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  1. 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.

  2. Ukrain (NSC 631570) ameliorates intestinal ischemia-reperfusion-induced acute lung injury by reducing oxidative stress

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    Kocak, Cengiz; Kocak, Fatma Emel; Akcilar, Raziye; Akcilar, Aydin; Savran, Bircan; Zeren, Sezgin; Bayhan, Zulfu; Bayat, Zeynep

    2016-01-01

    Intestinal ischemia-reperfusion (I/R) causes severe destruction in remote organs. Lung damage is a frequently seen complication after intestinal I/R. Ukrain (NSC 631570) is a synthetic thiophosphate derivative of alkaloids from the extract of the celandine (Chelidonium majus L.) plant. We investigated the effect of Ukrain in animals with lung injury induced by intestinal I/R. Adult male Spraque-Dawley rats were randomly divided into four groups: control, Ukrain, I/R, I/R with Ukrain. Before intestinal I/R was induced, Ukrain was administered intraperitoneally at a dose of 7.0 mg/body weight. After 1 h ischemia and 2 h reperfusion period, lung tissues were excised. Tissue levels of total oxidative status (TOS), total antioxidant status (TAS) were measured and oxidative stress indices (OSI) were calculated. Lung tissues were also examined histopathologically. TOS and OSI levels markedly increased and TAS levels decreased in the I/R group compared to the control group (P < 0.05). TOS and OSI levels markedly decreased and TAS levels increased in the I/R with Ukrain group compared with the group subjected to IR only (P < 0.05). Severe hemorrhage, alveolar septal thickening, and leukocyte infiltration were observed in the I/R group. In the I/R with Ukrain group, morphologic changes occurring as a result of lung damage attenuated and histopathological scores reduced compared to the I/R group (P < 0.05). Our results suggest that Ukrain pretreatment could reduce lung injury induced by intestinal I/R induced via anti-inflammatory and antioxidant effects. PMID:26773189

  3. Ukrain (NSC 631570 ameliorates intestinal ischemia-reperfusion-induced acute lung injury by reducing oxidative stress

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    Cengiz Kocak

    2016-01-01

    Full Text Available Intestinal ischemia-reperfusion (I/R causes severe destruction in remote organs. Lung damage is a frequently seen complication after intestinal I/R. Ukrain (NSC 631570 is a synthetic thiophosphate derivative of alkaloids from the extract of the celandine (Chelidonium majus L. plant. We investigated the effect of Ukrain in animals with lung injury induced by intestinal I/R. Adult male Spraque-Dawley rats were randomly divided into four groups: control, Ukrain, I/R, I/R with Ukrain. Before intestinal I/R was induced, Ukrain was administered intraperitoneally at a dose of 7.0 mg/body weight. After 1 h ischemia and 2 h reperfusion period, lung tissues were excised. Tissue levels of total oxidative status (TOS, total antioxidant status (TAS were measured and oxidative stress indices (OSI were calculated. Lung tissues were also examined histopathologically. TOS and OSI levels markedly increased and TAS levels decreased in the I/R group compared to the control group (P < 0.05. TOS and OSI levels markedly decreased and TAS levels increased in the I/R with Ukrain group compared with the group subjected to IR only (P < 0.05. Severe hemorrhage, alveolar septal thickening, and leukocyte infiltration were observed  in the I/R group. In the I/R with Ukrain group, morphologic changes occurring as a result of lung damage attenuated and histopathological scores reduced compared to the I/R group (P < 0.05. Our results suggest that Ukrain pretreatment could reduce lung injury induced by intestinal I/R induced via anti-inflammatory and antioxidant effects. 

  4. Pre-Conditioning with CDP-Choline Attenuates Oxidative Stress-Induced Cardiac Myocyte Death in a Hypoxia/Reperfusion Model

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    González-Pacheco, Héctor; Méndez-Domínguez, Aurelio; Hernández, Salomón; López-Marure, Rebeca; Vazquez-Mellado, Maria J.; Aguilar, Cecilia; Rocha-Zavaleta, Leticia

    2014-01-01

    Background. CDP-choline is a key intermediate in the biosynthesis of phosphatidylcholine, which is an essential component of cellular membranes, and a cell signalling mediator. CDP-choline has been used for the treatment of cerebral ischaemia, showing beneficial effects. However, its potential benefit for the treatment of myocardial ischaemia has not been explored yet. Aim. In the present work, we aimed to evaluate the potential use of CDP-choline as a cardioprotector in an in vitro model of ischaemia/reperfusion injury. Methods. Neonatal rat cardiac myocytes were isolated and subjected to hypoxia/reperfusion using the coverslip hypoxia model. To evaluate the effect of CDP-choline on oxidative stress-induced reperfusion injury, the cells were incubated with H2O2 during reperfusion. The effect of CDP-choline pre- and postconditioning was evaluated using the cell viability MTT assay, and the proportion of apoptotic and necrotic cells was analyzed using the Annexin V determination by flow cytometry. Results. Pre- and postconditioning with 50 mg/mL of CDP-choline induced a significant reduction of cells undergoing apoptosis after hypoxia/reperfusion. Preconditioning with CDP-choline attenuated postreperfusion cell death induced by oxidative stress. Conclusion. CDP-choline administration reduces cell apoptosis induced by oxidative stress after hypoxia/reperfusion of cardiac myocytes. Thus, it has a potential as cardioprotector in ischaemia/reperfusion-injured cardiomyocytes. PMID:24578622

  5. CART attenuates endoplasmic reticulum stress response induced by cerebral ischemia and reperfusion through upregulating BDNF synthesis and secretion.

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    Qiu, Bin; Hu, Shengdi; Liu, Libing; Chen, Man; Wang, Lai; Zeng, Xianwei; Zhu, Shigong

    2013-07-12

    Cocaine and amphetamine regulated transcript (CART), a neuropeptide, has shown strong neuroprotective effects against cerebral ischemia and reperfusion (I/R) injury in vivo and in vitro. Here, we report a new effect of CART on ER stress which is induced by cerebral I/R in a rat model of middle cerebral artery occlusion (MCAO) or by oxygen and glucose deprivation (OGD) in cultured cortical neurons, as well as a new functionality of BDNF in the neuroprotection by CART against the ER stress in cerebral I/R. The results showed that CART was effective in reducing the neuronal apoptosis and expression of ER stress markers (GRP78, CHOP and cleaved caspase12), and increasing the BDNF expression in I/R injury rat cortex both in vivo and in vitro. In addition, the effects of CART on ischemia-induced neuronal apoptosis and ER stress were suppressed by tyrosine receptor kinase B (TrkB) IgG, whereas the effects of CART on BDNF transcription, synthesis and secretion were abolished by CREB siRNA. This work suggests that CART is functional in inhibiting the cerebral I/R-induced ER stress and neuronal apoptosis by facilitating the transcription, synthesis and secretion of BDNF in a CREB-dependent way.

  6. Acute hepatic ischemic-reperfusion injury induces a renal cortical "stress response," renal "cytoresistance," and an endotoxin hyperresponsive state.

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    Zager, Richard A; Johnson, Ali C M; Frostad, Kirsten B

    2014-10-01

    Hepatic ischemic-reperfusion injury (HIRI) is considered a risk factor for clinical acute kidney injury (AKI). However, HIRI's impact on renal tubular cell homeostasis and subsequent injury responses remain ill-defined. To explore this issue, 30-45 min of partial HIRI was induced in CD-1 mice. Sham-operated or normal mice served as controls. Renal changes and superimposed injury responses (glycerol-induced AKI; endotoxemia) were assessed 2-18 h later. HIRI induced mild azotemia (blood urea nitrogen ∼45 mg/dl) in the absence of renal histologic injury or proteinuria, implying a "prerenal" state. However, marked renal cortical, and isolated proximal tubule, cytoprotective "stress protein" gene induction (neutrophil gelatinase-associated lipocalin, heme oxygenase-1, hemopexin, hepcidin), and increased Toll-like receptor 4 (TLR4) expression resulted (protein/mRNA levels). Ischemia caused release of hepatic heme-based proteins (e.g., cytochrome c) into the circulation. This corresponded with renal cortical oxidant stress (malondialdehyde increases). That hepatic derived factors can evoke redox-sensitive "stress protein" induction was implied by the following: peritoneal dialysate from HIRI mice, soluble hepatic extract, or exogenous cytochrome c each induced the above stress protein(s) either in vivo or in cultured tubule cells. Functional significance of HIRI-induced renal "preconditioning" was indicated by the following: 1) HIRI conferred virtually complete morphologic protection against glycerol-induced AKI (in the absence of hyperbilirubinemia) and 2) HIRI-induced TLR4 upregulation led to a renal endotoxin hyperresponsive state (excess TNF-α/MCP-1 gene induction). In conclusion, HIRI can evoke "renal preconditioning," likely due, in part, to hepatic release of pro-oxidant factors (e.g., cytochrome c) into the systemic circulation. The resulting renal changes can impact subsequent AKI susceptibility and TLR4 pathway-mediated stress.

  7. 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.

  8. Resveratrol attenuates oxidative stress and histological alterations induced by liver ischemia/reperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To investigate the effects of resveratrol on liver ischemia/reperfusion (I/R) injury in rats. METHODS: A total of 40 male Sprague-Dawley rats weighing 240-290 g were randomized into four groups often: (1) controls: data from unmanipulated animals; (2) sham group: rats subjected to the surgical procedure, except for liver I/R, and given saline; (3) I/R group: rats underwent liver ischemia for 45 min followed by reperfu-sion for 45 min; (4) I-R/Resveratrol group: rats pretreat-ed with resveratrol (10 μmol/L, iv). Liver tissues were obtained to determine antioxidant enzyme levels and for biochemical and histological evaluation. RESULTS: Plasma aminotransferase activities were higher in the I/R group than in the I-R/Resveratrol group. Malondialdehyde levels and the hepatic injury score decreased, while superoxide dismutase, catalase, and glutathione peroxidase levels increased in group 4 compared to group 3. In group 4, histopathological changes were significantly attenuated in resveratrol-treated livers.CONCLUSION: These results suggest that resveratrol has protective effects against hepatic I/R injury, and is a potential therapeutic drug for ischemia reperfusion-related liver injury.

  9. Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury.

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    Chandrika, Bhavya B; Yang, Cheng; Ou, Yang; Feng, Xiaoke; Muhoza, Djamali; Holmes, Alexandrea F; Theus, Sue; Deshmukh, Sarika; Haun, Randy S; Kaushal, Gur P

    2015-01-01

    We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase-3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase-3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.

  10. Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury.

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    Bhavya B Chandrika

    Full Text Available We examined whether endoplasmic reticulum (ER stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase-3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase-3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.

  11. Rapamycin protects testes against germ cell apoptosis and oxidative stress induced by testicular ischemia-reperfusion

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    Morteza Ghasemnejad-berenji

    2017-08-01

    Full Text Available Objective(s:Rapamycin is an immunosuppressant compound with a broad spectrum of pharmaco-logical activities. In recent years, it has been used successfully to decrease ischemia-reperfusion injury in several organ systems. The purpose of the present study was to examine the effect of rapamycin on testicular ischemia-reperfusion injury. Materials and Methods: Seventy-two adult male Wistar rats were divided into six groups: control (group1, sham-operated (Group2, T/D + DMSO as vehicle group (group3, and groups 4–6; respectively received 0.5, 1, and 1.5 mgkg-1 of rapamycin , IP 30 min before detorsion. Ischemia was achieved by twisting the right testis 720o clockwise for 1 hr. The right testis of 6 animals from each group were excised 4 hr after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD and TUNEL test in right testis of 6 animals per group, 24 hr after detorsion. Results: Testicular T/D caused increases in the apoptosis, malondialdehyde (MDA, and caspase-3 levels and decreases in the superoxide dismutase (SOD, catalase (CAT, and glutathione peroxidase (GPx activities in ipsilateral testis (P

  12. Thymoquinone prevents endoplasmic reticulum stress and mitochondria-induced apoptosis in a rat model of partial hepatic warm ischemia reperfusion.

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    Bouhlel, Ahlem; Ben Mosbah, Ismail; Hadj Abdallah, Najet; Ribault, Catherine; Viel, Roselyne; Mannaï, Saber; Corlu, Anne; Ben Abdennebi, Hassen

    2017-10-01

    This study was undertaken to evaluate the protective effect of thymoquinone (TQ), the bioactive compound of Nigella sativa seeds, against warm ischemia-reperfusion (I/R) injury in liver. Rats were given an oral administration of a vehicle solution (sham group) or TQ at the appropriate dose (10, 20, 30 and 40mg/kg) for ten days consecutively. Following, they were subjected to 60min of partial hepatic ischemia followed by 24h of reperfusion. .Transaminase activities, histopathological changes, TNFα and antioxidant parameters were evaluated. Also, endoplasmic reticulum (ER) stress, mitochondrial damage and apoptosis were studied. In addition, ERK and P38 phosphorylation was determined by Western blot technique. We found that TQ at 30mg/kg is the effective dose to protect rat liver against I/R injury. Moreover, 30mg/kg of TQ prevented histological damages, inflammation and oxidative stress. Interestingly, it decreased the expression of ER stress parameters including GRP78, CHOP and caspase-12. In parallel, it improved mitochondrial function and attenuated the expression of apoptotic parameters. Furthermore, TQ significantly enhanced ERK and P38 phosphorylation. In conclusion, we demonstrated the potential of TQ to protect the rat liver against I/R injury through the prevention of ER stress and mitochondrial dysfunction. These effects implicate the prevention of oxidative stress. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

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    Cui, Fei-Fei; Pan, Ying-Ying; Xie, Hao-Huang; Wang, Xiao-Hui; Shi, Hong-Xue; Xiao, Jian; Zhang, Hong-Yu; Chang, Hao-Teng; Jiang, Li-Ping

    2016-02-25

    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.

  14. Stress protein expression in early phase spinal cord ischemia/reperfusion injury*

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    Shanyong Zhang; Dankai Wu; Jincheng Wang; Yongming Wang; Guoxiang Wang; Maoguang Yang; Xiaoyu Yang

    2013-01-01

    Spinal cord ischemia/reperfusion injury is a stress injury to the spinal cord. Our previous studies using differential proteomics identified 21 differential y expressed proteins (n > 2) in rabbits with spinal cord ischemia/reperfusion injury. Of these proteins, stress-related proteins included protein disulfide isomerase A3, stress-induced-phosphoprotein 1 and heat shock cognate protein 70. In this study, we established New Zealand rabbit models of spinal cord ischemia/reperfusion injury by abdominal aorta occlusion. Results demonstrated that hind limb function initial y improved after spinal cord ischemia/reperfusion injury, but then deteriorated. The pathological morphology of the spinal cord became aggravated, but lessened 24 hours after reperfusion. However, the numbers of motor neurons and interneurons in the spinal cord gradual y decreased. The expression of protein disulfide isomerase A3, stress-induced-phosphoprotein 1 and heat shock cognate protein 70 was induced by ischemia/reperfusion injury. The expression of these proteins increased within 12 hours after reperfusion, and then decreased, reached a minimum at 24 hours, but subsequently increased again to similar levels seen at 6–12 hours, showing a characterization of induction-inhibition-induc-tion. These three proteins were expressed only in cytoplasm but not in the nuclei. Moreover, the expression was higher in interneurons than in motor neurons, and the survival rate of interneurons was greater than that of motor neurons. It is assumed that the expression of stress-related proteins exhibited a protective effect on neurons.

  15. Methanol extract of Desmodium gangeticum roots preserves mitochondrial respiratory enzymes, protecting rat heart against oxidative stress induced by reperfusion injury.

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    Kurian, Gino A; Yagnesh, N; Kishan, R Sanchit; Paddikkala, Jose

    2008-04-01

    Ischaemia and reperfusion result in mitochondrial dysfunction, with decreased oxidative capacity, loss of cytochrome c and generation of reactive oxygen species. The aim of this study was to evaluate the effect of a methanol extract of Desmodium gangeticum (L) DC (Fabaceae) (DG) on lipid peroxidation and antioxidants in mitochondria and tissue homogenates of normal, ischaemic and ischaemia-reperfused rats. Myocardial lipid peroxidation products (thiobarbituric acid reactive substances; TBARS) in cardiac tissue homogenates and mitochondrial fractions were significantly increased during ischaemia reperfusion. Antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase (GPx) and glutathione reductase) in the myocardial tissue homogenate and mitochondria decreased significantly during ischaemia reperfusion, accompanied by a decreased activity of mitochondrial respiratory enzymes. Daily pretreatment of rats with DG (50 or 100 mgkg(-1)) orally for 30 days had a significant effect on the activity of mitochondrial and antioxidant enzymes. In-vitro studies showed that DG inhibited lipid peroxidation, and also scavenged hydroxyl and superoxide radicals. The concentrations required to scavenge 50% of the superoxide and hydroxyl radicals were 21 and 50.5 microgmL(-1), respectively. Administration of DG to normal rats did not have any significant effect on any of the parameters studied. The results of our study showed that DG possesses the ability to scavenge the free radicals generated during ischaemia and ischaemia reperfusion and thereby preserves the mitochondrial respiratory enzymes that eventually lead to cardioprotection.

  16. Administration of aqueous extract of Desmodium gangeticum (L) root protects rat heart against ischemic reperfusion injury induced oxidative stress.

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    Kurian, Gino A; Paddikkala, Jose

    2009-02-01

    Myocardial reperfusion is believed to be associated with free radical injury. The present study evaluates the effect of aqueous extract of D. gangeticum (DG) on lipid peroxides and antioxidants in ischemic reperfused (IR) Wistar albino male rats. Significant elevation in lipid peroxide products (thiobarbituric acid reactive substances) and decreased activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) were observed in the rat hearts during ischemia reperfusion phase. Pre treatment of rats with aqueous extract of DG orally for 30 days showed significantly improved preservation of antioxidant enzymes and subsequent reduction in lipid peroxidation. But 2,3,5 triphenyl tetrazolium chloride (TTC) stained rat heart did not show much significant antioxidant enzyme activities and lipid peroxidation. On the other hand, TTC unstained rat heart showed significant improvement in the antioxidant activities indicating cardio protective effect of aqueous extract of DG in myocardium affected by ischemia reperfusion insult. The administration of DG to normal rats did not have any significant effect on any of the parameter studied. These results indicate that DG improves the antioxidant capacity of heart and attenuate the degree of lipid peroxidation after IR.

  17. Tyrosol attenuates ischemia-reperfusion-induced kidney injury via inhibition of inducible nitric oxide synthase.

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    Wang, Pengqi; Zhu, Qingjun; Wu, Nan; Siow, Yaw L; Aukema, Harold; O, Karmin

    2013-04-17

    Tyrosol is a natural phenolic antioxidant compound. Oxidative stress represents one of the important mechanisms underlying ischemia-reperfusion-induced kidney injury. The aim of this study was to investigate the effect of tyrosol against ischemia-reperfusion-induced acute kidney injury. The left kidney of Sprague-Dawley rats was subjected to 45 min of ischemia followed by reperfusion for 6 h. Ischemia-reperfusion caused an increase in peroxynitrite formation and lipid peroxidation. The level of nitric oxide (NO) metabolites and the mRNA of inducible nitric oxide synthase (iNOS) were elevated in ischemia-reperfused kidneys. Administration of tyrosol (100 mg/kg body weight) to rats prior to the induction of ischemia significantly reduced peroxynitrite formation, lipid peroxidation, and the level of NO metabolites. Tyrosol administration also attenuated ischemia-reperfusion-induced NF-κB activation and iNOS expression. Such a treatment improved kidney function. Results suggest that tyrosol may have a protective effect against acute kidney injury through inhibition of iNOS-mediated oxidative stress.

  18. Taurine inhibits ischemia/reperfusion-induced compartment syndrome in rabbits

    Institute of Scientific and Technical Information of China (English)

    Ji-xian WANG; Yan LI; Li-ke ZHANG; Jing ZHAO; Yong-zheng PANG; Chao-shu TANG; Jing ZHANG

    2005-01-01

    Aim: To investigate effects of taurine on ischemia/reperfusion (I/R)-induced compartment syndrome in rabbit hind limbs.Methods: Rabbits underwent femoral artery occ lusion after ligation of branches from terminal aorta to femoral artery.After a 7-h ischemia, reperfusion was established with the use of heparinized by iv infusion 10 min before shunt placement.During reperfusion, anterior compartment pressure (ACP) was monitored continuously in the left lower extremity.Gastrocnemius muscle triphenyltetrazolium chloride (TTC) level, taurine content and myeloperoxidase activity were assayed.Oxidative stress was induced in the in vitro gastrocnemius muscle slices by free radical generating systems (FRGS),and the malondialdehyde content was measured in presence or absence of taurine.Results: After 7 h of ischemia, none of the parameters that we measured were different from those before ischemia, except that TTC reduction decreased by 80%.In the control group, after 2 h of reperfusion, ACP increased 4.5-fold, and gastrocnemius muscle taurine content was reduced by 33%.In taurine-treated animals, at 2 h reperfusion, the mean arterial blood pressure and heart rate were increased, by 6% and 10%.ACP decreased by 39%, muscle edema decreased by 16%, TTC reduction increased by 150%, and lactate dehydrogenase decreased by 36% compared to control group.Plasma and muscle taurine content increased by 70% and 88%, respectively.In the taurine-treated group, at 2 h reperfusion, plasma malondialdehyde and conjugated diene content were decreased by 38% and 23%,respectively, and muscle malondialdehyde and conjugated diene content decreased by 22% and 30%, respectively compared to the control group.At 2 h reperfusion,myeloperoxidase activity was increased 3.5-fold in control animals.In the in vitro study, taurine decreased malondialdehyde content in muscle slices incubated with hypochlorous acid in a dose-dependent manner, but there was no change when incubated with hydrogen peroxide and

  19. Prostaglandin-E1 has a protective effect on renal ischemia/reperfusion-induced oxidative stress and inflammation mediated gastric damage in rats.

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    Gezginci-Oktayoglu, Selda; Orhan, Nurcan; Bolkent, Sehnaz

    2016-07-01

    Gastrointestinal complications are frequent in renal transplant recipients. In this regard, renal ischemia/reperfusion injury (IRI)-induced gastric damage seems to be important and there is no data available on the mechanism of this pathology. Because of its anti-inflammatory and anti-oxidant properties, it can be suggested that prostaglandin-E1 (PGE1) protects cells from renal IRI-induced gastric damage. The aim of this study was to investigate the molecular mechanisms of gastric damage induced by renal IRI and the effect of PGE1 on these mechanisms. We set an experiment with four different animal groups: physiological saline-injected and sham-operated rats, PGE1 (20μg/kg)-administered and sham operated rats, renal IRI subjected rats, and PGE1-administered and renal IRI subjected rats. The protective effect of PGE1 on renal IRI-induced gastric damage was determined based on reduced histological damage and lactate dehydrogenase activity. Moreover, we demonstrated that PGE1 shows its protective effect through reducing the production of reactive oxygen species and malondialdehyde levels. During histological examination, we observed the presence of common mononuclear cell infiltration. Therefore, pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β levels were measured and it has been shown that PGE1 suppressed both cytokines. Furthermore, it was found that PGE1 reduced the number of NF-κB(+) and caspase-3(+) inflammatory cells, and also NF-κB DNA-binding activity, while increasing proliferating cell nuclear antigen(+) epithelial cells in the stomach tissue of rats subjected to renal IR. Our data showed that PGE1 has a protective effect on renal IRI-induced oxidative stress and inflammation mediated gastric damage in rats.

  20. Ischemic conditioning by short periods of reperfusion attenuates renal ischemia/reperfusion induced apoptosis and autophagy in the rat

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    Chien Chiang-Ting

    2009-02-01

    Full Text Available Abstract Prolonged ischemia amplified iscehemia/reperfusion (IR induced renal apoptosis and autophagy. We hypothesize that ischemic conditioning (IC by a briefly intermittent reperfusion during a prolonged ischemic phase may ameliorate IR induced renal dysfunction. We evaluated the antioxidant/oxidant mechanism, autophagy and apoptosis in the uninephrectomized Wistar rats subjected to sham control, 4 stages of 15-min IC (I15 × 4, 2 stages of 30-min IC (I30 × 2, and total 60-min ischema (I60 in the kidney followed by 4 or 24 hours of reperfusion. By use of ATP assay, monitoring O2-. amounts, autophagy and apoptosis analysis of rat kidneys, I60 followed by 4 hours of reperfusion decreased renal ATP and enhanced reactive oxygen species (ROS level and proapoptotic and autophagic mechanisms, including enhanced Bax/Bcl-2 ratio, cytochrome C release, active caspase 3, poly-(ADP-ribose-polymerase (PARP degradation fragments, microtubule-associated protein light chain 3 (LC3 and Beclin-1 expression and subsequently tubular apoptosis and autophagy associated with elevated blood urea nitrogen and creatinine level. I30 × 2, not I15 × 4 decreased ROS production and cytochrome C release, increased Manganese superoxide dismutase (MnSOD, Copper-Zn superoxide dismutase (CuZnSOD and catalase expression and provided a more efficient protection than I60 against IR induced tubular apoptosis and autophagy and blood urea nitrogen and creatinine level. We conclude that 60-min renal ischemia enhanced renal tubular oxidative stress, proapoptosis and autophagy in the rat kidneys. Two stages of 30-min ischemia with 3-min reperfusion significantly preserved renal ATP content, increased antioxidant defense mechanisms and decreased ischemia/reperfusion enhanced renal tubular oxidative stress, cytosolic cytochrome C release, proapoptosis and autophagy in rat kidneys.

  1. Effect of pyrrolidine dithiocarbamate on hepatic vascular stress gene expression during ischemia and reperfusion.

    Science.gov (United States)

    Lee, Chan-Ho; Kim, Sung-Ho; Lee, Sun-Mee

    2008-10-24

    Pyrrolidine dithiocarbamate, an antioxidant and a potent inhibitor of nuclear factor-kappa B (NF-kappaB), is known to have protective effect against ischemia and reperfusion injury. This study examined the cytoprotective mechanism of pyrrolidine dithiocarbamate against the microcirculatory failure caused by hepatic ischemia and reperfusion. Rats were subjected to 60 min of hepatic ischemia followed by 5 h of reperfusion. Pyrrolidine dithiocarbamate (100 mg/kg) or the vehicle was administered intraperitoneally 24 h before ischemia. The level of serum aminotransferases and hepatic lipid peroxides significantly increased, and the glutathione contents fell in the ischemia/reperfusion group. Pyrrolidine dithiocarbamate prevented the increase in the level of serum enzymes and hepatic lipid peroxides, and the decrease in the glutathione contents. The NF-kappaB DNA-binding activity was inhibited by a pre-treatment with pyrrolidine dithiocarbamate. Ischemia and reperfusion significantly increased the mRNA expression of the endothelin-1 and endothelin ET(B) receptor, which was prevented by pyrrolidine dithiocarbamate. There were significant increases in the mRNA expressions of inducible nitric oxide synthase, tumor necrosis factor-alpha, and cyclooxygenase-2, in the livers after ischemia and reperfusion. These increases were attenuated by the pyrrolidine dithiocarbamate treatment. In a rat model of hepatic ischemia and reperfusion, our results suggest that the hepatoprotective actions of pyrrolidine dithiocarbamate may be mediated in part through the modulation of imbalanced expression of vascular stress genes.

  2. Exogenous ATP administration prevents ischemia/reperfusion-induced oxidative stress and tissue injury by modulation of hypoxanthine metabolic pathway in rat ovary

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    Serkan Kumbasar

    2014-07-01

    Full Text Available In this study, xanthine oxidase (XO, malondialdehyde (MDA, myeloperoxidase (MPO and glutathione (GSH levels in the ovarian tissues of rats during the development of ischemia and postischemia-induced reperfusion were investigated, and the effect of ATP on ischemia-reperfusion (I/R damage was biochemically and histopathologically examined. The results of the biochemical analyses demonstrated that ATP significantly reduced the level of XO and MDA and increased the amount of GSH in both ischemia and I/R-applied ovarian tissue at the doses administered. Furthermore, ATP significantly suppressed the increase in MPO activity that occurred following the application of post ischemia reperfusion in the ovarian tissue. The biochemical results obtained in the present study coincide with the histological findings. The severity of the pathological findings, such as dilatation, congestion, haemorrhage, oedema and polymorphonuclear nuclear leukocytes (PMNLs, increased in parallel with the increase observed in the products of XO metabolism. In conclusion, exogenously applied ATP prevented I/R damage by reducing the formation of XO in ischemic ovarian tissue.

  3. Trans-cinnamaldehyde protected PC12 cells against oxygen and glucose deprivation/reperfusion (OGD/R)-induced injury via anti-apoptosis and anti-oxidative stress.

    Science.gov (United States)

    Qi, Xue; Zhou, Ru; Liu, Yue; Wang, Jing; Zhang, Wan-Nian; Tan, Huan-Ran; Niu, Yang; Sun, Tao; Li, Yu-Xiang; Yu, Jian-Qiang

    2016-10-01

    Ischemia stroke is the major cause of mortality and permanent neurological disability with little definitive therapeutic options. This cerebral ischemic injury leads to the oxidative stress and eventually cell death. We hypothesized that treatment of this condition with the trans-cinnamaldehyde(TC) could protect cells from ischemic and reperfusion injury. Oxygen and glucose deprivation/reperfusion (OGD/R) was used as an in vitro model of hypoxic ischemic injury in present study. MTT was used to evaluate the protective effects of TC. Next, we tested whether TC reduced the production of reactive oxygen species (ROS). Besides, experiments were performed to determine whether or not the mitochondrial membrane potential was affected. Furthermore, the inhibiters of NO and PI3 K were used to determine the initial mechanisms. TC treatment improved cell viability, reduced intracellular ROS, and increased MMP. Further, the inhibition of NO or PI3 K significantly reduced TC's protective effects. These findings suggest that TC might be a promising agent for ischemic stroke.

  4. Ginkgo biloba extract (EGb 761) attenuates lung injury induced by intestinal ischemia/reperfusion in rats: Roles of oxidative stress and nitric oxide

    Institute of Scientific and Technical Information of China (English)

    Ke-Xuan Liu; Wei-Kang Wu; Wei He; Chui-Liang Liu

    2007-01-01

    AIM: To investigate the effect of ginkgo biloba extract (EGb 761) on lung injury induced by intestinal ischemia/reperfusion ( Ⅱ/R).METHODS: The rat model of Ⅱ/R injury was produced by clamping the superior mesenteric artery for 60 min followed by reperfusion for 180 min. The rats were randomly allocated into sham, Ⅱ/R, and EGb +Ⅱ/R groups. In EGb + Ⅱ/R group, EGb 761 (100 mg/kg per day) was given via a gastric tube for 7 consecutive days prior to surgery. Rats in Ⅱ/R and sham groups were treated with equal volumes of the vehicle of EGb 761.Lung injury was assessed by light microscopy, wet-todry lung weight ratio (W/D) and pulmonary permeability index (PPI). The levels of malondialdehyde (MDA) and nitrite/nitrate (NO2-/NO3-), as well as the activities of superoxide dismutase (SOD) and myeloperoxidase (MPO)were examined. Western blot was used to determine the expression of inducible nitric oxide synthase (iNOS).RESULTS: EGb 761 markedly improved mean arterial pressure and attenuated lung injury, manifested by the improvement of histological changes and significant decreases of pulmonary W/D and PPI (P < 0.05 or 0.01).Moreover, EGb 761 markedly increased SOD activity,reduced MDA levels and MPO activity, and suppressed NO generation accompanied by down-regulation of iNOS expression (P < 0.05 or 0.01).CONCLUSION: The results indicate that EGb 761has a protective effect on lung injury induced by Ⅱ /R, which may be related to its antioxidant property and suppressions of neutrophil accumulation and iNOSinduced NO generation. EGb 761 seems to be an effective therapeutic agent for critically ill patients with respiratory failure related to Ⅱ/R.

  5. Protective effects of Rosa canina L fruit extracts on renal disturbances induced by reperfusion injury in rats.

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    Changizi Ashtiyani, Saeed; Najafi, Houshang; Jalalvandi, Sepeideh; Hosseinei, Fatemeh

    2013-07-01

    This study aimed to investigate the effects of Rosa canina L fruit extracts on histological damages, oxidative stress, and functional disturbances induced by bilateral renal ischemia and reperfusion. Ischemia and reperfusion were induced on the kidneys of anesthetized male Sprague-Dawley rats. The rats in the reperfusion and Rosa canina groups were administered extract solvent and Rosa canina extract, respectively. In addition, in the sham group, surgery was done without ischemia. In the last 6 hours of the reperfusion period, urine sample were collected using metabolic cage and at the end of this period, blood samples were taken from the descending aorta. The kidney tissues were collected and subjected to microscopic study for histological damages, while oxidative stress was measured by determining malondialdehyde and ferric reducing/antioxidant power levels. The comparison between the reperfusion and sham groups indicated reductions in creatinine clearance, absolute excretion of potassium, urine osmilarity, and increase in absolute excretion of sodium in the reperfusion group. These changes were less pronounced with Rosa canina fruit extract. In addition, blood creatinine and urea concentrations which increased in the reperfusion group, were significantly lower in the Rosa canina group. In this group, the degree of histological damages and the level of malondialdehyde were lower than the reperfusion group, while ferric reducing/antioxidant power level was significantly higher. The findings of this study showed that Rosa canina fruit extract possesses protective effects against kidney function disturbances, oxidative stress, and histological damages.

  6. Classical and remote post-conditioning effects on ischemia/reperfusion-induced acute oxidant kidney injury.

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    Kadkhodaee, Mehri; Najafi, Atefeh; Seifi, Behjat

    2014-11-01

    The present study aimed to analyze and compare the effects of classical and remote ischemic postconditioning (POC) on rat renal ischemia/reperfusion (IR)-induced acute kidney injury. After right nephrectomy, male rats were randomly assigned into four groups (n = 8). In the IR group, 45 min of left renal artery occlusion was induced followed by 24 h of reperfusion. In the classical POC group, after induction of 45 min ischemia, 4 cycles of 10 s of intermittent ischemia and reperfusion were applied to the kidney before complete restoring of renal blood. In the remote POC group, 4 cycles of 5 min ischemia and reperfusion of left femoral artery were applied after 45 min renal ischemia and right at the time of renal reperfusion. There was a reduction in renal function (increase in blood urea and creatinine) in the IR group. Application of both forms of POC prevented the IR-induced reduction in renal function and histology. There were also significant improvements in kidney oxidative stress status in both POC groups demonstrated by a reduction in malondialdehyde (MDA) formation and preservation of antioxidant levels comparing to the IR group. We concluded that both methods of POC have protective effects on renal function and histology possibly by a reduction in IR-induced oxidative stress.

  7. Roles of mitochondrial Src tyrosine kinase and zinc in nitric oxide-induced cardioprotection against ischemia/reperfusion injury.

    Science.gov (United States)

    Zhang, Y; Xing, F; Zheng, H; Xi, J; Cui, X; Xu, Z

    2013-07-01

    While nitric oxide (NO) induces cardioprotection by targeting the mitochondrial permeability transition pore (mPTP), the precise mitochondrial signaling events that mediate the action of NO remain unclear. The purpose of this study was to test whether NO induces cardioprotection against ischemia/reperfusion by inhibiting oxidative stress through mitochondrial zinc and Src tyrosine kinase. The NO donor S-nitroso-N-acetyl penicillamine (SNAP) given before the onset of ischemia reduced cell death in rat cardiomyocytes subjected to simulated ischemia/reperfusion, and this was abolished by the zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and the Src tyrosine kinase inhibitor PP2. SNAP also prevented loss of mitochondrial membrane potential (ΔΨm) at reperfusion, an effect that was blocked by TPEN and PP2. SNAP increased mitochondrion-free zinc upon reperfusion and enhanced mitochondrial Src phosphorylation in a zinc-dependent manner. SNAP inhibited both mitochondrial complex I activity and mitochondrial reactive oxygen species (ROS) generation at reperfusion through zinc and Src tyrosine kinase. Finally, the anti-infarct effect of SNAP was abrogated by TPEN and PP2 applied at reperfusion in isolated rat hearts. In conclusion, NO induces cardioprotection at reperfusion by targeting mitochondria through attenuation of oxidative stress resulted from the inhibition of complex I at reperfusion. Activation of mitochondrial Src tyrosine kinase by zinc may account for the inhibition of complex I.

  8. 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.

  9. Ischemia/reperfusion-induced Kidney Injury in Heterozygous PACAP-deficient Mice.

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    Laszlo, E; Varga, A; Kovacs, K; Jancso, G; Kiss, P; Tamas, A; Szakaly, P; Fulop, B; Reglodi, D

    2015-09-01

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with very diverse distribution and functions. Among others, PACAP is a potent cytoprotective peptide due to its antiapoptotic, anti-inflammatory, and antioxidant actions. This also has been shown in different kidney pathologies, including ischemia/reperfusion-induced kidney injury. Similar protective effects of the endogenous PACAP are confirmed by the increased vulnerability of PACAP-deficient mice to different harmful stimuli. Kidneys of homozygous PACAP-deficient mice have more severe damages in renal ischemia/reperfusion and kidney cell cultures isolated from these mice show increased sensitivity to renal oxidative stress. In our present study we raised the question of whether the partial lack of the PACAP gene is also deleterious, i.e. whether heterozygous PACAP-deficient mice also display more severe damage after renal ischemia/reperfusion. Mice underwent 45 or 60 minutes of ischemia followed by 2 weeks reperfusion. Histological evaluation of the kidneys was performed and individual histopathological parameters were graded. Furthermore, we investigated apoptotic markers, cytokine expression, and the activity of superoxide dismutase (SOD) enzyme 24 hours after 60 minutes of renal ischemia/reperfusion. We found no difference between the intact kidneys of wild-type and heterozygous mice, but marked differences could be observed following ischemia/reperfusion. Heterozygous PACAP-deficient mice had more severe histological alterations, with significantly higher histopathological scores for most of the tested parameters. Higher level of the proapoptotic pp38 MAPK and of some proinflammatory cytokines, as well as lower activity of the antioxidant SOD could be found in these mice. In conclusion, the partial lack of the PACAP gene results in worse outcomes in cases of renal ischemia/reperfusion, confirming that PACAP functions as an endogenous protective factor in the kidney.

  10. Protective effects of erdosteine and vitamins C and E combination on ischemia-reperfusion-induced lung oxidative stress and plasma copper and zinc levels in a rat hind limb model.

    Science.gov (United States)

    Sirmali, Mehmet; Uz, Efkan; Sirmali, Rana; Kilbaş, Aynur; Yilmaz, H Ramazan; Altuntaş, Irfan; Naziroğlu, Mustafa; Delibaş, Namik; Vural, Hüseyin

    2007-07-01

    The aim of this study was to investigate the protective effects of erdosteine and vitamins C and E (VCE) on the lungs after performing hind limb ischemia-reperfusion (I/R) by assessing oxidative stress, plasma copper (Cu), and zinc (Zn) analysis. The animals were divided randomly into four groups as nine rats each as follows: control, I/R, I/R plus erdosteine, and I/R plus VCE combination. I/R period for 60 min was performed on the both hind limbs of all the rats in the groups of I/R, erdosteine with I/R, VCE with I/R allowing 120 min of reperfusion. The animals received orally erdosteine one time in a day and 3 days before I/R in the erdosteine group. In the VCE group, the animals VCE combination received one time in a day and 3 days before I/R, although placebo was given to control and I/R group animals. Lung lipid peroxidation (malondialdehyde [MDA]) level, superoxide dismutase (SOD), and catalase activities were increased, although lung glutathione (GSH) and plasma Zn levels decreased in I/R group in lung tissue compared with the control group. Serum MDA level, creatine kinase, and lactate dehydrogenase activities were increased in I/R group compared with the control. Lung MDA and plasma Zn levels and lung SOD activity were decreased by erdosteine administration, whereas lung GSH levels after I/R increased. The plasma Zn levels and lung SOD activity were decreased by VCE administration, although the plasma Cu and lung GSH levels increased after I/R. In conclusion, erdosteine has an antioxidant role on the values in the rat model, and it has more protective affect than in VCE in attenuating I/R-induced lung injury in rats.

  11. Remote postconditioning induced by brief pulmonary ischemia and reperfusion attenuates myocardial reperfusion injury in rabbits

    Institute of Scientific and Technical Information of China (English)

    TANG Yan-hua; XU Jian-jun; LI Ju-xiang; CHENG Xiao-shu

    2011-01-01

    Background The lung is one of the most important organs that are sensitive to ischemia. We hypothesized that remote postconditioning (RPostC) induced by brief occlusion and reperfusion of the pulmonary artery could attenuate myocardial reperfusion injury.Methods Thirty rabbits were randomized into three groups. Group ischemia-reperfusion (IR) (n=10) were anesthetized rabbits subjected to 30-minute occlusion of the left anterior descending coronary artery followed by 180-minute reperfusion. Group RPostC (n=10) had the left pulmonary artery blocked for five minutes followed by a 5-minute reperfusion, and the left anterior descending coronary artery (LAD) occluded for 30 minutes with a 180-minute reperfusion. Group L-Nw-nitro-L-arginine methylester (L-NAME) + RPostC (n=10) had the left pulmonary artery blocked for five minutes followed by a 5-minute reperfusion and intravenous infusion of L-NAME (10 mg/kg), and the LAD occluded for 30 minutes with a 180-minute reperfusion. Blood samples were taken for levels of creatine kinase (CK),superoxide dismutase (SOD) and malondialdehyde (MDA) at three different time points. At the end of the experiment,tissue samples of the infarcted region were harvested to calculate the cardiomyocyte apoptosis index (Al) by TUNEL. A piece of left and right lung tissue was harvested to evaluate the damage to the lung.Results After reperfusion for 180 minutes, the concentration of CK was lower in group RPostC, (4.79±0.27) U/ml, than that in group IR, (6.23±0.55) U/ml (P <0.01), and group L-NAME + RPsotC, (5.86±0.42) U/ml (P <0.01). The concentration of MDA was lower in group RPostC, (6.06±0.36) nmol/ml, than that in group IR, (11.41±0.91) nmol/ml (P <0.01), and group L-NAME + RPostC, (11.06±0.62) nmol/ml (P<0.01). The activity of SOD was higher in group RPostC,(242.34±25.02) U/ml, than that in group IR, (148.05±18.24) U/ml (P<0.01), and group L-NAME + RPostC, (160.66±9.55) U/ml (P<0.01). The apoptosis index was lower in

  12. Cardioprotective properties of citicoline against hyperthyroidism-induced reperfusion damage in rat hearts.

    Science.gov (United States)

    Hernández-Esquivel, Luz; Pavón, Natalia; Buelna-Chontal, Mabel; González-Pacheco, Héctor; Belmont, Javier; Chávez, Edmundo

    2015-06-01

    Hyperthyroidism represents an increased risk factor for cardiovascular morbidity, especially when the heart is subjected to an ischemia/reperfusion process. The aim of this study was to explore the possible protective effect of the nucleotide citicoline on the susceptibility of hyperthyroid rat hearts to undergo reperfusion-induced damage, which is associated with mitochondrial dysfunction. Hence, we analyzed the protective effect of citicoline on the electrical behavior and on the mitochondrial function in rat hearts. Hyperthyroidism was established after a daily i.p. injection of triiodothyronine (at 2 mg/kg of body weight) during 5 days. Thereafter, citicoline was administered i.p. (at 125 mg/kg of body weight) for 5 days. In hyperthyroid rat hearts, citicoline protected against reperfusion-induced ventricular arrhythmias. Moreover, citicoline maintained the accumulation of mitochondrial Ca(2+), allowing mitochondria to reach a high transmembrane electric gradient that protected against the release of cytochrome c. It also preserved the activity of the enzyme aconitase that inhibited the release of cytokines. The protection also included the inhibition of oxidative stress-induced mDNA disruption. We conclude that citicoline protects against the reperfusion damage that is found in the hyperthyroid myocardium. This effect might be due to its inhibitory action on the permeability transition in mitochondria.

  13. Selenium protects against ischemia-reperfusion- induced gastric lesions in rats

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    Mobarok Ali Abu Taib

    1997-01-01

    Full Text Available Recent studies have shown that selenium afforded protection against ethanol and stress-induced gastric lesions in rats. The present study was undertaken to investigate the effect of selenium on ischemia-reperfusion-induced gastric injuries in which rats were subjected to 30 minutes of ischemia in the presence of 100 mM HCI and a reperfusion for 60 minutes duration. Intraluminal bleeding was assessed macroscopically and gastric lesions were graded microscopically under an inverted microscope. Nonprotein sulphydryl levels were measured spectrophotometrically. The severity of gastric lesions, intraluminal bleeding as well as the depletion of nonprotein sulphydryls during the reperfusion periods was significantly different from that of control. Pretreatment with selenium (0.125-2.0 mg/kg, intraperitoneally 30 minutes before the ischemia-reperfusion, dose-dependently attenuated the gastric lesions, reduced the severity of intraluminal bleeding and prevented the depletion of nonprotein sulphydryls in the stomach. These results suggest that the gastric protection effect of selenium may be due to its antioxidant properties. Furthermore, endogenous nonprotein sulphydryls may play a significant role in the protective mechanisms of selenium.

  14. Organ-Protective Effects of Red Wine Extract, Resveratrol, in Oxidative Stress-Mediated Reperfusion Injury

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    Fu-Chao Liu

    2015-01-01

    Full Text Available Resveratrol, a polyphenol extracted from red wine, possesses potential antioxidative and anti-inflammatory effects, including the reduction of free radicals and proinflammatory mediators overproduction, the alteration of the expression of adhesion molecules, and the inhibition of neutrophil function. A growing body of evidence indicates that resveratrol plays an important role in reducing organ damage following ischemia- and hemorrhage-induced reperfusion injury. Such protective phenomenon is reported to be implicated in decreasing the formation and reaction of reactive oxygen species and pro-nflammatory cytokines, as well as the mediation of a variety of intracellular signaling pathways, including the nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, deacetylase sirtuin 1, mitogen-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, hemeoxygenase-1, and estrogen receptor-related pathways. Reperfusion injury is a complex pathophysiological process that involves multiple factors and pathways. The resveratrol is an effective reactive oxygen species scavenger that exhibits an antioxidative property. In this review, the organ-protective effects of resveratrol in oxidative stress-related reperfusion injury will be discussed.

  15. Evaluation of Chronic Physical and Psychological Stress Induction on Cardiac Ischemia / Reperfusion Injuries in Isolated Male Rat Heart: The Role of Sympathetic Nervous System.

    Science.gov (United States)

    Rakhshan, Kamran; Imani, Alireza; Faghihi, Mahdieh; Nabavizadeh, Fatemeh; Golnazari, Masoumeh; Karimian, SeyedMorteza

    2015-08-01

    Exposure to stress leads to physiological changes called "stress response" which are the result of the changes in the adrenomedullary hormone system, hypothalamus-pituitary-adrenal (HPA) and sympathetic nervous system (SNS) activity. In the present study, the effects of chronic physical and psychological stress and also the role of sympathetic system effects in stress on ischemia/reperfusion (I/R) injuries have been studied in isolated rat heart. Rat heart was isolated and subjected to 30 min regional ischemia and 120 min reperfusion. The daily stress was induced for one week prior to I/R induction. Sympathectomy was done chemically by injection of hydroxyl-dopamine prior to stress induction. There were no significant changes in heart rate and Coronary Flow between groups. Left ventricular developed pressure (LVDP) and rate product pressure (RPP) in both physical and psychological stress groups decreased significantly compared to those in control group (Pphysical and psychological stress groups. Infarct size significantly increased in both physical and psychological stress groups and control group(Pstress led to the elimination of the deleterious effects of stress as compared with stress groups (Presults show that induction of chronic physical and psychological stress prior to ischemia/reperfusion causes enhancement of myocardial injuries and it seems that increased sympathetic activity in response to stress is responsible for these adverse effects of stress on ischemic/reperfused heart.

  16. Cathepsin D is involved in the oxygen and glucose deprivation/reperfusion-induced apoptosis of astrocytes.

    Science.gov (United States)

    Liu, Jianlin; Yang, Lin; Tian, Hongyan; Ma, Qiang

    2016-10-01

    The lysosome and its associated protein cathe-psin D (Cat D) play critical roles in the pathological process of secondary damage following ischemia/reperfusion (I/R) injury. However, the roles of Cat D in I/R-exposed astrocytesremain unclear. In this study, we determined the roles of Cat D in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced apoptosis of astrocytes as well as the underlying mechanisms. We found that OGD/R markedly increased cell apoptosis and the production of inflammatory cytokines, namely IL-6, tumor necrosis factor (TNF)-α and FasL in a reperfusion time‑dependent manner and their elevation peaked at 24 h after reperfusion. Moreover, the cytosolic Cat D level and Cat D activity was significantly upregulated in response to OGD/R exposure. Furthermore, OGD/R exposure gradually disrupted the innate acidic conditions of the lysosome. Exogenous TNF-α and FasL administration elevated cytosolic Cat D levels and cell apoptosis whereas TNFR1 and Fas inhibition significantly reversed these effects induced by OGD/R. Cat D overexpression enhanced cell apoptosis and the levels of apoptogenic proteins, including Bax and caspase-3, whereas Cat D siRNA transfection had an inhibitory effect on cell apoptosis and the expression of proapoptotic proteins. In addition, we observed that Cat D upregulation disrupted mitochondrial membrane potential and induced the production of reactive oxygen species. In conclusion, OGD/R injury induced the production of TNF-α, IL-6 and FasL which promoted lysosomal dysfunction and Cat D leakage into the cytoplasm. This eventually resulted in caspase‑dependent apoptosis, mitochondrial membrane potential loss and oxidative stress in astrocytes.

  17. Pharmacological preconditioning with hyperbaric oxygen: can this therapy attenuate myocardial ischemic reperfusion injury and induce myocardial protection via nitric oxide?

    Science.gov (United States)

    Yogaratnam, Jeysen Zivan; Laden, Gerard; Guvendik, Lavent; Cowen, Mike; Cale, Alex; Griffin, Steve

    2008-09-01

    Ischemic reperfusion injury (IRI) is an inevitable part cardiac surgery such as coronary artery bypass graft (CABG). While ischemic hypoxia and the ensuing normoxic or hyperoxic reperfusion are critical to the initiation and propagation of IRI, conditioning myocardial cells to an oxidative stress prior to IRI may limit the consequences of this injury. Hyperbaric oxygen (HBO2) is a modality of treatment that is known to generate an oxidative stress. Studies have shown that treatment with HBO2 postischemia and reperfusion is useful in ameliorating myocardial IRI. Moreover, preconditioning the myocardium with HBO2 before reperfusion has demonstrated a myocardial protective effect by limiting the infarct size post ischemia and reperfusion. Current evidence suggests that HBO2 preconditioning may partly attenuate IRI by stimulating the endogenous production of nitric oxide (NO). As NO has the capacity to reduce neutrophil sequestration, adhesion and associated injury, and improve vascular flow, HBO2 preconditioning induced NO may play a role in providing myocardial protection during interventions that involve an inevitable episode of IRI. This current opinion review article attempts to suggest that HBO2 may be used to pharmacologically precondition and protect the myocardium from the effects of IRI that is known to occur during cardiac surgery.

  18. RTN1-C mediates cerebral ischemia/reperfusion injury via ER stress and mitochondria-associated apoptosis pathways.

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    Gong, Lingli; Tang, Yuewen; An, Ran; Lin, Muya; Chen, Lijian; Du, Jian

    2017-10-05

    The reticulon family has been found to induce apoptosis, inhibit axon regeneration and regulate protein trafficking. However, little is known about the mechanisms of how reticulon proteins are involved in neuronal death-promoting processes during ischemia. Here, we report that the expression of Reticulon Protein 1-C (RTN1-C) was associated with the progression of cerebral ischemia/reperfusion (I/R) injury. Using a combination of rat middle cerebral artery occlusion (MCAO) stroke and oxygen-glucose deprivation followed by reoxygenation (OGD/R) models, we determined that the expression of RTN1-C was significantly increased during cerebral ischemic/reperfusion. RTN1-C overexpression induced apoptosis and increased the cell vulnerability to ischemic injury, whereas RTN1-C knockdown reversed ischemia-induced apoptosis and attenuated the vulnerability of OGD/R-treated neural cells. Mechanistically, we demonstrated that RTN1-C mediated OGD/R-induced apoptosis through ER stress and mitochondria-associated pathways. RTN1-C interacted with Bcl-xL and increased its localization in the ER, thus reducing the anti-apoptotic activity of Bcl-xL. Most importantly, knockdown of Rtn1-c expression in vivo attenuated apoptosis in MCAO rats and reduced the extent of I/R-induced brain injury, as assessed by infarct volume and neurological score. Collectively, these data support for the first time that RTN1-C may represent a novel candidate for therapies against cerebral ischemia/reperfusion injury.

  19. 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.

  20. 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

  1. Combination of tadalafil and diltiazem attenuates renal ischemia reperfusion-induced acute renal failure in rats.

    Science.gov (United States)

    El-Sisi, Alaa E; Sokar, Samia S; Abu-Risha, Sally E; Ibrahim, Hanaa A

    2016-12-01

    Life threatening conditions characterized by renal ischemia/reperfusion (RIR) such as kidney transplantation, partial nephrectomy, renal artery angioplasty, cardiopulmonary bypass and aortic bypass surgery, continue to be among the most frequent causes of acute renal failure. The current study investigated the possible protective effects of tadalafil alone and in combination with diltiazem in experimentally-induced renal ischemia/reperfusion injury in rats. Possible underlying mechanisms were also investigated such as oxidative stress and inflammation. Rats were divided into sham-operated and I/R-operated groups. Anesthetized rats (urethane 1.3g/kg) were subjected to bilateral ischemia for 30min by occlusion of renal pedicles, then reperfused for 6h. Rats in the vehicle I/R group showed a significant (p˂0.05) increase in kidney malondialdehyde (MDA) content; myeloperoxidase (MPO) activity; TNF-α and IL-1β contents. In addition significant (p˂0.05) increase in intercellular adhesion molecule-1(ICAM-1) content, BUN and creatinine levels, along with significant decrease in kidney superoxide dismutase (SOD) activity. In addition, marked diffuse histopathological damage and severe cytoplasmic staining of caspase-3 were detected. Pretreatment with combination of tadalafil (5mg/kg bdwt) and diltiazem (5mg/kg bdwt) resulted in reversal of the increased biochemical parameters investigated. Also, histopathological examination revealed partial return to normal cellular architecture. In conclusion, pretreatment with tadalafil and diltiazem combination protected against RIR injury.

  2. Effect of sodium nitrite on ischaemia and reperfusion-induced arrhythmias in anaesthetized dogs: is protein S-nitrosylation involved?

    Directory of Open Access Journals (Sweden)

    Mária Kovács

    Full Text Available To provide evidence for the protective role of inorganic nitrite against acute ischaemia and reperfusion-induced ventricular arrhythmias in a large animal model.Dogs, anaesthetized with chloralose and urethane, were administered intravenously with sodium nitrite (0.2 µmol kg(-1 min(-1 in two protocols. In protocol 1 nitrite was infused 10 min prior to and during a 25 min occlusion of the left anterior descending (LAD coronary artery (NaNO2-PO; n = 14, whereas in protocol 2 the infusion was started 10 min prior to reperfusion of the occluded vessel (NaNO2-PR; n = 12. Control dogs (n = 15 were infused with saline and subjected to the same period of ischaemia and reperfusion. Severities of ischaemia and ventricular arrhythmias, as well as changes in plasma nitrate/nitrite (NOx levels in the coronary sinus blood, were assessed throughout the experiment. Myocardial superoxide and nitrotyrosine (NT levels were determined during reperfusion. Changes in protein S-nitrosylation (SNO and S-glutathionylation were also examined.Compared with controls, sodium nitrite administered either pre-occlusion or pre-reperfusion markedly suppressed the number and severity of ventricular arrhythmias during occlusion and increased survival (0% vs. 50 and 92% upon reperfusion. There were also significant decreases in superoxide and NT levels in the nitrite treated dogs. Compared with controls, increased SNO was found only in NaNO2-PR dogs, whereas S-glutathionylation occurred primarily in NaNO2-PO dogs.Intravenous infusion of nitrite profoundly reduced the severity of ventricular arrhythmias resulting from acute ischaemia and reperfusion in anaesthetized dogs. This effect, among several others, may result from an NO-mediated reduction in oxidative stress, perhaps through protein SNO and/or S-glutathionylation.

  3. Reducing the oxidative stress mediates the cardioprotection of bicyclol against ischemia-reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    Jie CUI; Zhi LI; Ling-bo QIAN; Qin GAO; Jue WANG; Meng XUE; Xiao-e LOU

    2013-01-01

    Objective:To investigate the beneficial effect of bicyclol on rat hearts subjected to ischemia-reperfusion (IR) injuries and its possible mechanism.Methods:Male Sprague-Dawley rats were intragastrically administered with bicyclol (25,50 or 100 mg/(kg·d)) for 3 d.Myocardial IR was produced by occlusion of the coronary artery for 1 h and reperfusion for 3 h.Left ventricular hemodynamics was continuously monitored.At the end of reperfusion,myocardial infarct was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining,and serum lactate dehydrogenase (LDH) level and myocardial superoxide dismutase (SOD) activity were determined by spectrophotometry.Isolated ventricular myocytes from adult rats were exposed to 60 min anoxia and 30 min reoxygenation to simulate IR injuries.After reperfusion,cell viability was determined with trypan blue; reactive oxygen species (ROS) and mitochondrial membrane potential of the cardiomyocytes were measured with the fluorescent probe.The mitochondrial permeability transition pore (mPTP) opening induced by Ca2+ (200 μmol/L) was measured with the absorbance at 520 nm in the isolated myocardial mitochondria.Results:Low dose of bicyclol (25 mg/(kg·d)) had no significant improving effect on all cardiac parameters,whereas pretreatment with high bicyclol markedly reduced the myocardial infarct and improved the left ventricular contractility in the myocardium exposed to IR (P<0.05).Medium dose of bicyclol (50 mg/(kg·d))markedly improved the myocardial contractility,left ventricular myocyte viability,and SOD activity,as well decreased infarct size,serum LDH level,ROS production,and mitochondrial membrane potential in rat myocardium exposed to IR.The reduction of ventricular myocyte viability in IR group was inhibited by pretreatment with 50 and 100 mg/(kg.d) bicyclol (P<0.05 vs.IR),but not by 25 mg/(kg·d) bicyclol.The opening of mPTP evoked by Ca2+ was significantly inhibited by medium bicyclol.Conclusions:Bicyclol exerts

  4. Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia.

    Science.gov (United States)

    Zheng, Yong-Qiu; Liu, Jian-Xun; Wang, Jan-Nong; Xu, Li

    2007-03-23

    This paper studied the effects of crocin, a pharmacologically active component of Crocus sativus L., on ischemia/reperfusion (I/R) injury in mice cerebral microvessels. Transient global cerebral ischemia (20 min), followed by 24 h of reperfusion, significantly promoted the generation of nitric oxide (NO) and malondialdehyde (MDA) in cortical microvascular homogenates, as well as markedly reduced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) and promoted the activity of nitric oxide synthase (NOs). Reperfusion for 24 h led to serous edema with substantial microvilli loss, vacuolation, membrane damage and mitochondrial injuries in cortical microvascular endothelial cells (CMEC). Furthermore, enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and decreased expression of matrix metalloproteinase-9 (MMP-9) were detected in cortical microvessels after I (20 min)/R (24 h). Reperfusion for 24 h also induced membrane (functional) G protein-coupled receptor kinase 2 (GRK2) expression, while it reduced cytosol GRK2 expression. Pretreatment with crocin markedly inhibited oxidizing reactions and modulated the ultrastructure of CMEC in mice with 20 min of bilateral common carotid artery occlusion (BCCAO) followed by 24 h of reperfusion in vivo. Furthermore, crocin inhibited GRK2 translocation from the cytosol to the membrane and reduced ERK1/2 phosphorylation and MMP-9 expression in cortical microvessels. We propose that crocin protects the brain against excessive oxidative stress and constitutes a potential therapeutic candidate in transient global cerebral ischemia.

