores, the expression of CXCL1 mRNA, iNOS level, and protein concentration of the bronchial alveolar lavage fluid (BALF. The tumor necrosis factor-α levels in the BALF and perfusate; the interleukin-10 level in the perfusate; and the malondialdehyde levels in the lung tissue and perfusate were also significantly increased by LIRI. Counterintuitively, adenine-induced CKD significantly attenuated the severity of lung injury induced by IR. CKD rats exhibited increased heat shock protein 70 expression and decreased activation of NF-κB signaling. In conclusion, adenine-induced CKD attenuated LIRI by inhibiting the NF-κB pathway.

  9. 13-Methyltetradecanoic acid mitigates cerebral ischemia/reperfusion injury

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    Juan Yu

    2016-01-01

    Full Text Available 13-Methyltetradecanoic acid can stabilize cell membrane and have anti-inflammatory, antioxidant and anti-apoptotic effects. Previous studies mainly focused on peripheral nerve injury, but seldom on the central nervous system. We investigated whether these properties of 13-methyltetradecanoic acid have a neuroprotective effect on focal cerebral ischemia/reperfusion injury, and detected the expression of basic fibroblast growth factor and vascular endothelial growth factor. This study established rat models of middle cerebral artery occlusion/reperfusion injury by ischemia for 2 hours and reperfusion for 24 hours. At the beginning of reperfusion, 13-methyltetradecanoic acid 10, 40 or 80 mg/kg was injected into the tail vein. Results found that various doses of 13-methyltetradecanoic acid effectively reduced infarct volume, mitigate cerebral edema, and increased the mRNA and protein expression of basic fibroblast growth factor and vascular endothelial growth factor at 24 hours of reperfusion. The effect was most significant in the 13-methyltetradecanoic acid 40 and 80 mg/kg groups. The findings suggest that 13-methyltetradecanoic acid can relieve focal ischemia/reperfusion injury immediately after reperfusion, stimulate the upregulation of basic fibroblast growth factor and vascular endothelial growth factor to exert neuroprotective effects.

  10. Ligustrazine monomer against cerebral ischemia-reperfusion injury

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    Hai-jun Gao

    2015-01-01

    Full Text Available Ligustrazine (2,3,5,6-tetramethylpyrazine is a major active ingredient of the Szechwan lovage rhizome and is extensively used in treatment of ischemic cerebrovascular disease. The mechanism of action of ligustrazine use against ischemic cerebrovascular diseases remains unclear at present. This study summarizes its protective effect, the optimum time window of administration, and the most effective mode of administration for clinical treatment of cerebral ischemia/reperfusion injury. We examine the effects of ligustrazine on suppressing excitatory amino acid release, promoting migration, differentiation and proliferation of endogenous neural stem cells. We also looked at its effects on angiogenesis and how it inhibits thrombosis, the inflammatory response, and apoptosis after cerebral ischemia. We consider that ligustrazine gives noticeable protection from cerebral ischemia/reperfusion injury. The time window of ligustrazine administration is limited. The protective effect and time window of a series of derivative monomers of ligustrazine such as 2-[(1,1-dimethylethyloxidoimino]methyl]-3,5,6-trimethylpyrazine, CXC137 and CXC195 after cerebral ischemia were better than ligustrazine.

  11. Metabolomic profiling to characterize acute intestinal ischemia/reperfusion injury.

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    Rachel G Khadaroo

    Full Text Available Sepsis and septic shock are the leading causes of death in critically ill patients. Acute intestinal ischemia/reperfusion (AII/R is an adaptive response to shock. The high mortality rate from AII/R is due to the severity of the disease and, more importantly, the failure of timely diagnosis. The objective of this investigation is to use nuclear magnetic resonance (NMR analysis to characterize urine metabolomic profile of AII/R injury in a mouse model. Animals were exposed to sham, early (30 min or late (60 min acute intestinal ischemia by complete occlusion of the superior mesenteric artery, followed by 2 hrs of reperfusion. Urine was collected and analyzed by NMR spectroscopy. Urinary metabolite concentrations demonstrated that different profiles could be delineated based on the duration of the intestinal ischemia. Metabolites such as allantoin, creatinine, proline, and methylamine could be predictive of AII/R injury. Lactate, currently used for clinical diagnosis, was found not to significantly contribute to the classification model for either early or late ischemia. This study demonstrates that patterns of changes in urinary metabolites are effective at distinguishing AII/R progression in an animal model. This is a proof-of-concept study to further support examination of metabolites in the clinical diagnosis of intestinal ischemia reperfusion injury in patients. The discovery of a fingerprint metabolite profile of AII/R will be a major advancement in the diagnosis, treatment, and prevention of systemic injury in critically ill patients.

  12. Effects of kefir on ischemia-reperfusion injury.

    Science.gov (United States)

    Yener, A U; Sehitoglu, M H; Ozkan, M T A; Bekler, A; Ekin, A; Cokkalender, O; Deniz, M; Sacar, M; Karaca, T; Ozcan, S; Kurt, T

    2015-01-01

    We aimed to investigate the effect of kefir on Ischemia-Reperfusion (I/R) injury on rats. 24 male Sprague-Dawley rats between 250-350 g were selected. Rats were divided into three groups, and there were eight rats in each group. Rats were fed for 60 days. All of the rats were fed with the same diet for the first 30 days. In the second thirty days, kefir [10 cc/kg/day body weight (2 x 109 cfu/kg/day)] was added to the diet of the study group by gavage method. In all groups, lung and kidney tissues were removed after the procedure and rats were sacrificed. The biochemical and histopathological changes were observed in the lung and kidney within the samples. Serum urea, creatinine and tumor necrosis factor (TNF-α) were determined. Kefir + I/R groups was compared with I/R groups, a significant decrease (p Kefir + I/R groups of renal tissues were significantly (p Kefir reduced the levels of serum urea, creatinine and TNF-α significantly.   This would be useful in this model against ischemia/reperfusion, and shows the protective effect of kefir in tissue and serum functions.

  13. Isoflurane produces sustained cardiac protection after ischemia-reperfusion injury in mice.

    Science.gov (United States)

    Tsutsumi, Yasuo M; Patel, Hemal H; Lai, N Chin; Takahashi, Toshiyuki; Head, Brian P; Roth, David M

    2006-03-01

    Isoflurane reduces myocardial ischemia-reperfusion injury within hours to days of reperfusion. Whether isoflurane produces sustained cardiac protection has never been examined. The authors studied isoflurane-induced cardiac protection in the intact mouse after 2 h and 2 weeks of reperfusion and determined the dependence of this protection on adenosine triphosphate-dependent potassium channels and the relevance of this protection to myocardial function and apoptosis. Mice were randomly assigned to receive oxygen or isoflurane for 30 min with 15 min of washout. Some mice received mitochondrial (5-hydroxydecanoic acid) or sarcolemmal (HMR-1098) adenosine triphosphate-dependent potassium channel blockers with or without isoflurane. Mice were then subjected to a 30-min coronary artery occlusion followed by 2 h or 2 weeks of reperfusion. Infarct size was determined at 2 h and 2 weeks of reperfusion. Cardiac function and apoptosis were determined 2 weeks after reperfusion. Isoflurane did not change hemodynamics. Isoflurane reduced infarct size after reperfusion when compared with the control groups (27.7 +/- 6.3 vs. 41.7 +/- 6.4% at 2 h and 19.6 +/- 5.9 vs. 28.8 +/- 9.0% at 2 weeks). Previous administration of 5-hydroxydecanoic acid, but not HMR-1098, abolished isoflurane-induced cardiac protection. At 2 weeks, left ventricular end-diastolic diameter was decreased significantly and end-systolic pressure and maximum and minimum dP/dt were improved by isoflurane. Isoflurane-treated mice subjected to ischemia and 2 weeks of reperfusion showed less expression of proapoptotic genes, significantly decreased expression of cleaved caspase-3, and significantly decreased deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling-positive nuclei compared with the control group. Cardiac protection induced by isoflurane against necrotic and apoptotic cell death is associated with an acute memory period that is sustained and functionally relevant 2 weeks after

  14. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice

    International Nuclear Information System (INIS)

    Cao Canxiang; Yang Qingwu; Lv Fenglin; Cui Jie; Fu Huabin; Wang Jingzhou

    2007-01-01

    Inflammatory reaction plays an important role in cerebral ischemia-reperfusion injury, however, its mechanism is still unclear. Our study aims to explore the function of Toll-like receptor 4 (TLR4) in the process of cerebral ischemia-reperfusion. We made middle cerebral artery ischemia-reperfusion model in mice with line embolism method. Compared with C3H/OuJ mice, scores of cerebral water content, cerebral infarct size and neurologic impairment in C3H/Hej mice were obviously lower after 6 h ischemia and 24 h reperfusion. Light microscopic and electron microscopic results showed that cerebral ischemia-reperfusion injury in C3H/Hej mice was less serious than that in C3H/OuJ mice. TNF-α and IL-6 contents in C3H/HeJ mice were obviously lower than that in C3H/OuJ mice with ELISA. The results showed that TLR4 participates in the process of cerebral ischemia-reperfusion injury probably through decrease of inflammatory cytokines. TLR4 may become a new target for prevention of cerebral ischemia-reperfusion injury. Our study suggests that TLR4 is one of the mechanisms of cerebral ischemia-reperfusion injury besides its important role in innate immunity

  15. Imaging of rat cerebral ischemia-reperfusion injury using99mTc-labeled duramycin

    International Nuclear Information System (INIS)

    Zhang Yuqing; Stevenson, Gail D.; Barber, Christy; Furenlid, Lars R.; Barrett, Harrison H.; Woolfenden, James M.; Zhao Ming; Liu Zhonglin

    2013-01-01

    Objectives: Prompt identification of necrosis and apoptosis in the infarct core and penumbra region is critical in acute stroke for delineating the underlying ischemic/reperfusion molecular pathologic events and defining therapeutic alternatives. The objective of this study was to investigate the capability of 99m Tc-labeled duramycin in detecting ischemia-reperfusion injury in rat brain after middle cerebral artery (MCA) occlusion. Methods: Ischemic cerebral injury was induced in ten rats by vascular insertion of a nylon suture in the left MCA for 3 hr followed by 21–24 hr reperfusion. After i.v. injection of 99m Tc-duramycin (1.0-3.5 mCi), dynamic cerebral images were acquired for 1 hr in six rats using a small-animal SPECT imager. Four other rats were imaged at 2 hr post-injection. Ex vivo images were obtained by autoradiography after sacrifice. Histologic analyses were performed to assess cerebral infarction and apoptosis. Results: SPECT images showed that 99m Tc-duramycin uptake in the left cerebral hemisphere was significantly higher than that in the right at 1 and 2 hr post-injection. The level of radioactive uptake in the ischemic brain varied based on ischemic severity. The average ratio of left cerebral hot-spot uptake to right hemisphere radioactivity, as determined by computerized ROI analysis, was 4.92 ± 0.79. Fractional washout at 1 hr was 38.2 ± 4.5% of peak activity for left cerebral hot-spot areas and 80.9 ± 2.0% for remote control areas (P 99m Tc-duramycin SPECT imaging may be useful for detecting and quantifying ongoing apoptotic neuronal cell loss induced by ischemia-reperfusion injury.

  16. Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction.

    Science.gov (United States)

    He, Qi; Li, Zhenyu; Wang, Yueting; Hou, Yanghao; Li, Lingyu; Zhao, Jing

    2017-09-01

    Resveratrol has been reported to protect against cerebral ischemia/reperfusion (I/R) injury in rats, but the underlying mechanism is unclear. In the current study, we examined whether resveratrol ameliorates cerebral I/R injury by inhibiting NLRP3 inflammasome-derived inflammation and whether autophagy is involved in this process. In addition, we explored the role of Sirt1 in resveratrol-mediated protective effects. To answer these questions, healthy male Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 1h followed by 24h reperfusion. We found that cerebral I/R increased levels of activated NLRP3 inflammasome, caspase-1, IL-1β, and IL-18 and enhanced autophagy activity (ratio of LC3B-II/LC3B-I and p62/SQSTM1). Treatment with resveratrol, a specific Sirt1 agonist, attenuated I/R-induced NLRP3 inflammasome-derived inflammation but upregulated autophagy. Furthermore, resveratrol treatment clearly reduced cerebral infarct volume, decreased brain water content, and improved neurological scores. In addition, inhibition of autophagy using 3-MA intracerebroventricular injection blocked the inhibitory effect of resveratrol on NLRP3 inflammasome activation. Finally, Sirt1 knockdown with siRNA significantly blocked resveratrol-induced enhancement of autophagy activity and suppression of NLRP3 inflammasome activation. In conclusion, our results demonstrate that resveratrol protects against cerebral I/R injury by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy activity. Copyright © 2017. Published by Elsevier B.V.

  17. Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System

    Science.gov (United States)

    Wang, Guoxing; Zhang, Qian; Yuan, Wei; Wu, Junyuan; Li, Chunsheng

    2015-01-01

    Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R) injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR) model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg) group. Thirty min after drug infusion, ventricular fibrillation (8 min) and cardiopulmonary resuscitation (up to 30 min) was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II) and Ang (1–7) levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE), ACE2, Ang II type 1 receptor (AT1R), and the Ang (1–7) receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafilfurther boosted the upregulation of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) and inducible nitric oxide synthase(iNOS). Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation. PMID:26569234

  18. Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System

    Directory of Open Access Journals (Sweden)

    Guoxing Wang

    2015-11-01

    Full Text Available Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg group. Thirty min after drug infusion, ventricular fibrillation (8 min and cardiopulmonary resuscitation (up to 30 min was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II and Ang (1–7 levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE, ACE2, Ang II type 1 receptor (AT1R, and the Ang (1–7 receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafilfurther boosted the upregulation of endothelial nitric oxide synthase (eNOS, cyclic guanosine monophosphate (cGMP and inducible nitric oxide synthase(iNOS. Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation.

  19. Novel curcumin analogue 14p protects against myocardial ischemia reperfusion injury through Nrf2-activating anti-oxidative activity

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    Li, Weixin [Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang (China); Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang (China); Wu, Mingchai [Department of Pharmacy, The Third Affiliated Hospital of Wenzhou Medical University, Wenzou, Zhejiang (China); Tang, Longguang; Pan, Yong; Liu, Zhiguo [Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang (China); Zeng, Chunlai [Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang (China); Wang, Jingying [Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang (China); Wei, Tiemin, E-mail: lswtm@sina.com [Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang (China); Liang, Guang, E-mail: wzmcliangguang@163.com [Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang (China)

    2015-01-15

    Background: Alleviating the oxidant stress associated with myocardial ischemia reperfusion has been demonstrated as a potential therapeutic approach to limit ischemia reperfusion (I/R)-induced cardiac damage. Curcumin, a natural compound with anti-oxidative activity, exerts beneficial effect against cardiac I/R injury, but poor chemical and metabolic stability. Previously, we have designed and synthesized a series of mono-carbonyl analogues of curcumin (MACs) with high stability. This study aims to find new anti-oxidant MACs and to demonstrate their effects and mechanisms against I/R-induced heart injury. Methods: H9c2 cells challenged with H{sub 2}O{sub 2} or TBHP were used for in vitro bio-screening and mechanistic studies. The MDA, H{sub 2}O{sub 2} and SOD levels in H9C2 cells were determined, and the cell viability was assessed by MTT assay. Myocardial I/R mouse models administrated with or without the compound were used for in vivo studies. Results: The in vitro cell-based screening showed that curcumin analogues 8d and 14p exhibited strong anti-oxidative effects. Pre-treatment of H9c2 cells with 14p activated Nrf2 signaling pathway, attenuated H{sub 2}O{sub 2}-increased MDA and SOD level, followed by the inhibition of TBHP-induced cell death and Bax/Bcl-2–caspase-3 pathway activation. Silencing Nrf2 significantly reversed the protective effects of 14p. In in vivo animal model of myocardial I/R, administration of low dose 14p (10 mg/kg) reduced infarct size and myocardial apoptosis to the same extent as the high dose curcumin (100 mg/kg). Conclusion: These data support the novel curcumin analogue 14p as a promising antioxidant to decrease oxidative stress and limit myocardial ischemia reperfusion injury via activating Nrf2. - Highlights: • Mono-carbonyl analogue of curcumin, 14p, exhibited better chemical stability. • Compound 14p inhibited TBHP-induced apoptosis through activating Nrf2 in vitro. • Compound 14p limited myocardial ischemia/reperfusion

  20. Melatonin and mitochondrial function during ischemia/reperfusion injury.

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    Ma, Zhiqiang; Xin, Zhenlong; Di, Wencheng; Yan, Xiaolong; Li, Xiaofei; Reiter, Russel J; Yang, Yang

    2017-11-01

    Ischemia/reperfusion (IR) injury occurs in many organs and tissues, and contributes to morbidity and mortality worldwide. Melatonin, an endogenously produced indolamine, provides a strong defense against IR injury. Mitochondrion, an organelle for ATP production and a decider for cell fate, has been validated to be a crucial target for melatonin to exert its protection against IR injury. In this review, we first clarify the mechanisms underlying mitochondrial dysfunction during IR and melatonin's protection of mitochondria under this condition. Thereafter, special focus is placed on the protective actions of melatonin against IR injury in brain, heart, liver, and others. Finally, we explore several potential future directions of research in this area. Collectively, the information compiled here will serve as a comprehensive reference for the actions of melatonin in IR injury identified to date and will hopefully aid in the design of future research and increase the potential of melatonin as a therapeutic agent.

  1. Oxidative Stress and Lung Ischemia-Reperfusion Injury

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    Renata Salatti Ferrari

    2015-01-01

    Full Text Available Ischemia-reperfusion (IR injury is directly related to the formation of reactive oxygen species (ROS, endothelial cell injury, increased vascular permeability, and the activation of neutrophils and platelets, cytokines, and the complement system. Several studies have confirmed the destructiveness of the toxic oxygen metabolites produced and their role in the pathophysiology of different processes, such as oxygen poisoning, inflammation, and ischemic injury. Due to the different degrees of tissue damage resulting from the process of ischemia and subsequent reperfusion, several studies in animal models have focused on the prevention of IR injury and methods of lung protection. Lung IR injury has clinical relevance in the setting of lung transplantation and cardiopulmonary bypass, for which the consequences of IR injury may be devastating in critically ill patients.

  2. Flurbiprofen, a Cyclooxygenase Inhibitor, Protects Mice from Hepatic Ischemia/Reperfusion Injury by Inhibiting GSK-3β Signaling and Mitochondrial Permeability Transition

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    Fu, Hailong; Chen, Huan; Wang, Chengcai; Xu, Haitao; Liu, Fang; Guo, Meng; Wang, Quanxing; Shi, Xueyin

    2012-01-01

    Flurbiprofen acts as a nonselective inhibitor for cyclooxygenases (COX-1 and COX-2), but its impact on hepatic ischemia/reperfusion (I/R) injury remains unclear. Mice were randomized into sham, I/R and flurbiprofen (Flurb) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 90 min and unclamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with flurbiprofen prior to I/R insult significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and prevented hepatocytes from I/R-induced apoptosis/necrosis. Moreover, flurbiprofen dramatically inhibited mitochondrial permeability transition (MPT) pore opening, and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that flurbiprofen markedly inhibited glycogen synthase kinase (GSK)-3β activity and increased phosphorylation of GSK-3β at Ser9, which, consequently, could modulate the adenine nucleotide translocase (ANT)–cyclophilin D (CyP-D) complex and the susceptibility to MPT induction. Therefore, administration of flurbiprofen prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through inhibition of MPT and inactivation of GSK-3β, and provides experimental evidence for clinical use of flurbiprofen to protect liver function in surgical settings in addition to its conventional use for pain relief. PMID:22714712

  3. Characterization of Microparticles after Hepatic Ischemia-Reperfusion Injury

    Science.gov (United States)

    Freeman, Christopher M.; Quillin, Ralph C.; Wilson, Gregory C.; Nojima, Hiroyuki; Johnson, Bobby L.; Sutton, Jeffrey M.; Schuster, Rebecca M.; Blanchard, John; Edwards, Michael J.; Caldwell, Charles C.; Lentsch, Alex B.

    2014-01-01

    Background Hepatic ischemia-reperfusion (I/R) is a well-studied model of liver injury and has demonstrated a biphasic injury followed by recovery and regeneration. Microparticles (MPs) are a developing field of study and these small membrane bound vesicles have been shown to have effector function in other physiologic and pathologic states. This study was designed to quantify the levels of MPs from various cell origins–platelets, neutrophils, and endolethial cells–following hepatic ischemia-reperfusion injury. Methods A murine model was used with mice undergoing 90 minutes of partial hepatic ischemia followed by various times of reperfusion. Following reperfusion, plasma samples were taken and MPs of various cell origins were labeled and levels were measured using flow cytometry. Additionally, cell specific MPs were further assessed by Annexin V, which stains for the presence of phosphatidylserine, a cell surface marker linked to apoptosis. Statistical analysis was performed using one-way analysis of variance with subsequent Student-Newman-Keuls test with data presented as the mean and standard error of the mean. Results MPs from varying sources show an increase in circulating levels following hepatic I/R injury. However, the timing of the appearance of different MP subtypes differs for each cell type. Platelet and neutrophil-derived MP levels demonstrated an acute elevation following injury whereas endothelial-derived MP levels demonstrated a delayed elevation. Conclusion This is the first study to characterize circulating levels of cell-specific MPs after hepatic I/R injury and suggests that MPs derived from platelets and neutrophils serve as markers of inflammatory injury and may be active participants in this process. In contrast, MPs derived from endothelial cells increase after the injury response during the reparative phase and may be important in angiogenesis that occurs in the regenerating liver. PMID:24879335

  4. Increased expression of IRE1α and stress-related signal transduction proteins in ischemia-reperfusion injured retina

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    Natsuyo Hata

    2008-08-01

    Full Text Available Natsuyo Hata1, Toshiyuki Oshitari1,2, Akiko Yokoyama1,3, Yoshinori Mitamura1, Shuichi Yamamoto11Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan; 2Department of Ophthalmology, Kimitsu Central Hospital, Kisarazu City, Chiba, Japan; 3Department of Ophthalmology, Inoue Memorial Hospital, Chuo-ku, Chiba, JapanAbstract: The purpose of this study was to determine whether the expression of ER stress-related factors IRE1α, apoptosis signal-regulating kinase 1 (ASK1, SAPK/ERK kinase 1 (SEK1 and c-Jun N-terminal kinase (JNK is associated with the damaged retinal neurons induced by ischemia-reperfusion injury. After 60 minutes of ischemia, the rat retinas were reperfused, and retinas were isolated and fixed after 6, 9, 12, 18, and 24 hours, and 2, 5, and 9 days of reperfusion. Cryosections were immunostained with Fluoro-Jade B, a degenerating neuron marker to label degenerating neurons. Semi-quantitative analysis of the expression of IRE1α, ASK1, SEK1, and JNK were performed in both control and ischemic retinas. In ischemic retinas, the intensities of IRE1α immunoreactivity in the ganglion cell layer (GCL were significantly higher than in the control retinas. In ischemic retinas, the numbers of SEK1-, ASK1-, and JNK-positive cells were significantly increased in the GCL compared to those in the control retinas. In addition, the cells that were positive for SEK1-, ASK1-, and JNK were also positive for Fluoro-Jade B-positive cells. These results indicate that the increased expression of ER stress-related factors was, in part, associated with the retinal neuronal abnormalities after ischemia-reperfusion injury in rat retinas.Keywords: endoplasmic reticulum, IRE1α, apoptosis signal-regulating kinase 1, SAPK/ERK kinase 1, c-Jun N-terminal kinase, Fluoro-Jade B, ischemia-reperfusion injury

  5. Sevoflurane postconditioning improves myocardial mitochondrial respiratory function and reduces myocardial ischemia-reperfusion injury by up-regulating HIF-1.

    Science.gov (United States)

    Yang, Long; Xie, Peng; Wu, Jianjiang; Yu, Jin; Yu, Tian; Wang, Haiying; Wang, Jiang; Xia, Zhengyuan; Zheng, Hong

    2016-01-01

    Sevoflurane postconditioning (SPostC) can exert myocardial protective effects similar to ischemic preconditioning. However, the exact myocardial protection mechanism by SPostC is unclear. Studies indicate that hypoxia-inducible factor-1 (HIF-1) maintains cellular respiration homeostasis by regulating mitochondrial respiratory chain enzyme activity under hypoxic conditions. This study investigated whether SPostC could regulate the expression of myocardial HIF-1α and to improve mitochondrial respiratory function, thereby relieving myocardial ischemia-reperfusion injury in rats. The myocardial ischemia-reperfusion rat model was established using the Langendorff isolated heart perfusion apparatus. Additionally, postconditioning was performed using sevoflurane alone or in combination with the HIF-1α inhibitor 2-methoxyestradiol (2ME2). The changes in hemodynamic parameters, HIF-1α protein expression levels, mitochondrial respiratory function and enzyme activity, mitochondrial reactive oxygen species (ROS) production rates, and mitochondrial ultrastructure were measured or observed. Compared to the ischemia-reperfusion (I/R) group, HIF-1α expression in the SPostC group was significantly up-regulated. Additionally, cardiac function indicators, mitochondrial state 3 respiratory rate, respiratory control ratio (RCR), cytochrome C oxidase (C c O), NADH oxidase (NADHO), and succinate oxidase (SUCO) activities, mitochondrial ROS production rate, and mitochondrial ultrastructure were significantly better than those in the I/R group. However, these advantages were completely reversed by the HIF-1α specific inhibitor 2ME2 ( P <0.05). The myocardial protective function of SPostC might be associated with the improvement of mitochondrial respiratory function after up-regulation of HIF-1α expression.

  6. Cellular infiltrates and injury evaluation in a rat model of warm pulmonary ischemia-reperfusion

    NARCIS (Netherlands)

    Van Putte, BP; Kesecioglu, J; Hendriks, JMH; Persy, VP; van Marck, E; Van Schil, PEY; De Broe, ME

    Introduction Beside lung transplantation, cardiopulmonary bypass, isolated lung perfusion and sleeve resection result in serious pulmonary ischemia - reperfusion injury, clinically known as acute respiratory distress syndrome. Very little is known about cells infiltrating the lung during ischemia -

  7. The pathways by which mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury

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    Chun Luo

    2015-01-01

    Full Text Available Several studies have demonstrated that mild hypothermia exhibits a neuroprotective role and it can inhibit endothelial cell apoptosis following ischemia/reperfusion injury by decreasing casp-ase-3 expression. It is hypothesized that mild hypothermia exhibits neuroprotective effects on neurons exposed to ischemia/reperfusion condition produced by oxygen-glucose deprivation. Mild hypothermia significantly reduced the number of apoptotic neurons, decreased the expression of pro-apoptotic protein Bax and increased mitochondrial membrane potential, with the peak of anti-apoptotic effect appearing between 6 and 12 hours after the injury. These findings indicate that mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury by protecting the mitochondria and that the effective time window is 6-12 hours after ischemia/reperfusion injury

  8. Passive targeting of lipid-based nanoparticles to mouse cardiac ischemia-reperfusion injury

    NARCIS (Netherlands)

    Geelen, T.; Paulis, L.E.M.; Coolen, B.F.; Nicolay, K.; Strijkers, G.J.

    2013-01-01

    Reperfusion therapy is commonly applied after a myocardial infarction. Reperfusion, however, causes secondary damage. An emerging approach for treatment of ischemia-reperfusion (IR) injury involves the delivery of therapeutic nanoparticles to the myocardium to promote cell survival and

  9. Borax partially prevents neurologic disability and oxidative stress in experimental spinal cord ischemia/reperfusion injury.

    Science.gov (United States)

    Koc, Emine Rabia; Gökce, Emre Cemal; Sönmez, Mehmet Akif; Namuslu, Mehmet; Gökce, Aysun; Bodur, A Said

    2015-01-01

    The aim of this study is to investigate the potential effects of borax on ischemia/reperfusion injury of the rat spinal cord. Twenty-one Wistar albino rats were divided into 3 groups: sham (no ischemia/reperfusion), ischemia/reperfusion, and borax (ischemia/reperfusion + borax); each group was consist of 7 animals. Infrarenal aortic cross clamp was applied for 30 minutes to generate spinal cord ischemia. Animals were evaluated functionally with the Basso, Beattie, and Bresnahan scoring system and inclined-plane test. The spinal cord tissue samples were harvested to analyze tissue concentrations of nitric oxide, nitric oxide synthase activity, xanthine oxidase activity, total antioxidant capacity, and total oxidant status and to perform histopathological examination. At the 72nd hour after ischemia, the borax group had significantly higher Basso, Beattie, and Bresnahan and inclined-plane scores than those of ischemia/reperfusion group. Histopathological examination of spinal cord tissues in borax group showed that treatment with borax significantly reduced the degree of spinal cord edema, inflammation, and tissue injury disclosed by light microscopy. Xanthine oxidase activity and total oxidant status levels of the ischemia/reperfusion group were significantly higher than those of the sham and borax groups (P borax group were significantly higher than those of the ischemia/reperfusion group (P borax groups in terms of total antioxidant capacity levels (P > .05). The nitric oxide levels and nitric oxide synthase activity of all groups were similar (P > .05). Borax treatment seems to protect the spinal cord against injury in a rat ischemia/reperfusion model and improve neurological outcome. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  10. The effect of aloe vera on ischemia--Reperfusion injury of sciatic nerve in rats.

    Science.gov (United States)

    Guven, Mustafa; Gölge, Umut Hatay; Aslan, Esra; Sehitoglu, Muserref Hilal; Aras, Adem Bozkurt; Akman, Tarik; Cosar, Murat

    2016-04-01

    Aloe vera is compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of aloe vera treatment in rats with experimental sciatic nerve ischemia/reperfusion injury. Twenty-eight male Wistar Albino rats were divided equally into 4 groups. Groups; Control group (no surgical procedure or medication), sciatic nerve ischemia/reperfusion group, sciatic nerve ischemia/reperfusion+aloe vera group and sciatic nerve ischemia/reperfusion+methylprednisolone group. Ischemia was performed by clamping the infrarenal abdominal aorta. 24 hours after ischemia, all animals were sacrificed. Sciatic nerve tissues were also examined histopathologically and biochemically. Ischemic fiber degeneration significantly decreased in the pre-treated with aloe vera and treated with methylprednisolone groups, especially in the pre-treated with aloe vera group, compared to the sciatic nerve ischemia/reperfusion group (paloe vera group was not statistically different compared to the MP group (p>0.05). Aloe vera is effective neuroprotective against sciatic nerve ischemia/reperfusion injury via antioxidant and anti-inflammatory properties. Also aloe vera was found to be as effective as MP. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  11. Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver

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    Weili Yang

    2018-04-01

    Full Text Available Liver ischemia-reperfusion injury (IRI is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, are useful for ameliorating liver IRI in animal models. However, these methods are difficult to perform in clinical surgeries. It has been reported that the activation of peroxisome proliferator activated receptor gamma (PPARγ protects the liver against IRI, but with unidentified direct target gene(s and unclear mechanism(s. Recently, FAM3A, a direct target gene of PPARγ, had been shown to mediate PPARγ’s protective effects in liver IRI. Moreover, noncoding RNAs, including LncRNAs and miRNAs, had also been reported to play important roles in the process of hepatic IRI. This review briefly discussed the roles and mechanisms of several classes of important molecules, including PPARγ, FAM3A, miRNAs, and LncRNAs, in liver IRI. In particular, oral administration of PPARγ agonists before liver surgery or liver transplantation to activate hepatic FAM3A pathways holds great promise for attenuating human liver IRI.

  12. Reduced ischemia-reperfusion injury with isoproterenol in non-heart-beating donor lungs.

    Science.gov (United States)

    Jones, D R; Hoffmann, S C; Sellars, M; Egan, T M

    1997-05-01

    Transplantation of lungs retrieved from non-heart-beating donors could expand the donor pool. Recent studies suggest that the ischemia-reperfusion injury (IRI) to the lung can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, as measured by Kfc, in lungs retrieved from non-heart-beating donors and reperfused with or without isoproterenol (iso). Using an in situ isolated perfused lung model, lungs were retrieved from non-heart-beating donor rats ventilated with O2 or not at varying intervals after death. The lungs were reperfused with or without iso (10 microM). Kfc, lung viability, and pulmonary hemodynamics were measured, and tissue levels of adenine nucleotides and cAMP were measured by HPLC. Iso-reperfusion decreased Kfc significantly (P Kfc in non-iso-reperfused (r = 0.65) and iso-perfused (r = 0.84) lungs. cAMP levels increased significantly with iso-reperfusion. cAMP levels correlated with Kfc (r = 0.87) in iso-reperfused lungs. Iso-reperfusion of lungs retrieved from non-heart-beating donor rats results in decreased capillary permeability and increased lung tissue cAMP levels. Pharmacologic augmentation of tissue TAN and cAMP levels may further ameliorate the increased capillary permeability seen in lungs retrieved from non-heart-beating donors.

  13. Histopathological study on the effects of turmeric (Curcuma longa linn. powdwer on renal ischemia-reperfusion injuryin rats

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    D Mohajeri

    2012-05-01

    Full Text Available Renal ischemia/reperfusion (I/R injury is a major cause of acute renal failure (ARF, which is faced in many clinical situations. This study was designed to investigate the effect of pre-treatment with turmeric (Curcuma longa linn powder on kidney histopathology and function markers in renal ischemia / reperfusion (IR induced injury in the rats. A total of 80 male Wistar rats were randomly divided into 4 groups: sham, IR model and two I/R+TREE (2%and4% - treated groups (n=20 per group. I/R groups’ kidneys were subjected to 60 min of global ischemia at 37oc followed by 30min of reperfusion. After 24h of reperfusion period, the rats were sacrificed. Kidney function tests and histopathological examination were also performed. Results were compared with a group of rats with sham operation. High serum creatinine, blood urea nitrogen and uric acid were observed in I/R rats compared to the sham rats. Pre-treatment of turmeric powder for 30 days prior to IR operation improved renal function reduced IR induced renal inflammatory and oxidative injury. The results of this study showed that turmeric powder significantly prevented renal I/R-induced functional and histological injuries.

  14. Coenzyme Q10 Protects Hippocampal Neurons against Ischemia/ Reperfusion Injury via Modulation of BAX/Bcl-2 Expression

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    Mohammad Zamani

    2012-09-01

    Full Text Available Introduction: Preliminary studies have con.rmed reduction in cell death following treatment with antioxidants. According to this .nding we study the relationship between consumption of CoQ10 and expression of Bax and Bcl2 in hippocampus following ischemia/reperfusion as proteins involved in cell programmed death or apoptosis. Methods: We studied the protective role of CoQ10 against ischemia-reperfusion. Experimental design includes four groups:  intact, ischemic control, sham control and treatment group with CoQ10. The mice were pre-treated with CoQ10 for a week, then ischemia was induced by common carotid artery ligation and following the reduction in in.ammation (a week the mice was treated with CoQ10.  Nissl staining was applied for counting the necrotic cells of hippocampus and the western blot was performed to measure the Bax and Bcl2 expression.Results: Cell death was signi.cantly lower when mice were treated with CoQ10. Bax expression was signi.cantly high in the ischemic group but low in the treatment group, and the bcl2 expression was lower in the ischemic group than the treatment and the vehicle groups.Discussion: Ischemia for 15 minutes induced cell death in hippocampus with more potent effect on CA1. CoQ10 intake signi.cantly reduced cell death and prevented the expression of Bax while inducing an increase in expression of bcl2.

  15. Coenzyme Q10 Protects Hippocampal Neurons Against Ischemia/Reperfusion Injury via Modulation of BAX/Bcl-2 Expression

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    M Zamani

    2012-12-01

    Full Text Available Introduction : Preliminary studies confirmed reduction in cell death following treatment with antioxidants. According to this finding we study the relationship between consumption of CoQ10 and expression of bax and bcl2 in hippocampus following ischemia/reperfusion as proteins involved in cell programmed death or apoptosis.Material & methods : We studied the protective role of CoQ10 against Ischemia-Reperfusion. Experimental design includes four groups: intact, ischemic control, sham control and treatment groups with CoQ10. The mice treated with CoQ10 as Pre - Treatment for a week. Then, ischemia induced by common carotid artery ligation and following the reduction in inflammation (a week the mice post-treated with CoQ10.Nissl staining applied to counting necrotic cells of hippocampus and the western blotting performed to measurement the bax and bcl2 expression.Results :. Cell death was significantly lower when mice treated with CoQ10. Bax expression was significantly high in ischemic group but in treatment group was less and reversely the bcl2 expression in ischemic group was lower than treatment and vehicle groups.Conclusion : Ischemia for 15 minutes induced cell death in hippocampus with more potent effect on CA1. CoQ10 intake significantly reduced cell death and prevented the expression of bax while inducing an increase in expression of bcl2.

  16. Ghrelin protects the heart against ischemia/reperfusion injury via inhibition of TLR4/NLRP3 inflammasome pathway.

    Science.gov (United States)

    Wang, Qin; Lin, Ping; Li, Peng; Feng, Li; Ren, Qian; Xie, Xiaofeng; Xu, Jing

    2017-10-01

    The aim of this study was to investigate the cardioprotective effects of ghrelin against myocardial ischemia/reperfusion (I/R) injury and the underlying mechanism. Sprague-Dawley rats were randomized into Sham, I/R and I/R+ghrelin groups. After 30 minutes ischemia, ghrelin (8nmol/kg) was injected intraperitoneally at the time of reperfusion in the I/R+ghrelin group. Then hemodynamic parameters were observed at 24h after reperfusion. Ghrelin exhibited dramatic improvement in cardiac functions, as manifested by increased LVSP and ±dP/dt max and decreased LVDP. At 24h after reperfusion, ghrelin significantly attenuated the myocardial infarction area and apoptosis, accompanied with a decrease in the levels of the myocyte injury marker enzymes. Oxidative stress injury and inflammatory response were also relieved by ghrelin. Western blot showed that the expression of TLR4, NLRP3, and caspase-1 were obviously increased in I/R group, while ghrelin significantly inhibited the I/R-induced TLR4, NLRP3, and caspase-1 expression. Ghrelin could inhibit the increased protein levels of NLRP3, caspase-1, and IL-1β induced by lipopolysacharide in primary cultured cardiomyocytes of neonatal rats. Ghrelin protected the heart against I/R injury by inhibiting oxidative stress and inflammation via TLR4/NLRP3 signaling pathway. Our results might provide new strategy and target for treatment of myocardial ischemia/reperfusion injury. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Effect of Panax notoginseng saponins on the content of IL-8 in serum after cerebral ischemia-reperfusion in rat

    International Nuclear Information System (INIS)

    He Wei; Zhu Zunping

    2002-01-01

    Objective: To investigate the effect of Panax notoginseng saponins (Pns) against cerebral ischemia-reperfusion injury. Methods: Focal cerebral ischemia-reperal ischemia-reperfusion model in rat was established by occlusion the middle cerebral artery for 2 h, after 3 h reperfusion. The serum concentration of IL-8 was detected with radioimmunoassay (RIA). Results: Png 50 mg·kg -1 ip, qd x 7d before MCAO decreased the serum content of IL-8 after ischemia-reperfusion. Conclusion: Pns has protective effect against cerebral ischemia-reperfusion injury by decreased the serum content of IL-8

  18. Antithrombin III prevents deleterious effects of remote ischemia-reperfusion injury on healing of colonic anastomoses.

    Science.gov (United States)

    Tekin, Koray; Aytekin, Faruk; Ozden, Akin; Bilgihan, Ayşe; Erdem, Ergün; Sungurtekin, Ugur; Güney, Yildiz

    2002-08-01

    Antithrombin III is known as the most important natural inhibitor of thrombin activity and has been shown to attenuate local harmful effects of ischemia-reperfusion injury in many organs. In recent animal studies, delaying effect of remote organ ischemia-reperfusion injury on healing of intestinal anastomoses has been demonstrated. In this study, we investigated whether antithrombin III reduces deleterious systemic effects of ischemia-reperfusion injury on healing of colonic anastomoses in rats. Anastomosis of the left colon was performed in 24 rats that were divided into three groups: sham operated control (group I, n = 8), 30 minutes of intestinal ischemia-reperfusion by superior mesenteric artery occlusion (group II, n = 8), antithrombin III treated group (250 U/kg before and after the ischemia-reperfusion, group III, n = 8). On postoperative day 6, all animals were sacrificed, and bursting pressure and tissue hydroxyproline content of the anastomoses were assessed and compared. On postoperative day 6 the mean bursting pressures were 149.6 +/- 4.8, 69.8 +/- 13.5, and 121.8 +/- 8.7 mm Hg for groups I, II, and III, respectively (P = 0.000). Mean tissue hydroxyproline concentration values were 389.5 +/- 29.6, 263.1 +/- 10.0, and 376.0 +/- 33.8 microg/mg for groups I, II, III respectively (P = 0.005). This study showed that, antithrombin III treatment significantly prevented the delaying effect of remote organ ischemia-reperfusion injury on anastomotic healing in the colon. Further clinical studies are needed to clarify whether antithrombin may be a useful therapeutic agent to increase the safety of the anastomosis during particular operations where remote organ ischemia-reperfusion injury takes place.

  19. Cordyceps sinensis protects against renal ischemia/reperfusion injury in rats.

    Science.gov (United States)

    Wang, Hua-Pin; Liu, Ching-Wen; Chang, Hsueh-Wen; Tsai, Jen-Wei; Sung, Ya-Zhu; Chang, Li-Ching

    2013-03-01

    Cordyceps sinensis (CS) is an entomogenous fungus used as a tonic food and Chinese medicine to replenish health. This study investigated the protective effects of CS in rats post-renal ischemia-reperfusion (I/R) sequence by analyzing the influence on stromal cell-derived factor-1α (SDF-1α and chemokine (C-X-C motif) receptor 4 (CXCR4) expressions and senescence during recovery. Chemokine SDF-1 [now called chemokine C-X-C motif ligand 12 (CXCL12)] and its receptor CXCR4 are crucial in kidney repair after ischemic acute renal failure. CS treatment significantly alleviated I/R-induced renal damage assessed by creatinine levels (p < 0.05) and abated renal tubular damages assessed by periodic acid-Schiff with diastase (PASD) staining. CS induced early SDF-1α expression and increased CXCR4 expression 1-6 h post-reperfusion. Histology studies have revealed that CS induced SDF-1α in squamous cells of Bowman's capsule, mesangial cells, distal convoluted tubules (DCT), and proximal convoluted tubules (PCT). CS also improved renal repair in I/R-induced injury by increasing Ki-67 staining. I/R induced renal senescence after 3 and 6 h of reperfusion. However, CS alleviated I/R-induced senescence at early stage (1 and 3 h). We conclude that CS protects against I/R injury via the SDF-1/CXCR4-signaling axis and alleviates senescence.

  20. The effect of melatonin on bacterial translocation following ischemia/reperfusion injury in a rat model of superior mesenteric artery occlusion.

    Science.gov (United States)

    Ozban, Murat; Aydin, Cagatay; Cevahir, Nural; Yenisey, Cigdem; Birsen, Onur; Gumrukcu, Gulistan; Aydin, Berrin; Berber, Ibrahim

    2015-03-08

    Acute mesenteric ischemia is a life-threatening vascular emergency resulting in tissue destruction due to ischemia-reperfusion injury. Melatonin, the primary hormone of the pineal gland, is a powerful scavenger of reactive oxygen species (ROS), including the hydroxyl and peroxyl radicals, as well as singlet oxygen, and nitric oxide. In this study, we aimed to investigate whether melatonin prevents harmful effects of superior mesenteric ischemia-reperfusion on intestinal tissues in rats. Rats were randomly divided into three groups, each having 10 animals. In group I, the superior mesenteric artery (SMA) was isolated but not occluded. In group II and group III, the SMA was occluded immediately distal to the aorta for 60 minutes. After that, the clamp was removed and the reperfusion period began. In group III, 30 minutes before the start of reperfusion, 10 mg/kg melatonin was administered intraperitonally. All animals were sacrified 24 hours after reperfusion. Tissue samples were collected to evaluate the I/R-induced intestinal injury and bacterial translocation (BT). There was a statistically significant increase in myeloperoxidase activity, malondialdehyde levels and in the incidence of bacterial translocation in group II, along with a decrease in glutathione levels. These investigated parameters were found to be normalized in melatonin treated animals (group III). We conclude that melatonin prevents bacterial translocation while precluding the harmful effects of ischemia/reperfusion injury on intestinal tissues in a rat model of superior mesenteric artery occlusion.

  1. [Effects of combined use of total alkaloids of Uncaria rhynchophylla and Coryadlis ambailis migo on cerebral ischemia-reperfusion injury in rats].

    Science.gov (United States)

    Hu, Xue-yong; Sun, An-sheng; Sui, Yu-xia

    2007-11-01

    To study the effects of combined use of total alkaloids (TA) of Uncaria rhynchophylla (UR) and Coryadlis ambailis migo (CAM) on cerebral ischemia/reperfusion injury in rats. Rat model of middle cerebral artery ischemia/reperfusion was established, the changes of neurological state was scored before and after treatment with the two kinds of TA, single or combined, and the changes of cerebral infarcted volume, cerebral water content, activities of NOS and SOD and content of MDA in rats' brain were estimated as well. After being treated with the combination of both TA, the average neurological score, cerebral infracted volume, cerebral water content, activity of NOS and content of MDA in the model rats significantly decreased, and the activity of SOD was significantly increased (all P < 0.05). The effect of combined use of the two TA was higher than that of use TA of UR or CAM alone (P <0.05). Moreover, the central nervous system inhibitory effect induced by combined TA was significantly weaker than that of UR. Combined use of TA of UR and CAM may facilitate the protection against cerebral ischemia/reperfusion damage, the action mechanism might be relevant to reducing the lipid peroxidation injury of brain cells through inhibiting the NOS activity and increasing the SOD activity.

  2. Evaluation of myocardial preconditioning and adenosine effects in cardioprotection in rat hearts with ischemia-reperfusion injury using 99MTc-glucarate imaging

    International Nuclear Information System (INIS)

    Liu Zhonglin; Barrett, H.H.; Koon Yan Pak

    2004-01-01

    Significant tolerance to myocardial ischemia-reperfusion injury, as assessed by biochemical assay and noninvasive infarct-avid imaging, was induced with an IPC protocol in the rat model. The cardioprotection of IPC could be simulated by adenosine receptor A1 agonist CCPA, or blocked by antagonist SPT. Thus, adenosine mediates protection by ischemic preconditioning in this specific rat heart model. 99mTc-glucarate imaging is not only useful in detecting early ischemia-reperfusion injury, but also invaluable in evaluating the effects of cardioprotective treatments. uantitative anal ses on dynamic images with 99m Tc-glucarate would make it possible to identify myocardial ischemia-reperfusion injury more accurate, and provide a unique tool for evaluation of cardioprotection. The FASTSPECT imaging with the ischenuc-reperfused rat heart model provides a solution-specific approach with high-resolution and fast dynamic acquisition for kinetic studies of new myocardial imaging agents as the evidence of its major role in the present study. (authors)

  3. Mathematical Modeling of Ischemia-Reperfusion Injury and Postconditioning Therapy.

    Science.gov (United States)

    Fong, D; Cummings, L J

    2017-11-01

    Reperfusion (restoration of blood flow) after a period of ischemia (interruption of blood flow) can paradoxically place tissues at risk of further injury: so-called ischemia-reperfusion injury or IR injury. Recent studies have shown that postconditioning (intermittent periods of further ischemia applied during reperfusion) can reduce IR injury. We develop a mathematical model to describe the reperfusion and postconditioning process following an ischemic insult, treating the blood vessel as a two-dimensional channel, lined with a monolayer of endothelial cells that interact (respiration and mechanotransduction) with the blood flow. We investigate how postconditioning affects the total cell density within the endothelial layer, by varying the frequency of the pulsatile flow and the oxygen concentration at the inflow boundary. We find that, in the scenarios we consider, the pulsatile flow should be of high frequency to minimize cellular damage, while oxygen concentration at the inflow boundary should be held constant, or subject to only low-frequency variations, to maximize cell proliferation.

  4. Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury.

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    Chen, Xing-miao; Chen, Han-sen; Xu, Ming-jing; Shen, Jian-gang

    2013-01-01

    Ischemic stroke accounts for nearly 80% of stroke cases. Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply, but the thrombolytic therapy often companies with cerebral ischemia-reperfusion injury, which are mediated by free radicals. As an important component of free radicals, reactive nitrogen species (RNS), including nitric oxide (NO) and peroxynitrite (ONOO(-)), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia-reperfusion results in the production of nitric oxide (NO) and peroxynitrite (ONOO(-)) in ischemic brain, which trigger numerous molecular cascades and lead to disruption of the blood brain barrier and exacerbate brain damage. There are few therapeutic strategies available for saving ischemic brains and preventing the subsequent brain damage. Recent evidence suggests that RNS could be a therapeutic target for the treatment of cerebral ischemia-reperfusion injury. Herein, we reviewed the recent progress regarding the roles of RNS in the process of cerebral ischemic-reperfusion injury and discussed the potentials of drug development that target NO and ONOO(-) to treat ischemic stroke. We conclude that modulation for RNS level could be an important therapeutic strategy for preventing cerebral ischemia-reperfusion injury.

  5. Neuroprotective effects of SMADs in a rat model of cerebral ischemia/reperfusion

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    Fang-fang Liu

    2015-01-01

    Full Text Available Previous studies have shown that up-regulation of transforming growth factor β1 results in neuroprotective effects. However, the role of the transforming growth factor β1 downstream molecule, SMAD2/3, following ischemia/reperfusion remains unclear. Here, we investigated the neuroprotective effects of SMAD2/3 by analyzing the relationships between SMAD2/3 expression and cell apoptosis and inflammation in the brain of a rat model of cerebral ischemia/reperfusion. Levels of SMAD2/3 mRNA were up-regulated in the ischemic penumbra 6 hours after cerebral ischemia/reperfusion, reached a peak after 72 hours and were then decreased at 7 days. Phosphorylated SMAD2/3 protein levels at the aforementioned time points were consistent with the mRNA levels. Over-expression of SMAD3 in the brains of the ischemia/reperfusion model rats via delivery of an adeno-associated virus containing the SMAD3 gene could reduce tumor necrosis factor-α and interleukin-1β mRNA levels, down-regulate expression of the pro-apoptotic gene, capase-3, and up-regulate expression of the anti-apoptotic protein, Bcl-2. The SMAD3 protein level was negatively correlated with cell apoptosis. These findings indicate that SMAD3 exhibits neuroprotective effects on the brain after ischemia/reperfusion through anti-inflammatory and anti-apoptotic pathways.

  6. 电针对脑缺血再灌注损伤大鼠海马诱导型一氧化氮合酶mRNA表达的影响%Effect of electroacupuncture on inducible nitric oxide synthase mRNA expression in hippocampus of the rats with cerebral ischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    周爽; 黄建华; 方邦江; 袁凌松

    2005-01-01

    注后大鼠海马诱导型一氧化氮合酶mRNA表达,从而减少一氧化氮的产生,有助于减轻脑缺血再灌注损伤.%BACKGROUND: Researches indicate that inducible nitric oxide synthase(iNOS) plays an important role in relieving destruction of blood brain barrier and protecting vascular endothelium and brain tissue in cerebral ischemia-reperfusion injury.OBJECTIVE: To observe the effect of Shuigou (DU26), Neiguan (PC6)and Zusanli (ST36) on the expression of inducible nitric oxide synthase messenger ribonucleic acid (iNOS mRNA) in hippocampus of the rats with cerebral ischemia-reperfusion.DESIGN: Randomized controlled study.SETTING: Shanghai University of Traditional Chinese Medicine, Shanghai Institute of Acupuncture and Meridian and Huashan Hospital Affiliated to Fudan University.METHODS: The experiment was completed at the Experimental Animal Center in Shanghai University of Traditional Chinese Medicine, Threegrade Acupuncture Immunological Laboratory of Shanghai Research Institute of Acupuncture and Meridian and Huashan Hospital Affiliated to Fudan University from December 2003 to December 2004. Totally 40 SD rats were randomly divided as normal group, sham operation group, model group and electroacupuncture group with 10 in each group. The hypertension model rats were induced with bi-kidney-bi-clip method, then the focal cerebral ischemia-reperfusion rat model was induced by reversible occlusion for a middle cerebral artery with a thread on the stroke prone renovascular hypertensive model rat. While the rats in sham operation group were operated without thread insertion. Shuigou (Du 26), bilateral Neiguan(PC 6) and bilateral Housanli (Zusanli, ST 36) were located according to"Atlas of Experimental Animal Acupoints" made by Hua's. Shuigou (Du26): 1 mm below nasal apex right on the Labium leporinum, be punctured 1 mm obliquely upward; Neiguan (PC 6): at the lateral palm of the forearm3 mm above wrist joint, between ulna and radius, be punctured 1 mm

  7. Involvement of Rho-kinase in cold ischemia-reperfusion injury after liver transplantation in rats.

    Science.gov (United States)

    Shiotani, Satoko; Shimada, Mitsuo; Suehiro, Taketoshi; Soejima, Yuji; Yosizumi, Tomoharu; Shimokawa, Hiroaki; Maehara, Yoshihiko

    2004-08-15

    Reperfusion of ischemic tissues is known to cause the generation of reactive oxygen species (ROS) with resultant tissue damage. However, the sources of ROS in reperfused tissues are not fully characterized. We hypothesized that the small GTPase Rho and its target effector Rho-kinase/ROK/ROCK are involved in the oxidative burst in reperfused tissue with resultant reperfusion injury. In an in vivo rat model of liver transplantation using cold ischemia for 12 hr followed by reperfusion, a specific Rho-kinase inhibitor, fasudil (30 mg/kg), was administered orally 1 hr before the transplantation. Fasudil suppressed the ischemia-reperfusion (I/R)-induced generation of ROS after reperfusion (P<0.01) and also suppressed the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta) 3 hr after reperfusion, resulting in a significant reduction of I/R-induced hepatocellular injury (P<0.05), necrosis, apoptosis (P<0.01), and neutrophil infiltration (P<0.0001) 12 hr after reperfusion. All animals receiving a graft without fasudil died within 3 days, whereas 40% of those receiving fasudil survived (P<0.001). The present study demonstrates that Rho-kinase-mediated production of ROS and inflammatory cytokines are substantially involved in the pathogenesis of hepatocellular necrosis and apoptosis induced by cold I/R in vivo and that Rho-kinase may be regarded as a novel therapeutic target for the disorder.

  8. Supplementing diet with Manitoba lingonberry juice reduces kidney ischemia-reperfusion injury.

    Science.gov (United States)

    Isaak, Cara K; Wang, Pengqi; Prashar, Suvira; O, Karmin; Brown, Daniel Cw; Debnath, Samir C; Siow, Yaw L

    2017-07-01

    Lingonberry (Vaccinium vitis-idaea L.) contains high levels of anthocyanins which are bioavailable in the kidney and may be protective against ischemia-reperfusion (IR)-induced acute kidney injury. This study investigated the effect of lingonberry juice on the IR-induced stress-activated signalling pathway and inflammatory response in the kidney. Sprague-Dawley rats subjected to kidney IR had significantly impaired kidney function, with increased activation of the JNK signalling pathway and increased inflammatory response, measured using a multiplex panel containing an extensive array of inflammatory biomarkers. In rats fed 1 mL lingonberry juice daily for 3 weeks prior to IR, kidney function was protected and attenuation of inflammatory response and JNK signalling was reflected in the reduction of the measured biomarkers. In vitro results in cultured HK-2 cells confirmed that lingonberry anthocyanins reduced JNK signalling and inflammatory gene expression after IR. This study shows, for the first time, that daily supplementation with lingonberry juice may protect against loss of kidney function induced by IR injury by modulating JNK signalling and inhibiting the subsequent inflammatory response. © 2017 Her Majesty the Queen in Right of Canada. Journal of the Science of Food and Agriculture © 2017 Society of Chemical Industry. © 2017 Her Majesty the Queen in Right of Canada. Journal of the Science of Food and Agriculture © 2017 Society of Chemical Industry.

  9. Protective Effect of N-Acetylcystein and Resveratrol on Ischemia-Reperfusion Injury in Rat Ovary

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    Avni Kılıç

    2016-06-01

    both drugs (8.68±1.88 vs. 7.85±2.08, P=0.968. Conclusion: Presented study showed that resveratrol and N-acetyl cysteine treatment can be effective in preventing tissue damage and oxidative stress, which is induced by ischemia-reperfusion that is created in rat ovaries. On the other hand, no difference was found between the resveratrol and N-acetyl cysteine with regards to protective activity.

  10. Hsp20 Protects against Oxygen-Glucose Deprivation/Reperfusion-Induced Golgi Fragmentation and Apoptosis through Fas/FasL Pathway

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    Bingwu Zhong

    2015-01-01

    Full Text Available Cerebral ischemia-reperfusion injury plays an important role in the development of tissue injury after acute ischemic stroke. Finding effective neuroprotective agents has become a priority in the treatment of ischemic stroke. The Golgi apparatus (GA is a pivotal organelle and its protection is an attractive target in the treatment of cerebral ischemia-reperfusion injury. Protective effects of Hsp20, a potential cytoprotective agent due to its chaperone-like activity and involvement in regulation of many vital processes, on GA were assessed in an ischemia-reperfusion injury model. Mouse neuroblastoma Neuro2a (N2a cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR insult. OGDR induces Golgi fragmentation, apoptosis, and p115 cleavage in N2a cells. However, transfection with Hsp20 significantly attenuates OGDR-induced Golgi fragmentation and apoptosis. Hsp20 interacts with Bax, decreases FasL and Bax expression, and inhibits caspases 3 and p115 cleavage in N2a cells exposed to OGDR. Our data demonstrate that increased Hsp20 expression protects against OGDR-induced Golgi fragmentation and apoptosis, likely through interaction with Bax and subsequent amelioration of the OGDR-induced elevation in p115 cleavage via the Fas/FasL signaling pathway. This neuroprotective potential of Hsp20 against OGDR insult and the underlying mechanism will pave the way for its potential clinical application for cerebral ischemia-reperfusion related disorders.

  11. Pharmacological preconditioning by milrinone: memory preserving and neuroprotective effect in ischemia-reperfusion injury in mice.

    Science.gov (United States)

    Saklani, Reetu; Jaggi, Amteshwar; Singh, Nirmal

    2010-07-01

    We tested the neuroprotective effect of milrinone, a phosphodiesterase III inhibitor, in pharmacological preconditioning. Bilateral carotid artery occlusion for 12 min followed by reperfusion for 24 h produced ischemia-reperfusion (I/R) cerebral injury in male Swiss albino mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using the Morris water maze test, and motor coordination was evaluated using the inclined beam walking test, rota-rod test, and lateral push test. Milrinone (50 microg/kg & 100 microg/kg i.v.) was administered 24 h before surgery in a separate group of animals to induce pharmacological preconditioning. I/R increased cerebral infarct size and impaired memory and motor coordination. Milrinone treatment significantly decreased cerebral infarct size and reversed I/R-induced impairments in memory and motor coordination. This neuroprotective effect was blocked by ruthenium red (3 mg/kg, s.c.), an intracellular ryanodine receptor blocker. These findings indicate that milrinone preconditioning exerts a marked neuroprotective effect on the ischemic brain, putatively due to increased intracellular calcium levels activating calcium-sensitive signal transduction cascades.

  12. Salutary Effects of Cepharanthine against Skeletal Muscle and Kidney Injuries following Limb Ischemia/Reperfusion

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    Ming-Chang Kao

    2015-01-01

    Full Text Available Limb ischemia/reperfusion (I/R causes oxidation and inflammation and subsequently induces muscle and kidney injuries. Cepharanthine, a natural plant alkaloid, possesses anti-inflammatory and antioxidative properties. We elucidated the salutary effects of cepharanthine against muscle and kidney injuries following limb I/R. Adult male rats were randomized to receive I/R or I/R plus cepharanthine. I/R was achieved by applying tourniquet high around each thigh for 3 hours followed by reperfusion for 24 hours. Cepharanthine (10 mg/kg, intraperitoneal was injected immediately before reperfusion. After euthanization, degrees of tissue injury, inflammation, and oxidation were examined. Our data revealed that the I/R group had significant increases in injury biomarker concentrations of muscle (creatine kinase and lactate dehydrogenase and kidney (creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Histological assays revealed moderate muscle and kidney injury characteristics in the I/R group. The I/R group also had significant increases in concentrations of inflammatory molecules (interleukin-6, macrophage inflammatory protein-2, and prostaglandin E2 and reactive nitrogen species (nitric oxide as well as lipid peroxidation (malondialdehyde. Of note, these effects of limb I/R could be mitigated by cepharanthine. These data confirmed that cepharanthine attenuated muscle and kidney injuries induced by limb I/R. The mechanisms may involve its anti-inflammatory and antioxidative capacities.

  13. Hydroxysafflor Yellow A protects spinal cords from ischemia/reperfusion injury in rabbits

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    Shan Le-qun

    2010-08-01

    Full Text Available Abstract Background Hydroxysafflor Yellow A (HSYA, which is one of the most important active ingredients of the Chinese herb Carthamus tinctorius L, is widely used in the treatment of cerebrovascular and cardiovascular diseases. However, the potential protective effect of HSYA in spinal cord ischemia/reperfusion (I/R injury is still unknown. Methods Thirty-nine rabbits were randomly divided into three groups: sham group, I/R group and HSYA group. All animals were sacrificed after neurological evaluation with modified Tarlov criteria at the 48th hour after reperfusion, and the spinal cord segments (L4-6 were harvested for histopathological examination, biochemical analysis and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL staining. Results Neurological outcomes in HSYA group were slightly improved compared with those in I/R group. Histopathological analysis revealed that HSYA treatment attenuated I/R induced necrosis in spinal cords. Similarly, alleviated oxidative stress was indicated by decreased malondialdehyde (MDA level and increased superoxide dismutase (SOD activity after HSYA treatment. Moreover, as seen from TUNEL results, HSYA also protected neurons from I/R-induced apoptosis in rabbits. Conclusions These findings suggest that HSYA may protect spinal cords from I/R injury by alleviating oxidative stress and reducing neuronal apoptosis in rabbits.

  14. Intravenous Administration of Lycopene, a Tomato Extract, Protects against Myocardial Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Tong, Chao; Peng, Chuan; Wang, Lianlian; Zhang, Li; Yang, Xiaotao; Xu, Ping; Li, Jinjin; Delplancke, Thibaut; Zhang, Hua; Qi, Hongbo

    2016-03-03

    Oral uptake of lycopene has been shown to be beneficial for preventing myocardial ischemia-reperfusion (I/R) injury. However, the strong first-pass metabolism of lycopene influences its bioavailability and impedes its clinic application. In this study, we determined an intravenous (IV) administration dose of lycopene protects against myocardial infarction (MI) in a mouse model, and investigated the effects of acute lycopene administration on reactive oxygen species (ROS) production and related signaling pathways during myocardial I/R. In this study, we established both in vitro hypoxia/reoxygenation (H/R) cell model and in vivo regional myocardial I/R mouse model by ligating left anterior artery descending. TTC dual staining was used to assess I/R induced MI in the absence and presence of acute lycopene administration via tail vein injection. Lycopene treatment (1 μM) before reoxygenation significantly reduced cardiomyocyte death induced by H/R. Intravenous administration of lycopene to achieve 1 μM concentration in circulating blood significantly suppressed MI, ROS production, and JNK phosphorylation in the cardiac tissue of mice during in vivo regional I/R. Elevating circulating lycopene to 1 μM via IV injection protects against myocardial I/R injury through inhibition of ROS accumulation and consequent inflammation in mice.

  15. Lateral intracerebroventricular injection of Apelin-13 inhibits apoptosis after cerebral ischemia/reperfusion injury

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    Xiao-ge Yan

    2015-01-01

    Full Text Available Apelin-13 inhibits neuronal apoptosis caused by hydrogen peroxide, yet apoptosis following cerebral ischemia-reperfusion injury has rarely been studied. In this study, Apelin-13 (0.1 µg/g was injected into the lateral ventricle of middle cerebral artery occlusion model rats. TTC, TUNEL, and immunohistochemical staining showed that compared with the cerebral ischemia/reperfusion group, infarct volume and apoptotic cell number at the ischemic penumbra region were decreased in the Apelin-13 treatment group. Additionally, Apelin-13 treatment increased Bcl-2 immunoreactivity and decreased caspase-3 immunoreactivity. Our findings suggest that Apelin-13 is neuroprotective against cerebral ischemia/reperfusion injury through inhibition of neuronal apoptosis.

  16. Research progress of NLRP3 inflammasome in organ ischemia-reperfusion injury

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    Pei-lei LI

    2017-04-01

    Full Text Available Ischemia-reperfusion injury is a common pathophysiological process in organ transplantation, ischemic stroke and organ resection surgery, and also an important factor causing organ dysfunction and severe postoperative complications. How to avoid or mitigate organ ischemia-reperfusion injury has always been a research hotspot. NLRP3 Inflammasome has been considered to be an important link in inflammatory response. It has an indispensable role in maturation process of IL -1βand IL -18. We reviewed the research in recent yeas about the role of NLRP3 Inflammasome in organ ischemia-reperfusion injury in this paper. DOI: 10.11855/j.issn.0577-7402.2017.02.17

  17. [The influence of estradiol on histomorphology of skin flaps with ischemia reperfusion injury].

    Science.gov (United States)

    Jianlong, Wu; Ruixing, Hou; Guangliang, Zhou; Jihui, Ju

    2015-09-01

    To study the influence of estradiol on histomorphology of skin flaps with ischemia reperfusion injury. 48 adult male Wistar rats aged 12-14 weeks old, were randomly divided into control group (group I), ischemia-reperfusion group (group II), saline group (group III), estradiol group (group IV). Superficial epigastric artery axial flap, 3 cm x 6 cm in size, was made in the left lower quadrant abdominal of each rat. Flap model with ischemia-reperfusion injury was established by using the nondestructive micro vascular clamp to clamp the superficial epigastric artery. The general condition of the flap was observed after operation. At 7 days after operation, the survival rate of the flap was detected, the flaps were harvested to receive histology and ultrastructural observation. The neutrophils level of the superficial epigastric vein were tested. 7 days after operation, the survival rate of the flap in group IV was significantly higher than that in group II, III (P organization structure in flap.

  18. Hydrogen sulfide intervention in focal cerebral ischemia/reperfusion injury in rats

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    Xin-juan Li

    2015-01-01

    Full Text Available The present study aimed to explore the mechanism underlying the protective effects of hydrogen sulfide against neuronal damage caused by cerebral ischemia/reperfusion. We established the middle cerebral artery occlusion model in rats via the suture method. Ten minutes after middle cerebral artery occlusion, the animals were intraperitoneally injected with hydrogen sulfide donor compound sodium hydrosulfide. Immunofluorescence revealed that the immunoreactivity of P2X 7 in the cerebral cortex and hippocampal CA1 region in rats with cerebral ischemia/reperfusion injury decreased with hydrogen sulfide treatment. Furthermore, treatment of these rats with hydrogen sulfide significantly lowered mortality, the Longa neurological deficit scores, and infarct volume. These results indicate that hydrogen sulfide may be protective in rats with local cerebral ischemia/reperfusion injury by down-regulating the expression of P2X 7 receptors.

  19. Effect of total flavonoids of Radix Ilicis pubescentis on cerebral ischemia reperfusion model

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    Xiaoli Yan

    2017-03-01

    Full Text Available This paper aims to observe the effects of total flavonoids of Radix Ilicis pubescentis on mouse model of cerebral ischemia reperfusion. Mice were orally given different doses of total flavonoids of Radix Ilicis pubescentis 10 d, and were administered once daily. On the tenth day after the administration of 1 h in mice after anesthesia, we used needle to hook the bilateral common carotid artery (CCA for 10 min, with 10 min ischemia reperfusion, 10 min ischemia. Then we restored their blood supply, copy the model of cerebral ischemia reperfusion; We then had all mice reperfused for 24 h, and then took their orbital blood samples and measured blood rheology. We quickly removed the brain, with half of the brain having sagittal incision. Then we fixed the brains and sectioned them to observe the pathological changes of brain cells in the hippocampus and cortex. We also measured the other half sample which was made of brain homogenate of NO, NOS, Na+-K+-, ATP enzyme Mg2+-ATPase and Ca2+-ATPase. Acupuncture needle hook occlusion of bilateral common carotid arteries can successfully establish the model of cerebral ischemia reperfusion. After comparing with the model mice, we concluded that Ilex pubescens flavonoids not only reduce damage to the brain nerve cells in the hippocampus and cortex, but also significantly reduce the content of NO in brain homogenate, the activity of nitric oxide synthase (NOS and increases ATP enzyme activity (P < 0.05, P < 0.01. In this way, cerebral ischemia reperfusion injury is improved. Different dosages of Ilex pubescens flavonoids on mouse cerebral ischemia reperfusion model have good effects.

  20. Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein

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    Rui-Xin Yang

    2017-06-01

    Full Text Available Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB, against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro. SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke.

  1. Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein.

    Science.gov (United States)

    Yang, Rui-Xin; Lei, Jie; Wang, Bo-Dong; Feng, Da-Yun; Huang, Lu; Li, Yu-Qian; Li, Tao; Zhu, Gang; Li, Chen; Lu, Fang-Fang; Nie, Tie-Jian; Gao, Guo-Dong; Gao, Li

    2017-01-01

    Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB), against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro . SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke.

  2. CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Kaasbøll, Ole Jørgen; Moe, Ingvild Tronstad; Ahmed, Mohammad Shakil; Stang, Espen; Hagelin, Else Marie Valbjørn; Attramadal, Håvard

    2016-01-01

    Previous studies of ischemia-reperfusion injury (IRI) in hearts from mice with cardiac-restricted overexpression of CCN2 have shown that CCN2 increases tolerance towards IRI. The objectives of this study were to investigate to what extent post-ischemic administration of recombinant human CCN2 (rhCCN2) would limit infarct size and improve functional recovery and what signaling pathways are involved. Isolated mice hearts were perfused ad modum Langendorff, subjected to no-flow, global ischemia, and subsequently, exposed to mammalian cell derived, full-length (38-40kDa) rhCCN2 (250 nM) or vehicle during the first 15 min of a 60 min reperfusion period. Post-ischemic administration of rhCCN2 resulted in attenuation of infarct size from 58 ± 4% to 34 ± 2% (p concentration-dependent increase of cardiac phospho-GSK3β (serine-9) contents. We demonstrate that post-ischemic administration of rhCCN2 increases the tolerance of ex vivo-perfused murine hearts to IRI. Mechanistically, this postconditioning effect of rhCCN2 appeared to be mediated by activation of the reperfusion injury salvage kinase pathway as demonstrated by sensitivity to PI3 kinase inhibition and increased CCN2-induced phosphorylation of GSK3β (Ser-9). Thus, the rationale for testing rhCCN2-mediated post-ischemic conditioning of the heart in more complex models is established.

  3. The Effect of Etoricoxib on Hepatic Ischemia-Reperfusion Injury in Rats

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    Celalettin Semih Kunak

    2015-01-01

    Full Text Available Ischemia-reperfusion (I/R damage is known to be a pathological process which continues with the increase of oxidants and expands with the inflammatory response. There is not any study about protective effect of etoricoxib on the liver I/R damage in literature. Objective. This study investigates the effect of etoricoxib on oxidative stress induced by I/R of the rat liver. Material and Methods. Experimental animals were divided into four groups as liver I/R control (LIRC, 50 mg/kg etoricoxib + liver I/R (ETO-50, 100 mg/kg etoricoxib + liver I/R (ETO-100, and healthy group (HG. ETO-50 and ETO-100 groups were administered etoricoxib, while LIRC and HG groups were orally given distilled water by gavage. Hepatic artery was clamped for one hour to provide ischemia, and then reperfusion was provided for 6 hours. Oxidant, antioxidant, and COX-2 gene expressions were studied in the liver tissues. ALT and AST were measured. Results. Etoricoxib in 50 and 100 mg/kg doses changed the levels of oxidant/antioxidant parameters such as MDA, MPO, tGSH, GSHRd, GST, SOD, NO, and 8-OH/Gua in favour of antioxidants. Furthermore, etoricoxib prevented increase of COX-2 gene expression and ALT and AST levels. This important protective effect of etoricoxib on the rat liver I/R can be tested in the clinical setting.

  4. Sildenafil citrate protects skeletal muscle of ischemia-reperfusion injury: immunohistochemical study in rat model

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    Dinani Matoso Fialho de Oliveira Armstrong

    2013-04-01

    Full Text Available PURPOSE: To investigate the effect of sildenafil citrate (SC on skeletal muscle ischemia-reperfusion (IR injury in rats. METHODS: Adult male Wistar rats were randomized into three groups: vehicle-treated control (CTG, sildenafil citrate-treated (SCG, and sham group (SG. CTG and SCG had femoral artery occluded for 6 hours. Saline or 1 mg/kg of SC was given 5.5 hours after occlusion. SG had a similar procedure without artery occlusion. Soleus muscle samples were acquired 4 or 24h after the reperfusion. Immunohistochemistry caspase-3 analysis was used to estimate apoptosis using the apoptotic ratio (computed as positive/negative cells. Wilcoxon rank-sum or Kruskal-Wallis tests were used to assess differences among groups. RESULTS: Eighteen animals were included in the 4h reperfusion groups and 21 animals in the 24h reperfusion groups. The mean apoptotic ratio was 0.18±0.1 for the total cohort; 0.14±0.06 for the 4h reperfusion groups and 0.19±0.08 for the 24h groups (p<0.05. The SCG had lower caspase-3 ratio compared to the control groups at the 24h reperfusion time point (p<0.05. CONCLUSION: Sildenafil citrate administration after the onset of the ischemic injury reduces IR-induced cellular damage in skeletal muscle in this rat hindlimb ischemia model.

  5. Comparative Effects of Triflusal, S-Adenosylmethionine, and Dextromethorphan over Intestinal Ischemia/Reperfusion Injury

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    Carlos R. Cámara-Lemarroy

    2011-01-01

    Full Text Available Ischemia/reperfusion (I/R is a condition that stimulates an intense inflammatory response. No ideal treatment exists. Triflusal is an antiplatelet salicylate derivative with anti-inflammatory effects. S-adenosylmethionine is a metabolic precursor for glutathione, an endogenous antioxidant. Dextromethorphan is a low-affinity N-methyl-D-aspartate receptor inhibitor. There is evidence that these agents modulate some of the pathways involved in I/R physiopathology. Intestinal I/R was induced in rats by clamping the superior mesenteric artery for 60 minutes, followed by 60 minutes of reperfusion. Rats either received saline or the drugs studied. At the end of the procedure, serum concentrations of tumor necrosis factor-alpha (TNF-alpha, malonaldehyde (MDA, and total antioxidant capacity (TAC were determined and intestinal morphology analyzed. I/R resulted in tissue damage, serum TNF-alpha and MDA elevations, and depletion of TAC. All drugs showed tissue protection. Only triflusal reduced TNF-alpha levels. All drugs lowered MDA levels, but only triflusal and S-adenosylmethionine maintained the serum TAC.

  6. Effects of silibinin and ethanol on skeletal muscle ischemia-reperfusion injury

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    Yusuf Ergün

    2013-03-01

    Full Text Available PURPOSE: To investigate the potential beneficial effect of silibinin in ischemia-reperfusion injury (IRI of skeletal muscle. METHODS: Under urethane anesthesia, four experimental groups were established in Balb/c mice: I Sham-control, II IRI (Tourniquet-induced (2+1 h, III IRI+ethanol (10%, and IV IRI+silibinin (50 mg/kg/IP. The viability of muscle (left was evaluated by the triphenyltetrazolium chloride dye method and calculated as the percentage of the contralateral control muscle (right. Malondialdehyde, superoxide dismutase, and catalase were measured in the gastrocnemius muscle via a spectrophotometer. RESULTS:The viability of gastrocnemius muscle in group II was significantly lower in comparison with that seen in group I. The administration of either ethanol or silibinin rendered the tissues to recover nearly to the baseline level. Additionally, malondialdehyde levels were higher in group II than those in group I. The application of silibinin prior to the reperfusion attenuated these to the control levels. However, malondialdehyde levels in the ethanol administrated group were reduced as well. The enhanced superoxide dismutase activity seen in the IRI group was not diminished in the animals treated with either silibinin or ethanol. Similarly, there were no differences between groups regarding the catalase activities. CONCLUSION: Ethanol seems to be effective in attenuating IRI in skeletal muscle and no definite conclusion can be made on silibinin effect.

  7. PARP Inhibition Attenuates Histopathological Lesion in Ischemia/Reperfusion Renal Mouse Model after Cold Prolonged Ischemia

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    Raimundo M. G. del Moral

    2013-01-01

    Full Text Available We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN and other renal lesions related to prolonged cold ischemia/reperfusion (IR in kidneys preserved at 4°C in University of Wisconsin (UW solution. Material and Methods. We used 30 male Parp1+/+ wild-type and 15 male Parp10/0 knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinylbutoxyl]-1(2H-isoquinolinone (DPQ at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ. We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp10/0 knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation.

  8. Protective effect of soluble eggshell membrane protein hydrolysate on cardiac ischemia/reperfusion injury

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    Tao Yang

    2015-12-01

    Full Text Available Background: Soluble eggshell membrane protein (SEP has been proved to hold the antioxidant activity. The functional role of SEP on cardioprotection was investigated in vivo and in vitro. Methods: Rats and cardiomyocytes were pretreated with SP2, a hydrolysate attained from SEP, and then subjected to ischemia/reperfusion (I/R or hypoxia/reoxygenation (H/R and hydrogen peroxide, respectively. The measurement of myocardial infarct size, cell apoptosis assay, cell viability assay, and caspase activity assay were performed on rats and cardiomyocytes. Results: The results showed that the treatment of SP2 induced the resistance to I/R or H/R injury on rats and cardiomyocytes as indicated by decreased infarct size and decreased cellular apoptosis. The cardioprotective roles of SP2 were partly resulted from the downregulated expression and activity of caspase-3 in which the effect was similar to the caspase inhibitor, z-VAD-fmk, and could be rescued by caspase activator, PAC-1. Conclusions: This investigation has demonstrated that SP2 attenuated the damage of I/R and H/R on rats and cardiomyocytes by the caspase-dependent pathway. This cardioprotective effect of SP2 suggested a novel therapeutic agent of SEP for ischemic-related heart diseases.

  9. Mechanism of the Protective Effect of Yulangsan Flavonoid on Myocardial Ischemia/Reperfusion Injury in Rats

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    Xudong Zhang

    2014-09-01

    Full Text Available Aims: Effect and mechanism of Yulangsan flavonoid (YLSF on rat myocardial ischemia/reperfusion injury (MI/RI has been investigated. Methods: Sprague-Dawley (SD rats were randomly divided into seven groups (sham group, model group and NS group: 2 mL of normal saline/kg body weight was administered; diltiazem group: 5 mg of diltiazem hydrochloride/kg body weight was administered; YLSFL, YLSFM and YLSFH groups: 20, 40 and 80 mg of YLSF/kg body weight was administered and the MI/RI model was established. Myocardial infarct area, levels of myocardial enzymes and nitric oxide synthase (NOS were measured. Caspase-3 and adenine nucleotide translocator-1 (ANT1 mRNA expression were evaluated by reverse transcription polymerase chain reaction (RT-PCR. Pathological structure and cardiocyte ultrastructure were also analysed. Results: Compared with the MI/RI group, pretreatment with YLSF or diltiazem hydrochloride decreased the infarct area, levels of inducible nitric oxide synthase (iNOS, caspase-3 as well as the leakage of myocardial enzyme and increased activities of total nitric oxide synthase (tNOS as well as constitutive nitric oxide synthase (cNOS. Cellular edema and the infiltration of inflammatory cells were alleviated. Conclusions: The experiment showed that YLSF protected the heart against MI/RI, possibly by reducing lipid peroxidation damage, regulating NOS activity and modulating the apoptosis genes expression.

  10. Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats.

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    Ozyigit, Filiz; Kucuk, Aysegul; Akcer, Sezer; Tosun, Murat; Kocak, Fatma Emel; Kocak, Cengiz; Kocak, Ahmet; Metineren, Hasan; Genc, Osman

    2015-08-26

    Ebselen is an organoselenium compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of ebselen pretreatment in rats with experimental sciatic nerve ischemia-reperfusion (I/R) injury. Adult male Sprague Dawley rats were divided into four groups (N = 7 in each group). Before sciatic nerve I/R was induced, ebselen was injected intraperitoneally at doses of 15 and 30 mg/kg. After a 2 h ischemia and a 3 h reperfusion period, sciatic nerve tissues were excised. Tissue levels of malondialdehyde (MDA) and nitric oxide (NO), and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured. Sciatic nerve tissues were also examined histopathologically. The 15 mg/kg dose of ebselen reduced sciatic nerve damage and apoptosis (pebselen. Conversely, the 30 mg/kg dose of ebselen increased sciatic nerve damage, apoptosis, iNOS positive cells (pebselen may cause different effects depending on the dose employed. Ebselen may be protective against sciatic nerve I/R injury via antioxidant and antiapoptotic activities at a 15 mg/kg dose, conversely higher doses may cause detrimental effects.

  11. Effects of ebselen on ischemia/reperfusion injury in rat brain.

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    Aras, M; Altaş, M; Meydan, S; Nacar, E; Karcıoğlu, M; Ulutaş, K T; Serarslan, Y

    2014-10-01

    Interruption of blood flow may result in considerable tissue damage via ischemia/reperfusion (I/R) injury-induced oxidative stress in brain tissues. The aim of the present study was to investigate the effects of Ebselen treatment in short-term global brain I/R injury in rats. The study was carried out on 27 Wistar-albino rats, divided into three groups including Sham group (n = 11), I/R group (n = 8) and I/R+Ebselen group (n = 8). Malondialdehyde (MDA) levels were significantly increased in I/R group in comparison with the Sham group and I/R+Ebselen group (p Ebselen (p Ebselen group when compared with Sham group (p Ebselen group when compared with Sham (p Ebselen showed morphological improvement. Ebselen has neuron-protective effects due to its antioxidant properties as shown by the decrease in MDA overproduction, increase in SOD activity and the histological improvement after administration of Ebselen to I/R in brain tissue.

  12. Colchicine protects rat skeletal muscle from ischemia/reperfusion injury by suppressing oxidative stress and inflammation

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    Liangrong Wang

    2016-06-01

    Full Text Available Objective(s: Neutrophils play an important role in ischemia/reperfusion (IR induced skeletal muscle injury. Microtubules are required for neutrophil activation in response to various stimuli. This study aimed to investigate the effects of colchicine, a microtubule-disrupting agent, on skeletal muscle IR injury in a rat hindlimb ischemia model. Materials and Methods: Twenty-one Sprague-Dawley rats were randomly allocated into three groups: IR group, colchicine treated-IR (CO group and sham operation (SM group. Rats of both the IR and CO groups were subjected to 3 hr of ischemia by clamping the right femoral artery followed by 2 hr of reperfusion. Colchicine (1 mg/kg was administrated intraperitoneally prior to hindlimb ischemia in the CO group. After 2 hr of reperfusion, we measured superoxide dismutase (SOD and myeloperoxidase (MPO activities, and malondialdehyde (MDA, tumor necrosis factor (TNF-α and interleukin (IL-1β levels in the muscle samples. Plasma creatinine kinase (CK and lactate dehydrogenase (LDH levels were measured. We also evaluated the histological damage score and wet/dry weight (W/D ratio. Results: The histological damage score, W/D ratio, MPO activity, MDA, TNF-α and IL-1β levels in muscle tissues were significantly increased, SOD activity was decreased, and plasma CK and LDH levels were remarkably elevated in both the IR and CO groups compared to the SM group (P

  13. Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion.

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    Yamamoto, Tsunehisa; Tamaki, Kayoko; Shirakawa, Kohsuke; Ito, Kentaro; Yan, Xiaoxiang; Katsumata, Yoshinori; Anzai, Atsushi; Matsuhashi, Tomohiro; Endo, Jin; Inaba, Takaaki; Tsubota, Kazuo; Sano, Motoaki; Fukuda, Keiichi; Shinmura, Ken

    2016-04-15

    Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol 308: H894-H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1(-/-)) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1(-/-)mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1(-/-)mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3(-/-)) mice treated with CR was similar to that in the ad libitum-fed C3(-/-)mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting

  14. Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury.

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    Pressly, Jeffrey D; Mustafa, Suni M; Adibi, Ammaar H; Alghamdi, Sahar; Pandey, Pankaj; Roy, Kuldeep K; Doerksen, Robert J; Moore, Bob M; Park, Frank

    2018-02-01

    Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with elevated rates of mortality. Therapies to treat AKI are currently not available, so identification of new targets that can be modulated to ameliorate renal damage upon diagnosis of AKI is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295 [3'-methyl-4-(2-(thiophen-2-yl)propan-2-yl)biphenyl-2,6-diol], was designed, synthesized, and tested in vitro and in silico. Molecular docking of SMM-295 into a CB2 active-state homology model showed that SMM-295 interacts well with key amino acids to stabilize the active state. In human embryonic kidney 293 cells, SMM-295 was capable of reducing cAMP production with 66-fold selectivity for CB2 versus cannabinoid receptor 1 and dose-dependently increased mitogen-activated protein kinase and Akt phosphorylation. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a common model to mimic human AKI, where SMM-295 was immediately administered upon reperfusion of the kidneys after the ischemia episode. Histologic damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with reduced plasma markers of renal dysfunction (i.e., creatinine and neutrophil gelatinase-associated lipocalin) in SMM-295-treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL)-positive cells compared with vehicle-treated kidneys after IRI. These data suggest that selective CB2 receptor activation could be a potential therapeutic target in the treatment of AKI. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  15. The effect of Aqueous Purslane (Portulaca Oleracea Extract on Renal Ischemia/Reperfusion Injury in Rat

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    syead Reza Fatemi Tabatabaei

    2015-07-01

    Full Text Available Background: According to the previous studies Portulaca oleracea (PO has antioxidative effects and several factors such as oxidative stress is involved in the renal injury caused by ischemia - reperfusion (I/R. Therefore, the goal of present study is to evaluate the renal I/R injury in rats received aqueous extracts of PO (AEPO. Material and Methods: First, the right nephrectomy was performed in adult male Wistar rats and after 20 days they were divided into 5 groups (6=n. Sham operated+vehicle (sham, sham operated+ AEPO300mg/kg (AEPO group, I/R, AEPO150+I/R and AEPO300+I/R. Each group was treated orally for 5 consecutive days by 150 or 300 mg/kg of either AEPO or saline. On the fifth day of treatment, I/R (45 min ischemia/24 hours reperfusion or sham operation was performed on the left kidney and amounts of urea and creatinine in serum and malondialdehyde (MDA, superoxide dismutase (SOD, glutathione (GSH and total antioxidant activity (TAA in the kidney tissue were measured. Comparisons between groups were analyzed by ANOVA and LSD test. P values of 0.05 or less were considered statistically significant. Results: Induction of I/R increased urea and creatinine levels. AEPO had no effect on serum urea and creatinine, of non-ischemic animals, but increased the levels of urea and creatinine in I/R and treatment groups. SOD activity was significantly higher in all groups (except AEPO300 group compared to the sham group. However the levels of MDA, GSH and TAA of I/R and treatment groups did not show any significant differences in comparison to sham group. Conclusion: According to the results of this study, the PO aqueous extract did not ameliorate the I/R injury and even possibly some ingredients in the extract aggravate the renal I/R injury.

  16. Hydrogen sulfide preconditioning protects rat liver against ischemia/reperfusion injury by activating Akt-GSK-3β signaling and inhibiting mitochondrial permeability transition.

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    Qingqing Zhang

    Full Text Available Hydrogen sulfide (H2S is the third most common endogenously produced gaseous signaling molecule, but its impact on hepatic ischemia/reperfusion (I/R injury, especially on mitochondrial function, remains unclear. In this study, rats were randomized into Sham, I/R, ischemia preconditioning (IPC or sodium hydrosulfide (NaHS, an H2S donor preconditioning groups. To establish a model of segmental (70% warm hepatic ischemia, the hepatic artery, left portal vein and median liver lobes were occluded for 60 min and then unclamped to allow reperfusion. Preconditioning with 12.5, 25 or 50 μmol/kg NaHS prior to the I/R insult significantly increased serum H2S levels, and, similar to IPC, NaHS preconditioning decreased alanine aminotransferase (ALT and aspartate aminotransferase (AST levels in the plasma and prevented hepatocytes from undergoing I/R-induced necrosis. Moreover, a sub-toxic dose of NaHS (25 μmol/kg did not disrupt the systemic hemodynamics but dramatically inhibited mitochondrial permeability transition pore (MPTP opening and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that NaHS preconditioning markedly increased the expression of phosphorylated protein kinase B (p-Akt, phosphorylated glycogen synthase kinase-3 beta (p-GSK-3β and B-cell lymphoma-2 (Bcl-2 and decreased the release of mitochondrial cytochrome c and cleaved caspase-3/9 levels. Therefore, NaHS administration prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through the inhibition of MPTP opening and the activation of Akt-GSK-3β signaling. Furthermore, this study provides experimental evidence for the clinical use of H2S to reduce liver damage after perioperative I/R injury.