  5. Moxonidine prevents ischemia/reperfusion-induced renal injury in rats.

    Science.gov (United States)

    Tsutsui, Hidenobu; Sugiura, Takahiro; Hayashi, Kentaro; Ohkita, Mamoru; Takaoka, Masanori; Yukimura, Tokihito; Matsumura, Yasuo

    2009-01-28

    Enhancement of renal sympathetic nerve activity during renal ischemia and its consequent effect on norepinephrine overflow from nerve endings after reperfusion play important roles in the development of ischemic acute kidney injury. In the present study, we evaluated whether moxonidine, an alpha(2)-adrenaline/I(1)-imidazoline receptor agonist which is known to elicit sympathoinhibitory action, would prevent the post-ischemic renal injury. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Intravenous (i.v.) injection of moxonidine at a dose of 360 nmol/kg to ischemic acute kidney injury rats suppressed the enhanced renal sympathetic nerve activity during the ischemic period, to a degree similar to findings with intracerebroventricular (i.c.v.) injection of moxonidine at a dose of 36 nmol/kg. On the other hand, suppressive effects of the i.v. treatment on renal venous norepinephrine overflow, renal dysfunction and tissue injury in the post-ischemic kidney were significantly greater than those elicited by the i.c.v. treatment. These results suggest that renoprotective effects of moxonidine on ischemic acute kidney injury probably result from its suppressive action on the ischemia-enhanced renal sympathetic nerve activity followed by norepinephrine spillover from the nerve endings of the post-ischemic kidney.

  6. NADPH oxidase inhibitor apocynin attenuates ischemia/reperfusion induced myocardial injury in rats

    Institute of Scientific and Technical Information of China (English)

    罗秀菊

    2013-01-01

    Objective To explore the role of NADPH oxidase inhibitor apocynin on ischemia/reperfusion(I/R)-induced myocardial injury. Methods Male SD rat hearts were divided into the normal control group; sham group;I/R group(1 h ischemia followed by 3 h reperfusion); I/R+ apocynin group(50 mg/kg,administrated at 30 min

  7. Evaluation of Chronic Physical and Psychological Stress Induction on Cardiac Ischemia / Reperfusion Injuries in Isolated Male Rat Heart: The Role of Sympathetic Nervous System

    Directory of Open Access Journals (Sweden)

    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.

  8. Melatonin treatment against remote organ injury induced by renal ischemia reperfusion injury in diabetes mellitus.

    Science.gov (United States)

    Fadillioglu, Ersin; Kurcer, Zehra; Parlakpinar, Hakan; Iraz, Mustafa; Gursul, Cebrail

    2008-06-01

    Oxidative stress may have a role in liver damage after acute renal injury due to various reasons such as ischemia reperfusion (IR). Diabetes mellitus (DM) is an important disease for kidneys and may cause nephropathy as a long term complication. The aim of this study was to investigate protective effect of melatonin, a potent antioxidant, against distant organ injury on liver induced by renal IR in rats with or without DM. The rats were divided into six groups: control (n=7), DM (n=5), IR (n=7), DM+IR (n=7), melatonin+IR (Mel+IR) (melatonin, 4 mg/ kg during 15 days) (n=7), and Mel+DM+IR groups (n=7). Diabetes developed 3 days after single i.p. dose of 45 mg/kg streptozotocin. After 15 day, the left renal artery was occluded for 30 min followed 24 h of reperfusion in IR performed groups. DM did not alter oxidative parameters alone in liver tissue. The levels of malondialdehyde, protein carbonyl and nitric oxide with activities of xanthine oxidase and myeloperoxidase were increased in liver tissues of diabetic and non-diabetic IR groups. Nitric oxide level in DM was higher than control. The activities of catalase and superoxide dismutase were increased in IR groups in comparison with control and DM. ALT and AST levels were higher in IR and DM+IR groups than control and DM. Melatonin treatment reversed all these oxidant and antioxidant parameters to control values as well as serum liver enzymes. We concluded that renal IR may affect distant organs such as liver and oxidative stress may play role on this injury, but DM has not an effect on kidney induced distant organ injury via oxidant stress. Also, it was concluded that melatonin treatment may prevent liver oxidant stress induced by distant injury of kidney IR.

  9. Mechanistic overview of reactive species-induced degradation of the endothelial glycocalyx during hepatic ischemia/reperfusion injury.

    Science.gov (United States)

    van Golen, Rowan F; van Gulik, Thomas M; Heger, Michal

    2012-04-15

    Endothelial cells are covered by a delicate meshwork of glycoproteins known as the glycocalyx. Under normophysiological conditions the glycocalyx plays an active role in maintaining vascular homeostasis by deterring primary and secondary hemostasis and leukocyte adhesion and by regulating vascular permeability and tone. During (micro)vascular oxidative and nitrosative stress, which prevails in numerous metabolic (diabetes), vascular (atherosclerosis, hypertension), and surgical (ischemia/reperfusion injury, trauma) disease states, the glycocalyx is oxidatively and nitrosatively modified and degraded, which culminates in an exacerbation of the underlying pathology. Consequently, glycocalyx degradation due to oxidative/nitrosative stress has far-reaching clinical implications. In this review the molecular mechanisms of reactive oxygen and nitrogen species-induced destruction of the endothelial glycocalyx are addressed in the context of hepatic ischemia/reperfusion injury as a model disease state. Specifically, the review focuses on (i) the mechanisms of glycocalyx degradation during hepatic ischemia/reperfusion, (ii) the molecular and cellular players involved in the degradation process, and (iii) its implications for hepatic pathophysiology. These topics are projected against a background of liver anatomy, glycocalyx function and structure, and the biology/biochemistry and the sources/targets of reactive oxygen and nitrogen species. The majority of the glycocalyx-related mechanisms elucidated for hepatic ischemia/reperfusion are extrapolatable to the other aforementioned disease states.

  10. Oxidative Stress and Lung Ischemia-Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    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.

  11. Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase

    Directory of Open Access Journals (Sweden)

    El-Shitany NA

    2015-09-01

    Full Text Available Nagla A El-Shitany,1,2 Karema El-Desoky3 1Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt; 3Department of Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt Abstract: Hepatic ischemia/reperfusion (ISCH/REP is a major clinical problem that is considered to be the most common cause of postoperative liver failure. Recently, mast cells have been proposed to play an important role in the pathophysiology of ISCH/REP in many organs. In contrast, the role played by mast cells during ISCH/REP-induced liver damage has remained an issue of debate. This study aimed to investigate the protective role of mast cells in order to search for an effective therapeutic agent that could protect against fatal ISCH/REP-induced liver damage. A model of warm ISCH/REP was induced in the liver of rats. Four groups of rats were used in this study: Group I: SHAM (normal saline, intravenously [iv]; Group II: ISCH/REP; Group III: sodium cromoglycate + ISCH/REP (CROM + ISCH/REP, and Group IV: ketotifen (KET + ISCH/REP (KET + ISCH/REP. Liver damage was assessed both histopathologically and biochemically. Mast cell degranulation was assessed histochemically. Lipid peroxidation (malondialdehyde [MDA] as well as the levels of glutathione (GSH, interleukin-6 (IL-6, and tumor necrosis factor alpha (TNF-α, the formation of nitric oxide (NO, and the expression of inducible NO synthase (iNOS were determined. The results of this study revealed increased mast cell degranulation in the liver during the acute phase of ISCH/REP. Moreover, CROM, but not KET, decreased the activity of alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase and maintained normal liver tissue histology. Both CROM and KET protected against mast cell degranulation in the liver. In addition, both CROM and KET decreased IL

  12. Novel monohydroxamate drugs attenuate myocardial reperfusion-induced arrhythmias

    DEFF Research Database (Denmark)

    Collis, C S; Rice-Evans, C; Davies, Michael Jonathan

    1996-01-01

    the first 5 min of reperfusion were quantified. Drugs (all at 150 microM) were introduced during the last 2 min of ischaemia and remained throughout reperfusion. Although the monohydroxamate- and desferrioxamine-treated hearts showed a reduction in the incidence of ventricular tachycardia and fibrillation...

  13. Hyperlipidemia exacerbates cerebral injury through oxidative stress, inflammation and neuronal apoptosis in MCAO/reperfusion rats.

    Science.gov (United States)

    Cao, Xiao-Lu; Du, Jing; Zhang, Ying; Yan, Jing-Ting; Hu, Xia-Min

    2015-10-01

    Recent studies showed that hyperglycemia enhanced brain damage when subjected to transient cerebral ischemic stroke. However, the etiologic link between them has been less known. In the present study, based on an experimental rat's model of hyperlipidemia combined with cerebral ischemia-reperfusion injury (I/R), we herein showed that hyperlipidemia induced by high-fat diet (HFD) resulted in considerable increase in serum triglycerides, cholesterol and low-density lipoprotein cholesterol, and remarkable decrease in serum high-density lipoprotein cholesterol, which associated with an exacerbation on neurological deficit, cerebral infarct and terminal deoxynucleotidyl transferase-mediated nick end labeling-positive cells in the ischemic hemisphere of cerebral I/R rats treated with HFD diet. The data showed that serum superoxide dismutase activity and glutathione peroxides content were significantly decreased, while malondialdehyde level was obviously increased by hyperlipidemia or cerebral I/R alone, especially by coexistence of hyperlipidemia and cerebral I/R; meantime, hyperlipidemia also enhanced cerebral I/R-induced protein expression of cytochrome P450 2E1 (CYP2E1) and the levels of pro-inflammatory factors tumor necrosis factor-α and IL-6 in the ischemic hemispheres. Furthermore, the combined action of hyperlipidemia and cerebral I/R resulted in a protein increase expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 compared to hyperlipidemia or cerebral I/R alone. Meanwhile, this study also showed that hyperlipidemia significantly enhanced cerebral I/R-induced transfer of cytochrome c from mitochondria to cytosolic and the protein expressions of Apaf-1 and caspase-3, but also decreased cerebral I/R-induced bcl-2 protein expression. The results reveal that hyperlipidemia exacerbates cerebral I/R-induced injury through the synergistic effect on CYP2E1 induction, which further induces reactive oxygen species formation, oxidative

  14. Xanthohumol suppresses inflammatory response to warm ischemia-reperfusion induced liver injury.

    Science.gov (United States)

    Dorn, Christoph; Massinger, Sabine; Wuzik, Andreas; Heilmann, Jörg; Hellerbrand, Claus

    2013-02-01

    Liver ischemia/reperfusion (I/R) leads to formation of reactive oxygen species (ROS), which cause hepatic injury and initiate an inflammatory response, which is a critical problem after liver surgery and transplantation. Xanthohumol, the major prenylated chalcone found in hops, has been discussed for its anti-inflammatory and ROS-scavenging properties, and thus, we aimed to investigate the effect of xanthohumol in a model of warm I/R liver injury. Xanthohumol was applied to BALB/c mice orally at a dose of 1 mg/g body weight for 5 days before I/R-injury was induced by clamping the vascular blood supply to the median and left lateral liver lobe for 1 h followed by a 6 h period of reperfusion. At this time, HPLC analysis revealed hepatic xanthohumol levels of approximately 2 μM, a concentration which has been shown to inhibit inflammatory effects in vitro. Assessment of hepatic HMOX1 expression, hepatic glutathione content and immunohistochemical analysis for proteins conjugated with the reactive aldehyde 4-hydroxynonenal indicated that I/R-induced oxidative stress was significantly inhibited in xanthohumol-fed compared to control mice. Histological analysis, TUNEL staining and determination of transaminase serum levels revealed no significant effects of xanthohumol on acute hepatocellular injury. However, at the same time point, pretreatment with xanthohumol almost completely blunted the I/R-induced AKT and NFκB activation and the expression of the proinflammatory genes IL-1alpha, IL-6, MCP-1 and ICAM-1, which are known to play a crucial role in the subacute phase of I/R-induced liver damage. In conclusion, these data indicate the potential of xanthohumol application to prevent adverse inflammatory responses to I/R-induced liver damage such as after surgical liver resection or transplantation.

  15. Pentoxifylline enhances the protective effects of hypertonic saline solution on liver ischemia reperfusion injury through inhibition of oxidative stress Pentoxifylline enhances the protective effects of hypertonic saline solution on liver ischemia reperfusion injury through inhibition of oxidative stress

    Institute of Scientific and Technical Information of China (English)

    Vinicius Rocha-Santos; Estela RR Figueira; Joel A Rocha-Filho; Ana MM Coelho; Rafael Soraes Pinheiro; Telesforo Bacchella; Marcel CC Machado; Luiz AC D'Albuquerque

    2015-01-01

    BACKGROUND:Liver ischemia reperfusion (IR) injury trig-gers a systemic inlfammatory response and is the main cause of organ dysfunction and adverse postoperative outcomes after liver surgery. Pentoxifylline (PTX) and hypertonic saline solution (HTS) have been identiifed to have beneifcial effects against IR injury. This study aimed to investigate if the addi-tion of PTX to HTS is superior to HTS alone for the preven-tion of liver IR injury. METHODS:Male Wistar rats were allocated into three groups. Control rats underwent 60 minutes of partial liver ischemia, HTS rats were treated with 0.4 mL/kg of intravenous 7.5%NaCl 15 minutes before reperfusion, and HPTX group were treated with 7.5% NaCl plus 25 mg/kg of PTX 15 minutes be-fore reperfusion. Samples were collected after reperfusion for determination of ALT, AST, TNF-α, IL-6, IL-10, mitochondrial respiration, lipid peroxidation, pulmonary permeability and myeloperoxidase. RESULTS:HPTX signiifcantly decreased TNF-α 30 minutes after reperfusion. HPTX and HTS signiifcantly decreased ALT, AST, IL-6, mitochondrial dysfunction and pulmonary myelo-peroxidase 4 hours after reperfusion. Compared with HTS only, HPTX signiifcantly decreased hepatic oxidative stress 4 hours after reperfusion and pulmonary permeability 4 and 12 hours after reperfusion. CONCLUSION:This study showed that PTX added the beneifcial effects of HTS on liver IR injury through decreases of hepatic oxidative stress and pulmonary permeability.

  16. The effect of Allium sativum on ischemic preconditioning and ischemia reperfusion induced cardiac injury

    Directory of Open Access Journals (Sweden)

    Bhatti Rajbir

    2008-01-01

    Full Text Available In the present study, the effect of garlic (Allium sativum extract on ischemic preconditioning and ischemia-reperfusion induced cardiac injury has been studied. Hearts from adult albino rats of Wistar strain were isolated and immediately mounted on Langendorff′s apparatus for retrograde perfusion. After 15 minutes of stabilization, the hearts were subjected to four episodes of 5 min ischemia, interspersed with 5 min reperfusion (to complete the protocol of ischemic preconditioning, 30 min global ischemia, followed by 120 min of reperfusion. In the control and treated groups, respective interventions were given instead of ischemic preconditioning. The magnitude of cardiac injury was quantified by measuring Lactate Dehydrogenase and creatine kinase concentration in the coronary effluent and myocardial infarct size by macroscopic volume method. Our study demonstrates that garlic extract exaggerates the cardio protection offered by ischemic preconditioning and per se treatment with garlic extract also protects the myocardium against ischemia reperfusion induced cardiac injury.

  17. Effect of tramadol on lung injury induced by skeletal muscle ischemia-reperfusion: an experimental study

    Directory of Open Access Journals (Sweden)

    Mohammad Ashrafzadeh Takhtfooladi

    2013-06-01

    Full Text Available OBJECTIVE: To determine whether tramadol has a protective effect against lung injury induced by skeletal muscle ischemia-reperfusion. METHODS: Twenty Wistar male rats were allocated to one of two groups: ischemia-reperfusion (IR and ischemia-reperfusion + tramadol (IR+T. The animals were anesthetized with intramuscular injections of ketamine and xylazine (50 mg/kg and 10 mg/kg, respectively. All of the animals underwent 2-h ischemia by occlusion of the femoral artery and 24-h reperfusion. Prior to the occlusion of the femoral artery, 250 IU heparin were administered via the jugular vein in order to prevent clotting. The rats in the IR+T group were treated with tramadol (20 mg/kg i.v. immediately before reperfusion. After the reperfusion period, the animals were euthanized with pentobarbital (300 mg/kg i.p., the lungs were carefully removed, and specimens were properly prepared for histopathological and biochemical studies. RESULTS: Myeloperoxidase activity and nitric oxide levels were significantly higher in the IR group than in the IR+T group (p = 0.001 for both. Histological abnormalities, such as intra-alveolar edema, intra-alveolar hemorrhage, and neutrophil infiltration, were significantly more common in the IR group than in the IR+T group. CONCLUSIONS: On the basis of our histological and biochemical findings, we conclude that tramadol prevents lung tissue injury after skeletal muscle ischemia-reperfusion.

  18. Role of Nuclear Factor kappaB in Intestine Injury Induced by Hepatic Ischemia Reperfusion

    Institute of Scientific and Technical Information of China (English)

    陈俊华; 王国斌

    2004-01-01

    Summary: The role of nuclear factor kappaB in intestine injury induced by hepatic ischemia reperfusion was investigated. Eighteen male Wistar rats were divided into 3 groups randomly: sham operation group (group A), hepatic ischemia reperfusion group (group B) and hepatic ischemia reperfusion plus pyrrolidine dithiocarbamate (PDTC) group (group C). The rats in group A were only subjected to laparotomy, those in group B underwent partial hepatic ischemia reperfusion (ischemia for 1 h and reperfusion for 2 h) and those in group C underwent the same procedure as that of group B but received PDTC 200 mg/kg i.v. before and after ischemia. After reperfusion, tissues of jejunum and venous blood were obtained for measurement of TNF-α, MDA and MPO. The levels of TNF-α in jejunum and venous blood, the levels of MPO in jejunum in group B were significantly higher than those in group A and group C (P<0.05). There was no significant different in the levels of MDA between group B and group C. The severity of histological intestinal injury in group B and group C was similar. Hepatic ischemia reperfusion caused intestine injury, NF-kappaB may play an important role in this course and the targeting of upstream components of the inflammatory response, such as NF-kappaB, may have important therapeutic applications.

  19. Role of mucus in gastric mucosal injury induced by local ischemia/reperfusion.

    Science.gov (United States)

    Seno, K; Joh, T; Yokoyama, Y; Itoh, M

    1995-09-01

    The role of gastric mucus was evaluated in a rat model of gastric epithelial damage induced by local ischemia/reperfusion (I/R) stress. In this model, blood-to-lumen chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) clearance served as an index of injury. Tetraprenyl acetone (TPA; 100 mg, 200 mg/kg IP) was used to stimulate mucus production. Administration of TPA increased both the hexosamine content in gastric tissue and the amount of alcian blue-periodic acid Schiff (AB-PAS) stained mucus in the mucosa in a dose-dependent manner. Increases in 51Cr-EDTA clearance induced by I/R were significantly attenuated by TPA in a dose-dependent manner. N-acetyl-L-cysteine (NAC; 0.6%, 0.8%) was perfused into the gastric lumen to assess the effect of reduction in mucus on the injury induced by I/R. Although mean values of hexosamine content were increased by perfusion with NAC, AB-PAS-stained mucus in the mucosa was significantly decreased in a dose-dependent manner. Perfusion of NAC did not change basal 51Cr-EDTA clearance but significantly exacerbated the increase in clearance induced by I/R in a dose-dependent manner. These results indicate that gastric mucus protects the gastric mucosa against I/R stress in vivo.

  20. Estrogen Sulfotransferase Is an Oxidative Stress-responsive Gene That Gender-specifically Affects Liver Ischemia/Reperfusion Injury.

    Science.gov (United States)

    Guo, Yan; Hu, Bingfang; Huang, Hai; Tsung, Allan; Gaikwad, Nilesh W; Xu, Meishu; Jiang, Mengxi; Ren, Songrong; Fan, Jie; Billiar, Timothy R; Huang, Min; Xie, Wen

    2015-06-05

    Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens. Liver ischemia and reperfusion (I/R) involves both hypoxia during the ischemic phase and oxidative damage during the reperfusion phase. In this report, we showed that the expression of EST was markedly induced by I/R. Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for the EST induction, which was abolished in Nrf2(-/-) mice. EST is a direct transcriptional target of Nrf2. In female mice, the I/R-responsive induction of EST compromised estrogen activity. EST ablation attenuated I/R injury as a result of decreased estrogen deprivation, whereas this benefit was abolished upon ovariectomy. The effect of EST ablation was sex-specific because the EST(-/-) males showed heightened I/R injury. Reciprocally, both estrogens and EST regulate the expression and activity of Nrf2. Estrogen deprivation by ovariectomy abolished the I/R-responsive Nrf2 accumulation, whereas the compromised estrogen deprivation in EST(-/-) mice was associated with increased Nrf2 accumulation. Our results suggested a novel I/R-responsive feedback mechanism to limit the activity of Nrf2 in which Nrf2 induces the expression of EST, which subsequently increases estrogen deactivation and limits the estrogen-responsive activation of Nrf2. Inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury.

  1. Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase

    Science.gov (United States)

    El-Shitany, Nagla A; El-Desoky, Karema

    2015-01-01

    Hepatic ischemia/reperfusion (ISCH/REP) is a major clinical problem that is considered to be the most common cause of postoperative liver failure. Recently, mast cells have been proposed to play an important role in the pathophysiology of ISCH/REP in many organs. In contrast, the role played by mast cells during ISCH/REP-induced liver damage has remained an issue of debate. This study aimed to investigate the protective role of mast cells in order to search for an effective therapeutic agent that could protect against fatal ISCH/REP-induced liver damage. A model of warm ISCH/REP was induced in the liver of rats. Four groups of rats were used in this study: Group I: SHAM (normal saline, intravenously [iv]); Group II: ISCH/REP; Group III: sodium cromoglycate + ISCH/REP (CROM + ISCH/REP), and Group IV: ketotifen (KET) + ISCH/REP (KET + ISCH/REP). Liver damage was assessed both histopathologically and biochemically. Mast cell degranulation was assessed histochemically. Lipid peroxidation (malondialdehyde [MDA]) as well as the levels of glutathione (GSH), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), the formation of nitric oxide (NO), and the expression of inducible NO synthase (iNOS) were determined. The results of this study revealed increased mast cell degranulation in the liver during the acute phase of ISCH/REP. Moreover, CROM, but not KET, decreased the activity of alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase and maintained normal liver tissue histology. Both CROM and KET protected against mast cell degranulation in the liver. In addition, both CROM and KET decreased IL-6 and TNF-α. However, CROM, but not KET, decreased MDA formation and increased GSH. Furthermore, KET, but not CROM, increased both NO formation and iNOS expression. In conclusion, this study clearly demonstrated mast cell degranulation in warm ISCH/REP in the liver of rats. More importantly, CROM, but not KET, ameliorated the effect of ISCH/REP-induced

  2. Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase.

    Science.gov (United States)

    El-Shitany, Nagla A; El-Desoky, Karema

    2015-01-01

    Hepatic ischemia/reperfusion (ISCH/REP) is a major clinical problem that is considered to be the most common cause of postoperative liver failure. Recently, mast cells have been proposed to play an important role in the pathophysiology of ISCH/REP in many organs. In contrast, the role played by mast cells during ISCH/REP-induced liver damage has remained an issue of debate. This study aimed to investigate the protective role of mast cells in order to search for an effective therapeutic agent that could protect against fatal ISCH/REP-induced liver damage. A model of warm ISCH/REP was induced in the liver of rats. Four groups of rats were used in this study: Group I: SHAM (normal saline, intravenously [iv]); Group II: ISCH/REP; Group III: sodium cromoglycate + ISCH/REP (CROM + ISCH/REP), and Group IV: ketotifen (KET) + ISCH/REP (KET + ISCH/REP). Liver damage was assessed both histopathologically and biochemically. Mast cell degranulation was assessed histochemically. Lipid peroxidation (malondialdehyde [MDA]) as well as the levels of glutathione (GSH), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), the formation of nitric oxide (NO), and the expression of inducible NO synthase (iNOS) were determined. The results of this study revealed increased mast cell degranulation in the liver during the acute phase of ISCH/REP. Moreover, CROM, but not KET, decreased the activity of alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase and maintained normal liver tissue histology. Both CROM and KET protected against mast cell degranulation in the liver. In addition, both CROM and KET decreased IL-6 and TNF-α. However, CROM, but not KET, decreased MDA formation and increased GSH. Furthermore, KET, but not CROM, increased both NO formation and iNOS expression. In conclusion, this study clearly demonstrated mast cell degranulation in warm ISCH/REP in the liver of rats. More importantly, CROM, but not KET, ameliorated the effect of ISCH/REP-induced

  3. Digital image analysis of striated skeletal muscle tissue injury during reperfusion after induced ischemia

    Science.gov (United States)

    Rosero Salazar, Doris Haydee; Salazar Monsalve, Liliana

    2015-01-01

    Conditions such as surgical procedures or vascular diseases produce arterial ischemia and reperfusion injuries, which generate changes in peripheral tissues and organs, for instance, in striated skeletal muscle. To determine such changes, we conducted an experimental method in which 42 male Wistar rat were selected, to be undergone to tourniquet application on the right forelimb and left hind limb, to induce ischemia during one and three hours, followed by reperfusion periods starting at one hour and it was prolonged up to 32 days. Extensor carpi radialis longus and soleus respectively, were obtained to be processed for histochemical and morphometric analysis. By means of image processing and detection of regions of interest, variations of areas occupied by muscle fibers and intramuscular extracellular matrix (IM-ECM) throughout reperfusion were observed. In extensor carpi radialis longus, results shown reduction in the area occupied by muscle fibers; this change is significant between one hour and three hours ischemia followed by 16 hours, 48 hours and 32 days reperfusión (p˂0.005). To compare only periods of reperfusión that continued to three hours ischemia, were found significant differences, as well. For area occupied by IM-ECM, were identified increments in extensor carpi radialis longus by three hours ischemia and eight to 16 days reperfusion; in soleus, was observed difference by one hour ischemia with 42 hours reperfusion, and three hours ischemia followed by four days reperfusion (p˂0.005). Skeletal muscle develops adaptive changes in longer reperfusion, to deal with induced injury. Descriptions beyond 32 days reperfusion, can determine recovering normal pattern.

  4. Selective heart rate reduction with ivabradine slows ischaemia-induced electrophysiological changes and reduces ischaemia–reperfusion-induced ventricular arrhythmias

    Science.gov (United States)

    Ng, Fu Siong; Shadi, Iqbal T.; Peters, Nicholas S.; Lyon, Alexander R.

    2013-01-01

    Heart rates during ischaemia and reperfusion are possible determinants of reperfusion arrhythmias. We used ivabradine, a selective If current inhibitor, to assess the effects of heart rate reduction (HRR) during ischaemia–reperfusion on reperfusion ventricular arrhythmias and assessed potential anti-arrhythmic mechanisms by optical mapping. Five groups of rat hearts were subjected to regional ischaemia by left anterior descending artery occlusion for 8 min followed by 10 min of reperfusion: (1) Control n = 10; (2) 1 μM of ivabradine perfusion n = 10; (3) 1 μM of ivabradine + 5 Hz atrial pacing throughout ischaemia–reperfusion n = 5; (4) 1 μM of ivabradine + 5 Hz pacing only at reperfusion; (5) 100 μM of ivabradine was used as a 1 ml bolus upon reperfusion. For optical mapping, 10 hearts (ivabradine n = 5; 5 Hz pacing n = 5) were subjected to global ischaemia whilst transmembrane voltage transients were recorded. Epicardial activation was mapped, and the rate of development of ischaemia-induced electrophysiological changes was assessed. HRR observed in the ivabradine group during both ischaemia (195 ± 11 bpm vs. control 272 ± 14 bpm, p hearts (27.7 ± 4.3 min vs. 14.5 ± 0.6 min, p Heart rate during ischaemia is a major determinant of reperfusion arrhythmias. Heart rate at reperfusion alone was not a determinant of reperfusion VF, as neither a bolus of ivabradine nor pacing immediately prior to reperfusion significantly altered reperfusion VF incidence. This anti-arrhythmic effect of heart rate reduction during ischaemia may reflect slower development of ischaemia-induced electrophysiological changes. PMID:23402927

  5. Edaravone attenuates ischemia-reperfusion injury by inhibiting oxidative stress in a canine lung transplantation model

    Institute of Scientific and Technical Information of China (English)

    XU Jin-zhi; SHEN Bao-zhong; LI Ye; ZHANG Tong; XU Wan-hai; LIU Xiao-wei; LU Hong-guang

    2008-01-01

    .Conclusions Edaravone attenuates IR-induced lung injury and preserves lung function by inhibiting oxidative stress and decreasing leukocyte extravasation in a canine lung transplantation model.

  6. Cardioprotective effect of the Hibiscus rosa sinensis flowers in an oxidative stress model of myocardial ischemic reperfusion injury in rat

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    Krishnamoorthy Karthikeyan K

    2006-09-01

    Full Text Available Abstract Background The present study investigates the cardioprotective effects of Hibiscus rosa sinensis in myocardial ischemic reperfusion injury, particularly in terms of its antioxidant effects. Methods The medicinal values of the flowers of Hibiscus rosa sinensis (Chinese rose have been mentioned in ancient literature as useful in disorders of the heart. Dried pulverized flower of Hibiscus rosa sinensis was administered orally to Wistar albino rats (150–200 gms in three different doses [125, 250 and 500 mg/kg in 2% carboxy methyl cellulose (CMC], 6 days per week for 4 weeks. Thereafter, rats were sacrificed; either for the determination of baseline changes in cardiac endogenous antioxidants [superoxide dismutase, reduced glutathione and catalase] or the hearts were subjected to isoproterenol induced myocardial necrosis. Results There was significant increase in the baseline contents of thiobarbituric acid reactive substances (TBARS [a measure of lipid per oxidation] with both doses of Hibiscus Rosa sinensis. In the 250 mg/kg treated group, there was significant increase in superoxide dismutase, reduced glutathione, and catalase levels but not in the 125 and 500 mg/kg treated groups. Significant rise in myocardial thiobarbituric acid reactive substances and loss of superoxide dismutase, catalase and reduced glutathione (suggestive of increased oxidative stress occurred in the vehicle treated hearts subjected to in vivo myocardial ischemic reperfusion injury. Conclusion It may be concluded that flower of Hibiscus rosa sinensis (250 mg/kg augments endogenous antioxidant compounds of rat heart and also prevents the myocardium from isoproterenol induced myocardial injury.

  7. Comparison of changes in markers of muscle damage induced by eccentric exercise and ischemia/reperfusion.

    Science.gov (United States)

    Su, Q-S; Zhang, J-G; Dong, R; Hua, B; Sun, J-Z

    2010-10-01

    To examine the effects of eccentric exercise (EE) and ischemia/reperfusion (I/R) on the markers of muscle damage, 72 rats were randomly assigned to the EE group, I/R group and control group (C), respectively. The rats in EE ran downhill on a treadmill with a 16 ° inclination at a constant speed for 90 min, and the rats in the I/R group underwent 90 min of four-limb ischemia, followed by 24, 48 and 72 h of reperfusion. Blood and tissue samples were collected immediately, 24, 48 and 72 h after exercise or reperfusion. Quantitative analyses showed that the I/R group had a significantly larger mitochondrial volume at 24 h after reperfusion compared with the C, and there were more disrupted Z-lines in the EE group and more disrupted mitochondria in the I/R group at 24 h after exercise or reperfusion. When compared with the C, a significantly lower total antioxidant capacity and higher interleukin-6 value were observed after exercise or reperfusion. Our data suggest that although EE and I/R result in some similar changes in the muscle damage markers, there are still some differences. The EE- and I/R-induced muscle damage may be due to different mechanisms.

  8. Role of interleukin 18 in acute lung inflammation induced by gut ischemia reperfusion

    Institute of Scientific and Technical Information of China (English)

    Yong-Jie Yang; Yun Shen; Song-Hua Chen; Xi-Rui Ge

    2005-01-01

    AIM: To study the changes of endogenous interleukin 18 (IL-18) levels and evaluate the role of IL-18 on lung injury following gut ischemia/reperfusion.METHODS: A superior mesenteric artery occlusion model was selected for this research. The mice were randomly divided into four groups: Sham operation (sham), ischemia (0.5 h) followed by different times of reperfusion (I/R),and I/R pretreated with exogenous IL-18 (I/R+IL-18) or IL-18 neutralizing antibody (I/R+IL-18Ab) 15 min before ischemia. Serum IL-18 levels were detected by Western blot and ELISA, and the levels of IL-18 in lung tissue were evaluated by immunohistochemical staining. For the study of pulmonary inflammation, the lung myeloperoxidase (MPO) contents and morphological changes were evaluated.RESULTS: Gut ischemia/reperfusion induced rapid increase of serum IL-18 levels, peaked at 1 h after reperfusion and then declined. The levels of IL-18 in lung tissue were gradually enhanced as the progress of reperfusion.Compared with I/R group, exogenous administration of IL-18 (I/R+IL-18) further remarkably enhanced the pulmonary MPO activity and inflammatory cell infiltration,and in I/R+IL-18Ab group, the content of MPO were significantly reduced and lung inflammation was also decreased.CONCLUSION: Gut ischemia/reperfusion induces the increase of IL-18 expression, which may make IL-18 act as an important proinflammatory cytokine and contribute to gut ischemia/reperfusion-induced lung inflammation.

  9. 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.

  10. Sulforaphane improves oxidative status without attenuating the inflammatory response or cardiac impairment induced by ischemia-reperfusion in rats.

    Science.gov (United States)

    Bonetto, Jéssica Hellen Poletto; Fernandes, Rafael Oliveira; Seolin, Bruna Gazzi de Lima; Müller, Dalvana Daneliza; Teixeira, Rayane Brinck; Araujo, Alex Sander; Vassallo, Dalton; Schenkel, Paulo Cavalheiro; Belló-Klein, Adriane

    2016-05-01

    Sulforaphane, a natural isothiocyanate, demonstrates cardioprotection associated with its capacity to stimulate endogenous antioxidants and to inhibit inflammation. The aim of this study was to investigate whether sulforaphane is capable of attenuating oxidative stress and inflammatory responses through the TLR4/MyD88/NFκB pathway, and thereby could modulate post-ischemic ventricular function in isolated rat hearts submitted to ischemia and reperfusion. Male Wistar rats received sulforaphane (10 mg·kg(-1)·day(-1)) or vehicle i.p. for 3 days. Global ischemia was performed using isolated hearts, 24 h after the last injection, by interruption of the perfusion flow. The protocol included a 20 min pre-ischemic period followed by 20 min of ischemia and a 20 min reperfusion. Although no changes in mechanical function were observed, sulforaphane induced a significant increase in superoxide dismutase and heme oxygenase-1 expression (both 66%) and significantly reduced reactive oxygen species levels (7%). No differences were observed for catalase and glutathione peroxidase expression or their activities, nor for thioredoxin reductase, glutaredoxin reductase and glutathione-S-transferase. No differences were found in lipid peroxidation or TLR4, MyD88, and NF-κB expression. In conclusion, although sulforaphane was able to stimulate endogenous antioxidants modestly, this result did not impact inflammatory signaling or cardiac function of hearts submitted to ischemia and reperfusion.

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

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    Hamed Ashrafzadeh Takhtfooladi

    2015-01-01

    Full Text Available Background: 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. Objective: This study evaluated the effects of tramadol on the heart as a remote organ after acute hindlimb IR. Methods: 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. Results: 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. Conclusion: From the histological and biochemical perspectives, treatment with tramadol alleviated the myocardial injuries induced by skeletal muscle IR in this experimental model.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  13. 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

  14. The Role of Oxidative Stress in Myocardial Ischemia and Reperfusion Injury and Remodeling: Revisited

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    Gino A. Kurian

    2016-01-01

    Full Text Available Oxidative and reductive stress are dual dynamic phases experienced by the cells undergoing adaptation towards endogenous or exogenous noxious stimulus. The former arises due to the imbalance between the reactive oxygen species production and antioxidant defenses, while the latter is due to the aberrant increase in the reducing equivalents. Mitochondrial malfunction is the common denominator arising from the aberrant functioning of the rheostat that maintains the homeostasis between oxidative and reductive stress. Recent experimental evidences suggest that the maladaptation during oxidative stress could play a pivotal role in the pathophysiology of major cardiovascular diseases such as myocardial infraction, atherosclerosis, and diabetic cardiovascular complications. In this review we have discussed the role of oxidative and reductive stress pathways in the pathogenesis of myocardial ischemia/reperfusion injury and diabetic cardiomyopathy (DCM. Furthermore, we have provided impetus for the development of subcellular organelle targeted antioxidant drug therapy for thwarting the deterioration of the failing myocardium in the aforementioned cardiovascular conditions.

  15. Role of mucus in ischemia/reperfusion-induced gastric mucosal injury in rats.

    Science.gov (United States)

    Mojzis, J; Hegedüsová, R; Mirossay, L

    2000-01-01

    Gastric mucus plays an important role in gastric mucosal protection. Apart from its "barrier" function, it has been demonstrated that mucus protects gastric epithelial cells against toxic oxygen metabolites derived from the xanthine/ xanthine oxidase system. In this study, we investigated the effect of malotilate and sucralfate (mucus production stimulators) and N-acetylcysteine (mucolytic agent) on ischemia/reperfusion-induced gastric mucosal injury. Gastric ischemia was induced by 30 min clamping of the coeliac artery followed by 30 min of reperfusion. The mucus content was determined by the Alcian blue method. Sucralfate (100 mg/kg), malotilate (100 mg/kg), and N-acetylcysteine (100 mg/kg) were given orally 30 min before surgery. Both sucralfate and malotilate increased the mucus production in control rats. On the other hand, N-acetyloysteine significantly decreased mucus content in control (sham) group. A significant decrease of mucus content was found in the control and the N-acetylcysteine pretreated group during the period of ischemia. On the other hand, sucralfate and malotilate prevented the decrease the content of mucus during ischemia. A similar result can be seen after ischemia/reperfusion. In the control group and N-acetylcysteine pretreated group a significant decrease of adherent mucus content was found. However, sucralfate and malotilate increased mucus production (sucralfate significantly). Sucralfate and malotilate also significantly protected the gastric mucosa against ischemia/reperfusion-induced injury. However, N-acetylcysteine significantly increased gastric mucosal injury after ischemia/reperfusion. These results suggest that gastric mucus may be involved in the protection of gastric mucosa after ischemia/reperfusion.

  16. Sulforaphane protects liver injury induced by intestinal ischemia reperfusion through Nrf2-ARE pathway

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM: To investigate the effect of sulforaphane (SFN) on regulation of NF-E2-related factor-2 (Nrf2)-antiox-idant response element (ARE) pathway in liver injury induced by intestinal ischemia/reperfusion (I/R). METHODS: Rats were divided randomly into four ex-perimental groups: control, SFN control, intestinal I/R and SFN pretreatment groups (n = 8 in each group). The intestinal I/R model was established by clamping the superior mesenteric artery for 1 h and 2 h reperfu-sion. In the SFN pretreatment group, s...

  17. The Modulatory Effect of Ischemia and Reperfusion on Arginine Vasopressin-Induced Arterial Reactions.

    Science.gov (United States)

    Szadujkis-Szadurska, Katarzyna; Malinowski, Bartosz; Piotrowska, Małgorzata; Grześk, Grzegorz; Wiciński, Michał; Gajdus, Marta

    2016-01-01

    Aim of the Study. The purpose of this study was to investigate the impact of ischemia and reperfusion on the resistance of arteries to AVP (arginine vasopressin), with a particular emphasis on the role of smooth muscle cells in the action of vasopressin receptors and the role of the cGMP-associated signalling pathway. Materials and Methods. Experiment was performed on the perfunded tail arteries from male Wistar rats. The constriction triggered by AVP after 30 minutes of ischemia and 30 and 90 minutes of reperfusion was analysed. Analogous experiments were also carried out in the presence of 8Br-cGMP. Results. Ischemia reduces and reperfusion increases in a time-dependent manner the arterial reaction to AVP. The presence of 8Br-cGMP causes a significant decrease of arterial reactivity under study conditions. Conclusions. Ischemia and reperfusion modulate arterial contraction triggered by AVP. The effect of 8Br-cGMP on reactions, induced by AVP after ischemia and reperfusion, indicates that signalling pathway associated with nitric oxide (NO) and cGMP regulates the tension of the vascular smooth muscle cells.

  18. Activation of TRPC6 Channels Is Essential for Lung Ischaemia–Reperfusion Induced Oedema in Mice

    OpenAIRE

    Weissmann, Norbert; Sydykov, Akylbek; Kalwa, Hermann; Storch, Ursula; Fuchs, Beate; Mederos y Schnitzler, Michael; Ralf P Brandes; Grimminger, Friedrich; Meissner, Marcel; Freichel, Marc; Offermanns, Stefan; Veit, Florian; Pak, Oleg; Krause, Karl-Heinz; Schermuly, Ralph T.

    2012-01-01

    Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2\\(^{y/−}\\)) or the classical transient receptor potential channel 6 TRPC6\\(^{−/-}\\) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that...

  19. Electroacupuncture regulates the stress-injury-repair chain of events after cerebral ischemia/reperfusion injury

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    Peng Shi

    2017-01-01

    Full Text Available Inflammation after stroke is the main cause of cerebral ischemia/reperfusion injury. Cascading events after injury can lead to cell death. Heat shock protein 70 and other endogenous injury-signaling molecules are released by damaged cells, which can lead to systemic stress reactions. Protecting the brain through repair begins with the stress-injury-repair signaling chain. This study aimed to verify whether acupuncture acts through this chain to facilitate effective treatment of ischemic stroke. Rat models of cerebral ischemia/reperfusion injury were established by Zea Longa's method, and injury sites were identified by assessing neurological function, 2,3,5-triphenyltetrazolium chloride staining, and hematoxylin-eosin staining. Electroacupuncture at acupoints Baihui (DU20 and Zusanli (ST36 was performed in the model rats with dilatational waves, delivered for 20 minutes a day at 2–100 Hz and an amplitude of 2 mA. We analyzed the blood serum from the rats and found that inflammatory cytokines affected the levels of adrenotrophin and heat shock protein 70, each of which followed a similar bimodal curve. Specifically, electroacupuncture lowered the peak levels of adrenocorticotrophic hormone and heat shock protein 70. Thus, electroacupuncture was able to inhibit excessive stress, reduce inflammation, and promote the repair of neurons, which facilitated healing of ischemic stroke.

  20. Glyceryl 1,3-Dipalmitate Produced from Lactobacillus paracasei subspecies. paracasei NTU 101 Inhibits Oxygen-Glucose Deprivation and Reperfusion-Induced Oxidative Stress via Upregulation of Peroxisome Proliferator-Activated Receptor γ in Neuronal SH-SY5Y Cells.

    Science.gov (United States)

    Cheng, Meng-Chun; Pan, Tzu-Ming

    2017-09-13

    Glyceryl 1,3-dipalmitate (GD) purified from Lactobacillus paracasei subsp. paracasei NTU 101-fermented products has been demonstrated to possess neuroprotective properties. We determined the effect of GD on oxygen-glucose deprivation and reperfusion (OGD/R)-induced SH-SY5Y neuroblastoma cell death. GD ameliorated OGD/R-induced apoptosis by elevating the protein expression of nuclear peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby attenuating reactive oxygen species (ROS) generation. Pretreatment with GD reduced nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) expression from 1.54 ± 0.27 to 0.84 ± 0.46, thereby attenuating the induction of pro-inflammatory mediators, and increased the plasma membrane Ca(2+) ATPase (PMCA) levels from 0.81 ± 0.02 to 1.08 ± 0.06, thus reducing the levels of cytosolic Ca(2+); this also correlated with reduced cell death. We conclude that GD prevents SH-SY5Y cells from injury after OGD/R insult, possibly by modulating oxidative stress and inflammatory response.

  1. Pretreatment with low doses of acenocoumarol inhibits the development of acute ischemia/reperfusion-induced pancreatitis.

    Science.gov (United States)

    Warzecha, Z; Sendur, P; Ceranowicz, P; Dembinski, M; Cieszkowski, J; Kusnierz-Cabala, B; Tomaszewska, R; Dembinski, A

    2015-10-01

    Coagulative disorders are known to occur in acute pancreatitis and are related to the severity of this disease. Various experimental and clinical studies have shown protective and therapeutic effect of heparin in acute pancreatitis. Aim of the present study was to determine the influence of acenocoumarol, a vitamin K antagonist, on the development of acute pancreatitis. Studies were performed on male Wistar rats weighing 250 - 270 g. Acenocoumarol at the dose of 50, 100 or 150 μg/kg/dose or vehicle were administered once a day for 7 days before induction of acute pancreatitis. Acute pancreatitis was induced in rats by pancreatic ischemia followed by reperfusion. The severity of acute pancreatitis was assessed after 5-h reperfusion. Pretreatment with acenocoumarol given at the dose of 50 or 100 μg/kg/dose reduced morphological signs of acute pancreatitis. These effects were accompanied with a decrease in the pancreatitis-evoked increase in serum activity of lipase and serum concentration of pro-inflammatory interleukin-1β. Moreover, the pancreatitis-evoked reductions in pancreatic DNA synthesis and pancreatic blood flow were partially reversed by pretreatment with acenocoumarol given at the dose of 50 and 100 μg/kg/dose. Administration of acenocoumarol at the dose of 150 μg/kg/dose did not exhibit any protective effect against ischemia/reperfusion-induced pancreatitis. We concluded that pretreatment with low doses of acenocoumarol reduces the severity of ischemia/reperfusion-induced acute pancreatitis.

  2. Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Intermittent hypoxia has been shown to provide myocardial protection against ishemia/reperfusion-induced injury.Cardiac myocyte loss through apoptosis has been reported in ischemia/reperfusion injury. Our aim was to investigate whether intermittent hypoxia could attenuate ischemia/reperfusion-induced apoptosis in cardiac myocytes and its potential mechanisms. Adult male Sprague-Dawley rats were exposed to hypoxia simulated 5000 m in a hypobaric chamber for 6 h/day, lasting 42 days. Normoxia group rats were kept under normoxic conditions. Isolated perfused hearts from both groups were subjected to 30 min of global ischemia followed by 60 min reperfusion.Incidence of apoptosis in cardiac myocytes was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and DNA agarose gel electrophoresis. Expressions of apoptosis related proteins,Bax and Bcl-2, in cytosolic and membrane fraction were detected by Western Blotting. After ischemia/reperfusion,enhanced recovery of cardiac function was observed in intermittent hypoxia hearts compared with normoxia group.Ischemia/reperfusion-induced apoptosis, as evidenced by TUNEL-positive nuclei and DNA fragmentation, was significantly reduced in intermittent hypoxia group compared with normoxia group. After ischemia/reperfusion,expression of Bax in both cytosolic and membrane fractions was decreased in intermittent hypoxia hearts compared with normoxia group. Although ischemia/reperfusion did not induce changes in the level of Bcl-2 expression in cytosolic fraction between intermittent hypoxia and normoxia groups, the expression of Bcl-2 in membrane fraction was upregulated in intermittent hypoxia group compared with normoxia group. These results indicated that the cardioprotection of intermittent hypoxia against ischemia/reperfusion injury appears to be in part due to reduce myocardial apoptosis. Intermittent hypoxia attenuated ischemia/reperfusion-induced apoptosis via increasing the ratio of Bcl

  3. High-fat, low-carbohydrate diet alters myocardial oxidative stress and impairs recovery of cardiac function after ischemia and reperfusion in obese rats.

    Science.gov (United States)

    Liu, Jian; Lloyd, Steven G

    2013-04-01

    Obesity is associated with elevated risk of heart disease. A solid understanding of the safety and potential adverse effects of high-fat, low-carbohydrate diet (HFLCD) similar to that used by humans for weight loss on the heart is crucial. High fat intake is known to promote increases in reactive oxygen species and mitochondrial damage. We hypothesized that there would be adverse effects of HFLCD on myocardial ischemia/reperfusion injury through enhancing oxidative stress injury and impairing mitochondrial biogenesis in a nongenetic, diet-induced rat model of obesity. To test the hypothesis, 250-g male Sprague-Dawley rats were fed an obesity-promoting diet for 7 weeks to induce obesity, then switched to HFLCD or a low-fat control diet for 2 weeks. Isolated hearts underwent global low flow ischemia for 60 minutes and reperfusion for 60 minutes. High-fat, low-carbohydrate diet resulted in greater weight gain and lower myocardial glycogen, plasma adiponectin, and insulin. Myocardial antioxidant gene transcript and protein expression of superoxide dismutase and catalase were reduced in HFLCD, along with increased oxidative gene NADPH oxidase-4 transcript and xanthine oxidase activity, and a 37% increase in nitrated protein (nitrotyrosine) in HFLCD hearts. The cardiac expression of key mitochondrial regulatory factors such as nuclear respiratory factor-1 and transcription factor A-mitochondrial were inhibited and myocardial mitochondrial DNA copy number decreased. The cardiac expression of adiponectin and its receptors was down-regulated in HFLCD. High-fat, low-carbohydrate diet impaired recovery of left ventricular rate-pressure product after ischemia/reperfusion and led to 3.5-fold increased injury as measured by lactate dehydrogenase release. In conclusion, HFLCD leads to increased ischemic myocardial injury and impaired recovery of function after reperfusion and was associated with attenuation of mitochondrial biogenesis and enhanced oxidative stress in obese rats

  4. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress.

    Science.gov (United States)

    Fukuda, Kei-ichi; Asoh, Sadamitsu; Ishikawa, Masahiro; Yamamoto, Yasuhiro; Ohsawa, Ikuroh; Ohta, Shigeo

    2007-09-28

    We have recently showed that molecular hydrogen has great potential for selectively reducing cytotoxic reactive oxygen species, such as hydroxyl radicals, and that inhalation of hydrogen gas decreases cerebral infarction volume by reducing oxidative stress [I. Ohsawa, M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K.-I. Katsura, Y. Katayama, S. Asoh, S. Ohta, Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Nat. Med., 13 (2007) 688-694]. Here we show that the inhalation of hydrogen gas is applicable for hepatic injury caused by ischemia/reperfusion, using mice. The portal triad to the left lobe and the left middle lobe of the liver were completely occluded for 90min, followed by reperfusion for 180min. Inhalation of hydrogen gas (1-4%) during the last 190min suppressed hepatic cell death, and reduced levels of serum alanine aminotransferase and hepatic malondialdehyde. In contrast, helium gas showed no protective effect, suggesting that the protective effect by hydrogen gas is specific. Thus, we propose that inhalation of hydrogen gas is a widely applicable method to reduce oxidative stress.

  5. Relevance of Endoplasmic Reticulum Stress Cell Signaling in Liver Cold Ischemia Reperfusion Injury

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    Emma Folch-Puy

    2016-05-01

    Full Text Available The endoplasmic reticulum (ER is involved in calcium homeostasis, protein folding and lipid biosynthesis. Perturbations in its normal functions lead to a condition called endoplasmic reticulum stress (ERS. This can be triggered by many physiopathological conditions such as alcoholic steatohepatitis, insulin resistance or ischemia-reperfusion injury. The cell reacts to ERS by initiating a defensive process known as the unfolded protein response (UPR, which comprises cellular mechanisms for adaptation and the safeguarding of cell survival or, in cases of excessively severe stress, for the initiation of the cell death program. Recent experimental data suggest the involvement of ERS in ischemia/reperfusion injury (IRI of the liver graft, which has been considered as one of major problems influencing outcome after liver transplantation. The purpose of this review is to summarize updated data on the molecular mechanisms of ERS/UPR and the consequences of this pathology, focusing specifically on solid organ preservation and liver transplantation models. We will also discuss the potential role of ERS, beyond the simple adaptive response and the regulation of cell death, in the modification of cell functional properties and phenotypic changes.

  6. Inhibition of Sevoflurane Postconditioning Against Cerebral Ischemia Reperfusion-Induced Oxidative Injury in Rats

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    Shi-Dong Zhang

    2011-12-01

    Full Text Available The volatile anesthetic sevoflurane is capable of inducing preconditioning and postconditioning effects in the brain. In this study, we investigated the effects of sevoflurane postconditioning on antioxidant and immunity indexes in cerebral ischemia reperfusion (CIR rats. Rats were randomly assigned to five separate experimental groups I–V. In the sham group (I, rats were subjected to the same surgery procedures except for occlusion of the middle cerebral artery and exposed to 1.0 MAC sevoflurane 90 min after surgery for 30 min. IR control rats (group II were subjected to middle cerebral artery occlusion (MCAO for 90 min and exposed to O2 for 30 min at the beginning of reperfusion. Sevoflurane 0.5, 1.0 and 1.5 groups (III, IV, V were all subjected to MCAO for 90 min, but at the beginning of reperfusion exposed to 0.5 MAC, 1.0 MAC or 1.5 MAC sevoflurane for 30 min, respectively. Results showed that sevoflurane postconditioning can decrease serum tumor necrosis factor-alpha (TNF-α, interleukin-1 beta (IL-1β, nitric oxide (NO, nitric oxide synthase (NOS and increase serum interleukin-10 (IL-10 levels in cerebral ischemia reperfusion rats. In addition, sevoflurane postconditioning can still decrease blood lipid, malondialdehyde (MDA levels, infarct volume and increase antioxidant enzymes activities, normal pyramidal neurons density in cerebral ischemia reperfusion rats. It can be concluded that sevoflurane postconditioning may decrease blood and brain oxidative injury and enhance immunity indexes in cerebral ischemia reperfusion rats.

  7. Cardioprotection by modulation of mitochondrial respiration during ischemia–reperfusion: Role of apoptosis-inducing factor

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Aijun [Department of Internal Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA 23298 (United States); Department of Anesthesiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030 (China); Szczepanek, Karol; Hu, Ying [Department of Internal Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA 23298 (United States); Lesnefsky, Edward J. [Department of Internal Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA 23298 (United States); Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298 (United States); Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298 (United States); McGuire Department of Veterans Affairs Medical Center, Richmond, VA 23249 (United States); Chen, Qun, E-mail: qchen8@vcu.edu [Department of Internal Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA 23298 (United States)

    2013-06-14

    Highlights: •Blockade of electron transport prevents the loss of AIF from mitochondria during IR. •Blockade of electron transport decreases caspase-independent cell death during IR. •Mitochondrial AIF content is down-regulated in Harlequin mice. •Blockade of electron transport protects Harlequin mouse hearts during IR. •Amobarbital protection is partially dependent on mitochondrial AIF content. -- Abstract: The transient, reversible blockade of electron transport (BET) during ischemia or at the onset of reperfusion protects mitochondria and decreases cardiac injury. Apoptosis inducing factor (AIF) is located within the mitochondrial intermembrane space. A release of AIF from mitochondria into cytosol and nucleus triggers caspase-independent cell death. We asked if BET prevents the loss of AIF from mitochondria as a mechanism of protection in the buffer perfused heart. BET during ischemia with amobarbital, a rapidly reversible inhibitor of mitochondrial complex I, attenuated a release of AIF from mitochondria into cytosol, in turn decreasing the formation of cleaved and activated PARP-1. These results suggest that BET-mediated protection may occur through prevention of the loss of AIF from mitochondria during ischemia–reperfusion. In order to further clarify the role of mitochondrial AIF in BET-mediated protection, Harlequin (Hq) mice, a genetic model with mitochondrial AIF deficiency, were used to test whether BET could still decrease cell injury in Hq mouse hearts during reperfusion. BET during ischemia protected Hq mouse hearts against ischemia–reperfusion injury and improved mitochondrial function in these hearts during reperfusion. Thus, cardiac injury can still be decreased in the presence of down-regulated mitochondrial AIF content. Taken together, BET during ischemia protects both hearts with normal mitochondrial AIF content and hearts with mitochondrial AIF deficiency. Although preservation of mitochondrial AIF content plays a key role in

  8. Protective effects of Saffron hydroalcoholic extract against renal tissue damages induced by ischemia-reperfusion in rats

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    Houshang Najafi

    2014-06-01

    Full Text Available Background: The aim of this study was to investigate the protective effects of saffron hydroalcoholic extract against tissue damages induced by renal ischemia/reperfusion. Methods: In this experimental study, 40 male rats were randomly divided into 5 groups; 1. sham group which underwent surgery with no vessel occlusion and passed equivalent reperfusion period, 2. Ischemia/reperfusion group which received solvent of extract and went through surgery, bilateral renal ischemia for 30 min and 24-h reperfusion period (I/R. The other three groups underwent ischemia/reperfusion receiving saffron extracts of 5, 10 or 20 mg/kg/ip, respectively. At the end of reperfusion period, the left kidney tissue was collected and stained with hematoxylin-eosin for histological studies. Statistical analysis was performed using one-way ANOVA and Mann-Whitney tests. Results: Following ischemia/reperfusion, the size of Bowman's space increased significantly (P<0.001. In addition, cell necrosis in the tubules of the cortex and outer medulla, vascular congestion and tubular casts in the outer and inner medulla increased. However, the number of RBCs in glomerular capillaries decreased. Administration of saffron extract could significantly improve all the injuries by all three doses. Nevertheless, the effect of 20 mg dose was smaller. Conclusion: Intraperitoneal administration of saffron hydroalcoholic extract has protective effects against tissue damages induced by 30 min ischemia and 24-h reperfusion in the rat’s kidney.

  9. Hydrogen-rich saline reduces cell death through inhibition of DNA oxidative stress and overactivation of poly (ADP-ribose) polymerase-1 in retinal ischemia-reperfusion injury.

    Science.gov (United States)

    Liu, Hongwei; Hua, Ning; Xie, Keliang; Zhao, Tingting; Yu, Yonghao

    2015-08-01

    Overactivation of poly (ADP-ribose) polymerase 1 (PARP-1), as a result of sustained DNA oxidation in ischemia-reperfusion injury, triggers programmed cell necrosis and apoptosis. The present study was conducted to demonstrate whether hydrogen-rich saline (HRS) has a neuroprotective effect on retinal ischemia reperfusion (RIR) injury through inhibition of PARP-1 activation. RIR was induced by transient elevation of intraocular pressure in rats. HRS (5 ml/kg) was administered peritoneally every day from the beginning of reperfusion in RIR rats until the rats were sacrificed. Retinal damage and cell death was determined using hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. DNA oxidative stress was evaluated by immunofluorescence staining of 8-hydroxy-2-deoxyguanosine. In addition, the expression of PARP-1 and caspase-3 was investigated by western blot analysis and/or immunohistochemical staining. The results demonstrated that HRS administration improved morphological alterations and reduced apoptosis following RIR injury. Furthermore, the present study found that HRS alleviated DNA oxidation and PARP-1 overactivation in RIR rats. HRS can protect RIR injury by inhibition of PARP-1, which may be involved in DNA oxidative stress and caspase-3-mediated apoptosis.

  10. Epilepsy-induced electrocardiographic alterations following cardiac ischemia and reperfusion in rats

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    J.G.P. Tavares

    2015-02-01

    Full Text Available The present study evaluated electrocardiographic alterations in rats with epilepsy submitted to an acute myocardial infarction (AMI model induced by cardiac ischemia and reperfusion. Rats were randomly divided into two groups: control (n=12 and epilepsy (n=14. It was found that rats with epilepsy presented a significant reduction in atrioventricular block incidence following the ischemia and reperfusion procedure. In addition, significant alterations were observed in electrocardiogram intervals during the stabilization, ischemia, and reperfusion periods of rats with epilepsy compared to control rats. It was noted that rats with epilepsy presented a significant increase in the QRS interval during the stabilization period in relation to control rats (P<0.01. During the ischemia period, there was an increase in the QRS interval (P<0.05 and a reduction in the P wave and QT intervals (P<0.05 for both in rats with epilepsy compared to control rats. During the reperfusion period, a significant reduction in the QT interval (P<0.01 was verified in the epilepsy group in relation to the control group. Our results indicate that rats submitted to an epilepsy model induced by pilocarpine presented electrical conductivity alterations of cardiac tissue, mainly during an AMI episode.

  11. Effects of Lipoteichoic Acid induced Delayed Preconditioning on Ischemia-reperfusion Injury in Isolated Rat Hearts

    Institute of Scientific and Technical Information of China (English)

    马世玉; 向继洲; 吴基良; 胡本容

    2003-01-01

    To explore the potential of lipoteichoic acid (LTA) induced cardioprotection against is-chemia-reperfusion (I/R) injury in isolated rat hearts and whether endogenous nitric oxide (NO)participates-in the protection, the rats were pretreated with LTA (1 mg/kg, i. p. ) 24 h before theexperiment, and the isolated hearts were subjected to 30 min no-flow normothermic global ischemiaand 60 min reperfusion after a 20-min stabilization period by the langendorff method. Cardiac func-tions were evaluated at the end of stabilization, and at 30 min, 60 min of reperfusion. The amountsof MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase(LDH) and total NO oxidationproducts in the coronary effluent were measured spectrophotometrically at the end of reperfusion. Itwas revealed that pretreatment with LTA could significantly improve the recovery of cardiac func-tion, reduce the release of CK-MB and LDH, and increase the concentrations of NO in coronary ef-fluent. The protective effects were abrogated by pretreatment of the rats with L-NAME. It wasconcluded that LTA could induce the delayed cardioprotection against I/R injury, and endogenousNO may be involved in the mechanisms.

  12. Epilepsy-induced electrocardiographic alterations following cardiac ischemia and reperfusion in rats

    Energy Technology Data Exchange (ETDEWEB)

    Tavares, J.G.P. [Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Universidade Iguaçu, Campos V, Itaperuna, RJ (Brazil); Faculdade de Minas, Muriaé, MG (Brazil); Vasques, E.R. [Departamento de Gastroenterologia, LIM 37, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Arida, R.M. [Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Cavalheiro, E.A. [Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Cabral, F.R.; Torres, L.B. [Hospital Israelita Albert Einstein, Instituto do Cérebro, São Paulo, SP (Brazil); Menezes-Rodrigues, F.S.; Jurkiewicz, A.; Caricati-Neto, A. [Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Godoy, C.M.G. [Departamento de Ciência e Tecnologia, Universidade Federal de São Paulo, São José dos Campos, SP (Brazil); Gomes da Silva, S. [Hospital Israelita Albert Einstein, Instituto do Cérebro, São Paulo, SP (Brazil); Núcleo de Pesquisas Tecnológicas, Programa Integrado em Engenharia Biomédica, Universidade de Mogi das Cruzes, Mogi das Cruzes, SP (Brazil)

    2015-01-13

    The present study evaluated electrocardiographic alterations in rats with epilepsy submitted to an acute myocardial infarction (AMI) model induced by cardiac ischemia and reperfusion. Rats were randomly divided into two groups: control (n=12) and epilepsy (n=14). It was found that rats with epilepsy presented a significant reduction in atrioventricular block incidence following the ischemia and reperfusion procedure. In addition, significant alterations were observed in electrocardiogram intervals during the stabilization, ischemia, and reperfusion periods of rats with epilepsy compared to control rats. It was noted that rats with epilepsy presented a significant increase in the QRS interval during the stabilization period in relation to control rats (P<0.01). During the ischemia period, there was an increase in the QRS interval (P<0.05) and a reduction in the P wave and QT intervals (P<0.05 for both) in rats with epilepsy compared to control rats. During the reperfusion period, a significant reduction in the QT interval (P<0.01) was verified in the epilepsy group in relation to the control group. Our results indicate that rats submitted to an epilepsy model induced by pilocarpine presented electrical conductivity alterations of cardiac tissue, mainly during an AMI episode.

  13. Mucosal injury induced by ischemia and reperfusion in the piglet intestine: Influences of age and feeding

    Energy Technology Data Exchange (ETDEWEB)

    Crissinger, K.D.; Granger, D.N. (Louisiana State Univ. Medical Center, Shreveport (USA))

    1989-10-01

    The pathogenesis of neonatal necrotizing enterocolitis is unknown, but enteral alimentation, infectious agents, and mesenteric ischemia have been frequently invoked as primary initiators of the disease. To define the vulnerability of the intestinal mucosa to ischemia and reperfusion in the developing piglet, we evaluated changes in mucosal permeability using plasma-to-lumen clearance of chromium 51-labeled ethylenediaminetetraacetic acid in the ileum of anesthetized 1-day-, 3-day-, 2-wk-, and 1-mo-old piglets as a function of (a) duration of intestinal ischemia (20, 40, or 60 min of total superior mesenteric artery occlusion), (b) feeding status (fasted or nursed), and (c) composition of luminal perfusate (balanced salt solution vs. predigested cow milk-based formula). Baseline chromium 51-labeled ethylenediaminetetraacetic acid clearance was not significantly altered by ischemia, irrespective of duration, or feeding in all age groups. However, clearances were significantly elevated during reperfusion after 1 h of total intestinal ischemia in all age groups, whether fasted or fed. Reperfusion-induced increases in clearance did not differ among age groups when the bowel lumen was perfused with a balanced salt solution. However, luminal perfusion with formula resulted in higher clearances in 1-day-old piglets compared with all older animals. Thus, the neonatal intestine appears to be more vulnerable to mucosal injury induced by ischemia and reperfusion in the presence of formula than the intestine of older animals.

  14. 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.

  15. Influence of edaravone on growth arrest and DNA damage-inducible protein 34 expression following focal cerebral ischemia-reperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    Wei Wang; Xiao-Mei Wu; Bo Jiang; Chun-Yu Wang; Hai-Nan Zhang; Xiang-Min Shen

    2014-01-01

    Objective:To investigate the influence of edaravone on the expression of growth arrest and DNA damage-inducible protein 34 (GADD34). Methods: A total of 108 healthy male Sprague-Dawley rats were randomly divided into sham operation group, model group and edaravone group (36 cases for each group). Transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h followed by reperfusion in Sprague-Dawley rats. Then, GADD34 expression was measured with immunohistochemistry at different time-points after reperfusion in the peri-infarct regions of all rats. Results: The GADD34 expression was detected in the peri-infarct regions of rats 1 h after reperfusion, which reached its peak 24 h after reperfusion. And edaravone could significantly down-regulate the GADD34 expression. Conclusions:Edaravon could down-regulate GADD34 expression, which suggests that edaravone may exert an important function in inhibiting endoplasmic reticulum stress reaction by scavenging free radicals in the upper stream.

  16. Influence of edaravone on growth arrest and DNA damage-inducible protein 34 expression following focal cerebral ischemia-reperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    Wei; Wang; Xiao-Mei; Wu; Bo; Jiang; Chun-Yu; Wang; Hai-Nan; Zhang; Xiang-Min; Shen

    2014-01-01

    Objective:To investigate the influence of edaravone on the expression of growth arrest and DNA damage-inducible protein 34(GADD34).Methods:A total of 108 healthy male Sprague-Dawlcy rats were randomly divided into sham operation group,model group and edaravone.group(36 cases for each group).Transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h followed by reperfusion in Sprague-Dawlev rats.Then.GAOD34 expression was measured with immunohistochemistry at different time-points after reperfusion in the peri-infarct regions of all rats.Results:The GADD34 expression was detected in the peri-infaret regions of rats 1 h after reperfusion,which reached its peak 24 h after reperfusion.And edaravone could significantly down-regulate the GAOD34 expression.Conclusions:Edaravon could down-regulate GADD34 expression,which suggests that edaravone may exert an important function in inhibiting endoplasmic reticulum stress reaction by scavenging free radicals in the upper stream.

  17. The protective effects of dexmedetomidine on liver injury-induced myocardial ischemia reperfusion.

    Science.gov (United States)

    Erer, D; Ozer, A; Arslan, M; Oktar, G L; Iriz, E; Elmas, C; Zor, M H; Tatar, T; Goktas, G

    2014-01-01

    The aim of this study was to evaluate the effect of dexmedetomidine (100 µg/kg-ip) on liver injury-induced myocardial ischemia and reperfusion (IR) in rats. Twenty-four Wistar Albino rats were separated into four groups. There were four experimental groups (Group C (Control; n = 6), Group IR (ischemia-reperfusion, n = 6), Group D (Dexmedetomidine; n = 6) that underwent left thoracotomy and received ip dexmedetomidine without IR administered via 100 µg/kg ip route 30 minutes before ligating the left coronary artery, and Group IR-D (IR-Dexmedetomidine; n = 6). A small plastic snare was threaded through the ligature and placed in contact with the heart. To produce IR, a branch of the left coronary artery was occluded for 30 min followed by two hours of reperfusion. However, after the above procedure, the coronary artery was not occluded or reperfused in the control rats. At the end of the study, liver tissue was obtained for histochemical and immunohistochemical determination.Some part of tissue samples were stained with Masson-trichrome for the evaluation of ultrastructural changes and inducible nitric oxide synthase (iNOS) expression was evaluated in other part of samples for immunohistochemical examination. Histopathological changes were detected in Group IR when compared with Group C. iNOS expression was found to be increased and stronger particularly in the vascular wall, perisinusoidal space and hepatocytes around vena centralis in this group compared to the control group. Perivascular oedema was detected to be decreased in Group IR-D compared to Group IR. It was also observed that the impairment in the radial arrangement of hepatocytes significantly recovered in Group IR-D. The immunoreactivity was found to be significantly decreased in the assessment of iNOS expression in the same group when compared with Group IR. Administration of dexmedetomidine ameliorates liver injury induced by myocardial ischemia and reperfusion (Fig. 8, Ref. 33).

  18. Renal ischemia/reperfusion-induced cardiac hypertrophy in mice: Cardiac morphological and morphometric characterization

    Science.gov (United States)

    Cirino-Silva, Rogério; Kmit, Fernanda V; Trentin-Sonoda, Mayra; Nakama, Karina K; Panico, Karine; Alvim, Juliana M; Dreyer, Thiago R; Martinho-Silva, Herculano

    2017-01-01

    Background Tissue remodeling is usually dependent on the deposition of extracellular matrix that may result in tissue stiffness and impaired myocardium contraction. Objectives We had previously demonstrated that renal ischemia/reperfusion (I/R) is able to induce development of cardiac hypertrophy in mice. Therefore, we aimed to characterize renal I/R-induced cardiac hypertrophy. Design C57BL/6 J mice were subjected to 60 minutes’ unilateral renal pedicle occlusion, followed by reperfusion (I/R) for 5, 8, 12 or 15 days. Gene expression, protein abundance and morphometric analyses were performed in all time points. Results Left ventricle wall thickening was increased after eight days of reperfusion (p < 0.05). An increase in the number of heart ventricle capillaries and diameter after 12 days of reperfusion (p < 0.05) was observed; an increase in the density of capillaries starting at 5 days of reperfusion (p < 0.05) was also observed. Analyses of MMP2 protein levels showed an increase at 15 days compared to sham (p < 0.05). Moreover, TGF-β gene expression was downregulated at 12 days as well TIMP 1 and 2 (p < 0.05). The Fourier-transform infrared spectroscopy analysis showed that collagen content was altered only in the internal section of the heart (p < 0.05); such data were supported by collagen mRNA levels. Conclusions Renal I/R leads to impactful changes in heart morphology, accompanied by an increase in microvasculature. Although it is clear that I/R is able to induce cardiac remodeling, such morphological changes is present in only a section of the heart tissue.

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

    Science.gov (United States)

    Derikx, Joep P M; Matthijsen, Robert A; de Bruïne, Adriaan P; van Bijnen, Annemarie A; Heineman, Erik; van Dam, Ronald M; Dejong, Cornelis H C; Buurman, Wim A

    2008-01-01

    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. 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 (pintestinal 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. At the same time, M30 immunoreactivity was absent in intact epithelial lining. This is the first human study to clarify intestinal IR induced cell damage and

  20. Tourniquet-induced ischaemia-reperfusion injury: the comparison of antioxidative effects of small-dose propofol and ketamine

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    Karaca Omer

    Full Text Available Abstract Objectives: The aim of the present study was to investigate the preventive effects of propofol and ketamine as small dose sedation during spinal anaesthesia on tourniquet-induced ischaemia-reperfusion injury. Methods: 30 patients were randomly assigned into two groups of 15 patients. In the propofol group, sedation was performed with propofol 0.2 mg·kg-1 followed by infusion at a rate of 2 mg·kg-1·h-1. In the ketamine group, a continuous infusion of ketamine 0.5 mg·kg-1·h-1 was used until the end of surgery. Intravenous administration of midazolam was not used in any patients. Ramsay sedation scale was used for assessing the sedation level. Venous blood samples were obtained before propofol and ketamine infusion (T1, at 30 minutes (min of tourniquet ischaemia (T2, and 5 min after tourniquet deflation (T3 for malondialdehyde (MDA measurements. Results: No differences were noted between the groups in haemodynamic (p > 0.05 and demographic data (p > 0.05. There was no statistically significant difference between the two groups in terms of T1, T2 and T3 periods (p > 0.05. There was a statistically increase observed in MDA values respectively both in Group P and Group K between the reperfusion period (1.95 ± 0.59, 2.31 ± 0.48 and pre-ischaemia (1.41 ± 0.38, 1.54 ± 0.45, and ischaemia (1.76 ± 0.70, 1.71 ± 0.38 (µmoL-1 periods (p < 0.05. Conclusions: Small-dose propofol and ketamine has similar potential to reduce the oxidative stress caused by tourniquet-induced ischaemia-reperfusion injury in patients undergoing arthroscopic knee surgery under spinal anaesthesia.

  1. [Tourniquet-induced ischaemia-reperfusion injury: the comparison of antioxidative effects of small-dose propofol and ketamine].

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    Omer, Karaca; Nermin, Gogus; Ali, Ahiskalioglu; Mehmet, Aksoy; Unal, Dogus; Sezen, Kumas Solak; Hakan, Kalafat

    The aim of the present study was to investigate the preventive effects of propofol and ketamine as small dose sedation during spinal anesthesia on tourniquet-induced ischemia-reperfusion injury. 30 patients were randomly assigned into two groups of 15 patients. In the propofol group, sedation was performed with propofol 0.2mg.kg(-1) followed by infusion at a rate of 2mg.kg(-1).h(-1). In the ketamine group, a continuous infusion of ketamine 0.5mg.kg(-1).h(-1) was used until the end of surgery. Intravenous administration of midazolam was not used in any patients. Ramsay sedation scale was used for assessing the sedation level. Venous blood samples were obtained before propofol and ketamine infusion (T1), at 30minutes (min) of tourniquet ischemia (T2), and 5min after tourniquet deflation (T3) for malondialdehyde (MDA) measurements. No differences were noted between the groups in hemodynamic (p>0.05) and demographic data (p>0.05). There was no statistically significant difference between the two groups in terms of T1, T2 and T3 periods (p>0.05). There was a statistically increase observed in MDA values respectively both in Group P and Group K between the reperfusion period (1.95±0.59, 2.31±0.48) and pre-ischemia (1.41±0.38, 1.54±0.45), and ischemia (1.76±0.70, 1.71±0.38) (μmoL(-1)) periods (p<0.05). Small-dose propofol and ketamine has similar potential to reduce the oxidative stress caused by tourniquet-induced ischemia-reperfusion injury in patients undergoing arthroscopic knee surgery under spinal anesthesia. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  2. Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling.

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    Erikson, John M; Valente, Anthony J; Mummidi, Srinivas; Kandikattu, Hemanth Kumar; DeMarco, Vincent G; Bender, Shawn B; Fay, William P; Siebenlist, Ulrich; Chandrasekar, Bysani

    2017-02-10

    Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both IκB kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses. Here we investigated the role of TRAF3IP2 in ischemia/reperfusion (I/R)-induced nitroxidative stress, inflammation, myocardial dysfunction, injury, and adverse remodeling. Our data show that I/R up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced nitroxidative stress, IKK/NF-κB and JNK/AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction. Furthermore, Traf3ip2 gene deletion blunts adverse remodeling 12 weeks post-I/R, as evidenced by reduced hypertrophy, fibrosis, and contractile dysfunction. Supporting the genetic approach, an interventional approach using ultrasound-targeted microbubble destruction-mediated delivery of phosphorothioated TRAF3IP2 antisense oligonucleotides into the LV in a clinically relevant time frame significantly inhibits TRAF3IP2 expression and myocardial injury in wild type mice post-I/R. Furthermore, ameliorating myocardial damage by targeting TRAF3IP2 appears to be more effective to inhibiting its downstream signaling intermediates NF-κB and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease.

  3. [Effect of electroacupuncture on inflammatory injury induced by intestinal ischemia/reperfusion in rats].

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    Yao, Jia-Rui; Shi, Xian; Hu, Sen; Zhong, Yu-Xian; Liu, Wei-Wei; Zhao, Ying

    2012-07-01

    To observe the protective effect of electroacupuncture (EA) at "Zusanli" (ST 36) on inflammatory injury induced by intestinal ischemia/reperfusion (I/R) in rats. Forty-eight Wistar rats were randomly divided into a sham injury group, a model group, an EA group and a sham EA group, 12 rats in each group. Intestinal I/R rat models were established by method of clamping with occlusion of superior mesenteric artery (SMA) for 45 min followed by reperfusion. The EA group was treated with EA (2.5 mA, 2 Hz/100 Hz, 0.5 h) at "Zusanli" (ST 36) 30 min before reperfusion, and at the same time, the sham EA group was treated with fast insertion at two non-meridian acupoints on skin surface (2 cm horizontally away from linea alba abdominis and about 5 cm paralleled to cartilago ensiformis downward). No interventions were added on the sham injury group and the model group. The degree of pathological injury in intestines, water rate of intestines, diamine oxidase (DAO) activity and intestinal mucosal blood flow (IMBF) were examined at 1 h and 3 h after reperfusion. At 1 h and 3 h after reperfusion, the intestinal pathological injury in EA group was significantly attenuated compared with that in model group, and the intestinal water rate of (74.00 +/- 2.11)% and (78.78 +/- 0.80)% in EA group were significantly lower than (80.69 +/- 1.66)% and (83.17 +/- 2.08)% in model group (both P 0.05). Electroacupuncture can not only reduce the inflammatory injury induced by intestinal IR but also increase intestinal blood supply so as to protect the intestine function.

  4. CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway

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    Xiao-Hui Guan

    2016-01-01

    Full Text Available Ischemia/reperfusion (I/R injury induces irreversible oxidative stress damage to the cardiac muscle. We previously observed that CD38 deficiency remarkably protects mouse embryonic fibroblasts (MEFs from oxidative stress-induced injury. However, whether CD38 deficiency protects from I/R injury in the heart is not explored. Here, we showed that the hearts of CD38 deficient mice or wild type mice supplied with exogenous NAD were significantly protected from ischemia/reperfusion injury, seen as reduction of the myocardial infarct sizes when the mice were subjected to 30 min ischemia followed by 24 hours of reperfusion. Consistently, the protection of CD38 deficiency on hypoxia/reoxygenation (H/R injury was confirmed with a CD38 knockdown H9c2 stable cell line. Furthermore, we observed that knockdown of CD38 remarkably inhibited ROS generation and intracellular Ca2+ overloading induced by H/R in H9c2 cells. The FOXO1 and FOXO3 expressions were significantly elevated by H/R injury in CD38 knockdown cells compared with normal H9c2 cells. The cell immunofluorescence assay showed that FOXO1 nuclear translocation was significantly increased in CD38 knockdown H9c2 cells. In addition, we demonstrated that the increase of FOXO1 nuclear translocation was associated with the increased expressions of antioxidant catalase and SOD2 and the attenuated expression of the ROS generation enzyme NOX4. In conclusion, our results provide new evidence that CD38 deficiency protects the heart from I/R injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway.

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

    Directory of Open Access Journals (Sweden)

    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

  6. The protective effect of niacinamide on ischemia-reperfusion-induced liver injury.

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    Chen, C F; Wang, D; Hwang, C P; Liu, H W; Wei, J; Lee, R P; Chen, H I

    2001-01-01

    Reperfusion of ischemic liver results in the generation of oxygen radicals, nitric oxide (NO) and their reaction product peroxynitrite, all of which may cause strand breaks in DNA, which activate the nuclear enzyme poly(ADP ribose)synthase (PARS). This results in rapid depletion of intracellular nicotinamide adenine dinucleotide and adenosine 5'-triphosphate (ATP) and eventually induces irreversible cytotoxicity. In this study, we demonstrated that niacinamide, a PARS inhibitor, attenuated ischemia/reperfusion (I/R)-induced liver injury. Ischemia was induced by clamping the common hepatic artery and portal vein of rats for 40 min. Thereafter, flow was restored and the liver was reperfused for 90 min. Blood samples collected prior to I and after R were analyzed for methyl guanidine (MG), NO, tumor necrosis factor (TNF-alpha) and ATP. Blood levels of aspartate transferase (AST), alanine transferase (ALT) and lactate dehydrogenase (LDH) which served as indexes of liver injury were measured. This protocol resulted in elevation of the blood NO level (p niacinamide (10 mM), liver injury was significantly attenuated, while blood ATP content was reversed. In addition, MG, TNF-alpha and NO release was attenuated. These results indicate that niacinamide, presumably by acting with multiple functions, exerts potent anti-inflammatory effects in I/R-induced liver injury.

  7. Intestinal ischemia/reperfusion induces bronchial hyperreactivity and increases serum TNF-alpha in rats

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    Arruda Marcio Jose Cristiano de

    2006-01-01

    Full Text Available INTRODUCTION: Intestinal or hepatic ischemia/reperfusion induces acute lung injury in animal models of multiple organ failure. Tumor necrosis factor (TNF- alpha is involved in the underlying inflammatory mechanism of acute respiratory distress syndrome. Although the inflammatory cascade leading to acute respiratory distress syndrome has been extensively investigated, the mechanical components of acute respiratory distress syndrome are not fully understood. Our hypothesis is that splanchnic ischemia/reperfusion increases airway reactivity and serum TNF-alpha levels. OBJECTIVE: To assess bronchial smooth muscle reactivity under methacholine stimulation, and to measure serum TNF-alpha levels following intestinal and/or hepatic ischemia/reperfusion in rats. METHOD: Rats were subjected to 45 minutes of intestinal ischemia, or 20 minutes of hepatic ischemia, or to both (double ischemia, or sham procedures (control, followed by 120 minutes of reperfusion. The animals were then sacrificed, and the bronchial response to increasing methacholine molar concentrations (10-7 to 3 x 10-4 was evaluated in an ex-vivo bronchial muscle preparation. Serum TNF-alpha was determined by the L929-cell bioassay. RESULTS: Bronchial response (g/100 mg tissue showed increased reactivity to increasing methacholine concentrations in the intestinal ischemia and double ischemia groups, but not in the hepatic ischemia group. Similarly, serum TNF-alpha (pg/mL concentration was increased in the intestinal ischemia and double ischemia groups, but not in the hepatic ischemia group. CONCLUSION: Intestinal ischemia, either isolated or associated with hepatic ischemia, increased bronchial smooth muscle reactivity, suggesting a possible role for bronchial constriction in respiratory dysfunction following splanchnic ischemia/reperfusion. This increase occurred in concomitance with serum TNF-alpha increase, but whether the increase in TNF-alpha caused this bronchial contractility remains

  8. Memory deficits and oxidative stress in cerebral ischemia-reperfusion: neuroprotective role of physical exercise and green tea supplementation.

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    Schimidt, Helen L; Vieira, Aline; Altermann, Caroline; Martins, Alexandre; Sosa, Priscila; Santos, Francielli W; Mello-Carpes, Pâmela B; Izquierdo, Ivan; Carpes, Felipe P

    2014-10-01

    Ischemic stroke is a major cause of morbidity and mortality all over the world. Among impairments observed in survivors there is a significant cognitive learning and memory deficit. Neuroprotective strategies are being investigated to minimize such deficits after an ischemia event. Here we investigated the neuroprotective potential of physical exercise and green tea in an animal model of ischemia-reperfusion. Eighty male rats were divided in 8 groups and submitted to either transient brain ischemia-reperfusion or a sham surgery after 8 weeks of physical exercise and/or green tea supplementation. Ischemia-reperfusion was performed by bilateral occlusion of the common carotid arteries during 30 min. Later, their memory was evaluated in an aversive and in a non-aversive task, and hippocampus and prefrontal cortex were removed for biochemical analyses of possible oxidative stress effects. Ischemia-reperfusion impaired learning and memory. Reactive oxygen species were increased in the hippocampus and prefrontal cortex. Eight weeks of physical exercise and/or green tea supplementation before the ischemia-reperfusion event showed a neuroprotective effect; both treatments in separate or together reduced the cognitive deficits and were able to maintain the functional levels of antioxidant enzymes and glutathione.

  9. Cerebral Ischemia Reperfusion Exacerbates and Pueraria Flavonoids Attenuate Depressive Responses to Stress in Mice

    Institute of Scientific and Technical Information of China (English)

    LAN Jiaqi; YAN Bin; ZHAO Yu'nan; WANG Daoyi; HU Jun; XING Dongming; DU Lijun

    2008-01-01

    Previous studies have shown that mice experiencing cerebral ischemia reperfusion (CIR) and stress can serve as a model of post stroke depression (PSD).The present study verified the acute antide-pressant effects of radix puerariae extract (PE) on PSD mice through behavior and gene expression ex-periments.CIR was found to reduce the sucrose consumption and tyrosine hydroxylase (TH) gene expres-sion.PE administration after CIR surgery was observed to significantly enhance the mRNA expression of TH in the hippocampus compared with the PSD group on Day 0 and Day 3 postsurgery.These findings in-dicate that PE contributes to the amelioration of behavior response in PSD mice,which is closely related with the protective effects of catecholamine synthesize against CIR brain damage.

  10. Ischemia/Reperfusion Induces Interferon-Stimulated Gene Expression in Microglia.

    Science.gov (United States)

    McDonough, Ashley; Lee, Richard V; Noor, Shahani; Lee, Chungeun; Le, Thu; Iorga, Michael; Phillips, Jessica L H; Murphy, Sean; Möller, Thomas; Weinstein, Jonathan R

    2017-08-23

    Innate immune signaling is important in the pathophysiology of ischemia/reperfusion (stroke)-induced injury and recovery. Several lines of evidence support a central role for microglia in these processes. Recent work has identified Toll-like receptors (TLRs) and type I interferon (IFN) signaling in both ischemia/reperfusion-induced brain injury and ischemic preconditioning-mediated neuroprotection. To determine the effects of "ischemia/reperfusion-like" conditions on microglia, we performed genomic analyses on wild-type (WT) and TLR4(-/-) cultured microglia after sequential exposure to hypoxia/hypoglycemia and normoxia/normoglycemia (H/H-N/N). We observed increased expression of type 1 IFN-stimulated genes (ISGs) as the predominant transcriptomal feature of H/H-N/N-exposed WT, but not TLR4(-/-), microglia. Microarray analysis on ex vivo sorted microglia from ipsilateral male mouse cortex after a transient in vivo ischemic pulse also demonstrated robust expression of ISGs. Type 1 IFNs, including the IFN-αs and IFN-β, activate the interferon-α/β receptor (IFNAR) complex. We confirmed both in vitro H/H-N/N- and in vivo ischemia/reperfusion-induced microglial ISG responses by quantitative real-time PCR and demonstrated that both were dependent on IFNAR1. We characterized the effects of hypoxia/hypoglycemia on phosphorylation of signal transducer and activator of transcription 1 (STAT1), release of type 1 IFNs, and surface expression of IFNAR1 in microglia. We demonstrated that IFN-β induces dose-dependent secretion of ISG chemokines in cultured microglia and robust ISG expression in microglia both in vitro and in vivo Finally, we demonstrated that the microglial ISG chemokine responses to TLR4 agonists were dependent on TLR4 and IFNAR1. Together, these data suggest novel ischemia/reperfusion-induced pathways for both TLR4-dependent and -independent, IFNAR1-dependent, type 1 IFN signaling in microglia.SIGNIFICANCE STATEMENT Stroke is the fifth leading cause of

  11. C1q/TNF-Related Protein 9 Protects Diabetic Rat Heart against Ischemia Reperfusion Injury: Role of Endoplasmic Reticulum Stress

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    Bai, Sanxing; Cheng, Liang; Yang, Yang; Fan, Chongxi; Zhao, Dajun; Qin, Zhigang; Feng, Xiao; Zhao, Lin; Ma, Jipeng; Wang, Xiaowu; Yang, Jian; Xu, Xuezeng

    2016-01-01

    As a newly identified adiponectin paralog, C1q/TNF-related protein 9 (CTRP9) reduces myocardial ischemia reperfusion (IR) injury through partially understood mechanisms. In the present study, we sought to identify the role of endoplasmic reticulum stress (ERS) in CTRP9 induced cardioprotection in diabetic heart. Isolated hearts from high-fat-diet (HFD) induced type 2 diabetic Sprague-Dawley rats were subjected to ex vivo IR protocol via a Langendorff apparatus at the presence of globular CTRP9. CTRP9 significantly improved post-IR heart function and reduced cardiac infarction, cardiomyocytes apoptosis, Caspase-3, Caspase-9, Caspase-12, TNF-α expression, and lactate dehydrogenase activity. The cardioprotective effect of CTRP9 was associated with reduced ERS and increased expression of disulfide-bond A oxidoreductase-like protein (DsbA-L) in diabetic heart. CTRP9 reduced ERS in thapsigargin (TG) treated cardiomyocytes and protected endoplasmic reticulum (ER) stressed H9c2 cells against simulated ischemia reperfusion (SIR) injury, concurrent with increased expression of DsbA-L. Knockdown of DsbA-L increased ERS and attenuated CTRP9 induced protection against SIR injury in H9c2 cells. Our findings demonstrated for the first time that CTRP9 exerts cardioprotection by reducing ERS in diabetic heart through increasing DsbA-L.

  12. Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury.

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    Kannan, Kolenkode B; Colorado, Iriana; Reino, Diego; Palange, David; Lu, Qi; Qin, Xiaofa; Abungu, Billy; Watkins, Anthony; Caputo, Francis J; Xu, Da-Zhong; Semenza, Gregg L; Deitch, Edwin A; Feinman, Rena

    2011-05-01

    Gut injury and loss of normal intestinal barrier function are key elements in the paradigm of gut-origin systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome (MODS). As hypoxia-inducible factor (HIF-1) is a critical determinant of the physiological and pathophysiological response to hypoxia and ischemia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Using partially HIF-1α-deficient mice in an isolated superior mesenteric artery occlusion (SMAO) intestinal ischemia reperfusion (I/R) injury model (45 min SMAO followed by 3 h of reperfusion), we showed a direct relationship between HIF-1 activation and intestinal I/R injury. Specifically, partial HIF-1α deficiency attenuated SMAO-induced increases in intestinal permeability, lipid peroxidation, mucosal caspase-3 activity, and IL-1β mRNA levels. Furthermore, partial HIF-1α deficiency prevented the induction of ileal mucosal inducible nitric oxide synthase (iNOS) protein levels after SMAO and iNOS deficiency ameliorated SMAO-induced villus injury. Resistance to SMAO-induced gut injury was also associated with resistance to lung injury, as reflected by decreased levels of myeloperoxidase, IL-6 and IL-10 in the lungs of HIF-1α(+/-) mice. In contrast, a short duration of SMAO (15 min) followed by 3 h of reperfusion neither induced mucosal HIF-1α protein levels nor caused significant gut and lung injury in wild-type or HIF-1α(+/-) mice. This study indicates that intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. However, the duration and severity of the gut I/R insult dictate whether HIF-1 plays a gut-protective or deleterious role.

  13. Repeated Glucose Deprivation/Reperfusion Induced PC-12 Cell Death through the Involvement of FOXO Transcription Factor

    Science.gov (United States)

    Han, Na; Kim, You Jeong; Park, Su Min; Kim, Seung Man; Lee, Ji Suk; Jung, Hye Sook; Lee, Eun Ju; Kim, Tae Kyoon; Kim, Tae Nyun; Kwon, Min Jeong; Lee, Soon Hee; Rhee, Byoung Doo

    2016-01-01

    Background Cognitive impairment and brain damage in diabetes is suggested to be associated with hypoglycemia. The mechanisms of hypoglycemia-induced neural death and apoptosis are not clear and reperfusion injury may be involved. Recent studies show that glucose deprivation/reperfusion induced more neuronal cell death than glucose deprivation itself. The forkhead box O (FOXO) transcription factors are implicated in the regulation of cell apoptosis and survival, but their role in neuronal cells remains unclear. We examined the role of FOXO transcription factors and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt and apoptosis-related signaling pathways in PC-12 cells exposed to repeated glucose deprivation/reperfusion. Methods PC-12 cells were exposed to control (Dulbecco's Modified Eagle Medium [DMEM] containing 25 mM glucose) or glucose deprivation/reperfusion (DMEM with 0 mM glucose for 6 hours and then DMEM with 25 mM glucose for 18 hours) for 5 days. MTT assay and Western blot analysis were performed for cell viability, apoptosis, and the expression of survival signaling pathways. FOXO3/4',6-diamidino-2-phenylindole staining was done to ascertain the involvement of FOXO transcription factors in glucose deprivation/reperfusion conditions. Results Compared to PC-12 cells not exposed to hypoglycemia, cells exposed to glucose deprivation/reperfusion showed a reduction of cell viability, decreased expression of phosphorylated Akt and Bcl-2, and an increase of cleaved caspase-3 expression. Of note, FOXO3 protein was localized in the nuclei of glucose deprivation/reperfusion cells but not in the control cells. Conclusion Repeated glucose deprivation/reperfusion caused the neuronal cell death. Activated FOXO3 via the PI3K/Akt pathway in repeated glucose deprivation/reperfusion was involved in genes related to apoptosis.

  14. Methylprednisolone improves microcirculation in streptozotocin-induced diabetic rats after myocardial ischemia/reperfusion

    Institute of Scientific and Technical Information of China (English)

    HU Zhi-cheng; CHEN Yun-dai; REN Yi-hong

    2011-01-01

    Background Methylprednisolone has been demonstrated to decrease inflammation, and it may protect organs from ischemia/reperfusion (I/R) injury. This study aimed to investigate the effects of methylprednisolone on diabetic myocardial I/R injury.Methods Forty adult male Sprague-Dawley (SD) rats were randomized into five groups (n=8 in each group) including a sham operation (sham) group, I/R group, diabetic sham operation (DMS) group, diabetic I/R (DM-I/R) group and methylprednisolone intervention (MP+DM-I/R) group. The diabetic model was produced by injection of streptozotocin (STZ). Body weight and blood glucose levels were determined after diabetes was established. Twelve weeks after induction of diabetes, a segmental I/R of the heart was induced by occluding the left anterior descending artery for one hour and then three hours of reperfusion in the I/R, DM-I/R and MP+DM-I/R groups. Blood pressure and electrocardiogram were continuously recorded during the procedure. IL-1β, IL-6 and TNF-α were measured at certain time points during the surgery. After reperfusion, a microcirculation scan was performed; myocardial biomarkers and tissue structure were utilized to evaluate the reperfusion damage. Intercellular adhesion molecule (ICAM)-1 and NF-κBp65 expression were quantified by immunohistological staining. Total Toil-like receptor 4 (TLR4) and nuclear NF-κBp65 protein were determined by Western blotting.Results Twelve weeks after diabetes was established, blood glucose levels were elevated and body weights were lower in diabetic rats. After reperfusion, infarction size was increased, myocardial biomarkers and inflammatory cytokines levels were elevated. Microcirculation perfusion was significantly reduced in the DM-I/R group compared with the I/R group, however it was improved in the MP+DM-I/R group. The expression of NF-κBp65 and ICAM-1 were increased in the DM-I/R group and decreased in the MP+DM-I/R group, Compared with the non-diabetic I/R group, TLR4 and NF

  15. Dexamethasone pretreatment attenuates lung and kidney injury in cholestatic rats induced by hepatic ischemia/reperfusion.

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    Zhou, Liangyi; Yao, Xiangqing; Chen, Yanling

    2012-02-01

    Hepatic ischemia followed by reperfusion (IR) results in mild to severe organ injury, in which tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) seem to be involved. Thus, we aim to assess the influence of hepatic ischemia/reperfusion injury on remote organs in addition to cholestasis and consider the possible efficacy of steroid pretreatment in reducing the injury. A common bile duct ligation model was done on 24 male Sprague-Dawley rats. After 7 days, the rats were divided randomly into control group, IR group, and dexamethasone (DEX) group. The IR group showed significant increases in serum alanine aminotransferase, aspartate aminotransferase, and creatinine levels compared with the control and DEX groups. By ELISA techniques, higher levels of TNF-α and IL-1β in lung and kidney tissues were measured in the IR group than in the control and DEX groups, these were verified by immunohistochemistry. The lung histology of the IR group rats showed neutrophil infiltration, interstitial edema, and alveolar wall thickening. Kidney histology of the IR group rats showed vacuolization of the proximal tubular epithelial cells and tubular dilatation with granular eosinophilic casts. Better morphological aspects were observed in the DEX-pretreated animals. Minimal lesions were observed in the control. The results suggest that hepatic ischemia/reperfusion injury in cholestatic rats induced lung and kidney injuries. Pretreatment with dexamethasone reduced the IR-induced injury in addition to cholestasis.

  16. Protective effects of apocynin and allopurinol on ischemia/reperfusion-induced liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Ping-Guo Liu; Song-Qing He; Yan-Hong Zhang; Jian Wu

    2008-01-01

    AIM: To determine the effects of allopurinol, an inhibitor of xanthine oxidase, and apocynin, an inhibitor of NADPH oxidase, on oxidant stress and liver injury caused by hepatic ischemia/reperfusion (I/R) procedure in mice. METHODS: Nice were pretreated with a xanthine oxidase inhibitor, allopurinol, or NADPH oxidase (NOX)inhibitor, apocynin before the hepatic I/R procedure. Then treated or untreated mice underwent the hepatic I/R procedure. The effects on hepatic injury and superoxide anions were determined after starting reperfusion. RESULTS: A standard warm hepatic I/R procedure led to a marked increase in superoxide anion production as indicated by a superoxide anion tracer, MCLA. At the same time, the procedure caused profound acute liver injury, as indicated by elevated serum alanine aminotransferase and tumor necrosis factor-αlevels, reduced liver glutathione levels and elevated malondialdehyde contents, as well as a high apoptotic cell count. All these changes were reversed by the use of apocynin or allopurinol prior to the hepatic I/R procedure. CONCLUSION: AIIopurinol and apocynin exerted protective effects on hepatic ischemia/reperfusion injury. The protection is associated with blocking the generation of superoxide anions during the hepatic I/R procedure by inhibiting xanthine oxidase and NADPH oxidase activity.

  17. The presence of oxidized low-density lipoprotein and inducible nitric oxide synthase expression in renal damage after intestinal ischemia reperfusion

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    Gamze Yurdakan

    2012-01-01

    Full Text Available Intestinal ischemia/reperfusion (I/R is a complex phenomenon that causes destruction of both local and remote tissues. The objective of this study was to investigate the possible participation of oxidized low-density lipoproteins (oxLDLs and inducible nitric oxide synthase (iNOS expression in renal tissue damage after intestinal I/R. The superior mesenteric artery was blocked for 30 minutes, followed by 24 hours of reperfusion. At the end of the reperfusion period, renal tissues were removed; the presence of oxLDL, superoxide dismutase enzyme activity, malondialdehyde levels, and iNOS expression were evaluated. I/R resulted in positive oxLDL staining in renal tissue. Compared with control rats, tissue from the I/R group showed significantly higher malondialdehyde levels and lower superoxide dismutase enzyme activity. Strong and diffuse iNOS expression was present in the I/R group. Our findings support the hypothesis that I/R of intestinal tissue results in oxidative and nitrosative stress and enhances lipid peroxidation in the end organ. These data show that oxLDL accumulates in rat renal tissue after intestinal I/R. Antioxidant strategies may provide organ protection in patients with reperfusion injury, at least by affecting interactions with free radicals, nitric oxide, and oxLDL. This study demonstrates for the first time that oxLDL may play a role in renal tissue damage after intestinal I/R. Antioxidant strategies may be beneficial for protection from reperfusion injury.

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

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    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. 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.

  20. 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

  1. Influence of remote ischemic conditioning and tramadol hydrochloride on oxidative stress in kidney ischemia/reperfusion injury in rats.

    Science.gov (United States)

    Oliveira, Rita de Cássia Silva de; Brito, Marcus Vinicius Henriques; Ribeiro, Rubens Fernando Gonçalves; Oliveira, Leonam Oliver Durval; Monteiro, Andrew Moraes; Brandão, Fernando Mateus Viegas; Cavalcante, Lainy Carollyne da Costa; Gouveia, Eduardo Henrique Herbster; Henriques, Higor Yuri Bezerra

    2017-03-01

    To evaluate the effects of tramadol hydrochloride associated to remote ischemic perconditioning on oxidative stress. Twenty five male rats (Wistar) underwent right nephrectomy and were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of renal ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during kidney ischemia; Tramadol group (T) treated with tramadol hydrochloride (40mg/kg); remote ischemic perconditioning + Tramadol group (Per+T) with both treatments. Oxidative stress was assessed after 24 hours of reperfusion. Statistical differences were observed in MDA levels between I/R group with all groups (pTramadol with Sham, Per and Per+T groups (ptramadol or association of both treatments.

  2. Adipose-Derived Mesenchymal Stem Cell Protects Kidneys against Ischemia-Reperfusion Injury through Suppressing Oxidative Stress and Inflammatory Reaction

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    Chua Sarah

    2011-05-01

    Full Text Available Abstract Background Reactive oxygen species are important mediators exerting toxic effects on various organs during ischemia-reperfusion (IR injury. We hypothesized that adipose-derived mesenchymal stem cells (ADMSCs protect the kidney against oxidative stress and inflammatory stimuli in rat during renal IR injury. Methods Adult male Sprague-Dawley (SD rats (n = 24 were equally randomized into group 1 (sham control, group 2 (IR plus culture medium only, and group 3 (IR plus immediate intra-renal administration of 1.0 × 106 autologous ADMSCs, followed by intravenous ADMSCs at 6 h and 24 h after IR. The duration of ischemia was 1 h, followed by 72 hours of reperfusion before the animals were sacrificed. Results Serum creatinine and blood urea nitrogen levels and the degree of histological abnormalities were markedly lower in group 3 than in group 2 (all p Conclusion ADMSC therapy minimized kidney damage after IR injury through suppressing oxidative stress and inflammatory response.

  3. Polydatin ameliorates renal ischemia/reperfusion injury by decreasing apoptosis and oxidative stress through activating sonic hedgehog signaling pathway.

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    Meng, Qiu-Hong; Liu, Hong-Bao; Wang, Jian-Bo

    2016-10-01

    Polydatin, a glucoside of resveratrol, recently has been demonstrated possibly to exert its biological effects by targeting sonic hedgehog (Shh). However, whether Shh signaling pathway is involved in the therapeutic effects of polydatin for renal ischemia/reperfusion (I/R) injury has not been evaluated. Our results showed that I/R induced the secretion of Shh, upregulated Patched and Smoothened, and enhanced the nuclear translocation and target gene transcription of Glioblastoma 1 in renal I/R injury models, which were further upregulated after the administration of polydatin significantly and in turn exerted prominent nephroprotective effects against cell apoptosis and oxidative stress. The treatment with cyclopamine (a specific inhibitor of Smoothened) or 5E1 (an anti-Shh antibody) not only markedly inhibited the activation of the Shh pathway, but also dramatically suppressed the nephroprotective effects of polydatin above-mentioned. These results advance our knowledge that polydatin can provide protection for kidneys against I/R injury by enhancing antioxidant capacity and decreasing cell apoptosis through activating Shh signaling pathway.

  4. Long Non-coding RNA H19 Induces Cerebral Ischemia Reperfusion Injury via Activation of Autophagy

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    Wang, Jue; Cao, Bin; Han, Dong; Sun, Miao; Feng, Juan

    2017-01-01

    Long non-coding RNA H19 (lncRNA H19) was found to be upregulated by hypoxia, its expression and function have never been tested in cerebral ischemia and reperfusion (I/R) injury. This study intended to investigate the role of lncRNA H19 and H19 gene variation in cerebral I/R injury with focusing on its relationship with autophagy activation. Cerebral I/R was induced in rats by middle cerebral artery occlusion followed by reperfusion. SH-SY5Y cells were subjected to oxygen and glucose deprivation and reperfusion (OGD/R) to simulate I/R injury. Real-time PCR, flow cytometry, immunofluorescence and Western blot were used to evaluate the level of lncRNA H19, apoptosis, autophagy and some related proteins. The modified multiple ligase reaction was used to analyze the gene polymorphism of six SNPs in H19, rs217727, rs2067051, rs2251375, rs492994, rs2839698 and rs10732516 in ischemic stroke patients. We found that the expression of lncRNA H19 was upregulated by cerebral I/R in rats, as well as by OGD/R in vitro in the cells. Inhibition of lncRNA H19 and autophagy protected cells from OGD/R-induced death, respectively. Autophagy activation induced by OGD/R was prevented by H19 siRNA. Autophagy inducer, rapamycin, abolished lncRNA H19 effect. Furthermore, we found that lncRNA H19 inhibited autophagy through DUSP5-ERK1/2 axis. The result from blood samples of ischemic patients revealed that the variation of H19 gene increased the risk of ischemic stroke. Taken together, the results of present study suggest that LncRNA H19 could be a new therapeutic target of ischemic stroke. PMID:28203482

  5. Influence of remote ischemic conditioning and tramadol hydrochloride on oxidative stress in kidney ischemia/reperfusion injury in rats

    OpenAIRE

    Oliveira,Rita de Cássia Silva de; BRITO, Marcus Vinicius Henriques; Ribeiro Júnior,Rubens Fernando Gonçalves; Oliveira,Leonam Oliver Durval; Monteiro,Andrew Moraes; Brandão,Fernando Mateus Viegas; Cavalcante,Lainy Carollyne da Costa; Gouveia,Eduardo Henrique Herbster; Henriques,Higor Yuri Bezerra

    2017-01-01

    Abstract Purpose: To evaluate the effects of tramadol hydrochloride associated to remote ischemic perconditioning on oxidative stress. Methods: Twenty five male rats (Wistar) underwent right nephrectomy and were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of renal ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during kidney ischemia; Tramadol group (T) treated with tramadol hydrochlori...

  6. Effects of KR-32570, a new sodium hydrogen exchanger inhibitor, on myocardial infarction and arrhythmias induced by ischemia and reperfusion.

    Science.gov (United States)

    Lee, Byung Ho; Yi, Kyu Yang; Lee, Sunkyung; Lee, Sunghou; Yoo, Sung-eun

    2005-10-31

    The present study was performed to evaluate the cardioprotective effects of [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) in rat and dog models of coronary artery occlusion and reperfusion. In addition, we sought to clarify the efficacy of KR-32570 on reperfusion-induced fatal ventricular arrhythmia. In anesthetized rats subjected to 45-min coronary occlusion and 90-min reperfusion, KR-32570 (i.v. bolus) dose-dependently reduced myocardial infarct size from 58.0% to 50.7%, 35.3%, 33.5% and 27.0% for 0.03, 0.1, 0.3 and 1.0 mg/kg, respectively (PKR-32570 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 28.9% in vehicle-treated group to 8.0% (PKR-32570 dose-dependently decreased the incidence of premature ventricular contraction, ventricular tachycardia or ventricular fibrillation induced by ischemia and reperfusion in rats. Similar results were obtained in dogs with reperfusion-induced arrhythmia. In separate experiments to assess the effects of timing of treatment, KR-32570 given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (40.9% and 46.1%, respectively) compared with vehicle-treated group. In all studies, KR-32570 caused no significant changes in any hemodynamic profiles. Taken together, these results indicate that KR-32570 significantly reduced the myocardial infarction and incidence of arrhythmias induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles. Thus, it could be potentially useful in the prevention and treatment of myocardial injuries and lethal ventricular arrhythmias.

  7. Lansoprazole ameliorates intestinal mucosal damage induced by ischemia-reperfusion in rats

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    Hiroshi Ichikawa; Toshikazu Yoshikawa; Norimasa Yoshida; Tomohisa Takagi; Naoya Tomatsuri; Kazuhiro Katada; Yutaka Isozaki; Kazuhiko Uchiyama; Yuji Naito; Takeshi Okanoue

    2004-01-01

    AIM: To investigate the protective effect of lansoprazole on ischemia and reperfusion (I/R)-induced rat intestinal mucosal injury in vivo.METHODS: Intestinal damage was induced by clamping both the superior mesenteric artery and the celiac trunk for 30 min followed by reperfusion in male Sprague-Dawley rats. Lansoprazole was given to rats intraperitoneally 1 h before vascular clamping.RESULTS: Both the intraluminal hemoglobin and protein levels, as indices of mucosal damage, significantly increased in I/R-groups comparion with those of shamoperation groups. These increases in intraluminal hemoglobin and protein levels were significantly inhibited by the treatment with lansoprazole at a dose of 1 mg/kg. Small intestine exposed to I/R resulted in mucosal inflammation that was characterized by significant increases in thiobarbituric acidreactive substances (TBARS), tissue-associated myeloperoxidase activity (MPO), and mucosal content of rat cytokine-induced neutrophil chemoattractant-1 (CINC-1).These increases in TBARS, MPO activities and CINC-1 content in the intestinal mucosa after I/R were all inhibited by pretreatment with lansoprazole at a dose of 1 mg/kg.Furthermore, the CINC-1 mRNA expression was increased during intestinal I/R, and this increase in mRNA expression was inhibited by treatment with lansoprazole.CONCLUSION: Lansoprazole inhibits lipid peroxidation and reduces development of intestinal mucosal inflammation induced by I/R in rats, suggesting that lansoprazole may have a therapeutic potential for I/R injury.

  8. Attenuation of mitochondrial, but not cytosolic, Ca2+ overload reduces myocardial injury induced by ischemia and reperfusion

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    Chun-mei CAO; Wing-yee YAN; Jing LIU; Kenneth WL KAM; Shi-zhong ZHAN; James SK SHAM; Tak-ming WONG

    2006-01-01

    Aim: Attenuation of mitochondrial Ca2+ ([Ca2+]m, but not cytosolic Ca2+ ([Ca2+]c), overload improves contractile recovery. We hypothesized that attenuation of [Ca2+]m, but not [Ca2+]c, overload confers cardioprotection against ischemia/ reperfusion-induced injury. Methods: Infarct size from isolated perfused rat heart, cell viability, and electrically-induced Ca2+ transient in isolated rat ventricular myocytes were measured. We determined the effects of BAPTA-AM, a Ca2+ chelator, at concentrations that abolish the overload of both [Ca2+]c and [Ca2+]m, and ruthenium red, an inhibitor of mitochondrial uniporter of Ca2+ transport, at concentrations that abolish the overload of [Ca2+]m, but not [Ca2+]c, on cardiac injury induced by ischemia/reperfusion. Results: Attenuation of both [Ca2+]m and [Ca2+]c by BAPTA-AM, and attenuation of [Ca2+]m, but not [Ca2+]c, overload by ruthenium red, reduced the cardiac injury observations, indicating the importance of [Ca2+]m in cardioprotection and contractile recovery in response to ischemia/reperfusion. Conclusion: The study has provided unequivocal evidence using a cause-effect approach that attenuation of [Ca2+]m, but not [Ca2+]c, overload is responsible for cardioprotection against ischemia/reperfusion-induced injury. We also confirmed the previous observation that attenuation of [Ca2+]m, but not [Ca2+]c, by ruthenium red improves contractile recovery following ischemia/ reperfusion.

  9. DRAM1 Protects Neuroblastoma Cells from Oxygen-Glucose Deprivation/Reperfusion-Induced Injury via Autophagy

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    Mengqiang Yu

    2014-10-01

    Full Text Available DNA damage-regulated autophagy modulator protein 1 (DRAM1, a multi-pass membrane lysosomal protein, is reportedly a tumor protein p53 (TP53 target gene involved in autophagy. During cerebral ischemia/reperfusion (I/R injury, DRAM1 protein expression is increased, and autophagy is activated. However, the functional significance of DRAM1 and the relationship between DRAM1 and autophagy in brain I/R remains uncertain. The aim of this study is to investigate whether DRAM1 mediates autophagy activation in cerebral I/R injury and to explore its possible effects and mechanisms. We adopt the oxygen-glucose deprivation and reperfusion (OGD/R Neuro-2a cell model to mimic cerebral I/R conditions in vitro, and RNA interference is used to knock down DRAM1 expression in this model. Cell viability assay is performed using the LIVE/DEAD viability/cytotoxicity kit. Cell phenotypic changes are analyzed through Western blot assays. Autophagy flux is monitored through the tandem red fluorescent protein–Green fluorescent protein–microtubule associated protein 1 light chain 3 (RFP–GFP–LC3 construct. The expression levels of DRAM1 and microtubule associated protein 1 light chain 3II/I (LC3II/I are strongly up-regulated in Neuro-2a cells after OGD/R treatment and peaked at the 12 h reperfusion time point. The autophagy-specific inhibitor 3-Methyladenine (3-MA inhibits the expression of DRAM1 and LC3II/I and exacerbates OGD/R-induced cell injury. Furthermore, DRAM1 knockdown aggravates OGD/R-induced cell injury and significantly blocks autophagy through decreasing autophagosome-lysosome fusion. In conclusion, our data demonstrate that DRAM1 knockdown in Neuro-2a cells inhibits autophagy by blocking autophagosome-lysosome fusion and exacerbated OGD/R-induced cell injury. Thus, DRAM1 might constitute a new therapeutic target for I/R diseases.

  10. Inducible nitric oxide synthase contributes to intermittent hypoxia against ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Hai-lei DING; Hai-feng ZHU; Jian-wen DONG; Wei-zhong ZHU; Wei-wei YANG; Huang-tian YANG; Zhao-nian ZHOU

    2005-01-01

    Aim: To investigate the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) in the cardioprotection of intermittent hypoxia (IH) against ischemia/reperfusion (I/R) injury. Methods: Langendorff-perfused isolated rat hearts were used to measure variables of left ventricular function during baseline perfusion, ischemia, and reperfusion period. Nitrate plus nitrite (NOx) content in myocardium was measured using a biochemical method, iNOS mRNA and protein expression in rat left ventricles were detected using reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Results: Myocardial function recovered better in IH rat hearts than in normoxic control hearts.The iNOS-selective inhibitor aminoguanidine (AG) (100 μmol/L) significantly inhibited the protective effects of IH, but had no influence on normoxic rat hearts.The baseline content of NOx in IH hearts was higher than that in normoxic hearts.After 30 min ischemia, the NOx level in normoxic hearts increased compared to the corresponding baseline level, whereas there was no significant change in IH hearts. However, the NOx level in IH hearts was still higher than that of normoxic hearts during ischemia and reperfusion period. AG 100 μmol/L significantly diminished the NOx content in IH and normoxic hearts during ischemia and reperfusion period. The baseline levels of iNOS mRNA and protein in IH hearts were higher than those of normoxic hearts. Compared to the corresponding baseline level,iNOS mRNA and protein levels in normoxic rat hearts increased and those in IH rat hearts decreased after reperfusion. The addition of AG 100 μmol/L significantly decreased iNOS mRNA and protein expression in IH rat hearts after I/R.Conclusion: IH upregulated the baseline level of iNOS mRNA and protein expression leading to an increase in NO production, which may play an important role in the cardiac protection of IH against I/R injury.

  11. Total salvianolic acid improves ischemia-reperfusion-induced microcirculatory disturbance in rat mesentery

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To investigate the effect of total salvianolic acid(TSA) on ischemia-reperfusion(I/R)-induced rat mesenteric microcirculatory dysfunctions.METHODS:Male Wistar rats were randomly distributed into 5 groups(n = 6 each):Sham group and I/R group(infused with saline),TSA group,TSA + I/R group and I/R + TSA group(infused with TSA,5 mg/kg per hour).Mesenteric I/R were conducted by a ligation of the mesenteric artery and vein(10 min) and subsequent release of the occlusion.TSA was continuously infused either sta...

  12. Effects of dexmedetomidine on renal tissue after lower limb ischemia reperfusion injury in streptozotocin induced diabetic rats

    Science.gov (United States)

    Erbatur, Meral Erdal; Sezen, Şaban Cem; Bayraktar, Aslıhan Cavunt; Arslan, Mustafa; Kavutçu, Mustafa; Aydın, Muhammed Enes

    2017-01-01

    ABSTRACT Aim: The aim of this study was to investigate whether dexmedetomidine – administered before ischemia – has protective effects against lower extremity ischemia reperfusion injury that induced by clamping and subsequent declamping of infra-renal abdominal aorta in streptozotocin-induced diabetic rats. Material and Methods: After obtaining ethical committee approval, four study groups each containing six rats were created (Control (Group C), diabetes-control (Group DM-C), diabetes I/R (Group DM-I/R), and diabetes-I/R-dexmedetomidine (Group DM-I/R-D). In diabetes groups, single-dose (55 mg/kg) streptozotocin was administered intraperitoneally. Rats with a blood glucose level above 250 mg/dl at the 72nd hour were accepted as diabetic. At the end of four weeks, laparotomy was performed in all rats. Nothing else was done in Group C and DM-C. In Group DM-I/R, ischemia reperfusion was produced via two-hour periods of clamping and subsequent declamping of infra-renal abdominal aorta. In Group DM-I/R-D, 100 μg/kg dexmedetomidine was administered intraperitoneally 30 minutes before ischemia period. At the end of reperfusion, period biochemical and histopathological evaluation of renal tissue specimen were performed. Results: Thiobarbituric acid reactive substance (TBARS), Superoxide dismutase (SOD), Nitric oxide synthase (NOS), Catalase (CAT) and Glutathion S transferase (GST) levels were found significantly higher in Group DM-I/R when compared with Group C and Group DM-C. In the dexmedetomidine-treated group, TBARS, NOS, CAT, and GST levels were significantly lower than those measured in the Group D-I/R. In histopathological evaluation, glomerular vacuolization (GV), tubular dilatation (TD), vascular vacuolization and hypertrophy (VVH), tubular cell degeneration and necrosis (TCDN), tubular hyaline cylinder (THC), leucocyte infiltration (LI), and tubular cell spillage (TCS) in Group DM-I/R were significantly increased when compared with the control group

  13. Ischemic post-conditioning attenuates acute lung injury induced by intestinal ischemia-reperfusion in mice: role of Nrf2.

    Science.gov (United States)

    Meng, Qing-Tao; Cao, Chen; Wu, Yang; Liu, Hui-Min; Li, Wei; Sun, Qian; Chen, Rong; Xiao, Yong-Guang; Tang, Ling-Hua; Jiang, Ying; Leng, Yan; Lei, Shao-Qing; Lee, Chris C; Barry, Devin M; Chen, Xiangdong; Xia, Zhong-Yuan

    2016-10-01

    Intestinal ischemic post-conditioning (IPo) protects against lung injury induced by intestinal ischemia-reperfusion (IIR) partly through promotion of expression and function of heme oxygenase-1 (HO-1). NF-E2-related factor-2 (Nrf2) is a key transcription factor that interacts with HO-1 and regulates antioxidant defense. However, the role of Nrf2 in IPo protection of IIR-induced pulmonary injury is not completely understood. Here we show that IPo significantly attenuated IIR-induced lung injury and suppressed oxidative stress and systemic inflammatory responses. IPo also increased the expression of both Nrf2 and HO-1. Consistently, the beneficial effects of IPo were abolished by ATRA and Brusatol, potent inhibitors of Nrf2. Moreover, the Nrf2 agonist t-BHQ showed similar activity as IPo. Taken together, our data suggest that Nrf2 activity, along with HO-1, plays an important role in the protective effects of IPo against IIR-induced acute lung injury.

  14. The stability of the atherosclerotic plaque depends on the extent of injured endothelium: results from a novel model of ischemia /reperfusion induced atherosclerosis in carotid artery of rats

    Institute of Scientific and Technical Information of China (English)

    晋学庆

    2014-01-01

    Objective To observe the atherogenic lesion progress in a novel ischemia/reperfusion induced atherosclerosis model in the carotid artery of rats.Methods Rats were divided into normal control,sham-operated control and ischemia-reperfusion injury(IRI)groups(n=10each).IRI was induced by 30 min carotid artery occlusion with a 2 cm

  15. Neuroprotective effects of atorvastatin against cerebral ischemia/reperfusion injury through the inhibition of endoplasmic reticulum stress

    Institute of Scientific and Technical Information of China (English)

    Jian-wen Yang; Zhi-ping Hu

    2015-01-01

    Cerebral ischemia triggers secondary ischemia/reperfusion injury and endoplasmic reticulum stress initiates cell apoptosis. However, the regulatory mechanism of the signaling pathway remains unclear. We hypothesize that the regulatory mechanisms are mediated by the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α in the endoplasmic reticulum stress signaling pathway. To verify this hypothesis, we occluded the middle cere-bral artery in rats to establish focal cerebral ischemia/reperfusion model. Results showed that the expression levels of protein kinase-like endoplasmic reticulum kinase and caspase-3, as well as the phosphorylation of eukaryotic initiation factor 2α, were increased after ischemia/reperfusion. Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2α, reduced the infarct volume and improved ultrastructure in the rat brain. After salubrinal, the speciifc inhibitor of phosphorylated eukaryotic initiation factor 2α was given into the rats in-tragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2α in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain. However, salubrinal had no impact on the expression of protein kinase-like endoplasmic reticulum kinase. Experimental ifndings indi-cate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects. The underlying mechanisms of attenuating ischemia/reperfusion injury are associated with the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/caspase-3 pathway.