  17. The Effect of Erythropoietin on Testosterone Levels During Ischemia Reperfusion Injury in Rats

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    Tsompos C.

    2016-11-01

    Full Text Available Objective: This experimental study examined the effect of erythropoietin (Epo in a rat model and particularly in an adrenal ischemia-reperfusion (IR protocol. The effect of that molecule was studied biochemically using blood mean testosterone levels (T.

  18. Study on pretreatment of FPS-1 in rats with hepatic ischemia-reperfusion injury.

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    Lin, Shiqing; Liu, Kexuan; Wu, Weikang; Chen, Chao; Wang, Zhi; Zhang, Xuanhong

    2009-01-01

    This study was designed to determine whether FPS-1, the water-soluble polysaccharide isolated from fuzi, protected against hepatic damage in hepatic ischemia-reperfusion injury in rats, and its mechanism. SD rats were subjected to 60 min of hepatic ischemia, followed by 120 min reperfusion. FPS-1 (160 mg/kg/day) was administered orally for 5 days before ischemia-reperfusion injury in treatment group. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin (ALB) were assayed to evaluate liver functions. Liver samples were taken for histological examination and determination of malondialdehyde (MDA), superoxide dismutase (SOD), that catalase (CAT) in liver. Na(+)-K(+)-ATPase and Ca(2+)-ATPase in mitochondria were measured with colorimetry method. Morphological changes were also investigated by using both light microscopy and electron microscopy (EM). In addition, apoptosis and oncosis were detected by Annexin V-FITC/PI immunofluorescent flow cytometry analysis. Serum AST and ALT levels were elevated in groups exposed to ischemia-reperfusion (p FPS-1 reversed all these biochemical parameters as well as histological alterations, evidently by increased SOD, CAT, reduced MDA and histological scores compared to the model group (p FPS-1 could attenuate the necrotic states by the detection of immunofluorescent flow cytometry analysis. Pretreatment with FPS-1 reduced hepatic ischemia-reperfusion injury through its potent antioxidative effects and attenuation of necrotic states.

  19. Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice

    NARCIS (Netherlands)

    J.R. Mitchell (James); M. Verweij (Marielle); K. Brand (Karl); H.W.M. van de Ven (Marieke); N.N.T. Goemaere (Natascha); S. van den Engel (Sandra); T. Chu (Timothy); F. Forrer (Flavio); C. Müller (Cristina); M. de Jong (Marion); W.F.J. van IJcken (Wilfred); J.N.M. IJzermans (Jan); J.H.J. Hoeijmakers (Jan); R.W.F. de Bruin (Ron)

    2010-01-01

    textabstractDietary restriction (DR) extends lifespan and increases resistance to multiple forms of stress, including ischemia reperfusion injury to the brain and heart in rodents. While maximal effects on lifespan require long-term restriction, the kinetics of onset of benefits against acute stress

  20. Hydrogen, a potential safeguard for graft-versus-host disease and graft ischemia-reperfusion injury?

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    Yuan, Lijuan; Shen, Jianliang

    2016-01-01

    Post-transplant complications such as graft-versus-host disease and graft ischemia-reperfusion injury are crucial challenges in transplantation. Hydrogen can act as a potential antioxidant, playing a preventive role against post-transplant complications in animal models of multiple organ transplantation. Herein, the authors review the current literature regarding the effects of hydrogen on graft ischemia-reperfusion injury and graft-versus-host disease. Existing data on the effects of hydrogen on ischemia-reperfusion injury related to organ transplantation are specifically reviewed and coupled with further suggestions for future work. The reviewed studies showed that hydrogen (inhaled or dissolved in saline) improved the outcomes of organ transplantation by decreasing oxidative stress and inflammation at both the transplanted organ and the systemic levels. In conclusion, a substantial body of experimental evidence suggests that hydrogen can significantly alleviate transplantation-related ischemia-reperfusion injury and have a therapeutic effect on graft-versus-host disease, mainly via inhibition of inflammatory cytokine secretion and reduction of oxidative stress through several underlying mechanisms. Further animal experiments and preliminary human clinical trials will lay the foundation for hydrogen use as a drug in the clinic. PMID:27652837

  1. Intestinal ischemia-reperfusion injury augments intestinal mucosal injury and bacterial translocation in jaundiced rats.

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    Yüksek, Yunus Nadi; Kologlu, Murat; Daglar, Gül; Doganay, Mutlu; Dolapci, Istar; Bilgihan, Ayse; Dolapçi, Mete; Kama, Nuri Aydin

    2004-01-01

    The aim of this study was to evaluate local effects and degree of bacterial translocation related with intestinal ischemia-reperfusion injury in a rat obstructive jaundice model. Thirty adult Sprague-Dawley rats (200-250 g) were divided into three groups; including Group 1 (jaundice group), Group 2 (jaundice-ischemia group) and Group 3 (ischemia group). All rats had 2 laparotomies. After experimental interventions, tissue samples for translocation; liver and ileum samples for histopathological examination, 25 cm of small intestine for mucosal myeloperoxidase and malondialdehyde levels and blood samples for biochemical analysis were obtained. Jaundiced rats had increased liver enzyme levels and total and direct bilirubin levels (p<0.05). Intestinal mucosal myeloperoxidase and malondialdehyde levels were found to be high in intestinal ischemia-reperfusion groups (p<0.05). Intestinal mucosal damage was more severe in rats with intestinal ischemia-reperfusion after bile duct ligation (p<0.05). Degree of bacterial translocation was also found to be significantly high in these rats (p<0.05). Intestinal mucosa is disturbed more severely in obstructive jaundice with the development of ischemia and reperfusion. Development of intestinal ischemia-reperfusion in obstructive jaundice increases bacterial translocation.

  2. The Effects of α-Lipoic Acid against Testicular Ischemia-Reperfusion Injury in Rats

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    Seda Ozbal

    2012-01-01

    Full Text Available Testicular torsion is one of the urologic emergencies occurring frequently in neonatal and adolescent period. Testis is sensitive to ischemia-reperfusion injury, and, therefore, ischemia and consecutive reperfusion cause an enhanced formation of reactive oxygen species that result in testicular cell damage and apoptosis. α-lipoic acid is a free radical scavenger and a biological antioxidant. It is widely used in the prevention of oxidative stress and cellular damage. We aimed to investigate the protective effect of α-lipoic acid on testicular damage in rats subjected to testicular ischemia-reperfusion injury. 35 rats were randomly divided into 5 groups: control, sham operated, ischemia, ischemia-reperfusion, and ischemia-reperfusion +lipoic acid groups, 2 h torsion and 2 h detorsion of the testis were performed. Testicular cell damage was examined by H-E staining. TUNEL and active caspase-3 immunostaining were used to detect germ cell apoptosis. GPx , SOD activity, and MDA levels were evaluated. Histological evaluation showed that α-lipoic acid pretreatment reduced testicular cell damage and decreased TUNEL and caspase-3-positive cells. Additionally, α-lipoic acid administration decreased the GPx and SOD activity and increased the MDA levels. The present results suggest that LA is a potentially beneficial agent in protecting testicular I/R in rats.

  3. Growth Arrest-Specific Protein 6 is Hepatoprotective Against Ischemia/Reperfusion Injury

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    Llacuna, Laura; Bárcena, Cristina; Bellido-Martín, Lola; Fernández, Laura; Stefanovic, Milica; Marí, Montserrat; García-Ruiz, Carmen; Fernández-Checa, José C.; de Frutos, Pablo García; Morales, Albert

    2010-01-01

    Growth arrest-specific gene 6 (GAS6) promotes growth and cell survival during tissue repair and development in different organs, including the liver. However, the specific role of GAS6 in liver ischemia/reperfusion (I/R) injury has not been previously addressed. Here, we report an early increase in serum GAS6 levels following I/R exposure. Moreover, unlike wild type mice, Gas6-/- mice were highly sensitive to partial hepatic I/R, with 90% of mice dying within 12 hours of reperfusion due to massive hepatocellular injury. I/R induced early hepatic AKT phosphorylation in wild type but not in Gas6-/- mice, without significant changes in JNK phosphorylation or nuclear NF-κB translocation, whereas hepatic IL-1β and TNF mRNA levels were higher in Gas6-/- mice compared to wild type mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes protecting them from hypoxia-induced cell death, while GAS6 diminished lipopolysaccharide (LPS)-induced cytokine expression (IL-1β and TNF) in murine macrophages. Finally, in vivo recombinant GAS6 treatment not only rescued GAS6 knockout mice from I/R-induced severe liver damage, but also attenuated hepatic damage in wild type mice following I/R. In conclusion, our data uncover GAS6 as a new player in liver I/R injury, emerging as a potential therapeutic target to reduce post-ischemic hepatic damage. PMID:20730776

  4. Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury.

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    Llacuna, Laura; Bárcena, Cristina; Bellido-Martín, Lola; Fernández, Laura; Stefanovic, Milica; Marí, Montserrat; García-Ruiz, Carmen; Fernández-Checa, José C; García de Frutos, Pablo; Morales, Albert

    2010-10-01

    Growth arrest-specific gene 6 (GAS6) promotes growth and cell survival during tissue repair and development in different organs, including the liver. However, the specific role of GAS6 in liver ischemia/reperfusion (I/R) injury has not been previously addressed. Here we report an early increase in serum GAS6 levels after I/R exposure. Moreover, unlike wild-type (WT) mice, Gas6(-/-) mice were highly sensitive to partial hepatic I/R, with 90% of the mice dying within 12 hours of reperfusion because of massive hepatocellular injury. I/R induced early hepatic protein kinase B (AKT) phosphorylation in WT mice but not in Gas6(-/-) mice without significant changes in c-Jun N-terminal kinase phosphorylation or nuclear factor kappa B translocation, whereas hepatic interleukin-1β (IL-1β) and tumor necrosis factor (TNF) messenger RNA levels were higher in Gas6(-/-) mice versus WT mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes and thus protected them from hypoxia-induced cell death, whereas GAS6 diminished lipopolysaccharide-induced cytokine expression (IL-1β and TNF) in murine macrophages. Finally, recombinant GAS6 treatment in vivo not only rescued GAS6 knockout mice from severe I/R-induced liver damage but also attenuated hepatic damage in WT mice after I/R. Our data have revealed GAS6 to be a new player in liver I/R injury that is emerging as a potential therapeutic target for reducing postischemic hepatic damage.

  5. Effects of propionyl-L-carnitine on ischemia-reperfusion injury in hamster cheek pouch microcirculation.

    Science.gov (United States)

    Lapi, Dominga; Sabatino, Lina; Altobelli, Giovanna Giuseppina; Mondola, Paolo; Cimini, Vincenzo; Colantuoni, Antonio

    2010-01-01

    Propionyl-l-carnitine (pLc) exerts protective effects in different experimental models of ischemia-reperfusion (I/R). The aim of the present study was to assess the effects of intravenously and topically applied pLc on microvascular permeability increase induced by I/R in the hamster cheek pouch preparation. The hamster cheek pouch microcirculation was visualized by fluorescence microscopy. Microvascular permeability, leukocyte adhesion to venular walls, perfused capillary length, and capillary red blood cell velocity (V(RBC)) were evaluated by computer-assisted methods. E-selectin expression was assessed by in vitro analysis. Lipid peroxidation and reactive oxygen species (ROS) formation were determined by thiobarbituric acid-reactive substances (TBARS) and 2'-7'-dichlorofluorescein (DCF), respectively. In control animals, I/R caused a significant increase in permeability and in the leukocyte adhesion in venules. Capillary perfusion and V(RBC) decreased. TBARS levels and DCF fluorescence significantly increased compared with baseline. Intravenously infused pLc dose-dependently prevented leakage and leukocyte adhesion, preserved capillary perfusion, and induced vasodilation at the end of reperfusion, while ROS concentration decreased. Inhibition of nitric oxide synthase prior to pLc caused vasoconstriction and partially blunted the pLc-induced protective effects; inhibition of the endothelium-derived hyperpolarizing factor (EDHF) abolished pLc effects. Topical application of pLc on cheek pouch membrane produced the same effects as observed with intravenous administration. pLc decreased the E-selectin expression. pLc prevents microvascular changes induced by I/R injury. The reduction of permeability increase could be mainly due to EDHF release induce vasodilatation together with NO. The reduction of E-selectin expression prevents leukocyte adhesion and permeability increase.

  6. Effects of propionyl-L-carnitine on ischemia-reperfusion injury in hamster cheek pouch microcirculation.

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    Dominga Lapi

    2010-10-01

    Full Text Available Background and Purpose Propionyl-L-carnitine (pLc exerts protective effects in different experimental models of ischemia-reperfusion (I/R. The aim of the present study was to assess the effects of intravenously and topically applied pLc on microvascular permeability increase induced by I/R in the hamster check pouch preparation. Methods The hamster check pouch microcirculation was visualized by fluorescence microscopy. Microvascular permeability, leukocyte adhesion to venular walls, perfused capillary length and capillary red blood cell velocity (VRBC were evaluated by computer-assisted methods. E-selectin expression was assessed by in vitro analysis. Lipid peroxidation and reactive oxygen species (ROS formation were determined by thiobarbituric acid-reactive substances (TBARS and 2’-7’-dichlorofluorescein (DCF, respectively. Results In control animals, I/R caused a significant increase in permeability and in the leukocyte adhesion in venules. Capillary perfusion and VRBC decreased. TBARS levels and DCF fluorescence significantly increased compared with baseline. Intravenously infused pLc dose-dependently prevented leakage and leukocyte adhesion, preserved capillary perfusion and induced vasodilation at the end of reperfusion, while ROS concentration decreased. Inhibition of nitric oxide synthase prior to pLc caused vasoconstriction and partially blunted the pLc-induced protective effects; inhibition of the endothelium-derived hyperpolarizing factor (EDHF abolished pLc effects. Topical application of pLc on check pouch membrane produced the same effects as observed with intravenous administration. pLc decreased the E-selectin expression. Conclusions pLc prevents microvascular changes induced by I/R injury. The reduction of permeability increase could be mainly due to EDHF release induce vasodilatation together with NO. The reduction of E-selectin expression prevents leukocyte adhesion and permeability increase.

  7. Glycogen synthase kinase-3 inhibition attenuates fibroblast activation and development of fibrosis following renal ischemia-reperfusion in mice

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    Shailendra P. Singh

    2015-08-01

    Full Text Available Glycogen synthase kinase-3β (GSK3β is a serine/threonine protein kinase that plays an important role in renal tubular injury and regeneration in acute kidney injury. However, its role in the development of renal fibrosis, often a long-term consequence of acute kidney injury, is unknown. Using a mouse model of renal fibrosis induced by ischemia-reperfusion injury, we demonstrate increased GSK3β expression and activity in fibrotic kidneys, and its presence in myofibroblasts in addition to tubular epithelial cells. Pharmacological inhibition of GSK3 using TDZD-8 starting before or after ischemia-reperfusion significantly suppressed renal fibrosis by reducing the myofibroblast population, collagen-1 and fibronectin deposition, inflammatory cytokines, and macrophage infiltration. GSK3 inhibition in vivo reduced TGF-β1, SMAD3 activation and plasminogen activator inhibitor-1 levels. Consistently in vitro, TGF-β1 treatment increased GSK3β expression and GSK3 inhibition abolished TGF-β1-induced SMAD3 activation and α-smooth muscle actin (α-SMA expression in cultured renal fibroblasts. Importantly, overexpression of constitutively active GSK3β stimulated α-SMA expression even in the absence of TGF-β1 treatment. These results suggest that TGF-β regulates GSK3β, which in turn is important for TGF-β–SMAD3 signaling and fibroblast-to-myofibroblast differentiation. Overall, these studies demonstrate that GSK3 could promote renal fibrosis by activation of TGF-β signaling and the use of GSK3 inhibitors might represent a novel therapeutic approach for progressive renal fibrosis that develops as a consequence of acute kidney injury.

  8. Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart.

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    Mourouzis, I; Dimopoulos, A; Saranteas, T; Tsinarakis, N; Livadarou, E; Spanou, D; Kokkinos, A D; Xinaris, C; Pantos, C; Cokkinos, D V

    2009-01-01

    There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (Phearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (Phearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.

  9. Baicalin Ameliorates H2O2 Induced Cytotoxicity in HK-2 Cells through the Inhibition of ER Stress and the Activation of Nrf2 Signaling

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    Miao Lin

    2014-07-01

    Full Text Available Renal ischemia-reperfusion injury plays a key role in renal transplantation and greatly affects the outcome of allograft. Our previous study proved that Baicalin, a flavonoid glycoside isolated from Scutellaria baicalensis, protects kidney from ischemia-reperfusion injury. This study aimed to study the underlying mechanism in vitro. Human renal proximal tubular epithelial cell line HK-2 cells were stimulated by H2O2 with and without Baicalin pretreatment. The cell viability, apoptosis and oxidative stress level were measured. The expression of endoplasmic reticulum (ER stress hallmarks, such as binding immunoglobulin protein (BiP and C/EBP homologous protein (CHOP, were analyzed by western blot and real-time PCR. NF-E2-related factor 2 (Nrf2 expression was also measured. In the H2O2 group, cell viability decreased and cell apoptosis increased. Reactive Oxygen Species (ROS and Glutathione/Oxidized Glutathione (GSH/GSSG analysis revealed increased oxidative stress. ER stress and Nrf2 signaling also increased. Baicalin pretreatment ameliorated H2O2-induced cytotoxicity, reduced oxidative stress and ER stress and further activated the anti-oxidative Nrf2 signaling pathway. The inducer of ER stress and the inhibitor of Nrf2 abrogated the protective effects, while the inhibitor of ER stress and the inducer of Nrf2 did not improve the outcome. This study revealed that Baicalin pretreatment serves a protective role against H2O2-induced cytotoxicity in HK-2 cells, where the inhibition of ER stress and the activation of downstream Nrf2 signaling are involved.

  10. Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury

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    He, Haiyan; Huh, Jin; Wang, Huihua; Kang, Yi; Lou, Jianshi; Xu, Zhelong

    2016-01-01

    Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2 h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured. Morphine reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. - Highlights: • Morphine induced mito-Src phosphorylation and reduced infarct size in rat hearts. • Morphine failed to reduce I/R-induced LDH release in Src-silencing HL-1 cells. • Morphine prevented mitochondria damage caused by I/R through Src. • Morphine reduced

  11. Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury

    Energy Technology Data Exchange (ETDEWEB)

    He, Haiyan [Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin 300070 (China); Department of Pharmacology, Tianjin Medical University, Tianjin 300070 (China); Huh, Jin [Department of Anesthesia and Pain Medicine, Medical College, Kangwon National University, Chuncheon City (Korea, Republic of); Wang, Huihua [Department of Anesthesiology, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province (China); Kang, Yi; Lou, Jianshi [Department of Pharmacology, Tianjin Medical University, Tianjin 300070 (China); Xu, Zhelong, E-mail: zxu@tmu.edu.cn [Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin 300070 (China)

    2016-01-01

    Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2 h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (ΔΨm) were measured. Morphine reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of ΔΨm at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. - Highlights: • Morphine induced mito-Src phosphorylation and reduced infarct size in rat hearts. • Morphine failed to reduce I/R-induced LDH release in Src-silencing HL-1 cells. • Morphine prevented mitochondria damage caused by I/R through Src. • Morphine

  12. Neuroprotective effect of resveratrol against brain ischemia reperfusion injury in rats entails reduction of DJ-1 protein expression and activation of PI3K/Akt/GSK3b survival pathway.

    Science.gov (United States)

    Abdel-Aleem, Ghada A; Khaleel, Eman F; Mostafa, Dalia G; Elberier, Lydia K

    2016-10-01

    In the current study, we aimed to investigate the mechanistic role of DJ-1/PI3K/Akt survival pathway in ischemia/reperfusion (I/R) induced cerebral damage and to investigate if the resveratrol (RES) mediates its ischemic neuroptotection through this pathway. RES administration to Sham rats boosted glutathione level and superoxide dismutase activity and downregulated inducible nitric oxide synthase expression without affecting redox levels of DJ-1 forms or components of PI3K/Akt pathway including PTEN, p-Akt or p/p-GSK3b. However, RES pre-administration to I/R rats reduced infarction area, oxidative stress, inflammation and apoptosis. Concomitantly, RES ameliorated the decreased levels of oxidized forms of DJ-1 and enhancing its reduction, increased the nuclear protein expression of Nfr-2 and led to activation of PI3K/Akt survival pathway. In conclusion, overoxidation of DJ-1 is a major factor that contributes to post-I/R cerebral damage and its reduction by RES could explain the neuroprotection offered by RES.

  13. IMPACT OF SEVOFLURANE AND ACETYLCYSTEINE ON ISCHEMIA-REPERFUSION INJURY OF THE LIVER FROM BRAIN-DEAD DONOR

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    A. E. Shcherba

    2013-01-01

    Full Text Available Aim. The purpose of our work was to estimate the impact of preconditioning with acetylcysteine and sevoflurane on ischemia-reperfusion injury of cadaveric donor liver with marginal features. Methods and results. In this prospective randomized controlled trial we recruited 21 heart beating donors with brain death. We assigned 11 donors to the study group, and 10 donors to the control group. Morphological characteristics of ischemia- reperfusion injury in both groups were analyzed. Conclusion. Use of pharmacological preconditioning with acetylcysteine and sevoflurane resulted in necrosis and hepatocyte apoptosis reduction as compared to the control group, thereby had a protective effect against ischemia-reperfusion injury. 

  14. Comparison of the effects of dexmedetomidine administered at two different times on renal ischemia/reperfusion injury in rats

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    Edip Gonullu

    2014-05-01

    Full Text Available Background and objectives: We investigated the effect of dexmedetomidine on ischemic renal failure in rats. Methods: In the present study, 26 male adult Wistar albino rats weighting 230–300 g were randomly separated into four groups: sham-operated (n = 5, ischemia reperfusion (IR (IR group, n = 7, IR/reperfusion treatment with dexmedetomidine (Dex. R group, n = 7 and IR/pre-ischemic treatment with dexmedetomidine (Dex. I group, n = 7. In the first group, sham operation was achieved and renal clamps were not applied. For the IR group, renal ischemia was induced by occlusion of the bilateral renal arteries and veins for 60 min followed by reperfusion for 24 h. For the Dex. R and Dex. I groups, the same surgical procedure as in the IR group was performed, and dexmedetomidine (100 mcg/kg intraperitoneal was administrated at the 5th min after reperfusion and before ischemia. At the end of reperfusion, blood samples were drawn, the rats were sacrificed, and the left kidney was processed for histopathology. Results: The blood urea nitrogen (BUN levels in groups Dex. R and Dex. I were significantly lower than in the IR group (p = 0.015, p = 0.043, although urine flow was significantly higher in group Dex. R (p = 0.003. The renal histopathological score in the IR group was significantly higher than in the other groups. There was no significant difference between the Dex. R and Dex. I groups. Conclusions: The results were shown that administration of dexmedetomidine reduced the renal IR injury histomorphologically. Administration of dexmedetomidine in the reperfusion period was considered as more effective due to increase in urinary output and decrease in BUN levels. Keywords: Kidney, Ischemia/reperfusion, Dexmedetomidine, Acute renal failure

  15. Down-regulated miR-448 relieves spinal cord ischemia/reperfusion injury by up-regulating SIRT1

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    Yun Wang

    2018-03-01

    Full Text Available MicroRNAs play a crucial role in the progression of spinal cord ischemia/reperfusion injury (SCII. The role of miR-448 and SIRT1 in SCII was investigated in this study, to provide further insights into prevention and improvement of this disorder. In this study, expressions of miR-448 and SIRT1 protein were determined by qRT-PCR and western blot, respectively. Flow cytometry was used to analyze cell apoptosis. The endogenous expression of genes was modulated by recombinant plasmids and cell transfection. Dual-luciferase reporter assay was performed to determine the interaction between miR-448 and SIRT1. The Basso, Beattie, and Bresnahan score was used to measure the hind-limb function of rat. The spinal cord ischemia reperfusion injury model of adult rats was developed by abdominal aorta clamping, and the nerve function evaluation was completed by motor deficit index score. In SCII tissues and cells treated with hypoxia, miR-448 was up-regulated while SIRT1 was down-regulated. Hypoxia treatment reduced the expression of SIRT1 through up-regulating miR-448 in nerve cells. Up-regulation of miR-448 induced by hypoxia promoted apoptosis of nerve cells through down-regulating SIRT1. Down-regulated miR-448 improved neurological function and hind-limb motor function of rats with SCII by up-regulating SIRT1. Down-regulated miR-448 inhibited apoptosis of nerve cells and improved neurological function by up-regulating SIRT1, which contributes to relieving SCII.

  16. Ischemia-reperfusion rat model of acute pancreatitis: protein carbonyl as a putative early biomarker of pancreatic injury.

    Science.gov (United States)

    Schanaider, Alberto; de Carvalho, Thales Penna; de Oliveira Coelho, Simone; Renteria, Juan Miguel; Eleuthério, Elis Cristina Araújo; Castelo-Branco, Morgana Teixeira Lima; Madi, Kalil; Baetas-da-Cruz, Wagner; de Souza, Heitor Siffert Pereira

    2015-08-01

    Acute pancreatitis (AP) is an inflammatory disorder that can affect adjacent and/or remote organs. Some evidence indicates that the production of reactive oxygen species is able to induce AP. Protein carbonyl (PC) derivatives, which can also be generated through oxidative cleavage mechanisms, have been implicated in several diseases, but there is little or no information on this biomarker in AP. We investigated the association between some inflammatory mediators and PC, with the severity of ischemia-reperfusion AP. Wistar rats (n = 56) were randomly assigned in the following groups : control; sham, 15- or 180-min clamping of splenic artery, with 24 or 72 h of follow-up. The relationships between serum level of PC and thiobarbituric acid reactive species (TBARS) to myeloperoxidase (MPO) activity in tissue homogenates and to cytokines in culture supernatants of pancreatic samples were analyzed. MPO activity was related to the histology scores and increased in all clamping groups. Tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin-6 were higher in the 180-min groups. Significant correlations were found between MPO activity and the concentrations of TNF-α and IL-1β. PC levels increased in the 15-min to 24-h group. TBARS levels were not altered substantially. MPO activity and TNF-α and IL-1β concentrations in pancreatic tissue are correlated with AP severity. Serum levels of PC appear to begin to rise early in the course of the ischemia-reperfusion AP and are no longer detected at later stages in the absence of severe pancreatitis. These data suggest that PC can be an efficient tool for the diagnosis of early stages of AP.

  17. The Effects of Spinal, Inhalation, and Total Intravenous Anesthetic Techniques on Ischemia-Reperfusion Injury in Arthroscopic Knee Surgery

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    Müge Koşucu

    2014-01-01

    Full Text Available Purpose. To compare the effects of different anesthesia techniques on tourniquet-related ischemia-reperfusion by measuring the levels of malondialdehyde (MDA, ischemia-modified albumin (IMA and neuromuscular side effects. Methods. Sixty ASAI-II patients undergoing arthroscopic knee surgery were randomised to three groups. In Group S, intrathecal anesthesia was administered using levobupivacaine. Anesthesia was induced and maintained with sevoflurane in Group I and TIVA with propofol in Group T. Blood samples were obtained before the induction of anesthesia (t1, 30 min after tourniquet inflation (t2, immediately before (t3, and 5 min (t4, 15 min (t5, 30 min (t6, 1 h (t7, 2 h (t8, and 6 h (t9 after tourniquet release. Results. MDA and IMA levels increased significantly compared with baseline values in Group S at t2–t9 and t2–t7. MDA levels in Group T and Group I were significantly lower than those in Group S at t2–t8 and t2–t9. IMA levels in Group T were significantly lower than those in Group S at t2–t7. Postoperatively, a temporary 1/5 loss of strength in dorsiflexion of the ankle was observed in 3 patients in Group S and 1 in Group I. Conclusions. TIVA with propofol can make a positive contribution in tourniquet-related ischemia-reperfusion.

  18. Remote Ischemic Conditioning to Protect against Ischemia-Reperfusion Injury: A Systematic Review and Meta-Analysis

    Science.gov (United States)

    Brevoord, Daniel; Kranke, Peter; Kuijpers, Marijn; Weber, Nina; Hollmann, Markus; Preckel, Benedikt

    2012-01-01

    Background Remote ischemic conditioning is gaining interest as potential method to induce resistance against ischemia reperfusion injury in a variety of clinical settings. We performed a systematic review and meta-analysis to investigate whether remote ischemic conditioning reduces mortality, major adverse cardiovascular events, length of stay in hospital and in the intensive care unit and biomarker release in patients who suffer from or are at risk for ischemia reperfusion injury. Methods and Results Medline, EMBASE and Cochrane databases were searched for randomized clinical trials comparing remote ischemic conditioning, regardless of timing, with no conditioning. Two investigators independently selected suitable trials, assessed trial quality and extracted data. 23 studies in patients undergoing cardiac surgery (15 studies), percutaneous coronary intervention (four studies) and vascular surgery (four studies), comprising in total 1878 patients, were included in this review. Compared to no conditioning, remote ischemic conditioning did not reduce mortality (odds ratio 1.22 [95% confidence interval 0.48, 3.07]) or major adverse cardiovascular events (0.65 [0.38, 1.14]). However, the incidence of myocardial infarction was reduced with remote ischemic conditioning (0.50 [0.31, 0.82]), as was peak troponin release (standardized mean difference −0.28 [−0.47, −0.09]). Conclusion There is no evidence that remote ischemic conditioning reduces mortality associated with ischemic events; nor does it reduce major adverse cardiovascular events. However, remote ischemic conditioning did reduce the incidence of peri-procedural myocardial infarctions, as well as the release of troponin. PMID:22860077

  19. Effect of a combined treatment with erythropoietin and melatonin on renal ischemia reperfusion injury in male rats.

    Science.gov (United States)

    Ahmadiasl, Nasser; Banaei, Shokofeh; Alihemati, Alireza; Baradaran, Behzad; Azimian, Ehsan

    2014-12-01

    Renal ischemia reperfusion (IR) is an important cause of renal dysfunction. It contributes to the development of acute renal failure. Oxidative damage from reactive oxygen species is considered to be the principal component involved in the pathophysiological tissue alterations observed during IR. The purpose of this study was to evaluate the effect of a combined treatment with erythropoietin (EPO) plus melatonin (MEL), which are known anti-inflammatory and antioxidant agents, in IR-induced renal injury in rats. Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h of reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to ischemia. After 24 h of reperfusion, blood samples were collected for the determination of superoxide dismutase (SOD), glutathione peroxidase (GPx), plasma levels of total antioxidant capacity (TAC), and malondialdehyde (MDA) and serum urea level. Also, renal samples were taken for histological evaluation. Ischemia reperfusion significantly increased urea, blood SOD, and GPx levels. Histological findings of the IR group indicated that there was increase in tubular and glomerular hyaline cast, thickening of Bowman capsule basement membrane, and renal impairment in the glomerular epithelium. Treatment with EPO and MEL significantly decreased blood SOD, GPx, and urea levels and increased TAC level. In the EPO + MEL group, while the histopathological changes were lower than those in EPO group, they were the same as MEL group. EPO and MEL combination treatment exerted more nephroprotective effects than EPO treatment and nearly had protective effects similar to MEL treatment.

  20. Effect of Intervention in Mast Cell Function Before Reperfusion on Renal Ischemia-Reperfusion Injury in Rats

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    Fei Tong

    2016-06-01

    Full Text Available Background/Aims: Mast cells are sparsely distributed in the kidneys under normal conditions; however, the number of mast cells increases dramatically during renal ischemia/reperfusion injury (RI/RI. When mast cells are stimulated, numerous mediators are released, and under pathological conditions, they produce a wide range of biological effects. The aim of this study was to investigate the effect of intervention in mast cell function before reperfusion on RI/RI. Methods: Sprague-Dawley (SD rats (n=50 were randomized into five groups: sham group, ischemia/reperfusion (I/R group, cromolyn sodium treatment group (CS+I/R group, ketotifen treatment group (K+I/Rgroup, and compound 48/80 treatment group (C+I/R group. I/R injury was induced by bilateral renal artery and vein occlusion for 45 min followed by 24 h of reperfusion. The agents were intravenously administered 5 min before reperfusion through the tail vein. The serum levels of blood urea nitrogen(BUN, serum creatinine (Scr and histamine and the kidney levels of malondialdehyde (MDA, superoxide dismutase (SOD, tumor necrosis factor α (TNF-α and interleukin-6 (IL-6 were assessed. The expression of intracellular adhesion molecule-1 (ICAM-1 in renal tissue was also measured. Results: I/R injury resulted in severe renal injury, as demonstrated by a large increase in injury scores; serum levels of BUN, Scr and histamine; and kidney levels of MDA, TNF-α, and IL-6; this was accompanied by reduced SOD activity and upregulated ICAM-1 expression. Treatment with cromolyn sodium or ketotifen markedly alleviated I/R-mediated kidney injury, whereas compound 48/80 further aggravated kidney injury. Conclusion: Intervention in mast cell activity prior to reperfusionhas a strong effect on RI/RI.

  1. Neuroprotective effect of olive oil in the hippocampus CA1 neurons following ischemia: Reperfusion in mice

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    M Zamani

    2013-01-01

    Full Text Available Introduction: Transient global ischemia induces selective, delayed neuronal death of pyramidal neurons in the hippocampal CA1. Oxidative Stress is considered to be involved in a number of human diseases including ischemia. Preliminary studies confirmed reduction of cell death in brain following treatment with antioxidants. Aim: According to this finding, we study the relationship between consumption of olive oil on cell death and memory disorder in brain ischemia. We studied the protective effect of olive oil against ischemia-reperfusion. Material and Methods: Experimental design includes three groups: Intact (n = 8, ischemic control (n = 8 and treatment groups with olive oil (n = 8. The mice treated with olive oil as pre-treatment for a week. Then, ischemia induced by common carotid artery ligation and following the reduction of inflammation [a week after ischemia], the mice post-treated with olive oil. Nissl staining applied for counting necrotic cells in hippocampus CA1. Tunnel kit was used to quantify apoptotic cell death while to short term memory scale, we apply y-maze and shuttle box tests and for detection the rate of apoptotic and treated cell, we used western blotting test for bax and bcl2 proteins. Results: High rate of apoptosis was seen in ischemic group that significantly associated with short-term memory loss. Cell death was significantly lower when mice treated with olive oil. The memory test results were adjusted with cell death results and bax and bcl2 expression in all groups′ comparison. Ischemia for 15 min induced cell death in hippocampus with more potent effect on CA1. Conclusion: Olive oil intake significantly reduced cell death and decreased memory loss.

  2. Myeloid differentiation protein 2-dependent mechanisms in retinal ischemia-reperfusion injury

    International Nuclear Information System (INIS)

    Ren, Luqing; Tao, Jianjian; Chen, Huaicheng; Bian, Yang; Yang, Xi; Chen, Gaozhi; Zhang, Xin; Liang, Guang; Wu, Wencan; Song, Zongming; Wang, Yi

    2017-01-01

    Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many eye disorders. Oxidative stress and inflammation play a role in retinal I/R injury. Recent studies show that toll-like receptor 4 (TLR4) is involved in initiating sterile inflammatory response in retinal I/R. However, the molecular mechanism by which TLR4 is activated is not known. In this study, we show that retinal I/R injury involves a co-receptor of TLR4, myeloid differentiation 2 (MD2). Inhibition of MD2 prevented cell death and preserved retinal function following retinal I/R injury. We confirmed these findings using MD2 knockout mice. Furthermore, we utilized human retinal pigment epithelial cells (ARPE-19 cells) to show that oxidative stress-induced cell death as well as inflammatory response are mediated through MD2. Inhibition of MD2 through a chemical inhibitor or knockdown prevented oxidative stress-induced cell death and expression of inflammatory cytokines. Oxidative stress was found to activate TLR4 in a MD2-dependent manner via increasing the expression of high mobility group box 1. In summary, our study shows that oxidative stress in retinal I/R injury can activate TLR4 signaling via MD2, resulting in induction of inflammatory genes and retinal damage. MD2 may represent an attractive therapeutic target for retinal I/R injury. - Highlights: • MD2 inhibition reduced retinal damage after I/R induction in mice. • TBHP induced TLR4/MD2 binding via increasing HMGB-1 expression. • TLR4/MD2 initiated inflammatory response via activation of MAPKs and NF-κB. • MD2 could be the therapeutic target for the treatment of retinal I/R.

  3. Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney.

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    Ebrahimkhani, Mohammad R; Daneshmand, Ali; Mazumder, Aprotim; Allocca, Mariacarmela; Calvo, Jennifer A; Abolhassani, Nona; Jhun, Iny; Muthupalani, Sureshkumar; Ayata, Cenk; Samson, Leona D

    2014-11-11

    Inflammation is accompanied by the release of highly reactive oxygen and nitrogen species (RONS) that damage DNA, among other cellular molecules. Base excision repair (BER) is initiated by DNA glycosylases and is crucial in repairing RONS-induced DNA damage; the alkyladenine DNA glycosylase (Aag/Mpg) excises several DNA base lesions induced by the inflammation-associated RONS release that accompanies ischemia reperfusion (I/R). Using mouse I/R models we demonstrate that Aag(-/-) mice are significantly protected against, rather than sensitized to, I/R injury, and that such protection is observed across three different organs. Following I/R in liver, kidney, and brain, Aag(-/-) mice display decreased hepatocyte death, cerebral infarction, and renal injury relative to wild-type. We infer that in wild-type mice, Aag excises damaged DNA bases to generate potentially toxic abasic sites that in turn generate highly toxic DNA strand breaks that trigger poly(ADP-ribose) polymerase (Parp) hyperactivation, cellular bioenergetics failure, and necrosis; indeed, steady-state levels of abasic sites and nuclear PAR polymers were significantly more elevated in wild-type vs. Aag(-/-) liver after I/R. This increase in PAR polymers was accompanied by depletion of intracellular NAD and ATP levels plus the translocation and extracellular release of the high-mobility group box 1 (Hmgb1) nuclear protein, activating the sterile inflammatory response. We thus demonstrate the detrimental effects of Aag-initiated BER during I/R and sterile inflammation, and present a novel target for controlling I/R-induced injury.

  4. Myeloid differentiation protein 2-dependent mechanisms in retinal ischemia-reperfusion injury

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    Ren, Luqing [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China); Tao, Jianjian; Chen, Huaicheng; Bian, Yang; Yang, Xi [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China); The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang (China); Chen, Gaozhi; Zhang, Xin; Liang, Guang [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China); Wu, Wencan, E-mail: wuwencan118@163.com [The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang (China); Song, Zongming, E-mail: szmeyes@126.com [The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang (China); Wang, Yi, E-mail: yi.wang1122@wmu.edu.cn [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China)

    2017-02-15

    Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many eye disorders. Oxidative stress and inflammation play a role in retinal I/R injury. Recent studies show that toll-like receptor 4 (TLR4) is involved in initiating sterile inflammatory response in retinal I/R. However, the molecular mechanism by which TLR4 is activated is not known. In this study, we show that retinal I/R injury involves a co-receptor of TLR4, myeloid differentiation 2 (MD2). Inhibition of MD2 prevented cell death and preserved retinal function following retinal I/R injury. We confirmed these findings using MD2 knockout mice. Furthermore, we utilized human retinal pigment epithelial cells (ARPE-19 cells) to show that oxidative stress-induced cell death as well as inflammatory response are mediated through MD2. Inhibition of MD2 through a chemical inhibitor or knockdown prevented oxidative stress-induced cell death and expression of inflammatory cytokines. Oxidative stress was found to activate TLR4 in a MD2-dependent manner via increasing the expression of high mobility group box 1. In summary, our study shows that oxidative stress in retinal I/R injury can activate TLR4 signaling via MD2, resulting in induction of inflammatory genes and retinal damage. MD2 may represent an attractive therapeutic target for retinal I/R injury. - Highlights: • MD2 inhibition reduced retinal damage after I/R induction in mice. • TBHP induced TLR4/MD2 binding via increasing HMGB-1 expression. • TLR4/MD2 initiated inflammatory response via activation of MAPKs and NF-κB. • MD2 could be the therapeutic target for the treatment of retinal I/R.

  5. Changes in metabolic profiles during acute kidney injury and recovery following ischemia/reperfusion.

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    Wei, Qingqing; Xiao, Xiao; Fogle, Paul; Dong, Zheng

    2014-01-01

    Changes of metabolism have been implicated in renal ischemia/reperfusion injury (IRI). However, a global analysis of the metabolic changes in renal IRI is lacking and the association of the changes with ischemic kidney injury and subsequent recovery are unclear. In this study, mice were subjected to 25 minutes of bilateral renal IRI followed by 2 hours to 7 days of reperfusion. Kidney injury and subsequent recovery was verified by serum creatinine and blood urea nitrogen measurements. The metabolome of plasma, kidney cortex, and medulla were profiled by the newly developed global metabolomics analysis. Renal IRI induced overall changes of the metabolome in plasma and kidney tissues. The changes started in renal cortex, followed by medulla and plasma. In addition, we identified specific metabolites that may contribute to early renal injury response, perturbed energy metabolism, impaired purine metabolism, impacted osmotic regulation and the induction of inflammation. Some metabolites, such as 3-indoxyl sulfate, were induced at the earliest time point of renal IRI, suggesting the potential of being used as diagnostic biomarkers. There was a notable switch of energy source from glucose to lipids, implicating the importance of appropriate nutrition supply during treatment. In addition, we detected the depressed polyols for osmotic regulation which may contribute to the loss of kidney function. Several pathways involved in inflammation regulation were also induced. Finally, there was a late induction of prostaglandins, suggesting their possible involvement in kidney recovery. In conclusion, this study demonstrates significant changes of metabolome kidney tissues and plasma in renal IRI. The changes in specific metabolites are associated with and may contribute to early injury, shift of energy source, inflammation, and late phase kidney recovery.

  6. Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury.

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    Penna, Claudia; Brancaccio, Mara; Tullio, Francesca; Rubinetto, Cristina; Perrelli, Maria-Giulia; Angotti, Carmelina; Pagliaro, Pasquale; Tarone, Guido

    2014-07-01

    Melusin is a muscle-specific protein which interacts with β1 integrin cytoplasmic domain and acts as chaperone protein. Its overexpression induces improved resistance to cardiac overload delaying left ventricle dilation and reducing the occurrence of heart failure. Here, we investigated possible protective effect of melusin overexpression against acute ischemia/reperfusion (I/R) injury with or without Postconditioning cardioprotective maneuvers. Melusin transgenic (Mel-TG) mice hearts were subjected to 30-min global ischemia followed by 60-min reperfusion. Interestingly, infarct size was reduced in Mel-TG mice hearts compared to wild-type (WT) hearts (40.3 ± 3.5 % Mel-TG vs. 59.5 ± 3.8 % WT hearts; n = 11 animals/group; P level of AKT, ERK1/2 and GSK3β phosphorylation, and displayed increased phospho-kinases level after I/R compared to WT mice. Post-ischemic Mel-TG hearts displayed also increased levels of the anti-apoptotic factor phospho-BAD. Importantly, pharmacological inhibition of PI3K/AKT (Wortmannin) and ERK1/2 (U0126) pathways abrogated the melusin protective effect. Notably, HSP90, a chaperone known to protect heart from I/R injury, showed high levels of expression in the heart of Mel-TG mice suggesting a possible collaboration of this molecule with AKT/ERK/GSK3β pathways in the melusin-induced protection. Postconditioning, known to activate AKT/ERK/GSK3β pathways, significantly reduced IS and LDH release in WT hearts, but had no additive protective effects in Mel-TG hearts. These findings implicate melusin as an enhancer of AKT and ERK pathways and as a novel player in cardioprotection from I/R injury.