  16. Carbon monoxide increases inducible NOS expression that mediates CO-induced myocardial damage during ischemia-reperfusion.

    Science.gov (United States)

    Meyer, Grégory; André, Lucas; Kleindienst, Adrien; Singh, François; Tanguy, Stéphane; Richard, Sylvain; Obert, Philippe; Boucher, François; Jover, Bernard; Cazorla, Olivier; Reboul, Cyril

    2015-04-01

    We investigated the role of inducible nitric oxide (NO) synthase (iNOS) on ischemic myocardial damage in rats exposed to daily low nontoxic levels of carbon monoxide (CO). CO is a ubiquitous environmental pollutant that impacts on mortality and morbidity from cardiovascular diseases. We have previously shown that CO exposure aggravates myocardial ischemia-reperfusion (I/R) injury partly because of increased oxidative stress. Nevertheless, cellular mechanisms underlying cardiac CO toxicity remain hypothetical. Wistar rats were exposed to simulated urban CO pollution for 4 wk. First, the effects of CO exposure on NO production and NO synthase (NOS) expression were evaluated. Myocardial I/R was performed on isolated perfused hearts in the presence or absence of S-methyl-isothiourea (1 μM), a NOS inhibitor highly specific for iNOS. Finally, Ca(2+) handling was evaluated in isolated myocytes before and after an anoxia-reoxygenation performed with or without S-methyl-isothiourea or N-acetylcystein (20 μM), a nonspecific antioxidant. Our main results revealed that 1) CO exposure altered the pattern of NOS expression, which is characterized by increased neuronal NOS and iNOS expression; 2) cardiac NO production increased in CO rats because of its overexpression of iNOS; and 3) the use of a specific inhibitor of iNOS reduced myocardial hypersensitivity to I/R (infarct size, 29 vs. 51% of risk zone) in CO rat hearts. These last results are explained by the deleterious effects of NO and reactive oxygen species overproduction by iNOS on diastolic Ca(2+) overload and myofilaments Ca(2+) sensitivity. In conclusion, this study highlights the involvement of iNOS overexpression in the pathogenesis of simulated urban CO air pollution exposure.

  17. Propofol Prevents Renal Ischemia-Reperfusion Injury via Inhibiting the Oxidative Stress Pathways

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    Yingjie Li

    2015-08-01

    Full Text Available Background/Aims: Renal ischemia/reperfusion injury (IRI is a risk for acute renal failure and delayed graft function in renal transplantation and cardiac surgery. The purpose of this study is to determine whether propofol could attenuate renal IRI and explore related mechanism. Methods: Male rat right kidney was removed, left kidney was subjected to IRI. Propofol was intravenously injected into rats before ischemia. The kidney morphology and renal function were analyzed. The expression of Bax, Bcl-2, caspase-3, cl-caspase-3, GRP78, CHOP and caspase-12 were detected by Western blot analysis. Results: IR rats with propofol pretreatment had better renal function and less tubular apoptosis than untreated IR rats. Propofol pretreated IR rats had lower Bax/Bcl-2 ratio and less cleaved caspase-3. The protein expression levels of GRP78, CHOP and caspase-12 decreased significantly in propofol pretreated IR rats. In vitro cell model showed that propofol significantly increased the viability of NRK-52E cells that were subjected to hypoxia/reoxygenation (H/R in a dose-dependent manner. The effect of propofol on the expression regulation of Bax, Bcl-2, caspase-3, GRP78, CHOP was consistent in both in vitro and in vivo models. Conclusion: Experimental results suggest that propofol prevents renal IRI via inhibiting oxidative stress.

  18. 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.

  19. Bone Morphogenetic Protein-7 Ameliorates Cerebral Ischemia and Reperfusion Injury via Inhibiting Oxidative Stress and Neuronal Apoptosis

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    Haitao Pei

    2013-11-01

    Full Text Available Previous studies have indicated that bone morphogenetic protein-7 (BMP-7 is neuroprotective against cerebral ischemia/reperfusion (IR injury. The present study was undertaken to determine the molecular mechanisms involved in this effect. Adult male Wistar rats were subjected to 2 h of transient middle cerebral artery occlusion (MCAO, followed by 24 h of reperfusion. BMP-7 (10−4 g/kg or vehicle was infused into rats at the onset of reperfusion via the tail vein. Neurological deficits, infarct volume, histopathological changes, oxidative stress-related biochemical parameters, neuronal apoptosis, and apoptosis-related proteins were assessed. BMP-7 significantly improved neurological and histological deficits, reduced the infarct volume, and decreased apoptotic cells after cerebral ischemia. BMP-7 also markedly enhanced the activities of antioxidant enzymes superoxide dismutase (SOD and glutathione peroxidase (GSH-PX, and reduced the level of malondialdehyde (MDA in IR rats. In addition, Western blot analysis indicated that BMP-7 prevented cytochrome c release, inhibited activation of caspase-3, caspase-9 and caspase-8. Our data suggested that BMP-7 has protective effects against cerebral IR injury in rats, and the neuroprotective effects may be attributed to attenuating oxidative stress and inhibiting neuronal apoptosis.

  20. Sex differences in ischemia/reperfusion-induced acute kidney injury are dependent on the renal sympathetic nervous system.

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    Tanaka, Ryosuke; Tsutsui, Hidenobu; Ohkita, Mamoru; Takaoka, Masanori; Yukimura, Tokihito; Matsumura, Yasuo

    2013-08-15

    Resistance to ischemic acute kidney injury has been shown to be higher in female rats than in male rats. We found that renal venous norepinephrine overflow after reperfusion played important roles in the development of ischemic acute kidney injury. In the present study, we investigated whether sex differences in the pathogenesis of ischemic acute kidney injury were derived from the renal sympathetic nervous system using male and female Sprague-Dawley rats. Ischemia/reperfusion-induced acute kidney injury was achieved by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function was impaired after reperfusion in both male and female rats; however, renal dysfunction and histological damage were more severe in male rats than in female rats. Renal venous plasma norepinephrine levels after reperfusion were markedly elevated in male rats, but were not in female rats. These sex differences were eliminated by ovariectomy or treatment with tamoxifen, an estrogen receptor antagonist, in female rats. Furthermore, an intravenous injection of hexamethonium (25mg/kg), a ganglionic blocker, 5 min before ischemia suppressed the elevation in renal venous plasma norepinephrine levels after reperfusion, and attenuated renal dysfunction and histological damage in male rats, and ovariectomized and tamoxifen-treated female rats, but not in intact females. Thus, the present findings confirmed sex differences in the pathogenesis of ischemic acute kidney injury, and showed that the attenuation of ischemia/reperfusion-induced acute kidney injury observed in intact female rats may be dependent on depressing the renal sympathetic nervous system with endogenous estrogen.

  1. Effect of recombinant erythropoietin on ischemia-reperfusion-induced apoptosis in rat liver.

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    Shawky, Heba M; Younan, Sandra M; Rashed, Leila A; Shoukry, Heba

    2012-03-01

    Ischemia-reperfusion (I/R) cannot be avoided in liver transplantation procedures, and apoptosis is a central mechanism of cell death after liver reperfusion. Protective effect of recombinant erythropoietin (rhEPO) on liver apoptosis has not been clearly investigated. This work investigated intraportal (IP) rhEPO-protective effect in a rat model of hepatic I/R-induced apoptosis and its appropriated time and dose of administration. Eight groups were included (n = 10/group): sham-operated, I/R (45 min ischemia and 2 h reperfusion), preconditioned rhEPO I/R (24 h or 30 min before ischemia), and postconditioned rhEPO I/R (before reperfusion) using two different rhEPO doses (1,000 and 5,000 IU/kg). When compared with the sham-operated group, the I/R group showed significant increase of serum levels of aspartate and alanine aminotransferases (AST, ALT), hepatic caspase-9 activity(894.99 ± 176.90 relative fluorescence units (RFU)/mg/min versus 458.48 ± 82.96 RFU/mg/min), and Fas ligand (FasL) expression, histopathological damages, and significant decrease in the antiapoptotic Bcl-xL/apoptotic Bax ratio(0.38 ± 0.21 versus 3.35 ± 0.77) rhEPO-improved ALT and AST but failed to reduce FasL expression in all groups compared with the I/R group. Thirty minutes and 24 h preconditioning with rhEPO (1,000 IU/kg) increased Bcl-xL/Bax ratio and reduced caspase-9 activity, and the same effect was observed when higher dose was given 24 h before ischemia. Preconditioning was more effective than postconditioning in improving caspase-9 activity, and no dose-dependent effect was observed. In conclusion, single IP rhEPO injection 30 min before ischemia has an advantage over rhEPO postconditioning in improving post-hepatic I/R-induced apoptosis with no additional time- and dose-dependent effects which may provide potentially useful guide in liver transplantation procedures.

  2. Protective effect of mangiferin on myocardial ischemia-reperfusion injury in streptozotocin-induced diabetic rats: role of AGE-RAGE/MAPK pathways.

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    Suchal, Kapil; Malik, Salma; Khan, Sana Irfan; Malhotra, Rajiv Kumar; Goyal, Sameer N; Bhatia, Jagriti; Kumari, Santosh; Ojha, Shreesh; Arya, Dharamvir Singh

    2017-02-09

    Hyperglycemia induced advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) activation is thought to involve in the development of cardiovascular disease in diabetics. Activation of AGE-RAGE axis results in the oxidative stress and inflammation. Mangiferin is found in the bark of mango tree and is known to treat diseases owing to its various biological activities. Thus, this study was designed to evaluate the effect of mangiferin in ischemia-reperfusion (IR) induced myocardial injury in diabetic rats. A single injection of STZ (70 mg/kg; i.p.) was injected to male albino Wistar rats to induce diabetes. After confirmation of diabetes, rats were administered vehicle (2 ml/kg; i.p.) and mangiferin (40 mg/kg; i.p.) for 28 days. On 28(th) day, left anterior descending coronary artery was ligated for 45 min and then reperfused for 60 min. Mangiferin treatment significantly improved cardiac function, restored antioxidant status, reduced inflammation, apoptosis and maintained myocardial architecture. Furthermore, mangiferin significantly inhibited the activation of AGE-RAGE axis, c-Jun N-terminal kinase (JNK) and p38 and increased the expression of extracellular regulated kinase 1/2 (ERK1/2) in the myocardium. Thus, mangiferin attenuated IR injury in diabetic rats by modulation of AGE-RAGE/MAPK pathways which further prevented oxidative stress, inflammation and apoptosis in the myocardium.

  3. Effects and Mechanism of Action of Inducible Nitric Oxide Synthase on Apoptosis in a Rat Model of Cerebral Ischemia-Reperfusion Injury.

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    Zheng, Li; Ding, Junli; Wang, Jianwei; Zhou, Changman; Zhang, Weiguang

    2016-02-01

    Inducible nitric oxide synthase (iNOS) is a key enzyme in regulating nitric oxide (NO) synthesis under stress, and NO has varying ability to regulate apoptosis. The aim of this study was to investigate the effects and possible mechanism of action of iNOS on neuronal apoptosis in a rat model of cerebral focal ischemia and reperfusion injury in rats treated with S-methylisothiourea sulfate (SMT), a high-selective inhibitor of iNOS. Seventy-two male Sprague-Dawley (SD) rats were randomly divided into three groups: the sham, middle cerebral artery occlusion (MCAO) + vehicle, and MCAO + SMT groups. Neurobehavioral deficits, infarct zone size, and cortical neuron morphology were evaluated through the modified Garcia scores, 2,3,5-triphenyltetrazolium chloride (TTC), and Nissl staining, respectively. Brain tissues and serum samples were collected at 72 hr post-reperfusion for immunohistochemical analysis, Western blotting, Terminal deoxynucleotidyl transferase-mediated dUTP-biotin Nick End Labeling assay (TUNEL) staining, and enzyme assays. The study found that inhibition of iNOS significantly attenuated the severity of the pathological changes observed as a result of ischemia-reperfusion injury: SMT reduced NO content as well as total nitric oxide synthase (tNOS) and iNOS activities in both ischemic cerebral hemisphere and serum, improved neurobehavioral scores, reduced mortality, reduced the infarct volume ratio, attenuated morphological changes in cortical neurons, decreased the rate of apoptosis (TUNEL and caspase-3-positive), and increased phospho (p)-AKT expression in ischemic penumbra. These results suggested that inhibition of iNOS might reduce the severity of ischemia-reperfusion injury by inhibiting neuronal apoptosis via maintaining p-AKT activity.

  4. Achyranthes bidentata Polypeptides Reduces Oxidative Stress and Exerts Protective Effects against Myocardial Ischemic/Reperfusion Injury in Rats

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    Haifeng Zhang

    2013-09-01

    Full Text Available Achyranthes bidentata, a Chinese medicinal herb, is reported to be neuroprotective. However, its role in cardioprotection remains largely unknown. Our present study aimed to investigate the effects of Achyranthes bidentata polypeptides (ABPP preconditioning on myocardial ischemia/reperfusion (MI/R injury and to test the possible mechanisms. Rats were treated with ABPP (10 mg/kg/d, i.p. or saline once daily for one week. Afterward, all the animals were subjected to 30 min of myocardial ischemia followed by 4 h of reperfusion. ABPP preconditioning for one week significantly improved cardiac function following MI/R. Meanwhile, ABPP reduced infarct size, plasma creatine kinase (CK/lactate dehydrogenase (LDH activities and myocardial apoptosis at the end of reperfusion in rat hearts. Moreover, ABPP preconditioning significantly inhibited superoxide generation, gp91phox expression, malonaldialdehyde formation and enhanced superoxide dismutase activity in I/R hearts. Furthermore, ABPP treatment inhibited PTEN expression and increased Akt phosphorylation in I/R rat heart. PI3K inhibitor wortmannin blocked Akt activation, and abolished ABPP-stimulated anti-oxidant effect and cardioprotection. Our study demonstrated for the first time that ABPP reduces oxidative stress and exerts cardioprotection against MI/R injury in rats. Inhibition of PTEN and activation of Akt may contribute to the anti-oxidant capacity and cardioprotection of ABPP.

  5. Protective Effect of Salvia miltiorrhiza Extract Against Renal Ischemia-Reperfusion-Induced Injury in Rats

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    Gang Chen

    2012-01-01

    Full Text Available The present study investigates the effect of pre-treatment with Salvia miltiorrhiza ethanol extracts (SMEE on renal function markers, immunity and antioxidant activities in renal ischemia and reperfusion (IR rats. Wistar rat kidneys were subjected to 60 min of global ischemia at 37 °C followed by 30 min of reperfusion, and were randomly assigned into the sham, IR model and three SMEE-treated groups (n = 8 per group. Results showed that high serum creatinin (Scr, blood urea nitrogen (BUN, interleukin-6 (IL-6, interleukin-8 (IL-8, tumor necrosis factor-alpha (TNF-α and malondialhehyde (MDA levels, and low antioxidant enzyme activities were observed in IR rats compared to the sham rats. Pre-treatment of Salvia miltiorrhiza ethanol extracts for 20 days prior to IR operation improved renal function, reduced IR induced renal inflammatory and oxidative injury. It is concluded that Salvia miltiorrhiza ethanol extracts could be beneficial in the treatment of renal ischemic injury.

  6. 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.

  7. Delivery of antioxidant enzyme genes to protect against ischemia/reperfusion-induced injury to retinal microvasculature.

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    Chen, Baihua; Caballero, Sergio; Seo, Soojung; Grant, Maria B; Lewin, Alfred S

    2009-12-01

    Retinal ischemia/reperfusion (I/R) injury results in the generation of reactive oxygen species (ROS). The aim of this study was to investigate whether delivery of the manganese superoxide dismutase gene (SOD2) or the catalase gene (CAT) could rescue the retinal vascular damage induced by I/R in mice. I/R injury to the retina was induced in mice by elevating intraocular pressure for 2 hours, and reperfusion was established immediately afterward. One eye of each mouse was pretreated with plasmids encoding manganese superoxide dismutase or catalase complexed with cationic liposomes and delivered by intravitreous injection 48 hours before initiation of the procedure. Superoxide ion, hydrogen peroxide, and 4-hydroxynonenal (4-HNE) protein modifications were measured by fluorescence staining, immunohistochemistry, and Western blot analysis 1 day after the I/R injury. At 7 days after injury, retinal vascular cell apoptosis and acellular capillaries were quantitated. Superoxide ion, hydrogen peroxide, and 4-HNE protein modifications increased at 24 hours after I/R injury. Administration of plasmids encoding SOD2 or CAT significantly reduced levels of superoxide ion, hydrogen peroxide, and 4-HNE. Retinal vascular cell apoptosis and acellular capillary numbers increased greatly by 7 days after the injury. Delivery of SOD2 or CAT inhibited the I/R-induced apoptosis of retinal vascular cell and retinal capillary degeneration. Delivery of antioxidant genes inhibited I/R-induced retinal capillary degeneration, apoptosis of vascular cells, and ROS production, suggesting that antioxidant gene therapy might be a treatment for I/R-related disease.

  8. 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.

  9. 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.

  10. Melatonin treatment protects liver of Zucker rats after ischemia/reperfusion by diminishing oxidative stress and apoptosis.

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    Kireev, Roman; Bitoun, Samuel; Cuesta, Sara; Tejerina, Alejandro; Ibarrola, Carolina; Moreno, Enrique; Vara, Elena; Tresguerres, Jesus A F

    2013-02-15

    Fatty livers occur in up to 20% of potential liver donors and increase cellular injury during the ischemia/reperfusion phase, so any intervention that could enable a better outcome of grafts for liver transplantation would be very useful. The effect of melatonin on liver ischemia/reperfusion injury in a rat model of obesity and hepatic steatosis has been investigated. Forty fa/fa Zucker rats were divided in 4 groups. 3 groups were subjected to 35 min of warm hepatic ischemia and 36 h of reperfusion. One experimental group remained untreated and 2 were given 10mg/kg melatonin intraperitoneally or orally. Another group was sham-operated. Plasma ALT, AST and hepatic content of ATP, MDA, hydroxyalkenals, NOx metabolites, antioxidant enzyme activity, caspase-9 and DNA fragmentation were determined in the liver. The expression of iNOS, eNOS, Bcl2, Bax, Bad and AIF were determined by RT-PCR Melatonin was effective at decreasing liver injury by both ways as assessed by liver transaminases, markers of apoptosis, of oxidative stress and improved liver ATP content. Melatonin administration decreased the activities or levels of most of the parameters measured in a beneficial way, and our study identified also some of the mechanisms of protection. We conclude that administration of melatonin improved liver function, as well as markers of pro/antioxidant status and apoptosis following ischemia/reperfusion in obese rats with fatty liver. These data suggest that this substance could improve outcome in patients undergoing liver transplantation who receive a fatty liver implant and suggest the need of clinical trials with it in liver transplantation. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Does stress induce bowel dysfunction?

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    Chang, Yu-Ming; El-Zaatari, Mohamad; Kao, John Y

    2014-08-01

    Psychological stress is known to induce somatic symptoms. Classically, many gut physiological responses to stress are mediated by the hypothalamus-pituitary-adrenal axis. There is, however, a growing body of evidence of stress-induced corticotrophin-releasing factor (CRF) release causing bowel dysfunction through multiple pathways, either through the HPA axis, the autonomic nervous systems, or directly on the bowel itself. In addition, recent findings of CRF influencing the composition of gut microbiota lend support for the use of probiotics, antibiotics, and other microbiota-altering agents as potential therapeutic measures in stress-induced bowel dysfunction.

  12. PUMA is invovled in ischemia/reperfusion-induced apoptosis of mouse cerebral astrocytes.

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    Chen, H; Tian, M; Jin, L; Jia, H; Jin, Y

    2015-01-22

    PUMA (p53-upregulated modulator of apoptosis), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and p53-independent forms of apoptosis. PUMA has been invovled in the onset and progress of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease. Although many studies have shown that ischemia and reperfusion (I/R) can induce the apoptosis of astrocytes, the role of PUMA in I/R-mediated apoptosis of cerebral astrocyte apoptosis remains unclear. To mimic in vivo I/R conditions, primary mouse cerebral astrocytes were incubated in a combinational cultural condition of oxygen, glucose, and serum deprivation (OSGD) for 1 h followed by reperfusion (OSGD/R). Cell death determination assays and cell viability assays indicated that OSGD and OSGD/R induce the apoptosis of primary cerebral astrocytes. The expression of PUMA was significantly elevated in primary cerebral astrocytes during OSGD/R. Moreover, targeted down-regulation of PUMA by siRNA transfection significantly decreased the OSGD/R-induced apoptosis of primary cerebral astrocytes. We also found that OSGD and OSGD/R triggered the release of cytochrome c in astrocytes, indicating the dependence on a mitochondrial apoptotic pathway. Reactive oxygen species (ROS) was extremely generated during OSGD and OSGD/R, and the elimination of ROS by treated with N-acetyl-L-cysteine (NAC) remarkably inhibited the expression of PUMA and the apoptosis of primary cerebral astrocytes. The activation of Caspase 3 and Caspase 9 was extremely elevated in primary cerebral astrocytes during OSGD. In addition, we found that knockdown of PUMA led to the depressed expression of Bax, cleaved caspase-9 and caspase-3 during OSGD/R. These results indicate that PUMA is invovled in the apoptosis of cerebral astrocytes upon I/R injury.

  13. The effect of levosimendan on myocardial ischemia–reperfusion injury in streptozotocin-induced diabetic rats

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    Kiraz, Hasan Ali; Poyraz, Fatih; Kip, Gülay; Erdem, Özlem; Alkan, Metin; Arslan, Mustafa; Özer, Abdullah; Şivgin, Volkan; Çomu, Faruk Metin

    2015-01-01

    Objective Ischemia/reperfusion (I/R) injury is an important cause of myocardial damage by means of oxidative, inflammatory, and apoptotic mechanisms. The aim of the present study was to examine the potential cardio protective effects of levosimendan in a diabetic rat model of myocardial I/R injury. Methods A total of 18 streptozotocin-induced diabetic Wistar Albino rats (55 mg/kg) were randomly divided into three equal groups as follows: the diabetic I/R group (DIR) in which myocardial I/R was induced following left thoracotomy, by ligating the left anterior descending coronary artery for 60 min, followed by 2 h of reperfusion; the diabetic I/R levosimendan group (DIRL), which underwent I/R by the same method while taking levosimendan intraperitoneal 12 µg kg−1; and the diabetic control group (DC) which underwent sham operations without tightening of the coronary sutures. As a control group (C), six healthy age-matched Wistar Albino rats underwent sham operations similar to the DC group. Two hours after the operation, the rats were sacrificed and the myocardial tissue samples were examined by light microscopy for evidence of myonecrosis and inflammatory cell infiltration. Results Myonecrosis findings were significantly different among groups (p=0.008). Myonecrosis was more pronounced in the DIR group compared with the C, DC, and DIRL groups (p=0.001, p=0.007 and p=0.037, respectively). Similarly, the degree of inflammatory cell infiltration showed significant difference among groups (p<0.0001). Compared with C, DC, and DIRL groups, the inflammatory cell infiltration was significantly higher among the DIR group (p<0.0001, p<0.0001, and p=0.020, respectively). Also, myocardial tissue edema was significantly different among groups (p=0.006). The light microscopic myocardial tissue edema levels were significantly higher in the DIR group than the C, DC, and DIRL groups (p=0.001, p=0.037, and p=0.014, respectively). Conclusion Taken together, our data indicate that

  14. The effect of levosimendan on myocardial ischemia–reperfusion injury in streptozotocin-induced diabetic rats

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    Hasan Ali Kiraz

    2015-12-01

    Full Text Available Objective: Ischemia/reperfusion (I/R injury is an important cause of myocardial damage by means of oxidative, inflammatory, and apoptotic mechanisms. The aim of the present study was to examine the potential cardio protective effects of levosimendan in a diabetic rat model of myocardial I/R injury. Methods: A total of 18 streptozotocin-induced diabetic Wistar Albino rats (55 mg/kg were randomly divided into three equal groups as follows: the diabetic I/R group (DIR in which myocardial I/R was induced following left thoracotomy, by ligating the left anterior descending coronary artery for 60 min, followed by 2 h of reperfusion; the diabetic I/R levosimendan group (DIRL, which underwent I/R by the same method while taking levosimendan intraperitoneal 12 µg kg−1; and the diabetic control group (DC which underwent sham operations without tightening of the coronary sutures. As a control group (C, six healthy age-matched Wistar Albino rats underwent sham operations similar to the DC group. Two hours after the operation, the rats were sacrificed and the myocardial tissue samples were examined by light microscopy for evidence of myonecrosis and inflammatory cell infiltration. Results: Myonecrosis findings were significantly different among groups (p=0.008. Myonecrosis was more pronounced in the DIR group compared with the C, DC, and DIRL groups (p=0.001, p=0.007 and p=0.037, respectively. Similarly, the degree of inflammatory cell infiltration showed significant difference among groups (p<0.0001. Compared with C, DC, and DIRL groups, the inflammatory cell infiltration was significantly higher among the DIR group (p<0.0001, p<0.0001, and p=0.020, respectively. Also, myocardial tissue edema was significantly different among groups (p=0.006. The light microscopic myocardial tissue edema levels were significantly higher in the DIR group than the C, DC, and DIRL groups (p=0.001, p=0.037, and p=0.014, respectively. Conclusion: Taken together, our data

  15. The early signal substances induced by heat stress in brains of mice

    Institute of Scientific and Technical Information of China (English)

    Chunxu WANG; Hanxing WANG

    2008-01-01

    To study the effects of early signal substances induced by heat stress in brains of Kunming mice, six-month-old mice (n=72) were pretreated with heat stress and subsequent ischemia/reperfusion by clipping of their bilateral cervical common arteries for 7 min. According to different treatments, animals were randomly divided into four groups: (1) normal control group; (2) heat stress pre-treatment followed by ischemia and reperfusion group (HS/IR); (3) ischemia and reperfusion group (IR); (4) heat stress group (HS). Animals in the later three groups were subdivided into 3 subgroups (1 day, 4 days, 14 days), respectively. The changes in the expression of cAMP res-ponse element binding protein (CREB) and calcitonin gene-related peptide (CGRP) were detected by immuno-histochemistry and computer image analysis methods. The results showed that compared with the normal group, the expressions of CREB in the hippocampal CA1 region increased significantly in the HS, HS/IR and IR groups (P<0.05). Compared to the normal group, heat stress could result in CGRP excretion and redistribution in the cerebrum, with the highest level in the 4 d HS/IR group. Following heat stress, CGRP immunoreactivity was observed in varicose fibers and neuronal perikarya within the CA1 region. The results indicate that heat stress can induce CREB expression, which in turn stimulates CGRP secretion.

  16. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress

    Science.gov (United States)

    Zhang, Meng; Yu, Li-ming; Zhao, Hang; Zhou, Xuan-xuan; Yang, Qian; Song, Fan; Yan, Li; Zhai, Meng-en; Li, Bu-ying; Zhang, Bin; Jin, Zhen-xiao; Duan, Wei-xun; Wang, Si-wang

    2017-01-01

    2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is a water-soluble active component extracted from Polygonum multiflorum Thunb. A number of studies demonstrate that TSG exerts cardioprotective effects. Since endoplasmic reticulum (ER) stress plays a key role in myocardial ischemia/reperfusion (MI/R)-induced cell apoptosis, we sought to determine whether modulation of the ER stress during MI/R injury was involved in the cardioprotective action of TSG. Male mice were treated with TSG (60 mg·kg−1·d−1, ig) for 2 weeks and then were subjected to MI/R surgery. Pre-administration of TSG significantly improved post-operative cardiac function, and suppressed MI/R-induced myocardial apoptosis, evidenced by the reduction in the myocardial apoptotic index, serum levels of LDH and CK after 6 h of reperfusion. TSG (0.1–1000 μmol/L) did not affect the viability of cultured H9c2 cardiomyoblasts in vitro, but pretreatment with TSG dose-dependently decreased simulated ischemia/reperfusion (SIR)-induced cell apoptosis. Furthermore, both in vivo and in vitro studies revealed that TSG treatment activated the Notch1/Hes1 signaling pathway and suppressed ER stress, as evidenced by increasing Notch1, Notch1 intracellular domain (NICD), Hes1, and Bcl-2 expression levels and by decreasing p-PERK/PERK ratio, p-eIF2α/eIF2α ratio, and ATF4, CHOP, Bax, and caspase-3 expression levels. Moreover, the protective effects conferred by TSG on SIR-treated H9c2 cardiomyoblasts were abolished by co-administration of DAPT (the Notch1 signaling inhibitor). In summary, TSG ameliorates MI/R injury in vivo and in vitro by activating the Notch1/Hes1 signaling pathway and attenuating ER stress-induced apoptosis. PMID:28112174

  17. Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics.

    Science.gov (United States)

    Alleman, Rick J; Tsang, Alvin M; Ryan, Terence E; Patteson, Daniel J; McClung, Joseph M; Spangenburg, Espen E; Shaikh, Saame Raza; Neufer, P Darrell; Brown, David A

    2016-05-15

    Mitochondria influence cardiac electrophysiology through energy- and redox-sensitive ion channels in the sarcolemma, with the collapse of energetics believed to be centrally involved in arrhythmogenesis. This study was conducted to determine if preservation of mitochondrial membrane potential (ΔΨm) contributes to the antiarrhythmic effect of exercise. We utilized perfused hearts, isolated myocytes, and isolated mitochondria exposed to metabolic challenge to determine the effects of exercise on cardiac mitochondria. Hearts from sedentary (Sed) and exercised (Ex; 10 days of treadmill running) Sprague-Dawley rats were perfused on a two-photon microscope stage for simultaneous measurement of ΔΨm and ECG. After ischemia-reperfusion, the collapse of ΔΨm was commensurate with the onset of arrhythmia. Exercise preserved ΔΨm and decreased the incidence of fibrillation/tachycardia (P < 0.05). Our findings in intact hearts were corroborated in isolated myocytes exposed to in vitro hypoxia-reoxygenation, with Ex rats demonstrating enhanced redox control and sustained ΔΨm during reoxygenation. Finally, we induced anoxia-reoxygenation in isolated mitochondria using high-resolution respirometry with simultaneous measurement of respiration and H2O2 Mitochondria from Ex rats sustained respiration with lower rates of H2O2 emission than Sed rats. Exercise helps sustain postischemic mitochondrial bioenergetics and redox homeostasis, which is associated with preserved ΔΨm and protection against reperfusion arrhythmia. The reduction of fatal ventricular arrhythmias through exercise-induced mitochondrial adaptations indicates that mitochondrial therapeutics may be an effective target for the treatment of heart disease. Copyright © 2016 the American Physiological Society.

  18. N-acetylcysteine attenuates ischemia/reperfusion-induced cardiocyte apoptosis in diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Li Ma; Shanglong Yao; Kezhong Li

    2006-01-01

    Objective: To study the effects of N-acetylcysteine (NAC) on iscbemia/ reperfusion (I/R)-induced myocyte apoptosis in diabetic rats. Methods:The I/R heart model was made by ligation of the left anterior descending coronary artery (LAD) close to its origin. The LAD was occluded for 30 min followed by removal of ligation to allow subsequent reperfusion for 3 h. 72 rats were randomly divided into two groups: non-diabetic group (C, n = 36) and diabetic group (D, n = 36).The animals in C group were randomly reassigned into sham-ope rated group (CS, n = 12) , I/R group (C I/R, n = 12) and treated with NAC group (CN, n = 12). The rats in D group were also reassigned to sham-operated group (DS, n = 12) , I/R group (DI/R, n = 12) and treated with NAC group (DN, n = 12). Malondialdehyde (MDA) and creatine kinase isoenzyme-MB (CK-MB) were measured. Infarct size(IS/AAR%), the apoptosis index(AI) by TUNEL staining, the number of the cells positive for Caspase-3 and positive expression index (PEI) were calculated. Results:After I/R, the IS/AAR%, CK-MB, MDA, AI and Caspase-3 PEI were higher in diabetic group than those in non-diabetic group. Treatment with NAC decreased the above parameters in both non-diabetic and diabetic rats, but the parameters in diabetic rats were higher than those in non-diabetic rats. Conclusion:Diabetic rat hearts are more susceptible to I/R-induced myocardial necrosis and myocyte apoptosis. NAC can decrease the infarct size and attenuate cardiomyocyte apoptosis in both non-diabetic and diabetic rats, but the therapeutic effects are less effective in diabetic rats than those in non-diabetic rats.

  19. The effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(l-lysine) block copolymer on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor.

    Science.gov (United States)

    Tong, Fei; Tang, Xiangyuan; Li, Xin; Xia, Wenquan; Liu, Daojun

    2016-01-01

    The aim of this study was to observe the therapeutic effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(l-lysine) block copolymer poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(l-lysine)) (PEG-b-(PELG-g-PLL) on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor (HIF) as compared to free insulin. Sprague Dawley rats were pretreated with 30 U/kg insulin or insulin/PEG-b-(PELG-g-PLL) complex, and then subjected to 45 minutes of ischemia and 24 hours of reperfusion. The blood and lungs were collected, the level of serum creatinine and blood urea nitrogen were measured, and the dry/wet lung ratios, the activity of superoxide dismutase and myeloperoxidase, the content of methane dicarboxylic aldehyde and tumor necrosis factor-α, and the expression of HIF-1α and vascular endothelial growth factor (VEGF) were measured in pulmonary tissues. Both insulin and insulin/PEG-b-(PELG-g-PLL) preconditioning improved the recovery of renal function, reduced pulmonary oxidative stress injury, restrained inflammatory damage, and downregulated the expression of HIF-1α and VEGF as compared to ischemia/reperfusion group, while insulin/PEG-b-(PELG-g-PLL) significantly improved this effect.

  20. The effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(l-lysine) block copolymer on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor

    Science.gov (United States)

    Tong, Fei; Tang, Xiangyuan; Li, Xin; Xia, Wenquan; Liu, Daojun

    2016-01-01

    The aim of this study was to observe the therapeutic effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(l-lysine) block copolymer poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(l-lysine)) (PEG-b-(PELG-g-PLL) on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor (HIF) as compared to free insulin. Sprague Dawley rats were pretreated with 30 U/kg insulin or insulin/PEG-b-(PELG-g-PLL) complex, and then subjected to 45 minutes of ischemia and 24 hours of reperfusion. The blood and lungs were collected, the level of serum creatinine and blood urea nitrogen were measured, and the dry/wet lung ratios, the activity of superoxide dismutase and myeloperoxidase, the content of methane dicarboxylic aldehyde and tumor necrosis factor-α, and the expression of HIF-1α and vascular endothelial growth factor (VEGF) were measured in pulmonary tissues. Both insulin and insulin/PEG-b-(PELG-g-PLL) preconditioning improved the recovery of renal function, reduced pulmonary oxidative stress injury, restrained inflammatory damage, and downregulated the expression of HIF-1α and VEGF as compared to ischemia/reperfusion group, while insulin/PEG-b-(PELG-g-PLL) significantly improved this effect. PMID:27175073

  1. Asiaticoside attenuates memory impairment induced by transient cerebral ischemia-reperfusion in mice through anti-inflammatory mechanism.

    Science.gov (United States)

    Chen, She; Yin, Zhu-Jun; Jiang, Chen; Ma, Zhan-Qiang; Fu, Qiang; Qu, Rong; Ma, Shi-Ping

    2014-07-01

    Asiaticoside (AS) is isolated from Centella asiatica (L.) which has been using for a long time as a memory enhancing drug in India. This study was to investigate the effects of AS on memory impairment and inflammatory cytokines expression induced by transient cerebral ischemia and reperfusion in mice, as well as the potential signaling pathway. Transient bilateral common carotid artery occlusion (tBCCAO) induced severe memory deficits in mice according to the Morris water maze task and the step-down passive avoidance test. Meanwhile the microglial activation and the gene expression of inflammatory cytokines including interleukin (IL)-1β, interleukin (IL)-6 and tumor necrosis factor (TNF)-α were increased in the hippocampus of the mice with cerebral ischemia and reperfusion. Oral administration of AS (40 and 60 mg/kg, once per day, started the day after surgery and lasted for 7 days) significantly ameliorated the memory impairment and the inflammation. Moreover, AS (20, 40 and 60 mg/kg) markedly reduced the microglial overactivation and the phosphorylation of p38 MAPK in hippocampus compared with the transient cerebral ischemia and reperfusion group. These results suggested that AS showed the neuroprotective effect against transient cerebral ischemia and reperfusion in mice, and this effect might be associated with the anti-inflammation effect of AS via inhibiting overactivation of p38 MAPK pathway.

  2. Hydrogen sulfide protects against cognitive impairment induced by hepatic ischemia and reperfusion via attenuating neuroinflammation.

    Science.gov (United States)

    Tu, Faping; Li, Jingdong; Wang, Ji; Li, Qiang; Chu, Weihua

    2016-03-01

    Previously, hepatic ischemia followed by reperfusion (hepatic I/R) has been found to cause cognitive impairment. Hydrogen sulfide (H2S) attenuates hepatectomy induced cognitive deficits and also protects against cognitive dysfunction induced by neurodegenerative diseases. In this study, we aim to determine whether sodium hydrosulfide (NaHS), a H2S donor, could alleviate hepatic I/R-induced cognitive impairment and the underlying mechanisms. Rats were injected intraperitoneally with NaHS (5 mg/kg/d) for 11 days. A segmental hepatic I/R model was established on the fourth day. Cognitive function, proinflammatory cytokines levels, and hippocampal ionized calcium-binding adaptor molecule 1 (Iba1) expression was analyzed. We found hepatic I/R increased proinflammatory cytokines levels in serum and hippocampus, up-regulated Iba1 expression, leading to cognitive impairment in rats. However, treatment with NaHS alleviated hepatic I/R induced these neuroinflammatory changes and effectively improved cognitive function. Thus, NaHS appears to protect against cognitive impairment in rats undergoing hepatic I/R by attenuating neuroinflammation in the hippocampus.

  3. Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice

    Science.gov (United States)

    Weissmann, Norbert; Sydykov, Akylbek; Kalwa, Hermann; Storch, Ursula; Fuchs, Beate; Schnitzler, Michael Mederos y; Brandes, Ralf P.; Grimminger, Friedrich; Meissner, Marcel; Freichel, Marc; Offermanns, Stefan; Veit, Florian; Pak, Oleg; Krause, Karl-Heinz; Schermuly, Ralph T.; Brewer, Alison C; Schmidt, Harald H.H.W.; Seeger, Werner; Shah, Ajay M.; Gudermann, Thomas; Ghofrani, Hossein A.; Dietrich, Alexander

    2012-01-01

    Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE. PMID:22337127

  4. Total salvianolic acid improves ischemia-reperfusion-induced microcirculatory disturbance in rat mesentery

    Science.gov (United States)

    Wang, Ming-Xia; Liu, Yu-Ying; Hu, Bai-He; Wei, Xiao-Hong; Chang, Xin; Sun, Kai; Fan, Jing-Yu; Liao, Fu-Long; Wang, Chuan-She; Zheng, Jun; Han, Jing-Yan

    2010-01-01

    AIM: To investigate the effect of total salvianolic acid (TSA) on ischemia-reperfusion (I/R)-induced rat mesenteric microcirculatory dysfunctions. METHODS: Male Wistar rats were randomly distributed into 5 groups (n = 6 each): Sham group and I/R group (infused with saline), TSA group, TSA + I/R group and I/R + TSA group (infused with TSA, 5 mg/kg per hour). Mesenteric I/R were conducted by a ligation of the mesenteric artery and vein (10 min) and subsequent release of the occlusion. TSA was continuously infused either starting from 10 min before the ischemia or 10 min after reperfusion. Changes in mesenteric microcirculatory variables, including diameter of venule, velocity of red blood cells in venule, leukocyte adhesion, free radicals released from venule, albumin leakage and mast cell degranulation, were observed through an inverted intravital microscope. Meanwhile, the expression of adhesion molecules CD11b/CD18 on neutrophils was evaluated by flow cytometry. Ultrastructural evidence of mesenteric venules damage was assessed after microcirculation observation. RESULTS: I/R led to multiple responses in mesenteric post-capillary venules, including a significant increase in the adhesion of leukocytes, production of oxygen radicals in the venular wall, albumin efflux and enhanced mast cell degranulation in vivo. All the I/R-induced manifestations were significantly reduced by pre- or post-treatment with TSA, with the exception that the I/R-induced increase in mast cell degranulation was inhibited only by pre-treatment with TSA. Moreover, pre- or post-treatment with TSA significantly attenuated the expression of CD11b/CD18 on neutrophils, reducing the increase in the number of caveolae in the endothelial cells of mesentery post-capillary venules induced by I/R. CONCLUSION: The results demonstrated that TSA protects from and ameliorates the microcirculation disturbance induced by I/R, which was associated with TSA inhibiting the production of oxygen-free radicals in

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Renoprotective effect of a combination of garlic and telmisartan against ischemia/reperfusion-induced kidney injury in obese rats.

    Science.gov (United States)

    Ali, Sousou Ibrahim; Alhusseini, Naglaa Fathy; Atteia, Hebatallah Husseini; Idris, Reham Abd El-Satar; Hasan, Rehab Abdallah

    2016-09-01

    Obesity enhances the frequency and severity of acute kidney injury (AKI). Telmisartan pre-treatment was used experimentally in the amelioration of ischemia/reperfusion (IR)-induced AKI. However, there is a lack of evidence regarding its beneficial effects on AKI in obese animals. The present study, therefore, aimed to explore the protective effects of garlic and/or telmisartan against renal damage induced by unilateral IR in obese rats. Meloxicam was used as a standard anti-inflammatory agent. Prophylactic oral administration of meloxicam (3 mg kg(-1)), garlic (500 mg kg(-1)) and/or telmisartan (5 and 10 mg kg(-1)) for 4 wk protected against renal function deterioration induced by IR in obese rats. Both doses of telmisartan significantly reduced serum total cholesterol and triacyglycerol levels as well as peri-renal adipocytes size and renal fibrosis. Renal nuclear factor-kappa B immunoreactivity, tumor necrosis factor-alpha content as well as interleukin-10, adiponectin receptor 1 and macrophages (M1, M2) polarization markers (CD11c, CD206) mRNA expressions were down-regulated in ischemic kidney tissues and white adipose tissues around them by all treatments. Moreover, garlic, telmisartan and their combinations significantly suppressed oxidative stress in renal ischemic tissues. Histological picture was also improved by these treatments. Interestingly, the combinations provided a greater protection than their monotherapy in a dose-dependent manner. We suppose that this combination may be a promising prophylactic regimen for managing AKI in case of obesity. Thus, future experimental and clinical large-scale studies are necessary.

  7. Antithrombin reduces reperfusion-induced hepatic metastasis of colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    Masanao Kurata; Kenji Okajima; Toru Kawamoto; Mitsuhiro Uchiba; Nobuhiro Ohkohchi

    2006-01-01

    AIM: To examine whether antithrombin (AT) could prevent hepatic ischemia/reperfusion (I/R)-induced hepatic metastasis by inhibiting tumor necrosis factor (TNF)-α-induced expression of E-selectin in rats.METHODS: Hepatic I/R was induced in rats and mice by clamping the left branches of the portal vein and the hepatic artery. Cancer cells were injected intrasplenically.The number of metastatic nodules was counted on day 7after I/R. TNF-α and E-selectin mRNA in hepatic tissue,serum fibrinogen degradation products and hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2,were measured.RESULTS: AT inhibited increases in hepatic metastasis of tumor cells and hepatic tissue mRNA levels of TNF-αand E-selectin in animals subjected to hepatic I/R.Argatroban, a thrombin inhibitor, did not suppress any of these changes. Both AT and argatroban inhibited I/R-induced coagulation abnormalities. I/R-induced increases of hepatic tissue levels of 6-keto-PGF1αwere significantly enhanced by AT. Pretreatment with indomethacin completely reversed the effects of AT.Administration of OP-2507, a stable PGI2 analog, showed effects similar to those of AT in this model. Hepatic metastasis in congenit.al AT-deficient mice subjected to hepatic I/R was significantly increased compared to that observed in wild-type mice. Administration of AT significantly reduced the number of hepatic metastases in congenital AT-deficient mice.CONCLUSION: AT might reduce I/R-induced hepatic metastasis of colon cancer cells by inhibiting TNF-α-induced expression of E-selectin through an increase in the endothelial production of PGI2. These findings also raise the possibility that AT might prevent hepatic metastasis of tumor cells if administered during the resection of liver tumors.

  8. Delayed hyperoxic ventilation attenuates oxygen-induced free radical accumulation during early reperfusion after global brain ischemia.

    Science.gov (United States)

    Wang, Yan; Yuan, Li; Liu, Ping; Zhao, Min

    2015-02-11

    To compare the effect of immediate and delayed administration of oxygen on the accumulation of free radicals in ischemia-reperfusion animal models. Thirty-two adult male Mongolian gerbils with microdialysis probes implanted in the right hippocampal CA1 were divided randomly into four groups (eight each). One group was sham-operated (Sham group) whereas the other three groups were subjected to 10 min bilateral carotid artery occlusion (BCAO). BCAO-treated animals were then subjected to the following: (a) immediate 30% O2 (near normoxia, NO group), (b) immediate 100% O2 (hyperoxia, HO group), and (c) 30% O2 for 60 min, followed by 100% O2 for 60 min (delayed hyperoxia, DHO group). Hippocampal accumulation of hydroxyl radicals (•OH) during reperfusion was estimated by measuring 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA in microdialysis perfusate. Hippocampi were removed 2 h after perfusion to measure malondialdehyde, pyruvate dehydrogenase activity, indices of lipid peroxidation, and cellular respiration. At 24 h after BCAO, the histology of hippocampi was analyzed to rate the injury. Immediately after the onset of reperfusion, all groups showed markedly elevated DHBA, which returned to baseline over 1-2 h. Compared with the NO group, the HO group showed significantly higher peak DHBA and slower recovery. In contrast, the DHO group was not significantly different from the NO group in terms of the DHBA level. DHO animals also showed significantly lower hippocampal malondialdehyde accumulation and higher pyruvate dehydrogenase activity at 2 h after reperfusion versus the HO group. Histology analysis also showed animals in the DHO group with ameliorated injury compared with the HO group. Hydroxyl radical accumulation was more sensitive to O2 during early reperfusion. Delayed hyperoxia may re-establish oxidative metabolism while minimizing oxidative stress after CA.

  9. Inhibition of vascular peroxidase alleviates cardiac dysfunction and apoptosis induced by ischemia-reperfusion.

    Science.gov (United States)

    Li, Ting-Ting; Zhang, Yi-Shuai; He, Lan; Liu, Bin; Shi, Rui-Zheng; Zhang, Guo-Gang; Peng, Jun

    2012-07-01

    Myeloperoxidase (MPO) is involved in myocardial ischemia-reperfusion (IR) injury and vascular peroxidase (VPO) is a newly identified isoform of MPO. This study was conducted to explore whether VPO is involved in IR-induced cardiac dysfunction and apoptosis. In a rat Langendorff model of myocardial IR, the cardiac function parameters (left ventricular pressure and the maximum derivatives of left ventricular pressure and coronary flow), creatine kinase (CK) activity, apoptosis, VPO1 activity were measured. In a cell (rat-heart-derived H9c2 cells) model of hypoxia-reoxygenation (HR), apoptosis, VPO activity, and VPO1 mRNA expression were examined. In isolated heart, IR caused a marked decrease in cardiac function and a significant increase in apoptosis, CK, and VPO activity. These effects were attenuated by pharmacologic inhibition of VPO. In vitro, pharmacologic inhibition of VPO activity or silencing of VPO1 expression significantly suppressed HR-induced cellular apoptosis. Our results suggest that increased VPO activity contributes to IR-induced cardiac dysfunction and inhibition of VPO activity may have the potential clinical value in protecting the myocardium against IR injury.

  10. Protective effect of hyperoside on cardiac ischemia reperfusion injury through inhibition of ER stress and activation of Nrf2 signaling

    Institute of Scientific and Technical Information of China (English)

    Jia-Yin Hou; Ying Liu; Liang Liu; Xin-Ming Li

    2016-01-01

    Objective: To study the protective effect of hyperoside (Hyp) on cardiac ischemia reperfusion injury and its potential mechanism. Methods: Rats were divided into two groups for the evaluation, the Hyp (50 μM Hyp; n=8) and the control group (n=8). Rat hearts were isolated and perfused with Krebs-Henseleit buffer (KHB) for 30 min. After being inhibited with cardioplegic solution, they were stored for 4 h in B21 solution at 4 ℃. Afterwards, rat hearts were perfused with KHB again for 45 min. In this period, Hyp was added into solutions of cardioplegia for storage and KHB. Parameters of cardiac functions, including heart rate, the systolic pressure of the left ventricle, the end-diastolic pressure of the left ventricle, the developed pressure of the left ventricle, the left-ventricular systolic pressure and the peak rise rate of the pressure of the left ventricle were recorded. The levels of adenosine triphosphate (ATP), the content of malondialdehyde and apoptotic cells were determined to evaluate the protective effect of Hyp on hearts suffered from ischemia reperfusion injury. Moreover, cultured cardiac myocytes were subjected to the process simulating ischemia/reperfusion. What were analyzed included the endoplasmic reticulum (ER) stress hallmarks expressions, such as binding immunoglobulin protein and C/EBP homologous protein, using the western blot and real-time PCR. Besides, the NF-E2-related factor 2 (Nrf2) expression was measured to explore the potential mechanism. Results: Compared with the control group, the Hyp group had better cardiac functional parameters and higher ATP levels; pretreatment of Hyp greatly relieved the apoptosis of myocyte, decreased oxidative stress as well as ER stress and activated the signaling pathway of anti-oxidative Nrf2 to a further extent. Conclusions: Hyp plays an important role in preserving cardiac function by improving ATP levels of tissue, easing oxidative injury of myocardium and reducing apoptosis following IRI

  11. A signature of renal stress resistance induced by short-Term dietary restriction, fasting, and protein restriction

    NARCIS (Netherlands)

    F. Jongbloed (Franny); T.C. Saat (Tanja); M. Verweij (Marcel); C. Payan-Gomez; J.H.J. Hoeijmakers; S. van den Engel (Sandra); C.T.M. van Oostrom (Conny); Ambagtsheer, G.; S. Imholz (Sandra); J.L.A. Pennings (Jeroen L.A.); H. van Steeg (Harry); Ijzermans, J.N.M.; M. Dollé (MartijnE.T.); R.W.F. de Bruin (Ron)

    2017-01-01

    textabstractDuring kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-Term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and

  12. Protection of Puerarin on Oxidative Stress Induced by Acute Myocardial Ischemia-Reperfusion Injury in Rats in Cardiopulmonary Bypass%葛根素对大鼠体外循环后心肌缺血再灌注损伤的保护作用及抗氧化应激机制的探讨

    Institute of Scientific and Technical Information of China (English)

    巩红岩; 秦元旭; 王更富; 王庆志

    2012-01-01

    目的:探讨葛根素对大鼠体外循环后心肌缺血再灌注损伤(myocardial ischemia-reperfusion injury,MIRI)的保护作用及抗氧化应激机制.方法:取健康雄性SD大鼠75只,随机分为5组:即假手术组(给予等体积的生理盐水)、MIRI模型组(给予等体积的生理盐水)、葛根素低、中、高剂量组(2,5,10 mg·kg-13个剂量).于再灌注开始时在储血槽内加入稀释葛根素10mL.在全麻手术下制造大鼠体外循环模型后,随即阻断大鼠升主动脉造成心肌缺血30 min然后开放升主动脉后再灌注180 min造成大鼠心肌缺血再灌注损伤模型(灌注24 h,用于测定心肌梗死面积).实验组和对照组分别给予葛根素和生理盐水.实验完成后留取大鼠心脏标本,观察大鼠心肌缺血区的心肌细胞凋亡情况;收集血清测定其抗氧化应激的指标:超氧化物歧化酶(SOD),丙二醛(MDA),谷胱甘肽(GSH),谷胱甘肽过氧化物酶(GSH-Px).结果:与模型组相比,葛根素的应用减少了MIRI大鼠的心肌细胞凋亡、心梗面积和血清中丙二醛的含量,增加了血清中超氧化物歧化酶、谷胱甘肽过氧化物酶的活性和谷胱甘肽的含量,并且随着剂量的增加保护效果尤为明显.结论:葛根素对MIRI大鼠具有抗氧化应激的作用,它能够剂量依赖性的减少心肌细胞凋亡,最终减少心肌梗死面积.%Objective: To investigate the protective mechanism of puerarin on acute myocardial ischemia -reperfusion injury( MIRI) in rats, and to explain the antioxidative mechanism involved. Method: Rat MIRI model was induced by ischemia for 30 min and reperfusion for 180 min. At the end of the 3 h reperfusion period (or 24 h for infarct. Size ), myocardial infarct size, myocardial apoptosis and the activity of antioxidative enzymes were measured. Result: Puerarin reduced infarct size, myocardial apoptosisand the serum level of malondialdehyde, increased the activity of superoxide dismutase and glutathione

  13. Vascular endothelial growth factor induced angiogenesis following focal cerebral ischemia/reperfusion injury in rabbits

    Institute of Scientific and Technical Information of China (English)

    Huaijun Liu; Jiping Yang; Fenghai Liu; Qiang Zhang; Hui Li

    2006-01-01

    BACKGROUND: Therapeutic angiogenesis has opened up new pathway for the treatment of ischemic cerebrovascular disease in recent years. The exploration of the effect of vascular endothelial growth factor (VEGF) on inducing angiogenesis following ischemia/reperfusion injury can provide better help for the long-term treatment of cerebrovascular disease in clinic.OBJECTIVE: To observe the effect of VEGF on inducing angiogenesis following focal cerebral ischemia/reperfusion injury in rabbits through the angiogenesis of microvessels reflected by the expression of the factors of vascular pseudohemophilia.DESIGN: A randomized controlled animal trial.SETTING: Department of Medical Imaging, Second Hospital of Hebei Medical University.MATERIALS: Sixty-five healthy male New Zealand rabbits of clean degree, weighing (2.6±0.2) kg, aged4.5-5 months, were used. The polyclonal antibody against vascular pseudohemophilia (Beijing Zhongshan Company), recombinant VEGF165 (Peprotech Company, USA), biotinylated second antibody and ABC compound (Wuhan Boster Company) were applied.METHODS: The experiments were carried out in the Laboratory of Neuromolecular Imaging and Neuropathy,Second Hospital of Hebei Medical University from May to August in 2005. ① The rabbits were randomly divided into three groups: sham-operated group (n=15), control group (n=25) and VEGF-treated group(n=25). In the control group and VEGF-treated group, models were established by middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia/reperfusion. In the VEGF-treated group, VEGF165(2.5 mg/L) was stereotactically injected into the surrounding regions of the infarcted sites immediately after the 2-hour ischemia/reperfusion; Saline of the same dosage was injected in the control group. But the rabobserved on the 3rd, 7th, 14th, 28th and 70th days of the experiment respectively, 3 rabbits in the sham-operated group and 5 in the control group and VEGF-treated group were observed at each time point. The

  14. Metabolic aspects of cardiac and skeletal muscle tissues in the condition of hypoxia, ischaemia and reperfusion induced by extracorporeal circulation.

    Science.gov (United States)

    Corbucci, G G; Menichetti, A; Cogliati, A; Ruvolo, C

    1995-01-01

    Extracorporeal circulation (ECC) during aortopulmonary bypass surgery allows the investigation of the metabolic and biochemical effects of hypoxia (skeletal muscle), ischaemia (cardiac muscle) and reperfusion (skeletal and cardiac muscle) in homogeneous groups of patients. In this study we examined the mitochondrial enzymic response to oxidative stress in 40 subjects, and analysis was carried out on heart and skeletal-muscle biopsies taken before, during and after aortic clamping and 115 min of ECC. The results obtained constitute a clinical and biochemical picture characterized by some peculiar adaptive changes of enzymic activities which thus antagonize the oxidative damage due to acute hypoxia, ischaemia and reperfusion. Consequently it seems that this cellular protective mechanism plays a crucial role in the reversibility of oxidative damage in hypoxic and ischaemic tissues.

  15. Knockout of Toll-Like Receptors 2 and 4 Prevents Renal Ischemia-Reperfusion-Induced Cardiac Hypertrophy in Mice.

    Science.gov (United States)

    Trentin-Sonoda, Mayra; da Silva, Rogério Cirino; Kmit, Fernanda Vieira; Abrahão, Mariana Vieira; Monnerat Cahli, Gustavo; Brasil, Guilherme Visconde; Muzi-Filho, Humberto; Silva, Paulo André; Tovar-Moll, Fernanda Freire; Vieyra, Adalberto; Medei, Emiliano; Carneiro-Ramos, Marcela Sorelli

    2015-01-01

    We investigated whether the pathways linked to Toll-like receptors 2 and 4 (TLRs) are involved in renal ischemia-reperfusion (I/R)-induced cardiac hypertrophy. Wild type (WT) C57BL/6J, TLR2-/- and TLR4-/- mice were subjected to left kidney ischemia for 60 min followed by reperfusion for 5, 8, 12 and 15 days. Proton density magnetic resonance showed alterations in the injured kidney from WT mice, together with signs of parenchymal edema and higher levels of vimentin mRNA, accompanied by: (i) small, but significant, increase in serum urea after 24 h, (ii) 100% increase in serum creatinine at 24 h. A serum peak of inflammatory cytokines occurred after 5 days of reperfusion. Heart weight/body weight and heart weight/tibia length ratios increased after 12 and 15 days of reperfusion, respectively. Cardiac hypertrophy markers, B-type natriuretic peptide (BNP) and α-actin, left ventricle mass, cardiac wall thickness and myocyte width increased after 15 days of reperfusion, together with longer QTc and action potential duration. Cardiac TLRs, MyD88, HSP60 and HSP70 mRNA levels also increased. After 15 days of reperfusion, absence of TLRs prevented cardiac hypertrophy, as reflected by similar values of left ventricular cardiac mass and heart weight/body weight ratio compared to the transgenic Sham. Renal tissular injury also ameliorated in both knockout mice, as revealed by the comparison of their vimentin mRNA levels with those found in the WT on the same day after I/R. The I/R TLR2-/- group had TNF-α, IFN-γ and IL-1β levels similar to the non-I/R group, whereas the TLR4-/- group conserved the p-NF-κB/NF- κB ratio contrasting with that found in TLR2-/-. We conclude: (i) TLRs are involved in renal I/R-induced cardiac hypertrophy; (ii) absence of TLRs prevents I/R-induced cardiac hypertrophy, despite renal lesions seeming to evolve towards those of chronic disease; (iii) TLR2 and TLR4 selectively regulate the systemic inflammatory profile and NF- κB activation.

  16. Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes

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    Dajun Zhao

    2017-01-01

    Full Text Available Diabetes mellitus (DM displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS and reactive nitrogen species (RNS, uncoupling nitric oxide synthase (NOS, and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress. mTOR signaling presents both cardioprotective and cardiotoxic effects on the diabetic heart, which interplays with oxidative stress directly or indirectly. Antihyperglycemic agent metformin and newly found free radicals scavengers, Sirt1 and CTRP9, may serve as promising pharmacological therapeutic targets. In this review, we will focus on the role of oxidative stress and mTOR signaling in the pathophysiology of MI/R injury in diabetes and discuss potential mechanisms and their interactions in an effort to provide some evidence for cardiometabolic targeted therapies for ischemic heart disease (IHD.

  17. Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes

    Science.gov (United States)

    Zhao, Dajun

    2017-01-01

    Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress. mTOR signaling presents both cardioprotective and cardiotoxic effects on the diabetic heart, which interplays with oxidative stress directly or indirectly. Antihyperglycemic agent metformin and newly found free radicals scavengers, Sirt1 and CTRP9, may serve as promising pharmacological therapeutic targets. In this review, we will focus on the role of oxidative stress and mTOR signaling in the pathophysiology of MI/R injury in diabetes and discuss potential mechanisms and their interactions in an effort to provide some evidence for cardiometabolic targeted therapies for ischemic heart disease (IHD).