  7. Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers

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    Kim, Jae-Sung, E-mail: Jae.Kim@surgery.ufl.edu; Wang, Jin-Hee, E-mail: jin-hee.wang@surgery.ufl.edu; Biel, Thomas G., E-mail: Thomas.Biel@surgery.ufl.edu; Kim, Do-Sung, E-mail: do-sung.kim@surgery.med.ufl.edu; Flores-Toro, Joseph A., E-mail: Joseph.Flores-Toro@surgery.ufl.edu; Vijayvargiya, Richa, E-mail: rvijayvargiya@ufl.edu; Zendejas, Ivan, E-mail: ivan.zendejas@surgery.ufl.edu; Behrns, Kevin E., E-mail: Kevin.Behrns@surgery.ufl.edu

    2013-12-15

    Onset of the mitochondrial permeability transition (MPT) plays a causative role in ischemia/reperfusion (I/R) injury. Current therapeutic strategies for reducing reperfusion injury remain disappointing. Autophagy is a lysosome-mediated, catabolic process that timely eliminates abnormal or damaged cellular constituents and organelles such as dysfunctional mitochondria. I/R induces calcium overloading and calpain activation, leading to degradation of key autophagy-related proteins (Atg). Carbamazepine (CBZ), an FDA-approved anticonvulsant drug, has recently been reported to increase autophagy. We investigated the effects of CBZ on hepatic I/R injury. Hepatocytes and livers from male C57BL/6 mice were subjected to simulated in vitro, as well as in vivo I/R, respectively. Cell death, intracellular calcium, calpain activity, changes in autophagy-related proteins (Atg), autophagic flux, MPT and mitochondrial membrane potential after I/R were analyzed in the presence and absence of 20 μM CBZ. CBZ significantly increased hepatocyte viability after reperfusion. Confocal microscopy revealed that CBZ prevented calcium overloading, the onset of the MPT and mitochondrial depolarization. Immunoblotting and fluorometric analysis showed that CBZ blocked calpain activation, depletion of Atg7 and Beclin-1 and loss of autophagic flux after reperfusion. Intravital multiphoton imaging of anesthetized mice demonstrated that CBZ substantially reversed autophagic defects and mitochondrial dysfunction after I/R in vivo. In conclusion, CBZ prevents calcium overloading and calpain activation, which, in turn, suppresses Atg7 and Beclin-1 depletion, defective autophagy, onset of the MPT and cell death after I/R. - Highlights: • A mechanism of carbamazepine (CBZ)-induced cytoprotection in livers is proposed. • Impaired autophagy is a key event contributing to lethal reperfusion injury. • The importance of autophagy is extended and confirmed in an in vivo model. • CBZ is a potential

  8. Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats

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    Filiz Ozyigit

    2015-08-01

    Full Text Available Ebselen is an organoselenium compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of ebselen pretreatment in rats with experimental sciatic nerve ischemia-reperfusion (I/R injury. Adult male Sprague Dawley rats were divided into four groups (N = 7 in each group. Before sciatic nerve I/R was induced, ebselen was injected intraperitoneally at doses of 15 and 30 mg/kg. After a 2 h ischemia and a 3 h reperfusion period, sciatic nerve tissues were excised. Tissue levels of malondialdehyde (MDA and nitric oxide (NO, and activities of superoxide dismutase (SOD, glutathione peroxidase (GPx, and catalase (CAT were measured. Sciatic nerve tissues were also examined histopathologically. The 15 mg/kg dose of ebselen reduced sciatic nerve damage and apoptosis (P < 0.01, levels of MDA, NO, and inducible nitric oxide synthase (iNOS positive cells (P < 0.01, P < 0.05, respectively, and increased SOD, GPx, and CAT activities (P < 0.001, P < 0.01, P < 0.05, respectively compared with the I/R group that did not receive ebselen. Conversely, the 30 mg/kg dose of ebselen increased sciatic nerve damage, apoptosis, iNOS positive cells (P < 0.01, P < 0.05, P < 0.001 and MDA and NO levels (P < 0.05, P < 0.01 and decreased SOD, GPx, and CAT activities (P < 0.05 compared with the sham group. The results of this study suggest that ebselen may cause different effects depending on the dose employed. Ebselen may be protective against sciatic nerve I/R injury via antioxidant and antiapoptotic activities at a 15 mg/kg dose, conversely higher doses may cause detrimental effects.

  9. Nicotine protects kidney from renal ischemia/reperfusion injury through the cholinergic anti-inflammatory pathway.

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    Claude Sadis

    Full Text Available Kidney ischemia/reperfusion injury (I/R is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR. Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the alpha7nAChR, as attested by the absence of protection in alpha7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-alpha and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic alpha7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.

  10. Vitamin E deficiency fails to affect myocardial performance during in vivo ischemia-reperfusion.

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    Coombes, J S; Powers, S K; Demirel, H A; Hamilton, K L; Jessup, J; Vincent, H K; Shanely, R A

    2000-12-01

    Vitamin E content of cardiac tissue has been proposed to play a major role in the damage caused by myocardial ischemia-reperfusion (I-R). Previous studies using in vitro models have examined vitamin E deficiency and I-R-induced myocardial damage with equivocal results. The purpose of this study was to use an in vivo model of myocardial I-R to determine the effects of vitamin E deficiency on myocardial I-R-induced damage. Female Sprague-Dawley rats (4-mo old) were assigned to either: 1) control diet (CON), or 2) vitamin E deficient diet (VE-DEF). The CON diet was prepared to meet AIN-93M standards, which contains 75 IU vitamin E/kg diet. The VE-DEF diet was the AIN-93M diet prepared with tocopherol stripped corn oil and no vitamin E. Following a 14-week feeding period, significant differences (p CON = 48.2 +/- 3.5; VE-DEF = 12.4 +/- 1.4 micrograms VE/g wet weight). Animals from both experimental groups were subjected to an in vivo I-R protocol consisting of 25 minutes of left coronary artery occlusion followed by 10 minutes of reperfusion. No group differences (p > 0.05) existed in cardiac performance (peak arterial pressure or ventricular work) or the incidence of ventricular arrhythmias during the I-R protocol. VE-DEF animals had significantly higher (p CON animals. These data suggest that although vitamin E deficiency increases oxidative damage resulting from myocardial I-R, it does not affect cardiac performance during the insult.

  11. Ischemia-reperfusion injury in the isolated rat lung. Role of flow and endogenous leukocytes.

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    Seibert, A F; Haynes, J; Taylor, A

    1993-02-01

    Microvascular lung injury caused by ischemia-reperfusion (IR) may occur via leukocyte-dependent and leukocyte-independent pathways. Leukocyte-endothelial adhesion may be a rate-limiting step in IR lung injury. Leukocyte adhesion to microvascular endothelium occurs when the attractant forces between leukocyte and endothelium are greater than the kinetic energy of the leukocyte and the vascular wall shear rate. We hypothesized (1) that isolated, buffer-perfused rat lungs are not free of endogenous leukocytes, (2) that endogenous leukocytes contribute to IR-induced microvascular injury as measured by the capillary filtration coefficient (Kfc), and (3) that a reduction of perfusate flow rate would potentiate leukocyte-dependent IR injury. Sixty lungs were divided into four groups: (1) low-flow controls, (2) high-flow controls, (3) low-flow IR, and (4) high-flow IR. Microvascular injury was linearly related to baseline perfusate leukocyte concentrations at both low (r = 0.78) and high (r = 0.82) flow rates. Kfc in the high-flow IR group (0.58 +/- 0.03 ml/min/cm H2O/100 g) was less (p Kfc in the low-flow IR group (0.82 +/- 0.07), and in both groups Kfc values were significantly greater than low-flow (0.34 +/- 0.03) and high-flow (0.31 +/- 0.01) control Kfc values after 75 min. Retention of leukocytes in the lung, evaluated by a tissue myeloperoxidase assay, was greatest in the low-flow IR group. We conclude (1) that isolated, buffer-perfused rat lungs contain significant quantities of leukocytes and that these leukocytes contribute to IR lung injury, and (2) that IR-induced microvascular injury is potentiated by low flow.

  12. Edaravone enhances the viability of ischemia/reperfusion flaps.

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    Zhang, Dong-Yi; Kang, Shen-Song; Zhang, Zheng-Wen; Wu, Rui

    2017-02-01

    The purpose of the experiment was to study the efficacy of edaravone in enhancing flap viability after ischemia/reperfusion (IR) and its mechanism. Forty-eight adult male SD rats were randomly divided into 3 groups: control group (n=16), IR group (n=16), and edaravone-treated IR group (n=16). An island flap at left lower abdomen (6.0 cm×3.0 cm in size), fed by the superficial epigastric artery and vein, was created in each rat of all the three groups. The arterial blood flow of flaps in IR group and edaravone-treated IR group was blocked for 10 h, and then the blood perfusion was restored. From 15 min before reperfusion, rats in the edaravone-treated IR group were intraperitoneally injected with edaravone (10 mg/kg), once every 12 h, for 3 days. Rats in the IR group and control group were intraperitoneally injected with saline, with the same method and frequency as the rats in the edaravone-treated IR group. In IR group and edaravone-treated IR group, samples of flaps were harvested after reperfusion of the flaps for 24 h. In the control group, samples of flaps were harvested 34 h after creation of the flaps. The content of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) were determined, and changes in organizational structure and infiltration of inflammatory cells were observed by hematoxylin-eosin (HE) staining, apoptotic cells of vascular wall were marked by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and the apoptotic rate of cells in vascular wall was calculated. The ultrastructural changes of vascular endothelial cells were observed by transmission electron microscopy (TEM). Seven days after the operation, we calculated the flap viability of each group, and marked vessels of flaps by immunohistochemical staining for calculating the average number of subcutaneous vessels. The results showed that the content of MDA, the number of multicore inflammatory cells and apoptotic rate of cells in vascular wall

  13. Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury

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    Edith Hochhauser

    2015-07-01

    Full Text Available Background/Aims: Ischemia/reperfusion (I/R injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts. Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury. Delta-9-tetrahydrocannabinol (THC, a cannabinoid agonist, is the active components of marijuana. In this study we examined the role of ultralow dose THC (0.002mg/kg in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults. Methods: C57Bl Mice were studied in in vivo model of hepatic segmental (70% ischemia for 60min followed by reperfusion for 6 hours. Results: THC administration 2h prior to the induction of hepatic I/R was associated with significant attenuated elevations of: serum liver transaminases ALT and AST, the hepatic oxidative stress (activation of the intracellular signaling CREB pathway, the acute proinflammatory response (TNF-α, IL-1α, IL-10 and c-FOS hepatic mRNA levels, and ERK signaling pathway activation. This was followed by cell death (the cleavage of the pro-apoptotic caspase 3, DNA fragmentation and TUNEL after 6 hours of reperfusion. Significantly less hepatic injury was detected in the THC treated I/R mice and fewer apoptotic hepatocytes cells were identified by morphological criteria compared with untreated mice. Conclusion: A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic I/R injury. THC may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation, liver resection and trauma.

  14. Bexarotene reduces blood-brain barrier permeability in cerebral ischemia-reperfusion injured rats.

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    Lu Xu

    Full Text Available Matrix metalloproteinase-9 (MMP-9 over-expression disrupts the blood-brain barrier (BBB in the ischemic brain. The retinoid X receptor agonist bexarotene suppresses MMP-9 expression in endothelial cells and displays neuroprotective effects. Therefore, we hypothesized that bexarotene may have a beneficial effect on I/R-induced BBB dysfunction.A total of 180 rats were randomized into three groups (n = 60 each: (i a sham-operation group, (ii a cerebral ischemia-reperfusion (I/R group, and (iii an I/R+bexarotene group. Brain water content was measured by the dry wet weight method. BBB permeability was analyzed by Evans Blue staining and the magnetic resonance imaging contrast agent Omniscan. MMP-9 mRNA expression, protein expression, and activity were assessed by reverse transcription polymerase chain reaction, Western blotting, and gelatin zymography, respectively. Apolipoprotein E (apoE, claudin-5, and occludin expression were analyzed by Western blotting.After 24 h, 48 h, and 72 h post-I/R, several effects were observed with bexarotene administration: (i brain water content and BBB permeability were significantly reduced; (ii MMP-9 mRNA and protein expression as well as activity were significantly decreased; (iii claudin-5 and occludin expression were significantly increased; and (iv apoE expression was significantly increased.Bexarotene decreases BBB permeability in rats with cerebral I/R injury. This effect may be due in part to bexarotene's upregulation of apoE expression, which has been previously shown to reduce BBB permeability through suppressing MMP-9-mediated degradation of the tight junction proteins claudin-5 and occludin. This work offers insight to aid future development of therapeutic agents for cerebral I/R injury in human patients.

  15. CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury.

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    Ole Jørgen Kaasbøll

    Full Text Available Previous studies of ischemia-reperfusion injury (IRI in hearts from mice with cardiac-restricted overexpression of CCN2 have shown that CCN2 increases tolerance towards IRI. The objectives of this study were to investigate to what extent post-ischemic administration of recombinant human CCN2 (rhCCN2 would limit infarct size and improve functional recovery and what signaling pathways are involved.Isolated mice hearts were perfused ad modum Langendorff, subjected to no-flow, global ischemia, and subsequently, exposed to mammalian cell derived, full-length (38-40kDa rhCCN2 (250 nM or vehicle during the first 15 min of a 60 min reperfusion period.Post-ischemic administration of rhCCN2 resulted in attenuation of infarct size from 58 ± 4% to 34 ± 2% (p < 0.001 which was abrogated by concomitant administration of the PI3 kinase inhibitor LY294002 (45 ± 3% vs. 50 ± 3%, ns. In congruence with reduction of infarct size rhCCN2 also improved recovery of left ventricular developed pressure (p < 0.05. Western blot analyses of extracts of ex vivo-perfused murine hearts also revealed that rhCCN2 evoked concentration-dependent increase of cardiac phospho-GSK3β (serine-9 contents.We demonstrate that post-ischemic administration of rhCCN2 increases the tolerance of ex vivo-perfused murine hearts to IRI. Mechanistically, this postconditioning effect of rhCCN2 appeared to be mediated by activation of the reperfusion injury salvage kinase pathway as demonstrated by sensitivity to PI3 kinase inhibition and increased CCN2-induced phosphorylation of GSK3β (Ser-9. Thus, the rationale for testing rhCCN2-mediated post-ischemic conditioning of the heart in more complex models is established.

  16. Cardiac Ischemia Reperfusion Injury Following Instillation of 20 nm Citrate-capped Nanosilver

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    Becak DP, Holland NA; Shannahan, Jonathan H.

    2015-01-01

    Background: Silver nanoparticles (AgNP) have garnered much interest due to their antimicrobial properties, becoming one of the most utilized nano scale materials. However, any potential evocable cardiovascular injury associated with exposure has not been previously reported. We have previously demonstrated expansion of myocardial infarction after intratracheal (IT) instillation of other nanomaterials. We hypothesized that pulmonary exposure to Ag core AgNP induces persistent increase in circulating cytokines, expansion of cardiac ischemia-reperfusion (I/R) injury and associated with altered coronary vessel reactivity. Methods: Male Sprague-Dawley rats were exposed to 200 µg of 20 nm citrate capped Ag core AgNP, or a citrate vehicle intratracheally (IT). One and 7 days following IT instillation lungs were evaluated for inflammation and silver presence, serum was analyzed for concentrations of selected cytokines, and cardiac I/R injury and coronary artery reactivity was assessed. Results: AgNP instillation resulted in modest pulmonary injury with detection of silver in lung tissue and infiltrating cells, elevation of serum cytokines: G-CSF, MIP-1α, IL-1β, IL-2, IL-6, IL-13, IL-10, IL-18, IL-17, TNFα, and RANTES, expansion of I/R injury and depression of the coronary vessel reactivity at 1 day post IT compared to vehicle treated rats. Seven days post IT instillation was associated with persistent detection of silver in lungs, elevation in cytokines: IL-2, IL-13, and TNFα and expansion of I/R injury. Conclusions: Based on these data, IT instillation of AgNP increases circulating levels of several cytokines, which may contribute to persistent expansion of I/R injury possibly through an impaired vascular responsiveness.

  17. Aging aggravates long-term renal ischemia-reperfusion injury in a rat model.

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    Xu, Xianlin; Fan, Min; He, Xiaozhou; Liu, Jipu; Qin, Jiandi; Ye, Jianan

    2014-03-01

    Ischemia-reperfusion injury (IRI) has been considered as the major cause of acute kidney injury and can result in poor long-term graft function. Functional recovery after IRI is impaired in the elderly. In the present study, we aimed to compare kidney morphology, function, oxidative stress, inflammation, and development of renal fibrosis in young and aged rats after renal IRI. Rat models of warm renal IRI were established by clamping left pedicles for 45 min after right nephrectomy, then the clamp was removed, and kidneys were reperfused for up to 12 wk. Biochemical and histologic renal damage were assessed at 12 wk after reperfusion. The immunohistochemical staining of monocyte macrophage antigen-1 (ED-1) and transforming growth factor beta 1 (TGF-β1) and messenger RNA level of TGF-β1 in the kidney were analyzed. Renal IRI caused significant increases of malondialdehyde and 8-hydroxydeoxyguanosine levels and a decrease of superoxide dismutase activity in young and aged IRI rats; however, these changes were more obvious in the aged rats. IRI resulted in severe inflammation and tubulointerstitial fibrosis with decreased creatinine (Cr) clearance and increased histologic damage in aged rats compared with young rats. Moreover, we measured the ratio of Cr clearance between young and aged IRI rats. It demonstrated that aged IRI rats did have poor Cr clearance compared with the young IRI rats. ED-1 and TGF-β1 expression levels in the kidney were significantly higher in aged rats than in young rats after IRI. Aged rats are more susceptible to IRI-induced renal failure, which may associate with the increased oxidative stress, increased histologic damage, and increased inflammation and tubulointerstitial fibrosis. Targeting oxidative stress and inflammatory response should improve the kidney recovery after IRI. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Characterization of the Structural and Functional Changes in the Myocardium Following Focal Ischemia-Reperfusion Injury

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    Ojha, Navdeep; Roy, Sashwati; Radtke, Jared; Simonetti, Orlando; Gnyawali, Surya; Zweier, Jay L.; Kuppusamy, Periannan; Sen, Chandan K.

    2015-01-01

    High resolution (11.7T) cardiac magnetic resonance imaging (MRI) and histological approaches have been employed in tandem to characterize the secondary damage suffered by the murine myocardium following the initial insult caused by ischemia-reperfusion (IR). IR induced changes in the myocardium were examined in five separate groups at the following time-points after IR: 1h, 1d, 3d, 7d and 14 d. Infarct volume increased from 1h to 1d post-IR. Over time, loss of myocardial function was observed to be associated with increased infarct volume and worsened regional wall motion. In the infarct region, IR caused a decrease in end-systolic thickness coupled with small changes in end-diastolic thickness, leading to massive wall thickening abnormalities. In addition, compromised wall thickening was also observed in left ventricular regions adjacent to the infarct region. A tight correlation (r2 = 0.86) between measured MRI and triphenyltetrazolium chloride (TTC) infarct volumes was noted. Our observation that until day 3 post-IR, the infarct size as measured by TTC staining and MRI were much larger than the myocyte-silent regions in trichrome or H&E stained sections is consistent with the literature and leads to the conclusion that at such early phase the infarct site contains structurally intact myocytes that are functionally compromised. Over time, such affected myocytes were noted to structurally disappear resulting in consistent infarct sizes obtained from MRI, TTC as well as trichrome and hematoxylin/eosin analyses on day 7 following IR. Myocardial remodeling following IR includes secondary myocyte death followed by loss of cardiac function over time. PMID:18375718

  19. Neuroprotective Effect of Curcumin Against Cerebral Ischemia-Reperfusion Via Mediating Autophagy and Inflammation.

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    Huang, Lifa; Chen, Chengwei; Zhang, Xin; Li, Xu; Chen, Zupeng; Yang, Chao; Liang, Xiaolong; Zhu, Guochong; Xu, Zhen

    2018-01-01

    Curcumin, a polyphenolic compound extracted from Curcuma longa, has drawn attention for its effective bioactivities against ischemia-induced injury. This study aimed to evaluate the neuroprotective effect of curcumin and investigate the underlying mechanism that mediates autophagy and inflammation in an animal model of middle cerebral artery occlusion (MCAO) in rats. Curcumin was delivered to Sprague Dawley male rats at a dose of 200 mg/kg curcumin by intraperitoneal injection 30 min after ischemia-reperfusion (I/R). LY294002, a specific inhibitor of the PI3K/Akt/mTOR pathway, as well as anisomycin, an activator of TLR4/p38/MAPK, was administered by ventricle injection 30 min before MCAO. The same volume of saline was given as a control. Brain infarction and neurological function were determined 24 h post-MCAO. Immunoblotting and immunofluorescence were used to detect alterations in autophagy-relevant proteins Akt, p-Akt, mTOR, p-mTOR, LC3-II, and LC3-I, and inflammation-related proteins TLR4, p-38, p-p38, and IL-1 in the ipsilateral hemisphere. Cerebral I/R injury resulted in significant alterations of LC3-II/LC3-I, IL-1, TLR4, and p-p38. Curcumin in MCAO rats significantly improved brain damage and neurological function by upregulating p-Akt and p-mTOR and downregulating LC3-II/LC3-I, IL-1, TLR4, p-38, and p-p38. However, these protective effects against ischemia could be suppressed when LY294002 or anisomycin was included. Curcumin exerts neuroprotective effects by attenuating autophagic activities through mediating the PI3K/Akt/mTOR pathway, while also suppressing an inflammatory reaction by regulating the TLR4/p38/MAPK pathway. Furthermore, this study indicates that curcumin could be an effective therapy for patients afflicted with ischemia.

  20. Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion.

    Directory of Open Access Journals (Sweden)

    Oumei Cheng

    Full Text Available Sleep deprivation (SD plays a complex role in central nervous system (CNS diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR.One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU and neuron-specific enolase (NSE, respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d.The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects.Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process.

  1. Delayed xenon post-conditioning mitigates spinal cord ischemia/reperfusion injury in rabbits by regulating microglial activation and inflammatory factors.

    Science.gov (United States)

    Yang, Yan-Wei; Wang, Yun-Lu; Lu, Jia-Kai; Tian, Lei; Jin, Mu; Cheng, Wei-Ping

    2018-03-01

    The neuroprotective effect against spinal cord ischemia/reperfusion injury in rats exerted by delayed xenon post-conditioning is stronger than that produced by immediate xenon post-conditioning. However, the mechanisms underlying this process remain unclear. Activated microglia are the main inflammatory cell type in the nervous system. The release of pro-inflammatory factors following microglial activation can lead to spinal cord damage, and inhibition of microglial activation can relieve spinal cord ischemia/reperfusion injury. To investigate how xenon regulates microglial activation and the release of inflammatory factors, a rabbit model of spinal cord ischemia/reperfusion injury was induced by balloon occlusion of the infrarenal aorta. After establishment of the model, two interventions were given: (1) immediate xenon post-conditioning-after reperfusion, inhalation of 50% xenon for 1 hour, 50% N 2 /50%O 2 for 2 hours; (2) delayed xenon post-conditioning-after reperfusion, inhalation of 50% N 2 /50%O 2 for 2 hours, 50% xenon for 1 hour. At 4, 8, 24, 48 and 72 hours after reperfusion, hindlimb locomotor function was scored using the Jacobs locomotor scale. At 72 hours after reperfusion, interleukin 6 and interleukin 10 levels in the spinal cord of each group were measured using western blot assays. Iba1 levels were determined using immunohistochemistry and a western blot assay. The number of normal neurons at the injury site was quantified using hematoxylin-eosin staining. At 72 hours after reperfusion, delayed xenon post-conditioning remarkably enhanced hindlimb motor function, increased the number of normal neurons at the injury site, decreased Iba1 levels, and inhibited interleukin-6 and interleukin-10 levels in the spinal cord. Immediate xenon post-conditioning did not noticeably affect the above-mentioned indexes. These findings indicate that delayed xenon post-conditioning after spinal cord injury improves the recovery of neurological function by reducing

  2. Inhibition of coagulation and inflammation by activated protein C or antithrombin reduces intestinal ischemia/reperfusion injury in rats

    NARCIS (Netherlands)

    Schoots, Ivo G.; Levi, Marcel; van Vliet, Arlène K.; Maas, Adrie M.; Roossink, E. H. Paulina; van Gulik, Thomas M.

    2004-01-01

    Objective: To examine whether administration of activated protein C or antithrombin reduces local splanchnic derangement of coagulation and inflammation and attenuates intestinal dysfunction and injury following intestinal ischemia/reperfusion. Design: Randomized prospective animal study. Setting:

  3. Liraglutide-induced reduction of myocardial ischemia- reperfusion ...

    African Journals Online (AJOL)

    However, the parameters were significantly lower (p ˂ 0.05) in liraglutide group than in I/R ... injection of chloral hydrate and placed on the ... PD group received the same dose of liraglutide ..... inhibitor PD98059 was combined with liraglutide.

  4. Protective Effect of Alpha Lipoic Acid on Rat Sciatic Nerve Ischemia Reperfusion Damage

    Directory of Open Access Journals (Sweden)

    Ozan Turamanlar

    2015-06-01

    Full Text Available Background: Alpha lipoic acid is a potent antioxidant that plays numerous roles in human health. This study examined the effect of ALA on rat sciatic nerve ischemia reperfusion damage. Aims: Protective effect of alpha lipoic acid (ALA on sciatic nerve following ischemia-reperfusion in rats was investigated by using light microscopy and biochemical methods. Provided that the protective effect of ALA on sciatic nerve is proven, we think the damage to the sciatic nerve that has already occurred or might occur in patients for various reasons maybe prevented or stopped by giving ALA in convenient doses. Study Design: Animal experiment. Methods: Forty-two adult male Sprague-Dawley rats (250-300 grams were used in this study. Rats were randomly divided into six groups including one control (Group 1, one sham (Group 2, two ischemia-reperfusion (Groups 3 and 4 and two treatment groups (Groups5 and 6. Doses of 60 and 100 mg/kg ALA were given (Group 5 and 6 intra peritoneally twice, 1 and 24 hours before the ischemia to each treatment group. Ischemia was carried out the abdominal aorta starting from the distal part of the renal vein for two hours followed by reperfusion for three hours. In immunohistochemical methods, fibronectin immunoreactivity was analyzed. For biochemical analyses, the tissues were taken in eppendorf microtubes and superoxide dismutase (SOD and glutathione peroxidase (GSHPx enzyme activities as well as malondialdehyde (MDA and nitricoxide (NO levels were measured. Results: Fibronectin was observed to have increased significantly in the ischemia group; on the other hand, it was observed to have decreased in parallel to the doses in the ALA groups. Biochemical studies showed that SOD and GSHPx declined with ischemia-reperfusion, but the activities of these enzymes were increased in the treatment groups in parallel with the dose. It was found that increased MDA levels with ischemia-reperfusion were decreased in parallel with ALA dose

  5. Total flavonoid of Litsea coreana leve exerts anti-oxidative effects and alleviates focal cerebral ischemia/reperfusion injury

    OpenAIRE

    Dong, Shuying; Tong, Xuhui; Li, Jun; Huang, Cheng; Hu, Chengmu; Jiao, Hao; Gu, Yuchen

    2013-01-01

    In this study, we hypothesized that total flavonoid of Litsea coreana leve (TFLC) protects against focal cerebral ischemia/reperfusion injury. TFLC (25, 50, 100 mg/kg) was administered orally to a rat model of focal ischemia/reperfusion injury, while the free radical scavenging agent, edaravone, was used as a positive control drug. Results of neurological deficit scoring, 2,3,5-triphenyl tetrazolium chloride staining, hematoxylin-eosin staining and biochemical tests showed that TFLC at differ...

  6. Bone marrow mesenchymal stem cells repair spinal cord ischemia/reperfusion injury by promoting axonal growth and anti-autophagy

    Science.gov (United States)

    Yin, Fei; Meng, Chunyang; Lu, Rifeng; Li, Lei; Zhang, Ying; Chen, Hao; Qin, Yonggang; Guo, Li

    2014-01-01

    Bone marrow mesenchymal stem cells can differentiate into neurons and astrocytes after transplantation in the spinal cord of rats with ischemia/reperfusion injury. Although bone marrow mesenchymal stem cells are known to protect against spinal cord ischemia/reperfusion injury through anti-apoptotic effects, the precise mechanisms remain unclear. In the present study, bone marrow mesenchymal stem cells were cultured and proliferated, then transplanted into rats with ischemia/reperfusion injury via retro-orbital injection. Immunohistochemistry and immunofluorescence with subsequent quantification revealed that the expression of the axonal regeneration marker, growth associated protein-43, and the neuronal marker, microtubule-associated protein 2, significantly increased in rats with bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Furthermore, the expression of the autophagy marker, microtubule-associated protein light chain 3B, and Beclin 1, was significantly reduced in rats with the bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Western blot analysis showed that the expression of growth associated protein-43 and neurofilament-H increased but light chain 3B and Beclin 1 decreased in rats with the bone marrow mesenchymal stem cell transplantation. Our results therefore suggest that bone marrow mesenchymal stem cell transplantation promotes neurite growth and regeneration and prevents autophagy. These responses may likely be mechanisms underlying the protective effect of bone marrow mesenchymal stem cells against spinal cord ischemia/reperfusion injury. PMID:25374587

  7. Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat.

    Science.gov (United States)

    Prakash, Prem; Singh, Vishal; Jain, Manish; Rana, Minakshi; Khanna, Vivek; Barthwal, Manoj Kumar; Dikshit, Madhu

    2014-03-15

    High dietary fructose causes insulin resistance syndrome (IRS), primarily due to simultaneous induction of genes involved in glucose, lipid and mitochondrial oxidative metabolism. The present study evaluates effect of a hepatoprotective agent, silymarin (SYM) on fructose-induced metabolic abnormalities in the rat and also assessed the associated thrombotic complications. Wistar rats were kept on high fructose (HFr) diet throughout the 12-week study duration (9 weeks of HFr feeding and subsequently 3 weeks of HFr plus SYM oral administration [once daily]). SYM treatment significantly reduced the HFr diet-induced increase expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α/β, peroxisome proliferator-activated receptor (PPAR)-α, forkhead box protein O1 (FOXO1), sterol regulatory element binding protein (SREBP)-1c, liver X receptor (LXR)-β, fatty acid synthase (FAS) and PPARγ genes in rat liver. SYM also reduced HFr diet mediated increase in plasma triglycerides (TG), non-esterified fatty acids (NEFA), uric acid, malondialdehyde (MDA), total nitrite and pro-inflammatory cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-gamma [IFN-γ] and tumor necrosis factor [TNF]) levels. Moreover, SYM ameliorated HFr diet induced reduction in glucose utilization and endothelial dysfunction. Additionally, SYM significantly reduced platelet activation (adhesion and aggregation), prolonged ferric chloride-induced blood vessel occlusion time and protected against exacerbated myocardial ischemia reperfusion (MI-RP) injury. SYM treatment prevented HFr induced mRNA expression of hepatic PGC-1α/β and also its target transcription factors which was accompanied with recovery in insulin sensitivity and reduced propensity towards thrombotic complications and aggravated MI-RP injury. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Kaempferol Attenuates Myocardial Ischemic Injury via Inhibition of MAPK Signaling Pathway in Experimental Model of Myocardial Ischemia-Reperfusion Injury

    Science.gov (United States)

    Suchal, Kapil; Malik, Salma; Gamad, Nanda; Malhotra, Rajiv Kumar; Goyal, Sameer N.; Chaudhary, Uma; Bhatia, Jagriti; Ojha, Shreesh; Arya, Dharamvir Singh

    2016-01-01

    Kaempferol (KMP), a dietary flavonoid, has antioxidant, anti-inflammatory, and antiapoptotic effects. Hence, we investigated the effect of KMP in ischemia-reperfusion (IR) model of myocardial injury in rats. We studied male albino Wistar rats that were divided into sham, IR-control, KMP-20 + IR, and KMP 20 per se groups. KMP (20 mg/kg; i.p.) was administered daily to rats for the period of 15 days, and, on the 15th day, ischemia was produced by one-stage ligation of left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed; heart was removed and processed for biochemical, morphological, and molecular studies. KMP pretreatment significantly ameliorated IR injury by maintaining cardiac function, normalizing oxidative stress, and preserving morphological alterations. Furthermore, there was a decrease in the level of inflammatory markers (TNF-α, IL-6, and NFκB), inhibition of active JNK and p38 proteins, and activation of ERK1/ERK2, a prosurvival kinase. Additionally, it also attenuated apoptosis by reducing the expression of proapoptotic proteins (Bax and Caspase-3), TUNEL positive cells, and increased level of antiapoptotic proteins (Bcl-2). In conclusion, KMP protected against IR injury by attenuating inflammation and apoptosis through the modulation of MAPK pathway. PMID:27087891

  9. Kaempferol Attenuates Myocardial Ischemic Injury via Inhibition of MAPK Signaling Pathway in Experimental Model of Myocardial Ischemia-Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Kapil Suchal

    2016-01-01

    Full Text Available Kaempferol (KMP, a dietary flavonoid, has antioxidant, anti-inflammatory, and antiapoptotic effects. Hence, we investigated the effect of KMP in ischemia-reperfusion (IR model of myocardial injury in rats. We studied male albino Wistar rats that were divided into sham, IR-control, KMP-20 + IR, and KMP 20 per se groups. KMP (20 mg/kg; i.p. was administered daily to rats for the period of 15 days, and, on the 15th day, ischemia was produced by one-stage ligation of left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed; heart was removed and processed for biochemical, morphological, and molecular studies. KMP pretreatment significantly ameliorated IR injury by maintaining cardiac function, normalizing oxidative stress, and preserving morphological alterations. Furthermore, there was a decrease in the level of inflammatory markers (TNF-α, IL-6, and NFκB, inhibition of active JNK and p38 proteins, and activation of ERK1/ERK2, a prosurvival kinase. Additionally, it also attenuated apoptosis by reducing the expression of proapoptotic proteins (Bax and Caspase-3, TUNEL positive cells, and increased level of antiapoptotic proteins (Bcl-2. In conclusion, KMP protected against IR injury by attenuating inflammation and apoptosis through the modulation of MAPK pathway.

  10. Maintenance of cAMP in non-heart-beating donor lungs reduces ischemia-reperfusion injury.

    Science.gov (United States)

    Hoffmann, S C; Bleiweis, M S; Jones, D R; Paik, H C; Ciriaco, P; Egan, T M

    2001-06-01

    Studies suggest that pulmonary vascular ischemia-reperfusion injury (IRI) can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, assessed by capillary filtration coeficient (Kfc), in lungs retrieved from non-heart-beating donors (NHBDs) and reperfused with the addition of the beta(2)-adrenergic receptor agonist isoproterenol (iso), and rolipram (roli), a phosphodiesterase (type IV) inhibitor. Using an in situ isolated perfused lung model, lungs were retrieved from NHBD rats at varying intervals after death and either ventilated with O(2) or not ventilated. The lungs were reperfused with Earle's solution with or without a combination of iso (10 microM) and roli (2 microM). Kfc, lung viability, and pulmonary hemodynamics were measured. Lung tissue levels of adenine nucleotides and cAMP were measured by HPLC. Combined iso and roli (iso/roli) reperfusion decreased Kfc significantly (p Kfc in non-iso/roli-reperfused (r = 0.89) and iso/roli-reperfused (r = 0.97) lungs. cAMP levels correlated with Kfc (r = 0.93) in iso/roli-reperfused lungs. Pharmacologic augmentation of tissue TAN and cAMP levels might ameliorate the increased capillary permeability observed in lungs retrieved from NHBDs.

  11. Effects of intracoronary melatonin on ischemia-reperfusion injury in ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Ekeløf, Sarah V; Halladin, Natalie L; Jensen, Svend E

    2016-01-01

    Acute coronary occlusion is effectively treated by primary percutaneous coronary intervention. However, myocardial ischemia-reperfusion injury is at the moment an unavoidable consequence of the procedure. Oxidative stress is central in the development of ischemia-reperfusion injury. Melatonin......, an endogenous hormone, acts through antioxidant mechanisms and could potentially minimize the myocardial injury. The aim of the experimental study was to examine the cardioprotective effects of melatonin in a porcine closed-chest reperfused infarction model. A total of 20 landrace pigs were randomized...... to a dosage of 200 mg (0.4 mg/mL) melatonin or placebo (saline). The intervention was administered intracoronary and intravenous. Infarct size, area at risk and microvascular obstruction were determined ex vivo by cardiovascular magnetic resonance imaging. Myocardial salvage index was calculated. The plasma...

  12. Neuroprotective effect of pretreatment with ganoderma lucidum in cerebral ischemia/reperfusion injury in rat hippocampus

    Science.gov (United States)

    Zhang, Wangxin; Zhang, Quiling; Deng, Wen; Li, Yalu; Xing, Guoqing; Shi, Xinjun; Du, Yifeng

    2014-01-01

    Ganoderma lucidum is a traditional Chinese medicine, which has been shown to have both anti-oxidative and anti-inflammatory effects, and noticeably decreases both the infarct area and neuronal apoptosis of the ischemic cortex. This study aimed to investigate the protective effects and mechanisms of pretreatment with ganoderma lucidum (by intragastric administration) in cerebral ischemia/reperfusion injury in rats. Our results showed that pretreatment with ganoderma lucidum for 3 and 7 days reduced neuronal loss in the hippocampus, diminished the content of malondialdehyde in the hippocampus and serum, decreased the levels of tumor necrosis factor-α and interleukin-8 in the hippocampus, and increased the activity of superoxide dismutase in the hippocampus and serum. These results suggest that pretreatment with ganoderma lucidum was protective against cerebral ischemia/reperfusion injury through its anti-oxidative and anti-inflammatory actions. PMID:25317156

  13. Effects of valproic acid and dexamethasone administration on early bio-markers and gene expression profile in acute kidney ischemia-reperfusion injury in the rat.

    Directory of Open Access Journals (Sweden)

    Ryan W Speir

    Full Text Available Renal ischemia-reperfusion (IR causes acute kidney injury (AKI with high mortality and morbidity. The objective of this investigation was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Under general anesthesia, left renal ischemia was induced in Wister rats by occluding renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n = 8/group received Valproic Acid (150 mg/kg; VPA, Dexamethasone (3 mg/kg; Dex or Vehicle (saline intraperitoneally. Animals were sacrificed at 3, 24 or 120 h post-IR. Plasma creatinine (mg/dL at 24 h was reduced (P<0.05 in VPA (2.7±1.8 and Dex (2.3±1.2 compared to Vehicle (3.8±0.5 group. At 3 h, urine albumin (mg/mL was higher in Vehicle (1.47±0.10, VPA (0.84±0.62 and Dex (1.04±0.73 compared to naïve (uninjured/untreated control (0.14±0.26 group. At 24 h post-IR urine lipocalin-2 (μg/mL was higher (P<0.05 in VPA, Dex and Vehicle groups (9.61-11.36 compared to naïve group (0.67±0.29; also, kidney injury molecule-1 (KIM-1; ng/mL was higher (P<0.05 in VPA, Dex and Vehicle groups (13.7-18.7 compared to naïve group (1.7±1.9. Histopathology demonstrated reduced (P<0.05 ischemic injury in the renal cortex in VPA (Grade 1.6±1.5 compared to Vehicle (Grade 2.9±1.1. Inflammatory cytokines IL1β and IL6 were downregulated and anti-apoptotic molecule BCL2 was upregulated in VPA group. Furthermore, kidney DNA microarray demonstrated reduced injury, stress, and apoptosis related gene expression in the VPA administered rats. VPA appears to ameliorate kidney IR injury via reduced inflammatory cytokine, apoptosis/stress related gene expression, and improved regeneration. KIM-1, lipocalin-2 and albumin appear to be promising early urine biomarkers for the diagnosis of AKI.

  14. Research progress of traditional Chinese medicine extract for retinal ischemia-reperfusion injury

    Directory of Open Access Journals (Sweden)

    Qian-Yu Jia

    2015-05-01

    Full Text Available Retinal ischemia-reperfusion injury(RIRIis a common clinical disease, and the producing mechanism is still in research. Experimental and clinical research in recent years have showed that the mechanism of RIRI and oxygen free radicals, gene regulation, calcium overload, inflammatory cytokines and other factors are closely related. In this article, we summarized the current situation that the scholars at home and abroad study traditional Chinese medicine extract of prevention and treatment of RIRI.

  15. Role of cytosolic NADP+-dependent isocitrate dehydrogenase in ischemia-reperfusion injury in mouse kidney

    OpenAIRE

    Kim, Jinu; Kim, Ki Young; Jang, Hee-Seong; Yoshida, Takumi; Tsuchiya, Ken; Nitta, Kosaku; Park, Jeen-Woo; Bonventre, Joseph V.; Park, Kwon Moo

    2008-01-01

    Cytosolic NADP+-dependent isocitrate dehydrogenase (IDPc) synthesizes reduced NADP (NADPH), which is an essential cofactor for the generation of reduced glutathione (GSH), the most abundant and important antioxidant in mammalian cells. We investigated the role of IDPc in kidney ischemia-reperfusion (I/R) in mice. The activity and expression of IDPc were highest in the cortex, modest in the outer medulla, and lowest in the inner medulla. NADPH levels were greatest in the cortex. IDPc expressio...

  16. Multifocal electroretinogram for functional evaluation of retinal injury following ischemia-reperfusion in pigs

    DEFF Research Database (Denmark)

    Morén, Håkan; Gesslein, Bodil; Andreasson, Sten

    2010-01-01

    Multifocal electroretinogram (mfERG) has the power to discriminate between localized functional losses and overall retinal changes when evaluating retinal injury. So far, full-field ERG has been the gold standard for examining retinal ischemia and the effects of different neuroprotectants...... in experimental conditions. The aim of the present study was to establish mfERG, with simultaneous fundus monitoring, for analyzing the localized functional response in the retina after ischemia-reperfusion in the porcine eye....

  17. CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion.

    Science.gov (United States)

    Rogers, Natasha M; Zhang, Zheng J; Wang, Jiao-Jing; Thomson, Angus W; Isenberg, Jeffrey S

    2016-08-01

    Defects in renal tubular epithelial cell repair contribute to renal ischemia reperfusion injury, cause acute kidney damage, and promote chronic renal disease. The matricellular protein thrombospondin-1 and its receptor CD47 are involved in experimental renal ischemia reperfusion injury, although the role of this interaction in renal recovery is unknown. We found upregulation of self-renewal genes (transcription factors Oct4, Sox2, Klf4 and cMyc) in the kidney of CD47(-/-) mice after ischemia reperfusion injury. Wild-type animals had minimal self-renewal gene expression, both before and after injury. Suggestive of cell autonomy, CD47(-/-) renal tubular epithelial cells were found to increase expression of the self-renewal genes. This correlated with enhanced proliferative capacity compared with cells from wild-type mice. Exogenous thrombospondin-1 inhibited self-renewal gene expression in renal tubular epithelial cells from wild-type but not CD47(-/-) mice, and this was associated with decreased proliferation. Treatment of renal tubular epithelial cells with a CD47 blocking antibody or CD47-targeting small interfering RNA increased expression of some self-renewal transcription factors and promoted cell proliferation. In a syngeneic kidney transplant model, treatment with a CD47 blocking antibody increased self-renewal transcription factor expression, decreased tissue damage, and improved renal function compared with that in control mice. Thus, thrombospondin-1 via CD47 inhibits renal tubular epithelial cell recovery after ischemia reperfusion injury through inhibition of proliferation/self-renewal. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  18. Ultrasound Imaging of Mouse Fetal Intracranial Hemorrhage Due to Ischemia/Reperfusion

    Directory of Open Access Journals (Sweden)

    Kenichi Funamoto

    2017-05-01

    Full Text Available Despite vast improvement in perinatal care during the 30 years, the incidence rate of neonatal encephalopathy remains unchanged without any further Progress towards preventive strategies for the clinical impasse. Antenatal brain injury including fetal intracranial hemorrhage caused by ischemia/reperfusion is known as one of the primary triggers of neonatal injury. However, the mechanisms of antenatal brain injury are poorly understood unless better predictive models of the disease are developed. Here we show a mouse model for fetal intracranial hemorrhage in vivo developed to investigate the actual timing of hypoxia-ischemic events and their related mechanisms of injury. Intrauterine growth restriction mouse fetuses were exposed to ischemia/reperfusion cycles by occluding and opening the uterine and ovarian arteries in the mother. The presence and timing of fetal intracranial hemorrhage caused by the ischemia/reperfusion were measured with histological observation and ultrasound imaging. Protein-restricted diet increased the risk of fetal intracranial hemorrhage. The monitoring of fetal brains by ultrasound B-mode imaging clarified that cerebral hemorrhage in the fetal brain occurred after the second ischemic period. Three-dimensional ultrasound power Doppler imaging visualized the disappearance of main blood flows in the fetal brain. These indicate a breakdown of cerebrovascular autoregulation which causes the fetal intracranial hemorrhage. This study supports the fact that the ischemia/reperfusion triggers cerebral hemorrhage in the fetal brain. The present method enables us to noninvasively create the cerebral hemorrhage in a fetus without directly touching the body but with repeated occlusion and opening of the uterine and ovarian arteries in the mother.