  18. Protective effect of salvianolate on lung injury induced by ischemia reperfusion injury of liver in mice

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    Zheng-xin WANG

    2011-11-01

    Full Text Available Objective To evaluate the protective effect of salvianolate on lung injury induced by hepatic ischemia reperfusion(IR injury in mice and its underlying mechanisms.Methods A hepatic IR model of mice was reproduced,and 24 animals were assigned into 3 groups(8 each: sham operation(SO group,control group and salvianolate(SV group.Just before ischemia induction,animals in SV group received salvianolate injection at a dose of 60 mg/kg via tail vein,while in control group the mice received normal saline with an equal volume,and in SO group the mice received the same operation as in SV group but without producing liver ischemia.Four hours after reperfusion,the serum,liver and lung tissue were collected.The alanine aminotransferase(ALT and aspartate aminotransferase(AST levels in serum were detected and the histological changes in liver and lung were examined.The wet-to-dry weight ratio of pulmonary tissue was measured.The contents of tumor necrosis factor α(TNF-α,interleukin(IL-6,IL-1β and IL-10 in bronchoalveolar lavage fluid(BALF were detected by enzyme linked immunosorbent assay(ELISA,and the relative mRNA levels of TNF-α,IL-6,IL-1β and IL-10 in pulmonary tissue were analyzed by real-time reverse transcription PCR(RT-PCR.The activaty of transcription factor NF-κB was measured with Western blotting analysis.Results No significant pathologic change was found in mice of SO group.Compared with the mice in control group,those in SV group exhibited lower levels of ALT and AST(P < 0.01,lighter histological changes in liver and lung(P < 0.05,lower levels of wet-to-dry weight ratio of lung tissue(P < 0.05,lower expression levels of TNF-α,IL-6,IL-1β and IL-10 in BALF and lung tissue(P < 0.05 or P < 0.01.Further examination demonstrated that the activity of NF-κB in SV group was significantly down-regulated as compared with that in control group.Conclusion Salvianolate can attenuate lung injury induced by hepatic IR in mice,the mechanism may inclade

  19. Neuroprotective effect of melatonin against ischemia/reperfusion-induced neuronal apoptosis in mouse cerebellum

    Institute of Scientific and Technical Information of China (English)

    Qiuhong Duan; Tao Lu; Yixiang Han; Zhiqiang Lu; Ximing Wang

    2007-01-01

    BACKGROUND: Some experiments have demonstrated that melatonin (N-aceyl-5-methoxytryptamine, Mel) has antioxidation. However, whether it has neuroprotective effect in the ischemia/reperfusion injury of central nervous system is unclear.OBJECTIVE: To observe the protective effect of Mel on ischemia/reperfusion-induced cerebellar neuronal apoptosis of rats, and the action mechanism. DESIGN: Controlled observation experiment.SETTING: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology.MATERIALS: Eight Sprague-Dawley rats aged 7-8 days and weighing 10-12 g were provided by Medical Experimental Animal Center, Tongji Medical College, Huazhong University of Science and Technology. Anti-cytochrome C monoclonal antibody was purchased from R & D Company; 7-dichlorodihydrofluorescein diacetate(DCFH-DA), rhodamine 123 and Mel were purchased from Sigma Company (USA). Lactate dehydrogenase (LDH) kit was purchased from Nanjing Jiancheng Bioengineering Institute.METHODS: This experiment was carried out in the laboratory for Department of Biochemistry and Molecule Biology, Tongji Medical College between October 2002 and March 2004. Cerebellar neurons of rats were cultured in vitro. After oxygen-glucose deprivation (OGD) for 90 minutes, 1×10-4, 1×10-6, 1×10-9 mol/L Mel was added, respectively, namely high-, middle-, and low-concentration Mel groups. Cells, which were cultured by OGD, served as model group, and control group, in which OGD intervention was omitted, was set. ①Cytochrome C level of mitochondrial cells in each group was detected by ELISA method. ②LDH activity in the cell culture fluid was measured, and cell membrane permeability change was analyzed. The cells in the Mel group with the lowest LDH activity served as Mel treatment group, I.e. Cells were cultured with OGD, and then Mel was added; Meanwhile, Mel prevention group was set, I.e. Mel was added before OGD. Intervention was not changed in the

  20. cPKCγ membrane translocation is involved in herkinorin‑induced neuroprotection against cerebral ischemia/reperfusion injury in mice.

    Science.gov (United States)

    Gui, Xiaochen; Cui, Xu; Wei, Haiping; Feng, Guang; Zhang, Xuezheng; He, Yongjin; Li, Junfa; Li, Tianzuo

    2017-01-01

    Herkinorin is an opiate analgesic with limited adverse effects, functioning as a primary selective atypical opioid µ agonist. The present study aimed to identify whether herkinorin has a positive effect on ischemic/reperfusion (I/R) injury. Adult male C57BL/6 mice were randomly divided into five groups: i) Naïve, ii) sham, iii) I/R, iv) I/R with dimethyl sulfoxide (I/R+D) and v) I/R with herkinorin (I/R+H). The I/R injury model was induced by occluding the middle cerebral artery for 1 h followed by 24 h or 7 days of reperfusion. Neurobehavioral scores and sensorimotor functions were examined 24 h and 7 days following reperfusion. In addition, infarct volumes were examined at these time points using a 2,3,5‑triphenyltetrazolium chloride assay. Herkinorin treatment improved neurobehavioral and sensorimotor functional recovery from I/R‑induced brain injury. There was a significant decrease in infarct volume in the I/R+H group at 24 h or 7 days following reperfusion compared with the I/R and I/R+D groups. Western blotting suggested that the decrease in conventional protein kinase C γ (cPKCγ) membrane translocation in the peri‑infarct region may be attenuated by herkinorin pretreatment. These results indicated that herkinorin may be beneficial in I/R‑induced mouse brain injury, and this may be attributed to the membrane translocation of cPKCγ following activation.

  1. Triptolide inhibits NF-κB activation and reduces injury of donor lung induced by ischemia/reperfusion

    Institute of Scientific and Technical Information of China (English)

    Jing-kang HE; Shu-dong YU; Hong-Jun ZHU; Jun-chao WU; Zhen-ghong QIN

    2007-01-01

    Aim: To investigate the protective effect of triptolide (TRI) on ischemia/reperfusion- induced injury of transplanted rabbit lungs and to investigate the mechanisms underlying the actions of TRI. Methods: We established the rabbit lung trans- plantation model and studied lung injury induced by ischemia/reperfusion and the inhibitory effect of TRI on NF-r,B. The severity of lung injury was determined by a gradual decline in PvO2, the degree of lung edema, the increase in the myeloperoxidase (MPO) activity, and the ultrastructural changes of transplanted lungs. The activation of NF-r,B was measured by immunohistochemistry. The increase in intercellular adhesion molecule- 1 (ICAM- 1), which is the target gene of NF-κB, was evaluated by ELISA. Results: After reperfusion, there was a gradual decline in the PvO2 level in the control group (group I). The level of PvO2 in the group treated with lipopolysaccharide (group Ⅱ) was significantly decreased, whereas that of the group treated with TRI (group Ⅲ) was markedly improved (P<0.01). In group Ⅲ, the activity of MPO was downregulated, and the pulmonary edema did not become severe and the ultrastructure of the donor lung remained normal. The activity of NF-κB and the expression of ICAM-1 was significantly increased in the donor lungs. TRI blocked NF-κB activation and ICAM-1 expression. Conclusion: The effects of TRI on reducing injury to donor lungs induced by ischemia/reperfusion may possibly be mediated by inhibiting the activity of NF-κB and the expression of the NF-rd3 target gene ICAM-1. Thus, TRI could be used in lung transplantations for improving the function of donor lungs.

  2. Anti-apoptotic, anti-oxidant, and anti-inflammatory effects of thalidomide on cerebral ischemia/reperfusion injury in rats.

    Science.gov (United States)

    Palencia, Guadalupe; Medrano, Juan Ángel Núñez-; Ortiz-Plata, Alma; Farfán, Dolores Jiménez; Sotelo, Julio; Sánchez, Aurora; Trejo-Solís, Cristina

    2015-04-15

    Thalidomide has shown protective effects in different models of ischemia/reperfusion damage. To elucidate the mechanisms of such protection, this study assessed the effects of thalidomide on the oxidative stress and inflammatory response induced by ischemia/reperfusion episodes in rats. Rats underwent middle cerebral artery occlusion (MCAO) for 2hours. All animals were sacrificed after different reperfusion times. Rats were administered either DMSO or thalidomide (20mg/kg (i.p.)) at different times before or during reperfusion: 1) 1h before reperfusion; the infarct area was measured 2h after reperfusion. 2) 10min before reperfusion and 80min after reperfusion; the infarct area was measured 24h after reperfusion; and 3) 10min before reperfusion and 1h, 24h, 48h, and 68h after reperfusion; the infarct area was measured 72h after reperfusion. Thalidomide reduced the infarct area 24h and 72h after MCAO, and decreased the neurological deficit in all groups with respect to controls. Thalidomide also lowered significantly the number of TUNEL-positive cells, levels of Bax, caspase-3, lipoperoxidation, and pro-inflammatory cytokines, and increased the levels of SOD1, Bcl-2 and pAkt. These results show that thalidomide has neuroprotective effects, apparently due to its anti-apoptotic, anti-oxidant, and anti-inflammatory effects.

  3. Protective effects of Ping-Lv-Mixture (PLM), a medicinal formula on arrhythmias induced by myocardial ischemia-reperfusion.

    Science.gov (United States)

    An, Wei; Yang, Jing

    2006-11-03

    Ping-Lv-Mixture (PLM) is a Chinese medicinal formula. The present study aimed to determine the effects of PLM on myocardial ischemia-reperfusion (MI/R) induced arrhythmias in rats. Arrhythmia model was established by occlusion of the left arterial descending coronary artery and thereafter reperfusion. A lead II electrocardiogram was monitored throughout the experiment. The results showed that pretreatment of PLM to MI/R rats significantly reduced the incidence and duration of ventricular tachycardia and ventricular fibrillation. On induction of MI/R, the activities of creatine kinase and lactate dehydrogenase were increased in vehicle group. PLM (0.04-1.00 g/kg) administration prevented the increase of these enzymes. Moreover, a significant increase of myocardium superoxide dismutase and decrease of malondialdehyde contents were observed in rats of PLM groups. On the other hand, the expressions of platelet activating factor (PAF) receptor mRNA was down-regulated in a dose-dependent manner in the PLM-treated groups by RT-PCR. Thus, it can be concluded that pretreatment with PLM inhibited lipid peroxidation in rats through suppressing the expression of PAF receptor, which may contribute to its preventive effect on myocardial ischemia-reperfusion induced arrhythmias.

  4. Forebrain Ischemia-Reperfusion Simulating Cardiac Arrest in Mice Induces Edema and DNA Fragmentation in the Brain

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    Christina H. Liu

    2007-05-01

    Full Text Available Brain injury affects one-third of persons who survive after heart attack, even with restoration of spontaneous circulation by cardiopulmonary resuscitation. We studied brain injury resulting from transient bilateral carotid artery occlusion (BCAO and reperfusion by simulating heart attack and restoration of circulation, respectively, in live C57Black6 mice. This model is known to induce neuronal death in the hippocampus, striatum, and cortex. We report the appearance of edema after transient BCAO of 60 minutes and 1 day of reperfusion. Hyperintensity in diffusion-weighted magnetic resonance imaging (MRI was detectable in the striatum, thalamus, and cortex but not in the hippocampus. To determine whether damage to the hippocampus can be detected in live animals, we infused a T2 susceptibility magnetic resonance contrast agent (superparamagnetic iron oxide nanoparticles [SPIONs] that was linked to single-stranded deoxyribonucleic acid (DNA complementary in sequence to c-fos messenger ribonucleic acid (SPION-cfos; we acquired in vivo T2*-weighted MRI 3 days later. SPION retention was measured as T2* (milliseconds signal reduction or R2* value (s−1 elevation. We found that animals treated with 60-minute BCAO and 7-day reperfusion exhibited significantly less SPION retention in the hippocampus and cortex than sham-operated animals. These findings suggest that brain injury induced by cardiac arrest can be detected in live animals.

  5. Danhong injection attenuates cardiac injury induced by ischemic and reperfused neuronal cells through regulating arginine vasopressin expression and secretion.

    Science.gov (United States)

    Yang, Mingzhu; Orgah, John; Zhu, Jie; Fan, Guanwei; Han, Jihong; Wang, Xiaoying; Zhang, Boli; Zhu, Yan

    2016-07-01

    Ischemic stroke is associated with cardiac myocyte vulnerability through some unknown mechanisms. Arginine vasopressin (AVP) may exert considerable function in the relationship of brain damage and heart failure. Danhong injection (DHI) can protect both stroke and heart failure patients with good efficacy in clinics. The aim of this study is to investigate the mechanism of DHI in heart and brain co-protection effects to determine whether AVP plays key role in this course. In the present study, we found that both the supernatant from oxygen-glucose deprivation (OGD) and reperfused primary rat neuronal cells (PRNCs) and AVP treatment caused significant reduction in cell viability and mitochondrial activity in primary rat cardiac myocytes (RCMs). Besides, DHI had the same protective effects with conivaptan, a dual vasopressin V1A and V2 receptor antagonist, in reducing the RCM damage induced by overdose AVP. DHI significantly decreased the injury of both PRNCs and RCMs. Meanwhile, the AVP level was elevated dramatically in OGD and reperfusion PRNCs, and DHI was able to decrease the AVP expression in the injured PRNCs. Therefore, our present results suggested that OGD and reperfusion PRNCs might induce myocyte injury by elevating the AVP expression in PRNCs. The ability of DHI to reinstate AVP level may be one of the mechanisms of its brain and heart co-protection effects.

  6. 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.

  7. Iloprost and vitamin C attenuates acute myocardial injury induced by suprarenal aortic ischemia-reperfusion in rabbits.

    Science.gov (United States)

    Iriz, E; Iriz, A; Take, G; Ozgul, H; Oktar, L; Demirtas, H; Helvacioglu, F; Arslan, M

    2015-01-01

    The aim of this study was to evaluate antioxidant and cytoprotective effects of iloprost and Vitamin C in a distant organ after abdominal aorta ischemia-reperfusion injury. Twenty-eight New Zealand rabbits weighing 2,400-2,800 g were used for this study. The rabbits were divided into four equal groups. These groups are control group, sham group, iloprost group, and iloprost+vitamin C group. Suprarenal aorta was occluded with a vascular clamp. Following 30 minutes of ischemia, the vascular clamp was removed. Rabbits in group 3 received 10 ng/kg/min iloprost and those in group 4 received 10 ng/kg/min iloprost and 10 mg/kg vitamin C. At the end of the reperfusion period, the rabbits were sacrificed by a high intraperitoneal dose of xylazine+ketamine injection. Myocardial tissue samples were taken for electron microscopic analysis. We evaluated SOD, MDA and catalase in myocardial tissue samples. Iloprost and iloprost+vitamin C groups significantly reduced the oxidative stress markers in tissue samples (pvitamin C administration (pvitamin C showed an attenuation of ischemia-reperfusion injury in distant organs (Tab. 3, Fig. 4, Ref. 30).

  8. Protective effect of moxonidine on ischemia/reperfusion-induced acute kidney injury through α2/imidazoline I1 receptor.

    Science.gov (United States)

    Tsutsui, Hidenobu; Sugiura, Takahiro; Hayashi, Kentaro; Yukimura, Tokihito; Ohkita, Mamoru; Takaoka, Masanori; Matsumura, Yasuo

    2013-10-15

    Enhancement of renal sympathetic nerve activity during renal ischemia and norepinephrine overflow from the kidney after reperfusion play important roles in the development of ischemic acute kidney injury. Recently, we have found that moxonidine, an α2/imidazoline Ι1-receptor agonist, has preventive effects on ischemic acute kidney injury by suppressing the excitation of renal sympathetic nervous system after reperfusion. In the present study, to clarify the renoprotective mechanisms of moxonidine (360 nmol/kg, i.v.) against ischemic acute kidney injury, we investigated the effect of intravenous (i.v.) and intracerebroventricular (i.c.v.) injection of efaroxan, an α2/Ι1 receptor antagonist, on the moxonidine-exhibited actions. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. The suppressive effect of moxonidine on enhanced renal sympathetic nerve activity during renal ischemia was not observed in the rat treated with either i.v. (360 nmol/kg) or i.c.v. (36 nmol/kg) of efaroxan. Furthermore, i.v. injection of efaroxan eliminated the preventive effect of moxonidine on ischemia/reperfusion-induced kidney injury and norepinephrine overflow, and i.c.v. injection of efaroxan did not completely inhibit the moxonidine's effects. These results indicate that moxonidine prevents the ischemic kidney injury by sympathoinhibitory effect probably via α2/Ι1 receptors in central nervous system and by suppressing the norepinephrine overflow through α2/Ι1 receptors on sympathetic nerve endings.

  9. Neuroprotective effects of rutaecarpine on cerebral ischemia reperfusion injury**

    Institute of Scientific and Technical Information of China (English)

    Chunlin Yan; Ji Zhang; Shu Wang; Guiping Xue; Yong Hou

    2013-01-01

    Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia reperfusion injury. Because both cardiovascular and cerebrovascular diseases are forms of ischemic vascular disease, they are closely related. We hypothesized that rutaecarpine also has neuroprotective effects on cerebral ischemia reperfusion injury. A cerebral ischemia reperfusion model was established after 84, 252 and 504 µg/kg carpine were given to mice via intraperitoneal injection, daily for 7 days. Results of the step through test, 2,3,5-triphenyl tetrazolium chloride dyeing and oxidative stress indicators showed that rutae-carpine could improve learning and memory ability, neurological symptoms and reduce infarction volume and cerebral water content in mice with cerebral ischemia reperfusion injury. Rutaecarpine could significantly decrease the malondialdehyde content and increase the activities of superoxide dismutase and glutathione peroxidase in mouse brain. Therefore, rutaecarpine could improve neu-rological function fol owing injury induced by cerebral ischemia reperfusion, and the mechanism of this improvement may be associated with oxidative stress. These results verify that rutaecarpine has neuroprotective effects on cerebral ischemia reperfusion in mice.

  10. Antioxidant-Induced Stress

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    Robert D. Kross

    2012-02-01

    Full Text Available Antioxidants are among the most popular health-protecting products, sold worldwide without prescription. Indeed, there are many reports showing the benefits of antioxidants but only a few questioning the possible harmful effects of these “drugs”. The normal balance between antioxidants and free radicals in the body is offset when either of these forces prevails. The available evidence on the harmful effects of antioxidants is analyzed in this review. In summary, a hypothesis is presented that “antioxidant-induced stress” results when antioxidants overwhelm the body’s free radicals.

  11. Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy.

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    Yun Wang

    Full Text Available BACKGROUND: Growing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR. Heme oxygenase-1 (HO-1 is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC. The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy. METHODS: RIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II. The HO-1/extracellular signal-related kinase (ERK/p38/mitogen-activated protein kinase (MAPK pathway was detected in an autophagy model and mineral oil-induced IR in vitro. RESULTS: In liver IR, the expression of LC3-II peaked 12-24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA. CONCLUSIONS: RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.

  12. Stress proteins induced by arsenic.

    Science.gov (United States)

    Del Razo, L M; Quintanilla-Vega, B; Brambila-Colombres, E; Calderón-Aranda, E S; Manno, M; Albores, A

    2001-12-01

    The elevated expression of stress proteins is considered to be a universal response to adverse conditions, representing a potential mechanism of cellular defense against disease and a potential target for novel therapeutics. Exposure to arsenicals either in vitro or in vivo in a variety of model systems has been shown to cause the induction of a number of the major stress protein families such as heat shock proteins (Hsp). Among them are members with low molecular weight, such as metallotionein and ubiquitin, as well as ones with masses of 27, 32, 60, 70, 90, and 110 kDa. In most of the cases, the induction of stress proteins depends on the capacity of the arsenical to reach the target, its valence, and the type of exposure, arsenite being the biggest inducer of most Hsp in several organs and systems. Hsp induction is a rapid dose-dependent response (1-8 h) to the acute exposure to arsenite. Thus, the stress response appears to be useful to monitor the sublethal toxicity resulting from a single exposure to arsenite. The present paper offers a critical review of the capacity of arsenicals to modulate the expression and/or accumulation of stress proteins. The physiological consequences of the arsenic-induced stress and its usefulness in monitoring effects resulting from arsenic exposure in humans and other organisms are discussed.

  13. Modulation of Hypercholesterolemia-Induced Oxidative/Nitrative Stress in the Heart

    Science.gov (United States)

    Sárközy, Márta; Pipicz, Márton; Dux, László; Csont, Tamás

    2016-01-01

    Hypercholesterolemia is a frequent metabolic disorder associated with increased risk for cardiovascular morbidity and mortality. In addition to its well-known proatherogenic effect, hypercholesterolemia may exert direct effects on the myocardium resulting in contractile dysfunction, aggravated ischemia/reperfusion injury, and diminished stress adaptation. Both preclinical and clinical studies suggested that elevated oxidative and/or nitrative stress plays a key role in cardiac complications induced by hypercholesterolemia. Therefore, modulation of hypercholesterolemia-induced myocardial oxidative/nitrative stress is a feasible approach to prevent or treat deleterious cardiac consequences. In this review, we discuss the effects of various pharmaceuticals, nutraceuticals, some novel potential pharmacological approaches, and physical exercise on hypercholesterolemia-induced oxidative/nitrative stress and subsequent cardiac dysfunction as well as impaired ischemic stress adaptation of the heart in hypercholesterolemia. PMID:26788247

  14. The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors.

    Science.gov (United States)

    Gonca, Ersöz; Darıcı, Faruk

    2015-01-01

    Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid with anti-inflammatory activity mediated by enhancing adenosine signaling. As the adenosine A1 receptor activation confers protection against ischemia/reperfusion (I/R)-induced ventricular arrhythmias, we hypothesized that CBD may have antiarrhythmic effect through the activation of adenosine A1 receptor. Cannabidiol has recently been shown to suppress ischemia-induced ventricular arrhythmias. We aimed to research the effect of CBD on the incidence and the duration of I/R-induced ventricular arrhythmias and to investigate the role of adenosine A1 receptor activation in the possible antiarrhythmic effect of CBD. Myocardial ischemia and reperfusion was induced in anesthetized male rats by ligating the left anterior descending coronary artery for 6 minutes and by loosening the bond at the coronary artery, respectively. Cannabidiol alone was given in a dose of 50 µg/kg, 10 minutes prior to coronary artery occlusion and coadministrated with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) in a dose of 100 µg/kg, 15 minutes prior to coronary artery occlusion to investigate whether the antiarrhythmic effect of CBD is modified by the activation of adenosine A1 receptors. The experimental groups were as follows: (1) vehicle control (n = 10), (2) CBD (n = 9), (3) DPCPX (n = 7), and (4) CBD + DPCPX group (n = 7). Cannabidiol treatment significantly decreased the incidence and the duration of ventricular tachycardia, total length of arrhythmias, and the arrhythmia scores compared to control during the reperfusion period. The DPCPX treatment alone did not affect the incidence and the duration of any type of arrhythmias. However, DPCPX aborted the antiarrhythmic effect of CBD when it was combined with it. The present results demonstrated that CBD has an antiarrhythmic effect against I/R-induced arrhythmias, and the antiarrhythmic effect of CBD may be mediated through the activation of adenosine

  15. Myocardial ischemia and reperfusion-induced cell death depends on JNK activation and leads to phosphorylation of mitochondrial p46

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    @@ Multiple signaling pathways, including the c-Jun N-terminal kinase (JNK) pathway, are activated in myocardial ischemia and reperfusion (MI/R) and correlate with cell death. However, the role of the JNK pathway with respect to protection or destruction in MI/R-induced cell death is poorly understood. In a rabbit model, we found that ischemia followed by reperfusion resulted in JNK activation which could be detected in cytosol as well as in mitochondria. To address the functional role of the JNK activation, we examined the consequences of blockade of JNK activation in isolated cardiomyocytes under conditions of simulated ischemia. The JNK activity was stimulated ~6-fold by simulated ischemia and reperfusion (simulated MI). When a dominant negative mutant of JNK kinase-2(dnJNKK2), an upstream regulator of JNK, and JNK-interacting protein-1 (JIP-1) were expressed in myocytes by recombinant adenovirus, the activation of JNK by simulated MI was reduced 53%. Furthermore, the TNFα-activated JNK activity in H9c2 cells was completely abolished by dnJNKK2 and JIP-1. In correlation, when dnJNKK2 and JIP-1 were expressed in cardiomyocytes, both constructs significantly reduced cell death after simulated MI compared to vector controls.

  16. Intravenous Administration of Cilostazol Nanoparticles Ameliorates Acute Ischemic Stroke in a Cerebral Ischemia/Reperfusion-Induced Injury Model

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    Noriaki Nagai

    2015-12-01

    Full Text Available It was reported that cilostazol (CLZ suppressed disruption of the microvasculature in ischemic areas. In this study, we have designed novel injection formulations containing CLZ nanoparticles using 0.5% methylcellulose, 0.2% docusate sodium salt, and mill methods (CLZnano dispersion; particle size 81 ± 59 nm, mean ± S.D., and investigated their toxicity and usefulness in a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice. The pharmacokinetics of injections of CLZnano dispersions is similar to that of CLZ solutions prepared with 2-hydroxypropyl-β-cyclodextrin, and no changes in the rate of hemolysis of rabbit red blood cells, a model of cell injury, were observed with CLZnano dispersions. In addition, the intravenous injection of 0.6 mg/kg CLZnano dispersions does not affect the blood pressure and blood flow, and the 0.6 mg/kg CLZnano dispersions ameliorate neurological deficits and ischemic stroke in MCAO/reperfusion mice. It is possible that the CLZnano dispersions will provide effective therapy for ischemic stroke patients, and that injection preparations of lipophilic drugs containing drug nanoparticles expand their therapeutic usage.

  17. Energy charge restoration, mitochondrial protection and reversal of preservation induced liver injury by hypothermic oxygenation prior to reperfusion.

    Science.gov (United States)

    Stegemann, Judith; Minor, Thomas

    2009-06-01

    We investigated the benefit of two different techniques for resuscitating marginally preserved liver grafts, unexpectedly subjected to long storage times. Rat livers were cold-stored for 22h (CS22). Some grafts were subsequently subjected to 90min of hypothermic reconditioning by venous systemic oxygen persufflation (VSOP) or oxygenated hypothermic machine perfusion (HMP). Livers stored for only 6h (CS6) served as reference. Viability of the livers was assessed thereafter by warm reperfusion in vitro. VSOP and HMP significantly increased endischemic tissue energy charge, and abrogated cellular enzyme loss upon reperfusion even significantly below control values. Ammonia clearance and bile production were more than 3-fold improved to similar values as CS6. Hypothermic reconditioning by both techniques induced mitochondrial chaperone expression (HSP70 family) and significantly improved early resumption of oxygen utilisation upon reperfusion. Viability of long preserved liver grafts can be augmented by transient hypothermic reconditioning using either machine perfusion or gaseous oxygen persufflation, both preventing initial mitochondrial dysfunction and subsequent tissue injury.

  18. Effects of polydeoxyribonucleotide on the histological damage and the altered spermatogenesis induced by testicular ischaemia and reperfusion in rats.

    Science.gov (United States)

    Minutoli, L; Antonuccio, P; Squadrito, F; Bitto, A; Nicotina, P A; Fazzari, C; Polito, F; Marini, H; Bonvissuto, G; Arena, S; Morgia, G; Romeo, C; Caputi, A P; Altavilla, D

    2012-04-01

    The effects of polydeoxyribonucleotide (PDRN), an agonist of the A2A adenosine receptors which when activated positively influences sperm activity, were tested in an experimental testicular ischaemia/reperfusion injury model. Anaesthetized male Sprague-Dawley rats were subjected to testicular torsion-induced ischaemia, followed by reperfusion (TI/R). Immediately after detorsion, randomized animals, including SHAM, received intraperitoneal injections of: (i) vehicle (1 mL/kg 0.9% NaCl solution); (ii) PDRN (8 mg/kg); (iii) DMPX (3,7-dimethyl-1-propargilxanthine, 0.1 mg/kg); or (iv) PDRN (8 mg/kg) + DMPX (0.1 mg/kg). Animals were euthanized at 1, 7 and 30 days following reperfusion. Vascular endothelial growth factor (VEGF) expression is normally associated with adenosine A2A receptor stimulation. After treatment, VEGF mRNA/protein expression quantified by qPCR and Western blot, vascular endothelial growth factor receptor-1 (VEGFR1) and endothelial nitric oxide synthase (eNOS) mRNA measured by qPCR, VEGF and VEGFR1 assessed using immunohistochemical methods, histological staining and spermatogenic activity were all analysed. Testis ischaemia-reperfusion (TI/R) injury caused increases in VEGF mRNA and protein, VEGFR1 and eNOS mRNA, histological damage and reduced spermatogenic activity. Immunostaining showed a lower expression of VEGF in germinal epithelial cells and a strong expression of VEGFR1 in Leydig cells after TI/R. PDRN administration increased significantly VEGF message/protein, VEGFR1 and eNOS message, decreased histological damage and ameliorated spermatogenic activity. PDRN might be useful in the management of testicular torsion.

  19. Ischemic preconditioning increases endothelial progenitor cell number to attenuate partial nephrectomy-induced ischemia/reperfusion injury.

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    Hao Liu

    Full Text Available OBJECTIVES: The objective of this study was to investigate the role of endothelial progenitor cells (EPCs in the modulation of ischemia-reperfusion injury (IRI in a partial nephrectomy (PN rat model using early-phase ischemic preconditioning (IPC. MATERIALS AND METHODS: Ninety male Sprague-Dawley rats were randomly divided into three groups following right-side nephrectomy: Sham-operated rats (surgery without vascular clamping; PN rats (renal blood vessels were clamped for 40 min and PN was performed; and IPC rats (pretreated with 15 min ischemia and 10 min reperfusion. At 1, 3, 6, 12, 24 h, and 3 days after reperfusion, the pool of circulating EPCs and kidneys were harvested. The extent of renal injury was assessed, along with EPC number, cell proliferation, angiogenesis, and vascular growth factor expression. RESULTS: Pretreated rats exhibited significant improvements in renal function and morphology. EPC numbers in the kidneys were increased at 12 h following reperfusion in the IPC group as compared to the PN or Sham groups. Cell proliferation (including endothelial and tubular epithelial cells and angiogenesis in peritubular capillaries were markedly increased in kidneys treated with IPC. In addition, vascular endothelial growth factor-A (VEGF-A and stromal cell-derived factor-1α (SDF-1α expression in the kidneys of pretreated rats was increased compared to rats subjected to PN. CONCLUSIONS: OUR INVESTIGATION SUGGESTED THAT: (1 the early phase of IPC may attenuate renal IRI induced by PN; (2 EPCs play an important role in renal protection, involving promotion of cell proliferation and angiogenesis through release of several angiogenic factors.

  20. Protective role of µ opioid receptor activation in intestinal inflammation induced by mesenteric ischemia/reperfusion in mice

    Science.gov (United States)

    Francesca, Saccani; Laura, Anselmi; Jaramillo, Ingrid; Simona, Bertoni; Elisabetta, Barocelli; Sternini, Catia

    2012-01-01

    Intestinal ischemia is a clinical emergency with high morbidity and mortality. We investigated whether activation of µ opioid receptor (µOR) protects from the inflammation induced by intestinal ischemia and reperfusion (I/R) in mice. Ischemia was induced by occlusion of the superior mesenteric artery (45 min) and followed by reperfusion (5 hours). Sham Operated (SO) and normal (N) mice served as controls. Each group received subcutaneously: (1) saline solution; (2) the µOR selective agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) (0.01 mg.kg−1); (3) DAMGO and the selective µOR antagonist [H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2] (CTAP) (0.1 mg.kg−1) or (4) CTAP alone. I/R induced intestinal inflammation as indicated by histological damage and the significant increase in myeloperoxidase (MPO) activity, index of tissue neutrophil accumulation. TNF-α and IL-10 mRNA levels were also increased in I/R mice compared to SO. DAMGO significantly reduced tissue damage, MPO activity and TNF-α mRNA levels in I/R and these effects were reversed by CTAP. By contrast, DAMGO did not modify IL-10 mRNA levels and gastrointestinal transit. DAMGO effects are receptor-mediated and are likely due to activation of peripheral µORs since it does not readily cross the blood brain barrier. These findings suggest that activation of peripheral µOR protects from the inflammatory response induced by I/R through a pathway involving the pro-inflammatory cytokine, TNF-α. Reduction of acute inflammation might prevent I/R complications, including motility impairment, which develop at a later stage of reperfusion and are likely due to inflammatory cell infiltrates. PMID:22806643

  1. Nifedipine does not affect free radical induced lipid peroxidation following renal allograft reperfusion.

    Science.gov (United States)

    Davenport, A; Hopton, M; Bolton, C

    1994-01-01

    We prospectively measured lipid peroxidation following reperfusion during 44 renal allograft transplant operations. Twenty-four (55%) recipients were taking nifedipine pre- and then postoperatively, and 20 (45%) were not. There were no differences between the groups in terms of recipient or donor status. Plasma malondialdehyde (MDA), mean 2.2 (0.2) mumol/L (SEM) vs. 1.73 (0.1) was greater in the group not prescribed nifedipine, p nifedipine group to 0.38 (0.02) at 30 min after reperfusion and 0.38 (0.03) at 60 min, p nifedipine and no-nifedipine groups, respectively. There was no difference in postoperative renal function between the groups. This study suggests that the oral administration of nifedipine may not prevent the production of lipid peroxides, as measured by changes in plasma malondialdehyde, following renal allograft reperfusion and that it does not affect renal function in the early postoperative period.

  2. Ischemic post-conditioning attenuates the intestinal injury induced by limb ischemia/reperfusion in rats

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    Y.F. Leng

    2011-05-01

    Full Text Available The purpose of this study was to investigate the protective effects of ischemic post-conditioning on damage to the barrier function of the small intestine caused by limb ischemia-reperfusion injury. Male Wistar rats were randomly divided into 3 groups (N = 36 each: sham operated (group S, lower limb ischemia-reperfusion (group LIR, and post-conditioning (group PC. Each group was divided into subgroups (N = 6 according to reperfusion time: immediate (0 h; T1, 1 h (T2, 3 h (T3, 6 h (T4, 12 h (T5, and 24 h (T6. In the PC group, 3 cycles of reperfusion followed by ischemia (each lasting 30 s were applied immediately. At all reperfusion times (T1-T6, diamine oxidase (DAO, superoxide dismutase (SOD, and myeloperoxidase (MPO activity, malondialdehyde (MDA intestinal tissue concentrations, plasma endotoxin concentrations, and serum DAO, tumor necrosis factor-α (TNF-α, and interleukin-10 (IL-10 concentrations were measured in sacrificed rats. Chiu’s pathology scores for small intestinal mucosa were determined under a light microscope and showed that damage to the small intestinal mucosa was lower in group PC than in group LIR. In group PC, tissue DAO and SOD concentrations at T2 to T6, and IL-10 concentrations at T2 to T5 were higher than in group LIR (P < 0.05; however, tissue MPO and MDA concentrations, and serum DAO and plasma endotoxin concentrations at T2 to T6, as well as TNF-α at T2 and T4 decreased significantly (P < 0.05. These results show that ischemic post-conditioning attenuated the permeability of the small intestines after limb ischemia-reperfusion injury. The protective mechanism of ischemic post-conditioning may be related to inhibition of oxygen free radicals and inflammatory cytokines that cause organ damage.

  3. The effect of insulin-loaded linear poly(ethylene glycol-brush-like poly(L-lysine block copolymer on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor

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    Tong F

    2016-04-01

    Full Text Available Fei Tong, Xiangyuan Tang, Xin Li, Wenquan Xia, Daojun Liu Department of Chemistry, Medical College, Shantou University, Shantou, People’s Republic of China Abstract: The aim of this study was to observe the therapeutic effect of insulin-loaded linear poly(ethylene glycol-brush-like poly(L-lysine block copolymer poly(ethylene glycol-b-(poly(ethylenediamine L-glutamate-g-poly(L-lysine (PEG-b-(PELG-g-PLL on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor (HIF as compared to free insulin. Sprague Dawley rats were pretreated with 30 U/kg insulin or insulin/PEG-b-(PELG-g-PLL complex, and then subjected to 45 minutes of ischemia and 24 hours of reperfusion. The blood and lungs were collected, the level of serum creatinine and blood urea nitrogen were measured, and the dry/wet lung ratios, the activity of superoxide dismutase and myeloperoxidase, the content of methane dicarboxylic aldehyde and tumor necrosis factor-α, and the expression of HIF-1α and vascular endothelial growth factor (VEGF were measured in pulmonary tissues. Both insulin and insulin/PEG-b-(PELG-g-PLL preconditioning improved the recovery of renal function, reduced pulmonary oxidative stress injury, restrained inflammatory damage, and downregulated the expression of HIF-1α and VEGF as compared to ischemia/reperfusion group, while insulin/PEG-b-(PELG-g-PLL significantly improved this effect. Keywords: insulin, block copolymer, RI/RILI, HIF-1α, VEGF

  4. Plasma levels of oxidative stress-responsive apoptosis inducing protein (ORAIP) in rats subjected to physicochemical oxidative stresses.

    Science.gov (United States)

    Yao, Takako; Fujimura, Tsutomu; Murayama, Kimie; Seko, Yoshinori

    2016-01-01

    Oxidative stress is known to play a pivotal role in the pathogenesis of various disorders including atherosclerosis, aging and especially ischaemia/reperfusion injury. It causes cell damage that leads to apoptosis. However, the precise mechanism has been uncertain. Recently, we identified an apoptosis-inducing humoral factor in a hypoxia/reoxygenated medium of cardiac myocytes. We named this novel post-translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A) as oxidative stress-responsive apoptosis inducing protein (ORAIP). We developed a sandwich ELISA and confirmed that myocardial ischaemia/reperfusion markedly increased plasma levels of ORAIP. To investigate whether the role of ORAIP is common to various types of oxidative stress, we measured plasma ORAIP levels in rats subjected to three physicochemical models of oxidative stress including N2/O2 inhalation, cold/warm-stress (heat shock) and blood acidification. In all three models, plasma ORAIP levels significantly increased and reached a peak level at 10-30 min after stimulation, then decreased within 60 min. The (mean±S.E.M.) plasma ORAIP levels before and after (peak) stimulation were (16.4±9.6) and (55.2±34.2) ng/ml in N2/O2 inhalation, (14.1±12.4) and (34.3±14.6) ng/ml in cold/warm-stress, and (18.9±14.3) and (134.0±67.2) ng/ml in blood acidification study. These data strongly suggest that secretion of ORAIP in response to oxidative stress is universal mechanism and plays an essential role. ORAIP will be an important novel biomarker as well as a specific therapeutic target of these oxidative stress-induced cell injuries. © 2016 The Author(s).

  5. Protective effect of hemoglobin- induced heme oxygenase- 1on injured lungs caused by limb ischemia-reperfusion inrats

    Institute of Scientific and Technical Information of China (English)

    周君琳; 朱晓光; 张桂生; 凌彤

    2002-01-01

    Objective: To determine the role of hemoglobin(HB) -induced heme oxygenase- 1 ( HO- 1 ) in injured lungscaused by limb ischemia-reperfusion (I/R) in rats.Methods: A rat model of ischemia in the hind limbswas made by clamping the infrarenal aorta with amicrovascular clip, and lung injury occurred afterreperfusion. To induce the expression of HO-1 in the lungs,Hb was administrated intraperitoneally at 16 hours beforereperfusion. Northern blotting and Western blotting wereused to detect the expression of HO-1 in the lungs, and thecarboxyhemoglobin (COHb) level in arterial blood wasassayed. The effect of hemoglobin (Hb) on the injuredlungs after limb I/R was determined by measuring thechanges of lung histology, polymorphonuclear (PMN)count, malondialdehyde (MDA) content and wet-to-dryweight ratio (W/D). Zinc protoporphyrin (ZnPP), aninhibitor of HO, was used to determine whether HO-1 wasinduced by Hb after lung injury.Results: Hb led to a significant increase in HO-1mRNA and protein expression in the lungs, accompanied bythe increase of COHb level in arterial blood. Comparedwith the sham controls, the lung PMN count, MDA contentand W/D significantly increased at 4 hours after limb I/R,which reversed by the pretreatment with Hb at 16 hoursbefore reperfusion. ZnPP blocked this protective role of Hbin the injured lungs.Conclusions: Hb can induce the lung HO-1expression, which plays an important role in the defenseagainst I/R-induced lung injury in rats.

  6. 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.

  7. Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice.

    Science.gov (United States)

    Chen, Zong; Ding, Tao; Ma, Chuan-Gen

    2017-08-04

    Hepatic ischemia/reperfusion (I/R) injury could arise as a complication of liver surgery and transplantation. No specific therapeutic strategies are available to attenuate I/R injury. NOD-, LRR-and CARD-containing 5 (NLRC5), a member of the NOD-like protein family, has been suggested to negatively regulate nuclear factor kappa B (NF-κB) through interacting with IKKα and blocking their phosphorylation. Dexmedetomidine (DEX) has been shown to attenuate liver injury. In the current study, we investigated the pre-treatment of DEX on hepatic I/R injury in wild type (WT) and NLRC5 knockout (NLRC5(-/-)) mice. Our results indicated that NLRC5(-/-) showed significantly stronger histologic damage, inflammatory response, oxidative stress and apoptosis after I/R compared to the WT group of mice, indicating the protective role of NLRC5 against liver I/R injury. Importantly, I/R-induced increase of NLRC5 was reduced by DEX pre-treatment. After hepatic I/R injury, WT and NLRC5(-/-) mice pre-treated with DEX exhibited attenuated histological disruption, and reduced pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β and inducible nitric oxide synthase (iNOS), which was associated with the inactivated NF-κB pathway. Moreover, suppression of oxidative stress and apoptosis was observed in DEX-treated mice with I/R injury, probably through enhancing nuclear factor erythroid 2-related factor 2 (Nrf2), reducing mitogen-activated protein kinases (MAPKs) and Caspase-3/poly (ADP-ribose) polymerase (PARP) pathways. In vitro, the results were further confirmed in WT and NLRC5(-/-) hepatocytes pre-treated with or without DEX. Together, the findings illustrated that lack of NLRC5 resulted in severer liver I/R injury, which could be alleviated by DEX pre-treatment. Copyright © 2017. Published by Elsevier Inc.

  8. Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury.

    Science.gov (United States)

    Horikawa, Yousuke T; Patel, Hemal H; Tsutsumi, Yasuo M; Jennings, Michelle M; Kidd, Michael W; Hagiwara, Yasuko; Ishikawa, Yoshihiro; Insel, Paul A; Roth, David M

    2008-01-01

    Volatile anesthetics protect the heart from ischemia/reperfusion injury but the mechanisms for this protection are poorly understood. Caveolae, sarcolemmal invaginations, and caveolins, scaffolding proteins in caveolae, localize molecules involved in cardiac protection. We tested the hypothesis that caveolae and caveolins are essential for volatile anesthetic-induced cardiac protection using cardiac myocytes (CMs) from adult rats and in vivo studies in caveolin-3 knockout mice (Cav-3(-/-)). We incubated CM with methyl-beta-cyclodextrin (MbetaCD) or colchicine to disrupt caveolae formation, and then exposed the myocytes to the volatile anesthetic isoflurane (30 min, 1.4%), followed by simulated ischemia/reperfusion (SI/R). Isoflurane protected CM from SI/R [23.2+/-1.6% vs. 71.0+/-5.8% cell death (assessed by trypan blue exclusion), Pprotection was abolished by MbetaCD or colchicine (84.9+/-5.5% and 64.5+/-6.1% cell death, Pprotection in vivo was assessed by measurement of infarct size relative to the area at risk and cardiac troponin levels. Isoflurane-induced a reduction in infarct size and cardiac troponin relative to control (infarct size: 26.5%+/-2.6% vs. 45.3%+/-5.4%, Pprotection was abolished in Cav-3(-/-) mice (infarct size: 53.4%+/-6.1% vs. 53.2%+/-3.5%, Pprotection is thus dependent on the presence of caveolae and the expression of caveolin-3. We conclude that caveolae and caveolin-3 are critical for volatile anesthetic-induced protection of the heart from ischemia/reperfusion injury.

  9. NITRIC OXIDE (NO, CITRULLINE - NO CYCLE ENZYMES, GLUTAMINE SYNTHETASE AND OXIDATIVE STRESS IN ANOXIA (HYPOBARIC HYPOXIA AND REPERFUSION IN RAT BRAIN

    Directory of Open Access Journals (Sweden)

    M. Swamy, Mohd Jamsani Mat Salleh, K. N .S. Sirajudeen, Wan Roslina Wan Yusof, G. Chandran

    2010-01-01

    Full Text Available Nitric oxide is postulated to be involved in the pathophysiology of neurological disorders due to hypoxia/ anoxia in brain due to increased release of glutamate and activation of N-methyl-D-aspartate receptors. Reactive oxygen species have been implicated in pathophysiology of many neurological disorders and in brain function. To understand their role in anoxia (hypobaric hypoxia and reperfusion (reoxygenation, the nitric oxide synthase, argininosuccinate synthetase, argininosuccinate lyase, glutamine synthetase and arginase activities along with the concentration of nitrate /nitrite, thiobarbituric acid reactive substances and total antioxidant status were estimated in cerebral cortex, cerebellum and brain stem of rats subjected to anoxia and reperfusion. The results of this study clearly demonstrated the increased production of nitric oxide by increased activity of nitric oxide synthase. The increased activities of argininosuccinate synthetase and argininosuccinate lyase suggest the increased and effective recycling of citrulline to arginine in anoxia, making nitric oxide production more effective and contributing to its toxic effects. The decreased activity of glutamine synthetase may favor the prolonged availability of glutamic acid causing excitotoxicity leading to neuronal damage in anoxia. The increased formation of thiobarbituric acid reactive substances and decreased total antioxidant status indicate the presence of oxidative stress in anoxia and reperfusion. The increased arginase and sustained decrease of GS activity in reperfusion group likely to be protective.

  10. Protective effects of hyperbaric oxygen and iloprost on ischemia/reperfusion-induced lung injury in a rabbit model

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    Bozok Ş

    2012-06-01

    Full Text Available Abstract Background The role of multiorgan damage in the mortality caused by ischemic limb injury is still not clarified. The objective of this study was to examine the potential protective effects of hyperbaric oxygen (HBO and iloprost (IL therapy on lung damage induced by limb ischemia/reperfusion injury in a rabbit model, using both biochemical and histopathological aspects. Methods Forty New Zealand white rabbits were randomly allocated into one of five study groups: HBO group (single session of HBO treatment; IL group (25 ng/kg/min infusion of IL; HBO + IL group (both HBO and IL; Control group (0.9% saline only; and a sham group. Acute hind limb ischemia-reperfusion was established by clamping the abdominal aorta for 1 h. HBO treatment and IL infusion were administrated during 60 min of ischemia and 60 min of reperfusion period. Blood pH, partial pressure of oxygen, partial pressure of carbon dioxide and levels of bicarbonate, sodium, potassium, creatine kinase, lactate dehydrogenase, and tumor necrosis factor alpha were determined at the end of the reperfusion period. Malondialdehyde was measured in the plasma and lung as an indicator of free radicals. After sacrifice, left lungs were removed and histopathological examination determined the degree of lung injury. Results In the control group, blood partial pressure of oxygen and bicarbonate levels were significantly lower and creatine kinase, lactate dehydrogenase, malondialdehyde and tumor necrosis factor-α levels were significantly higher than those of the HBO group, IL group, HBO + IL group and sham group. Similarly, the malondialdehyde levels in the lung tissue and plasma levels were significantly lower in the treatment groups compared with the control group. The extent of lung injury according to the histological findings was significantly higher in the control group. Conclusions These results suggest that both HBO and IL therapies and their combination might be

  11. 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...... greatly exacerbate the damage. For the latter, no medical treatment exist. In this study the aim was to characterize Ca(2+) sensitivity in coronary arteries following experimental ischemia/reperfusion injury. METHODS: Arteries were isolated from hearts exposed to a well-established rat ischemia...

  12. Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics

    OpenAIRE

    Alleman, Rick J; Tsang, Alvin M.; Ryan, Terence E; Patteson, Daniel J.; McClung, Joseph M.; Spangenburg, Espen E.; Shaikh, Saame Raza; Neufer, P. Darrell; Brown, David A.

    2016-01-01

    While the cardiac benefits of exercise are clear, the underlying mechanism(s) are not completely understood. This is the first study to demonstrate, in intact hearts, isolated myocytes, and isolated mitochondria, that exercise confers an intrinsic protective phenotype by sustaining mitochondrial energetics and reducing reactive oxygen species in early reperfusion.

  13. Treatment of Tourniquet-Induced Ischemia Reperfusion Injury with Muscle Progenitor Cells

    Science.gov (United States)

    2011-09-01

    Weinstein AL, et al. Therapeutic met- abolic inhibition: Hydrogen sulfide significantly mitigates skele- tal muscle ischemia reperfusion injury in vitro...muscle function in animal models of muscular diseases, dener- vation, toxins , cryo-injuries, and volumetricmuscle loss [21–24], and have been used to

  14. Myocardial ischemia-reperfusion induces upregulation of contractile endothelin ETB receptor in rat coronary arteries

    DEFF Research Database (Denmark)

    Skovsted, Gry Freja; Sheykhzade, Majid; Trautner, Simon;

    2011-01-01

    ETB receptor upregulation. Methods and Results Thirteen Sprague-Dawley male rats (body weight 260-410 g) were anaesthetized with Hypnorm-Midazolam and subjected to 15 min occlusion of left anterior descending coronary artery (LAD) followed by 22 h of reperfusion. The contractile response...

  15. Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions.

    Science.gov (United States)

    Miclescu, Adriana; Sharma, Hari Shanker; Martijn, Cécile; Wiklund, Lars

    2010-11-01

    To investigate the effects of cardiac arrest and the reperfusion syndrome on blood-brain barrier permeability and evaluate whether methylene blue counteracts blood-brain barrier disruption in a pig model of controlled cardiopulmonary resuscitation. Randomized, prospective, laboratory animal study. University-affiliated research laboratory. Forty-five piglets. Forty-five anesthetized piglets were subjected to cardiac arrest alone or 12-min cardiac arrest followed by 8 mins cardiopulmonary resuscitation. The first group (n = 16) was used to evaluate blood-brain barrier disruptions after untreated cerebral ischemia after 0, 15, or 30 mins after untreated cardiac arrest. The other two groups received either an infusion of saline (n = 10) or infusion of saline with methylene blue (n = 12) 1 min after the start of cardiopulmonary resuscitation and continued 50 mins after return of spontaneous circulation. In these groups, brains were removed for immunohistological analyses at 30, 60, and 180 mins after return of spontaneous circulation. An increase of injured neurons and albumin immunoreactivity was demonstrated with increasing duration of ischemia/reperfusion. Less blood-brain barrier disruption was observed in subjects receiving methylene blue as demonstrated by decreased albumin leakage (p blue treatment reduced cerebral tissue nitrite/nitrate content (p blood-brain barrier permeability and neurologic injury were increased early in reperfusion after cardiac arrest. Methylene blue exerted neuroprotective effects against the brain damage associated with the ischemia/reperfusion injury and ameliorated the blood-brain barrier disruption by decreasing nitric oxide metabolites.

  16. Comparative proteomic analysis of histone post-translational modifications upon ischemia/reperfusion-induced retinal injury

    DEFF Research Database (Denmark)

    Zhao, Xiaolu; Sidoli, Simone; Wang, Leilei;

    2014-01-01

    We present a detailed quantitative map of single and coexisting histone post-translational modifications (PTMs) in rat retinas affected by ischemia and reperfusion (I/R) injury. Retinal I/R injury contributes to serious ocular diseases, which can lead to vision loss and blindness. We applied linear...

  17. Myocardial ischemia-reperfusion induces upregulation of contractile endothelin ETB receptor in rat coronary arteries

    DEFF Research Database (Denmark)

    Skovsted, Gry Freja; Sheykhzade, Majid; Trautner, Simon

    2011-01-01

    ETB receptor upregulation. Methods and Results Thirteen Sprague-Dawley male rats (body weight 260-410 g) were anaesthetized with Hypnorm-Midazolam and subjected to 15 min occlusion of left anterior descending coronary artery (LAD) followed by 22 h of reperfusion. The contractile response...

  18. Secoisolariciresinol Diglucoside Induces Neovascularization Mediated Cardioprotection against Ischemic-Reperfusion Injury In Hypercholesterolemic Myocardium

    Science.gov (United States)

    Penumathsa, Suresh Varma; Koneru, Srikanth; Zhan, Lijun; John, Saji; Menon, Venogopal P; Prasad, Kailash; Maulik, Nilanjana

    2009-01-01

    Background Hypercholesterolemia (HC) induced endothelial cell dysfunction and decreased endothelial nitric oxide formation result in impaired angiogenesis & subsequent cardiovascular disorders. Therapeutic angiogenesis is known to be a novel strategy for treatment of those patients with ischemic heart disease. We have shown that secoisolariciresinol diglucoside (SDG) is angiogenic & cardioprotective against myocardial ischemia. In the present study we examined the efficacy of SDG in a hypercholesterolemic myocardial infarction (MI) model. Methods The rats were maintained on a normal and high cholesterol diet (2%) for 8 weeks followed by oral administration of SDG (20mg/kg) for 2 weeks. The rats were divided into 4 groups (n=12 in each): Control (C); SDG control (SDG); HC; & HC + SDG (HSDG). Isolated hearts subjected to 30 min of global ischemia followed by 120 min of reperfusion were used to measure the cardiac functions, infarct size & examine the protein expression profile. After treatment MI was induced by ligating the left anterior descending artery. Echocardiographic parameters were examined 30 days after MI. Results Significant reduction in total cholesterol, LDL-cholesterol, triglycerides and increase in HDL-cholesterol levels were observed in HSDG as compared to HC. Decreased infarct size was observed in the HSDG group (43%) compared to the HC (54%). Increased phosphorylation of endothelial nitric oxide synthase (p-eNOS) (3.1 fold), Vascular endothelial growth factor (1.9 fold) and Heme Oxygenase-1(2.3 fold) was observed in the HSDG group as compared to the HC group. Significant improvement in left ventricular functions was also observed in the HSDG group as evidenced by increased ejection fraction (55 vs 45%), fractional shortening (28 vs 22%) & decreased left ventricular inner diameter in systole (8 vs 6 mm) in HSDG compared to HC. Moreover, MI model has shown increased capillary density (2531 vs 1901) and arteriolar density (2.6 vs 1.8) in SDG treated

  19. Protective effects of pretreatment with Radix Paeoniae Rubra on acute lung injury induced by intestinal ischemia/ reperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    CHEN Chang; ZHANG Fan; XIA Zhong-yuan; LIN Hui; MO An-sheng

    2008-01-01

    Objective: To investigate the effect of pretreatment with Radix Paeoniae Rubra (RPR) on acute lung injury induced by intestinal ischemia/reperfusion in rats and its protective mechanism.Methods:n lung tissues was detected by immunohistochemistry and morphometry computer image analysis. Arterial blood gas analysis, lung permeability index, malondialdehyde (MDA) and superoxide dismutase (SOD) contents in lungs were measured. The histological changes of lung tissue were observed under light microscope.Results:The expression of HO-1 in RPR-pretreatment group and hemin group was obviously higher than that in sham-operation group and I/R group (P < 0.01). The level of MDA and lung permeability index in RPR-pretreatment and hemin group were significantly lower than those in I/R group (P<0.01 or P<0.05), while the activity of SOD in RPR-pretreatment and hemin group was obviously higher than that in I/R group (P<0.01 ). Under light microscope, the pathologic changes induced by I/R were significantly attenuated by RPR.Conclusion : Intestinal ischemia/reperfusion may result in acute lung injury and pretreatment with RPR injection can attenuate the injury. The protective effect of RPR on the acute lung injury is related to its property of inducing HO-1 expression and inhibiting lipid peroxidation.

  20. Prolonged Helium Postconditioning Protocols during Early Reperfusion Do Not Induce Cardioprotection in the Rat Heart In Vivo: Role of Inflammatory Cytokines

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    Gezina Tanya Mei Ling Oei

    2015-01-01

    Full Text Available Postconditioning of myocardial tissue employs short cycles of ischemia or pharmacologic agents during early reperfusion. Effects of helium postconditioning protocols on infarct size and the ischemia/reperfusion-induced immune response were investigated by measurement of protein and mRNA levels of proinflammatory cytokines. Rats were anesthetized with S-ketamine (150 mg/kg and diazepam (1.5 mg/kg. Regional myocardial ischemia/reperfusion was induced; additional groups inhaled 15, 30, or 60 min of 70% helium during reperfusion. Fifteen minutes of helium reduced infarct size from 43% in control to 21%, whereas 30 and 60 minutes of helium inhalation led to an infarct size of 47% and 39%, respectively. Increased protein levels of cytokine-induced neutrophil chemoattractant (CINC-3 and interleukin-1 beta (IL-1β were found after 30 or 60 min of helium inhalation, in comparison to control. 30 min of helium increased mRNA levels of CINC-3, IL-1β, interleukin 6 (IL-6, and tumor necrosis factor alpha (TNF-α in myocardial tissue not directly subjected to ischemia/reperfusion. These results suggest that the effectiveness of the helium postconditioning protocol is very sensitive to duration of noble gas application. Additionally, helium was associated with higher levels of inflammatory cytokines; however, it is not clear whether this is causative of nature or part of an epiphenomenon.

  1. Effects of Chronic Oral Administration of Natural Honey on Ischemia/Reperfusion-induced Arrhythmias in Isolated Rat Heart

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    Moslem Najafi

    2011-01-01

    Full Text Available Objective(sIn this study, effects of chronic administration of oral natural honey against ischemia/reperfusion (I/R-induced cardiac arrhythmias were investigated in isolated rat heart. Materials and MethodsMale Wistar rats were divided into four groups (n= 10-14 rats in each group and fed with natural honey (1%, 2% and 4% dissolved in the drinking water for 45 days except for the control group. After anesthesia, the rats’ hearts were isolated quickly, mounted on a Langendorff apparatus and perfused with a modified Krebs-Henseleit solution during stabilization, 30 min regional ischemia followed by 30 min reperfusion. The ECGs were recorded throughout the experiments to analyze cardiac arrhythmias based on the Lambeth conventions. ResultsIn the ischemic phase, honey (1% significantly reduced (P<0.05 the number and duration of ventricular tachycardia (VT. Honey (1% and 2% also significantly decreased number of ventricular ectopic beats (VEBs. In addition, incidence and duration of reversible ventricular fibrillation (Rev VF were lowered by honey 2% (P<0.05. During reperfusion time, VT incidence was 73% in the control group, however natural honey (1% decreased it to 22% (P<0.05. Honey also produced significant reduction in the incidences of total VF, Rev VF, duration and number of VT. ConclusionFor the first time, the results of present study demonstrated protective effects of chronic oral honey administration against I/R-induced arrhythmias in isolated rat heart. Antioxidant activity, the existence of energy sources such as glucose and fructose and improvement of some hemodynamic functions might be responsible for these effects.

  2. Strophanthus hispidus attenuates the Ischemia-Reperfusion induced myocardial Infarction and reduces mean arterial pressure in renal artery occlusion

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    Rohit Gundamaraju

    2014-01-01

    Full Text Available Background: The myocardium is generally injured in the case of reperfusion injury and arterial damage is caused by hypertension. In reference to these statements, the present study was focused. Cardiac glycosides were said to have protective effects against myocardial infarction and hypertension. Strophanthus hispidus was thus incorporated in the study. Objective: The prime objective of the study was to investigate the protective effects of Strophanthus hispidus against ischemia-reperfusion myocardial Infarction and renal artery occluded hypertension in rats. Materials and Methods: The animal model adopted was surgically-induced myocardial ischemia, performed by means of left anterior descending coronary artery occlusion (LAD for 30 min followed by reperfusion for another 4 h. Infarct size was assessed by using the staining agent TTC (2,3,5-triphenyl tetrazolium chloride. Hypertension was induced by clamping the renal artery with renal bulldog clamp for 4 h. Results: The study was fruitful by the effect of Strophanthus hispidus on infarction size, which got reduced to 27.2 ± 0.5and 20.0 ± 0.2 by 500 mg/Kg and 1000 mg/Kg ethanolic extracts which was remarkably significant when compared with that of the control group 52.8 ± 4.6. The plant extract did reduce heart rate at various time intervals. There was also a protective effect in the case of mean arterial blood pressure were the 500 mg/Kg and 1000 mg/Kg of the plant extract did reduce the hypertension after 60 minutes was 60.0 ± 4.80 and 50.50 ± 6.80. Conclusion: The results suggest that 500 mg/Kg and 100 mg/Kg ethanolic extract of Strophanthus hispidus was found to possess significant cardiac protective and anti-hypertensive activity.