  19. [Protective effects of endogenous carbon monoxide against myocardial ischemia-reperfusion injury in rats].

    Science.gov (United States)

    Zhou, Zhen; Ma, Shuang; Liu, Jie; Ji, Qiao-Rong; Cao, Cheng-Zhu; Li, Xiao-Na; Tang, Feng; Zhang, Wei

    2018-04-25

    The present study is aimed to explore the effects of endogenous carbon monoxide on the ischemia-reperfusion in rats. Wistar rats were intraperitoneally injected with protoporphyrin cobalt chloride (CoPP, an endogenous carbon monoxide agonist, 5 mg/kg), zinc protoporphyrin (ZnPP, an endogenous carbon monoxide inhibitor, 5 mg/kg) or saline. Twenty-four hours after injection, the myocardial ischemia-reperfusion model was made by Langendorff isolated cardiac perfusion system, and cardiac function parameters were collected. Myocardial cGMP content was measured by ELISA, and the endogenous carbon monoxide in plasma and myocardial enzymes in perfusate at 10 min after reperfusion were measured by colorimetry. The results showed that before ischemia the cardiac functions of CoPP, ZnPP and control groups were stable, and there were no significant differences. After reperfusion, cardiac functions had significant differences among the three groups (P endogenous carbon monoxide can maintain cardiac function, shorten the time of cardiac function recovery, and play a protective role in cardiac ischemia-reperfusion.

  20. Thymoquinone protects end organs from abdominal aorta ischemia/reperfusion injury in a rat model

    Directory of Open Access Journals (Sweden)

    Mehmet Salih Aydin

    2015-02-01

    Full Text Available Introduction: Previous studies have demonstrated that thymoquinone has protective effects against ischemia reperfusion injury to various organs like lungs, kidneys and liver in different experimental models. Objective: We aimed to determine whether thymoquinone has favorable effects on lung, renal, heart tissues and oxidative stress in abdominal aorta ischemia-reperfusion injury. Methods: Thirty rats were divided into three groups as sham (n=10, control (n=10 and thymoquinone (TQ treatment group (n=10. Control and TQ-treatment groups underwent abdominal aorta ischemia for 45 minutes followed by a 120-min period of reperfusion. In the TQ-treatment group, thymoquinone was given 5 minutes. before reperfusion at a dose of 20 mg/kg via an intraperitoneal route. Total antioxidant capacity, total oxidative status (TOS, and oxidative stress index (OSI in blood serum were measured and lung, kidney, and heart tissue histopathology were evaluated with light microscopy. Results: Total oxidative status and oxidative stress index activity in blood samples were statistically higher in the control group compared to the sham and TQ-treatment groups (P<0.001 for TOS and OSI. Control group injury scores were statistically higher compared to sham and TQ-treatment groups (P<0.001 for all comparisons. Conclusion: Thymoquinone administered intraperitoneally was effective in reducing oxidative stress and histopathologic injury in an acute abdominal aorta ischemia-reperfusion rat model.

  1. Hemorheological changes in ischemia-reperfusion: an overview on our experimental surgical data.

    Science.gov (United States)

    Nemeth, Norbert; Furka, Istvan; Miko, Iren

    2014-01-01

    Blood vessel occlusions of various origin, depending on the duration and extension, result in tissue damage, causing ischemic or ischemia-reperfusion injuries. Necessary surgical clamping of vessels in vascular-, gastrointestinal or parenchymal organ surgery, flap preparation-transplantation in reconstructive surgery, as well as traumatological vascular occlusions, all present special aspects. Ischemia and reperfusion have effects on hemorheological state by numerous ways: besides the local metabolic and micro-environmental changes, by hemodynamic alterations, free-radical and inflammatory pathways, acute phase reactions and coagulation changes. These processes may be harmful for red blood cells, impairing their deformability and influencing their aggregation behavior. However, there are still many unsolved or non-completely answered questions on relation of hemorheology and ischemia-reperfusion. How do various organ (liver, kidney, small intestine) or limb ischemic-reperfusionic processes of different duration and temperature affect the hemorheological factors? What is the expected magnitude and dynamics of these alterations? Where is the border of irreversibility? How can hemorheological investigations be applied to experimental models using laboratory animals in respect of inter-species differences? This paper gives a summary on some of our research data on organ/tissue ischemia-reperfusion, hemorheology and microcirculation, related to surgical research and experimental microsurgery.

  2. Experimental study of pulmonary thromboembolism ischemia-reperfusion injury in canine model

    International Nuclear Information System (INIS)

    Li Jianjun; Zhai Renyou; Zhang Dongpo; Huang Qiang; Yu Ping; Dai Dingke; Bao Na

    2009-01-01

    Objective: To establish a canine model of pulmonary thromboembolism ischemia- reperfusion injury (PTE IRI) that may be used for imaging study. Methods: Ten male and 10 female healthy mongrel canines with (18.6±0.8) kg/body weight, were used. A Swan-Ganz catheter was introduced into the right internal jugular vein via a preset percutaneous sheath using the Seldinger technique, and then was with further insertion the pulmonary artery. Balloon occlusion of the right inferior lobe pulmonary artery for 4 hours was followed by removing the catheter and ending with 4 hours of reperfusion. CT was performed before ischemia, 4 h after ischemia and 4 h after reperfusion. At last, dogs were killed and the bilateral inferior lung tissues were prepared for the examination by light and electronic microscopy. Results: All canine models were successfully developed pulmonary thromboembolism ischemia-reperfusion injury. The examination of CT, light and electron microscopy consistently indicated the presence of permeability pulmonary edema after reperfusion. Conclusions: A closed-chest canine model in vivo of pulmonary thromboembolism ischemia-reperfusion injury can be established with virtual pathophysiological process in human and be as well as for imaging experimental study. (authors)

  3. Short-term dietary restriction and fasting precondition against ischemia reperfusion injury in mice.

    Science.gov (United States)

    Mitchell, James R; Verweij, Mariëlle; Brand, Karl; van de Ven, Marieke; Goemaere, Natascha; van den Engel, Sandra; Chu, Timothy; Forrer, Flavio; Müller, Cristina; de Jong, Marion; van IJcken, Wilfred; IJzermans, Jan N M; Hoeijmakers, Jan H J; de Bruin, Ron W F

    2010-02-01

    Dietary restriction (DR) extends lifespan and increases resistance to multiple forms of stress, including ischemia reperfusion injury to the brain and heart in rodents. While maximal effects on lifespan require long-term restriction, the kinetics of onset of benefits against acute stress is not known. Here, we show that 2-4 weeks of 30% DR improved survival and kidney function following renal ischemia reperfusion injury in mice. Brief periods of water-only fasting were similarly effective at protecting against ischemic damage. Significant protection occurred within 1 day, persisted for several days beyond the fasting period and extended to another organ, the liver. Protection by both short-term DR and fasting correlated with improved insulin sensitivity, increased expression of markers of antioxidant defense and reduced expression of markers of inflammation and insulin/insulin-like growth factor-1 signaling. Unbiased transcriptional profiling of kidneys from mice subject to short-term DR or fasting revealed a significant enrichment of signature genes of long-term DR. These data demonstrate that brief periods of reduced food intake, including short-term daily restriction and fasting, can increase resistance to ischemia reperfusion injury in rodents and suggest a rapid onset of benefits of DR in mammals.

  4. Inhibition of microRNA-153 protects neurons against ischemia/reperfusion injury in an oxygen-glucose deprivation and reoxygenation cellular model by regulating Nrf2/HO-1 signaling.

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    Ji, Qiong; Gao, Jianbo; Zheng, Yan; Liu, Xueli; Zhou, Qiangqiang; Shi, Canxia; Yao, Meng; Chen, Xia

    2017-07-01

    MicroRNAs are emerging as critical regulators in cerebral ischemia/reperfusion injury; however, their exact roles remain poorly understood. miR-153 is reported to be a neuron-related miRNA involved in neuroprotection. In this study, we aimed to investigate the precise role of miR-153 in regulating neuron survival during cerebral ischemia/reperfusion injury using an oxygen-glucose deprivation and reoxygenation (OGD/R) cellular model. We found that miR-153 was significantly upregulated in neurons subjected to OGD/R treatment. Inhibition of miR-153 significantly attenuated OGD/R-induced injury and oxidative stress in neurons. Nuclear factor erythroid 2-related factor 2 (Nrf2) was identified as a target gene of miR-153. Inhibition of miR-153 significantly promoted the expression of Nrf2 and heme oxygenase-1 (HO-1). However, silencing of Nrf2 significantly blocked the protective effects of miR-153 inhibition. Our study indicates that the inhibition of miR-153 protects neurons against OGD/R-induced injury by regulating Nrf2/HO-1 signaling and suggests a potential therapeutic target for cerebral ischemia/reperfusion injury. © 2017 Wiley Periodicals, Inc.

  5. Protective effect of Urtica dioica L. on renal ischemia/reperfusion injury in rat.

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    Sayhan, Mustafa Burak; Kanter, Mehmet; Oguz, Serhat; Erboga, Mustafa

    2012-12-01

    Renal ischemia-reperfusion (I/R) injury may occur after renal transplantation, thoracoabdominal aortic surgery, and renal artery interventions. This study was designed to investigate the effect of Urtica dioica L. (UD), in I/R induced renal injury. A total of 32 male Sprague-Dawley rats were divided into four groups: control, UD alone, I/R and I/R + UD; each group contain 8 animals. A rat model of renal I/R injury was induced by 45-min occlusion of the bilateral renal pedicles and 24-h reperfusion. In the UD group, 3 days before I/R, UD (2 ml/kg/day intraperitoneal) was administered by gastric gavage. All animals were sacrificed at the end of reperfusion and kidney tissues samples were obtained for histopathological investigation in all groups. To date, no more histopathological changes on intestinal I/R injury in rats by UD treatment have been reported. Renal I/R caused severe histopathological injury including tubular damage, atrophy dilatation, loss of brush border and hydropic epithelial cell degenerations, renal corpuscle atrophy, glomerular shrinkage, markedly focal mononuclear cell infiltrations in the kidney. UD treatment significantly attenuated the severity of intestinal I/R injury and significantly lowered tubulointerstitial damage score than the I/R group. The number of PCNA and TUNEL positive cells in the control and UD alone groups was negligible. When kidney sections were PCNA and TUNEL stained, there was a clear increase in the number of positive cells in the I/R group rats in the renal cortical tissues. However, there is a significant reduction in the activity of PCNA and TUNEL in kidney tissue of renal injury induced by renal I/R with UD therapy. Our results suggest that administration of UD attenuates renal I/R injury. These results suggest that UD treatment has a protective effect against renal damage induced by renal I/R. This protective effect is possibly due to its ability to inhibit I/R induced renal damage, apoptosis and cell proliferation.

  6. Evaluation of Chronic Physical and Psychological Stress Induction on Cardiac Ischemia / Reperfusion Injuries in Isolated Male Rat Heart: The Role of Sympathetic Nervous System

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    Kamran Rakhshan

    2015-10-01

    Full Text Available Exposure to stress leads to physiological changes called “stress response” which are the result ofthe changes in the adrenomedullary hormone system, hypothalamus-pituitary-adrenal (HPA and sympatheticnervous system (SNS activity. In the present study, the effects of chronic physical and psychological stressand also the role of sympathetic system effects in stress on ischemia/reperfusion (I/R injuries have beenstudied in isolated rat heart. Rat heart was isolated and subjected to 30 min regional ischemia and 120 minreperfusion. The daily stress was induced for one week prior to I/R induction. Sympathectomy was donechemically by injection of hydroxyl-dopamine prior to stress induction. There were no significant changes inheart rate and Coronary Flow between groups. Left ventricular developed pressure (LVDP and rate productpressure (RPP in both physical and psychological stress groups decreased significantly compared to those incontrol group (Pgroups. Infarct size significantly increased in both physical and psychological stress groups and control group(Pas compared with stress groups (Ppsychological stress prior to ischemia/reperfusion causes enhancement of myocardial injuries and it seemsthat increased sympathetic activity in response to stress is responsible for these adverse effects of stress onischemic/reperfused heart.

  7. The Protective Effects of Alpha-Lipoic Acid and Coenzyme Q10 Combination on Ovarian Ischemia-Reperfusion Injury: An Experimental Study

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    Ahmet Ali Tuncer

    2016-01-01

    Full Text Available Objective. This study aims to evaluate whether alpha-lipoic acid and/or coenzyme Q10 can protect the prepubertal ovarian tissue from ischemia-reperfusion injury in an experimental rat model of ovarian torsion. Materials and Methods. Forty-two female preadolescent Wistar-Albino rats were divided into 6 equal groups randomly. The sham group had laparotomy without torsion; the other groups had torsion/detorsion procedure. After undergoing torsion, group 2 received saline, group 3 received olive oil, group 4 received alpha-lipoic acid, group 5 received coenzyme Q10, and group 6 received both alpha-lipoic acid and coenzyme Q10 orally. The oxidant-antioxidant statuses of these groups were compared using biochemical measurement of oxidized/reduced glutathione, glutathione peroxidase and malondialdehyde, pathological evaluation of damage and apoptosis within the ovarian tissue, and immunohistochemical assessment of nitric oxide synthase. Results. The left ovaries of the alpha-lipoic acid + coenzyme Q10 group had significantly lower apoptosis scores and significantly higher nitric oxide synthase content than the left ovaries of the control groups. The alpha-lipoic acid + coenzyme Q10 group had significantly higher glutathione peroxidase levels and serum malondialdehyde concentrations than the sham group. Conclusions. The combination of alpha-lipoic acid and coenzyme Q10 has beneficial effects on oxidative stress induced by ischemia-reperfusion injury related to ovarian torsion.

  8. Toll-like receptor 2 mediates ischemia-reperfusion injury of the small intestine in adult mice.

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    Toshio Watanabe

    Full Text Available Toll-like receptor 2 (TLR2 recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO, a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α, intercellular adhesion molecule-1 (ICAM-1, and cyclooxygenase-2 (COX-2 in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory

  9. ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury

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    Arfian, Nur [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Emoto, Noriaki, E-mail: emoto@med.kobe-u.ac.jp [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe (Japan); Vignon-Zellweger, Nicolas; Nakayama, Kazuhiko; Yagi, Keiko [Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe (Japan); Hirata, Ken-ichi [Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Ischemia/reperfusion injury (IRI) induced increased endothelin-1 (ET-1) expression. Black-Right-Pointing-Pointer IRI was accompanied by tubular injury and remodeling of renal arteries. Black-Right-Pointing-Pointer IRI increased oxidative stress and inflammation. Black-Right-Pointing-Pointer Genetic suppression of ET-1 in endothelial cells attenuates IRI in the kidney. Black-Right-Pointing-Pointer The mechanisms include the inhibition of oxidative stress and inflammation. -- Abstract: Background: The prognosis of patients after acute kidney injury (AKI) is poor and treatment is limited. AKI is mainly caused by renal ischemia/reperfusion injury (IRI). During the extension phase of IRI, endothelial damage may participate in ischemia and inflammation. Endothelin-1 (ET-1) which is mostly secreted by endothelial cells is an important actor of IRI, particularly through its strong vasoconstrictive properties. We aimed to analyze the specific role of ET-1 from the endothelial cells in AKI. Methods: We used mice lacking ET-1 in the vascular endothelial cells (VEETKO). We induced IRI in VEETKO mice and wild type controls by clamping both kidneys for 30 min. Sham operated mice were used as controls. Mice were sacrificed one day after IRI in order to investigate the extension phase of IRI. Kidney function was assessed based on serum creatinine concentration. Levels of expression of ET-1, its receptor ET{sub A}, protein kinase C, eNOS, E-Cadherin and inflammation markers were evaluated by real time PCR or western blot. Tubular injury was scored on periodic acid Schiff stained kidney preparations. Lumen and wall area of small intrarenal arteries were measured on kidney slices stained for alpha smooth muscle cell actin. Oxidative stress, macrophage infiltration and cell proliferation was evaluated on slices stained for 8-hydroxy-2 Prime -deoxyguanosine, F4/80 and PCNA, respectively. Results: IRI induced kidney failure and increased ET-1 and

  10. Anticancer Drug 2-Methoxyestradiol Protects against Renal Ischemia/Reperfusion Injury by Reducing Inflammatory Cytokines Expression

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    Ying-Yin Chen

    2014-01-01

    Full Text Available Background. Ischemia/reperfusion (I/R injury is a major cause of acute renal failure and allograft dysfunction in kidney transplantation. ROS/inflammatory cytokines are involved in I/R injury. 2-Methoxyestradiol (2ME2, an endogenous metabolite of estradiol, inhibits inflammatory cytokine expression and is an antiangiogenic and antitumor agent. We investigated the inhibitory effect of 2ME2 on renal I/R injury and possible molecular actions. Methods. BALB/c mice were intraperitoneally injected with 2ME2 (10 or 20 mg/kg or vehicle 12 h before and immediately after renal I/R experiments. The kidney weight, renal function, tubular damages, and apoptotic response were examined 24 h after I/R injury. The expression of mRNA of interleukin-1β, tumor necrosis factor- (TNF α, caspase-3, hypoxia inducible factor- (HIF 1α, and proapoptotic Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3 in kidney tissue was determined using RT-PCR, while the expression of nuclear factor κB (NF-κB, BCL-2, and BCL-xL, activated caspase-9, and HIF-1α was determined using immunoblotting. In vitro, we determined the effect of 2ME2 on reactive oxygen species (ROS production and cell viability in antimycin-A-treated renal mesangial (RMC and tubular (NRK52E cells. Results. Serum creatinine and blood urea nitrogen were significantly higher in mice with renal I/R injury than in sham control and in I/R+2ME2-treated mice. Survival in I/R+2ME2-treated mice was higher than in I/R mice. Histological examination showed that 2ME2 attenuated tubular damage in I/R mice, which was associated with lower expression TNF-α, IL-1β, caspase-9, HIF-1α, and BNIP3 mRNA in kidney tissue. Western blotting showed that 2ME2 treatment substantially decreased the expression of activated caspase-9, NF-κB, and HIF-1α but increased the antiapoptotic proteins BCL-2 and BCL-xL in kidney of I/R injury. In vitro, 2MR2 decreased ROS production and increased cell viability in antimycin

  11. Gaseous hydrogen sulfide protects against myocardial ischemia-reperfusion injury in mice partially independent from hypometabolism.

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    Pauline M Snijder

    Full Text Available BACKGROUND: Ischemia-reperfusion injury (IRI is a major cause of cardiac damage following various pathological processes. Gaseous hydrogen sulfide (H2S is protective during IRI by inducing a hypometabolic state in mice which is associated with anti-apoptotic, anti-inflammatory and antioxidant properties. We investigated whether gaseous H2S administration is protective in cardiac IRI and whether non-hypometabolic concentrations of H2S have similar protective properties. METHODS: Male C57BL/6 mice received a 0, 10, or 100 ppm H2S-N2 mixture starting 30 minutes prior to ischemia until 5 minutes pre-reperfusion. IRI was inflicted by temporary ligation of the left coronary artery for 30 minutes. High-resolution respirometry equipment was used to assess CO2-production and blood pressure was measured using internal transmitters. The effects of H2S were assessed by histological and molecular analysis. RESULTS: Treatment with 100 ppm H2S decreased CO2-production by 72%, blood pressure by 14% and heart rate by 25%, while treatment with 10 ppm H2S had no effects. At day 1 of reperfusion 10 ppm H2S showed no effect on necrosis, while treatment with 100 ppm H2S reduced necrosis by 62% (p<0.05. Seven days post-reperfusion, both 10 ppm (p<0.01 and 100 ppm (p<0.05 H2S showed a reduction in fibrosis compared to IRI animals. Both 10 ppm and 100 ppm H2S reduced granulocyte-influx by 43% (p<0.05 and 60% (p<0.001, respectively. At 7 days post-reperfusion both 10 and 100 ppm H2S reduced expression of fibronectin by 63% (p<0.05 and 67% (p<0.01 and ANP by 84% and 63% (p<0.05, respectively. CONCLUSIONS: Gaseous administration of H2S is protective when administered during a cardiac ischemic insult. Although hypometabolism is restricted to small animals, we now showed that low non-hypometabolic concentrations of H2S also have protective properties in IRI. Since IRI is a frequent cause of myocardial damage during percutaneous coronary intervention and cardiac

  12. Dynamic Contrast-Enhanced MR Imaging of Renal Ischemia-Reperfusion Injury

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    Baik, Jun Hyun; Ahn, Myeong Im; Park, Young Ha; Chung, Soo Kyo [Catholic University, Seoul (Korea, Republic of)

    2010-02-15

    To evaluate the usefulness of magnetic resonance imaging (MRI) in a renal ischemia-reperfusion injury. Twenty-four rabbits were randomly divided into four groups, including a sham operated group (n=3). Renal ischemia was induced for 30 minutes (group 1), 60 minutes (group 2) and 120 minutes (group 3). MR imaging was performed before ischemia as well as one hour, 24 hours, and 72 hours after reperfusion. A 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy was performed before ischemia, as well as 24 hours and 72 hours after reperfusion. The signal-to-noise ratio (SNR) on the T2WI, time-relative signal intensity (%RSI) curve on dynamic enhanced images, and relative left renal uptake (%) on DMSA scan were obtained and compared to the histologic findings. The SNR of the cortex on the T2WI changed significantly over the course of the reperfusion time (p<0.001), but was not significantly different among the ischemia groups. The area under the time-%RSI curve gradually decreased from cortex to inner medulla before ischemia, which was reversed and gradually increased after reperfusion. The areas under the time-%RSI curve of outer and inner medulla were significantly different among the ischemia groups (p=0.04, p=0.008). The relative renal uptake (%) of left kidney decreased significantly over the reperfusion time (p=0.03), and was also significantly different among the ischemia groups (p=0.005). Tubular cell necrosis was observed in 16 rabbits (76.2%). The histologic grades of group 3 were higher than those of group 1 and group 2 (p=0.002). Even in rabbits without tubular cell necrosis, the areas under the time-%RSI curves of the cortex, outer, and inner medulla after a 72 hour reperfusion time were significantly lower than those before ischemia (p=0.007, p=0.005, p=0.004). The results of this study suggest that dynamic enhanced MR imaging could be a useful tool for the evaluation of renal ischemia and reperfusion injury.

  13. Change in iron metabolism in rats after renal ischemia/reperfusion injury.

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    Guang-Liang Xie

    Full Text Available Previous studies have indicated that hepcidin, which can regulate iron efflux by binding to ferroportin-1 (FPN1 and inducing its internalization and degradation, acts as the critical factor in the regulation of iron metabolism. However, it is unknown whether hepcidin is involved in acute renal ischemia/reperfusion injury (IRI. In this study, an IRI rat model was established via right renal excision and blood interruption for 45 min in the left kidney, and iron metabolism indexes were examined to investigate the change in iron metabolism and to analyze the role of hepcidin during IRI. From 1 to 24 h after renal reperfusion, serum creatinine and blood urea nitrogen were found to be time-dependently increased with different degrees of kidney injury. Regular variations in iron metabolism indexes in the blood and kidneys were observed in renal IRI. Renal iron content, serum iron and serum ferritin increased early after reperfusion and then declined. Hepcidin expression in the liver significantly increased early after reperfusion, and its serum concentration increased beginning at 8 h after reperfusion. The splenic iron content decreased significantly in the early stage after reperfusion and then increased time-dependently with increasing reperfusion time, and the hepatic iron content showed a decrease in the early stage after reperfusion. The early decrease of the splenic iron content and hepatic iron content might indicate their contribution to the increase in serum iron in renal IRI. In addition, the duodenal iron content showed time-dependently decreased since 12 h after reperfusion in the IRI groups compared to the control group. Along with the spleen, the duodenum might contribute to the decrease in serum iron in the later stage after reperfusion. The changes in iron metabolism indexes observed in our study demonstrate an iron metabolism disorder in renal IRI, and hepcidin might be involved in maintaining iron homeostasis in renal IRI. These

  14. The role of curcumin on intestinal oxidative stress, cell proliferation and apoptosis after ischemia/reperfusion injury in rats.

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    Yucel, Ahmet Fikret; Kanter, Mehmet; Pergel, Ahmet; Erboga, Mustafa; Guzel, Ahmet

    2011-12-01

    The aim of this study was to demonstrate the role of curcumin on oxidative stress, cell proliferation and apoptosis in the rat intestinal mucosa after ischemia/reperfusion (I/R). A total of 30 male Wistar albino rats were divided into three groups: sham, I/R and I/R+ curcumin; each group contain 10 animals. Sham group animals underwent laparotomy without I/R injury. After I/R groups animals underwent laparotomy, 1 h of superior mesenteric artery ligation were followed by 1 h of reperfusion. In the curcumin group, 3 days before I/R, curcumin (100 mg/kg) was administered by gastric gavage. All animals were sacrificed at the end of reperfusion and intestinal tissues samples were obtained for biochemical and histopathological investigation in all groups. Curcumin treatment significantly decreased the elevated tissue malondialdehyde levels and increased of reduced superoxide dismutase, and glutathione peroxidase enzyme activities in intestinal tissues samples. I/R caused severe histopathological injury including mucosal erosions and villous congestion and hemorrhage. Curcumin treatment significantly attenuated the severity of intestinal I/R injury, with inhibiting of I/R-induced apoptosis and cell proliferation. These results suggest that curcumin treatment has a protective effect against intestinal damage induced by intestinal I/R. This protective effect is possibly due to its ability to inhibit I/R-induced oxidative stress, apoptosis and cell proliferation.

  15. Restoration of normal pH triggers ischemia-reperfusion injury in lung by Na+/H+ exchange activation.

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    Moore, T M; Khimenko, P L; Taylor, A E

    1995-10-01

    The effects of acidotic extracellular pH and Na+/H+ exchange inhibition on ischemia-reperfusion (I/R)-induced microvascular injury were studied in the isolated, buffer-perfused rat lung. When lungs were subjected to 45 min of ischemia followed by 30 min of reperfusion, the capillary filtration coefficient (Kfc) increased significantly, resulting in a change in Kfc (delta Kfc) of 0.360 +/- 0.09 ml.min-1.cmH2O-1.100 g-1. Addition of hydrochloric acid to the perfusate before ischemia at a concentration sufficient to reduce perfusate pH from 7.38 +/- 0.03 to 7.09 +/- 0.04 completely prevented the increase in Kfc associated with I/R (delta Kfc = 0.014 +/- 0.034 ml.min-1.cmH2O-1.100 g-1). Addition of a Na+/H+ exchange inhibitor, 5-(N,N-dimethyl)-amiloride, to the perfusate either before ischemia or at reperfusion also prevented the I/R-induced permeability increase (delta Kfc = 0.01 +/- 0.02 and -0.001 +/- 0.02 ml.min-1.cmH2O-1.100 g-1, respectively). We conclude that restoration of flow at physiological pH to the postischemic lung activates the Na+/H+ exchange system, which may represent the "triggering mechanism" responsible for initiating reperfusion-induced microvascular injury.

  16. L-carnitine pretreatment protects slow-twitch skeletal muscles in a rat model of ischemia-reperfusion injury.

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    Demirel, Mert; Kaya, Burak; Cerkez, Cem; Ertunc, Mert; Sara, Yildirim

    2013-10-01

    Ischemia-reperfusion (I/R) injury negatively affects the outcome of surgical interventions for amputated or severely traumatized extremities. This study aimed to evaluate the protective role of l-carnitine on the contractile properties of fast-twitch (extensor digitorum longus [EDL]) and slow-twitch (soleus [SOL]) skeletal muscles following I/R-induced injury in a rat model. Rats were divided into 4 groups (1) saline pretreatment, (2) l-carnitine pretreatment, (3) saline pretreatment and I/R, and (4) l-carnitine pretreatment and I/R. Twitch and tetanic contractions in the EDL and SOL muscles in each group were recorded. Additionally, a fatigue protocol was performed in these muscles. Twitch and tetanic contraction amplitudes were lower in the EDL and SOL muscles in which I/R was induced (P contraction amplitude in the SOL muscles following I/R (P muscles. l-Carnitine pretreatment did not alter the fatigue response in any of the muscles.

  17. Mannan-Binding Lectin Is Involved in the Protection against Renal Ischemia/Reperfusion Injury by Dietary Restriction.

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    Shushimita Shushimita

    Full Text Available Preoperative fasting and dietary restriction offer robust protection against renal ischemia/reperfusion injury (I/RI in mice. We recently showed that Mannan-binding lectin (MBL, the initiator of the lectin pathway of complement activation, plays a pivotal role in renal I/RI. Based on these findings, we investigated the effect of short-term DR (30% reduction of total food intake or three days of water only fasting on MBL in 10-12 weeks old male C57/Bl6 mice. Both dietary regimens significantly reduce the circulating levels of MBL as well as its mRNA expression in liver, the sole production site of MBL. Reconstitution of MBL abolished the protection afforded by dietary restriction, whereas in the fasting group the protection persisted. These data show that modulation of MBL is involved in the protection against renal I/RI induced by dietary restriction, and suggest that the mechanisms of protection induced by dietary restriction and fasting may be different.

  18. Nephroprotective Effects of Polydatin against Ischemia/Reperfusion Injury: A Role for the PI3K/Akt Signal Pathway

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    Hong-Bao Liu

    2015-01-01

    Full Text Available Oxidative stress and inflammation are involved in the pathogenesis in renal ischemia/reperfusion (I/R injury. It has been demonstrated that polydatin processed the antioxidative, anti-inflammatory, and nephroprotective properties. However, whether it has beneficial effects and the possible mechanisms on renal I/R injury remain unclear. In our present study I/R models were simulated both in vitro and in vivo. Compared with vehicle control, the administration of polydatin significantly improved the renal function, accelerated the mitogenic response and reduced cell apoptosis in renal I/R injury models, strongly suppressed the I/R-induced upregulation of the expression of tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, inducible nitric oxide synthase, prostaglandin E-2, and nitric oxide levels, and dramatically decreased contents of malondialdehyde, but it increased the activity of superoxide dismutase, glutathione transferase, glutathione peroxidase and catalase, and the level of glutathione. Further investigation showed that polydatin upregulated the phosphorylation of Akt in kidneys of I/R injury dose-dependently. However, all beneficial effects of polydatin mentioned above were counteracted when we inhibited PI3K/Akt pathway with its specific inhibitor, wortmannin. Taken together, the present findings provide the first evidence demonstrating that PD exhibited prominent nephroprotective effects against renal I/R injury by antioxidative stress and inflammation through PI3-K/Akt-dependent molecular mechanisms.

  19. Hyperoxic preconditioning fails to confer additional protection against ischemia-reperfusion injury in acute diabetic rat heart.

    Science.gov (United States)

    Pourkhalili, Khalil; Hajizadeh, Sohrab; Akbari, Zahra; Dehaj, Mansour Esmaili; Akbarzadeh, Samad; Alizadeh, Alimohammad

    2012-01-01

    Experimental studies show that detrimental effects of ischemia-reperfusion (I/R) injury can be attenuated by hyperoxic preconditioning in normal hearts, however, there are few studies about hyperoxia effects in diseased myocardium. The present study was designed to assess the cardioprotective effects of hyperoxia pretreatment (≥ 95 % O2) in acute diabetic rat hearts. Normal and one week acute diabetic rats were either exposed to 60 (H60) and 180 (H180) min of hyperoxia or exposed to normal atmospheric air (21 % O2). Then hearts were isolated immediately and subjected to 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size, cardiomyocyte apoptosis, enzymes release and ischemia induced arrhythmias were determined. Heart of diabetic control rats had less infarct size and decreased LDH and CK-MB release compared to normal hearts. 60 and 180 min of hyperoxia reduced myocardial infarct size and enzymes release in normal hearts. 180 min of hyperoxia also decreased cardiomyocytes apoptosis in normal state. On the other hand, protective values of hyperoxia were not significantly different in diabetic hearts. Moreover, hyperoxia reduced severity of ventricular arrhythmias in normal rat hearts whereas; it did not confer any additional antiarrhythmic protection in diabetic hearts. These findings suggest that diabetic hearts are less susceptible to ischemia-induced arrhythmias and infarction. Hyperoxia greatly protects rat hearts against I/R injury in normal hearts, however, it could not provide added cardioprotective effects in acute phase of diabetes.

  20. Cardioprotective Effect of Aloe vera Biomacromolecules Conjugated with Selenium Trace Element on Myocardial Ischemia-Reperfusion Injury in Rats.

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    Yang, Yang; Yang, Ming; Ai, Fen; Huang, Congxin

    2017-06-01

    The present study was undertaken to evaluate the cardioprotection potential and underlying molecular mechanism afforded by a selenium (Se) polysaccharide (Se-AVP) from Aloe vera in the ischemia-reperfusion (I/R) model of rats in vivo. Myocardial I/R injury was induced by occluding the left anterior descending coronary artery (LAD) for 30 min followed by 2-h continuous reperfusion. Pretreatment with Se-AVP (100, 200, and 400 mg/kg) attenuated myocardial damage, as evidenced by reduction of the infarct sizes, increase in serum and myocardial endogenous antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GSH), and catalase (CAT)), and decrease in the malondialdehyde (MDA) level in the rats suffering I/R injury. This cardioprotective activity afforded by Se-AVP is further supported by the decreased levels of cardiac marker enzymes creatine kinase (CK) and lactate dehydrogenase (LDH), as well as the rise of myocardial Na + -K + -ATPase and Ca 2+ -Mg 2+ -ATPase activities in I/R rats. Additionally, cardiomyocytic apoptosis was measured by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining and the result showed that the percent of TUNEL-positive cells in myocardium of Se-AVP-treated groups was lower than I/R rats. In conclusion, we clearly demonstrated that Se-AVP had a protective effect against myocardial I/R injury in rats by augmenting endogenous antioxidants and protecting rat hearts from oxidative stress-induced myocardial apoptosis.

  1. The Effect of Lidocaine Enriched Cardioplegia on Myocardial Ischemia-Reperfusion Injury

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    Emin Ata

    2016-07-01

    Full Text Available Aim: Most of the complications after open heart surgery is usually associated with ischemia reperfusion injury that develops during cardiopulmoner bypass. In ischemia and reperfusion periods lidocaine blocks intracelluler sodium and calcium channels and protect cell membrane against reactive oxygen metabolites. In this study, lidocaine added to cardioplegia solution and its effects on myocardial ischemia-reperfusion injury was examined. Material and Method: 36 patients who underwent elective coronary artery bypass surgery in our clinic between September 2005 and April 2006 was studied. Patients included into two groups. In study group patients (groupe I 2 mg/kg lidocaine was added into cardioplegia solution that is used during aortic cross clamp period; standart cardioplegia solution was used in control group patients (group II. Postoperative 6. and 24. hours cardiac enzyme levels, inotropic support requirement and atrial fibrilation incidence were compared in both groups. Results: In this study, 36 patients (13 women, 23 man whose average age was 63(±5,5, age range 50-70 years and ventriculer functions were not deformed (EF>40% were involved. There were no significantly differences in demographic datas between towo groups. There were no significantly differences in postoperative 6. and 24. hours troponin-I and CK-MB levels, inotropic support or defibrilation requirement and postoperative atrial fibrilation incidence between two groups. Discussion: Addition of 2 mg/kg dosage lidocaine into cardioplegia solution dont effect cardiac enzyme levels, inotropic support requirement and postoperative atrial fibrilation insidence and it doesnt prevent ischemia-reperfusion injury.

  2. Gender difference and sex hormone production in rodent renal ischemia reperfusion injury and repair

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    Ghazali Daniel

    2011-06-01

    Full Text Available Abstract Background Several lines of evidence suggest a protective effect of female sex hormones in several organs subjected to ischemia-reperfusion injury. The aim of the study was to investigate sex hormone production in male rats after a renal ischemia-reperfusion sequence and analyze the influence of gender differences on tissue remodelling during the recovery process. Method Age-matched sexually mature male and female rats were subjected to 60 min of renal unilateral ischemia by pedicle clamping with contralateral nephrectomy and followed for 1 or 5 days after reperfusion. Plasma creatinine, systemic testosterone, progesterone and estradiol levels were determined. Tubular injury, cell proliferation and inflammation, were evaluated as well as proliferating cell nuclear antigen, vimentin and translocator protein (TSPO expressions by immunohistochemistry. Results After 1 and 5 days of reperfusion, plasma creatinine was significantly higher in males than in females, supporting the high mortality in this group. After reperfusion, plasma testosterone levels decreased whereas estradiol significantly increased in male rats. Alterations of renal function, associated with tubular injury and inflammation persisted during the 5 days post-ischemia-reperfusion, and a significant improvement was observed in females at 5 days of reperfusion. Proliferating cell nuclear antigen and vimentin expression were upregulated in kidneys from males and attenuated in females, in parallel to injury development. TSPO expression was transiently increased in proximal tubules in male rats. Conclusions After ischemia, renal function recovery and tissue injury is gender-dependent. These differences are associated with a modulation of sex hormone production and a modification of tissue remodeling and proliferative cell processes.

  3. Impairment of endothelial-myocardial interaction increases the susceptibility of cardiomyocytes to ischemia/reperfusion injury.

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    Thorsten M Leucker

    Full Text Available Endothelial-myocardial interactions may be critically important for ischemia/reperfusion injury. Tetrahydrobiopterin (BH4 is a required cofactor for nitric oxide (NO production by endothelial NO synthase (eNOS. Hyperglycemia (HG leads to significant increases in oxidative stress, oxidizing BH4 to enzymatically incompetent dihydrobiopterin. How alterations in endothelial BH4 content impact myocardial ischemia/reperfusion injury remains elusive. The aim of this study was to examine the effect of endothelial-myocardial interaction on ischemia/reperfusion injury, with an emphasis on the role of endothelial BH4 content. Langendorff-perfused mouse hearts were treated by triton X-100 to produce endothelial dysfunction and subsequently subjected to 30 min of ischemia followed by 2 h of reperfusion. The recovery of left ventricular systolic and diastolic function during reperfusion was impaired in triton X-100 treated hearts compared with vehicle-treated hearts. Cardiomyocytes (CMs were co-cultured with endothelial cells (ECs and subsequently subjected to 2 h of hypoxia followed by 2 h of reoxygenation. Addition of ECs to CMs at a ratio of 1∶3 significantly increased NO production and decreased lactate dehydrogenase activity compared with CMs alone. This EC-derived protection was abolished by HG. The addition of 100 µM sepiapterin (a BH4 precursor or overexpression of GTP cyclohydrolase 1 (the rate-limiting enzyme for BH4 biosynthesis in ECs by gene trasfer enhanced endothelial BH4 levels, the ratio of eNOS dimer/monomer, eNOS phosphorylation, and NO production and decreased lactate dehydrogenase activity in the presence of HG. These results demonstrate that increased BH4 content in ECs by either pharmacological or genetic approaches reduces myocardial damage during hypoxia/reoxygenation in the presence of HG. Maintaining sufficient endothelial BH4 is crucial for cardioprotection against hypoxia/reoxygenation injury.

  4. Effect of limb ischemic preconditioning on myocardial apoptosis-related proteins in ischemia-reperfusion injury

    OpenAIRE

    GAO, JIANZHI; ZHAO, LINJING; WANG, YONGLING; TENG, QINGLEI; LIANG, LIDONG; ZHANG, JINYING

    2013-01-01

    The aim of this study was to investigate the effect of limb ischemic preconditioning (LIPC) on myocardial apoptosis in myocardial ischemia-reperfusion injury (MIRI), as well as the regulation of caspase-3 and the B cell lymphoma 2 (Bcl-2) gene in LIPC. A total of 50 rats were divided randomly into 5 groups (n=10). Four rats in each group were drawn out for detection of apoptosis. The sham, MIRI and LIPC groups underwent surgery without additional treatment. In the LY294002 group, LY294002 pre...

  5. Sulfatide-Reactive Natural Killer T Cells Abrogate Ischemia-Reperfusion Injury

    OpenAIRE

    Yang, Seung Hee; Lee, Jung Pyo; Jang, Hye Ryoun; Cha, Ran-hui; Han, Seung Seok; Jeon, Un Sil; Kim, Dong Ki; Song, Junghan; Lee, Dong-Sup; Kim, Yon Su

    2011-01-01

    There is a significant immune response to ischemia-reperfusion injury (IRI), but the role of immunomodulatory natural killer T (NKT) cell subtypes is not well understood. Here, we compared the severity of IRI in mice deficient in type I/II NKT cells (CD1d−/−) or type I NKT cells (Jα18−/−). The absence of NKT cells, especially type II NKT cells, accentuated the severity of renal injury, whereas repletion of NKT cells attenuated injury. Adoptively transferred NKT cells trafficked into the tubul...

  6. Bcl-2–associated athanogene 3 protects the heart from ischemia/reperfusion injury

    OpenAIRE

    Su, Feifei; Myers, Valerie D.; Knezevic, Tijana; Wang, JuFang; Gao, Erhe; Madesh, Muniswamy; Tahrir, Farzaneh G.; Gupta, Manish K.; Gordon, Jennifer; Rabinowitz, Joseph; Ramsey, Frederick V.; Tilley, Douglas G.; Khalili, Kamel; Cheung, Joseph Y.; Feldman, Arthur M.

    2016-01-01

    Bcl-2–associated athanogene 3 (BAG3) is an evolutionarily conserved protein expressed at high levels in the heart and the vasculature and in many cancers. While altered BAG3 expression has been associated with cardiac dysfunction, its role in ischemia/reperfusion (I/R) is unknown. To test the hypothesis that BAG3 protects the heart from reperfusion injury, in vivo cardiac function was measured in hearts infected with either recombinant adeno-associated virus serotype 9–expressing (rAAV9-expre...

  7. Heat Shock Proteins and Mitogen-activated Protein Kinases in Steatotic Livers Undergoing Ischemia-Reperfusion: Some Answers

    Science.gov (United States)

    Massip-Salcedo, Marta; Casillas-Ramirez, Araní; Franco-Gou, Rosah; Bartrons, Ramón; Ben Mosbah, Ismail; Serafin, Anna; Roselló-Catafau, Joan; Peralta, Carmen

    2006-01-01

    Ischemic preconditioning protects steatotic livers against ischemia-reperfusion (I/R) injury, but just how this is achieved is poorly understood. Here, I/R or preconditioning plus I/R was induced in steatotic and nonsteatotic livers followed by investigating the effect of pharmacological treatments that modulate heat shock proteins (HSPs) and mitogen-activated protein kinases (MAPKs). MAPKs, HSPs, protein kinase C, and transaminase levels were measured after reperfusion. We report that preconditioning increased HSP72 and heme-oxygenase-1 (HO-1) at 6 and 24 hours of reperfusion, respectively. Unlike nonsteatotic livers, steatotic livers benefited from HSP72 activators (geranylgeranylacetone) throughout reperfusion. This protection seemed attributable to HO-1 induction. In steatotic livers, preconditioning and geranylgeranylacetone treatment (which are responsible for HO-1 induction) increased protein kinase C activity. HO-1 activators (cobalt(III) protoporphyrin IX) protected both liver types. Preconditioning reduced p38 MAPK and c-Jun N-terminal kinase (JNK), resulting in HSP72 induction though HO-1 remained unmodified. Like HSP72, both p38 and JNK appeared not to be crucial in preconditioning, and inhibitors of p38 (SB203580) and JNK (SP600125) were less effective against hepatic injury than HO-1 activators. These results provide new data regarding the mechanisms of preconditioning and may pave the way to the development of new pharmacological strategies in liver surgery. PMID:16651615

  8. Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway

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    Wang, Y.; Zhang, Z.Z.; Wu, Y.; Ke, J.J.; He, X.H.; Wang, Y.L. [Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan (China)

    2013-09-24

    Quercetin (Que), a plant-derived flavonoid, has multiple benefical actions on the cardiovascular system. The current study investigated whether Que postconditioning has any protective effects on myocardial ischemia/reperfusion (I/R) injury in vivo and its potential cardioprotective mechanisms. Male Sprague-Dawley rats were randomly allocated to 5 groups (20 animals/group): sham, I/R, Que postconditioning, Que+LY294002 [a phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway inhibitor], and LY294002+I/R. I/R was produced by 30-min coronary occlusion followed by 2-h reperfusion. At the end of reperfusion, myocardial infarct size and biochemical changes were compared. Apoptosis was evaluated by both TUNEL staining and measurement of activated caspase-3 immunoreactivity. The phosphorylation of Akt and protein expression of Bcl-2 and Bax were determined by Western blotting. Que postconditioning significantly reduced infarct size and serum levels of creatine kinase and lactate dehydrogenase compared with the I/R group (all P<0.05). Apoptotic cardiomyocytes and caspase-3 immunoreactivity were also suppressed in the Que postconditioning group compared with the I/R group (both P<0.05). Akt phosphorylation and Bcl-2 expression increased after Que postconditioning, but Bax expression decreased. These effects were inhibited by LY294002. The data indicate that Que postconditioning can induce cardioprotection by activating the PI3K/Akt signaling pathway and modulating the expression of Bcl-2 and Bax proteins.