  3. Adenosine A2 receptor activation ameliorates mitochondrial oxidative stress upon reperfusion through the posttranslational modification of NDUFV2 subunit of complex I in the heart.

    Science.gov (United States)

    Xu, Jingman; Bian, Xiyun; Liu, Yuan; Hong, Lan; Teng, Tianming; Sun, Yuemin; Xu, Zhelong

    2017-02-20

    While it is well known that adenosine receptor activation protects the heart from ischemia/reperfusion injury, the precise mitochondrial mechanism responsible for the action remains unknown. This study probed the mitochondrial events associated with the cardioprotective effect of 5'-(N-ethylcarboxamido) adenosine (NECA), an adenosine A2 receptor agonist. Isolated rat hearts were subjected to 30min ischemia followed by 10min of reperfusion, whereas H9c2 cells experienced 20min ischemia and 10min reperfusion. NECA prevented mitochondrial structural damage, decreases in respiratory control ratio (RCR), and collapse of mitochondrial membrane potential (ΔΨm). Both the adenosine A2A receptor antagonist SCH58261 and A2B receptor antagonist MRS1706 inhibited the action of NECA. NECA reduced mitochondrial proteins carbonylation, H2O2, and superoxide generation at reperfusion, but did not change superoxide dismutase (SOD) activity. In support, the protective effects of NECA and Peg-SOD on ΔΨm upon reperfusion were additive, implying that NECA's protection is attributable to the reduced superoxide generation but not to the enhancement of the superoxide-scavenging capacity. NECA increased the mitochondrial Src tyrosine kinase activity and suppressed complex I activity at reperfusion in a Src-dependent manner. NECA also reduced mitochondrial superoxide through Src tyrosine kinase. Studies with liquid chromatography-mass spectrometer (LC-MS) identified Tyr118 of the NDUFV2 subunit of complex 1 as a likely site of the tyrosine phosphorylation. Furthermore, the complex I activity of cells transfected with the Y118F mutant was increased, suggesting that this site might be a negative regulator of complex I activity. In support, NECA failed to suppress complex I activity at reperfusion in cells transfected with the Y118F mutant of NDUFV2. In conclusion, NECA prevents mitochondrial oxidative stress by decreasing mitochondrial superoxide generation through inhibition of complex I

  4. Role of microRNA-195 in cardiomyocyte apoptosis induced by myocardial ischaemia–reperfusion injury

    Indian Academy of Sciences (India)

    Chang-Kui Gao; Hui Liu; Cheng-Ji Cui; Zhao-Guang Liang; Hong Yao; Ye Tian

    2016-03-01

    This study aims to investigate microRNA-195 (miR-195) expression in myocardial ischaemia–reperfusion (I/R) injury and the roles of miR-195 in cardiomyocyte apoptosis though targeting Bcl-2. A mouse model of I/R injury was established. MiR-195 expression levels were detected by real-time quantitative PCR (qPCR), and the cardiomyocyte apoptosis was detected by TUNEL assay. After cardiomyocytes isolated from neonatal rats and transfected with miR-195 mimic or inhibitor, the hypoxia/reoxygenation (H/R) injury model was established. Cardiomyocyte apoptosis and mitochondrial membrane potential were evaluated using flow cytometry. Bcl-2 and Bax mRNA expressions were detected by RT-PCR. Bcl-2, Bax and cytochrome c (Cyt-c) protein levels were determined by Western blot. Caspase-3 and caspase-9 activities were assessed by luciferase assay. Compared with the sham group, miR-195 expression levels and rate of cardiomyocyte apoptosis increased significantly in I/R group (both < 0.05). Compared to H/R + negative control (NC) group, rate of cardiomyocyte apoptosis increased in H/R + miR-195 mimic group while decreased in H/R + miR-195 inhibitor group (both < 0.05). MiR-195 knockdown alleviated the loss of mitochondrial membrane potential ( < 0.05). MiR-195 overexpression decreased Bcl-2 mRNA and protein expression, increased BaxmRNA and protein expression, Cyt-c protein expression and caspase-3 and caspase-9 activities (all < 0.05). While, downregulated MiR-195 increased Bcl-2 mRNA and protein expression, decreased Bax mRNA and protein expression, Cyt-c protein expression and caspase-3 and caspase-9 activities (all < 0.05). Our study identified that miR-195 expression was upregulated in myocardial I/R injury, and miR-195 overexpression may promote cardiomyocyte apoptosis by targeting Bcl-2 and inducing mitochondrial apoptotic pathway.

  5. Protective Effect of Sevoflurane Postconditioning against Cardiac Ischemia/Reperfusion Injury via Ameliorating Mitochondrial Impairment, Oxidative Stress and Rescuing Autophagic Clearance.

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    Peng Yu

    Full Text Available Myocardial infarction leads to heart failure. Autophagy is excessively activated in myocardial ischemia/reperfusion (I/R in rats. The aim of this study is to investigate whether the protection of sevoflurane postconditioning (SPC in myocardial I/R is through restored impaired autophagic flux.Except for the sham control (SHAM group, each rat underwent 30 min occlusion of the left anterior descending coronary (LAD followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC staining. Cardiac function was examined by hemodynamics and echocardiography. The activation of autophagy was evaluated by autophagosome accumulation, LC3 conversion and p62 degradation. Potential molecular mechanisms were investigated by immunoblotting, real-time PCR and immunofluorescence staining.SPC improved the hemodynamic parameters, cardiac dysfunction, histopathological and ultrastructural damages, and decreased myocardial infarction size after myocardial I/R injury (P < 0.05 vs. I/R group. Compared with the cases in I/R group, myocardial ATP and NAD+ content, mitochondrial function related genes and proteins, and the expressions of SOD2 and HO-1 were increased, while the expressions of ROS and Vimentin were decreased in the SPC group (P < 0.05 vs. I/R group. SPC significantly activated Akt/mTOR signaling, and inhibited the formation of Vps34/Beclin1 complex via increasing expression of Bcl2 protein (P < 0.05 vs. I/R group. SPC suppressed elevated expressions of LC3 II/I ratio, Beclin1, Atg5 and Atg7 in I/R rat, which indicated that SPC inhibited over-activation of autophagy, and promoted autophagosome clearance. Meanwhile, SPC significantly suppressed the decline of Opa1 and increases of Drp1 and Parkin induced by I/R injury (P < 0.05 vs. I/R group. Moreover, SPC maintained the contents of ATP by reducing impaired mitochondria.SPC protects rat hearts against I/R injury via ameliorating mitochondrial impairment

  6. 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.

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

    Science.gov (United States)

    Tao, Xufeng; Sun, Xiance; Xu, Lina; Yin, Lianhong; Han, Xu; Qi, Yan; Xu, Youwei; Zhao, Yanyan; Wang, Changyuan; Peng, Jinyong

    2016-07-08

    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.

  8. Japanese herbal medicine, Saiko-keishi-to, prevents gut ischemia/reperfusion-induced liver injury in rats via nitric oxide

    Institute of Scientific and Technical Information of China (English)

    Yoshinori Horie; Mikio Kajihara; Shuka Mori; Yoshiyuki Yamagishi; Hiroyuki Kimura; Hironao Tamai; Shinzo Kato; Hiromasa Jshii

    2004-01-01

    AIM: To determine whether Saiko-keishi-to (TJ-10), a Japanese herbal medicine, could protect liver injury induced by gut ischemia/reperfusion (I/R), and to investigate the role of NO.METHODS: Male Wistar rats were exposed to 30-min gut ischemia followed by 60 min of reperfusion. Intravital microscopy was used to monitor leukocyte recruitment. Plasma tumor necrosis factor (TNF) levels and alanine aminotransferase intragastrically administered to rats for 7 d. A NO synthase inhibitor was administered.RESULTS: In control rats, gut I/R elicited increases in the number of stationary leukocytes, and plasma TNF levels and ALT activities were mitigated by pretreatment with TJ-10. Pretreatment with the NO synthase inhibitor diminished the protective effects of TJ-10 on leukostasis in the liver, and the increase of plasma TNF levels and ALT activities. Pretreatment with TJ-10 increased plasma nitrite/nitrate levels.CONCLUSION: TJ-10 attenuates the gut I/R-induced hepatic microvascular dysfunction and sequential hepatocellular injury via enhancement of NO production.

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

    Science.gov (United States)

    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.

  10. Sildenafil citrate (viagra) induces cardioprotective effects after ischemia/reperfusion injury in infant rabbits.

    Science.gov (United States)

    Bremer, Yvonne A; Salloum, Fadi; Ockaili, Ramzi; Chou, Eric; Moskowitz, William B; Kukreja, Rakesh C

    2005-01-01

    Infants undergoing surgery for congenital heart disease are at risk for myocardial ischemia during cardiopulmonary bypass, circulatory arrest, or low-flow states. The purpose of this study was to demonstrate the effects of sildenafil, a selective phosphodiesterase-5 (PDE-5) inhibitor on myocardial functional improvement and infarct size reduction during ischemia/reperfusion injury in infant rabbits. Infant rabbits (aged 8 wk) were treated with sildenafil citrate (0.7 mg/kg i.v.) or normal saline 30 min before sustained ischemia for 30 min and reperfusion for 3 h. Transesophageal echocardiography (TEE) was used to assess left ventricular cardiac output (LVCO) and aortic velocity time integral (VTI). After ischemia/reperfusion, risk area was demarcated by Evan's blue dye and infarct size determined by computer morphometry of triphenyltetrazolium chloride-stained sections. The sildenafil-treated group had preservation and elevation in LVCO (143% of baseline, p sildenafil group compared with controls (n = 6/group, p sildenafil-treated group had significant reduction in infarct size (15.5 +/- 1.2 versus 33 +/- 2.3 in the saline group, % risk area, mean +/- SEM, n = 10-15/group, p sildenafil citrate promotes myocardial protection in infant rabbits as evidenced by postischemic preservation and elevation in LVCO and aortic VTI and reduction in infarct size.

  11. The effects of iloprost on lung injury induced by skeletal muscle ischemia-reperfusion.

    Science.gov (United States)

    Erer, D; Dursun, A D; Oktar, G L; Iriz, E; Zor, M H; Elmas, C; Donmez, T; Kirisci, M; Comu, F M; Arslan, M

    2014-01-01

    The aim of this study was to investigate the effects of iloprost (I) on lung injury as a remote organ following skeletal muscle ischemia-reperfusion injury in a rat model. Twenty-four Wistar Albino rats were randomized into four groups (n = 6). Laparotomy was performed in all groups under general anesthesia. Only laparotomy was applied in Group S (Sham). Ischemia reperfusion group (Group I/R) underwent ischemia and reperfusion performed by clamping and declamping of the infrarenal abdominal aorta for 120 minutes. Group iloprost (Group I) received intravenous infusion of iloprost 0.5 ng/kg/min, without ischemia and reperfusion. Group I/R/I received intravenous infusion of iloprost 0.5 ng/kg/min immediately after 2 hours of ischemia. At the end of the study, lung tissue was obtained for determining total oxidant status (TOS) and total antioxidant status (TAS) levels, histochemical and immunohistochemical determination. Diffuse lymphocyte infiltration was detected in immunohistochemical examination of lung tissue in Group I/R. The connective tissue around bronchi, bronchioles and vessel walls was found to be increased. Although minimal local lymphocyte infiltration was detected in some fields in Group I/R/I, the overall tissue was found to be similar to Group S. iNOS expression was significantly higher in Group I/R, when compared with Group S and significantly lower in Group I/R/I compared to Group I/R.TOS levels were significantly higher in Group I/R, when compared with groups S and I (p = 0.028, p = 0.016, respectively) and significantly lower in group I/R/I, when compared with Group I/R (p = 0.048). TAS levels were significantly higher in Group I/R, when compared with groups S, I (p = 0.014, p = 0.027, respectively) and significantly lower in Group I/R/I, when compared with Group I/R (p = 0.032). These results indicate that administration of iloprost may have protective effects against ischemia reperfusion injury (Fig. 8, Tab. 1, Ref. 30)

  12. 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

  13. Hypoxia inducible factor 1-alpha (HIF-1 alpha is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival.

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    Elisa Conde

    Full Text Available Acute tubular necrosis (ATN caused by ischemia/reperfusion (I/R during renal transplantation delays allograft function. Identification of factors that mediate protection and/or epithelium recovery could help to improve graft outcome. We studied the expression, regulation and role of hypoxia inducible factor 1-alpha (HIF-1 α, using in vitro and in vivo experimental models of I/R as well as human post-transplant renal biopsies. We found that HIF-1 α is stabilized in proximal tubule cells during ischemia and unexpectedly in late reperfusion, when oxygen tension is normal. Both inductions lead to gene expression in vitro and in vivo. In vitro interference of HIF-1 α promoted cell death and in vivo interference exacerbated tissue damage and renal dysfunction. In pos-transplant human biopsies, HIF-1 α was expressed only in proximal tubules which exhibited normal renal structure with a significant negative correlation with ATN grade. In summary, using experimental models and human biopsies, we identified a novel HIF-1 α induction during reperfusion with a potential critical role in renal transplant.

  14. 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.

  15. Protective effects of branched-chain amino acids on hepatic ischemia-reperfusion-induced liver injury in rats: a direct attenuation of Kupffer cell activation.

    Science.gov (United States)

    Kitagawa, Tomomi; Yokoyama, Yukihiro; Kokuryo, Toshio; Nagino, Masato

    2013-02-15

    We determined whether there is a protective effect of branched-chain amino acid (BCAA) on hepatic ischemia-reperfusion (I/R)-induced acute liver injury. Wister rats were divided into the following four groups: simple laparotomy with vehicle; simple laparotomy with BCAA (1 g/kg body wt orally); I/R (30 min clamp) with vehicle; and I/R with BCAA. Serum liver function tests and the gene expression of adhesion molecules (intercellular adhesion molecule and vascular cell adhesion molecule) and vasoconstrictor-related genes (endothelin-1) in the liver were examined. In the in vivo study, portal venous pressure, leukocyte adhesion, and hepatic microcirculation were evaluated. Furthermore, Kupffer cells were isolated and cultured with various concentrations of BCAA in the presence or absence of lipopolysaccharide (LPS). Increased levels of liver function tests following I/R were significantly attenuated by BCAA treatment. The increased expression of adhesion molecules and endothelin-1 was also significantly attenuated by BCAA treatment. Moreover, increased portal venous pressure, enhanced leukocyte adhesion, and deteriorated hepatic microcirculation following I/R were all improved by BCAA treatment. In the experiment using isolated Kupffer cells, the expression of interleukin-6, interleukin-1β, and endothelin-1 in response to LPS stimulation was attenuated by BCAA in a dose-dependent fashion. These results indicate that perioperative oral administration of BCAA has excellent therapeutic potential to reduce I/R-induced liver injury. These beneficial effects may result from the direct attenuation of Kupffer cell activation under stressful conditions.

  16. Protective effects of curcumin supplementation on intestinal ischemia reperfusion injury.

    Science.gov (United States)

    Okudan, N; Belviranlı, M; Gökbel, H; Oz, M; Kumak, A

    2013-07-15

    The aim of this study was to investigate the effects curcumin on inflammation and oxidative stress markers in the intestinal ischemia reperfusion (IIR) injury induced rats. Rats were divided into four groups: sham (S), intestinal IR (IIR), curcumin plus sham (CS), and curcumin plus intestinal IR (CIIR). Curcumin was given 200 mg kg⁻¹ for 20 days. IIR was produced by 45 min of intestinal ischemia followed by a 120 min of reperfusion. Although interleukin-6 levels tended to increase in IIR group tumor necrosis factor-α levels were not different. Intestinal myeloperoxidase activity in CS group was lower than IIR group. In intestine and heart tissues, malondialdehyde levels in CS and CIIR groups were lower than S and IIR groups. Superoxide dismutase activity in CIIR group was higher than IIR group in intestine and lung tissues. Curcumin has a protective role against ischemia reperfusion injury.

  17. Protective effect of nitric oxide induced by ischemic preconditioning on reperfusion injury of rat liver graft

    Institute of Scientific and Technical Information of China (English)

    Jian-Ping Gong; Bing Tu; Wei Wang; Yong Peng; Shou-Bai Li; Lu-Nan Yan

    2004-01-01

    AIM: Ischemic preconditioning (IP) is a brief ischemic episode,which confers a state of protection against the subsequent long-term ischemia-reperfusion injuries. However, little is known regarding the use of IP before the sustained cold storage and liver transplantation. The present study was designed to evaluate the protective effect of IP on the long-term preservation of liver graft and the prolonged anhepatic-phase injury.METHODS: Male Sprague-Dawley rats were used as donors and recipients of orthotopic liver transplantation. All livers underwent 10 min of ischemia followed by 10 min of reperfusion before harvest. Rat liver transplantation was performed with the portal vein clamped for 25 min. Tolerance of transplanted liver to the reperfusion injury and liverdamage were investigated. The changes in adenosineconcentration in hepatic tissue and those of nitric oxide (NO)and tumor necrosis factor (TNF) in serum were also assessed.RESULTS: Recipients with IP significantly improved theirone-week survival rate and liver function, they had increasedlevels of circulating NO and hepatic adenosine, and a reducedlevel of serum TNF, as compared to controls. Histologicalchanges indicating hepatic injuries appeared improved in theIP group compared with those in control group. The protectiveeffect of IP was also obtained by administration of adenosine,while blockage of the NO pathway using Nω-nitro-L-argininemethyl ester abolished the protective effect of IRCONCLUSION: IP appears to have a protective effect onthe long-term preservation of liver graft and the prolongedanhepatic-phase injuries. NO may be involved in this process.

  18. Poloxamer-188 Reduces Muscular Edema After Tourniquet-Induced Ischemia-Reperfusion Injury in Rats

    Science.gov (United States)

    2011-05-01

    Trauma. 2011;70: 1192–1197) Muscle injury, such as ischemia-reperfusion injury (I-R),1blunt trauma injury, electrocution ,2 burn, crush,3 and laceration, is...188 solution (SythRx, Bellaire, TX) contained 150 mg/mL highly purified P-188, 3.08 mg/mL sodium chlo- ride, 2.38 mg/mL sodium citrate, and 0.366 mg...mL citric acid. The placebo solution contained the same ingredients with the exception of P-188. Doses consisted of 1.0 mL/kg body weight of P-188

  19. Cardioprotective effects of simvastatin on reversing electrical remodeling induced by myocardial ischemia-reperfusion in normocholesterolemic rabbits

    Institute of Scientific and Technical Information of China (English)

    DING Chao; FU Xiang-hua; HE Zhen-shan; CHEN Hui-xiao; XUE Ling; LI Jun-xia

    2008-01-01

    (P>0.05).The Ito current density(at+60mV)was significantly decreased in I-R((9.49±1.91)pA/pF,n=11)compared with CON ((17.41±3.13)pA/pF,n=15,P<0.01)and Statin((14.54±9.41)pA/pF,n=11,P<0.01),although there was a slight reduction in the Statin group compared with CON(P<0.05).Conclusions It is implied that ischemia-reperfusion induces significant down-regulation of Ina and Ito and up-regulation of Ica-L,which may underlie the altered electrical activity and long abnormal transmembrane action potential duration of the surviving ventricular myocytes,thus contributing to ventricular arrhythmias during acute ischemia-reperfusion period.Pretreatment with simvastatin could attenuate these changes and reverse this electrical remodeling without lowering the serum cholesterol level,contributing to the ionic mechanism of statin in treatment of arrhythmia independent of a decrease in cholesterol.

  20. Mild episodes of tourniquet-induced forearm ischaemia-reperfusion injury results in leukocyte activation and changes in inflammatory and coagulation markers

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    Bastawrous Salah S

    2007-05-01

    Full Text Available Abstract Background Monocytes and neutrophils are examples of phagocytic leukocytes, with neutrophils being considered as the 'chief' phagocytic leukocyte. Both monocytes and neutrophils have been implicated to play a key role in the development of ischaemia-reperfusion injury, where they are intrinsically involved in leukocyte-endothelial cell interactions. In this pilot study we hypothesised that mild episodes of tourniquet induced forearm ischaemia-reperfusion injury results in leukocyte activation and changes in inflammatory and coagulation markers. Methods Ten healthy human volunteers were recruited after informed consent. None had any history of cardiovascular disease with each subject volunteer participating in the study for a 24 hour period. Six venous blood samples were collected from each subject volunteer at baseline, 10 minutes ischaemia, 5, 15, 30, 60 minutes and 24 hours reperfusion, by means of a cannula from the ante-cubital fossa. Monocyte and neutrophil leukocyte sub-populations were isolated by density gradient centrifugation techniques. Leukocyte trapping was investigated by measuring the concentration of leukocytes in venous blood leaving the arm. The cell surface expression of CD62L (L-selectin, CD11b and the intracellular production of hydrogen peroxide (H2O2 were measured via flow cytometry. C-reactive protein (CRP was measured using a clinical chemistry analyser. Plasma concentrations of D-dimer and von Willebrand factor (vWF were measured using enzyme-linked fluorescent assays (ELFA. Results During ischaemia-reperfusion injury, there was a decrease in CD62L and an increase in CD11b cell surface expression for both monocytes and neutrophils, with changes in the measured parameters reaching statistical significance (p =2O2 production by leukocyte sub-populations, which was measured as a marker of leukocyte activation. Intracellular production of H2O2 in monocytes during ischaemia-reperfusion injury reached statistical

  1. Oral delivery of insulin withDesmodium gangeticum root aqueous extract protects rat hearts against ischemia reperfusion injury in streptozotocin induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Gino A Kurian; Jose Paddikkala

    2010-01-01

    Objective:To evaluate the effect of insulin administered via oral route with the help of aqueous extract ofDesmodium gangeticum (DG) root in rendering cardio protection against ischemia reperfusion injury in diabetic rats.Methods: Diabetes mellitus was induced in rats by theβ-cell toxin, streptozotocin (STZ, 60 mg/kg). Isolated rat (IR) heart was used to investigate the effect of insulin mixed DG pretreatment on ischemia reperfusion injury. Mitochondrial respiratory enzymes and microsomal enzymes were used to assess the metabolic recovery of myocardium. Cardiac marker enzymes were used to find the functional recovery, which were compared with that of the STZ treated IR rats.Results: Compared with IR control group, rat treated with insulin mixed DG showed a significant functional and metabolic recovery of myocardium from the insult of ischemia reperfusion. Even though orally administered insulin mixed DG displayed a slow but prolonged hypoglycemic effect, the cardio protection it provided was more significant than when it was given intra peritoneal. Furthermore the above result indicates that insulin mixed DG can overcome the barriers in the gastrointestinal tract and be absorbed.Conclusions: The above results indicate the efficacy of insulin mixed DG in protecting the heart from ischemia reperfusion induced injury in diabetic rats. Furthermore the study gives additional information that herbal extracts can be used to transport insulin across the membrane and found to be a feasible approach for developing the oral delivery of insulin, as well as other peptide drugs.

  2. Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore

    Energy Technology Data Exchange (ETDEWEB)

    Gharanei, M.; Hussain, A. [Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB (United Kingdom); Janneh, O. [Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB (United Kingdom); Pharmacology Research Laboratories, 70, Pembroke Place, The University of Liverpool, Liverpool. L69 3GF (United Kingdom); Maddock, H.L., E-mail: h.maddock@coventry.ac.uk [Department of Biomolecular and Sport Sciences, Coventry University, Cox Street, Coventry, CV1 5FB (United Kingdom)

    2013-04-15

    Chemotherapeutic agents such as doxorubicin are known to cause or exacerbate cardiovascular cell death when an underlying heart condition is present. However, the mechanism of doxorubicin-induced cardiotoxicity is unclear. Here we assess the cardiotoxic effects of doxorubicin in conditions of myocardial ischaemia reperfusion and the mechanistic basis of protection, in particular the role of the mitochondrial permeability transition pore (mPTP) in such protection. The effects of doxorubicin (1 μM) ± cyclosporine A (CsA, 0.2 μM; inhibits mPTP) were investigated in isolated male Sprague–Dawley rats using Langendorff heart and papillary muscle contraction models subjected to simulated ischaemia and reperfusion injury. Isolated rat cardiac myocytes were used in an oxidative stress model to study the effects of drug treatment on mPTP by confocal microscopy. Western blot analysis evaluated the effects of drug treatment on p-Akt and p-Erk 1/2 levels. Langendorff and the isometric contraction models showed a detrimental effect of doxorubicin throughout reperfusion/reoxygenation as well as increased p-Akt and p-Erk levels. Interestingly, CsA not only reversed the detrimental effects of doxorubicin, but also reduced p-Akt and p-Erk levels. In the sustained oxidative stress assay to study mPTP opening, doxorubicin decreased the time taken to depolarization and hypercontracture, but these effects were delayed in the presence of CsA. Collectively, our data suggest for the first that doxorubicin exacerbates myocardial injury in an ischaemia reperfusion model. If the inhibition of mPTP ameliorates the cardiotoxic effects of doxorubicin, then more selective inhibitors of mPTP should be further investigated for their utility in patients receiving doxorubicin. - Highlights: ► Doxorubicin exacerbates myocardial ischaemia reperfusion injury. ► Co-treatment with CsA protects against doxorubicin induced myocardial injury. ► CsA delays doxorubicin induced mPTP opening in laser

  3. Tyrosol prevents ischemia/reperfusion-induced cardiac injury in H9c2 cells: involvement of ROS, Hsp70, JNK and ERK, and apoptosis.

    Science.gov (United States)

    Sun, Liwei; Fan, Hang; Yang, Lingguang; Shi, Lingling; Liu, Yujun

    2015-02-25

    Ischemia-Reperfusion (I/R) injury causes ROS overproduction, creating oxidative stress, and can trigger myocyte death, resulting in heart failure. Tyrosol is an antioxidant abounded in diets and medicine. Our objective was to investigate the protective effect of tyrosol on I/R-caused mortality in H9c2 cardiomyocytes through its influence on ROS, Hsp70, ERK, JNK, Bcl-2, Bax and caspase-8. A simulated I/R model was used, myocytes loss was examined by MTT, and ROS levels were measured using DCFH-DA. Nuclear condensation and caspase-3 activity were assessed by DAPI staining and fluorometric assay. Phosphorylated ERK and JNK were determined by electrochemiluminescent ELISA, and Hsp70, Bcl-2, Bax and caspase-8 were examined by Western blotting. Results show that tyrosol salvaged myocyte loss, inhibited nuclear condensation and caspase-3 activity dose-dependently, indicating its protection against I/R-caused myocyte loss. Furthermore, tyrosol significantly inhibited ROS accumulation and activation of ERK and JNK, augmenting Hsp70 expression. Besides, tyrosol inhibited I/R-induced apoptosis, associated with retained anti-apoptotic Bcl-2 protein, and attenuated pro-apoptotic Bax protein, resulting in a preservation of Bcl-2/Bax ratio. Finally, tyrosol notably decreased cleaved caspase-8 levels. In conclusion, cytoprotection of tyrosol in I/R-caused myocyte mortality was involved with the mitigation of ROS, prohibition of the activation of ERK, JNK and caspase-8, and elevation of Hsp70 and Bcl-2/Bax ratio.

  4. Tyrosol Prevents Ischemia/Reperfusion-Induced Cardiac Injury in H9c2 Cells: Involvement of ROS, Hsp70, JNK and ERK, and Apoptosis

    Directory of Open Access Journals (Sweden)

    Liwei Sun

    2015-02-01

    Full Text Available Ischemia-Reperfusion (I/R injury causes ROS overproduction, creating oxidative stress, and can trigger myocyte death, resulting in heart failure. Tyrosol is an antioxidant abounded in diets and medicine. Our objective was to investigate the protective effect of tyrosol on I/R-caused mortality in H9c2 cardiomyocytes through its influence on ROS, Hsp70, ERK, JNK, Bcl-2, Bax and caspase-8. A simulated I/R model was used, myocytes loss was examined by MTT, and ROS levels were measured using DCFH-DA. Nuclear condensation and caspase-3 activity were assessed by DAPI staining and fluorometric assay. Phosphorylated ERK and JNK were determined by electrochemiluminescent ELISA, and Hsp70, Bcl-2, Bax and caspase-8 were examined by Western blotting. Results show that tyrosol salvaged myocyte loss, inhibited nuclear condensation and caspase-3 activity dose-dependently, indicating its protection against I/R-caused myocyte loss. Furthermore, tyrosol significantly inhibited ROS accumulation and activation of ERK and JNK, augmenting Hsp70 expression. Besides, tyrosol inhibited I/R-induced apoptosis, associated with retained anti-apoptotic Bcl-2 protein, and attenuated pro-apoptotic Bax protein, resulting in a preservation of Bcl-2/Bax ratio. Finally, tyrosol notably decreased cleaved caspase-8 levels. In conclusion, cytoprotection of tyrosol in I/R-caused myocyte mortality was involved with the mitigation of ROS, prohibition of the activation of ERK, JNK and caspase-8, and elevation of Hsp70 and Bcl-2/Bax ratio.

  5. Remote ischemic perconditioning prevents liver transplantation-induced ischemia/reperfusion injury in rats: Role of ROS/RNS and eNOS

    Science.gov (United States)

    He, Ning; Jia, Jun-Jun; Li, Jian-Hui; Zhou, Yan-Fei; Lin, Bing-Yi; Peng, Yi-Fan; Chen, Jun-Jie; Chen, Tian-Chi; Tong, Rong-Liang; Jiang, Li; Xie, Hai-Yang; Zhou, Lin; Zheng, Shu-Sen

    2017-01-01

    AIM To investigate the underlying mechanisms of the protective role of remote ischemic perconditioning (RIPerC) in rat liver transplantation. METHODS Sprague-Dawley rats were subjected to sham, orthotopic liver transplantation (OLT), ischemic postconditioning (IPostC) or RIPerC. After 3 h reperfusion, blood samples were taken for measurement of alanine aminotransferase, aspartate aminotransferase, creatinine (Cr) and creatinine kinase-myocardial band (CK-MB). The liver lobes were harvested for the following measurements: reactive oxygen species (ROS), H2O2, mitochondrial membrane potential (ΔΨm) and total nitric oxide (NO). These measurements were determined using an ROS/H2O2, JC1 and Total NOx Assay Kit, respectively. Endothelial NO synthase (eNOS) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting, and peroxynitrite was semi-quantified by western blotting of 3-nitrotyrosine. RESULTS Compared with the OLT group, the grafts subjected to RIPerC showed significantly improved liver and remote organ functions (P < 0.05). ROS (P < 0.001) including H2O2 (P < 0.05) were largely elevated in the OLT group as compared with the sham group, and RIPerC (P < 0.05) reversed this trend. The collapse of ΔΨm induced by OLT ischemia/reperfusion (I/R) injury was significantly attenuated in the RIPerC group (P < 0.001). A marked increase of NO content and phosphoserine eNOS, both in protein and mRNA levels, was observed in liver graft of the RIPerC group as compared with the OLT group (P < 0.05). I/R-induced 3-nitrotyrosine content was significantly reduced in the RIPerC group as compared with the OLT group (P < 0.05). There were no significant differences between the RIPerC and IPostC groups for all the results except Cr. The Cr level was lower in the RIPerC group than in the IPostC group (P < 0.01). CONCLUSION Liver graft protection by RIPerC is similar to or better than that of IPostC, and involves inhibition of oxidative stress and up

  6. Putative role of ischemic postconditioning in a rat model of limb ischemia and reperfusion: involvement of hypoxia-inducible factor-1? expression

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    T. Wang

    2014-09-01

    Full Text Available Hypoxia-inducible factor-1α (HIF-1α is one of the most potent angiogenic growth factors. It improves angiogenesis and tissue perfusion in ischemic skeletal muscle. In the present study, we tested the hypothesis that ischemic postconditioning is effective for salvaging ischemic skeletal muscle resulting from limb ischemia-reperfusion injury, and that the mechanism involves expression of HIF-1α. Wistar rats were randomly divided into three groups (n=36 each: sham-operated (group S, hindlimb ischemia-reperfusion (group IR, and ischemic postconditioning (group IPO. Each group was divided into subgroups (n=6 according to reperfusion time: immediate (0 h, T0, 1 h (T1, 3 h (T3, 6 h (T6, 12 h (T12, and 24 h (T24. In the IPO group, three cycles of 30-s reperfusion and 30-s femoral aortic reocclusion were carried out before reperfusion. At all reperfusion times (T0-T24, serum creatine kinase (CK and lactate dehydrogenase (LDH activities, as well as interleukin (IL-6, IL-10, and tumor necrosis factor-α (TNF-α concentrations, were measured in rats after they were killed. Histological and immunohistochemical methods were used to assess the skeletal muscle damage and HIF-1α expression in skeletal muscle ischemia. In groups IR and IPO, serum LDH and CK activities and TNF-α, IL-6, and IL-10 concentrations were all significantly increased compared to group S, and HIF-1α expression was up-regulated (P<0.05 or P<0.01. In group IPO, serum LDH and CK activities and TNF-α and IL-6 concentrations were significantly decreased, IL-10 concentration was increased, HlF-1α expression was down-regulated (P<0.05 or P<0.01, and the pathological changes were reduced compared to group IR. The present study suggests that ischemic postconditioning can reduce skeletal muscle damage caused by limb ischemia-reperfusion and that its mechanisms may be related to the involvement of HlF-1α in the limb ischemia-reperfusion injury-triggered inflammatory response.

  7. Putative role of ischemic postconditioning in a rat model of limb ischemia and reperfusion: involvement of hypoxia-inducible factor-1α expression

    Energy Technology Data Exchange (ETDEWEB)

    Wang, T. [Department of Anesthesiology, Shuyang People' s Hospital, JiangSu (China); Zhou, Y.T. [Department of General Surgery, Shuyang People' s Hospital, JiangSu (China); Chen, X.N. [Institute of Pathophysiology, School of Basic Medical Sciences, LanZhou University, Lanzhou, Gansu (China); Zhu, A.X. [Department of Pharmacy, Shuyang People' s Hospital, JiangSu (China)

    2014-07-25

    Hypoxia-inducible factor-1α (HIF-1α) is one of the most potent angiogenic growth factors. It improves angiogenesis and tissue perfusion in ischemic skeletal muscle. In the present study, we tested the hypothesis that ischemic postconditioning is effective for salvaging ischemic skeletal muscle resulting from limb ischemia-reperfusion injury, and that the mechanism involves expression of HIF-1α. Wistar rats were randomly divided into three groups (n=36 each): sham-operated (group S), hindlimb ischemia-reperfusion (group IR), and ischemic postconditioning (group IPO). Each group was divided into subgroups (n=6) according to reperfusion time: immediate (0 h, T{sub 0}), 1 h (T{sub 1}), 3 h (T{sub 3}), 6 h (T{sub 6}), 12 h (T{sub 12}), and 24 h (T{sub 24}). In the IPO group, three cycles of 30-s reperfusion and 30-s femoral aortic reocclusion were carried out before reperfusion. At all reperfusion times (T{sub 0}-T{sub 24}), serum creatine kinase (CK) and lactate dehydrogenase (LDH) activities, as well as interleukin (IL)-6, IL-10, and tumor necrosis factor-α (TNF-α) concentrations, were measured in rats after they were killed. Histological and immunohistochemical methods were used to assess the skeletal muscle damage and HIF-1α expression in skeletal muscle ischemia. In groups IR and IPO, serum LDH and CK activities and TNF-α, IL-6, and IL-10 concentrations were all significantly increased compared to group S, and HIF-1α expression was up-regulated (P<0.05 or P<0.01). In group IPO, serum LDH and CK activities and TNF-α and IL-6 concentrations were significantly decreased, IL-10 concentration was increased, HlF-1α expression was down-regulated (P<0.05 or P<0.01), and the pathological changes were reduced compared to group IR. The present study suggests that ischemic postconditioning can reduce skeletal muscle damage caused by limb ischemia-reperfusion and that its mechanisms may be related to the involvement of HlF-1α in the limb ischemia-reperfusion injury

  8. Overexpression of Heme Oxygenase-1 in Mesenchymal Stem Cells Augments Their Protection on Retinal Cells In Vitro and Attenuates Retinal Ischemia/Reperfusion Injury In Vivo against Oxidative Stress

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    Li Li

    2017-01-01

    Full Text Available Retinal ischemia/reperfusion (I/R injury, involving several ocular diseases, seriously threatens human ocular health, mainly treated by attenuating I/R-induced oxidative stress. Currently, mesenchymal stem cells (MSCs could restore I/R-injured retina through paracrine secretion. Additionally, heme oxygenase-1 (HO-1 could ameliorate oxidative stress and thus retinal apoptosis, but the expression of HO-1 in MSC is limited. Here, we hypothesized that overexpression of HO-1 in MSC (MSC-HO-1 may significantly improve their retina-protective potentials. The overexpression of HO-1 in MSC was achieved by lentivirus transduction. Then, MSC or MSC-HO-1 was cocultured with retinal ganglion cells (RGC-5 in H2O2-simulated oxidative condition and their protection on RGC-5 was systemically valuated in vitro. Compared with MSC, MSC-HO-1 significantly attenuated H2O2-induced injury of RGC-5, including decrease in cellular ROS level and apoptosis, activation of antiapoptotic proteins p-Akt and Bcl-2, and blockage of proapoptotic proteins cleaved caspase 3 and Bax. In retinal I/R rats model, compared with control MSC, MSC-HO-1-treated retina significantly retrieved its structural thickness, reduced cell apoptosis, markedly attenuated retinal oxidative stress level, and largely regained the activities of typical antioxidant enzymes, SOD and CAT. Therefore, it could be concluded that overexpression of HO-1 provides a promising strategy to enhance the MSC-based therapy for I/R-related retinal injury.

  9. Hydrogen Sulfide Ameliorates Ischemia/Reperfusion-Induced Hepatitis by Inhibiting Apoptosis and Autophagy Pathways

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    Ping Cheng

    2014-01-01

    Full Text Available Background. Hepatic ischemia/reperfusion (I/R injury is an important clinical problem, and its consequences can seriously threaten human health. Apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. Hydrogen sulfide (H2S is the third most common endogenously produced gaseous signaling molecule and is known to exert a protective effect against hepatic I/R injury. In this study, the purpose is to explore both the effect and mechanism of H2S on hepatic I/R injury. Methods. Balb/c mice were randomized into Sham, I/R, or two doses (14 μmol/kg and 28 μmol/kg of sodium hydrosulfide (NaHS, an H2S donor preconditioning groups. Results. NaHS significantly reduced the levels of TNF-α and IL-6 at 12 h and 24 h after injection compared with ischemia/reperfusion challenge alone. The expression of Bcl-2, Bax, Beclin-1, and LC3, which play important roles in the regulation of the apoptosis and autophagy pathways, was also clearly affected by NaHS. Furthermore, NaHS affected the p-JNK1, p-ERK1, and p-p38. Conclusion. Our results indicate that H2S attenuates hepatic I/R injury, at least in part, by regulating apoptosis through inhibiting JNK1 signaling. The autophagy agonist rapamycin potentiated this hepatoprotective effect by reversing the inhibition of autophagy by H2S.

  10. Effect of Curcuma longa and Ocimum sanctum on myocardial apoptosis in experimentally induced myocardial ischemic-reperfusion injury

    Science.gov (United States)

    Mohanty, Ipseeta; Arya, Dharamvir Singh; Gupta, Suresh Kumar

    2006-01-01

    Background In the present investigation, the effect of Curcuma longa (Cl) and Ocimum sanctum (Os) on myocardial apoptosis and cardiac function was studied in an ischemia and reperfusion (I-R) model of myocardial injury. Methods Wistar albino rats were divided into four groups and orally fed saline once daily (sham, control IR) or Cl (100 mg/kg; Cl-IR) or Os (75 mg/kg; Os-IR) respectively for 1 month. On the 31st day, in the rats of the control IR, Cl-IR and Os-IR groups LAD occlusion was undertaken for 45 min, and reperfusion was allowed for 1 h. The hemodynamic parameters{mean arterial pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular peak positive (+) LVdP/dt (rate of pressure development) and negative (-) LVdP/dt (rate of pressure decline)} were monitored at pre-set points throughout the experimental duration and subsequently, the animals were sacrificed for immunohistopathological (Bax, Bcl-2 protein expression & TUNEL positivity) and histopathological studies. Results Chronic treatment with Cl significantly reduced TUNEL positivity (p < 0.05), Bax protein (p < 0.001) and upregulated Bcl-2 (p < 0.001) expression in comparison to control IR group. In addition, Cl demonstrated mitigating effects on several myocardial injury induced hemodynamic {(+)LVdP/dt, (-) LVdP/dt & LVEDP} and histopathological perturbations. Chronic Os treatment resulted in modest modulation of the hemodynamic alterations (MAP, LVEDP) but failed to demonstrate any significant antiapoptotic effects and prevent the histopathological alterations as compared to control IR group. Conclusion In the present study, significant cardioprotection and functional recovery demonstrated by Cl may be attributed to its anti-apoptotic property. In contrast to Os, Cl may attenuate cell death due to apoptosis and prevent the impairment of cardiac performance. PMID:16504000

  11. 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.

  12. Allopurinol Reduces Oxidative Stress in the Ovine Fetal Cardiovascular System After Repeated Episodes of Ischemia-Reperfusion

    NARCIS (Netherlands)

    Derks, Jan B.; Oudijk, Martijn A.; Torrance, Helen L.; Rademaker, Carin M. A.; Benders, Manon J.; Rosen, Karl G.; Cindrova-Davies, Tereza; Thakor, Avnesh S.; Visser, Gerard H. A.; Burton, Graham J.; van Bel, Frank; Giussani, Dino A.

    2010-01-01

    In complicated labor, neonatal outcome may depend not only on the extent of fetal asphyxia and acidosis but also on the effects on the fetal cardiovascular system of reactive oxygen species (ROS) generated during the ischemia-reperfusion (I/R) associated with repeated compressions of the umbilical c

  13. Far red/near infrared light-induced protection against cardiac ischemia and reperfusion injury remains intact under diabetic conditions and is independent of nitric oxide synthase

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    Agnes eKeszler

    2014-08-01

    Full Text Available Far red/near-infrared light (NIR promotes a wide range of biological effects including tissue protection but whether and how NIR is capable of acutely protecting myocardium against ischemia and reperfusion injury in vivo is not fully elucidated. Our previous work indicates that NIR exposure immediately before and during early reperfusion protects the myocardium against infarction through mechanisms that are nitric oxide (NO-dependent. Here we tested the hypothesis that NIR elicits protection in a diabetic mouse model where other cardioprotective interventions such as pre- and postconditioning fail, and that the protection is independent of nitric oxide synthase (NOS. NIR reduced infarct size dose dependently. Importantly, NIR-induced protection was preserved in a diabetic mouse model (db/db and during acute hyperglycemia, as well as in endothelial NOS-/- mice and in wild type mice treated with NOS inhibitor L-NAME. In in vitro experiments NIR light liberates NO from nitrosyl hemoglobin (HbNO and nitrosyl myoglobin (MbNO in a wavelength (660-830 nm and dose-dependent manner. Irradiation at 660 nm yields the highest release of NO, while at longer wavelengths a dramatic decrease of NO release can be observed. Similar wavelength dependence was observed for the protection of mice against cardiac ischemia and reperfusion injury in vivo. NIR-induced NO release from deoxymyoglobin in the presence of nitrite mildly inhibits respiration of isolated mitochondria after hypoxia. In summary, NIR applied during reperfusion protects the myocardium against infarction in an NO dependent, but NOS-independent mechanisms, whereby mitochondria may be a target of NO released by NIR, leading to reduced reactive oxygen species generation during reperfusion. This unique mechanism preserves protection even during diabetes where other protective strategies fail.

  14. Pretreatment with 2-(4-methoxyphenylethyl-2-acetamido-2-deoxy-β-D-pyranoside attenuates cerebral ischemia/reperfusion-induced injury in vitro and in vivo.

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    Xia Chen

    Full Text Available Salidroside, extracted from the root of Rhodiola rosea L, is known for its pharmacological properties, in particular its neuroprotective effects. 2-(4-Methoxyphenyl ethyl-2-acetamido-2-deoxy-β-D-pyranoside (GlcNAc-Sal, an analog of salidroside, was recently synthesized and shown to possess neuroprotective properties. The purpose of the current study was to investigate the neuroprotective effects of GlcNAc-Sal against oxygen-glucose deprivation-reperfusion (OGD-R-induced neurotoxicity in vitro and global cerebral ischemia-reperfusion (GCI-R injury in vivo. Cell viability tests and Hoechst 33342 staining confirmed that GlcNAc-Sal pretreatment markedly attenuated OGD-R induced apoptotic cell death in immortalized mouse hippocampal HT22 cells. Western blot, immunofluorescence and PCR analyses revealed that GlcNAc-Sal pretreatment restored the balance of pro- and anti-apoptotic proteins and inhibited the activation of caspase-3 and PARP induced by OGD-R treatment. Further analyses showed that GlcNAc-Sal pretreatment antagonized reactive oxygen species (ROS generation, iNOS-derived NO production and NO-related apoptotic cell death during OGD-R stimulation. GCI-R was induced by bilateral common carotid artery occlusion (BCCAO and reperfusion in mice in vivo. Western blot analysis showed that GlcNAc-Sal pretreatment decreased the expression of caspase-3 and increased the expression of Bcl-2 (B-cell lymphoma 2/Bax (Bcl-2-associated X protein induced by GCI-R treatment. Our findings suggest that GlcNAc-Sal pretreatment prevents brain ischemia reperfusion injury by the direct or indirect suppression of cell apoptosis and GlcNAc-Sal could be developed as a broad-spectrum agent for the prevention and/or treatment of cerebral ischemic injury.

  15. High-intensity training reduces intermittent hypoxia-induced ER stress and myocardial infarct size.

    Science.gov (United States)

    Bourdier, Guillaume; Flore, Patrice; Sanchez, Hervé; Pepin, Jean-Louis; Belaidi, Elise; Arnaud, Claire

    2016-01-15

    Chronic intermittent hypoxia (IH) is described as the major detrimental factor leading to cardiovascular morbimortality in obstructive sleep apnea (OSA) patients. OSA patients exhibit increased infarct size after a myocardial event, and previous animal studies have shown that chronic IH could be the main mechanism. Endoplasmic reticulum (ER) stress plays a major role in the pathophysiology of cardiovascular disease. High-intensity training (HIT) exerts beneficial effects on the cardiovascular system. Thus, we hypothesized that HIT could prevent IH-induced ER stress and the increase in infarct size. Male Wistar rats were exposed to 21 days of IH (21-5% fraction of inspired O2, 60-s cycle, 8 h/day) or normoxia. After 1 wk of IH alone, rats were submitted daily to both IH and HIT (2 × 24 min, 15-30m/min). Rat hearts were either rapidly frozen to evaluate ER stress by Western blot analysis or submitted to an ischemia-reperfusion protocol ex vivo (30 min of global ischemia/120 min of reperfusion). IH induced cardiac proapoptotic ER stress, characterized by increased expression of glucose-regulated protein kinase 78, phosphorylated protein kinase-like ER kinase, activating transcription factor 4, and C/EBP homologous protein. IH-induced myocardial apoptosis was confirmed by increased expression of cleaved caspase-3. These IH-associated proapoptotic alterations were associated with a significant increase in infarct size (35.4 ± 3.2% vs. 22.7 ± 1.7% of ventricles in IH + sedenary and normoxia + sedentary groups, respectively, P < 0.05). HIT prevented both the IH-induced proapoptotic ER stress and increased myocardial infarct size (28.8 ± 3.9% and 21.0 ± 5.1% in IH + HIT and normoxia + HIT groups, respectively, P = 0.28). In conclusion, these findings suggest that HIT could represent a preventive strategy to limit IH-induced myocardial ischemia-reperfusion damages in OSA patients. Copyright © 2016 the American Physiological Society.

  16. Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on ischemia and reperfusion-induced myocardial infarction in rats and dogs.

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    Oh, Kwang-Seok; Seo, Ho Won; Yi, Kyu Yang; Lee, Sunkyung; Yoo, Sung-eun; Lee, Byung Ho

    2007-06-01

    The present study was performed to evaluate the cardioprotective effects of KR-33028, a novel Na+/H+ exchanger subtype 1 (NHE-1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, KR-33028 at 5 min before occlusion (i.v. bolus) dose-dependently reduced myocardial infarct size from 58.0% to 46.6%, 40.3%, 39.7%, 33.1%, and 27.8% for 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg respectively (P KR-33028 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 45.6% in vehicle-treated group to 16.4% (P KR-33028 (1 mg/kg, i.v. bolus) given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (46.3% and 44.1% respectively) compared with vehicle-treated group. In all studies, KR-33028 caused no significant changes in any hemodynamic profiles. In an isolated rat heart model of hypothermic cardioplegia, KR-33028 (30 mum), which was added to the heart preservation solution (histidin-tryptophan-ketoglutarate) during hypothermic cardioplegic arrest, significantly improved the recovery of left ventricular developed pressure, heart rate and dP/dt(max) after reperfusion. Taken together, these results indicate that KR-33028 significantly reduced the myocardial infarction induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles.

  17. The role of curcumin as an inhibitor of oxidative stress caused by ischaemia re-perfusion injury in tetralogy of Fallot patients undergoing corrective surgery.

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    Sukardi, Rubiana; Sastroasmoro, Sudigdo; Siregar, Nurjati C; Djer, Mulyadi M; Suyatna, Fransciscus D; Sadikin, Mohammad; Ibrahim, Nurhadi; Rahayuningsih, Sri E; Witarto, Arief B

    2016-03-01

    Cardiopulmonary bypass during tetralogy of Fallot corrective surgery is associated with oxidative stress, and contributes to peri-operative problems. Curcumin has been known as a potent scavenger of reactive oxygen species, which enhances the activity of antioxidants and suppresses phosphorylation of transcription factors involved in inflamation and apoptosis. To evaluate the effects of curcumin as an antioxidant by evaluating the concentrations of malondialdehyde and glutathione, activity of nuclear factor-kappa B, c-Jun N-terminal kinase, caspase-3, and post-operative clinical outcomes. Tetralogy of Fallot patients for corrective surgery were randomised to receive curcumin (45 mg/day) or placebo orally for 14 days before surgery. Malondialdehyde and glutathione concentrations were evaluated during the pre-ischaemia, ischaemia, re-perfusion phases, and 6 hours after aortic clamping-off. Nuclear factor-kappa B, c-Jun N-terminal kinase, and caspase-3, taken from the infundibulum, were assessed during the pre-ischaemia, ischaemia, and re-perfusion phases. Haemodynamic parameters were monitored until day 5 after surgery. In all the observation phases, malondialdehyde and glutathione concentrations were similar between groups. There was no significant difference in nuclear factor-kappa B activity between the groups for three observations; however, in the curcumin group, c-Jun N-terminal kinase significantly decreased from the pre-ischaemia to the re-perfusion phases, and caspase-3 expression was lower in the ischaemia phase. Patients in the curcumin group had lower temperature and better ventricular functions, but no significant differences were found in mechanical ventilation day or length of hospital stay in the two groups. Cardioprotective effects of curcumin may include inhibition of the c-Jun N-terminal kinase pathway and caspase-3 in cardiomyocytes, particularly in the ischaemia phase.

  18. Dexmedetomidine Attenuates Blood-Spinal Cord Barrier Disruption Induced by Spinal Cord Ischemia Reperfusion Injury in Rats

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    Bo Fang

    2015-05-01

    Full Text Available Background/Aims: Dexmedetomidine has beneficial effects on ischemia reperfusion (I/R injury to the spinal cord, but the underlying mechanisms are not fully understood. This study investigated the effects and possible mechanisms of dexmedetomidine on blood-spinal cord barrier (BSCB disruption induced by spinal cord I/R injury. Methods: Rats were intrathecally pretreated with dexmedetomidine or PBS control 30 minutes before undergoing 14-minute occlusion of aortic arch. Hind-limb motor function was assessed using Tarlov criteria, and motor neurons in the ventral gray matter were counted by histological examination. The permeability of the BSCB was examined using Evans blue (EB as a vascular tracer. The spinal cord edema was evaluated using the wet-dry method. The expression and localization of matrix metalloproteinase-9 (MMP-9, Angiopoietin-1 (Ang1 and Tie2 were assessed by western blot, real-time polymerase chain reaction, and immunofluorescence. Results: Intrathecal preconditioning with dexmedetomidine minimized the neuromotor dysfunction and histopathological deficits, and attenuated EB extravasation after spinal cord I/R injury. In addition, dexmedetomidine preconditioning suppressed I/R-induced increase in MMP-9. Finally, Dexmedetomidine preconditioning enhanced the Ang1-Tie2 system activity after spinal cord I/R injury. Conclusions: Dexmedetomidine preconditioning stabilized the BSCB integrity against spinal cord I/R injury by inhibition of MMP-9, and enhancing the Ang1-Tie2 system.

  19. Neuroprotective Effects of Inhibiting Fyn S-Nitrosylation on Cerebral Ischemia/Reperfusion-Induced Damage to CA1 Hippocampal Neurons.

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    Hao, Lingyun; Wei, Xuewen; Guo, Peng; Zhang, Guangyi; Qi, Suhua

    2016-07-12

    Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the effects of Fyn S-nitrosylation on brain damage. In vitro, Fyn could be S-nitrosylated by S-nitrosoglutathione (GSNO, an exogenous NO donor), and in vivo, endogenous NO synthesized by NO synthases (NOS) could enhance Fyn S-nitrosylation. Application of GSNO, 7-nitroindazole (7-NI, an inhibitor of neuronal NOS) and hydrogen maleate (MK-801, the N-methyl-d-aspartate receptor (NMDAR) antagonist) could decrease the S-nitrosylation and phosphorylation of Fyn induced by cerebral ischemia/reperfusion (I/R). Cresyl violet staining validated that these compounds exerted neuroprotective effects against the cerebral I/R-induced damage to hippocampal CA1 neurons. Taken together, in this study, we demonstrated that Fyn can be S-nitrosylated both in vitro and in vivo and that inhibiting S-nitrosylation can exert neuroprotective effects against cerebral I/R injury, potentially via NMDAR-mediated mechanisms. These findings may lead to a new field of inquiry to investigate the underlying pathogenesis of stroke and the development of novel treatment strategies.

  20. 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.

  1. 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.

  2. 上肢骨骼肌缺血再灌注对血小板聚集活性和血钠水平的影响%Impact of transient upper limb skeletal muscle ischemia and reperfusion on platelet reactivity and stress induced sodium retention in healthy subjects

    Institute of Scientific and Technical Information of China (English)

    宋冬林; 刘军翔; 刘新林

    2011-01-01

    Objective To determine whether or not skeletal muscle I/R procedure has clinically relevant impact on platelet aggregability, and to investigate its relationship to individuals ability of sodium retention under stress challenge, we serially measured platelet aggregation and related plasma biochemical changes before and after skeletal muscle I/R protocol in healthy subjects.Methods We enrolled 24 healthy subjects to receive a RIPC protocol consisting of a three 5 min cycles of unilateral upper arm I/R by blood pressure cuff to 200 mm Hg, and harvested the whole blood samples at baseline, 1 h after, and 24 h after I/R stress.Platelet aggregation was performed using a light transmission aggregometer in stirred platelet rich plasma.Results In general ,this limb I/R procedure did not result in significant change in platelet aggregation and blood biochemistry, except for a transient decrease of plasma glucose level 1 h after I/R stress(P <0.05).To further explore potential link between individuals responsiveness to stress-induced sodium retention and platelet reactivity, we dichotomized all subjects into sodium-retention responders [those with positive A plasma sodium level after ischemia, defined as plasma sodium (1 h after I/R) minus plasma sodium ( before I/R)]and non responders (the rest of subjects ).By this category, one third ( 8/24) of subjects were responders to I/R stress-induced sodium retention.Compared with non-responders, the responders had significantly increased platelet aggregation [(12.88±8.47)% vs (5.44±3.07)%, P < 0.05 )].Moreover, plasma sodium was positively correlated with platelet aggregation ( r = 0.488, P < 0.05 ).Conclusions In a subset of population characterized by increased plasma sodium retention after transient limb skeletal muscle I/R challenge, there is a transient increase of platelet aggregability.%目的 探讨骨骼肌缺血再灌注是否会影响血小板聚集率,以及血小板聚集与应激时血钠

  3. STRESS INDUCED OBESITY: LESSONS FROM RODENT MODELS OF STRESS

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    Zachary Robert Patterson

    2013-07-01

    Full Text Available Stress is defined as the behavioral and physiological responses generated in the face of, or in anticipation of, a perceived threat. The stress response involves activation of the sympathetic nervous system and recruitment of the hypothalamic-pituitary-adrenal (HPA axis. When an organism encounters a stressor (social, physical, etc., these endogenous stress systems are stimulated in order to generate a fight-or-flight response, and manage the stressful situation. As such, an organism is forced to liberate energy resources in attempt to meet the energetic demands posed by the stressor. A change in the energy homeostatic balance is thus required to exploit an appropriate resource and deliver useable energy to the target muscles and tissues involved in the stress response. Acutely, this change in energy homeostasis and the liberation of energy is considered advantageous, as it is required for the survival of the organism. However, when an organism is subjected to a prolonged stressor, as is the case during chronic stress, a continuous irregularity in energy homeostasis is considered detrimental and may lead to the development of metabolic disturbances such as cardiovascular disease, type II diabetes mellitus and obesity. This concept has been studied extensively using animal models, and the neurobiological underpinnings of stress induced metabolic disorders are beginning to surface. However, different animal models of stress continue to produce divergent metabolic phenotypes wherein some animals become anorexic and loose body mass while others increase food intake and body mass and become vulnerable to the development of metabolic disturbances. It remains unclear exactly what factors associated with stress models can be used to predict the metabolic outcome of the organism. This review will explore a variety of rodent stress models and discuss the elements that influence the metabolic outcome in order to further our understanding of stress-induced

  4. Ischemia and reperfusion induce differential expression of calpastatin and its homologue high molecular weight calmodulin-binding protein in murine cardiomyocytes.

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    Sreejit Parameswaran

    Full Text Available In the heart, calpastatin (Calp and its homologue high molecular weight calmodulin-binding protein (HMWCaMBP regulate calpains (Calpn by inhibition. A rise in intracellular myocardial Ca2+ during cardiac ischemia activates Calpn thereby causing damage to myocardial proteins, which leads to myocyte death and consequently to loss of myocardial structure and function. The present study aims to elucidate expression of Calp and HMWCaMBP with respect to Calpn during induced ischemia and reperfusion in primary murine cardiomyocyte cultures. Ischemia and subsequently reperfusion was induced in ∼ 80% confluent cultures of neonatal murine cardiomyocytes (NMCC. Flow cytometric analysis (FACS has been used for analyzing protein expression concurrently with viability. Confocal fluorescent microscopy was used to observe protein localization. We observed that ischemia induces increased expression of Calp, HMWCaMBP and Calpn. Calpn expressing NMCC on co-expressing Calp survived ischemic induction compared to NMCC co-expressing HMWCaMBP. Similarly, living cells expressed Calp in contrast to dead cells which expressed HMWCaMBP following reperfusion. A significant difference in the expression of Calp and its homologue HMWCaMBP was observed in localization studies during ischemia. The current study adds to the existing knowledge that HMWCaMBP could be a putative isoform of Calp. NMCC on co-expressing Calp and Calpn-1 survived ischemic and reperfusion inductions compared to NMCC co-expressing HMWCaMBP and Calpn-1. A significant difference in expression of Calp and HMWCaMBP was observed in localization studies during ischemia.

  5. Drug-Induced Oxidative Stress and Toxicity

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    Damian G. Deavall

    2012-01-01

    Full Text Available Reactive oxygen species (ROS are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

  6. Reperfusion injury and reactive oxygen species: The evolution of a concept☆

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    Granger, D. Neil; Kvietys, Peter R.

    2015-01-01

    Reperfusion injury, the paradoxical tissue response that is manifested by blood flow-deprived and oxygen-starved organs following the restoration of blood flow and tissue oxygenation, has been a focus of basic and clinical research for over 4-decades. While a variety of molecular mechanisms have been proposed to explain this phenomenon, excess production of reactive oxygen species (ROS) continues to receive much attention as a critical factor in the genesis of reperfusion injury. As a consequence, considerable effort has been devoted to identifying the dominant cellular and enzymatic sources of excess ROS production following ischemia-reperfusion (I/R). Of the potential ROS sources described to date, xanthine oxidase, NADPH oxidase (Nox), mitochondria, and uncoupled nitric oxide synthase have gained a status as the most likely contributors to reperfusion-induced oxidative stress and represent priority targets for therapeutic intervention against reperfusion-induced organ dysfunction and tissue damage. Although all four enzymatic sources are present in most tissues and are likely to play some role in reperfusion injury, priority and emphasis has been given to specific ROS sources that are enriched in certain tissues, such as xanthine oxidase in the gastrointestinal tract and mitochondria in the metabolically active heart and brain. The possibility that multiple ROS sources contribute to reperfusion injury in most tissues is supported by evidence demonstrating that redox-signaling enables ROS produced by one enzymatic source (e.g., Nox) to activate and enhance ROS production by a second source (e.g., mitochondria). This review provides a synopsis of the evidence implicating ROS in reperfusion injury, the clinical implications of this phenomenon, and summarizes current understanding of the four most frequently invoked enzymatic sources of ROS production in post-ischemic tissue. PMID:26484802

  7. 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.

  8. Role of Opioid Receptors Signaling in Remote Electrostimulation--Induced Protection against Ischemia/Reperfusion Injury in Rat Hearts.

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    Hsin-Ju Tsai

    Full Text Available Our previous studies demonstrated that remote electro-stimulation (RES increased myocardial GSK3 phosphorylation and attenuated ischemia/ reperfusion (I/R injury in rat hearts. However, the role of various opioid receptors (OR subtypes in preconditioned RES-induced myocardial protection remains unknown. We investigated the role of OR subtype signaling in RES-induced cardioprotection against I/R injury of the rat heart.Male Spraque-Dawley rats were used. RES was performed on median nerves area with/without pretreatment with various receptors antagonists such as opioid receptor (OR subtype receptors (KOR, DOR, and MOR. The expressions of Akt, GSK3, and PKCε expression were analyzed by Western blotting. When RES was preconditioned before the I/R model, the rat's hemodynamic index, infarction size, mortality and serum CK-MB were evaluated. Our results showed that Akt, GSK3 and PKCε expression levels were significantly increased in the RES group compared to the sham group, which were blocked by pretreatment with specific antagonists targeting KOR and DOR, but not MOR subtype. Using the I/R model, the duration of arrhythmia and infarct size were both significantly attenuated in RES group. The mortality rates of the sham RES group, the RES group, RES group + KOR antagonist, RES group + DOR/MOR antagonists (KOR left, RES group + DOR antagonist, and RES group + KOR/MOR antagonists (DOR left were 50%, 20%, 67%, 13%, 50% and 55%, respectively.The mechanism of RES-induced myocardial protection against I/R injury seems to involve multiple target pathways such as Akt, KOR and/or DOR signaling.

  9. Electroacupuncture preconditioning and postconditioning inhibit apoptosis and neuroinflammation induced by spinal cord ischemia reperfusion injury through enhancing autophagy in rats.

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    Fang, Bo; Qin, Meiman; Li, Yun; Li, Xiaoqian; Tan, Wenfei; Zhang, Ying; Ma, Hong

    2017-03-06

    Electroacupuncture (EA) has beneficial effects on spinal cord ischemia reperfusion (I/R) injury, but the underlying mechanisms are not fully understood. This study aimed to investigate the role of autophagy in the protection of EA preconditioning and postconditioning against spinal cord I/R injury. For this, spinal cord I/R injury was induced by 14min occlusion of the aortic arch, and rats were treated with EA for 20min before or after the surgery. The expression of autophagy components, light chain 3 and Beclin 1, was assessed by Western blot. The hind-limb motor function was assessed using the Basso-Beattie-Bresnahan (BBB) criteria, and motor neurons in the ventral gray matter were counted by histological examination. The apoptosis of neurocyte was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and matrix metalloproteinase-9 (MMP-9) was also measured using Western blot or enzyme-linked immunosorbent assay (ELISA). Either EA preconditioning or postconditioning enhanced autophagy, and minimized the neuromotor dysfunction and histopathological deficits after spinal cord I/R injury. In addition, EA suppressed I/R-induced apoptosis and increased in the expression of TNF-α, IL-1β, and MMP-9. In contrast, the autophagic inhibitor (3-methyladenine, 3-MA) inhibited the neuroprotective effects of EA. Moreover, 3-MA increased the apoptosis and the expression of TNF-α, IL-1β, and MMP-9. In summary, these findings suggested that EA preconditioning and postconditioning could alleviate spinal cord I/R injury, which was partly mediated by autophagy upregulation-induced inhibition of apoptosis and neuroinflammation.

  10. Stimulation of the sphenopalatine ganglion induces reperfusion and blood-brain barrier protection in the photothrombotic stroke model.

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    Haviv Levi

    Full Text Available PURPOSE: The treatment of stroke remains a challenge. Animal studies showing that electrical stimulation of the sphenopalatine ganglion (SPG exerts beneficial effects in the treatment of stroke have led to the initiation of clinical studies. However, the detailed effects of SPG stimulation on the injured brain are not known. METHODS: The effect of acute SPG stimulation was studied by direct vascular imaging, fluorescent angiography and laser Doppler flowmetry in the sensory motor cortex of the anaesthetized rat. Focal cerebral ischemia was induced by the rose bengal (RB photothrombosis method. In chronic experiments, SPG stimulation, starting 15 min or 24 h after photothrombosis, was given for 3 h per day on four consecutive days. Structural damage was assessed using histological and immunohistochemical methods. Cortical functions were assessed by quantitative analysis of epidural electro-corticographic (ECoG activity continuously recorded in behaving animals. RESULTS: Stimulation induced intensity- and duration-dependent vasodilation and increased cerebral blood flow in both healthy and photothrombotic brains. In SPG-stimulated rats both blood brain-barrier (BBB opening, pathological brain activity and lesion volume were attenuated compared to untreated stroke animals, with no apparent difference in the glial response surrounding the necrotic lesion. CONCLUSION: SPG-stimulation in rats induces vasodilation of cortical arterioles, partial reperfusion of the ischemic lesion, and normalization of brain functions with reduced BBB dysfunction and stroke volume. These findings support the potential therapeutic effect of SPG stimulation in focal cerebral ischemia even when applied 24 h after stroke onset and thus may extend the therapeutic window of currently administered stroke medications.

  11. Amelioration of ischemia/reperfusion-induced myocardial infarction by the 2-alkynyladenosine derivative 2-octynyladenosine (YT-146).

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    Sasamori, Jun; Aihara, Kazuyuki; Yoneyama, Fumiya; Sato, Isamu; Kogi, Kentaro; Takeo, Satoshi

    2006-04-01

    The present study was aimed at determining whether the novel adenosine A2-agonist YT-146 may have cardioprotective effects against ischemia-reperfusion injury. Anesthetized open-chest dogs underwent 90-min occlusion of the left anterior descending artery and subsequent 300-min reperfusion. The animals were randomly assigned to receive vehicle, 3, or 10 microg/kg YT-146 or ischemic preconditioning (4 episodes of 5 min occlusion followed by 5 min of reperfusion). Blood pressure, heart rate, and regional myocardial blood flow throughout the experiment were measured, as was the myocardial infarct size after reperfusion. The infarct size of the vehicle-treated dog was 56.2% +/- 2.7% (n = 5), whereas that of 3 or 10 microg/kg YT-146-treated dog was smaller (ie, 29.5% +/- 8.7% or 20.2% +/- 7.0%, respectively; n = 5). The infarct size of the dog treated with 10 microg/kg YT-146 was reduced to a degree similar to that of the ischemic preconditioning (19.2% +/- 6.3%, n = 5). YT-146 at both doses elicited a dose-dependent increase in acute hyperemic coronary flow immediately after reperfusion. The cardioprotective effect may be attributed to the limitation of the infarct size, probably via A2-receptor-mediated coronary artery dilatation during the early period of reperfusion.

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

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    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.

  13. Anti-arrhythmic effect of diosgenin in reperfusion-induced myocardial injury in a rat model: activation of nitric oxide system and mitochondrial KATP channel.

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    Badalzadeh, Reza; Yousefi, Bahman; Majidinia, Maryam; Ebrahimi, Hadi

    2014-11-01

    This study was designed to investigate the anti-arrhythmic effect of diosgenin preconditioning in myocardial reperfusion injury in rat, focusing on the involvement of the nitric oxide (NO) system and mitochondrial ATP-dependent potassium (mitoKATP) channels in this scenario. After isolation of the hearts of male Wister rats, the study was conducted in an isolated buffer-perfused heart model. Global ischemia (for 30 min) was induced by interruption of the aortic supply, which was followed by 90-min reperfusion. Throughout the experiment, the electrocardiograms of hearts were monitored using three golden surface electrodes connected to a data acquisition system. Arrhythmias were assessed based on the Lambeth convention and were categorized as number, duration and incidence of ventricular tachycardia (VT), ventricular fibrillation (VF), and premature ventricular complexes (PVC), and arrhythmic score. Additionally, lactate dehydrogenase (LDH) levels in coronary effluent were estimated colorimetrically. Diosgenin pre-administration for 20 min before ischemia reduced the LDH release into the coronary effluent, as compared with control hearts (P PVC, VT and VF, a reduced duration and incidence of VT and VF, and less severe arrhythmia at reperfusion phase, in comparison with controls. Blocking the mitoKATP channels using 5-hydroxydecanoate as well as inhibiting the NO system through prior administration of L-NAME significantly reduced the positive effects of diosgenin. Our finding showed that pre-administration of diosgenin could provide cardioprotection through anti-arrhythmic effects against ischemia-reperfusion (I/R) injury in isolated rat hearts. In addition, mitoKATP channels and NO system may be the key players in diosgenin-induced cardioprotective mechanisms.

  14. Effect of transplantation of BMP-2-induced bone marrow mesenchymal stem cells on myocardial infarction of rats after reperfusion

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    Zhong-cheng MIAO

    2014-10-01

    Full Text Available Objective To observe whether the bone morphogenetic protein-2 (BMP-2 could induce bone marrow mesenchymal stem cells (BMSCs to differentiate into cardiomyocyte-like cells, and investigate its effect on cardiac function in rats. Methods IBMSCs were isolated, cultured, amplified and identified in vitro. The expression of specific cardiac proteins was identified after pre-induction of BMP-2, and BMSCs were marked in vitro by DAPI. In order to reproduce the reperfusion after acute myocardial infarction (AMI model, the left anterior descending (LAD coronary artery was interrupted for 100min and then freed in SD rat. The rats with successful manipulation were randomly assigned into 3 groups, i.e. control group: the culture medium was injected with micro syringe at 4 points around infarcted zone; stem cell group: non-induced BMSCs were injected with the same amount and at the same sites as in control group; and pre-induction group: induced BMSCs were injected with the same amount and at the same sites as in control group. The surviving state of transplanted cells in myocardial tissue was observed with fluorescence microscopy at 4 hours, 4 days and 4 weeks postoperatively. Cardiac function was evaluated by employing color Doppler echocardiography, and the morphology of rat myocardial tissue was observed at 4 weeks after operation by HE and Masson staining, and the therapeutic effect was compared among 3 groups. Results After the BMP-2 pre-induction, changes in morphology were found in a part of BMSCs, and the specific cardiomyocyte protein connexin 43 (Cx43 and cardiac troponin T (cTnT were expressed. Fluorescence microscopy revealed that DAPI-labeled BMSCs survived in myocardial infarction in pre-induction group and stem cell group 4 hours, 4 days and 4 weeks postoperatively. Compared with the control group, the left ventricular ejection fraction (LVEF and left ventricular fractional shortening (FS significantly increased in stem cell group and

  15. Aldehyde dehydrogenase 2 overexpression inhibits neuronal apoptosis after spinal cord ischemia/reperfusion injury

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    Xing-zhen Liu

    2017-01-01

    Full Text Available Aldehyde dehydrogenase 2 (ALDH2 is an important factor in inhibiting oxidative stress and has been shown to protect against renal ischemia/reperfusion injury. Therefore, we hypothesized that ALDH2 could reduce spinal cord ischemia/reperfusion injury. Spinal cord ischemia/reperfusion injury was induced in rats using the modified Zivin's method of clamping the abdominal aorta. After successful model establishment, the agonist group was administered a daily consumption of 2.5% alcohol. At 7 days post-surgery, the Basso, Beattie, and Bresnahan score significantly increased in the agonist group compared with the spinal cord ischemia/reperfusion injury group. ALDH2 expression also significantly increased and the number of apoptotic cells significantly decreased in the agonist group than in the spinal cord ischemia/reperfusion injury group. Correlation analysis revealed that ALDH2 expression negatively correlated with the percentage of TUNEL-positive cells (r = −0.485, P < 0.01. In summary, increased ALDH2 expression protected the rat spinal cord against ischemia/reperfusion injury by inhibiting apoptosis.

  16. Acute heat stress induces oxidative stress in broiler chickens.

    Science.gov (United States)

    Lin, Hai; Decuypere, Eddy; Buyse, Johan

    2006-05-01

    The stress responses and possible oxidative damage in plasma, liver and heart were investigated in broiler chickens acutely exposed to high temperature. Eighty 5-week old broiler chickens were exposed to 32 degrees C for 6h. The extent of lipid peroxidation, activities of superoxide dismutase and total antioxidant power in plasma, liver and heart tissues were investigated. Meanwhile, the blood metabolites such as glucose, urate, triiodothyronine, thyroxine, corticosterone, ceruloplasmin and creatine kinase were measured before and after 3 and 6h of heat exposure. The results showed that oxidative stress could be induced in 5-week old broiler chickens by acute heat exposure (32 degrees C, 6h). The results suggest that the elevated body temperature can induce the metabolic changes that are involved in the induction of oxidative stress. The liver is more susceptible to oxidative stress than heart during acute heat exposure in broiler chickens. The oxidative stress should be considered as part of the stress response of broiler chickens to heat exposure.

  17. Acetylcholine- and sodium hydrosulfide-induced endothelium-dependent relaxation and hyperpolarization in cerebral vessels of global cerebral ischemia-reperfusion rat.

    Science.gov (United States)

    Han, Jun; Chen, Zhi-Wu; He, Guo-Wei

    2013-01-01

    We investigated the effects of endothelium-derived hyperpolarizing factor (EDHF) and the role of hydrogen sulphide (H2S) in the cerebral vasorelaxation induced by acetylcholine (ACh) in global cerebral ischemia-reperfusion (CIR) rats. CIR was induced by occlusion of bilateral carotid and vertebral arteries. Isolated arterial segments from the cerebral basilar (CBA) and middle artery (MCA) of CIR rats were studied in a pressurized chamber. Transmembrane potential was recorded using glass microelectrodes to evaluate hyperpolarization. In the CIR CBAs and MCAs preconstricted by 30 mM KCl, ACh induced concentration-dependent vasorelaxation and hyperpolarization that were partially attenuated by NG-nitro-l-arginine methyl ester (l-NAME, 30 μM) and l-NAME plus indomethacin (10 μM). The residual responses were abolished by the H2S inhibitor dl-propargylglycine (PPG, 100 μM). The H2S donor NaHS and l-Cys, the substrate of endogenous H2S synthase, elicited similar responses to ACh and was inhibited by tetraethylamonine (1 mM) or PPG. ACh induces EDHF-mediated vasorelaxation and hyperpolarization in rat cerebral arteries. These responses are up-regulated by ischemia-reperfusion while NO-mediated responses are down-regulated. Further, the ACh-induced, EDHF-mediated relaxation, and hyperpolarization and the inhibition of these responses are similar to the H2S-induced responses, suggesting that H2S is a possible candidate for EDHF in rat cerebral vessels.

  18. 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.

  19. Berberine Attenuates Myocardial Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Inflammation Response: Role of Silent Information Regulator 1

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    Liming Yu

    2016-01-01

    Full Text Available Berberine (BBR exerts potential protective effect against myocardial ischemia/reperfusion (MI/R injury. Activation of silent information regulator 1 (SIRT1 signaling attenuates MI/R injury by reducing oxidative damage and inflammation response. This study investigated the antioxidative and anti-inflammatory effects of BBR treatment in MI/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with BBR in the absence or presence of the SIRT1 inhibitor sirtinol (Stnl and then subjected to MI/R injury. BBR conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, upregulating SIRT1, Bcl-2 expressions, and downregulating Bax and caspase-3 expressions. Stnl attenuated these effects by inhibiting SIRT1 signaling. BBR treatment also reduced myocardium superoxide generation, gp91phox expression, malondialdehyde (MDA level, and cardiac inflammatory markers and increased myocardium superoxide dismutase (SOD level. However, these effects were also inhibited by Stnl. Consistently, BBR conferred similar antioxidative and anti-inflammatory effects against simulated ischemia reperfusion injury in cultured H9C2 cardiomyocytes. SIRT1 siRNA administration also abolished these effects. In summary, our results demonstrate that BBR significantly improves post-MI/R cardiac function recovery and reduces infarct size against MI/R injury possibly due to its strong antioxidative and anti-inflammatory activity. Additionally, SIRT1 signaling plays a key role in this process.

  20. The effect of lidocaine on in vitro neutrophil and endothelial adhesion molecule expression induced by plasma obtained during tourniquet-induced ischaemia and reperfusion.

    LENUS (Irish Health Repository)

    Lan, W

    2012-02-03

    BACKGROUND: Changes in neutrophil and endothelial adhesion molecule expression occur during perioperative ischaemia and reperfusion (I\\/R) injury. We investigated the effects of lidocaine on neutrophil-independent changes in neutrophil and endothelial adhesion molecule expression associated with tourniquet-induced I\\/R. METHODS: Plasma was obtained from venous blood samples (tourniquet arm) taken before (baseline), during, 15 min, 2 and 24 h following tourniquet release in seven patients undergoing elective upper limb surgery with tourniquet application. Isolated neutrophils from healthy volunteers (n = 7) were pretreated in the presence or absence of lidocaine (0.005, 0.05 and 0.5 mg mL(-1) for 1 h, and then incubated with I\\/R plasma for 2 h. Human umbilical vein endothelial cells (HUVECs) were pretreated in the presence or absence of lidocaine (0.005, 0.05 and 0.5 mg mL(-1)) for 1 h, and then incubated with the plasma for 4 h. Adhesion molecule expression was estimated using flow cytometry. Data were analysed using ANOVA and post hoc Student-Newman-Keuls tests. RESULTS: I\\/R plasma (withdrawn 15 min following tourniquet release) increased isolated neutrophil CD11b (P = 0.03), CD18 (P = 0.01) and endothelial intercellular adhesion molecule-1 (ICAM-1) (P = 0.008) expression compared to baseline. CD11b, CD18 and ICAM-1 expression on lidocaine (0.005 mg mL(-1)) treated neutrophils was similar to control. CD11b (P < 0.001), CD18 (P = 0.03) and ICAM-1 (P = 0.002) expression on lidocaine (0.05 mg mL(-1)) treated neutrophils and HUVECs was less than that on controls. CONCLUSION: Increased in vitro neutrophil and endothelial cell adhesion molecule expression on exposure to plasma obtained during the early reperfusion phase is diminished by lidocaine at greater than clinically relevant plasma concentrations.

  1. Transient focal cerebral ischemia/reperfusion induces early and chronic axonal changes in rats: its importance for the risk of Alzheimer's disease.

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    Qinan Zhang

    Full Text Available The dementia of Alzheimer's type and brain ischemia are known to increase at comparable rates with age. Recent advances suggest that cerebral ischemia may contribute to the pathogenesis of Alzheimer's disease (AD, however, the neuropathological relationship between these two disorders is largely unclear. It has been demonstrated that axonopathy, mainly manifesting as impairment of axonal transport and swelling of the axon and varicosity, is a prominent feature in AD and may play an important role in the neuropathological mechanisms in AD. In this study, we investigated the early and chronic changes of the axons of neurons in the different brain areas (cortex, hippocampus and striatum using in vivo tracing technique and grading analysis method in a rat model of transient focal cerebral ischemia/reperfusion (middle cerebral artery occlusion, MCAO. In addition, the relationship between the changes of axons and the expression of β-amyloid 42 (Aβ42 and hyperphosphorylated Tau, which have been considered as the key neuropathological processes of AD, was analyzed by combining tracing technique with immunohistochemistry or western blotting. Subsequently, we found that transient cerebral ischemia/reperfusion produced obvious swelling of the axons and varicosities, from 6 hours after transient cerebral ischemia/reperfusion even up to 4 weeks. We could not observe Aβ plaques or overexpression of Aβ42 in the ischemic brain areas, however, the site-specific hyperphosphorylated Tau could be detected in the ischemic cortex. These results suggest that transient cerebral ischemia/reperfusion induce early and chronic axonal changes, which may be an important mechanism affecting the clinical outcome and possibly contributing to the development of AD after stroke.

  2. Gravity-induced stresses in finite slopes

    Science.gov (United States)

    Savage, W.Z.

    1994-01-01

    An exact solution for gravity-induced stresses in finite elastic slopes is presented. This solution, which is applied for gravity-induced stresses in 15, 30, 45 and 90?? finite slopes, has application in pit-slope design, compares favorably with published finite element results for this problem and satisfies the conditions that shear and normal stresses vanish on the ground surface. The solution predicts that horizontal stresses are compressive along the top of the slopes (zero in the case of the 90?? slope) and tensile away from the bottom of the slopes, effects which are caused by downward movement and near-surface horizontal extension in front of the slope in response to gravity loading caused by the additional material associated with the finite slope. ?? 1994.

  3. Early recovery of microvascular perfusion induced by t-PA in combination with abciximab or eptifibatide during postischemic reperfusion

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    Giusti Andrea

    2002-06-01

    Full Text Available Abstract Background GPIIb/IIIa inhibitors abciximab and eptifibatide have been shown to inhibit platelet aggregation in ischemic heart disease. Our aim was to test the efficacy of abiciximab (Reo Pro or eptifibatide (Integrilin alone or in combination with plasminogen activator (t-PA in an experimental model of ischemia reperfusion (I/R in hamster cheek pouch microcirculation visualized by fluorescence microscopy. Hamsters were treated with saline, or abiciximab or eptifibatide or these drugs combined with t-PA infused intravenously 10 minutes before ischemia and through reperfusion. We measured the microvessel diameter changes, the arteriolar red blood cell (RBC velocity, the increase in permeability, the perfused capillary length (PCL, and the platelet and leukocyte adhesion on microvessels. Results I/R elicited large increases in the platelet and leukocyte adhesion and a decrease in microvascular perfusion. These responses were significantly attenuated by abiciximab or eptifibatide (PCL:70 and 65% at 5–10 mins of reperfusion and 85 and 87% at 30 mins of reperfusion, respectively, p Conclusions Platelets are crucial in I/R injury, as shown by the treatment with abicixmab or eptifibatide, which decreased platelet aggregation in microvessels, and also decreased leukocyte adhesion in venules. Arterial vasoconstriction, decreased arterial RBC velocity and alterations in the endothelial barrier with increased permeability delayed the complete restoration of blood flow, while t-PA combined with inhibition of platelet aggregation speeded up the capillary perfusion after reperfusion.

  4. 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.

  5. Diabetic Cardiovascular Disease Induced by Oxidative Stress

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    Yosuke Kayama

    2015-10-01

    Full Text Available Cardiovascular disease (CVD is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM. DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD, cardiac hypertrophy, and heart failure (HF. HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS. ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.

  6. Diabetic Cardiovascular Disease Induced by Oxidative Stress.

    Science.gov (United States)

    Kayama, Yosuke; Raaz, Uwe; Jagger, Ann; Adam, Matti; Schellinger, Isabel N; Sakamoto, Masaya; Suzuki, Hirofumi; Toyama, Kensuke; Spin, Joshua M; Tsao, Philip S

    2015-10-23

    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.

  7. Bilateral ovarian ischemia/reperfusion injury and treatment options in rats with an induced model of diabetes

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    Omer Erkan Yapca

    2014-04-01

    Full Text Available Objective(s:This study investigated the effects of melatonin, famotidine, mirtazapine, and thiamine pyrophosphate on ischemia/reperfusion (I/R injury in diabetic rats and evaluated oxidant and antioxidant marker measurement results. It also examined the effects of the drugs aimed at preventing infertility that may result from I/R injury. Materials and Methods: Diabetic rats were divided into a control group (IRC to be exposed to I/R, an ovarian I/R + 2.2 mg/kg melatonin (IRML group, an ovarian I/R + famotidine (IRFA group, an ovarian I/R + 20 mg/kg mirtazapine (IRMR group, an ovarian I/R + 20 mg/kg thiamine pyrophosphate (IRTP group, and a sham operation (SO group. Results: In the control group exposed to I/R, the levels of the oxidant parameters Malondialdehyde (MDA and Myeloperoxidase(MPO were significantly higher compared with the SO group, while the levels of the antioxidant parameters glutathione (GSH, Glutathioneperoxidase(GPO, Glutathione reductase (GSHRd, Glutathione S - transferase (GST, and[y1]   Superoxide dismutase (SOD were significantly lower. Melatonin, famotidine, mirtazapine, and thiamin pyrophosphate prevented a rise in oxidant parameters and a decrease in antioxidants in ovarian tissue exposed to I/R. However, apart from thiamin pyrophosphate, none of the drugs were able to prevent infertility caused by I/R injury.   Conclusion: Prevention of ovarian I/R injury-related infertility in rats with induced diabetes is not through antioxidant activity. Thiamine pyrophosphate prevents infertility through an as yet unknown mechanism. This study suggests that thiamine pyrophosphate may be useful in the prevention of I/R-related infertility in diabetics.

  8. Morphine Preconditioning-induced Endothelial Protection against in vitro Simulated Ischemia-reperfusion Injury

    Institute of Scientific and Technical Information of China (English)

    Long-yun PENG; Ai-zhen YAN; Xiu-ren GAO; Gui-fu WU; Wei-yi MAI; Hong MA; Zhi-yi ZUO

    2009-01-01

    Objectives To determine whether morphine induced a preconditioning effect in endothelial cells. Methods Human umbilical vein endothelial cells (HUVEC) were subjected to oxygen-glucose deprivation (OGD) to simulate ischemia in vitro. Cell viability was evaluated by the 3-(4, 5-dimethylthiazol -2-yl) -2, 5-diphenyltetrazolium bromide assay. Results OGD time-dependently decreased the HUVEC viability. Morphine pretreatment applied 5 min or 24 hr before a 20-hr OGD dose-dependently attenuated the OGD-reduced cell viability. The ECS0 for this effect was 1.84 and 0. 26μM, respectively, for morphine applied 5 min or 24 hr before the OGD. Conclusion morphine induces ischemic tol-erance in endothelial cells.

  9. [Stress-induced cellular adaptive mutagenesis].

    Science.gov (United States)

    Zhu, Linjiang; Li, Qi

    2014-04-01

    The adaptive mutations exist widely in the evolution of cells, such as antibiotic resistance mutations of pathogenic bacteria, adaptive evolution of industrial strains, and cancerization of human somatic cells. However, how these adaptive mutations are generated is still controversial. Based on the mutational analysis models under the nonlethal selection conditions, stress-induced cellular adaptive mutagenesis is proposed as a new evolutionary viewpoint. The hypothetic pathway of stress-induced mutagenesis involves several intracellular physiological responses, including DNA damages caused by accumulation of intracellular toxic chemicals, limitation of DNA MMR (mismatch repair) activity, upregulation of general stress response and activation of SOS response. These responses directly affect the accuracy of DNA replication from a high-fidelity manner to an error-prone one. The state changes of cell physiology significantly increase intracellular mutation rate and recombination activity. In addition, gene transcription under stress condition increases the instability of genome in response to DNA damage, resulting in transcription-associated DNA mutagenesis. In this review, we summarize these two molecular mechanisms of stress-induced mutagenesis and transcription-associated DNA mutagenesis to help better understand the mechanisms of adaptive mutagenesis.

  10. Reperfusion-induced myocardial dysfunction is prevented by endogenous annexin-A1 and its N-terminal-derived peptide Ac-ANX-A1(2-26).

    Science.gov (United States)

    Qin, Chengxue; Buxton, Keith D; Pepe, Salvatore; Cao, Anh H; Venardos, Kylie; Love, Jane E; Kaye, David M; Yang, Yuan H; Morand, Eric F; Ritchie, Rebecca H

    2013-01-01

    Annexin-A1 (ANX-A1) is an endogenous, glucocorticoid-regulated anti-inflammatory protein. The N-terminal-derived peptide Ac-ANX-A1(2-26) preserves cardiomyocyte viability, but the impact of ANX-A1-peptides on cardiac contractility is unknown. We now test the hypothesis that ANX-A1 preserves post-ischaemic recovery of left ventricular (LV) function. Ac-ANX-A1(2-26) was administered on reperfusion, to adult rat cardiomyocytes as well as hearts isolated from rats, wild-type mice and mice deficient in endogenous ANX-A1 (ANX-A1(-/-)). Myocardial viability and recovery of LV function were determined. Ischaemia-reperfusion markedly impaired both cardiomyocyte viability and recovery of LV function by 60%. Treatment with exogenous Ac-ANX-A1(2-26) at the onset of reperfusion prevented cardiomyocyte injury and significantly improved recovery of LV function, in both intact rat and wild-type mouse hearts. Ac-ANX-A1(2-26) cardioprotection was abolished by either formyl peptide receptor (FPR)-nonselective or FPR1-selective antagonists, Boc2 and cyclosporin H, but was relatively insensitive to the FPR2-selective antagonist QuinC7. ANX-A1-induced cardioprotection was associated with increased phosphorylation of the cell survival kinase Akt. ANX-A1(-/-) exaggerated impairment of post-ischaemic recovery of LV function, in addition to selective LV FPR1 down-regulation. These data represent the first evidence that ANX-A1 affects myocardial function. Our findings suggest ANX-A1 is an endogenous regulator of post-ischaemic recovery of LV function. Furthermore, the ANX-A1-derived peptide Ac-ANX-A1(2-26) on reperfusion rescues LV function, probably via activation of FPR1. ANX-A1-based therapies may thus represent a novel clinical approach for the prevention and treatment of myocardial reperfusion injury. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  11. Glycyrrhiza glabra protects from myocardial ischemia-reperfusion injury by improving hemodynamic, biochemical, histopathological and ventricular function.

    Science.gov (United States)

    Ojha, Shreesh; Golechha, Mahaveer; Kumari, Santosh; Bhatia, Jagriti; Arya, Dharamvir S

    2013-01-01

    Present study evaluated the cardioprotective effect of Glycyrrhiza glabra against ischemia-reperfusion injury (I-R) induced by ligation of left anterior descending coronary artery (LADCA) in rats. Ligation of LADCA for 45 min followed by 60 min of reperfusion has induced significant (pglabra significantly (pglabra also prevented GSH depletion and inhibited lipid peroxidation in heart. In addition to improving biochemical indices of myocardial function, G. glabra also significantly (pglabra. Taken together, results of the present study clearly suggest the cardioprotective potential of G. glabra against myocardial infarction by amelioration of oxidative stress and favorable modulation of cardiac function.

  12. Efficacy of angiotensin II type 1 receptor blockade on reperfusion-induced arrhythmias and mortality early after myocardial infarction is increased in transgenic rats with cardiac angiotensin II type 1 overexpression

    NARCIS (Netherlands)

    de Boer, RA; van Geel, PP; Pinto, YM; Suurmeijer, AJH; Crijns, HJGM; van Gilst, WH; van Veldhuisen, DJ

    2002-01-01

    Angiotensin II induces ischemia/reperfusion (I/R)-induced arrhythmias and blockade of the angiotensin II type I receptor (AT1R) may therefore be beneficial in preventing arrhythmias and decreasing mortality after myocardial infarction (MI). Because the AT1R is upregulated after myocardial ischemia,

  13. 5′-Adenosine Monophosphate-Induced Hypothermia Attenuates Brain Ischemia/Reperfusion Injury in a Rat Model by Inhibiting the Inflammatory Response

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    Yi-Feng Miao

    2015-01-01

    Full Text Available Hypothermia treatment is a promising therapeutic strategy for brain injury. We previously demonstrated that 5′-adenosine monophosphate (5′-AMP, a ribonucleic acid nucleotide, produces reversible deep hypothermia in rats when the ambient temperature is appropriately controlled. Thus, we hypothesized that 5′-AMP-induced hypothermia (AIH may attenuate brain ischemia/reperfusion injury. Transient cerebral ischemia was induced by using the middle cerebral artery occlusion (MCAO model in rats. Rats that underwent AIH treatment exhibited a significant reduction in neutrophil elastase infiltration into neuronal cells and matrix metalloproteinase 9 (MMP-9, interleukin-1 receptor (IL-1R, tumor necrosis factor receptor (TNFR, and Toll-like receptor (TLR protein expression in the infarcted area compared to euthermic controls. AIH treatment also decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL- positive neuronal cells. The overall infarct volume was significantly smaller in AIH-treated rats, and neurological function was improved. By contrast, rats with ischemic brain injury that were administered 5′-AMP without inducing hypothermia had ischemia/reperfusion injuries similar to those in euthermic controls. Thus, the neuroprotective effects of AIH were primarily related to hypothermia.

  14. Neutrophil elastase contributes to the development of ischemia/reperfusion-induced liver injury by decreasing the production of insulin-like growth factor-I in rats.

    Science.gov (United States)

    Kawai, Miho; Harada, Naoaki; Takeyama, Hiromitsu; Okajima, Kenji

    2010-06-01

    Neutrophil elastase (NE) decreases the endothelial production of prostacyclin (PGI(2)) through the inhibition of endothelial nitric oxide synthase (NOS) activation and thereby contributes to the development of ischemia/reperfusion (I/R)-induced liver injury. We previously demonstrated that calcitonin gene-related peptide (CGRP) released from sensory neurons increases the insulin-like growth factor- I (IGF-I) production and thereby reduces I/R-induced liver injury. Because PGI(2) is capable of stimulating sensory neurons, we hypothesized that NE contributes to the development of I/R-induced liver injury by decreasing IGF-I production. In the present study, we examined this hypothesis in rats subjected to hepatic I/R. Ischemia/reperfusion-induced decreases of hepatic tissue levels of CGRP and IGF-I were prevented significantly by NE inhibitors, sivelestat, and L-658, 758, and these effects of NE inhibitors were reversed completely by the nonselective cyclooxygenase inhibitor indomethacin (IM) and the nonselective NOS inhibitor L-NAME but not by the selective inducible NOS inhibitor 1400W. I/R-induced increases of hepatic tissue levels of caspase-3, myeloperoxidase and the number of apoptotic cells were inhibited by NE inhibitors, and these effects of NE inhibitors were reversed by IM and L-NAME but not by 1400W. Administration of iloprost, a stable PGI(2) analog, produced effects similar to those induced by NE inhibitors. Taken together, these observations strongly suggest that NE may play a critical role in the development of I/R-induced liver injury by decreasing the IGF-I production through the inhibition of sensory neuron stimulation, which may lead to an increase of neutrophil accumulation and hepatic apoptosis through activation of caspase-3 in rats.

  15. Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration.

    Science.gov (United States)

    Solskov, Lasse; Løfgren, Bo; Kristiansen, Steen B; Jessen, Niels; Pold, Rasmus; Nielsen, Torsten T; Bøtker, Hans Erik; Schmitz, Ole; Lund, Sten

    2008-07-01

    The UK Prospective Diabetes Study demonstrated that the hypoglycaemic drug metformin is associated with a reduction in cardiovascular events in a group of obese type 2 diabetes patients. The energy sensing enzyme AMP-activated protein kinase (AMPK) has been indicated to play an important protective role in the ischaemic heart and is activated by metformin. The aim of this study was to determine whether a single dose of metformin protects the myocardium against experimentally induced ischaemia 24 hr after the administration, and furthermore to determine whether a single dose of metformin results in an acute increase in myocardial AMPK activity. Wistar rats were given either a single oral dose of metformin (250 mg/kg body weight), or a single oral dose of saline. After 24 hr, the hearts were Langendorff-perfused and subjected to 45 min. of coronary artery occlusion. Infarct size was determined by staining with triphenyltetrazoliumchloride (TTC) and Evans Blue and expressed as a percentage of the risk zone (IS/AAR %). Isoform specific AMPK activity was measured 2 hr after administration of metformin or saline. Infarct size was significantly reduced in the metformin treated (I/R: 19.9 +/- 3.9%versus 36.7 +/- 3.6%, P < 0.01, n = 8-14) compared to the control group. A single oral dose of metformin resulted in an approximately ~2-fold increase in AMPK-alpha2 activity 2 hr after administration (P < 0.015, n = 10). In conclusion, a single dose of metformin results in an acute increase in myocardial AMPK activity measured 2 hr after administration and induces a significant reduction in myocardial infarct size 24 hr after metformin administration. Increased AMPK activity may be an important signal mediator involved in the mechanisms behind the cardioprotective effects afforded by metformin.

  16. The Effect of Dexmedetomidine on Oxidative Stress Response Following Cerebral Ischemia-Reperfusion in Rats and the Expression of Intracellular Adhesion Molecule-1 (ICAM-1) and S100B

    Science.gov (United States)

    Li, Yanwen; Liu, Shikun

    2017-01-01

    Background Ischemia-reperfusion injury of whole brain involves a complicated pathophysiology mechanism. Dexmedetomidine (Dex) has been shown to have neuro protective functions. This study observed the effect of Dex on serum S100B and cerebral intracellular adhesion molecule-1 (ICAM-1) in a rat model of cerebral ischemia-reperfusion. Material/Methods Healthy Sprague Dawley (SD) rats (males, 7 weeks old) were randomly divided into sham, model, and Dex groups (n=20 each). A cerebral ischemia-reperfusion model was prepared by clipping of the bilateral common carotid artery combined with hypotension. Dex (9 μg/kg) was infused intravenously immediately after reperfusion in the Dex group, while the other two groups received an equal volume of saline. Neural defect score (NDS) was measured at 6 hours, 24 hours, and 72 hours after surgery, with pathological observation of brain tissues. ELISA was then used to test serum S100B protein level. Malondialdehyde (MDA) and superoxide dismutase (SOD) were assayed by spectrometry. Nuclear factor-kappa B (NF-κB) and ICAM-1 levels were determined by real-time (RT)-PCR. Results Model rats had significant injury in the hippocampal CA1 region as shown by elevated NDS, S100B, and MDA levels, higher NF-κB and ICAM-1 mRNA expression, and lower SOD levels (poxidative stress and inflammatory response. PMID:28212354

  17. Mitochondria: mitochondrial participation in ischemia-reperfusion injury in skeletal muscle.

    Science.gov (United States)

    Lejay, Anne; Meyer, Alain; Schlagowski, Anna-Isabel; Charles, Anne-Laure; Singh, François; Bouitbir, Jamal; Pottecher, Julien; Chakfé, Nabil; Zoll, Joffrey; Geny, Bernard

    2014-05-01

    Irrespective of the organ involved, restoration of blood flow to ischemic tissue is vital, although reperfusion per se is deleterious. In the setting of vascular surgery, even subtle skeletal muscle ischemia contributes to remote organ injuries and perioperative and long-term morbidities. Reperfusion-induced injury is thought to participate in up to 40% of muscle damage. Recently, the pathophysiology of lower limb ischemia-reperfusion (IR) has been largely improved, acknowledging a key role for mitochondrial dysfunction mainly characterized by impaired mitochondrial oxidative capacity and premature mitochondrial permeability transition pore opening. Increased oxidative stress triggered by an imbalance between reactive oxygen species (ROS) production and clearance, and facilitated by enhanced inflammation, appears to be both followed and instigated by mitochondrial dysfunction. Mitochondria are both actors and target of IR and therapeutic strategies modulating degree of ROS production could enhance protective signals and allow for mitochondrial protection through a mitohormesis mechanism. Copyright © 2014. Published by Elsevier Ltd.

  18. Blood carbonyl protein measurement as a specific oxidative stress biomarker after intestinal reperfusion in rats Dosagem da proteína carbonilada sanguínea como biomarcador específico do estresse oxidativo após reperfusão intestinal em ratos

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    Márcio José Jamel

    2010-02-01

    Full Text Available PURPOSE: An experimental study was performed to investigate the use of protein carbonyl group as a specific biological marker for oxidative stress in a rat model of intestinal ischaemia-reperfusion. METHODS: Twenty four male Wistar rats were randomly distributed into three groups with eight animals each: Group 1 - Control group; Group 2 - Sham; Group 3 - Intestinal ischaemia by clamping ileal branches of the superior mesenteric artery for one hour, followed by another hour of reperfusion. Blood samples were taken in order to analyze the protein carbonyl level by Slot blotting assay. RESULTS: In group 3 a significant increase of protein carbonyl level was observed if compared to the homogenous levels of groups 1 and 2. CONCLUSION: From the results it may be concluded that the protein carbonylation may be used as a specific marker for measuring oxidative stress in rat intestinal reperfusion model.OBJETIVO: Realizou-se um estudo experimental com a finalidade de investigar o uso da proteína carbonilada como um marcador biológico específico do estresse oxidativo em um modelo de isquemia e reperfusão intestinal, em ratos. MÉTODOS: Vinte e quarto ratos da linhagem Wistar, machos foram distribuídos, aleatoriamente, em três grupos compostos por oito animais cada: Grupo 1 - Controle; Grupo 2 - Simulação e Grupo 3 - Submetido à isquemia, mediante clampeamento de ramos ileais da artéria mesentérica superior por uma hora, seguida de reperfusão, por igual período. Amostras sanguíneas obtidas foram utilizadas para analise dos níveis de proteína carbonilada, através do método Slot blotting. RESULTADOS: No grupo 3 houve uma elevação significante da concentração de proteína carbonilada sérica se comparada aos níveis sanguíneos homogêneos encontrados nos grupos 1 e 2. CONCLUSÃO: Fundamentado nos resultados é possível concluir que, a carbonilação protéica pode ser utilizada como um marcador específico para a mensuração do

  19. Protective role of fibrates in cardiac ischemia/reperfusion

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    G Singh

    2012-01-01

    Full Text Available Prevention of myocardial injury has been considered as the most important therapeutic challenge of today. Fibrates, the agonists of the peroxisome proliferator-activated receptor (PPAR-a receptor, have been regarded as potent therapeutic agents in this context. Hence, the present study has been designed to investigate the effect of fibrates, i.e., Clofibrate and Fenofibrate, the potent agonists PPAR-a, on ischemia-reperfusion (I/R-induced myocardial injury. The isolated Langendorff-perfused rat hearts were subjected to global ischemia for 30 minutes followed by reperfusion for 120 minutes. Myocardial infarct size and the release of lactate dehydrogenase (LDH and creatine kinase (CK in coronary effluent have been conducted to assess the degree of cardiac injury. Moreover, the oxidative stress in the heart was assessed by measuring lipid peroxidation, superoxide anion generation, and reduced glutathione. Clofibrate and Fenofibrate showed cardioprotection against I/R-induced myocardial injury in rat hearts as assessed in terms of reductions in myocardial infarct size, LDH, and CK levels in coronary effluent along with reduction in I/R-induced oxidative stress. It may be concluded that the observed cardioprotective potential of Clofibrate and Fenofibrate against I/R-induced myocardial injury was due to the reductions in infarct size and oxidative stress.

  20. [Preventive effects of troxipide on a newly developed model of acute gastric mucosal lesion (AGML) induced by ischemia/reperfusion plus ammonia in the rat].

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    Momo, K; Hoshina, K; Ishibashi, Y; Saito, T

    1994-10-01

    We have developed a unique rat AGML model produced by ischemia/reperfusion plus 0.2% ammonia (I/R.NH3), either treatment which would not induce mucosal injury when used alone. The effects of troxipide and other gastric mucosal defensive drugs were investigated with this I/R.NH3-induced AGML model and other AGML models in rats. The following results were obtained: 1) Like allopurinol, troxipide at 50-200 mg/kg, p.o. dose-dependently prevented I/R.NH3-induced development of AGML and also the ischemia/reperfusion-induced increase of gastric mucosal thiobarbituric acid (TBA)-reactive substances; 2) Troxipide at 10(-6)-10(-4) M, like allopurinol, inhibited concentration-dependently in vitro xanthine oxidase activity in gastric mucosal homogenates; 3) Troxipide at 50-200 mg/kg, p.o. inhibited AGMLs induced by bleeding plus 0.2% ammonia and by 1.0% ammonia alone; and 4) Troxipide and sofalcone were similar in preventing all AGMLs tested and also the increase of mucosal TBA-reactive substances, but somewhat differed from teprenone, cetraxate hydrochloride, azulene plus L-glutamine and sucralfate. These findings suggest that troxipide may inhibit I/R.NH3-induced AGML development by preventing generation of oxygen free radicals and by protecting against mucosal fragility due to reduced energy metabolism from poor blood flow and also against ammonia-induced disruption of the gastric mucosal barrier. Therefore, troxipide may be highly effective for various AGMLs with multifactor involvement.

  1. Cold stress induces lower urinary tract symptoms.

    Science.gov (United States)

    Imamura, Tetsuya; Ishizuka, Osamu; Nishizawa, Osamu

    2013-07-01

    Cold stress as a result of whole-body cooling at low environmental temperatures exacerbates lower urinary tract symptoms, such as urinary urgency, nocturia and residual urine. We established a model system using healthy conscious rats to explore the mechanisms of cold stress-induced detrusor overactivity. In this review, we summarize the basic findings shown by this model. Rats that were quickly transferred from room temperature (27 ± 2°C) to low temperature (4 ± 2°C) showed detrusor overactivity including increased basal pressure and decreased voiding interval, micturition volume, and bladder capacity. The cold stress-induced detrusor overactivity is mediated through a resiniferatoxin-sensitve C-fiber sensory nerve pathway involving α1-adrenergic receptors. Transient receptor potential melastatin 8 channels, which are sensitive to thermal changes below 25-28°C, also play an important role in mediating the cold stress responses. Additionally, the sympathetic nervous system is associated with transient hypertension and decreases of skin surface temperature that are closely correlated with the detrusor overactivity. With this cold stress model, we showed that α1-adrenergic receptor antagonists have the potential to treat cold stress-exacerbated lower urinary tract symptoms. In addition, we showed that traditional Japanese herbal mixtures composed of Hachimijiogan act, in part, by increasing skin temperature and reducing the number of cold sensitive transient receptor potential melastatin channels in the skin. The effects of herbal mixtures have the potential to treat and/or prevent the exacerbation of lower urinary tract symptoms by providing resistance to the cold stress responses. Our model provides new opportunities for utilizing animal disease models with altered lower urinary tract functions to explore the effects of novel therapeutic drugs.

  2. Acute stress may induce ovulation in women

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    Cano Antonio

    2010-05-01

    Full Text Available Abstract Background This study aims to gather information either supporting or rejecting the hypothesis that acute stress may induce ovulation in women. The formulation of this hypothesis is based on 2 facts: 1 estrogen-primed postmenopausal or ovariectomized women display an adrenal-progesterone-induced ovulatory-like luteinizing hormone (LH surge in response to exogenous adrenocorticotropic hormone (ACTH administration; and 2 women display multiple follicular waves during an interovulatory interval, and likely during pregnancy and lactation. Thus, acute stress may induce ovulation in women displaying appropriate serum levels of estradiol and one or more follicles large enough to respond to a non-midcycle LH surge. Methods A literature search using the PubMed database was performed to identify articles up to January 2010 focusing mainly on women as well as on rats and rhesus monkeys as animal models of interaction between the hypothalamic-pituitary-adrenal (HPA and hypothalamic-pituitary-gonadal (HPG axes. Results Whereas the HPA axis exhibits positive responses in practically all phases of the ovarian cycle, acute-stress-induced release of LH is found under relatively high plasma levels of estradiol. However, there are studies suggesting that several types of acute stress may exert different effects on pituitary LH release and the steroid environment may modulate in a different way (inhibiting or stimulating the pattern of response of the HPG axis elicited by acute stressors. Conclusion Women may be induced to ovulate at any point of the menstrual cycle or even during periods of amenorrhea associated with pregnancy and lactation if exposed to an appropriate acute stressor under a right estradiol environment.

  3. Isoquercetin protects cortical neurons from oxygen-glucose deprivation-reperfusion induced injury via suppression of TLR4-NF-кB signal pathway.

    Science.gov (United States)

    Wang, Cai-Ping; Li, Jian-Long; Zhang, Lu-Zhong; Zhang, Xiao-Chuan; Yu, Shu; Liang, Xin-Miao; Ding, Fei; Wang, Zhi-Wei

    2013-12-01

    In the present study, oxygen-glucose deprivation followed by reperfusion (OGD/R), an in vitro model of ischemia, was used to evaluate the neuroprotective effect of isoquercetin in primary culture of rat cortical neuronal cells. It was found that isoquercetin administered prior to the insult could prevent OGD/R-induced intracellular calcium concentrations ([Ca(2+)]i) increase, lactate dehydrogenase (LDH) release and cell viability decrease. For the first time, isoquercetin is described as a neuroprotective agent that potentially explains the alleviation and prevention from OGD/R-induced injury in neurons. Mechanistic studies showed that the neuroprotective effect of isoquercetin was carried out by anti-inflammatory signaling pathway of inhibiting protein expression of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB), and mRNA expression of TNF-α and IL-6, accompanied by the anti-apoptotic signaling pathway of deactivation of extracellular-regulated kinase (ERK), Jun kinase (JNK) and p38, and inhibition of activity of caspase-3. Therefore, these studies highlighted the confirmation of isoquercetin, a flavonoid compound, as an anti-inflammation and anti-apoptosis factor which might be used as a therapeutic strategy for the ischemia/reperfusion (I/R) brain injury and related diseases.

  4. 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

  5. Hyperlipidemia does not prevent the cardioprotection by postconditioning against myocardial ischemia/reperfusion injury and the involvement of hypoxia inducible factor-1α upregulation

    Institute of Scientific and Technical Information of China (English)

    Huanxin Zhao; Yehong Wang; Ye Wu; Xiaoyu Li; Guangzhao Yang; Xiurui Ma; gongrui Zhao; Huirong Liu

    2009-01-01

    Hyperlipidemia is regarded as an independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia/reperfusion (I/R) injury, lschemic postcondi-tioning (Postcon) has been demonstrated to attenuate the myocardial injury induced by I/R in normal con-ditions. But the effect of ischemic Postcon on hyperlipi-demic animals is unknown. Hypoxia inducible factor-1 (HIF-1) has been demonstrated to play a central role in the cardioprotection by preconditioning, which is one of the protective strategies except for Postcon. The aim of this study was to determine whether Postcon could reduce myocardial injury in hyperlipidemic animals and to assess whether HIF-1 was involved in Postcon mechanisms. Male Wistar rats underwent the left anterior descending coronary occlusion for 30 min fol-lowed by 180 min of reperfusion with or without Postcon after fed with high fat diet or normal diet for 8 weeks. The detrimental indices induced by the I/R insult included infarct size, plasma creatine kinase activity and caspase-3 activity. Results showed that hyperlipidemia remarkably enhanced the myocardial injury induced by I/R, while Postcon significantly decreased the myocardial injury in both normolipi-demic and hyperlipidemic rats. Moreover, both hyperli-pidemia and IfR promoted the HIF-1α expression. Most importantly, we have for the first time demon-strated that Postcon further induced a significant increase in HIF-1α protein level not only in normolipi-demic but also in hyperlipidemic conditions. Thus, Postcon reduces the myocardial injury induced by I/R in normal and hyperlipidemic animals, and HIF-1αupregulation may involve in the Postcon-mediated car-dioprotective mechanisms.

  6. Reduction of infarct size by gentle reperfusion without activation of reperfusion injury salvage kinases in pigs.

    Science.gov (United States)

    Musiolik, Judith; van Caster, Patrick; Skyschally, Andreas; Boengler, Kerstin; Gres, Petra; Schulz, Rainer; Heusch, Gerd

    2010-01-01

    Reperfusion is mandatory to salvage ischaemic myocardium from infarction, but also induces additional reperfusion injury and contributes to infarct size (IS). Gentle reperfusion (GR) has been proposed to attenuate reperfusion injury, but this remains contentious. We now investigated whether (i) GR reduces IS and (ii) GR is associated with the activation of reperfusion injury salvage kinases (RISK). Anaesthetized pigs were subjected to 90 min left anterior descending coronary artery hypoperfusion and 120 min reperfusion. GR was induced by slowly increasing coronary inflow back to baseline over 30 min, using an exponential algorithm [F(t) = F(i)+e(-(0.1)(t)((min)-3)).(F(b)-F(i)); F(b), coronary inflow at baseline; F(i), coronary inflow during ischaemia; n = 12]. Pigs subjected to immediate full reperfusion (IFR; n = 13) served as controls. IS was determined by triphenyl tetrazolium chloride staining. The expression level of phosphorylated RISK proteins was determined by western blot analysis in myocardial biopsies taken at baseline, after 80-85 min ischaemia and at 10, 30, and 120 min reperfusion. In additional experiments with IFR (n = 3) and GR (n = 3), the PI3-AKT and MEK1/2-ERK1/2 pathways were pharmacologically blocked (BL). IS was 37 +/- 2% (mean +/- SEM) of the area at risk with IFR and 29 +/- 1% (P < 0.05) with GR. RISK phosphorylation was similar between GR and IFR at baseline and 85 min ischaemia. At 10 min reperfusion, RISK phosphorylation was increased with IFR, but not with GR. At 30 and 120 min reperfusion, RISK phosphorylation was still greater with IFR than GR. RISK blockade did not abolish the IS reduction by GR (BL-IFR: 27 +/- 4% of the area at risk; BL-GR: 42 +/- 5%; P < 0.05). Gentle reperfusion reduces infarct size in pigs, but RISK activation is not causally involved in this infarct size reduction.

  7. Endogenous nitric oxide induces activation of apoptosis signal-regulating kinase 1 via S-nitrosylation in rat hippocampus during cerebral ischemia-reperfusion.

    Science.gov (United States)

    Liu, D-H; Yuan, F-G; Hu, S-Q; Diao, F; Wu, Y-P; Zong, Y-Y; Song, T; Li, C; Zhang, G-Y

    2013-01-15

    Apoptosis signal-regulating kinase 1 (ASK1) is a general mediator of cell death in response to a variety of stimuli, including reactive oxygen species, tumor necrosis factor α, lipopolysaccharide, endoplasmic reticulum stress, calcium influx and ischemia. Here we reported ASK1 was activated by nitric oxide (NO) through S-nitrosylation during cerebral ischemia-reperfusion. The reagents that abrogate neuronal nitric oxide synthase (nNOS) activity such as nNOS inhibitor 7NI and N-methyl-D-aspartate receptor antagonist MK801 prevented ASK1 activation via decreasing ASK1 S-nitrosylation. In HEK293 cells, over-expressed ASK1 could be S-nitrosylated by both exogenous and endogenous NO and Cys869 was identified as the site of ASK1 S-nitrosylation. S-nitrosylation increased the level of ASK1 phosphorylation at Thr845, which represents ASK1 activation. Our results further confirmed that S-nitrosylation led to the increment of ASK1 dimerization. S-nitrosylation of ASK1 also activated the downstream JNK signaling and JNK-mediated nucleic pathway. The exogenous NO (SNP and GSNO) reversed the effect of endogenous NO by suppressing S-nitrosylation of ASK1 and exerted neuroprotection during ischemia-reperfusion. These results suggest that inhibiting ASK1 S-nitrosylation may be a novel approach for stroke therapy. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    He, Xiaolin; Han, Bing; Mura, Marco; Li, Li; Cypel, Marcelo; Soderman, Avery; Picha, Kristen; Yang, Jing; Liu, Mingyao

    2008-01-30

    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. 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. 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.

  9. Targeted delivery of erythropoietin by transcranial focused ultrasound for neuroprotection against ischemia/reperfusion-induced neuronal injury: a long-term and short-term study.

    Directory of Open Access Journals (Sweden)

    Sheng-Kai Wu

    Full Text Available Erythropoietin (EPO is a neuroprotective agent against cerebral ischemia/reperfusion (I/R-induced brain injury. However, its crossing of blood-brain barrier is limited. Focused ultrasound (FUS sonication with microbubbles (MBs can effectively open blood-brain barrier to boost the vascular permeability. In this study, we investigated the effects of MBs/FUS on extending the therapeutic time window of EPO and its neuroprotective effects in both acute and chronic phases. Male Wistar rats were firstly subjected to two common carotid arteries and right middle cerebral artery occlusion (three vessels occlusion, 3VO for 50 min, and then the rats were treated with hEPO (human recombinant EPO, 5000 IU/kg with or without MBs/FUS at 5 h after occlusion/reperfusion. Acute phase investigation (I/R, I/R+MBs/FUS, I/R+hEPO, and I/R+hEPO+MBs/FUS was performed 24 h after I/R; chronic tests including cylinder test and gait analysis were performed one month after I/R. The experimental results showed that MBs/FUS significantly increased the cerebral content of EPO by bettering vascular permeability. In acute phase, both significant improvement of neurological score and reduction of infarct volume were found in the I/R+hEPO+MBs/FUS group, as compared with I/R and I/R+hEPO groups. In chronic phase, long-term behavioral recovery and neuronal loss in brain cortex after I/R injury was significantly improved in the I/R+hEPO+MBs/FUS group. This study indicates that hEPO administration with MBs/FUS sonication even at 5 h after occlusion/reperfusion can produce a significant neuroprotection.

  10. Comparative Effect of Grape Seed Extract (Vitis Vinifera) and Ascorbic Acid in Oxidative Stress Induced by On-pump Coronary Artery Bypass Surgery

    Science.gov (United States)

    Safaei, Naser; Babaei, Hossein; Azarfarin, Rasoul; Jodati, Ahmad-Reza; Yaghoubi, Alireza; Sheikhalizadeh, Mohammad-Ali

    2017-01-01

    Background: This study aimed to test the beneficial effect of grape seed extract (GSE) (Vitis vinifera) and Vitamin C in oxidative stress and reperfusion injury induced by cardiopulmonary bypass (CPB) in coronary artery bypass surgery. Patients and Methods: In this randomized trial, 87 patients undergoing elective and isolated coronary bypass surgery included. The patients were randomly assigned into three groups (n = 29 each): (1) Control group with no treatment, (2) GSE group who received the extract 24 h before operation, 100 mg every 6 h, orally, (3) Vitamin C group who received 25 mg/kg Vitamin C through CPB during surgery. Blood samples were taken from coronary sinus at (T1) just before aortic cross clamp; (T2) just before starting controlled aortic root reperfusion; and (T3) 10 min after root reperfusion. Some clinical parameters and biochemical markers were compared among the groups. Results: There were significant differences in tracheal intubation times, sinus rhythm return, and left ventricular function between treatment groups compared with control (P Vitamin C groups at T2 and T3 times. In reperfusion period, malondialdehyde level was increased in control group; however, it was significantly lower for the grape seed group (P = 0.04). The differences in the mean levels of superoxide dismutase and glutathione peroxidase among the three groups were not significant (P > 0.05 in all cases). Conclusions: In our patients, GSE and Vitamin C had antioxidative effects and reduced deleterious effects of CPB during coronary artery bypass grafting surgery. PMID:28074795

  11. MRI Dynamically Evaluates the Therapeutic Effect of Recombinant Human MANF on Ischemia/Reperfusion Injury in Rats

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    Xian-Yun Wang

    2016-09-01

    Full Text Available As an endoplasmic reticulum (ER stress-inducible protein, mesencephalic astrocyte-derived neurotrophic factor (MANF has been proven to protect dopaminergic neurons and nondopaminergic cells. Our previous studies had shown that MANF protected against ischemia/reperfusion injury. Here, we developed a magnetic resonance imaging (MRI technology to dynamically evaluate the therapeutic effects of MANF on ischemia/reperfusion injury. We established a rat focal ischemic model by using middle cerebral artery occlusion (MCAO. MRI was performed to investigate the dynamics of lesion formation. MANF protein was injected into the right lateral ventricle at 3 h after reperfusion following MCAO for 90 min, when the obvious lesion firstly appeared according to MRI investigation. T2-weighted imaging for evaluating the therapeutic effects of MANF protein was performed in ischemia/reperfusion injury rats on Days 1, 2, 3, 5, and 7 post-reperfusion combined with histology methods. The results indicated that the administration of MANF protein at the early stage after ischemia/reperfusion injury decreased the mortality, improved the neurological function, reduced the cerebral infarct volume, and alleviated the brain tissue injury. The findings collected from MRI are consistent with the morphological and pathological changes, which suggest that MRI is a useful technology for evaluating the therapeutic effects of drugs.