  9. Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway

    Directory of Open Access Journals (Sweden)

    Y. Wang

    2013-09-01

    Full Text Available Quercetin (Que, a plant-derived flavonoid, has multiple benefical actions on the cardiovascular system. The current study investigated whether Que postconditioning has any protective effects on myocardial ischemia/reperfusion (I/R injury in vivo and its potential cardioprotective mechanisms. Male Sprague-Dawley rats were randomly allocated to 5 groups (20 animals/group: sham, I/R, Que postconditioning, Que+LY294002 [a phosphatidylinositol 3-kinase (PI3K/Akt signaling pathway inhibitor], and LY294002+I/R. I/R was produced by 30-min coronary occlusion followed by 2-h reperfusion. At the end of reperfusion, myocardial infarct size and biochemical changes were compared. Apoptosis was evaluated by both TUNEL staining and measurement of activated caspase-3 immunoreactivity. The phosphorylation of Akt and protein expression of Bcl-2 and Bax were determined by Western blotting. Que postconditioning significantly reduced infarct size and serum levels of creatine kinase and lactate dehydrogenase compared with the I/R group (all P<0.05. Apoptotic cardiomyocytes and caspase-3 immunoreactivity were also suppressed in the Que postconditioning group compared with the I/R group (both P<0.05. Akt phosphorylation and Bcl-2 expression increased after Que postconditioning, but Bax expression decreased. These effects were inhibited by LY294002. The data indicate that Que postconditioning can induce cardioprotection by activating the PI3K/Akt signaling pathway and modulating the expression of Bcl-2 and Bax proteins.

  10. Effect of systemic piracetam treatment on flap survival and vascular endothelial growth factor expression after ischemia-reperfusion injury.

    Science.gov (United States)

    Tuncer, Serhan; Ayhan, Suhan; Findikcioglu, Kemal; Ergun, Hakan; Tuncer, Ilhan

    2011-09-01

    The effects of piracetam on flap survival, ischemia-reperfusion (I/R) injury, and vascular endothelial growth factor (VEGF) expression were evaluated in this study. Unipedicled epigastric flap model was used in 36 rats and was evaluated within 4 groups. The flap was elevated and untreated in Group 1. Postoperative piracetam treatment was given for 7 days in Group 2. In Group 3, 4 hours of ischemia and 2 hours of reperfusion were applied. I/R was applied to Group 4 and piracetam was given 30 minutes before reperfusion and postoperatively for 7 days. Laser Doppler flowmetry was used to measure blood flow changes. VEGF expression was determined using immunohistochemical methods on tissue samples taken after the completion of 2 hours reperfusion in groups 3 and 4. Flap necrosis was measured on the day 7 in all groups. Blood flow rates did not show significant difference between piracetam treated and untreated I/R groups. Piracetam significantly reduced necrosis area both in ischemic and nonischemic flaps ( P piracetam-treated Group 4 compared with Group 3 ( P = 0.005). This experimental study demonstrates that systemic piracetam treatment improves survival of pedicled flaps, reduces necrosis amounts, and increases VEGF expression in I/R induced flaps. © Thieme Medical Publishers.

  11. Anti-inflammatory and antioxidant effects of infliximab in a rat model of intestinal ischemia/reperfusion injury.

    Science.gov (United States)

    Pergel, Ahmet; Kanter, Mehmet; Yucel, Ahmet Fikret; Aydin, Ibrahim; Erboga, Mustafa; Guzel, Ahmet

    2012-11-01

    The aim of this study was to investigate the possible protective effects of infliximab on oxidative stress, cell proliferation and apoptosis in the rat intestinal mucosa after ischemia/reperfusion (I/R). A total of 30 male Wistar albino rats were divided into three groups: sham, I/R and I/R+ infliximab; each group comprised 10 animals. Sham group animals underwent laparotomy without I/R injury. I/R groups after undergoing laparotomy, 1 hour of superior mesenteric artery ligation occurred, which was followed by 1 hour of reperfusion. In the infliximab group, 3 days before I/R, infliximab (3 mg/kg) was administered intravenously. All animals were killed at the end of reperfusion and intestinal tissues samples were obtained for biochemical and histopathological investigation in all groups. To date, no biochemical and histopathological changes have been reported regarding intestinal I/R injury in rats due to infliximab treatment. Infliximab treatment significantly decreased the elevated tissue malondialdehyde levels and increased reduced superoxide dismutase and glutathione peroxidase enzyme activities in intestinal tissues samples. I/R caused severe histopathological injury including mucosal erosions, inflammatory cell infiltration, necrosis, hemorrhage, and villous congestion. Infliximab treatment significantly attenuated the severity of intestinal I/R injury, inhibiting I/R-induced apoptosis, and cell proliferation. Because of its anti-inflammatory and antioxidant effects, infliximab pretreatment may have protective effects on the experimental intestinal I/R model of rats.

  12. Effect of ligustrazine on levels of amino acid neurotransmitters in rat striatum after cerebral ischemia-reperfusion injury.

    Science.gov (United States)

    Han, Jin; Wan, Hai-Tong; Yang, Jie-Hong; Zhang, Yu-Yan; Ge, Li-Jun; Bie, Xiao-Dong

    2014-01-01

    This study aimed to evaluate the effect of ligustrazine on levels of amino acid transmitters in the extracellular fluid of striatum following cerebral ischemia/reperfusion (I/R) in male Sprague-Dawley rats. A microdialysis cannula guide was implanted into the right striatum. After recovery, animals underwent a sham operation or middle cerebral artery occlusion (MCAO). Those that developed cerebral ischemia after MCAO were randomized to receive propylene glycol salt water and ligustrazine respectively. Striatal fluid samples were collected from all animals at 15-min intervals after treatment and were subjected to HPLC analysis of aspartic acid, glutamic acid, taurine, and γ-amino butyric acid. Upon the last sample collection, animals were sacrificed and brain tissue specimens were collected for triphenyltetrazolium chloride staining and NeuN staining. Compared with the sham operation, MCAO induced significant neurological deficits and increased striatal concentrations of the four neurotransmitters assessed in a time-dependent manner (P cerebral infarction-protective agent may have potential clinical implications for I/R-related brain damage.

  13. Therapeutic time window and underlying therapeutic mechanism of breviscapine injection against cerebral ischemia/reperfusion injury in rats.

    Science.gov (United States)

    Guo, Chao; Zhu, Yanrong; Weng, Yan; Wang, Shiquan; Guan, Yue; Wei, Guo; Yin, Ying; Xi, Miaomaio; Wen, Aidong

    2014-01-01

    Breviscapine injection is a Chinese herbal medicine standardized product extracted from Erigeron breviscapus (Vant.) Hand.-Mazz. It has been widely used for treating cardiovascular and cerebrovascular diseases. However, the therapeutic time window and the action mechanism of breviscapine are still unclear. The present study was designed to investigate the therapeutic time window and underlying therapeutic mechanism of breviscapine injection against cerebral ischemic/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 2h followed by 24h of reperfusion. Experiment part 1 was used to investigate the therapeutic time window of breviscapine. Rats were injected intravenously with 50mg/kg breviscapine at different time-points of reperfusion. After 24h of reperfusion, neurologic score, infarct volume, brain water content and serum level of neuron specific enolase (NSE) were measured in a masked fashion. Part 2 was used to explore the therapeutic mechanism of breviscapine. 4-Hydroxy-2-nonenal (4-HNE), 8-hydroxyl-2'- deoxyguanosine (8-OHdG) and the antioxidant capacity of ischemia cortex were measured by ELISA and ferric-reducing antioxidant power (FRAP) assay, respectively. Immunofluorescence and western blot analysis were used to analyze the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Part 1: breviscapine injection significantly ameliorated neurologic deficit, reduced infarct volume and water content, and suppressed the levels of NSE in a time-dependent manner. Part 2: breviscapine inhibited the increased levels of 4-HNE and 8-OHdG, and enhanced the antioxidant capacity of cortex tissue. Moreover, breviscapine obviously raised the expression of Nrf2 and HO-1 proteins after 24h of reperfusion. The therapeutic time window of breviscapine injection for cerebral ischemia/reperfusion injury seemed to be within 5h after reperfusion. By up-regulating the expression of Nrf2/HO-1 pathway

  14. Beneficial effects of enteral nutrition containing with hydrolyzed whey peptide on warm ischemia/reperfusion injury in the rat liver.

    Science.gov (United States)

    Hanaoka, Jun; Shimada, Mitsuo; Utsunomiya, Toru; Morine, Yuji; Imura, Satoru; Ikemoto, Tetsuya; Mori, Hiroki; Sugimoto, Koji; Saito, Yu; Yamada, Shinichiro; Asanoma, Michihito

    2014-01-01

    This study examined the efficacy of enteral nutrition containing hydrolyzed whey peptide (HWP) on warm ischemia/reperfusion (I/R) injury in the rat liver. Male Wistar rats were subjected to 30 min of warm hepatic ischemia followed by immediate p.o. intake of enteral nutrition with WHP (HWP group) or 20% glucose solution (control group) (0.025 mL/g). The animals were killed at 6 or 12 h after reperfusion. The serum aspartate aminotransferase (AST) and alanine aminotransferase alt (ALT) levels were measured. The necrotic areas were assessed histologically. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activation were assessed to evaluate apoptosis. The expressions of hepatic tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nuclear factor (NF)-κB in the liver tissue were assessed by real time reverse transcription polymerase chain reaction. Significant reductions in the serum AST and ALT levels were seen in the HWP group compared with the control group at both 6 and 12 h after reperfusion. The necrotic areas and numbers of TUNEL positive cells were significantly decreased in the HWP group at 6 and 12 h after reperfusion. The caspase-3/7 activities were significantly decreased in HWP group at 6 and 12 h after reperfusion. The mRNA expressions of TNF-α and IL-6 were significantly reduced in the HWP group at 12 h after reperfusion. NF-κB mRNA expression was significantly increased in the HWP group at 6 and 12 h after reperfusion. Enteral nutrition containing HWP ameliorated the hepatic warm I/R injury possibly through the suppression of pro-inflammatory cytokine expressions and the induction of NF-κB in the rat liver. © 2013 The Japan Society of Hepatology.

  15. Pretreatment with soluble ST2 reduces warm hepatic ischemia/reperfusion injury

    International Nuclear Information System (INIS)

    Yin Hui; Huang Baojun; Yang Heng; Huang Yafei; Xiong Ping; Zheng Fang; Chen Xiaoping; Chen Yifa; Gong Feili

    2006-01-01

    The interleukin-1 receptor-like protein ST2 exists in both membrane-bound (ST2L) and soluble form (sST2). ST2L has been found to play an important regulatory role in Th2-type immune response, but the function of soluble form of ST2 remains to be elucidated. In this study, we report the protective effect of soluble ST2 on warm hepatic ischemia/reperfusion injury. We constructed a eukaryotic expression plasmid, psST2-Fc, which expresses functional murine soluble ST2-human IgG1 Fc (sST2-Fc) fusion protein. The liver damage after ischemia/reperfusion was significantly attenuated by the expression of this plasmid in vivo. sST2-Fc remarkably inhibited the activation of Kupffer cells and the production of proinflammatory mediators TNF-α and IL-6. Furthermore, the levels of TLR4 mRNA and the nuclear translocation of NF-κB were also suppressed by pretreatment with sST2-Fc. These results thus identified soluble ST2 as a negative regulator in hepatic I/R injury, possibly via ST2-TLR4 pathway

  16. Discussion on the treatment of cerebral ischemia-reperfusion injuries following intra-arterial thrombolysis

    International Nuclear Information System (INIS)

    Tian Hong; Song Chuan; Fan Ruxiong; Zhou Huchuan; Zhang Yubo; Zang Qiaoli; Zhang Yunquan; Liu Lei

    2011-01-01

    Objective: To investigate the therapeutic method of cerebral ischemia-reperfusion injuries occurred after arterial thrombolytic therapy for acute cerebral infarction. Methods: Thirty-five patients, encountered in authors' Department since Oct. 2005, with cerebral ischemia-reperfusion injuries, which occurred after thrombolytic therapy by using arterial perfusion of urokinase for acute cerebral infarction, were enrolled in this study. The clinical data were retrospectively analyzed. Results: After the thrombolytic therapy, completer or partial recanalization of the occluded cerebral arteries was obtained in 33 cases, while secondary cerebral hemorrhage occurred in 13 cases, of whom cerebral parenchyma bleeding was seen in 2 and hemorrhagic infarction in 11. Different degrees of cerebral edema were found in all 33 cases. Among them significant shift of the midline structures was detected in 18 (54.5%), which was manifested clinically as the worsening of disturbance of consciousness. Strict control of blood pressure, prompt adjustment of dehydration medication, strengthening the cerebral protection measures, cerebral decompression by fenestration, etc. were carried out. All the patients took a turn for the better and were out of danger with remarkable improvement of neurological functions except one patient who died from massive intracerebral hemorrhage. Conclusion: Usually, different degrees of reperfusion injuries will develop after thrombolytic therapy for cerebral arterial infarction. Strictly controlling blood pressure, promptly adjusting dehydration medication and strengthening cerebral protection are the keys to reduce the severity of cerebral reperfusion injuries. (authors)

  17. Dietary broccoli sprouts protect against myocardial oxidative damage and cell death during ischemia-reperfusion.

    Science.gov (United States)

    Akhlaghi, Masoumeh; Bandy, Brian

    2010-09-01

    Cruciferous vegetables are known for antioxidant and anti-carcinogenic effects. In the current study we asked whether dietary broccoli sprouts can protect the heart from ischemia-reperfusion. Rats were fed either control diet (sham and control groups) or a diet mixed with 2% dried broccoli sprouts for 10 days. After 10 days the isolated hearts were subjected to ischemia for 20 min and reperfusion for 2 h, and evaluated for cell death, oxidative damage, and Nrf2-regulated phase 2 enzyme activities. Broccoli sprouts feeding inhibited markers of necrosis (lactate dehydrogenase release) and apoptosis (caspase-3 activity) by 78-86%, and decreased indices of oxidative stress (thiobarbituric acid reactive substances and aconitase inactivation) by 82-116%. While broccoli sprouts increased total glutathione and activities of the phase 2 enzymes glutamate cysteine ligase and quinone reductase in liver, they did not affect these in ischemic-reperfused heart. While the mechanism is not clear, the results show that a relatively short dietary treatment with broccoli sprouts can strongly protect the heart against oxidative stress and cell death caused by ischemia-reperfusion.

  18. Dynamic alteration of the colonic microbiota in intestinal ischemia-reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Fan Wang

    Full Text Available Intestinal ischemia-reperfusion (I/R plays an important role in critical illnesses. Gut flora participate in the pathogenesis of the injury. This study is aimed at unraveling colonic microbiota alteration pattern and identifying specific bacterial species that differ significantly as well as observing colonic epithelium change in the same injury model during the reperfusion time course.Denaturing gradient gel electrophoresis (DGGE was used to monitor the colonic microbiota of control rats and experimental rats that underwent 0.5 hour ischemia and 1, 3, 6, 12, 24, and 72 hours following reperfusion respectively. The microbiota similarity, bacterial diversity and species that characterized the dysbiosis were estimated based on the DGGE profiles using a combination of statistical approaches. The interested bacterial species in the gel were cut and sequenced and were subsequently quantified and confirmed with real-time PCR. Meanwhile, the epithelial barrier was checked by microscopy and D-lactate analysis. Colonic flora changed early and differed significantly at 6 hours after reperfusion and then started to recover. The shifts were characterized by the increase of Escherichia coli and Prevotella oralis, and Lactobacilli proliferation together with epithelia healing.This study shows for the first time that intestinal ischemia-reperfusion results in colonic flora dysbiosis that follows epithelia damage, and identifies the bacterial species that contribute most.

  19. Effects of Urtica dioica on hepatic ischemia-reperfusion injury in rats.

    Science.gov (United States)

    Kandis, Hayati; Karapolat, Sami; Yildirim, Umran; Saritas, Ayhan; Gezer, Suat; Memisogullari, Ramazan

    2010-01-01

    To evaluate the effects of Urtica dioica on hepatic ischemia-reperfusion injury. Thirty adult male Wistar albino rats were divided into three groups: sham group (group 1), control group (group 2), and Urtica dioica group (group 3). All the rats were exposed to hepatic ischemia for 60 min, followed by 60 min of reperfusion. In group 2, a total of 2 ml/kg 0.9% saline solution was given intraperitoneally. In group 3, a total of 2 ml/kg Urtica dioica was given intraperitoneally. At the end of the procedure, liver tissue and blood samples were taken from all rats. Serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, ceruloplasmin, catalase, paraoxonase, arylesterase, and lipid hydroperoxide levels were measured. Liver tissue histopathologies were also evaluated by light microscopy. Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase levels were significantly higher in group 2 than in group 1, and significantly lower in group 3 than in group 2. Also, group 2 had higher serum lipid hydroperoxides and ceruloplasmin levels but lower catalase, paraoxonase, and arylesterase levels than group 1. In group 3, serum lipid hydroperoxides and ceruloplasmin levels were significantly lower, and catalase, paraoxonase, and arylesterase levels were higher than those in group 2. Histopathological examination showed that liver tissue damage was significantly decreased in group 3 compared with group 2. Urtica dioica has a protective effect on the liver in hepatic ischemia-reperfusion-injured rats.

  20. Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury.

    Science.gov (United States)

    Pachori, Alok S; Melo, Luis G; Hart, Melanie L; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D; Stahl, Gregory L; Pratt, Richard E; Dzau, Victor J

    2004-08-17

    Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

  1. Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

    Science.gov (United States)

    Pachori, Alok S.; Melo, Luis G.; Hart, Melanie L.; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D.; Stahl, Gregory L.; Pratt, Richard E.; Dzau, Victor J.

    2004-08-01

    Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

  2. Curcumin-loaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury.

    Science.gov (United States)

    Kalani, Anuradha; Chaturvedi, Pankaj; Kamat, Pradip K; Maldonado, Claudio; Bauer, Philip; Joshua, Irving G; Tyagi, Suresh C; Tyagi, Neetu

    2016-10-01

    We tested whether the combined nano-formulation, prepared with curcumin (anti-inflammatory and neuroprotective molecule) and embryonic stem cell exosomes (MESC-exo cur ), restored neurovascular loss following an ischemia reperfusion (IR) injury in mice. IR-injury was created in 8-10 weeks old mice and divided into two groups. Out of two IR-injured groups, one group received intranasal administration of MESC-exo cur for 7days. Similarly, two sham groups were made and one group received MESC-exo cur treatment. The study determined that MESC-exo cur treatment reduced neurological score, infarct volume and edema following IR-injury. As compared to untreated IR group, MESC-exo cur treated-IR group showed reduced inflammation and N-methyl-d-aspartate receptor expression. Treatment of MESC-exo cur also reduced astrocytic GFAP expression and alleviated the expression of NeuN positive neurons in IR-injured mice. In addition, MESC-exo cur treatment restored vascular endothelial tight (claudin-5 and occludin) and adherent (VE-cadherin) junction proteins in IR-injured mice as compared to untreated IR-injured mice. These results suggest that combining the potentials of embryonic stem cell exosomes and curcumin can help neurovascular restoration following ischemia-reperfusion injury in mice. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Thymoquinone protects end organs from abdominal aorta ischemia/reperfusion injury in a rat model.

    Science.gov (United States)

    Aydin, Mehmet Salih; Kocarslan, Aydemir; Kocarslan, Sezen; Kucuk, Ahmet; Eser, İrfan; Sezen, Hatice; Buyukfirat, Evren; Hazar, Abdussemet

    2015-01-01

    Previous studies have demonstrated that thymoquinone has protective effects against ischemia reperfusion injury to various organs like lungs, kidneys and liver in different experimental models. We aimed to determine whether thymoquinone has favorable effects on lung, renal, heart tissues and oxidative stress in abdominal aorta ischemia-reperfusion injury. Thirty rats were divided into three groups as sham (n=10), control (n=10) and thymoquinone (TQ) treatment group (n=10). Control and TQ-treatment groups underwent abdominal aorta ischemia for 45 minutes followed by a 120-min period of reperfusion. In the TQ-treatment group, thymoquinone was given 5 minutes. before reperfusion at a dose of 20 mg/kg via an intraperitoneal route. Total antioxidant capacity, total oxidative status (TOS), and oxidative stress index (OSI) in blood serum were measured and lung, kidney, and heart tissue histopathology were evaluated with light microscopy. Total oxidative status and oxidative stress index activity in blood samples were statistically higher in the control group compared to the sham and TQ-treatment groups (POSI). Control group injury scores were statistically higher compared to sham and TQ-treatment groups (Pmodel.

  4. Effect of selective hepatic inflow occlusion during liver cancer resection on liver ischemia-reperfusion injury

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    Yin-Tian Deng

    2016-11-01

    Full Text Available Objective: To study the effect of selective hepatic inflow occlusion during liver cancer resection on liver ischemia-reperfusion injury. Methods: A total of 68 patients with primary liver cancer who underwent left liver resection in our hospital between May 2012 and August 2015 were selected for study and divided into group A (selective hepatic inflow occlusion of left liver and group B (Prignle hepatic inflow occlusion according to different intraoperative blood occlusion methods, serum was collected before and after operation to determine liver enzyme content, the removed liver tissue was collected to determine energy metabolism indexes, inflammation indexes and oxidative stress indexes. Results: 1 d, 3 d and 5 d after operation, GPT, GOT, GGT, LDH and ALP content in serum of both groups were significantly higher than those before operation, and GPT, GOT, GGT, LDH and ALP content in serum of group A 1 d, 3 d and 5 d after operation were significantly lower than those of group B; ATP, ADP, AMP, PI3K, AKT, GSK3β, T-AOC, PrxI and Trx content in liver tissue of group A were significantly higher than those of group B while PTEN, IL-12p40, MDA and MPO content were significantly lower than those of group B. Conclusions: Selective hepatic inflow occlusion during liver cancer resection can reduce the liver ischemia-reperfusion injury, improve the energy metabolism of liver cells and inhibit inflammation and oxidative stress in liver tissue.

  5. Protective Effect Of Bosentan In Experimental Cerebral Ischemia-Reperfusion Injury

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    Eser Ataş

    2013-02-01

    Full Text Available OBJECTIVE: In cerebral ischemia, there are many factors that start the events leading to cell death. These factors contain free radical production, excitotoxicity, sodium and calcium flow disruption, enzymatic changes, stimulation of the inflamatuar process, the activation of platelets and leukocytes, delayed coagulation, endothelial dysfunction and endothelin (ET release. Bosentan is the competitive antagonist of endothelin receptors; ETA and ETB. The aim of this study is to determine whether the protective effects of bosentan in experimental cerebral ischemia reperfusion injury. MATERIAL and METHODS: In this study, after ischemia-reperfusion procedure, bosentan molecule was regularly given to rats for 5 days. The brain tissues of decapitated rats were histopathologically examined. The levels of oxidant and antioxidant were determined in these brain tissues. RESULTS: It was observed that antioxidant levels and histopathological examinations were in rats given bosentan better than control group rats. CONCLUSION: In conclusion, this study has showed that bosentan may be an agent which could reduce negative effects resulting from neuronal death associated with ischemic stroke.

  6. Ciclosporin Does Not Influence Bone Marrow-Derived Cell Differentiation to Myofibroblasts Early after Renal Ischemia/Reperfusion

    NARCIS (Netherlands)

    Broekema, Martine; Harmsen, Martin C.; Koerts, Jasper A.; van Kooten, Theo G.; Uges, Donald R. A.; Petersen, Arjen H.; van Luyn, Marja J. A.; Navis, Gerjan; Popa, Eliane R.

    2009-01-01

    Background: Ischemia/reperfusion injury (IRI) is a risk factor for the development of interstitial fibrosis. Previously we had shown that after renal IRI, bone marrow-derived cells (BMDC) can differentiate to interstitial myofibroblasts. Here we hypothesized that the immunosuppressant ciclosporin A

  7. Mannan-binding lectin is involved in the protection against renal ischemia/ reperfusion injury by dietary restriction

    NARCIS (Netherlands)

    Shushimita; P. van der Pol (Pieter); R.W.F. de Bruin (Ron); J.N.M. IJzermans (Jan); C. van Kooten (Cees); F.J.M.F. Dor (Frank)

    2015-01-01

    textabstractPreoperative fasting and dietary restriction offer robust protection against renal ischemia/ reperfusion injury (I/RI) in mice.We recently showed that Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, plays a pivotal role in renal I/RI. Based on

  8. Reduction in Hexokinase II Levels Results in Decreased Cardiac Function and Altered Remodeling After Ischemia/Reperfusion Injury

    NARCIS (Netherlands)

    Wu, Rongxue; Smeele, Kirsten M.; Wyatt, Eugene; Ichikawa, Yoshihiko; Eerbeek, Otto; Sun, Lin; Chawla, Kusum; Hollmann, Markus W.; Nagpal, Varun; Heikkinen, Sami; Laakso, Markku; Jujo, Kentaro; Wasserstrom, J. Andrew; Zuurbier, Coert J.; Ardehali, Hossein

    2011-01-01

    Rationale: Cardiomyocytes switch substrate utilization from fatty acid to glucose under ischemic conditions; however, it is unknown how perturbations in glycolytic enzymes affect cardiac response to ischemia/reperfusion (I/R). Hexokinase (HK)II is a HK isoform that is expressed in the heart and can

  9. Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury

    NARCIS (Netherlands)

    Poppelaars, Felix; van Werkhoven, Maaike B; Kotimaa, Juha; Veldhuis, Zwanida J; Ausema, Albertina; Broeren, Stefan G M; Damman, Jeffrey; Hempel, Julia C.; Leuvenink, Henri G D; Daha, Mohamed R; van Son, Willem J; van Kooten, Cees; van Os, Ronald P; Hillebrands, Jan-Luuk; Seelen, Marc A

    The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The 2 receptors for complement anaphylatoxin C5a (C5aR1 and C5aR2) are expressed on leukocytes as well as on renal epithelium. Extensive evidence shows that C5aR1 inhibition protects kidneys from IR

  10. L-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats

    NARCIS (Netherlands)

    Legrand, Matthieu; Almac, Emre; Mik, Egbert G.; Johannes, Tanja; Kandil, Asli; Bezemer, Rick; Payen, Didier; Ince, Can

    2009-01-01

    Legrand M, Almac E, Mik EG, Johannes T, Kandil A, Bezemer R, Payen D, Ince C. L-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats. Am J Physiol Renal Physiol 296: F1109-F1117, 2009. First published February 18, 2009;

  11. Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia/reperfusion of the intact heart

    NARCIS (Netherlands)

    R. Nederlof (Rianne); Gürel-Gurevin, E. (Ebru); O. Eerbeek (Otto); C. Xie (Chaoqin); Deijs, G.S.; Konkel, M. (Moritz); Hu, J. (Jun); N.C. Weber (Nina); C. Schumacher (Cees); A. Baartscheer (Antonius); E.G. Mik (Egbert); M.W. Hollmann (Markus); F.G. Akar (Fadi); C.J. Zuurbier (Coert J.)

    2016-01-01

    textabstractIschemia/reperfusion (I/R) of the heart becomes injurious when duration of the ischemic insult exceeds a certain threshold (approximately ≥20 min). Mitochondrial bound hexokinase II (mtHKII) protects against I/R injury, with the amount of mtHKII correlating with injury. Here, we examine

  12. Therapeutic metabolic inhibition: hydrogen sulfide significantly mitigates skeletal muscle ischemia reperfusion injury in vitro and in vivo

    NARCIS (Netherlands)

    Henderson, Peter W.; Singh, Sunil P.; Weinstein, Andrew L.; Nagineni, Vijay; Rafii, Daniel C.; Kadouch, Daniel; Krijgh, David D.; Spector, Jason A.

    2010-01-01

    BACKGROUND:: Recent evidence suggests that hydrogen sulfide is capable of mitigating the degree of cellular damage associated with ischemia-reperfusion injury. The purpose of this study was to determine whether it is protective in skeletal muscle. METHODS:: This study used both in vitro (cultured

  13. Carbon monoxide-Releasing Molecule-2 (CORM-2 attenuates acute hepatic ischemia reperfusion injury in rats

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    Zhang Weihui

    2010-05-01

    Full Text Available Abstract Background Hepatic ischemia-reperfusion injury (I/Ri is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO by application of so-called CO-releasing molecules (CORMs. Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model. Methods Forty male Wistar rats were randomly assigned into four groups (n = 10. Sham group underwent a sham operation and received saline. I/R group underwent hepatic I/R procedure by partial clamping of portal structures to the left and median lobes with a microvascular clip for 60 minutes, yielding ~70% hepatic ischemia and subsequently received saline. CORM-2 group underwent the same procedure and received 8 mg/kg of CORM-2 at time of reperfusion. iCORM-2 group underwent the same procedure and received iCORM-2 (8 mg/kg, which does not release CO. Therapeutic effects of CORM-2 on hepatic I/Ri was assessed by measuring serum damage markers AST and ALT, liver histology score, TUNEL-scoring of apoptotic cells, NFkB-activity in nuclear liver extracts, serum levels of pro-inflammatory cytokines TNF-α and IL-6, and hepatic neutrophil infiltration. Results A single systemic infusion with CORM-2 protected the liver from I/Ri as evidenced by a reduction in serum AST/ALT levels and an improved liver histology score. Treatment with CORM-2 also up-regulated expression of the anti-apoptotic protein Bcl-2, down-regulated caspase-3 activation, and significantly reduced the levels of apoptosis after I/Ri. Furthermore, treatment with CORM-2 significantly inhibited the activity of the pro-inflammatory transcription factor NF-κB as measured in

  14. Relations between CT perfusion parameters and degree of hepatic ischemia reperfusion injury in a rabbit model

    International Nuclear Information System (INIS)

    Guo Chengwei; Shen Sandi; Yi Xianlin; Zhang Zhonglin; Liu Zaiyi; Liang Changhong

    2011-01-01

    Objective: To observe the changes of hepatic CT perfusion parameters and their correlation with serum aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) in a rabbit hepatic ischemia reperfusion injury (IRI) model. Methods: Hepatic IRI was produced in rabbits by inducing left liver lobe ischemia (60 min) followed by 6 h, 12 h and 24 h reperfusion (6 rabbits were used for each reperfusion interval). Additional 6 rabbits were served as sham-operated controls. All the rabbits were scanned with a dynamic iCT protocol. Blood samples were taken from the superior mesenteric vein to measure the levels of serum amylase (ALT, AST, and ALP) in various groups, and liver samples were taken for histological examinations after scanning. One-way analysis of variance (ANOVA) was used to determine differences between groups. The correlations of CT perfusion parameters with serum levels were analyzed using Pearson correlation coefficient. Results: Heterogeneity of CT perfusion patterns appeared in the 6 h groups, which presented as low enhanced area [(25.1±9.3) ml · min -1 · 100 mg -1 ]. In reduced perfusion regions of IRI group, HAP of 12 h IRI group [(19.5± 13.6) ml · min -1 · 100 mg -1 ], 24 h IRI group (8.0±2.7) ml · min -1 · 100 mg -1 ], HPP of 6 h IRI group [(10.8±5.5) ml · min -1 · 100 mg -1 ], 12 h IRI group [(14.4±5.2) ml · min -1 · 100 mg -1 ] , 24 h IRI group [(7.8±3.3) ml · min -1 · 100 mg -1 ] and TLP of 6 h IRI group [(35.9±14.0) ml · min -1 · 100 mg -1 ], 12 h IRI group [(33.9±16.1) ml · min -1 · 100 mg -1 ], 24 h IRI group [(16.0± 5.5) ml · min -1 · 100 mg -1 ] were lower than those of sham group [HAP (21.2±10.5) ml · min -1 · 100 mg -1 , HPP (63.5±24.0) ml · min -1 · 100 mg -1 , TLP (81.4±24.8) ml · min -1 · 100 mg -1 ] (F=8.376, 25.950, 16.925, P<0.01). However, HPI of 6 h IRI group [(65.9±3.9)%], 12 h IRI group [(54.2±16.7)%], and 24 h IRI group [(48.9±10.0)%] were higher compared to sham

  15. Extracellular vesicles from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) protect against renal ischemia/reperfusion injury via delivering specificity protein (SP1) and transcriptional activating of sphingosine kinase 1 and inhibiting necroptosis.

    Science.gov (United States)

    Yuan, Xiaodong; Li, Dawei; Chen, Xiaosong; Han, Conghui; Xu, Longmei; Huang, Tao; Dong, Zhen; Zhang, Ming

    2017-12-11

    Renal ischemia-reperfusion is a main cause of acute kidney injury (AKI), which is associated with high mortality. Here we show that extracellular vesicles (EVs) secreted from hiPSC-MSCs play a critical role in protection against renal I/R injury. hiPSC-MSCs-EVs can fuse with renal cells and deliver SP1 into target cells, subsequently active SK1 expression and increase S1P formation. Chromatin immunoprecipitation (ChIP) analyses and luciferase assay were used to confirm SP1 binds directly to the SK1 promoter region and promote promoter activity. Moreover, SP1 inhibition (MIT) or SK1 inhibition (SKI-II) completely abolished the renal protective effect of hiPSC-MSCs-EVs in rat I/R injury mode. However, pre-treatment of necroptosis inhibitor Nec-1 showed no difference with the administration of hiPSC-MSCs-EVs only. We then generated an SP1 knockout hiPSC-MSC cell line by CRISPR/Cas9 system and found that SP1 knockout failed to show the protective effect of hiPSC-MSCs-EVs unless restoring the level of SP1 by Ad-SP1 in vitro and in vivo. In conclusion, this study describes an anti-necroptosis effect of hiPSC-MSCs-EVs against renal I/R injury via delivering SP1 into target renal cells and intracellular activating the expression of SK1 and the generation of S1P. These findings suggest a novel mechanism for renal protection against I/R injury, and indicate a potential therapeutic approach for a variety of renal diseases and renal transplantation.

  16. Phosphatase and tensin homolog-β-catenin signaling modulates regulatory T cells and inflammatory responses in mouse liver ischemia/reperfusion injury.

    Science.gov (United States)

    Zhu, Qiang; Li, Changyong; Wang, Kunpeng; Yue, Shi; Jiang, Longfeng; Ke, Michael; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Zhang, Feng; Lu, Ling; Ke, Bibo

    2017-06-01

    The phosphatase and tensin homolog (PTEN) deleted on chromosome 10 plays an important role in regulating T cell activation during inflammatory response. Activation of β-catenin is crucial for maintaining immune homeostasis. This study investigates the functional roles and molecular mechanisms by which PTEN-β-catenin signaling promotes regulatory T cell (Treg) induction in a mouse model of liver ischemia/reperfusion injury (IRI). We found that mice with myeloid-specific phosphatase and tensin homolog knockout (PTEN M-KO ) exhibited reduced liver damage as evidenced by decreased levels of serum alanine aminotransferase, intrahepatic macrophage trafficking, and proinflammatory mediators compared with the PTEN-proficient (floxed phosphatase and tensin homolog [PTEN FL/FL ]) controls. Disruption of myeloid PTEN-activated b-catenin promoted peroxisome proliferator-activated receptor gamma (PPARγ)-mediated Jagged-1/Notch signaling and induced forkhead box P3 (FOXP3)1 Tregs while inhibiting T helper 17 cells. However, blocking of Notch signaling by inhibiting γ-secretase reversed myeloid PTEN deficiency-mediated protection in ischemia/reperfusion-triggered liver inflammation with reduced FOXP3 + and increased retinoid A receptor-related orphan receptor gamma t-mediated interleukin 17A expression in ischemic livers. Moreover, knockdown of β-catenin or PPARγ in PTEN-deficient macrophages inhibited Jagged-1/Notch activation and reduced FOXP3 + Treg induction, leading to increased proinflammatory mediators in macrophage/T cell cocultures. In conclusion, our findings demonstrate that PTEN-β-catenin signaling is a novel regulator involved in modulating Treg development and provides a potential therapeutic target in liver IRI. Liver Transplantation 23 813-825 2017 AASLD. © 2017 by the American Association for the Study of Liver Diseases.

  17. The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

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    Hua, Fang, E-mail: fhua2@emory.edu [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States); Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G. [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States)

    2009-12-18

    TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-{kappa}B). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-{kappa}B and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-{kappa}B activity and phosphorylation of the inhibitor of kappa B (I{kappa}B{alpha}) increased in ischemic brains, but IRF3, inhibitor of {kappa}B kinase complex-{epsilon} (IKK{epsilon}), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-{kappa}B activity or p-I{kappa}B{alpha} induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-{kappa}B signaling and brain injury after acute cerebral I/R.

  18. The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

    International Nuclear Information System (INIS)

    Hua, Fang; Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G.

    2009-01-01

    TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-κB and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-κB activity and phosphorylation of the inhibitor of kappa B (IκBα) increased in ischemic brains, but IRF3, inhibitor of κB kinase complex-ε (IKKε), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-κB activity or p-IκBα induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-κB signaling and brain injury after acute cerebral I/R.

  19. Sodium Hypochlorite-Modified Hemosorbents in the Treatment of Limb Ischemia-Reperfusion Syndrome: Experimental Study

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    V. I. Sergiyenko

    2007-01-01

    Full Text Available Objective: to enhance the efficiency of treatment for limb ischemia-reperfusion syndrome in an experiment, by using the modified hemosorbents that have oxidative properties.Materials and methods. The investigation was conducted on 94 mongrel male dogs divided into 3 groups: 1 intact animals (n=20; 2 animals treated with hemocarboperfusion on the standard sorbent CKH-1K (n=36; 3 animals received hemocarboperfusion on sodium hypochloride-modified sorbent CKH-1K (n=38. A model of acute ischemia-reperfusion syndrome was created by the method of V. D. Pasechnikov et al. Partial oxygen tension (pO2 was determined by pin polarography. The levels of vasoactive eicosanoids were measured by enzyme immunoassay.Results. In the animals with leg ischemia syndrome, there is a significant pO2 reduction in the muscles of the hip and shin, which does not completely recover after reperfusion. Standard CKN-1K sorbent hemocarboperfusion reduces pO2 as compared with the reperfusion period while the use of modified CKH-1K hemosorbent increased pO2 in the study hind limb muscles to the level observed in intact animals. The development of ischemia and reperfusion is accompanied by the elevated levels of inflammatory mediators that have vasoconstrictive properties (thromboxane B2, endothelin-1, leukotrienes C4/D4/E4 and the lower concentration of the vasodilator prostacyclin. Standard CKN-1K sorbent hemocarboperfusion results in a further increase in the concentrations of thromboxane B2 and leukotrienes C4/D4/E4, a decrease in the concentration of endothelin-1, and an elevation of the levels of prostacyclin and prostaglandin E2. When sodium hypochlorite-modified CKN-1K sorbent hemocarboperfusion is employed, the concentrations of thromboxane B2, endothelin-1, and leukotrienes C4/D4/E4 decrease, and the level of prostacyclin increases.Conclusion. Hemocarboperfusion used in the treatment of leg ischemia-reperfusion syndrome leads to restoration of tissue oxygenation and

  20. CD4+ Foxp3+ T-cells contribute to myocardial ischemia-reperfusion injury.

    Science.gov (United States)

    Mathes, Denise; Weirather, Johannes; Nordbeck, Peter; Arias-Loza, Anahi-Paula; Burkard, Matthias; Pachel, Christina; Kerkau, Thomas; Beyersdorf, Niklas; Frantz, Stefan; Hofmann, Ulrich

    2016-12-01

    The present study analyzed the effect of CD4 + Forkhead box protein 3 negative (Foxp3 - ) T-cells and Foxp3 + CD4 + T-cells on infarct size in a mouse myocardial ischemia-reperfusion model. We examined the infarct size as a fraction of the area-at-risk as primary study endpoint in mice after 30minutes of coronary ligation followed by 24hours of reperfusion. CD4 + T-cell deficient MHC-II KO mice showed smaller histologically determined infarct size (34.5±4.7% in MHCII KO versus 59.4±4.9% in wildtype (WT)) and better preserved ejection fraction determined by magnetic resonance tomography (56.9±2.8% in MHC II KO versus 39.0±4.2% in WT). MHC-II KO mice also displayed better microvascular perfusion than WT mice after 24hours of reperfusion. Also CD4 + T-cell sufficient OT-II mice, which express an in this context irrelevant T-cell receptor, revealed smaller infarct sizes compared to WT mice. However, MHC-II blocking anti-I-A/I-E antibody treatment was not able to reduce infarct size indicating that autoantigen recognition is not required for the activation of CD4 + T-cells during reperfusion. Flow-cytometric analysis also did not detect CD4 + T-cell activation in heart draining lymph nodes in response to 24hours of ischemia-reperfusion. Adoptive transfer of CD4 + T-cells in CD4 KO mice increased the infarct size only when including the Foxp3 + CD25 + subset. Depletion of CD4 + Foxp3 + T-cells in DEREG mice enabling specific conditional ablation of this subset by treatment with diphtheria toxin attenuated infarct size as compared to diphtheria toxin treated WT mice. CD4 + Foxp3 + T-cells enhance myocardial ischemia-reperfusion injury. CD4 + T-cells exert injurious effects without the need for prior activation by MHC-II restricted autoantigen recognition. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Rosiglitazone Affects Nitric Oxide Synthases and Improves Renal Outcome in a Rat Model of Severe Ischemia/Reperfusion Injury

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    Boris Betz

    2012-01-01

    Full Text Available Background. Nitric oxide (NO-signal transduction plays an important role in renal ischemia/reperfusion (I/R injury. NO produced by endothelial NO-synthase (eNOS has protective functions whereas NO from inducible NO-synthase (iNOS induces impairment. Rosiglitazone (RGZ, a peroxisome proliferator-activated receptor (PPAR-γ agonist exerted beneficial effects after renal I/R injury, so we investigated whether this might be causally linked with NOS imbalance. Methods. RGZ (5 mg/kg was administered i.p. to SD-rats (f subjected to bilateral renal ischemia (60 min. Following 24 h of reperfusion, inulin- and PAH-clearance as well as PAH-net secretion were determined. Morphological alterations were graded by histopathological scoring. Plasma NOx-production was measured. eNOS and iNOS expression was analyzed by qPCR. Cleaved caspase 3 (CC3 was determined as an apoptosis indicator and ED1 as a marker of macrophage infiltration in renal tissue. Results. RGZ improves renal function after renal I/R injury (PAH-/inulin-clearance, PAH-net secretion and reduces histomorphological injury. Additionally, RGZ reduces NOx plasma levels, ED-1 positive cell infiltration and CC3 expression. iNOS-mRNA is reduced whereas eNOS-mRNA is increased by RGZ. Conclusion. RGZ has protective properties after severe renal I/R injury. Alterations of the NO pathway regarding eNOS and iNOS could be an explanation of the underlying mechanism of RGZ protection in renal I/R injury.

  2. A novel imidazopyridine derivative, X22, prevents the retinal ischemia-reperfusion injury via inhibition of MAPKs.

    Science.gov (United States)

    Bian, Yang; Ren, Luqing; Wang, Lei; Xu, Shanmei; Tao, Jianjian; Zhang, Xiuhua; Huang, Yi; Qian, Yuanyuan; Zhang, Xin; Song, Zongming; Wu, Wencan; Wang, Yi; Liang, Guang

    2015-06-01

    Inflammation is a pathological hallmark of ischemia reperfusion (I/R) injury. The present study was conducted to explore the ability of a new anti-inflammatory compound, X22, to attenuate retinal I/R injury via cytokine-inhibitory mechanism. For the in vitro experiment, ARPE-19 cells were pretreated with X22 (5 or 10 μM) or saline for 2 h, followed by stimulation with tert-butyl hydroperoxide (TBHP, 1000 μM) for an indicated amount of time. The expression of inflammatory mediators, cell viability, and cell apoptosis were evaluated. For the in vivo experiment, the rats were randomized to receive treatment with saline or X22 (0.1 μM/kg, 3 μL) before the induction of I/R injury. Histological evaluation, apoptosis of retinal cells, macrophage infiltration, and retina functional changes were further determined. Our data showed that pretreatment with X22 significantly inhibited TBHP-induced inflammatory cytokine expression in ARPE-19 cells. The anti-inflammatory activity of X22 may be associated with its inhibition on MAPKs, rather than NF-κB. Subsequently, our data proved that TBHP induced apoptosis in ARPE-19 cells, while pretreatment of X22 significantly suppressed TBHP-caused ARPE-19 apoptosis. Finally, the in vivo data revealed that X22 administration maintained better inner retinal layer structures, reduced apoptosis of retinal ganglion cell, and improved retinal function in retinal I/R rat models, which were accompanied with a remarkable decrease in retinal macrophage infiltration. These results suggest that the novel compound X22 is a potential agent for the treatment of retinal I/R-related diseases via the MAPKs-targeting anti-inflammatory mechanism and deserves the further development. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.

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    Takanobu Nagata

    Full Text Available Myocardial ischemia reperfusion injury (IRI adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS-3, an intrinsic negative feedback regulator of the Janus kinase (JAK-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO. The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1 was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

  4. Beneficial Effects of N-acetylcysteine and N-mercaptopropionylglycine on Ischemia Reperfusion Injury in the Heart.

    Science.gov (United States)

    Bartekova, Monika; Barancik, Miroslav; Ferenczyova, Kristina; Dhalla, Naranjan S

    2018-01-30

    Ischemia-reperfusion (I/R) injury of the heart as a consequence of myocardial infarction or cardiac surgery represents a serious clinical problem. One of the most prominent mechanisms of I/R injury is the development of oxidative stress in the heart. In this regard, I/R has been shown to enhance the production of reactive oxygen/nitrogen species in the heart which lead to the imbalance between the pro-oxidants and antioxidant capacities of the endogenous radical-scavenging systems. Increasing the antioxidant capacity of the heart by the administration of exogenous antioxidants is considered beneficial for the heart exposed to I/R. N-acetylcysteine (NAC) and Nmercaptopropionylglycine (MPG) are two sulphur containing amino acid substances, which belong to the broad category of exogenous antioxidants that have been tested for their protective potential in cardiac I/R injury. Pretreatment of hearts with both NAC and MPG has demonstrated that these agents attenuate the I/R-induced alterations in sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils in addition to improving cardiac function. While experimental studies have revealed promising data suggesting beneficial effects of NAC and MPG in cardiac I/R injury, the results of clinical trials are not conclusive because both positive and no effects of these substances have been reported on the post-ischemic recovery of heart following cardiac surgery or myocardial infarction. It is concluded that both NAC and MPG exert beneficial effects in preventing the I/Rinduced injury; however, further studies are needed to establish their effectiveness in reversing the I/R-induced abnormalities in the heart. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Effect of denervation and ischemia reperfusion injury on serum nitricoxide levels in rats

    International Nuclear Information System (INIS)

    Ozsoy, U.; Sindel, S.; Oygur, N.; Akbas, H.; Mutluay, R.

    2008-01-01

    Objective was to evaluate the effect of renal denervation and serumnitric oxide level with a different time course of renal ischemia-reperfusioninjury. Thirty-six male Wistar rats were randomized into 6 groups. All ratsunderwent right nephrectomy to create a single kidney model. Renal denervatedand innerved rats were subjected to renal clamping for 30-60 minutes. Thestudy was performed in the Department of Anatomy, Akdeniz University,Antalya, Turkey, between June and November 2005. Combined effects ofdenervation and ischemia may cause significant increase in serum nitric oxidelevels and decrease in glomerular filtration rates. Our results indicate thatkidney denervation did not cause any changes in renal functions, but withischemia it worsens the deleterious effect of ischemia-reperfusion injury andcauses a significant increase in serum nitric oxide levels. (author)

  6. Comments and hypotheses on the mechanism of methane against ischemia/reperfusion injury

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    He Li

    2017-01-01

    Full Text Available As we all know, methane is a kind of fuel. Previous studies have shown that methanogens in the colon can react with carbon dioxide and hydrogen to produce methane. In a recent study, the anti-inflammatory effects of methane were shown in a dog model of small intestinal ischemia/reperfusion. The mechanism of this anti-inflammatory effect needs further investigation. Recently, studies have shown anti-inflammatory, anti-apoptotic and anti-oxidative effects of methane on different organic injuries. According to the results of these studies, we hypothesize that the initial effects of methane are to react with free radicals and enhance expression of antioxidase through forkhead box transcription factor class O pathway. The anti-inflammatory effect is following the anti-oxidative effect, and the anti-apoptotic effect relies on anti-inflammatory and anti-oxidative effects.

  7. Inhibition of Long Chain Fatty Acyl-CoA Synthetase (ACSL) and Ischemia Reperfusion Injury

    Science.gov (United States)

    Prior, Allan M.; Zhang, Man; Blakeman, Nina; Datta, Palika; Pham, Hung; Young, Lindon H.; Weis, Margaret T.; Hua, Duy H.

    2014-01-01

    Various triacsin C analogs, containing different alkenyl chains and carboxylic acid bioisoteres including 4-aminobenzoic acid, isothiazolidine dioxide, hydroxylamine, hydroxytriazene, and oxadiazolidine dione, were synthesized and their inhibitions of long chain fatty acyl-CoA synthetase (ACSL) were examined. Two methods, a cell-based assay of ACSL activity and an in situ [14C]-palmitate incorporation into extractable lipids were used to study the inhibition. Using an in vivo leukocyte recruitment inhibition protocol, the translocation of one or more cell adhesion molecules from the cytoplasm to the plasma membrane on either the endothelium or leukocyte or both was inhibited by inhibitors 1, 9, and triacsin C. The results suggest that inhibition of ACSL may attenuate the vascular inflammatory component associated with ischemia reperfusion injury and lead to a decrease of infarct expansion. PMID:24480468

  8. Impact of intestinal ischemia/reperfusion and lymph drainage on distant organs in rats

    Science.gov (United States)

    He, Gui-Zhen; Zhou, Kai-Guo; Zhang, Rui; Wang, Yu-Kang; Chen, Xue-Feng

    2012-01-01

    AIM: To investigate the impact of intestinal ischemia/reperfusion (I/R) injury and lymph drainage on distant organs in rats. METHODS: Thirty-two Sprague-Dawley male rats, weighing 280-320 g, were randomly divided into blank, sham, I/R, and ischemia/reperfusion and drainage (I/R + D) groups (n = 8). All rats were subjected to 60 min ischemia by clamping the superior mesenteric artery, followed by 120 min reperfusion. The rats in the I/R + D group received intestinal lymph drainage for 180 min. In the sham group, the abdominal cavity was opened for 180 min, but the rats received no treatment. The blank group served as a normal and untreated control. A chromogenic limulus assay kit was used for quantitative detection of serum endotoxin. The serum concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, soluble cell adhesion molecules (sICAM-1), and high mobility group protein box 1 (HMGB1) were determined with an enzyme-linked immunosorbent assay kit. Histological evaluations of the intestine, liver, kidney, and lung were performed by hematoxylin and eosin staining and immunohistochemistry. HMGB1 protein expression was assayed by western blot analysis. RESULTS: The serum levels of endotoxin and HMGB1 in the I/R and I/R + D groups were significantly higher than those in the sham group (endotoxin, I/R and I/R + D vs sham: 0.033 ± 0.004 EU/mL, 0.024 ± 0.003 EU/mL vs 0.017 ± 0.009 EU/mL, respectively, P drainage could block the “gut-lymph” pathway, improve intestinal barrier function, and attenuate distant organ injury incurred by intestinal I/R. PMID:23326132

  9. X-ray phase-contrast tomography of renal ischemia-reperfusion damage.

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    Astrid Velroyen

    Full Text Available The aim of the study was to investigate microstructural changes occurring in unilateral renal ischemia-reperfusion injury in a murine animal model using synchrotron radiation.The effects of renal ischemia-reperfusion were investigated in a murine animal model of unilateral ischemia. Kidney samples were harvested on day 18. Grating-Based Phase-Contrast Imaging (GB-PCI of the paraffin-embedded kidney samples was performed at a Synchrotron Radiation Facility (beam energy of 19 keV. To obtain phase information, a two-grating Talbot interferometer was used applying the phase stepping technique. The imaging system provided an effective pixel size of 7.5 µm. The resulting attenuation and differential phase projections were tomographically reconstructed using filtered back-projection. Semi-automated segmentation and volumetry and correlation to histopathology were performed.GB-PCI provided good discrimination of the cortex, outer and inner medulla in non-ischemic control kidneys. Post-ischemic kidneys showed a reduced compartmental differentiation, particularly of the outer stripe of the outer medulla, which could not be differentiated from the inner stripe. Compared to the contralateral kidney, after ischemia a volume loss was detected, while the inner medulla mainly retained its volume (ratio 0.94. Post-ischemic kidneys exhibited severe tissue damage as evidenced by tubular atrophy and dilatation, moderate inflammatory infiltration, loss of brush borders and tubular protein cylinders.In conclusion GB-PCI with synchrotron radiation allows for non-destructive microstructural assessment of parenchymal kidney disease and vessel architecture. If translation to lab-based approaches generates sufficient density resolution, and with a time-optimized image analysis protocol, GB-PCI may ultimately serve as a non-invasive, non-enhanced alternative for imaging of pathological changes of the kidney.

  10. Study of the influence and molecular mechanism of ticagrelor on cerebral ischemia reperfusion injury in rats

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    Gui-Fa Chen

    2017-06-01

    Full Text Available Objective: To study the influence and molecular mechanism of ticagrelor on cerebral ischemia reperfusion injury in rats. Methods: SD rats were selected as experimental animals and divided into control group, model group, ticagrelor group and clopidogrel group, cerebral ischemic reperfusion injury models were made, then ticagrelor group were given intragastric administration of 150 mg ticagrelor, clopidogrel group were given intragastric administration of 90 mg clopidogrel. 1 week after intervention, the brain water content as well as the contents of oxidative stress molecules and inflammatory factors were measured. Results: Water content in brain, MDA, Ox-LDL, NF-kB, TNF-α, IL-1β and IL-6 contents in brain tissue as well as TNF-α, IL-1β and IL-6 contents in serum of model group were significantly higher than those of control group while SOD, GSH-Px and Prdx6 contents in brain tissue were significantly lower than those of control group; water content in brain, MDA, Ox-LDL, NFkB, TNF-α, IL-1β and IL-6 contents in brain tissue as well as TNF-α, IL-1β and IL-6 contents in serum of ticagrelor group and clopidogrel group were significantly lower than those of model group while SOD, GSH-Px and Prdx6 contents in brain tissue were significantly higher than those of model group; water content in brain, MDA, Ox-LDL, NF-kB, TNF-α, IL-1β and IL-6 contents in brain tissue as well as TNF-α, IL-1β and IL-6 contents in serum of ticagrelor group were significantly lower than those of clopidogrel group while SOD, GSHPx and Prdx6 contents in brain tissue were significantly higher than those of clopidogrel group. Conclusion: Ticagrelor can be more effective in inhibiting oxidative stress response and inflammatory response, and reducing the cerebral ischemia reperfusion injury than clopidogrel.

  11. Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats.

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    Laurens J Ceulemans

    Full Text Available The farnesoid X receptor (FXR is abundantly expressed in the ileum, where it exerts an enteroprotective role as a key regulator of intestinal innate immunity and homeostasis, as shown in pre-clinical models of inflammatory bowel disease. Since intestinal ischemia reperfusion injury (IRI is characterized by hyperpermeability, bacterial translocation and inflammation, we aimed to investigate, for the first time, if the FXR-agonist obeticholic acid (OCA could attenuate intestinal ischemia reperfusion injury.In a validated rat model of intestinal IRI (laparotomy + temporary mesenteric artery clamping, 3 conditions were tested (n = 16/group: laparotomy only (sham group; ischemia 60min+ reperfusion 60min + vehicle pretreatment (IR group; ischemia 60min + reperfusion 60min + OCA pretreatment (IR+OCA group. Vehicle or OCA (INT-747, 2*30mg/kg was administered by gavage 24h and 4h prior to IRI. The following end-points were analyzed: 7-day survival; biomarkers of enterocyte viability (L-lactate, I-FABP; histology (morphologic injury to villi/crypts and villus length; intestinal permeability (Ussing chamber; endotoxin translocation (Lipopolysaccharide assay; cytokines (IL-6, IL-1-β, TNFα, IFN-γ IL-10, IL-13; apoptosis (cleaved caspase-3; and autophagy (LC3, p62.It was found that intestinal IRI was associated with high mortality (90%; loss of intestinal integrity (structurally and functionally; increased endotoxin translocation and pro-inflammatory cytokine production; and inhibition of autophagy. Conversely, OCA-pretreatment improved 7-day survival up to 50% which was associated with prevention of epithelial injury, preserved intestinal architecture and permeability. Additionally, FXR-agonism led to decreased pro-inflammatory cytokine release and alleviated autophagy inhibition.Pretreatment with OCA, an FXR-agonist, improves survival in a rodent model of intestinal IRI, preserves the gut barrier function and suppresses inflammation. These results turn

  12. Carvacrol, a food-additive, provides neuroprotection on focal cerebral ischemia/reperfusion injury in mice.

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    Hailong Yu

    Full Text Available Carvacrol (CAR, a naturally occurring monoterpenic phenol and food additive, has been shown to have antimicrobials, antitumor, and antidepressant-like activities. A previous study demonstrated that CAR has the ability to protect liver against ischemia/reperfusion injury in rats. In this study, we investigated the protective effects of CAR on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model. We found that CAR (50 mg/kg significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. This neuroprotection was in a dose-dependent manner. Post-treatment with CAR still provided protection on infarct volume when it was administered intraperitoneally at 2 h after reperfusion; however, intracerebroventricular post-treatment reduced infarct volume even when the mice were treated with CAR at 6 h after reperfusion. These findings indicated that CAR has an extended therapeutic window, but delivery strategies may affect the protective effects of CAR. Further, we found that CAR significantly decreased the level of cleaved caspase-3, a marker of apoptosis, suggesting the anti-apoptotic activity of CAR. Finally, our data indicated that CAR treatment increased the level of phosphorylated Akt and the neuroprotection of CAR was reversed by a PI3K inhibitor LY-294002, demonstrating the involvement of the PI3K/Akt pathway in the anti-apoptotic mechanisms of CAR. Due to its safety and wide use in the food industry, CAR is a promising agent to be translated into clinical trials.

  13. Oxidative stress gene expression profile in inbred mouse after ischemia/reperfusion small bowel injury.

    Science.gov (United States)

    Bertoletto, Paulo Roberto; Ikejiri, Adauto Tsutomu; Somaio Neto, Frederico; Chaves, José Carlos; Teruya, Roberto; Bertoletto, Eduardo Rodrigues; Taha, Murched Omar; Fagundes, Djalma José

    2012-11-01

    To determine the profile of gene expressions associated with oxidative stress and thereby contribute to establish parameters about the role of enzyme clusters related to the ischemia/reperfusion intestinal injury. Twelve male inbred mice (C57BL/6) were randomly assigned: Control Group (CG) submitted to anesthesia, laparotomy and observed by 120 min; Ischemia/reperfusion Group (IRG) submitted to anesthesia, laparotomy, 60 min of small bowel ischemia and 60 min of reperfusion. A pool of six samples was submitted to the qPCR-RT protocol (six clusters) for mouse oxidative stress and antioxidant defense pathways. On the 84 genes investigated, 64 (76.2%) had statistic significant expression and 20 (23.8%) showed no statistical difference to the control group. From these 64 significantly expressed genes, 60 (93.7%) were up-regulated and 04 (6.3%) were down-regulated. From the group with no statistical significantly expression, 12 genes were up-regulated and 8 genes were down-regulated. Surprisingly, 37 (44.04%) showed a higher than threefold up-regulation and then arbitrarily the values was considered as a very significant. Thus, 37 genes (44.04%) were expressed very significantly up-regulated. The remained 47 (55.9%) genes were up-regulated less than three folds (35 genes - 41.6%) or down-regulated less than three folds (12 genes - 14.3%). The intestinal ischemia and reperfusion promote a global hyper-expression profile of six different clusters genes related to antioxidant defense and oxidative stress.

  14. Isoproterenol reduces ischemia-reperfusion lung injury despite beta-blockade.

    Science.gov (United States)

    Takashima, Seiki; Schlidt, Scott A; Koukoulis, Giovanna; Sevala, Mayura; Egan, Thomas M

    2005-06-01

    If lungs could be retrieved from non-heart-beating donors (NHBDs), the shortage of lungs for transplantation could be alleviated. The use of lungs from NHBDs is associated with a mandatory warm ischemic interval, which results in ischemia-reperfusion injury upon reperfusion. In an earlier study, rat lungs retrieved 2-h postmortem from NHBDs had reduced capillary leak measured by filtration coefficient (Kfc) when reperfused with isoproterenol (iso), associated with an increase in lung tissue levels of cyclic AMP (cAMP). The objective was to determine if this decrease in Kfc was because of beta-stimulation, or would persist despite beta-blockade. Donor rats were treated intraperitoneally with beta-blockade (propranolol or pindolol) or carrier, sacrificed, and lungs were retrieved immediately or 2 h postmortem. The lungs were reperfused with or without iso and the beta-blockers in the reperfusate. Outcome measures were Kfc, wet:dry weight ratio (W/D), lung levels of adenine nucleotides and cAMP. Lungs retrieved immediately after death had normal Kfc and W/D. After 2 h of ischemia, Kfc and W/D were markedly elevated in controls (no drug) and lungs reperfused with beta-blockers alone. Isoproterenol-reperfusion decreased Kfc and W/D significantly (P < 0.01) even in the presence of beta-blockade. Lung cAMP levels were increased only with iso in the absence of beta-blockade. The attenuation of ischemia-reperfusion injury because of iso occurs even in the presence of beta-blockade, and may not be a result of beta-stimulated increased cAMP.

  15. Comparison of the effects of dexmedetomidine administered at two different times on renal ischemia/reperfusion injury in rats

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    Edip Gonullu

    2014-06-01

    Full Text Available Background and objectives: We investigated the effect of dexmedetomidine on ischemic renal failure in rats. Methods: In the present study, 26 male adult Wistar albino rats weighting 230-300 g were randomly separated into four groups: sham-operated (n = 5, ischemia reperfusion (IR (IR group, n = 7, IR/reperfusion treatment with dexmedetomidine (Dex. R group, n = 7 and IR/pre-ischemic treatment with dexmedetomidine (Dex. I group, n = 7. In the first group, sham operation was achieved and renal clamps were not applied. For the IR group, renal ischemia was induced by occlusion of the bilateral renal arteries and veins for 60 min followed by reperfusion for 24 h. For the Dex. R and Dex. I groups, the same surgical procedure as in the IR group was performed, and dexmedetomidine (100 mcg/kg intraperitoneal was administrated at the 5th min after reperfusion and before ischemia. At the end of reperfusion, blood samples were drawn, the rats were sacrificed, and the left kidney was processed for histopathology. Results: The blood urea nitrogen (BUN levels in groups Dex. R and Dex. I were significantly lower than in the IR group (p = 0.015, p = 0.043, although urine flow was significantly higher in group Dex. R (p = 0.003. The renal histopathological score in the IR group was significantly higher than in the other groups. There was no significant difference between the Dex. R and Dex. I groups. Conclusions: The results were shown that administration of dexmedetomidine reduced the renal IR injury histomorphologically. Administration of dexmedetomidine in the reperfusion period was considered as more effective due to increase in urinary output and decrease in BUN levels.

  16. Testing Danegaptide Effects on Kidney Function after Ischemia/Reperfusion Injury in a New Porcine Two Week Model.

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    Chris Amdisen

    Full Text Available Ischemia/reperfusion injury (I/R-I is a leading cause of acute kidney injury (AKI and is associated with increased mortality. Danegaptide is a selective modifier of the gap junction protein connexion 43. It has cytoprotective as well as anti-arrhythmic properties and has been shown to reduce the size of myocardial infarct in pigs. The aim of this study was to investigate the ischemia-protective effect of Danegaptide in a porcine renal I/R-I model with two weeks follow up.Unilateral renal I/R-I was induced in pigs by clamping the left renal artery over a two hour period. The model allowed examination of renal blood flow by magnetic resonance imaging (MRI and the measurement of single kidney GFR two weeks after injury. Eleven animals were randomized to Danegaptide-infusion while nine animals received placebo. Kidney histology and urinary neutrophil gelatinase-associated lipocalin (NGAL excretion were included as markers of AKI.Unilateral kidney I/R-I resulted in an immediate ~50% GFR reduction, associated with a four-fold increase in urinary NGAL-excretion. Fourteen days after I/R-I, the total GFR was ~75% of baseline with a significantly lower GFR in the injured left kidney compared to the right kidney. No differences in GFR were observed between the treated and non-treated animals immediately after I/R-I or at Day 14. Furthermore, no differences were observed in the urinary excretion of NGAL, renal blood flow or other markers of renal function.As expected this porcine renal I/R-I model was associated with reduced GFR two weeks after injury. Danegaptide did not improve renal function after I/R-I.

  17. Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation

    Science.gov (United States)

    Day, Judy D.; Metes, Diana M.; Vodovotz, Yoram

    2015-01-01

    A mathematical model of the early inflammatory response in transplantation is formulated with ordinary differential equations. We first consider the inflammatory events associated only with the initial surgical procedure and the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft. These events release damage-associated molecular pattern molecules (DAMPs), thereby initiating an acute inflammatory response. In simulations of this model, resolution of inflammation depends on the severity of the tissue damage caused by these events and the patient’s (co)-morbidities. We augment a portion of a previously published mathematical model of acute inflammation with the inflammatory effects of T cells in the absence of antigenic allograft mismatch (but with DAMP release proportional to the degree of graft damage prior to transplant). Finally, we include the antigenic mismatch of the graft, which leads to the stimulation of potent memory T cell responses, leading to further DAMP release from the graft and concomitant increase in allograft damage. Regulatory mechanisms are also included at the final stage. Our simulations suggest that surgical injury and I/R-induced graft damage can be well-tolerated by the recipient when each is present alone, but that their combination (along with antigenic mismatch) may lead to acute rejection, as seen clinically in a subset of patients. An emergent phenomenon from our simulations is that low-level DAMP release can tolerize the recipient to a mismatched allograft, whereas different restimulation regimens resulted in an exaggerated rejection response, in agreement with published studies. We suggest that mechanistic mathematical models might serve as an adjunct for patient- or sub-group-specific predictions, simulated clinical studies, and rational design of immunosuppression. PMID:26441988

  18. Acute sleep deprivation preconditions the heart against ischemia/ reperfusion injury: the role of central GABA-A receptors.

    Science.gov (United States)

    Parsa, Hoda; Imani, Alireza; Faghihi, Mahdieh; Riahi, Esmail; Badavi, Mohammad; Shakoori, Abbas; Rastegar, Tayebeh; Aghajani, Marjan; Rajani, Sulail Fatima

    2017-11-01

    Central γ-aminobutyric acid (GABA) neurotransmission modulates cardiovascular functions and sleep. Acute sleep deprivation (ASD) affects functions of various body organs via different mechanisms. Here, we evaluated the effect of ASD on cardiac ischemia/reperfusion injury (IRI), and studied the role of GABA-A receptor inhibition in central nucleus of amygdala (CeA) by assessing nitric oxide (NO) and oxidative stress. The CeA in sixty male Wistar rats was cannulated for saline or bicuculline (GABA-A receptor antagonist) administration. All animals underwent 30 min of coronary occlusion (ischemia), followed by 2 hr reperfusion (IR). The five experimental groups (n=12) included are as follows: IR: received saline; BIC+IR: received Bicuculline; MLP+IR: received saline, followed by the placement of animals in an aquarium with multiple large platforms; ASD+IR: underwent ASD in an aquarium with multiple small platforms; and BIC+ASD+IR: received bicuculline prior to ASD. Bicuculline administration increased the malondialdehyde levels and infarct size, and decreased the NO metabolites levels and endothelial nitric oxide synthase (eNOS) gene expression in infarcted and non-infarcted areas in comparison to IR group. ASD reduced malondialdehyde levels and infarct size and increased NO metabolites, corticosterone levels and eNOS expression in infarcted and non-infarcted areas as compared to the IR group. Levels of malondialdehyde were increased while levels of NO metabolites, corticosterone and eNOS expression in infarcted and non-infarcted areas were reduced in the BIC+ASD+IR as compared to the ASD+IR group. Blockade of GABA-A receptors in the CeA abolishes ASD-induced cardioprotection by suppressing oxidative stress and NO production.

  19. Acute sleep deprivation preconditions the heart against ischemia/ reperfusion injury: the role of central GABA-A receptors

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    Hoda Parsa

    2017-11-01

    Full Text Available Objective(s: Central γ-aminobutyric acid (GABA neurotransmission modulates cardiovascular functions and sleep. Acute sleep deprivation (ASD affects functions of various body organs via different mechanisms. Here, we evaluated the effect of ASD on cardiac ischemia/reperfusion injury (IRI, and studied the role of GABA-A receptor inhibition in central nucleus of amygdala (CeA by assessing nitric oxide (NO and oxidative stress. Materials and Methods: The CeA in sixty male Wistar rats was cannulated for saline or bicuculline (GABA-A receptor antagonist administration. All animals underwent 30 min of coronary occlusion (ischemia, followed by 2 hr reperfusion (IR. The five experimental groups (n=12 included are as follows: IR: received saline; BIC+IR: received Bicuculline; MLP+IR: received saline, followed by the placement of animals in an aquarium with multiple large platforms; ASD+IR: underwent ASD in an aquarium with multiple small platforms; and BIC+ASD+IR: received bicuculline prior to ASD. Results: Bicuculline administration increased the malondialdehyde levels and infarct size, and decreased the NO metabolites levels and endothelial nitric oxide synthase (eNOS gene expression in infarcted and non-infarcted areas in comparison to IR group. ASD reduced malondialdehyde levels and infarct size and increased NO metabolites, corticosterone levels and eNOS expression in infarcted and non-infarcted areas as compared to the IR group. Levels of malondialdehyde were increased while levels of NO metabolites, corticosterone and eNOS expression in infarcted and non-infarcted areas were reduced in the BIC+ASD+IR as compared to the ASD+IR group. Conclusion: Blockade of GABA-A receptors in the CeA abolishes ASD-induced cardioprotection by suppressing oxidative stress and NO production.

  20. Lycium barbarum polysaccharides reduce neuronal damage, blood-retinal barrier disruption and oxidative stress in retinal ischemia/reperfusion injury.

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    Suk-Yee Li

    Full Text Available Neuronal cell death, glial cell activation, retinal swelling and oxidative injury are complications in retinal ischemia/reperfusion (I/R injuries. Lycium barbarum polysaccharides (LBP, extracts from the wolfberries, are good for "eye health" according to Chinese medicine. The aim of our present study is to explore the use of LBP in retinal I/R injury. Retinal I/R injury was induced by surgical occlusion of the internal carotid artery. Prior to induction of ischemia, mice were treated orally with either vehicle (PBS or LBP (1 mg/kg once a day for 1 week. Paraffin-embedded retinal sections were prepared. Viable cells were counted; apoptosis was assessed using TUNEL assay. Expression levels of glial fibrillary acidic protein (GFAP, aquaporin-4 (AQP4, poly(ADP-ribose (PAR and nitrotyrosine (NT were investigated by immunohistochemistry. The integrity of blood-retinal barrier (BRB was examined by IgG extravasations. Apoptosis and decreased viable cell count were found in the ganglion cell layer (GCL and the inner nuclear layer (INL of the vehicle-treated I/R retina. Additionally, increased retinal thickness, GFAP activation, AQP4 up-regulation, IgG extravasations and PAR expression levels were observed in the vehicle-treated I/R retina. Many of these changes were diminished or abolished in the LBP-treated I/R retina. Pre-treatment with LBP for 1 week effectively protected the retina from neuronal death, apoptosis, glial cell activation, aquaporin water channel up-regulation, disruption of BRB and oxidative stress. The present study suggests that LBP may have a neuroprotective role to play in ocular diseases for which I/R is a feature.

  1. Quantitative phosphoproteomics using acetone-based peptide labeling: Method evaluation and application to a cardiac ischemia/reperfusion model

    Science.gov (United States)

    Wijeratne, Aruna B.; Manning, Janet R.; Schultz, Jo El J.; Greis, Kenneth D.

    2013-01-01

    Mass spectrometry (MS) techniques to globally profile protein phosphorylation in cellular systems that are relevant to physiological or pathological changes have been of significant interest in biological research. In this report, an MS-based strategy utilizing an inexpensive acetone-based peptide labeling technique known as reductive alkylation by acetone (RABA) for quantitative phosphoproteomics was explored to evaluate its capacity. Since the chemistry for RABA-labeling for phosphorylation profiling had not been previously reported, it was first validated using a standard phosphoprotein and identical phosphoproteomes from cardiac tissue extracts. A workflow was then utilized to compare cardiac tissue phosphoproteomes from mouse hearts not expressing FGF2 vs. hearts expressing low molecular weight fibroblast growth factor-2 (LMW FGF2) to relate low molecular weight fibroblast growth factor-2 (LMW FGF2) mediated cardioprotective phenomena induced by ischemia/reperfusion (I/R) injury of hearts, with downstream phosphorylation changes in LMW FGF2 signaling cascades. Statistically significant phosphorylation changes were identified at 14 different sites on 10 distinct proteins including some with mechanisms already established for LMW FGF2-mediated cardioprotective signaling (e.g. connexin-43), some with new details linking LMW FGF2 to the cardioprotective mechanisms (e.g. cardiac myosin binding protein C or cMyBPC), and also several new downstream effectors not previously recognized for cardio-protective signaling by LMW FGF2. Additionally, one of the phosphopeptides, cMyBPC/pSer-282, identified was further verified with site-specific quantification using an SRM (selected reaction monitoring)-based approach that also relies on isotope labeling of a synthetic phosphopeptide with deuterated acetone as an internal standard. Overall, this study confirms that the inexpensive acetone-based peptide labeling can be used in both exploratory and targeted quantification

  2. The Protective Effect of Spinal Cord Stimulation Postconditioning Against Spinal Cord Ischemia/Reperfusion Injury in Rabbits.

    Science.gov (United States)

    Li, Huixian; Dong, Xiuhua; Jin, Mu; Cheng, Weiping

    2018-01-18

    Delayed paraplegia due to spinal cord ischemia/reperfusion injury (IRI) remains one of the most severe complications of thoracoabdominal aneurysm surgery, for which effective prevention and treatment is still lacking. The current study investigates whether spinal cord stimulation (SCS) postconditioning has neuroprotective effects against spinal cord IRI. Ninety-six New Zealand white male rabbits were randomly divided into four groups as follows: a sham group and three experimental groups (C group, 2 Hz group, and 50 Hz group) n = 24/group. Spinal cord ischemia was induced by transient infrarenal aortic balloon occlusion for 28 min, after which rabbits in group C underwent no additional intervention, while rabbits in the other two experimental groups underwent 2 Hz or 50 Hz epidural SCS for 30 min at the onset of reperfusion and then daily until sacrifice. Hind limb neurologic function of rabbits was assessed using Jacob scale. Lumbar spinal cords were harvested immediately after sacrifice for histological examination and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. The number of viable α-motor neurons in ventral horn was counted and TUNEL-positive rate of α-motor neurons was calculated. Spinal cord IRI was caused by transient infrarenal aorta occlusion for 28 min. Both 2 Hz and 50 Hz SCS postconditioning had neuroprotective effects, particularly the 2 Hz SCS postconditioning. Comparing to C group and 50 Hz group, rabbits in the 2 Hz group demonstrated better hind limb motor function and a lower rate of TUNEL-positive α-motor neuron after eight hours, one day, three days, and seven days of spinal cord reperfusion. More viable α-motor neurons were preserved after one and three days of spinal cord reperfusion in 2 Hz group rabbits than in C group and 50 Hz group rabbits. SCS postconditioning at 2 Hz protected the spinal cord from IRI. © 2018 International Neuromodulation Society.

  3. Cardioprotection by minocycline in a rabbit model of ischemia/reperfusion injury : Detection of cell death by in vivo (111)In-GSAO SPECT

    NARCIS (Netherlands)

    Yamaki, Takayoshi; de Haas, Hans J; Tahara, Nobuhiro; Petrov, Artiom; Mohar, Dilbahar; Haider, Nezam; Zhou, Jun; Tahara, Atsuko; Takeishi, Yasuchika; Boersma, Hendrikus H; Scarabelli, Tiziano; Kini, Annapoorna; Strauss, H William; Narula, Jagat

    BACKGROUND: Preclinical studies indicate that minocycline protects against myocardial ischemia/reperfusion injury. In these studies, minocycline was administered before ischemia, which can rarely occur in clinical practice. The current study aimed to evaluate cardioprotection by minocycline

  4. PEG-b-(PELG-g-PLL nanoparticles as TNF-α nanocarriers: potential cerebral ischemia/reperfusion injury therapeutic applications

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    Xu G

    2017-03-01

    , and nitric oxide (NO, as well as the expression of glial fibrillary acidic protein (GFAP, intercellular adhesion molecule-1 (ICAM-1, and cysteine aspartase-3 (caspase-3, in the brain tissue. We provide evidence that TNF-α preconditioning attenuated the oxidative stress injury, the inflammatory activity, and the apoptosis level in I/R-induced cerebral injury, while the application of block copolymer PEG-b-(PELG-g-PLL as a potential TNF-α nanocarrier with sustained release significantly enhanced the bioavailability of TNF-α. We propose that the block copolymer PEG-b-(PELG-g-PLL may function as a potent nanocarrier for augmenting BI/RI pharmacotherapy, with unprecedented clinical benefits. Further studies are needed to better clarify the underlying mechanisms. Keywords: PEG-b-(PELG-g-PLL, TNF-α, ischemia/reperfusion, brain

  5. Assessment of the effects of levosimendan and thymoquinone on lung injury after myocardial ischemia reperfusion in rats

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    Sezen SC

    2018-05-01

    Full Text Available Şaban Cem Sezen,1 Aysegul Kucuk,2 Abdullah Özer,3 Yiğit Kılıç,4 Barış Mardin,3 Metin Alkan,5 Fatmanur Duruk Erkent,5 Mustafa Arslan,5 Yusuf Ünal,5 Gürsel Levent Oktar,3 Murat Tosun6 1Department of Histology and Embryology, Kirikkale University Medical Faculty, Kirikkale, Turkey; 2Department of Physiology, Dumlupinar University Medical Faculty, Kutahya, Turkey; 3Department of Cardiovascular Surgery, Gazi University Medical Faculty, Ankara, Turkey; 4Pediatric Cardiovascular Surgery Clinic, Dr Siyami Ersek Cardiovascular and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey; 5Department of Anaesthesiology and Reanimation, Gazi University Medical Faculty, Ankara, Turkey; 6Department of Histology and Embryology, Afyon Kocatepe University Medical Faculty, Afyonkarahisar, Turkey Aim: The aim of this study was to investigate the effects of levosimendan and thymoquinone (TQ on lung injury after myocardial ischemia/reperfusion (I/R. Materials and methods: Twenty-four Wistar albino rats were included in the study. The animals were randomly assigned to 1 of 4 experimental groups. In Group C (control group, left anterior descending artery was not occluded or reperfused. Myocardial I/R was induced by ligation of the left anterior descending artery for 30 min, followed by 2 h of reperfusion in the I/R, I/R-levosimendan (24 μg/kg (IRL group, and I/R-thymoquinone (0.2 mL/kg (IRTQ group. Tissue samples taken from the lungs of rats were histochemically stained with H&E and immunohistochemically stained with p53, Bcl 2, Bax, and caspase 3 primer antibodies. Results: Increased expression of p53 and Bax was observed (4+, especially in the I/R group. In IRTQ and IRL groups, expression was also observed at various locations (2+, 3+. H&E staining revealed that that the lungs were severely damaged and the walls of the alveoli were too thick, the number of areas examined was increased during the evaluation. Caspase 3 expression was observed to

  6. Effects of thyroid hormone analogue and a leukotrienes pathway-blocker on renal ischemia/reperfusion injury in mice

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    Hadi Najah R

    2011-12-01

    Full Text Available Abstract Background Acute renal failure (ARF is an important clinical problem with a high mortality and morbidity. One of the primary causes of ARF is ischemia/reperfusion (I/R. Inflammatory process and oxidative stress are thought to be the major mechanisms causing I/R. MK-886 is a potent inhibitor of leukotrienes biosynthesis which may have anti-inflammatory and antioxidant effects through inhibition of polymorphonuclear leukocytes (PMNs infiltration into renal tissues. 3, 5-diiodothyropropionic acid (DITPA have evidences of improving effects on I/R in heart through modulation of cellular signaling in response to ischemic stress. The objective of present study was to assess the effects of MK-886 and DITPA on renal I/R injury. Methods A total of 24 Adult males of Swiss albino mice were randomized to four groups: I/R group (n = 6, mice underwent 30 minute bilateral renal ischemia and 48 hr reperfusion. Sham group (n = 6, mice underwent same anesthetic and surgical procedures except for ischemia induction. MK-886-treated group: (n = 6, I/R + MK-886 (6 mg/kg by intraperitoneal injection. DITPA-treated group: (n = 6, I/R + DITPA (3.75 mg/kg by intraperitoneal injection. After the end of reperfusion phase mice were sacrificed, blood samples were collected directly from the heart for determination of serum TNF-a, IL-6, urea and Creatinine. Both kidney were excised, the right one homogenized for oxidative stress parameters (MDA and GSH measurements and the left kidney fixed in formalin for histological examination. Results Serum TNF-α, IL-6, urea and Creatinine, kidney MDA levels and scores of histopathological changes were significantly (P 0.05 changes in levels of all study parameters as compared with that of I/R group. Conclusion The results of the present study show that MK-886 significantly ameliorated kidney damage that resulted from I/R. For DITPA, as its administration might not be successful, administration using a different protocol may

  7. Carbon Monoxide Protects against Hepatic Ischemia/Reperfusion Injury via ROS-Dependent Akt Signaling and Inhibition of Glycogen Synthase Kinase 3β

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    Hyo Jeong Kim

    2013-01-01

    Full Text Available Carbon monoxide (CO may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3 and phosphatidylinositol 3-kinase (PI3K-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.

  8. Carbon monoxide protects against hepatic ischemia/reperfusion injury via ROS-dependent Akt signaling and inhibition of glycogen synthase kinase 3β.

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    Kim, Hyo Jeong; Joe, Yeonsoo; Kong, Jin Sun; Jeong, Sun-Oh; Cho, Gyeong Jae; Ryter, Stefan W; Chung, Hun Taeg

    2013-01-01

    Carbon monoxide (CO) may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R) injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β) in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.

  9. Cardiac Imaging Using Clinical 1.5 T MRI Scanners in a Murine Ischemia/Reperfusion Model

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    Jakob G. J. Voelkl

    2011-01-01

    Full Text Available To perform cardiac imaging in mice without having to invest in expensive dedicated equipment, we adapted a clinical 1.5 Tesla (T magnetic resonance imaging (MRI scanner for use in a murine ischemia/reperfusion model. Phase-sensitive inversion recovery (PSIR sequence facilitated the determination of infarct sizes in vivo by late gadolinium enhancement. Results were compared to histological infarct areas in mice after ischemia/reperfusion procedure with a good correlation (=0.807, <.001. In addition, fractional area change (FAC was assessed with single slice cine MRI and was matched to infarct size (=−0.837 and fractional shortening (FS measured with echocardiography (=0.860; both <.001. Here, we demonstrate the use of clinical 1.5 MRI scanners as a feasible method for basic phenotyping in mice. These widely available scanners are capable of investigating in vivo infarct dimensions as well as assessment of cardiac functional parameters in mice with reasonable throughput.

  10. Protective effects of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate in bladder ischemia-reperfusion injury in rats.

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    Yucel, Mehmet; Kucuk, Aysegul; Bayraktar, Aslihan Cavunt; Tosun, Murat; Yalcinkaya, Soner; Hatipoglu, Namik Kemal; Erkasap, Nilufer; Kavutcu, Mustafa

    2013-10-01

    The aim of the present study was to evaluate the protective effects of the NF-кB inhibition with pyrrolidine-dithiocarbamate (PDTC) in ischemia-reperfusion (I/R) injury in the rat bladder. Twenty-four Sprague-Dawley male rats were divided into three groups. Group I; (n = 8) control, group II; (n = 8) I/R group; group III (n = 8) I/R and PDTC treatment. Superoxide dismutase (SOD), catalase (CAT), and gluatathione-S-transferase (GST) enzymes was studied in bladder tissue. Lipid peroxidation (as TBARS) levels in tissue homogenate were measured with thiobarbituric acid reaction. All the slides were stained with NF-кB, p53 and HSP60 immunohistochemistry for detection genome destruction and tissue stress, respectively. Our results show that the mean TBARS levels were significantly higher in group II (p effects on ischemia/reperfusion stress related bladder tissue destruction.

  11. Knockout of the interleukin-36 receptor protects against renal ischemia-reperfusion injury by reduction of proinflammatory cytokines.

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    Nishikawa, Hirofumi; Taniguchi, Yoshinori; Matsumoto, Tatsuki; Arima, Naoki; Masaki, Mamoru; Shimamura, Yoshiko; Inoue, Kosuke; Horino, Taro; Fujimoto, Shimpei; Ohko, Kentaro; Komatsu, Toshihiro; Udaka, Keiko; Sano, Shigetoshi; Terada, Yoshio

    2018-03-01

    IL-36, a newly named member of the IL-1 cytokine family, includes 3 isoforms, IL-36α, IL-36β, and IL-36γ, all of which bind to a heterodimer containing the IL-36 receptor (IL-36R). Little is known about the role of the IL-36 axis in acute kidney injury (AKI) pathogenesis. Therefore, we evaluated IL-36 function in the bilateral renal ischemia-reperfusion injury model of AKI using IL-36R knockout and wild-type mice. IL-36R was found to be expressed in the kidney, mainly in proximal tubules. In IL-36R knockout mice, plasma creatinine, blood urea nitrogen, and IL-6 levels after ischemia-reperfusion injury were significantly lower than those in wild-type mice. Immunohistological analysis revealed mild tubular injury. IL-36α/β/γ levels were increased after ischemia-reperfusion injury, and IL-36α was expressed in lymphocytes and proximal tubular cells, but post-ischemia-reperfusion injury mRNA levels of IL-6 and TNF-α were low in IL-36R knockout mice. In primary cultures of renal tubular epithelial cells, IL-36α treatment upregulated NF-κB activity and Erk phosphorylation. Notably, in patients with AKI, urine IL-36α levels were increased, and IL-36α staining in renal biopsy samples was enhanced. Thus, IL-36α/IL-36R blockage could serve as a potential therapeutic target in AKI. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  12. Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury.

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    Laila Elsherif

    Full Text Available Mice expressing the tetracycline transactivator (tTA transcription factor driven by the rat α-myosin heavy chain promoter (α-MHC-tTA are widely used to dissect the molecular mechanisms involved in cardiac development and disease. However, these α-MHC-tTA mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury in both in vitro and in vivo models in the absence of associated cardiac hypertrophy or remodeling. Cardiac function, as assessed by echocardiography, did not differ between α-MHC-tTA and control animals, and there were no noticeable differences observed between the two groups in HW/TL ratio or LV end-diastolic and end-systolic dimensions. Protection against ischemia/reperfusion injury was assessed using isolated perfused hearts where α-MHC-tTA mice had robust protection against ischemia/reperfusion injury which was not blocked by pharmacological inhibition of PI3Ks with LY294002. Furthermore, α-MHC-tTA mice subjected to coronary artery ligation exhibited significantly reduced infarct size compared to control animals. Our findings reveal that α-MHC-tTA transgenic mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury similar to cardiac pre- and post-conditioning effects. However, in contrast to classical pre- and post-conditioning, the α-MHC-tTA phenotype is not inhibited by the classic preconditioning inhibitor LY294002 suggesting involvement of a non-PI3K-AKT signaling pathway in this phenotype. Thus, further study of the α-MHC-tTA model may reveal novel molecular targets for therapeutic intervention during ischemic injury.

  13. The Cardioprotective Effects of Citric Acid and L-Malic Acid on Myocardial Ischemia/Reperfusion Injury

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    Tang, Xilan; Liu, Jianxun; Dong, Wei; Li, Peng; Li, Lei; Lin, Chengren; Zheng, Yongqiu; Hou, Jincai; Li, Dan

    2013-01-01

    Organic acids in Chinese herbs, the long-neglected components, have been reported to possess antioxidant, anti-inflammatory, and antiplatelet aggregation activities; thus they may have potentially protective effect on ischemic heart disease. Therefore, this study aims to investigate the protective effects of two organic acids, that is, citric acid and L-malic acid, which are the main components of Fructus Choerospondiatis, on myocardial ischemia/reperfusion injury and the underlying mechanisms. In in vivo rat model of myocardial ischemia/reperfusion injury, we found that treatments with citric acid and L-malic acid significantly reduced myocardial infarct size, serum levels of TNF-α, and platelet aggregation. In vitro experiments revealed that both citric acid and L-malic acid significantly reduced LDH release, decreased apoptotic rate, downregulated the expression of cleaved caspase-3, and upregulated the expression of phosphorylated Akt in primary neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation injury. These results suggest that both citric acid and L-malic acid have protective effects on myocardial ischemia/reperfusion injury; the underlying mechanism may be related to their anti-inflammatory, antiplatelet aggregation and direct cardiomyocyte protective effects. These results also demonstrate that organic acids, besides flavonoids, may also be the major active ingredient of Fructus Choerospondiatis responsible for its cardioprotective effects and should be attached great importance in the therapy of ischemic heart disease. PMID:23737849

  14. Effects of Remote Ischemic Conditioning Methods on Ischemia-Reperfusion Injury in Muscle Flaps: An Experimental Study in Rats

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    Durdane Keskin

    2017-09-01

    Full Text Available Background The aim of this study was to investigate the effects of remote ischemic conditioning on ischemia-reperfusion injury in rat muscle flaps histopathologically and biochemically. Methods Thirty albino rats were divided into 5 groups. No procedure was performed in the rats in group 1, and only blood samples were taken. A gracilis muscle flap was elevated in all the other groups. Microclamps were applied to the vascular pedicle for 4 hours in order to achieve tissue ischemia. In group 2, no additional procedure was performed. In groups 3, 4, and 5, the right hind limb was used and 3 cycles of ischemia-reperfusion for 5 minutes each (total, 30 minutes was applied with a latex tourniquet (remote ischemic conditioning. In group 3, this procedure was performed before flap elevation (remote ischemic preconditoning. In group 4, the procedure was performed 4 hours after flap ischemia (remote ischemic postconditioning. In group 5, the procedure was performed after the flap was elevated, during the muscle flap ischemia episode (remote ischemic perconditioning. Results The histopathological damage score in all remote conditioning ischemia groups was lower than in the ischemic-reperfusion group. The lowest histopathological damage score was observed in group 5 (remote ischemic perconditioning. Conclusions The nitric oxide levels were higher in the blood samples obtained from the remote ischemic perconditioning group. This study showed the effectiveness of remote ischemic conditioning procedures and compared their usefulness for preventing ischemia-reperfusion injury in muscle flaps.

  15. Neuroprotective capabilities of TSA against cerebral ischemia/reperfusion injury via PI3K/Akt signaling pathway in rats.

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    Ma, Xiao-Hui; Gao, Qiang; Jia, Zhen; Zhang, Ze-Wei

    2015-02-01

    Hundreds of previous studies demonstrated the cytoprotective effect of trichostatin-A (TSA), a kind of histone deacetylases inhibitors (HDACIs), against cerebral ischemia/reperfusion insult. Meanwhile, phosphatidylinositol-3 kinase/Akt (PI3K/Akt) is a well-known, important signaling pathway that mediates neuroprotection. However, it should be remains unclear whether the neuroprotective capabilities of TSA against cerebral ischemia/reperfusion is mediated by activation of the PI3K/Akt signaling pathway. Five groups rats (n = 12 each), with middle cerebral artery occlusion (MCAO) except sham group, were used to investigate the neuroprotective effect of certain concentration (0.05 mg/kg) of TSA, and whether the neuroprotective effect of TSA is associated with activation of the PI3K/Akt signaling pathway through using of wortmannin (0.25 mg/kg). TSA significantly increased the expression of p-Akt protein, reduced infarct volume, and attenuated neurological deficit in rats with transient MCAO, wortmannin weakened such effect of TSA dramatically. TSA could significantly decrease the neurological deficit scores and reduce the cerebral infarct volume during cerebral ischemia/reperfusion injury, which was achieved partly by activation of the PI3K/Akt signaling pathway via upgrading of p-Akt protein.

  16. Correlation of QRS complex after percutaneous coronary intervention with myocardial ischemia reperfusion injury and apoptosis molecule contents

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    Ming-Min Jiang

    2017-11-01

    Full Text Available Objective: To study the correlation of QRS complex after percutaneous coronary intervention (PCI with myocardial ischemia reperfusion injury and apoptosis molecule contents. Methods: Patients with non-ST-segment elevation myocardial infarction who were treated in Nanchong Central Hospital between June 2014 and August 2016 were selected and divided into the PCI group who received emergency PCI surgery and the control group who accepted selective PCI or refused emergency PCI after the medical data were retrospectively analyzed. The fQRS as well as the contents of ischemia reperfusion injury indexes and apoptosis molecules was determined after 1 week of treatment. Results: The incidence of fQRS in PCI group was significantly lower than that in control group; serum MDA, cTnI, H-FABP, sTWEAK, sFas, sTRAIL and Caspase-3 contents as well as peripheral blood Nrf-2 and HO-1 expression of PCI group were greatly lower than those of control group; serum MDA, cTnI, H-FABP, sTWEAK, sFas, sTRAIL and Caspase-3 contents as well as peripheral blood Nrf-2 and HO-1 expression of PCI group of patients with fQRS complex (+ were greatly higher than those of patients with fQRS complex (-. Conclusion: The occurrence of fQRS after PCI is closely related to myocardial ischemia reperfusion injury and apoptosis.

  17. Blood rheology of angina pectoris patients with myocardial injury after ischemia reperfusion and its effect on thromboxane B2 levels.

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    Wang, Wenlong; Huang, Xiaohui; Sun, Yiyong; Zhang, Jinying

    2018-01-01

    This study investigated the changes in the blood rheology of patients with angina pectoris and ischemia reperfusion injury and their effect on thromboxane B 2 (TXB 2 ) levels to examine their relationship. Forty patients with unstable angina pectoris who underwent elective percutaneous coronary intervention (PCI) were selected for the unstable angina group (UA group) and forty patients deemed free of coronary heart disease by coronary angiography were selected for the control group. Venous blood samples were drawn from all participants; patients in the UA group had blood drawn 1 day before and 1 day after the PCI procedure. Blood samples were used to analyze blood rheology and examine hemodynamic parameters, at the same time radioimmunoassay was applied to measure the concentrations of serum endothelin-1 (ET-1) and TXB 2 , and an automatic biochemical analyzer was used to detect the content of superoxide dismutase (SOD) and malondialdehyde (MDA). Our results showed the patients in the UA group all presented hyperviscosity; however the levels were higher for the patients in the UA group (after surgery) than for those in the UA group (before surgery). Patients in the control group exhibited normal levels, and the differences among groups were significant in pairwise comparisons (Pangina pectoris and ischemia reperfusion injury. The higher than normal TXB 2 levels can be used as a marker of platelet activation and a reference for clinical risk stratification, thus having great significance for the prevention and treatment of ischemia reperfusion injury and assessment of disease progression.

  18. Protective effect of tetraethyl pyrazine against focal cerebral ischemia/reperfusion injury in rats: therapeutic time window and its mechanism.

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    Jia, Jie; Zhang, Xi; Hu, Yong-Shan; Wu, Yi; Wang, Qing-Zhi; Li, Na-Na; Wu, Cai-Qin; Yu, Hui-Xian; Guo, Qing-Chuan

    2009-03-01

    Tetramethyl pyrazine has been considered an effective agent in treating neurons ischemia/reperfusion injury, but the mechanism of its therapeutic effect remains unclear. This study was to explore the therapeutic time window and mechanism of tetramethyl pyrazine on temporary focal cerebral ischemia/reperfusion injury. Middle cerebral artery occlusion was conducted in male Sprague-Dawley rats and 20 mg/kg of tetramethyl pyrazine was intraperitoneally injected at different time points. At 72 h after reperfusion, all animals' neurologic deficit scores were evaluated. Cerebrums were removed and cerebral infarction volume was measured. The expression of thioredoxin and thioredoxin reductase mRNA was determined at 6 and 24 h after reperfusion. Cerebral infarction volume and neurological deficit scores were significantly decreased in the group with tetramethyl pyrazine treatment. The expression of thioredoxin-1/thioredoxin-2 and thioredoxin reductase-1/thioredoxin reductase-2 was significantly decreased in rats with ischemia/reperfusion injury, while it was increased by tetramethyl pyrazine administration. Treatment with tetramethyl pyrazine, within 4 h after reperfusion, protects the brain from ischemic reperfusion injury in rats. The neuroprotective mechanism of tetramethyl pyrazine treatment is, in part, mediated through the upregulation of thioredoxin transcription.

  19. Effects of Remote Ischemic Conditioning Methods on Ischemia-Reperfusion Injury in Muscle Flaps: An Experimental Study in Rats.

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    Keskin, Durdane; Unlu, Ramazan Erkin; Orhan, Erkan; Erkilinç, Gamze; Bogdaycioglu, Nihal; Yilmaz, Fatma Meric

    2017-09-01

    The aim of this study was to investigate the effects of remote ischemic conditioning on ischemia-reperfusion injury in rat muscle flaps histopathologically and biochemically. Thirty albino rats were divided into 5 groups. No procedure was performed in the rats in group 1, and only blood samples were taken. A gracilis muscle flap was elevated in all the other groups. Microclamps were applied to the vascular pedicle for 4 hours in order to achieve tissue ischemia. In group 2, no additional procedure was performed. In groups 3, 4, and 5, the right hind limb was used and 3 cycles of ischemia-reperfusion for 5 minutes each (total, 30 minutes) was applied with a latex tourniquet (remote ischemic conditioning). In group 3, this procedure was performed before flap elevation (remote ischemic preconditoning). In group 4, the procedure was performed 4 hours after flap ischemia (remote ischemic postconditioning). In group 5, the procedure was performed after the flap was elevated, during the muscle flap ischemia episode (remote ischemic perconditioning). The histopathological damage score in all remote conditioning ischemia groups was lower than in the ischemic-reperfusion group. The lowest histopathological damage score was observed in group 5 (remote ischemic perconditioning). The nitric oxide levels were higher in the blood samples obtained from the remote ischemic perconditioning group. This study showed the effectiveness of remote ischemic conditioning procedures and compared their usefulness for preventing ischemia-reperfusion injury in muscle flaps.

  20. Neuroprotective effect of TAT-14-3-3ε fusion protein against cerebral ischemia/reperfusion injury in rats.

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    Yuanjun Zhu

    Full Text Available Stroke is the major cause of death and disability worldwide, and the thrombolytic therapy currently available was unsatisfactory. 14-3-3ε is a well characterized member of 14-3-3 family, and has been reported to protect neurons against apoptosis in cerebral ischemia. However, it cannot transverse blood brain barrier (BBB due to its large size. A protein transduction domain (PTD of HIV TAT protein, is capable of delivering a large variety of proteins into the brain. In this study, we generated a fusion protein TAT-14-3-3ε, and evaluated its potential neuroprotective effect in rat focal ischemia/reperfusion (I/R model. Western blot analysis validated the efficient transduction of TAT-14-3-3ε fusion protein into brain via a route of intravenous injection. TAT-14-3-3ε pre-treatment 2 h before ischemia significantly reduced cerebral infarction volume and improved neurologic score, while post-treatment 2 h after ischemia was less effective. Importantly, pre- or post-ischemic treatment with TAT-14-3-3ε significantly increased the number of surviving neurons as determined by Nissl staining, and attenuated I/R-induced neuronal apoptosis as showed by the decrease in apoptotic cell numbers and the inhibition of caspase-3 activity. Moreover, the introduction of 14-3-3ε into brain by TAT-mediated delivering reduced the formation of autophagosome, attenuated LC3B-II upregulation and reversed p62 downregulation induced by ischemic injury. Such inhibition of autophagy was reversed by treatment with an autophagy inducer rapamycin (RAP, which also attenuated the neuroprotective effect of TAT-14-3-3ε. Conversely, autophagy inhibitor 3-methyladenine (3-MA inhibited I/R-induced the increase in autophagic activity, and attenuated I/R-induced brain infarct. These results suggest that TAT-14-3-3ε can be efficiently transduced into brain and exert significantly protective effect against brain ischemic injury through inhibiting neuronal apoptosis and autophagic

  1. Limb Remote Ischemic Postconditioning Reduces Ischemia-Reperfusion Injury by Inhibiting NADPH Oxidase Activation and MyD88-TRAF6-P38MAP-Kinase Pathway of Neutrophils

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    Gangling Chen

    2016-11-01

    Full Text Available Limb remote ischemic postconditioning (LRIP has been confirmed to reduce the ischemia-reperfusion injury but its mechanisms are still not clear. This study clarified the mechanism of LRIP based on the nicotinamide-adenine dinucleotide phosphate (NADPH oxidase and Myeloid differentiation factor 88 (MyD88-Tumor necrosis factor (TNF receptor-associated factor 6 (TRAF6-P38 pathway of neutrophils. Rat middle cerebral artery occlusion (MCAO model was used in this study. Ischemia-reperfusion injury was carried out by MCAO 1.5 h followed by 24 h reperfusion. LRIP operation was performed to the left femoral artery at 0, 1 or 3 h after reperfusion. Behavioral testing, including postural reflex test, vibrissae-elicited forelimb placing test and tail hang test, showed that LRIP operated at 0 h of reperfusion could significantly ameliorate these behavioral scores. Pathological examinations, infarct size, Myeloperoxidase (MPO activity showed that LRIP operated at 0 h of reperfusion could significantly ameliorate the pathological scores, reduce the infarct size and MPO activity in the brain and increase the MPO activity in the left leg. By using Neutrophil counting, immunofluorescence and real-time PCR techniques, we found that LRIP operated at 0 h of reperfusion could reduce neutrophil counts in the peripheral blood and downregulate the activation of neutrophil in the peripheral blood and rat brain. Western blots revealed that MyD88, TRAF6, p38 mitogen-activated protein kinase (p38-MAPK in neutrophils and the phosphorylation of p47phox (Ser 304 and Ser 345 in neutrophil could be downregulated by LRIP. Our study suggests that LRIP inhibits the number and activation of neutrophils in the rat brain and peripheral blood linked to down-regulating the activation of NADPH oxidase in neutrophils by MyD88/TRAF6/p38-MAPK pathway.

  2. KCNMA1 encoded cardiac BK channels afford protection against ischemia-reperfusion injury.

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    Ewa Soltysinska

    Full Text Available Mitochondrial potassium channels have been implicated in myocardial protection mediated through pre-/postconditioning. Compounds that open the Ca2+- and voltage-activated potassium channel of big-conductance (BK have a pre-conditioning-like effect on survival of cardiomyocytes after ischemia/reperfusion injury. Recently, mitochondrial BK channels (mitoBKs in cardiomyocytes were implicated as infarct-limiting factors that derive directly from the KCNMA1 gene encoding for canonical BKs usually present at the plasma membrane of cells. However, some studies challenged these cardio-protective roles of mitoBKs. Herein, we present electrophysiological evidence for paxilline- and NS11021-sensitive BK-mediated currents of 190 pS conductance in mitoplasts from wild-type but not BK-/- cardiomyocytes. Transmission electron microscopy of BK-/- ventricular muscles fibres showed normal ultra-structures and matrix dimension, but oxidative phosphorylation capacities at normoxia and upon re-oxygenation after anoxia were significantly attenuated in BK-/- permeabilized cardiomyocytes. In the absence of BK, post-anoxic reactive oxygen species (ROS production from cardiomyocyte mitochondria was elevated indicating that mitoBK fine-tune the oxidative state at hypoxia and re-oxygenation. Because ROS and the capacity of the myocardium for oxidative metabolism are important determinants of cellular survival, we tested BK-/- hearts for their response in an ex-vivo model of ischemia/reperfusion (I/R injury. Infarct areas, coronary flow and heart rates were not different between wild-type and BK-/- hearts upon I/R injury in the absence of ischemic pre-conditioning (IP, but differed upon IP. While the area of infarction comprised 28±3% of the area at risk in wild-type, it was increased to 58±5% in BK-/- hearts suggesting that BK mediates the beneficial effects of IP. These findings suggest that cardiac BK channels are important for proper oxidative energy supply of

  3. Effects of the Rabdosia rubescens total flavonoids on focal cerebral ischemia reperfusion model in rats

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    Mingsan Miao

    2017-05-01

    Full Text Available The effect of the Rabdosia rubescens total flavonoids on focal cerebral ischemia reperfusion model in rats was observed. The model group, nimodipine group, cerebral collateral group, and large, medium and small dose group of the Rabdosia rubescens total flavonoids were administered with corresponding drugs but sham operation group and model group were administered the same volume of 0.5%CMC, 1 times a day, continuous administration of 7 d. After 1 h at 7 d to medicine, left incision in the middle of the neck of rats after anesthesia, we can firstly expose and isolate the left common carotid artery (CCA, and then expose external carotid artery (ECA and internal carotid artery (ICA. The common carotid artery and the external carotid artery are ligated. Then internal carotid artery with arterial clamp is temporarily clipped. Besides, cut the incision of 0.2 mm from 5 cm of the bifurcation of the common carotid artery. A thread Line bolt is inserted with more than 18–20 mm from bifurcation of CCA into the internal carotid artery until there is resistance. Then the entrance of the middle cerebral artery is blocked and internal carotid artery is ligated (the blank group only exposed the left blood vessel without Plugging wire. Finally it is gently pulled out the plug line after 2 h. Results: Compared with the model mice, Rabdosia rubescens total flavonoids can significantly relieve the injury of brain in hippocampus and cortex nerve cells; experimental rat focal cerebral ischemia was to improve again perfusion model of nerve function defect score mortality; significantly reduce brain homogenate NOS activity and no content, MDA, IL-1, TNF-a, ICAM-1 content; increase in brain homogenate SOD and ATPase activity (P < 0.05, P < 0.01; and reduce the serum S-100β protein content. Each dose group of the Rabdosia rubescens total flavonoids has a better Improvement effect on focal cerebral ischemia reperfusion model in rats.

  4. Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis.

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    Vilatoba, Mario; Eckstein, Christopher; Bilbao, Guadalupe; Smyth, Cheryl A; Jenkins, Stacie; Thompson, J Anthony; Eckhoff, Devin E; Contreras, Juan L

    2005-08-01

    Evidence is emerging that the endoplasmic reticulum (ER) participates in initiation of apoptosis induced by the unfolded protein response and by aberrant Ca(++) signaling during cellular stress such as ischemia/reperfusion injury (I/R injury). ER-induced apoptosis involves the activation of caspase-12 and C/EBP homologous protein (CHOP), and the shutdown of translation initiated by phosphorylation of eIF2alpha. Sodium 4-phenylbutyrate (PBA) is a low molecular weight fatty acid that acts as a chemical chaperone reducing the load of mutant or unfolded proteins retained in the ER during cellular stress and also exerting anti-inflammatory activity. It has been used successfully for treatment of urea cycle disorders and sickle cell disease. Thus, we hypothesized that PBA may reduce ER-induced apoptosis triggered by I/R injury to the liver. Groups of male C57BL/6 mice were subjected to warm ischemia (70% of the liver mass, 45 minutes). Serum aspartate aminotransferase was assessed 6 hours after reperfusion; apoptosis was evaluated by enzyme-linked immunosorbent assays of caspase-12 and plasma tumor necrosis factor alpha, Western blot analyses of eIF2alpha, and reverse transcriptase-polymerase chain reaction of CHOP expression. A dose-dependent decrease in aspartate aminotransferase was demonstrated in mice given intraperitoneal PBA (1 hour before and 12 hours after reperfusion), compared with vehicle-treated controls; this effect was associated with reduced pyknosis, parenchymal hemorrhages, and neutrophil infiltrates in PBA-treated mice, compared with controls. In a lethal model of total liver I/R injury, all vehicle-treated controls died within 3 days after reperfusion. In contrast, 50% survival (>30 days) was observed in animals given PBA. The beneficial effects of PBA were associated with a greater than 45% reduction in apoptosis, decreased ER-mediated apoptosis characterized by significant reduction in caspase-12 activation, and reduced levels of both phosphorylated

  5. Dual Gas Treatment With Hydrogen and Carbon Monoxide Attenuates Oxidative Stress and Protects From Renal Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Nishida, T; Hayashi, T; Inamoto, T; Kato, R; Ibuki, N; Takahara, K; Takai, T; Yoshikawa, Y; Uchimoto, T; Saito, K; Tanda, N; Kouno, J; Minami, K; Uehara, H; Hirano, H; Nomi, H; Okada, Y; Azuma, H

    Hydrogen (H 2 ) and carbon monoxide (CO) gas are both reported to reduce reactive oxygen species and alleviate tissue ischemia-reperfusion (I-R) injury. The present study was conducted to evaluate the effects of a mixture of H 2 gas and CO gas (dual gas) in comparison with hydrogen gas (H 2 : 2%) alone on I-R renal injury (composition of dual gas; N 2 : 77.8%; O 2 : 20.9%; H 2 : 1.30%; CO: 250 parts per million). Adult male Sprague-Dawley rats (body weight 250-280 g) were divided into 5 groups: (1) sham operation control, (2) dual gas inhalation (dual treatment) without I-R treatment, (3) I-R renal injury, (4) H 2 gas alone inhalation (H 2 treatment) with I-R renal injury, and (5) dual treatment with I-R renal injury. I-R renal injury was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, and then contralateral nephrectomy was performed 2 weeks later. Renal function was markedly decreased at 24 hours after reperfusion, and thereafter the effects of dual gas were assessed by histologic examination and determination of the superoxide radical, together with functional and molecular analyses. Pathologic examination of the kidney of I-R rats revealed severe renal damage. Importantly, cytoprotective effects of the dual treatment in comparison with H 2 treatment and I-R renal injury were observed in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment and I-R renal injury showed significant decreases in blood urea nitrogen. Increased expression of several inflammatory cytokines (tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, nuclear factor-κB, hypoxia inducible factor-1α, and heme oxygenase-1) was attenuated by the dual treatment. Dual gas inhalation decreases oxidative stress and markedly improves I-R-induced renal injury. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Intra-Abdominal Cooling System Limits Ischemia-Reperfusion Injury During Robot-Assisted Renal Transplantation.

    Science.gov (United States)

    Meier, R P H; Piller, V; Hagen, M E; Joliat, C; Buchs, J-B; Nastasi, A; Ruttimann, R; Buchs, N C; Moll, S; Vallée, J-P; Lazeyras, F; Morel, P; Bühler, L

    2018-01-01

    Robot-assisted kidney transplantation is feasible; however, concerns have been raised about possible increases in warm ischemia times. We describe a novel intra-abdominal cooling system to continuously cool the kidney during the procedure. Porcine kidneys were procured by standard open technique. Groups were as follows: Robotic renal transplantation with (n = 11) and without (n = 6) continuous intra-abdominal cooling and conventional open technique with intermittent 4°C saline cooling (n = 6). Renal cortex temperature, magnetic resonance imaging, and histology were analyzed. Robotic renal transplantation required a longer anastomosis time, either with or without the cooling system, compared to the open approach (70.4 ± 17.7 min and 74.0 ± 21.5 min vs. 48.7 ± 11.2 min, p-values system compared to the open approach group (6.5 ± 3.1°C vs. 22.5 ± 6.5°C; p = 0.001) or compared to the robotic group without the cooling system (28.7 ± 3.3°C; p system that suppresses the noncontrolled rewarming of donor kidneys during the transplant procedure and prevents ischemia-reperfusion injuries. © 2017 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.

  7. Curcumin-carrying nanoparticles prevent ischemia-reperfusion injury in human renal cells.

    Science.gov (United States)

    Xu, Yong; Hu, Ning; Jiang, Wei; Yuan, Hong-Fang; Zheng, Dong-Hui

    2016-12-27

    Renal ischemia-reperfusion injury (IRI) is a major complication in clinical practice. However, despite its frequency, effective preventive/treatment strategies for this condition are scarce. Curcumin possesses antioxidant properties and is a promising potential protective agent against renal IRI, but its poor water solubility restricts its application. In this study, we constructed curcumin-carrying distearoylphosphatidylethanolamine-polyethylene glycol nanoparticles (Cur-NPs), and their effect on HK-2 cells exposed to IRI was examined in vitro. Curcumin encapsulated in NPs demonstrated improved water solubility and slowed release. Compared with the IRI and Curcumin groups, Cur-NP groups displayed significantly improved cell viability, downregulated protein expression levels of caspase-3 and Bax, upregulated expression of Bcl-2 protein, increased antioxidant superoxide dismutase level, and reduced apoptotic rate, reactive oxygen species level, and malondialdehyde content. Results clearly showed that Cur-NPs demonstrated good water solubility and slow release, as well as exerted protective effects against oxidative stress in cultured HK-2 cells exposed to IRI.

  8. The Neuroprotective Effect of Kefir on Spinal Cord Ischemia/Reperfusion Injury in Rats

    Science.gov (United States)

    Akman, Tarik; Yener, Ali Umit; Sehitoglu, Muserref Hilal; Yuksel, Yasemin; Cosar, Murat

    2015-01-01

    Objective The main causes of spinal cord ischemia are a variety of vascular pathologies causing acute arterial occlusions. We investigated neuroprotective effects of kefir on spinal cord ischemia injury in rats. Methods Rats were divided into three groups : 1) sham operated control rats; 2) spinal cord ischemia group fed on a standard diet without kefir pretreatment; and 3) spinal cord ischemia group fed on a standard diet plus kefir. Spinal cord ischemia was performed by the infrarenal aorta cross-clamping model. The spinal cord was removed after the procedure. The biochemical and histopathological changes were observed within the samples. Functional assessment was performed for neurological deficit scores. Results The kefir group was compared with the ischemia group, a significant decrease in malondialdehyde levels was observed (pkefir group were significantly higher than ischemia group (pkefir group is compared with ischemia group, there was a significant decrease in numbers of dead and degenerated neurons (pkefir group compared with ischemia group (pkefir group were significantly higher than ischemia group at 24 h (pkefir pretreatment in spinal cord ischemia/reperfusion reduced oxidative stress and neuronal degeneration as a neuroprotective agent. Ultrastructural studies are required in order for kefir to be developed as a promising therapeutic agent to be utilized for human spinal cord ischemia in the future. PMID:26113960

  9. The effect of ozone and naringin on intestinal ischemia/reperfusion injury in an experimental model.

    Science.gov (United States)

    Isik, Arda; Peker, Kemal; Gursul, Cebrail; Sayar, Ilyas; Firat, Deniz; Yilmaz, Ismayil; Demiryilmaz, Ismail

    2015-09-01

    The aim of the study was to evaulate the effect of ozone and naringin on the intestine after intestinal ischemia-reperfusion(II/R) injury. Thirty five rats divided into 5 groups of 7 animals: control, II/R, ozone, naringin and naringin + ozone. Only laparotomy and exploration of the superior mesenteric artery (SMA) were done in control group. In the experimental groups, SAM was occluded for 1 h and reperfused for 1 h. 15 min after ischemia, ozone (25 μg/ml, 0.5 mg/kg), naringin (80 mg/kg) and naringin + ozone(80 mg/kg + 25 μg/ml, 0.5 mg/kg) were infused intraperitoneally to each groups. Ileum tissues were harvested to determine intestinal mucosal injury and oxidative stress markers. For SMA occlusion, different than literature, silk suture binding was used. Oxidative stress markers were significantly low in experimental groups compared with II/R group (p < 0.05). Histopathologically, the injury score was significantly low at experimental groups compared with II/R group (p < 0.05). The lowest injury score was encountered at naringine + ozone group. Ozone alone or combined with naringin has a protective effect for mesenteric ischemia. Instead of using instruments such as clamps in the II/R rat model, silk binding may be used safely. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

  10. Heterozygosity for fibrinogen results in efficient resolution of kidney ischemia reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Amrendra Kumar Ajay

    Full Text Available Fibrinogen (Fg has been recognized to play a central role in coagulation, inflammation and tissue regeneration. Several studies have used Fg deficient mice (Fg(-/- in comparison with heterozygous mice (Fg(+/- to point the proinflammatory role of Fg in diverse pathological conditions and disease states. Although Fg(+/- mice are considered 'normal', plasma Fg is reduced to ~75% of the normal circulating levels present in wild type mice (Fg(+/+. We report that this reduction in Fg protein production in the Fg(+/- mice is enough to protect them from kidney ischemia reperfusion injury (IRI as assessed by tubular injury, kidney dysfunction, necrosis, apoptosis and inflammatory immune cell infiltration. Mechanistically, we observed binding of Fg to ICAM-1 in kidney tissues of Fg(+/+ mice at 24 h following IRI as compared to a complete absence of binding observed in the Fg(+/- and Fg(-/- mice. Raf-1 and ERK were highly activated as evident by significantly higher phosphorylation in the Fg(+/+ kidneys at 24 h following IRI as compared to Fg(+/- and Fg(-/- mice kidneys. On the other hand Cyclin D1 and pRb, indicating higher cell proliferation, were significantly increased in the Fg(+/- and Fg(-/- as compared to Fg(+/+ kidneys. These data suggest that Fg heterozygosity allows maintenance of a critical balance of Fg that enables regression of initial injury and promotes faster resolution of kidney damage.

  11. Quantitative cardiac phosphoproteomics profiling during ischemia-reperfusion in an immature swine model

    Energy Technology Data Exchange (ETDEWEB)

    Ledee, Dolena R.; Kang, Min A.; Kajimoto, Masaki; Purvine, Samuel O.; Brewer, Heather M.; Pasa Tolic, Ljiljana; Portman, Michael A.

    2017-07-01

    Ischemia-reperfusion (I/R) results in altered metabolic and molecular responses, and phosphorylation is one of the most noted regulatory mechanisms mediating signaling mechanisms during physiological stresses. To expand our knowledge of the potential phosphoproteomic changes in the myocardium during I/R, we used Isobaric Tags for Relative and Absolute Quantitation-based analyses in left ventricular samples obtained from porcine hearts under control or I/R conditions. The data are available via ProteomeXchange with identifier PXD006066. We identified 1,896 phosphopeptides within left ventricular control and I/R porcine samples. Significant differential phosphorylation between control and I/R groups was discovered in 111 phosphopeptides from 86 proteins. Analysis of the phosphopeptides using Motif-x identified five motifs: (..R..S..), (..SP..), (..S.S..), (..S…S..), and (..S.T..). Semiquantitative immunoblots confirmed site location and directional changes in phosphorylation for phospholamban and pyruvate dehydrogenase E1, two proteins known to be altered by I/R and identified by this study. Novel phosphorylation sites associated with I/R were also identified. Functional characterization of the phosphopeptides identified by our methodology could expand our understanding of the signaling mechanisms involved during I/R damage in the heart as well as identify new areas to target therapeutic strategies.

  12. S-Adenosylmethionine attenuates bile duct early warm ischemia reperfusion injury after rat liver transplantation.

    Science.gov (United States)

    Tang, Yong; Chu, Hongpeng; Cao, Guojun; Du, Xiaolong; Min, Xiaobo; Wan, Chidan

    2018-03-01

    Warm ischemia reperfusion injury (IRI) plays a key role in biliary complication, which is a substantial vulnerability of liver transplantation. The early pathophysiological changes of IRI are characterized by an excessive inflammatory response. S-Adenosylmethionine (SAM) is an important metabolic intermediate that modulates inflammatory reactions; however, its role in bile duct warm IRI is not known. In this study, male rats were treated with or without SAM (170 μmol/kg body weight) after orthotopic autologous liver transplantation. The histopathological observations showed that bile duct injury in the IRI group was more serious than in the SAM group. The alanine aminotransferase (ALT), alkaline phosphatase (ALP) and direct bilirubin (DBIL) levels in the serum of the IRI group were significantly increased compared to the SAM group (P liver and bile duct tissues, down-regulated TNF-α levels and up-regulated IL-10 expression in bile duct tissues compared to the IRI group (P livers were much higher compared to those in SAM-treated rats at 24 h after liver transplantation (P bile ducts against warm IRI by suppressing oxidative stress, inflammatory reactions and apoptosis of biliary epithelial cells after liver transplantation.α. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. Lipoxin A4 Preconditioning and Postconditioning Protect Myocardial Ischemia/Reperfusion Injury in Rats

    Directory of Open Access Journals (Sweden)

    Qifeng Zhao

    2013-01-01

    Full Text Available This study aims to investigate the pre- and postconditioning effects of lipoxin A4 (LXA4 on myocardial damage caused by ischemia/reperfusion (I/R injury. Seventy-two rats were divided into 6 groups: sham groups (C1 and C2, I/R groups (I/R1 and I/R2, and I/R plus LXA4 preconditioning and postconditioning groups (LX1 and LX2. The serum levels of IL-1β, IL-6, IL-8, IL-10, TNF-α, and cardiac troponin I (cTnI were measured. The content and the activity of Na+-K+-ATPase as well as the superoxide dismutase (SOD, and malondialdehyde (MDA levels were determined. Along with the examination of myocardium ultrastructure and ventricular arrhythmia scores (VAS, connexin 43 (Cx43 expression were also detected. Lower levels of IL-1β, IL-6, IL-8, TNF-α, cTnI, MDA content, and VAS and higher levels of IL-10, SOD activity, Na+-K+-ATPase content and activity, and Cx43 expression appeared in LX groups than I/R groups. Besides, H&E staining, TEM examination as well as analysis of gene, and protein confirmed that LXA4 preconditioning was more effective than postconditioning in preventing arrhythmogenesis via the upregulation of Cx43. That is, LXA4 postconditioning had better protective effect on Na+-K+-ATPase and myocardial ultrastructure.

  14. Renalase as a Novel Biomarker for Evaluating the Severity of Hepatic Ischemia-Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Huili Li

    2016-01-01

    Full Text Available Hepatic ischemia-reperfusion (I/R injury is a serious complication in clinical practice. However, no efficient biomarkers are available for the evaluation of the severity of I/R injury. Recently, renalase has been reported to be implicated in the I/R injury of various organs. This protein is secreted into the blood in response to increased oxidative stress. To investigate the responsiveness of renalase to oxidative stress, we examined the changes of renalase in cell and mouse models. We observed a significant increase of renalase expression in HepG2 cells in a time- and dose-dependent manner when treated with H2O2. Renalase expression also increased significantly in liver tissues that underwent the hepatic I/R process. The increased renalase levels could be efficiently suppressed by antioxidants in vitro and in vivo. Furthermore, serum renalase levels were significantly increased in the mouse models and also efficiently suppressed by antioxidants treatment. The variation trends are consistent between renalase and liver enzymes in the mouse models. In conclusion, renalase is highly sensitive and responsive to oxidative stress in vitro and in vivo. Moreover, renalase can be detected in the blood. These properties make renalase a highly promising biomarker for the evaluation of the severity of hepatic I/R injury.

  15. Effects of iloprost and piracetam in spinal cord ischemia-reperfusion injury in the rabbit.

    Science.gov (United States)

    Kalkan, E; Keskin, F; Kaya, B; Esen, H; Tosun, M; Kalkan, S S; Erdi, F; Unlü, A; Avunduk, M C; Cicek, O

    2011-01-01

    Experimental Study. The aim of this study was to investigate the neuroprotective effects of iloprost and piracetam on spinal cord ischemia/reperfusion (I/R) injury in the rabbit. The Experimental Research Center of Selcuk University, Konya, Turkey. A total of 24 rabbits were divided into four groups of six rabbits each, as follows: group 1 (n = 6) sham, laparotomy only; group 2 (n = 6) I/R; group 3 (n = 6) I/R+iloprost; and group 4 (n = 6) I/R+piracetam. I/R was established in groups 2, 3 and 4. Subsequently, they were followed up neurologically for 24 h until the rabbits were killed; biochemical and histopathological examinations of samples from the spinal cord were carried out. Neurological examination results were significantly better in the iloprost and piracetam groups compared with the I/R group (P piracetam by suppressing malondialdehyde (P piracetam groups were statistically different from the I/R group in terms of the number of apoptotic neurons in gray matter and white matter, as well as in terms of degenerated neurons and glial cells (P 0.05). This study has shown that iloprost and piracetam have neuroprotective effects in I/R injury both neurologically and histopathologically because of inhibition of lipid peroxidation.

  16. Polyethylene glycol rinse solution: An effective way to prevent ischemia-reperfusion injury

    Science.gov (United States)

    Zaouali, Mohamed Amine; Bejaoui, Mohamed; Calvo, Maria; Folch-Puy, Emma; Pantazi, Eirini; Pasut, Gianfranco; Rimola, Antoni; Ben Abdennebi, Hassen; Adam, René; Roselló-Catafau, Joan

    2014-01-01

    AIM: To test whether a new rinse solution containing polyethylene glycol 35 (PEG-35) could prevent ischemia-reperfusion injury (IRI) in liver grafts. METHODS: Sprague-Dawley rat livers were stored in University of Wisconsin preservation solution and then washed with different rinse solutions (Ringer’s lactate solution and a new rinse solution enriched with PEG-35 at either 1 or 5 g/L) before ex vivo perfusion with Krebs-Heinseleit buffer solution. We assessed the following: liver injury (transaminase levels), mitochondrial damage (glutamate dehydrogenase activity), liver function (bile output and vascular resistance), oxidative stress (malondialdehyde), nitric oxide, liver autophagy (Beclin-1 and LCB3) and cytoskeleton integrity (filament and globular actin fraction); as well as levels of metalloproteinases (MMP2 and MMP9), adenosine monophosphate-activated protein kinase (AMPK), heat shock protein 70 (HSP70) and heme oxygenase 1 (HO-1). RESULTS: When we used the PEG-35 rinse solution, reduced hepatic injury and improved liver function were noted after reperfusion. The PEG-35 rinse solution prevented oxidative stress, mitochondrial damage, and liver autophagy. Further, it increased the expression of cytoprotective heat shock proteins such as HO-1 and HSP70, activated AMPK, and contributed to the restoration of cytoskeleton integrity after IRI. CONCLUSION: Using the rinse solution containing PEG-35 was effective for decreasing liver graft vulnerability to IRI. PMID:25473175

  17. Antioxidant and antiapoptotic effects of erdosteine in a rat model of ovarian ischemia-reperfusion injury

    Directory of Open Access Journals (Sweden)

    Vedat Ugurel

    2017-01-01

    Full Text Available Objective(s: To evaluate the protective effect of erdosteine, an antiapoptotic and antioxidant agent, on torsion–detorsion evoked histopathological changes in experimental ovarian ischemia-reperfusion (IR injury. Materials and Methods: Eighteen female Wistar albino rats were used in control, IR, and IR+Edosteine (IR-E groups, (n=6 in each. The IR-E group received the erdosteine for seven days before the induction of torsion/retorsion, (10 mg/kg/days. The IR and IR-E groups were exposed to right unilateral adnexal torsion for 3 hr. Three hours later, re-laparotomy was performed, and the right ovaries were surgically excised. Oxidant and antioxidants levels were determined in serum. The ovarian tissue samples were received and fixed with 10% neutral buffered formalin. The sections were stained with H&E, anti-PCNA, and TUNEL. Results: The IR group were showed severe acute inflammation, polynuclear leukocytes and macrophages, stromal oedema and haemorrhage. Treatment with erdosteine in rats significantly retained degenerative changes in the ovaryPCNA (+ cell numbers were significantly decreased in the IR and IR-E groups unlike the control group. However, its numbers were significantly increased in the IR-E group unlike the IR group. TUNEL (+ cell numbers were significantly increased in the IR group unlike the control and the IR-E groups. In erdosteine treated group, TUNEL (+ cells were detected significantly less than the IR group (P

  18. Mesenchymal stem cells increase antioxidant capacity in intestinal ischemia/reperfusion damage.

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    Inan, M; Bakar, E; Cerkezkayabekir, A; Sanal, F; Ulucam, E; Subaşı, C; Karaöz, E

    2017-07-01

    Mesenchymal stem cells (MSCs) may have beneficial effects in reversing intestinal damage resulting from circulatory disorders. The hypothesis of this study is that MSCs increase antioxidant capacity of small bowel tissue following intestinal ischemia reperfusion (I/R) damage. A total of 100 rats were used for the control group and three experimental groups, as follows: the sham control, local MSC, and systemic MSC groups. Each group consisted of 10 animals on days 1, 4, and 7 of the experiment. Ischemia was established by clamping the superior mesenteric artery (SMA) for 45min; following this, reperfusion was carried out for 1, 4, and 7days in all groups. In the local and systemic groups, MSCs were administered intravenously and locally just after the ischemia, and they were investigated after 1, 4, and 7days. The superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (Gpx) activities, as well as malondialdehyde (MDA) and total protein levels, were measured. Histopathological analysis was performed using light and electron microscopy. The indicators of proliferation from the effects of anti- and pro-inflammatory cytokines were evaluated using immunohistochemistry. MDA was increased (Pcytokines interleukin-1β (IL1β), transforming growth factor-β1 (TGFβ1), tumor necrosis factor-α (TNFα), IL6, MIP2, and MPO decreased (Pcytokines EP3 and IL1ra increased (poxygen radicals, suppression of pro-inflammatory cytokines, and increasing the expression of anti-inflammatory cytokines. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Protective Effect of Platelet Rich Plasma on Experimental Ischemia/Reperfusion Injury in Rat Ovary.

    Science.gov (United States)

    Bakacak, Murat; Bostanci, Mehmet Suhha; İnanc, Fatma; Yaylali, Asli; Serin, Salih; Attar, Rukset; Yildirim, Gazi; Yildirim, Ozge Kizilkale

    2016-01-01

    Ovarian torsion is a common cause of local ischemic damage, reduced follicular activity and infertility. Platelet-rich plasma (PRP) contains growth factors with demonstrated cytoprotective properties; so we evaluated PRP efficacy in a rat ischemia/reperfusion (I/R) model. Sixty adult female Sprague-Dawley albino rats were randomly assigned to 6 groups of 8 animals each: Sham, Ischemia, I/R, Sham + PRP, I + PRP and I/R + PRP; and the remaining 12 used to prepare PRP. Ischemia groups were subjected to bilateral adnexal torsion for 3 h, while I/R and I/R + PRP groups received subsequent detorsion for 3 h. Intraperitoneal PRP was administered 30 min prior to ischemia (Ischemia + PRP) or reperfusion (I/R + PRP). Total oxidant status (TOS), oxidative stress index (OSI) and total ovarian histopathological scores were higher in Ischemia and I/R groups than in the Sham group (p OSI and histopathological scores in I + PRP and I/R + PRP groups compared to the corresponding Ischemia and I/R groups (p OSI (r = 0.877, p < 0.001). Peritoneal vascular endothelial growth factor was significantly higher in PRP-treated groups than corresponding untreated groups (p < 0.05). PRP is effective for the prevention of ischemia and reperfusion damage in rat ovary. © 2015 S. Karger AG, Basel.

  20. Effect of 2-aminoethoxydiphenyl borate on ischemia-reperfusion injury in a rat ovary model.

    Science.gov (United States)

    Taskin, Mine Islimye; Hismiogullari, Adnan Adil; Yay, Arzu; Adali, Ertan; Gungor, Aysenur Cakir; Korkmaz, Gozde Ozge; Inceboz, Umit

    2014-07-01

    The aim of this study is to evaluate the effects of 2-aminoethoxydiphenyl borate (2-APB) as an antioxidant and analyze biochemical and histopathologic changes in experimental ischemia-reperfusion (I/R) injury in rat ovaries. Thirty female rats were utilized to create four groups. Group 1: I/R and 2-APB (2mg/kg); Group 2: I/R and 2-APB (4mg/kg); Group 3: I/R; Group 4: sham operation. Ovarian tissue and serum malondialdehyde, nitric oxide (NO) levels; ovarian tissue and serum total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI) were determined. In ovarian tissue samples histopathologic examination, immunoflourescence staining by TUNEL method was studied. Tissue TOS, serum TOS, and OSI levels were elevated in I/R group. After treatment with 2-APB, tissue and serum TOS levels and OSI levels were markedly decreased. There was a significant difference in terms of tissue and serum NO levels between the sham group and I/R group. Elevation in tissue NO and serum NO levels were decreased after treatment with 2-APB. TUNEL-positive cell number gradually decreased with dose of 2-APB in groups 1 and 2. Conservative treatment with 2-APB is beneficial for mitigation of I/R injury, and the ovarian protective eff