  12. Effect of Salvia leriifolia Benth. root extracts on ischemia-reperfusion in rat skeletal muscle

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    Nassiri-Asl Marjan

    2007-07-01

    Full Text Available Abstract Background Salvia leriifolia have been shown to decrease ischemia-reperfusion (I/R injury in brain tissues. In this study, the effects of S. leriifolia aqueous and ethanolic extracts were evaluated on an animal model of I/R injury in the rat hind limb. Methods Ischemia was induced using free-flap surgery in skeletal muscle. The aqueous and ethanolic extracts of S. leriifolia (100, 200 and 400 mg/kg root and normal saline (10 ml/kg were administered intraperitoneally 1 h prior reperfusion. During preischemia, ischemia and reperfusion conditions the electromyographic (EMG potentials in the muscles were recorded. The markers of oxidative stress including thiobarbituric acid reactive substances (TBARS, total sulfhydryl (SH groups and antioxidant capacity of muscle (using FRAP assay were measured. Results In peripheral ischemia, the average peak-to-peak amplitude during ischemic-reperfusion was found to be significantly larger in extracts groups in comparison with control group. Following extracts administration, the total SH contents and antioxidant capacity were elevated in muscle flap. The MDA level was also declined significantly in test groups. Conclusion It is concluded that S. leriifolia root extracts have some protective effects on different markers of oxidative damage in muscle tissue injury caused by lower limb ischemia-reperfusion.

  13. Nanoparticle-Mediated Delivery of Irbesartan Induces Cardioprotection from Myocardial Ischemia-Reperfusion Injury by Antagonizing Monocyte-Mediated Inflammation

    Science.gov (United States)

    Nakano, Yasuhiro; Matoba, Tetsuya; Tokutome, Masaki; Funamoto, Daiki; Katsuki, Shunsuke; Ikeda, Gentaro; Nagaoka, Kazuhiro; Ishikita, Ayako; Nakano, Kaku; Koga, Jun-Ichiro; Sunagawa, Kenji; Egashira, Kensuke

    2016-07-01

    Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effect of early reperfusion therapy for acute myocardial infarction (AMI), in which the recruitment of inflammatory monocytes plays a causative role. Here we develop bioabsorbable poly-lactic/glycolic acid (PLGA) nanoparticles incorporating irbesartan, an angiotensin II type 1 receptor blocker with a peroxisome proliferator-activated receptor (PPAR)γ agonistic effect (irbesartan-NP). In a mouse model of IR injury, intravenous PLGA nanoparticles distribute to the IR myocardium and monocytes in the blood and in the IR heart. Single intravenous treatment at the time of reperfusion with irbesartan-NP (3.0 mg kg‑1 irbesartan), but not with control nanoparticles or irbesartan solution (3.0 mg kg‑1), inhibits the recruitment of inflammatory monocytes to the IR heart, and reduces the infarct size via PPARγ-dependent anti-inflammatory mechanisms, and ameliorates left ventricular remodeling 21 days after IR. Irbesartan-NP is a novel approach to treat myocardial IR injury in patients with AMI.

  14. Neuroprotective effects of thymoquinone against spinal cord ischemia-reperfusion injury by attenuation of inflammation, oxidative stress, and apoptosis.

    Science.gov (United States)

    Gökce, Emre Cemal; Kahveci, Ramazan; Gökce, Aysun; Cemil, Berker; Aksoy, Nurkan; Sargon, Mustafa Fevzi; Kısa, Üçler; Erdoğan, Bülent; Güvenç, Yahya; Alagöz, Fatih; Kahveci, Ozan

    2016-06-01

    OBJECTIVE Ischemia-reperfusion (I/R) injury of the spinal cord following thoracoabdominal aortic surgery remains the most devastating complication, with a life-changing impact on the patient. Thymoquinone (TQ), the main constituent of the volatile oil from Nigella sativa seeds, is reported to possess strong antioxidant, antiinflammatory, and antiapoptotic properties. This study investigated the effects of TQ administration following I/R injury to the spinal cord. METHODS Thirty-two rats were randomly allocated into 4 groups. Group 1 underwent only laparotomy. For Group 2, aortic clip occlusion was introduced to produce I/R injury. Group 3 was given 30 mg/kg of methylprednisolone intraperitoneally immediately after the I/R injury. Group 4 was given 10 mg/kg of TQ intraperitoneally for 7 days before induction of spinal cord I/R injury, and administration was continued until the animal was euthanized. Locomotor function (Basso, Beattie, and Bresnahan scale and inclined plane test) was assessed at 24 hours postischemia. Spinal cord tissue samples were harvested to analyze tissue concentrations of malondialdehyde, nitric oxide, tumor necrosis factor-α, interleukin-1, superoxide dismutase, glutathione-peroxidase, catalase, and caspase-3. In addition, histological and ultrastructural evaluations were performed. RESULTS Thymoquinone treatment improved neurological outcome, which was supported by decreased levels of oxidative products (malondialdehyde and nitric oxide) and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1), increased activities of antioxidant enzymes (superoxide dismutase, glutathione-peroxidase, and catalase), as well as reduction of motor neuron apoptosis. Light microscopy and electron microscopy results also showed preservation of tissue structure in the treatment group. CONCLUSIONS As shown by functional, biochemical, histological, and ultrastructural analysis, TQ exhibits an important protective effect against I/R injury of the

  15. Neuroprotection of GST, an extract of traditional Chinese herb, against ischemic brain injury induced by transient brain ischemia and reperfusion in rat hippocampus.

    Science.gov (United States)

    Sun, Ya-Feng; Pei, Dong-Sheng; Zhang, Qing-Xiu; Zhang, Guang-Yi

    2008-06-01

    In this study, we investigated the effect of GST, an extract of Chinese traditional herb, on transient brain ischemia/reperfusion-induced neuronal cell death. Immunoblotting was used to detect the phosphorylation of MLK, JNK and c-jun. Transient (15 minutes) brain ischemia was induced by the four-vessel occlusion in Sprague-Dawley rats. GST was administrated to the SD rats 20 minutes before ischemia or 1 hour after ischemia. Our data showed that the pretreatment of GST could inhibit phosphorylation of MLK, JNK and c-jun. Moreover, GST showed potent neuroprotective effects on ischemic brain damage in vivo and administration of it 1 hour after ischemia also achieved the protective effects. These results indicate that GST has a prominent neuroprotection action against brain ischemic damage and provides a promising therapeutic approach for ischemic brain injury.

  16. Mechanically induced residual stresses: Modelling and characterisation

    Science.gov (United States)

    Stranart, Jean-Claude E.

    Accurate characterisation of residual stress represents a major challenge to the engineering community. This is because it is difficult to validate the measurement and the accuracy is doubtful. It is with this in mind that the current research program concerning the characterisation of mechanically induced residual stresses was undertaken. Specifically, the cold expansion of fastener holes and the shot peening treatment of aerospace alloys, aluminium 7075 and titanium Ti-6Al-4V, are considered. The objective of this study is to characterise residual stresses resulting from cold working using three powerful techniques. These are: (i) theoretical using three dimensional non-linear finite element modelling, (ii) semi-destructive using a modified incremental hole drilling technique and (iii) nondestructive using a newly developed guided wave method supplemented by traditional C-scan measurements. The three dimensional finite element results of both simultaneous and sequential cold expansion of two fastener holes revealed the importance of the separation distance, the expansion level and the loading history upon the development and growth of the plastic zone and unloading residual stresses. It further showed that the commonly adopted two dimensional finite element models are inaccurate and incapable of predicting these residual stresses. Similarly, the dynamic elasto-plastic finite element studies of shot peening showed that the depth of the compressed layer, surface and sub-surface residual stresses are significantly influenced by the shot characteristics. Furthermore, the results reveal that the separation distance between two simultaneously impacting shots governs the plastic zone development and its growth. In the semi-destructive incremental hole drilling technique, the accuracy of the newly developed calibration coefficients and measurement techniques were verified with a known stress field and the method was used to measure peening residual stresses. Unlike

  17. Studies on effect of stress preconditioning in restrain stress-induced behavioral alterations.

    Science.gov (United States)

    Kaur, Rajneet; Jaggi, Amteshwar Singh; Singh, Nirmal

    2010-02-01

    Stress preconditioning has been documented to confer on gastroprotective effects on stress-induced gastric ulcerations. However, the effects of prior exposure of stress preconditioning episodes on stress-induced behavioral changes have not been explored yet. Therefore the present study was designed to investigate the ameliorative effects of stress preconditioning in immobilization stress-induced behavioral alterations in rats. The rats were subjected to restrain stress by placing in restrainer (5.5 cm in diameter and 18 cm in length) for 3.5 h. Stress preconditioning was induced by subjecting the rats to two cycles of restraint and restrain-free periods of 15 min each. Furthermore, a similar type of stress preconditioning was induced using different time cycles of 30 and 45 min. The extent and severity of the stress-induced behavioral alterations were assessed using different behavioral tests such as hole-board test, social interaction test, open field test, and actophotometer. Restrain stress resulted in decrease in locomotor activity, frequency of head dips and rearing in hole board, line crossing and rearing in open field, and decreased following and increased avoidance in social interaction test. Stress preconditioning with two cycles of 15, 30 or 45 min respectively, did not attenuate stress-induced behavioral changes to any extent. It may be concluded that stress preconditioning does not seem to confer any protective effect in modulating restrain stress-induced behavioral alterations.

  18. Nortriptyline protects testes against germ cell apoptosis and oxidative stress induced by testicular ischaemia/reperfusion.

    Science.gov (United States)

    Yazdani, I; Ghazi-Khansari, M; Saeedi Saravi, S S; Nobakht, M; Majdani, R; Rezayat, S M; Mousavi, S E; Yari, A; Dehpour, A R

    2017-03-01

    We designed this experiment to evaluate the effects of nortriptyline on testicular injury after torsion/detorsion (T/D). Ninety-six adult Wistar rats were divided into six groups 16 each in control group (Group 1), sham operated (Group 2), T/D + saline (Group 3), and in groups 4-6; were administered 2, 10 and 20 mg kg(-1) , i.p. of nortriptyline 30 and 90 min after torsion respectively. Testicular torsion was created by twisting the right testis 720° in clockwise direction for 1 h. In six rats of each group, tissue MDA level and caspase-3 activity increased and the activities of catalase, superoxide dismutase and glutathione peroxidase decreased in compared with control group 4 h after detorsion (P testicular T/D cell damages.

  19. Calcineurin is involved in cardioprotection induced by ischemic postconditioning through attenuating endoplasmic reticulum stress

    Institute of Scientific and Technical Information of China (English)

    CHEN Yi-hong; WU Xu-dong; YAO Shu-tong; SUN Seng; LIU Xiu-hua

    2011-01-01

    Background Ischemic postconditioning (I-postC) is a newly discovered and more amenable cardioprotective strategy capable of protecting the myocardium from ischemia/reperfusion (I/R) injury.Endoplasmic reticulum (ER) is a principal site for secretary protein synthesis and calcium storage.Myocardial I/R causes ER stress and emerging studies suggest that the cardioprotection has been linked to the modulation of ER stress.The aim of the present study was to determine whether cardioprotection of I-postC involves reduction in ER stress through calcineurin pathway.Methods In the in vivo model of rat myocardial I/R,myocardial infarct size was measured by triphenyltetrazolium chloride (TTC) staining and apoptosis was detected using terminal eoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay.Expression of calreticulin,C/EBP homologous protein (CHOP),caspase-12,and activation of caspase-12 in myocardium were detected by Western blotting.The activity and expression of calcineurin in myocardium were also detected.Results I-postC protected the I/R heart against apoptosis,myocardial infarction,and leakage of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB).I-postC suppressed I/R-induced ER stress,as shown by a decrease in the expression of calreticulin and CHOP,and caspase-12 activation.I-postC downregulated calcineurin activation in myocardium subjected to I/R.Conclusion I-postC protects myocardium from I/R injury by suppressing ER stress and calcineurin pathways are not associated with the I-postC-induced suppression of ER stress-related apoptosis.

  20. 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.

  1. Electroacupuncture ameliorates learning and memory in rats with cerebral ischemia-reperfusion injury by inhibiting oxidative stress and promoting p-CREB expression in the hippocampus.

    Science.gov (United States)

    Lin, Ruhui; Lin, Yukun; Tao, Jing; Chen, Bin; Yu, Kunqiang; Chen, Jixiang; Li, Xiaojie; Chen, Li-Dian

    2015-11-01

    The present study aimed to investigate the mechanisms by which electroacupuncture (EA) ameliorates learning and memory in rats with cerebral ischemic‑reperfusion (I/R) injury. Focal cerebral ischemia was induced in adult male Sprague‑Dawley (SD) rats by transient middle cerebral artery occlusion (MCAO). Following MCAO surgery, the rats received EA at the Shenting (DU24) and Baihui (DU20) acupoints. The results of the present study demonstrated that treatment with EA significantly ameliorated neurological deficits and reduced cerebral infarct volume (Plearning and memory ability of the rats, and markedly activated the cyclic adenosine monophosphate (cAMP) response element‑binding protein (CREB) signaling pathway, resulting in the inhibition of cerebral cell apoptosis in the ischemic penumbra. Furthermore, EA increased the activity of superoxide dismutase and glutathione peroxidase, the protein expression levels of phosphorylated‑CREB and B‑cell lymphoma 2 (Bcl‑2), and the mRNA expression levels of Bcl‑2. Conversely, EA decreased the levels of malondialdehyde and inhibited the expression levels of Bcl2‑associated X protein. The results of the present study suggest that treatment with EA may result in the amelioration of learning and memory ability in rats with cerebral I/R injury.

  2. KLF5 overexpression attenuates cardiomyocyte inflammation induced by oxygen-glucose deprivation/reperfusion through the PPARγ/PGC-1α/TNF-α signaling pathway.

    Science.gov (United States)

    Li, Yang; Li, Jian; Hou, Zhiwen; Yu, Yang; Yu, Bo

    2016-12-01

    The primary physiological function of Krüppel-like zinc-finger transcription factor (KLF5) is the regulation of cardiovascular remodeling. Vascular remodeling is closely related to the amelioration of various ischemic diseases. However, the underlying correlation of KLF5 and ischemia is not clear. In this study, we aim to investigate the role of KLF5 in myocardial ischemia reperfusion (IR) injury and the potential mechanisms involved. Cultured H9C2 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/Rep) to mimic myocardial IR injury in vivo. Expressions of KLF5 and PPARγ were distinctly inhibited, and PGC-1α expression was activated at 24h after myocardial OGD/Rep injury. After myocardial OGD/Rep injury, we found that KLF5 overexpression down-regulated levels of TNF-α, IL-1β, IL-6 and IL-8. Through the analysis of lactate dehydrogenase (LDH) release, we demonstrate that KLF5 overexpression reduced the release of OGD/Rep-induced LDH. KLF5 overexpression significantly enhanced cell activity and decreased cell apoptosis during OGD/Rep injury. Compared with the OGD/Rep group, cells overexpressing KLF5 showed anti-apoptotic effects, such as decreased expression of Bax and cleaved caspase-3 as well as increased Bcl-2 expression. KLF5 overexpression activated PPARγ, a protein involved in OGD/Rep injury, and increased levels of PGC-1α, while TNF-α expression was remarkably inhibited. In addition, GW9662, a PPARγ receptor antagonist, reversed the expression of PPARγ/PGC-1α/TNF-α and cell activity induced by KLF5 overexpression. The effects of KLF5 overexpression on PPARγ/PGC-1α/TNF-α and cell activity were abolished by co-treatment with GW9662. Taken together, these results suggest that KLF5 can efficiently alleviate OGD/Rep-induced myocardial injury, perhaps through regulation of the PPARγ/PGC-1α/TNF-α pathway.

  3. Influence of Fiber-Type Composition on Recovery from Tourniquet-Induced Skeletal Muscle Ischemia-Reperfusion Injury

    Science.gov (United States)

    2008-03-11

    Animals were provided with food and water ad libitum before and after all procedures. The United States Army Institute of Surgical Research Institutional...Elander, A., and Bylund-Fellenius, A.C. 1990. Purine metabolism after in vivo ischemia and reperfusion in rat skeletal muscle. Am. J. Physiol. 258...hindlimb muscle are ac- companied by changes in HSP72 content . Am. J. Physiol. 266: C1240–C1246. PMID:8203488. Lomo, T., Westgaard, R.H., and Dahl, H.A

  4. Hydrogen-increased dezincification layer-induced stress and susceptibility to stress corrosion cracking of brass

    Institute of Scientific and Technical Information of China (English)

    李会录; 高克玮; 褚武扬; 刘亚萍; 乔利杰

    2003-01-01

    Dezincification layer formed during corrosion or stress corrosion cracking (SCC) of brass in an ammonia solution could induce an additive stress. The effect of hydrogen on the dezincification layer-induced stress and the susceptibility to SCC were studied. The dezincification layer-induced stress was measured using the deflection method and the flowing stress differential method, respectively. The latter measures the difference between the flowing stress of a specimen before unloading and the yield stress of the same specimen after unloading and forming a dezincification layer. The susceptibility to SCC was measured using slow strain rate test. Results show that both the dezincification layer-induced stress and the susceptibility to SCC increase with increasing hydrogen concentration in a specimen. This implies that hydrogen-enhanced dezincification layer-induced stress is consistence with the hydrogen-increased susceptibility to SCC of brass in the ammonia solution.

  5. Endoplasmic reticulum stress-related protective effect of pioglitazone on the myocardium with ischemia-reperfusion injury%吡格列酮对大鼠缺血再灌注诱导的内质网应激相关的心肌保护作用

    Institute of Scientific and Technical Information of China (English)

    李艳; 陈还珍; 范学秀; 王妍妍

    2013-01-01

    Objective To observe influence of pioglitazone on the expression of JNK/p-JNK and cas-pase-12 in ischemia-reperfusion in rats, and discuss the myocardial protective effect of pioglitazone to the endo-plasnnc reticulurn stress way through the JNK pathway. Methods Forty rats were randomly divided into lour groups: sham operation group (n-10). ischemia-reperfusion group (n=10). pioglitazone 10 mg treated group (n= 10), pioglitazone 10 mg treated and SP600125 group (n= 10). Left anterior descending coronary artery was ligated for 30 mm and reperfused for 2 hour to establish the model of ischemia-reperfusion. TUNEL was performed to detect apoplosis of myocardial cells, immunohistochemislry was performed to detect the expression of caspase -12, Western blot was performed to detect the expression of JNK and p-JNK, Results The apoptosis index and the expression of caspase-12 and the expression of p-JNK in ischemia-reperfusion group increased after ischemia-reper - fusion compared with sham operation group and pioglitazone treatment reduced the above index, SP600125 augmented the reducing effect. Conclusion Ischemia-reperfusion can activate INK access and induce severe ER then aggravate cell apoptosis induced by ERS. Pioglitazone could reduce the myocardial apoptosis induced by ERS, which are important protection factors are mediated by JNK.%目的 观察吡格列酮对大鼠心肌缺血再灌注损伤(MIRI)时JNK、p-JNK及caspase-12蛋白表达的影响,探讨吡格列酮通过JNK通路对内质网应激途径的心肌保护作用.方法 Wistar大鼠40只随机分为假手术组(sham组)、缺血再灌注组(I/R组)、I/R+Pio(吡格列酮)组及I/R+Pio+SP600125组各10只.制作大鼠MIRI模型;TUNEL检测心肌细胞凋亡,免疫组织化学检测各组caspase-12表达变化,western Blot法检测各组JNK、p-JNK的表达.结果 吡格列酮预处理组大鼠心肌细胞凋亡、JNK磷酸化率及caspase-12蛋白表达水平明显比I/R组降低(P<0.05),

  6. The role of cyclooxygenase-2/prostanoid pathway in visceral pain induced liver stress response in rats

    Institute of Scientific and Technical Information of China (English)

    PISTON Donald; WANG Shan; FENG Yi; YE Ying-jiang; ZHOU Jing; JIANG Ke-wei; XU Feng; ZHAO Yong; CUI Zhi-rong

    2007-01-01

    Background Cyclooxygenase (COX) is the rate-limiting enzyme in the production of prostanoids from arachidonic acid.COX-2 is the inducible enzyme in the COX family, together with the prostanoids forms the COX-2/prostanoid pathway.Research showed that the COX-2/prostanoid pathway is activated in hepatic diseases and liver stress reaction, such as fibrogenesis, portal hypertension, carcinogenesis, and ischemic/reperfusion injury. But there was no report on visceral pain induced liver stress. This study was to investigate the role of the COX-2/prostanoid pathway in liver stress response in rat acute colitis visceral pain liver stress model.Methods Fifty-three male SD rats were randomly divided into Naive, Model, NS398 treatment, and Morphine treatment groups. The rat acute colitis visceral pain liver stress model was established under anesthesia by the colonic administration of 0.5 ml of 6% acetic acid using a urethral catheter. NS398 and morphine were administrated 30 minutes prior to model establishment in NS398 and Morphine treatment groups respectively. Spontaneous activities and pain behavior were counted and the extent of colonic inflammation was assessed histologically. Liver tissue levels of Glutathione-S-Transferase (GST) activity, COX-2 mRNA, prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and 6-Ketone-prostaglandin F1α (6-K-PGF1α) contents were assessed.Results Thirty minutes after the colonic administration of acetic acid, a significant decrease in spontaneous activities and an increase in pain behaviors were observed in Model group (P<0.01 and P<0.05 respectively), accompanied by colonic inflammation. Liver GST activity levels significantly dropped (P<0.05). Liver COX-2 mRNA expression significantly increased, accompanied by an increase in liver concentrations of PGE2 and TXB2, but no obvious change in 6-K-PGF1α concentrations. NS398 and morphine both ameliorated post-stress liver GST activity (P<0.05 and P<0.01respectively), decreased stress-induced

  7. Delayed reperfusion deficits after experimental stroke account for increased pathophysiology.

    Science.gov (United States)

    Burrows, Fiona E; Bray, Natasha; Denes, Adam; Allan, Stuart M; Schiessl, Ingo

    2015-02-01

    Cerebral blood flow and oxygenation in the first few hours after reperfusion following ischemic stroke are critical for therapeutic interventions but are not well understood. We investigate changes in oxyhemoglobin (HbO2) concentration in the cortex during and after ischemic stroke, using multispectral optical imaging in anesthetized mice, a remote filament to induce either 30 minute middle cerebral artery occlusion (MCAo), sham surgery or anesthesia alone. Immunohistochemistry establishes cortical injury and correlates the severity of damage with the change of oxygen perfusion. All groups were imaged for 6 hours after MCAo or sham surgery. Oxygenation maps were calculated using a pathlength scaling algorithm. The MCAo group shows a significant drop in HbO2 during occlusion and an initial increase after reperfusion. Over the subsequent 6 hours HbO2 concentrations decline to levels below those observed during stroke. Platelets, activated microglia, interleukin-1α, evidence of BBB breakdown and neuronal stress increase within the stroked hemisphere and correlate with the severity of the delayed reperfusion deficit but not with the ΔHbO2 during stroke. Despite initial restoration of HbO2 after 30 min MCAo there is a delayed compromise that coincides with inflammation and could be a target for improved stroke outcome after thrombolysis.

  8. Stress state in turbopump bearing induced by shrink fitting

    Science.gov (United States)

    Sims, P.; Zee, R.

    1991-01-01

    The stress generated by shrink fitting in bearing-like geometries is studied. The feasibility of using strain gages to determine the strain induced by shrink fitting process is demonstrated. Results from a ring with a uniform cross section reveal the validity of simple stress mechanics calculations for determining the stress state induced in this geometry by shrink fitting.

  9. HDAC2 selectively regulates FOXO3a-mediated gene transcription during oxidative stress-induced neuronal cell death.

    Science.gov (United States)

    Peng, Shengyi; Zhao, Siqi; Yan, Feng; Cheng, Jinbo; Huang, Li; Chen, Hong; Liu, Qingsong; Ji, Xunming; Yuan, Zengqiang

    2015-01-21

    All neurodegenerative diseases are associated with oxidative stress-induced neuronal death. Forkhead box O3a (FOXO3a) is a key transcription factor involved in neuronal apoptosis. However, how FOXO3a forms complexes and functions in oxidative stress processing remains largely unknown. In the present study, we show that histone deacetylase 2 (HDAC2) forms a physical complex with FOXO3a, which plays an important role in FOXO3a-dependent gene transcription and oxidative stress-induced mouse cerebellar granule neuron (CGN) apoptosis. Interestingly, we also found that HDAC2 became selectively enriched in the promoter region of the p21 gene, but not those of other target genes, and inhibited FOXO3a-mediated p21 transcription. Furthermore, we found that oxidative stress reduced the interaction between FOXO3a and HDAC2, leading to an increased histone H4K16 acetylation level in the p21 promoter region and upregulated p21 expression in a manner independent of p53 or E2F1. Phosphorylation of HDAC2 at Ser 394 is important for the HDAC2-FOXO3a interaction, and we found that cerebral ischemia/reperfusion reduced phosphorylation of HDAC2 at Ser 394 and mitigated the HDAC2-FOXO3a interaction in mouse brain tissue. Our study reveals the novel regulation of FOXO3a-mediated selective gene transcription via epigenetic modification in the process of oxidative stress-induced cell death, which could be exploited therapeutically.

  10. Effects of captopril, telmisartan and bardoxolone methyl (CDDO-Me) in ischemia-reperfusion-induced acute kidney injury in rats: an experimental comparative study.

    Science.gov (United States)

    Kocak, Cengiz; Kocak, Fatma Emel; Akcilar, Raziye; Bayat, Zeynep; Aras, Bekir; Metineren, Mehmet Huseyin; Yucel, Mehmet; Simsek, Hasan

    2016-02-01

    Renal ischemia-reperfusion (IR) injury is one of the most common causes of acute kidney injury. This study investigated the effects of captopril (CAP), telmisartan (TEL) and bardoxolone methyl (BM) in animals with renal IR injury. Adult male Wistar-Albino rats were divided into six groups: control, vehicle, IR, IR with CAP, IR with TEL and IR with BM. Before IR was induced, drugs were administered by oral gavage. After a 60-min ischemia and a 120-min reperfusion period, bilateral nephrectomies were performed. Serum urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) levels, tissue total oxidant status (TOS), total antioxidant status (TAS), total thiol (TT), asymmetric dimethylarginine (ADMA) levels, superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) activity were measured. Tissue mRNA expression levels of peroxisome proliferator-activated receptor-ɣ (PPAR-ɣ), nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were analyzed. In addition, renal tissues were evaluated histopathologically and immunohistochemically. All tested drugs reduced renal damage, apoptosis, urea, creatinine, NGAL, TOS, nitric oxide (NO) and ADMA levels, NF-κB, inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) expressions (P < 0.001). All tested drugs increased SOD activity, GSH-Px activity, TAS levels, TT levels, endothelial nitric oxide synthase (eNOS) expression, dimethylarginine dimethylaminohydrolases (DDAHs) expression, Nrf2 expression and PPAR-ɣ expression (P < 0.001, P < 0.003). These results suggest that CAP, TEL and BM pretreatment could reduce renal IR injury via anti-inflammatory, antioxidant and anti-apoptotic effects. © 2016 John Wiley & Sons Australia, Ltd.

  11. Melamine Induces Oxidative Stress in Mouse Ovary.

    Science.gov (United States)

    Dai, Xiao-Xin; Duan, Xing; Cui, Xiang-Shun; Kim, Nam-Hyung; Xiong, Bo; Sun, Shao-Chen

    2015-01-01

    Melamine is a nitrogen heterocyclic triazine compound which is widely used as an industrial chemical. Although melamine is not considered to be acutely toxic with a high LD50 in animals, food contaminated with melamine expose risks to the human health. Melamine has been reported to be responsible for the renal impairment in mammals, its toxicity on the reproductive system, however, has not been adequately assessed. In the present study, we examined the effect of melamine on the follicle development and ovary formation. The data showed that melamine increased reactive oxygen species (ROS) levels, and induced granulosa cell apoptosis as well as follicle atresia. To further analyze the mechanism by which melamine induces oxidative stress, the expression and activities of two key antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPX) were analyzed, and the concentration of malondialdehyde (MDA) were compared between control and melamine-treated ovaries. The result revealed that melamine changed the expression and activities of SOD and GPX in the melamine-treated mice. Therefore, we demonstrate that melamine causes damage to the ovaries via oxidative stress pathway.

  12. Melamine Induces Oxidative Stress in Mouse Ovary.

    Directory of Open Access Journals (Sweden)

    Xiao-Xin Dai

    Full Text Available Melamine is a nitrogen heterocyclic triazine compound which is widely used as an industrial chemical. Although melamine is not considered to be acutely toxic with a high LD50 in animals, food contaminated with melamine expose risks to the human health. Melamine has been reported to be responsible for the renal impairment in mammals, its toxicity on the reproductive system, however, has not been adequately assessed. In the present study, we examined the effect of melamine on the follicle development and ovary formation. The data showed that melamine increased reactive oxygen species (ROS levels, and induced granulosa cell apoptosis as well as follicle atresia. To further analyze the mechanism by which melamine induces oxidative stress, the expression and activities of two key antioxidant enzymes superoxide dismutase (SOD and glutathione peroxidase (GPX were analyzed, and the concentration of malondialdehyde (MDA were compared between control and melamine-treated ovaries. The result revealed that melamine changed the expression and activities of SOD and GPX in the melamine-treated mice. Therefore, we demonstrate that melamine causes damage to the ovaries via oxidative stress pathway.

  13. Interindividual differences in stress sensitivity: basal and stress-induced cortisol levels differentially predict neural vigilance processing under stress.

    Science.gov (United States)

    Henckens, Marloes J A G; Klumpers, Floris; Everaerd, Daphne; Kooijman, Sabine C; van Wingen, Guido A; Fernández, Guillén

    2016-04-01

    Stress exposure is known to precipitate psychological disorders. However, large differences exist in how individuals respond to stressful situations. A major marker for stress sensitivity is hypothalamus-pituitary-adrenal (HPA)-axis function. Here, we studied how interindividual variance in both basal cortisol levels and stress-induced cortisol responses predicts differences in neural vigilance processing during stress exposure. Implementing a randomized, counterbalanced, crossover design, 120 healthy male participants were exposed to a stress-induction and control procedure, followed by an emotional perception task (viewing fearful and happy faces) during fMRI scanning. Stress sensitivity was assessed using physiological (salivary cortisol levels) and psychological measures (trait questionnaires). High stress-induced cortisol responses were associated with increased stress sensitivity as assessed by psychological questionnaires, a stronger stress-induced increase in medial temporal activity and greater differential amygdala responses to fearful as opposed to happy faces under control conditions. In contrast, high basal cortisol levels were related to relative stress resilience as reflected by higher extraversion scores, a lower stress-induced increase in amygdala activity and enhanced differential processing of fearful compared with happy faces under stress. These findings seem to reflect a critical role for HPA-axis signaling in stress coping; higher basal levels indicate stress resilience, whereas higher cortisol responsivity to stress might facilitate recovery in those individuals prone to react sensitively to stress. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  14. Work-Induced Stress and Its Influence on Organizational ...

    African Journals Online (AJOL)

    Toshiba

    2013-04-28

    Apr 28, 2013 ... induced stress, and workers effectiveness and productivity are relatively ..... employees time management and relaxation techniques, or suggesting ... Management can take active steps to minimize undesirable stress in them ...

  15. Pretreatment with adenosine and adenosine A1 receptor agonist protects against intestinal ischemia-reperfusion injury in rat

    Institute of Scientific and Technical Information of China (English)

    V Haktan Ozacmak; Hale Sayan

    2007-01-01

    AIM: To examine the effects of adenosine and A1 receptor activation on reperfusion-induced small intestinal injury.METHODS: Rats were randomized into groups with sham operation, ischemia and reperfusion, and systemic treatments with either adenosine or 2-chloro-N6-cyclopentyladenosine, A1 receptor agonist or 8-cyclopentyl-1,3-dipropylxanthine, A1 receptor antagonist, plus adenosine before ischemia. Following reperfusion, contractions of ileum segments in response to KCl, carbachol and substance P were recorded. Tissue myeloperoxidase,malondialdehyde, and reduced glutathione levels were measured.RESULTS: Ischemia significantly decreased both contraction and reduced glutathione level which were ameliorated by adenosine and agonist administration. Treatment also decreased neutrophil infiltration and membrane lipid peroxidation. Beneficial effects of adenosine were abolished by pretreatment with A1 receptor antagonist.CONCLUSION: The data suggest that adenosine and A1 receptor stimulation attenuate ischemic intestinal injury via decreasing oxidative stress, lowering neutrophil infiltration, and increasing reduced glutathione content.

  16. Ginsenoside Rb1 Preconditioning Enhances eNOS Expression and Attenuates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Rui Xia

    2011-01-01

    Full Text Available Diabetes mellitus is associated with decreased NO bioavailability in the myocardium. Ginsenoside Rb1 has been shown to confer cardioprotection against ischemia reperfusion injury. The aim of this study was to investigate whether Ginsenoside Rb1 exerts cardioprotective effects during myocardial ischemia-reperfusion in diabetic rats and whether this effect is related to increase the production of NO via enhancing eNOS expression in the myocardium. The myocardial I/R injury were induced by occluding the left anterior descending artery for 30 min followed by 120 min reperfusion. An eNOS inhibitor L-NAME or Rb1 were respectively administered 25 min or 10 min before inducing ischemia. Ginsenoside Rb1 preconditioning reduced myocardial infarct size when compared with I/R group. Ginsenoside Rb1 induced myocardial protection was accompanied with increased eNOS expression and NO concentration and reduced plasma CK and LDH (P<0.05. Moreover, the myocardial oxidative stress and tissue histological damage was attenuated by Ginsenoside Rb1 (P<0.05. L-NAME abolished the protective effects of Ginsenoside Rb1. It is concluded that Ginsenoside Rb1 protects against myocardium ischemia/reperfusion injury in diabetic rat by enhancing the expression of eNOS and increasing the content of NO as well as inhibiting oxidative stress.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Hippophae salicifolia D.Don berries attenuate cerebral ischemia reperfusion injury in a rat model of middle cerebral artery occlusion

    Institute of Scientific and Technical Information of China (English)

    Santhrani Thakur; Pradeepthi Chilikuri; Bindu Pulugurtha; Lavanya Yaidikar

    2015-01-01

    Objective: To investigate the protective effect of Hippophae salicifolia D.Don (H. salicifolia) berries extract against cerebral reperfusion injury induced neurobehavioral and neurochemical changes in a rat model of middle cerebral artery occlusion (MCAO). Methods: Rats were pretreated with alcoholic extract of H. salicifolia (250 and 500 mg/kg) for 14 d and focal cerebral ischemia was induced by MCAO. After 60 min of MCAO, reperfused for 24 h, a battery of behavioral tests were assessed the extent of neurological deficits. Infarct volume and brain edema were measured in 2,3,5-triphenyltetrazolium chloride stained brain sections. TNF-α, oxidative stress parameters like reduced glutathione, calcium, glutamate, malondialdehyde and apoptotic parameters like caspase-3, and caspase-9 were estimated in the brain homogenates. Results:Pretreatment with alcoholic extract of H. salicifolia at doses of 250 and 500 mg/kg significantly improved the neurobehavioral alterations and reduced the infarct volume, edema induced by ischemia reperfusion injury. H. salicifolia significantly prevented ischemia induced increase in malondialdehyde, glutamate, calcium, caspase-3, caspase-9 and TNF-αlevels as compared to ischemic animals. Conclusions: Our results indicate that H. salicifolia mitigated the ischemia reperfusion induced neuronal damage.

  19. The effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(l-lysine) block copolymer on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor

    OpenAIRE

    Tong F; Tang XY; Li X.; Xia WQ; Liu DJ

    2016-01-01

    Fei Tong, Xiangyuan Tang, Xin Li, Wenquan Xia, Daojun Liu Department of Chemistry, Medical College, Shantou University, Shantou, People’s Republic of China Abstract: The aim of this study was to observe the therapeutic effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(L-lysine) block copolymer poly(ethylene glycol)-b-(poly(ethylenediamine L-glutamate)-g-poly(L-lysine)) (PEG-b-(PELG-g-PLL) on renal ischemia/reperfusion-induced lung injury through downregulating ...

  20. Isoprostanes--markers of ischaemia reperfusion injury.

    LENUS (Irish Health Repository)

    Sakamoto, H

    2012-02-03

    Ischaemia reperfusion injury is a common and important phenomenon that occurs predictably in patients undergoing such procedures as cardiopulmonary bypass, thrombolysis, surgery under tourniquet, organ transplantation or embolectomy. Oxidative stress and the resulting lipid peroxidation play a major role in reperfusion injury. Membrane and cellular dysfunction result and, subsequently, organ injury or failure may ensue. Traditional methods of quantifying ischaemia reperfusion injury, including measurement of malondialdehyde, lack specificity and sensitivity. It was reported in 1990 that isoprostanes, a series of prostaglandin-like compounds, are produced by the free radical-catalyzed peroxidation of arachidonic acid. Measurement of the isoprostane concentration in urine or plasma provides the most reliable, non-invasive method currently available to assess oxidative stress in vivo. Serial measurement of isoprostanes in biological fluids has enhanced our understanding of the mechanisms underlying ischaemia reperfusion injury itself and its role in certain diseases. Furthermore, measurement of the isoprostane concentration provides a means to assess the effects of prophylactic and therapeutic interventions. In the future, the development of rapid, simple assays for isoprostanes offers the potential to assess prognosis during and after ischaemia reperfusion events.

  1. Stress induced phase transitions in silicon

    Science.gov (United States)

    Budnitzki, M.; Kuna, M.

    2016-10-01

    Silicon has a tremendous importance as an electronic, structural and optical material. Modeling the interaction of a silicon surface with a pointed asperity at room temperature is a major step towards the understanding of various phenomena related to brittle as well as ductile regime machining of this semiconductor. If subjected to pressure or contact loading, silicon undergoes a series of stress-driven phase transitions accompanied by large volume changes. In order to understand the material's response for complex non-hydrostatic loading situations, dedicated constitutive models are required. While a significant body of literature exists for the dislocation dominated high-temperature deformation regime, the constitutive laws used for the technologically relevant rapid low-temperature loading have severe limitations, as they do not account for the relevant phase transitions. We developed a novel finite deformation constitutive model set within the framework of thermodynamics with internal variables that captures the stress induced semiconductor-to-metal (cd-Si → β-Si), metal-to-amorphous (β-Si → a-Si) as well as amorphous-to-amorphous (a-Si → hda-Si, hda-Si → a-Si) transitions. The model parameters were identified in part directly from diamond anvil cell data and in part from instrumented indentation by the solution of an inverse problem. The constitutive model was verified by successfully predicting the transformation stress under uniaxial compression and load-displacement curves for different indenters for single loading-unloading cycles as well as repeated indentation. To the authors' knowledge this is the first constitutive model that is able to adequately describe cyclic indentation in silicon.

  2. Genistein attenuates ischemia/reperfusion injury in rat kidneys via ...

    African Journals Online (AJOL)

    by oral gavage for 7 consecutive days and then subjected to 45 min of renal bilateral ... Keywords: Oxidative stress, Genistein, Ischemic reperfusion injury, Renal ... radical production ultimately leading to cellular ... serum biomarker analysis.

  3. A study on anti-stress property of Nardostachys jatamamsi on stress induced Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Shilpashree R.

    2011-09-01

    Full Text Available Stress is a feeling that’s created when we react to particular events. It s the body’s way of rising to a challenge and preparing to meet a tough situation with focus, strength, stamina, and heightened alertness. As a result of the stress immune system can be suppressed by chronic stress opening to increased infections and increasing the risk of autoimmune diseases. So one has to learn away to overcome stress. Here is an attempt made to overcome the stress induced in Drosophila melanogaster a model organism, in this study. Methotrexate is used to induce the stress at different concentration taking different group of flies and a Nardostachys jatamamsi plant extract having antistress property is used to relieve the stress induced. This stress relieve measured by the various stress related enzymes like catalase and Superoxide dismutase by this antistress property of the plant Nardostachys jatamamsi was shown.

  4. Effects of extract F of red-rooted Salvia on mucosal lesions of gastric corpus and antrum induced by hemorrhagic shock-reperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    Li-Hong Zhang; Chang-Bai Yao; He-Quan Li

    2001-01-01

    AIM To compare the effects of extract F of red-rooted Salvia (EFRRS) on mucosal lesions of gastric corpus and antrum induced by hemorrhagic shock and reperfusion in rats.``METHODS The rats were subject to hemorrhagic shock and followed by reperfusion, and were divided randomly into two groups. Group 1 received saline, and group 2received EFRRS intravenously. The index of gastric mucosal lesions (IGML) was expressed as the percentage of lesional area in the corpus or antrum. The degree of gastric mucosal lesions (DGML) was catalogued grade 0,1. 2 and 3. The concentrations of prostaglandins (lags)were measured by radioimmunoassay. The concentration of MDA was measured according to the procedures of Asakawa. The activity of SOD was measured by the biochemical way. The growth rates or inhibitory rates of above-mentioned parametes were calculated.``RESULTS As compared with IGML (%), grade 3 damage (%) and MDA content (nmol/g tissue) of gastric antrum which were respectively 7.96 ± 0.59, 34.86± 4.96 and 156.98± 16.12. those of gastric corpus which were respectively 23.18 ± 6.82, 58.44 ± 9.07 and 230.56 ± 19.37increased markedly (P<0.01), whereas the grade 0damage, grade 1 damage, the concentrations of PGE2 and PGI2(pg/ mg tissue), the ratio of PGI2/ TXA2 and the activity of SOD (U/ g tissue) of corpus which were respectively 3.01 _- 1.01, 8.35 + 1.95, 540.48 _+ 182.78,714.38 ± 123.74, 17.38 ± 5.93 and 134.29 ± 13.35 were markedly lower than those of antrum which were respectively 13.92 ± 2.25, 26.78 ± 6.06, 2218.56 ± 433.12,2531.76 ± 492.35, 43.46 ± 8.51 and 187.45 ± 17.67( P<0.01 ) after hemorrhagic shock and reperfusion. After intravenous EFRRS, the growth rates (%) of grade 0damage, grade 1 damage, the concentrations of PGE2 and PGI2, the ratio of PGI2/TXA2 and the activity of SOD of corpus which were respectively 632.56, 308.62, 40.75,74.75, 92.29 and 122.25 were higher than those in antrum which were respectively 104,89, 58.40, 11.12, 56.58,30.65 and

  5. Traditional Chinese Medicine Shuang Shen Ning Xin Attenuates Myocardial Ischemia/Reperfusion Injury by Preserving of Mitochondrial Function

    Directory of Open Access Journals (Sweden)

    Xueli Li

    2014-01-01

    Full Text Available To investigate the potential cardioprotective effects of Shuang Shen Ning Xin on myocardial ischemia/reperfusion injury. Wistar rats were treated with trimetazidine (10 mg/kg/day, ig, Shuang Shen Ning Xin (22.5, 45 mg/kg/day, ig, or saline for 5 consecutive days. Myocardial ischemia/reperfusion injury was induced by ligation of the left anterior descending coronary artery for 40 min and reperfusion for 120 min on the last day of administration. It is found that Shuang Shen Ning Xin pretreatment markedly decreased infarct size and serum LDH levels, and this observed protection was associated with reduced myocardial oxidative stress and cardiomyocyte apoptosis after myocardial ischemia/reperfusion injury. In addition, further studies on mitochondrial function showed that rats treated with Shuang Shen Ning Xin displayed decreased mitochondrial swelling and cytosolic cytochrome c levels, which were accompanied by a preservation of complex I activities and inhibition of mitochondrial permeability transition. In conclusion, the mitochondrial protective effect of Shuang Shen Ning Xin could be a new mechanism, by which Shuang Shen Ning Xin attenuates myocardial ischemia/reperfusion injury.

  6. Ginkgo Biloba Ameliorates Subfertility Induced by Testicular Ischemia/Reperfusion Injury in Adult Wistar Rats: A Possible New Mitochondrial Mechanism

    Directory of Open Access Journals (Sweden)

    Asmaa Ibrahim Ahmed

    2016-01-01

    Full Text Available Testicular torsion, a surgical emergency, could affect the endocrine and exocrine testicular functions. This study demonstrates histopathological and physiological effects of testicular ischemia/perfusion (I/R injury and the possible protective effects of Ginkgo biloba treatment. Fifty adult male Wistar rats, 180–200 gm, were randomly divided into sham-operated, Gingko biloba supplemented, ischemia only, I/R, and Gingko biloba treated I/R groups. Overnight fasted rats were anaesthetized by Pentobarbital; I/R was performed by left testis 720° rotation in I/R and treated I/R groups. Orchiectomy was performed for histopathological studies and detection of mitochondrial NAD+. Determination of free testosterone, FSH, TNF-α, and IL1-β in plasma was performed. Plasma-free testosterone was significantly decreased, while plasma FSH, TNF-α, IL-1β, and testicular mitochondrial NAD+ were significantly increased in I/R group compared to control group. These parameters were reversed in Gingko biloba treated I/R group compared to I/R group. I/R caused marked testicular damage and increased APAF-1 in the apoptotic cells which were reversed by Ginkgo biloba treatment. It could be concluded that I/R caused subfertility induced by apoptosis and oxidative stress manifested by the elevated testicular mitochondrial NAD+, which is considered a new possible mechanism. Also, testicular injury could be reduced by Gingko biloba administration alone.

  7. Ginkgo Biloba Ameliorates Subfertility Induced by Testicular Ischemia/Reperfusion Injury in Adult Wistar Rats: A Possible New Mitochondrial Mechanism

    Science.gov (United States)

    Ahmed, Asmaa Ibrahim; El-Zawahry, Khaled Mohamed

    2016-01-01

    Testicular torsion, a surgical emergency, could affect the endocrine and exocrine testicular functions. This study demonstrates histopathological and physiological effects of testicular ischemia/perfusion (I/R) injury and the possible protective effects of Ginkgo biloba treatment. Fifty adult male Wistar rats, 180–200 gm, were randomly divided into sham-operated, Gingko biloba supplemented, ischemia only, I/R, and Gingko biloba treated I/R groups. Overnight fasted rats were anaesthetized by Pentobarbital; I/R was performed by left testis 720° rotation in I/R and treated I/R groups. Orchiectomy was performed for histopathological studies and detection of mitochondrial NAD+. Determination of free testosterone, FSH, TNF-α, and IL1-β in plasma was performed. Plasma-free testosterone was significantly decreased, while plasma FSH, TNF-α, IL-1β, and testicular mitochondrial NAD+ were significantly increased in I/R group compared to control group. These parameters were reversed in Gingko biloba treated I/R group compared to I/R group. I/R caused marked testicular damage and increased APAF-1 in the apoptotic cells which were reversed by Ginkgo biloba treatment. It could be concluded that I/R caused subfertility induced by apoptosis and oxidative stress manifested by the elevated testicular mitochondrial NAD+, which is considered a new possible mechanism. Also, testicular injury could be reduced by Gingko biloba administration alone. PMID:28101298

  8. Ion beam induced stress formation and relaxation in germanium

    Energy Technology Data Exchange (ETDEWEB)

    Steinbach, T., E-mail: Tobias.Steinbach@uni-jena.de [Institut für Festkörperphysik, Friedrich-Schiller-Universität Jena, Max-Wien-Platz 1, D-07743 Jena (Germany); Reupert, A.; Schmidt, E.; Wesch, W. [Institut für Festkörperphysik, Friedrich-Schiller-Universität Jena, Max-Wien-Platz 1, D-07743 Jena (Germany)

    2013-07-15

    Ion irradiation of crystalline solids leads not only to defect formation and amorphization but also to mechanical stress. In the past, many investigations in various materials were performed focusing on the ion beam induced damage formation but only several experiments were done to investigate the ion beam induced stress evolution. Especially in microelectronic devices, mechanical stress leads to several unwanted effects like cracking and peeling of surface layers as well as changing physical properties and anomalous diffusion of dopants. To study the stress formation and relaxation process in semiconductors, crystalline and amorphous germanium samples were irradiated with 3 MeV iodine ions at different ion fluence rates. The irradiation induced stress evolution was measured in situ with a laser reflection technique as a function of ion fluence, whereas the damage formation was investigated by means of Rutherford backscattering spectrometry. The investigations show that mechanical stress builds up at low ion fluences as a direct consequence of ion beam induced point defect formation. However, further ion irradiation causes a stress relaxation which is attributed to the accumulation of point defects and therefore the creation of amorphous regions. A constant stress state is reached at high ion fluences if a homogeneous amorphous surface layer was formed and no further ion beam induced phase transition took place. Based on the results, we can conclude that the ion beam induced stress evolution seems to be mainly dominated by the creation and accumulation of irradiation induced structural modification.

  9. 1H-magnetic resonance spectroscopy of vascular endothelial growth factor-induced neuroprotection following acute cerebral ischemia and reperfusion

    Institute of Scientific and Technical Information of China (English)

    Li Yi; Haiou Zhang; Hao Lei; Li Wei

    2008-01-01

    BACKGROUND: It has become generally accepted that measuring N-acetyI-L-aspartic acid through the use of 1H-magnetic resonance spectroscopy (1H-MRS) could be used to evaluate neuronal injury. OBJECTIVE: To study metabolic changes of N-acetyl-L-aspanic acid surrounding the acute cerebral ischcmia area following vascular endothelial growth factor (VEGF) treatment using 1H-MRS imaging, and to evaluate the neuroprotective effects of VEGE.DESIGN, TIME AND SETTING: Randomly controlled animal study, according to one-factor analysis of variance, was performed at the Shenzhen Hospital of Peking University and State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences from August 2003 to December 2005.MATERIALS: Twelve healthy, adult, Sprague Dawley rats were used to establish an ischemia/reperfusion model through the use of middle cerebral artery occlusion. The 4.7T superconducting nuclear magnetic resonance meter was provided by Brucker Company. VEGF164 was purchased from Shenzhen Jingmei Bioengineering Co., Ltd. Titus ancsthesia machine was purchased from Draeger Medical AG & Co. KG.METHODS: The rats were randomly divided into model control (n = 6) and VEGF-injected (n = 6) groups. All animals received 60-minute middle cerebral artery occlusion and 24-hour repcrfusion. Lateral cerebral ventricle injection was performed by stereotaxic technique at respective time points. The VEGF group received 0. 1 μ g/μ L VEGF (5 μL), and the model group received the same amount of normal saline, once daily for 3 days.MAIN OUTCOME MEASURES: Metabolic changes of N-acetyl-L-aspartic acid and lactic acid following cerebral ischemia and reperfusion were detected using 1H-MRS, and the ischemic volume was measured.RESULTS: Twelve rats were included in the final analysis. =H-MRS results revealed that the ischemic volume increased in the control group compared with prior to injection (P < 0.01). In the

  10. Contrast-induced nephrotoxicity: possible synergistic effect of stress hyperglycemia.

    LENUS (Irish Health Repository)

    O'Donnell, David H

    2010-07-01

    Oxidative stress on the renal tubules has been implicated as a mechanism of injury in both stress hyperglycemia and contrast-induced nephrotoxicity. The purpose of this study was to determine whether the combination of these effects has a synergistic effect on accentuating renal tubular apoptosis and therefore increasing the risk of contrast-induced nephrotoxicity.

  11. Mesenteric lymph reperfusion exacerbates spleen injury caused by superior mesenteric artery occlusion shock

    Energy Technology Data Exchange (ETDEWEB)

    Li, L.L.; Zhang, C.H.; Liu, J.C.; Yang, L.N.; Niu, C.Y.; Zhao, Z.G. [Institute of Microcirculation, Hebei North University, Zhangjiakou, Hebei, China, Institute of Microcirculation, Hebei North University, Zhangjiakou, Hebei (China)

    2014-04-15

    The intestinal lymph pathway plays an important role in the pathogenesis of organ injury following superior mesenteric artery occlusion (SMAO) shock. We hypothesized that mesenteric lymph reperfusion (MLR) is a major cause of spleen injury after SMAO shock. To test this hypothesis, SMAO shock was induced in Wistar rats by clamping the superior mesenteric artery (SMA) for 1 h, followed by reperfusion for 2 h. Similarly, MLR was performed by clamping the mesenteric lymph duct (MLD) for 1 h, followed by reperfusion for 2 h. In the MLR+SMAO group rats, both the SMA and MLD were clamped and then released for reperfusion for 2 h. SMAO shock alone elicited: 1) splenic structure injury, 2) increased levels of malondialdehyde, nitric oxide (NO), intercellular adhesion molecule-1, endotoxin, lipopolysaccharide receptor (CD14), lipopolysaccharide-binding protein, and tumor necrosis factor-α, 3) enhanced activities of NO synthase and myeloperoxidase, and 4) decreased activities of superoxide dismutase and ATPase. MLR following SMAO shock further aggravated these deleterious effects. We conclude that MLR exacerbates spleen injury caused by SMAO shock, which itself is associated with oxidative stress, excessive release of NO, recruitment of polymorphonuclear neutrophils, endotoxin translocation, and enhanced inflammatory responses.

  12. Schisandrin B decreases the sensitivity of mitochondria to calcium ion-induced permeability transition and protects against ischemia-reperfusion injury in rat hearts

    Institute of Scientific and Technical Information of China (English)

    Po-yee CHIU; Hoi-yan LEUNG; Ada HL SIU; Michel KT POON; Kam-ming KO

    2007-01-01

    Aim: In order to elucidate the molecular mechanism underlying the cardioprotection afforded by schisandrin B (Sch B), the effect of Sch B treatment on the sensitivity of mitochondria to Ca2+-stimulated permeability transition (PT) was investigated in rat hearts under normal and ischemia-reperfusion (I-R) conditions. Results:Myocardial I-R injury caused an increase in the sensitivity of mitochondria to Ca2+-stimulated PT in vitro. The enhanced sensitivity to mitochondrial PT was associated with increases in mitochondrial Ca2+ content as well as the extent of reactive oxidant species production in vitro and cytochrome c release in vivo.The cardioprotection afforded by Sch B pretreatment against I-R-induced injury was paralleled by the decrease in the sensitivity of myocardial mitochondria to Ca2+-stimulated PT, particularly under I-R conditions. Conclusion: The results suggest that Sch B treatment increases the resistance of myocardial mitochondria to Ca2+-stimulated PT and protects against I-R-induced tissue injury.

  13. Stress, stress-induced cortisol responses, and eyewitness identification performance.

    Science.gov (United States)

    Sauerland, Melanie; Raymaekers, Linsey H C; Otgaar, Henry; Memon, Amina; Waltjen, Thijs T; Nivo, Maud; Slegers, Chiel; Broers, Nick J; Smeets, Tom

    2016-07-01

    In the eyewitness identification literature, stress and arousal at the time of encoding are considered to adversely influence identification performance. This assumption is in contrast with findings from the neurobiology field of learning and memory, showing that stress and stress hormones are critically involved in forming enduring memories. This discrepancy may be related to methodological differences between the two fields of research, such as the tendency for immediate testing or the use of very short (1-2 hours) retention intervals in eyewitness research, while neurobiology studies insert at least 24 hours. Other differences refer to the extent to which stress-responsive systems (i.e., the hypothalamic-pituitary-adrenal axis) are stimulated effectively under laboratory conditions. The aim of the current study was to conduct an experiment that accounts for the contemporary state of knowledge in both fields. In all, 123 participants witnessed a live staged theft while being exposed to a laboratory stressor that reliably elicits autonomic and glucocorticoid stress responses or while performing a control task. Salivary cortisol levels were measured to control for the effectiveness of the stress induction. One week later, participants attempted to identify the thief from target-present and target-absent line-ups. According to regression and receiver operating characteristic analyses, stress did not have robust detrimental effects on identification performance. Copyright © 2016 John Wiley & Sons, Ltd. © 2016 The Authors Behavioral Sciences & the Law Published by John Wiley & Sons Ltd.

  14. Enteral glutamine pretreatment does not decrease plasma endotoxin level induced by ischemia-reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    Arda Demirkan; Erkin Orazakunov; Berna Savas; M Ayhan Kuzu; Mehmet Melli

    2008-01-01

    AIM: To investigate whether oral glutamine pretreatment prevents impairment of intestinal mucosal integrity during ischemia-reperfusion (I/R) in rats. METHODS: The study was performed as two series with 40 rats in each. Each series of animals was divided into four groups. The first group was used as a control. Animals in the second group were only pretreated with oral glutamine, 1 g/kg for 4 d. The third group received a normal diet, and underwent intestinal I/R, while the fourth group was pretreated with oral glutamine in the same way, and underwent intestinal I/R. Intestinal mucosal permeability to 51Cr-labeled EDTA was measured in urine in the first series of animals. In the second series, histopathological changes in intestinal tissue and plasma endotoxin levels were evaluated. RESULTS: Intestinal I/R produced a significant increase in intestinal permeability, plasma endotoxin level and worsened histopathological alterations. After intestinal I/R, permeability was significantly lower in glutamine- treated rats compared to those which received a normal diet. However, no significant change was observed in plasma endotoxin levels or histopathological findings. CONCLUSION: Although glutamine pretreatment seems to be protective of intestinal integrity, upon I/R injury, such an effect was not observable in the histopathological changes or plasma endotoxin level.

  15. Astaxanthin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy via the ROS/MAPK Pathway in Mice

    Directory of Open Access Journals (Sweden)

    Jingjing Li

    2015-05-01

    Full Text Available Background: Hepatic ischemia reperfusion (IR is an important issue in complex liver resection and liver transplantation. The aim of the present study was to determine the protective effect of astaxanthin (ASX, an antioxidant, on hepatic IR injury via the reactive oxygen species/mitogen-activated protein kinase (ROS/MAPK pathway. Methods: Mice were randomized into a sham, IR, ASX or IR + ASX group. The mice received ASX at different doses (30 mg/kg or 60 mg/kg for 14 days. Serum and tissue samples at 2 h, 8 h and 24 h after abdominal surgery were collected to assess alanine aminotransferase (ALT, aspartate aminotransferase (AST, inflammation factors, ROS, and key proteins in the MAPK family. Results: ASX reduced the release of ROS and cytokines leading to inhibition of apoptosis and autophagy via down-regulation of the activated phosphorylation of related proteins in the MAPK family, such as P38 MAPK, JNK and ERK in this model of hepatic IR injury. Conclusion: Apoptosis and autophagy caused by hepatic IR injury were inhibited by ASX following a reduction in the release of ROS and inflammatory cytokines, and the relationship between the two may be associated with the inactivation of the MAPK family.

  16. Bone marrow-derived cells can acquire renal stem cells properties and ameliorate ischemia-reperfusion induced acute renal injury

    Directory of Open Access Journals (Sweden)

    Jia Xiaohua

    2012-09-01

    Full Text Available Abstract Background Bone marrow (BM stem cells have been reported to contribute to tissue repair after kidney injury model. However, there is no direct evidence so far that BM cells can trans-differentiate into renal stem cells. Methods To investigate whether BM stem cells contribute to repopulate the renal stem cell pool, we transplanted BM cells from transgenic mice, expressing enhanced green fluorescent protein (EGFP into wild-type irradiated recipients. Following hematological reconstitution and ischemia-reperfusion (I/R, Sca-1 and c-Kit positive renal stem cells in kidney were evaluated by immunostaining and flow cytometry analysis. Moreover, granulocyte colony stimulating factor (G-CSF was administrated to further explore if G-CSF can mobilize BM cells and enhance trans-differentiation efficiency of BM cells into renal stem cells. Results BM-derived cells can contribute to the Sca-1+ or c-Kit+ renal progenitor cells population, although most renal stem cells came from indigenous cells. Furthermore, G-CSF administration nearly doubled the frequency of Sca-1+ BM-derived renal stem cells and increased capillary density of I/R injured kidneys. Conclusions These findings indicate that BM derived stem cells can give rise to cells that share properties of renal resident stem cell. Moreover, G-CSF mobilization can enhance this effect.

  17. Antioxidative and cardioprotective effects of total flavonoids extracted from Dracocephalum moldavica L. against acute ischemia/reperfusion-induced myocardial injury in isolated rat heart.

    Science.gov (United States)

    Jiang, Jiangtao; Yuan, Xuan; Wang, Ting; Chen, Hongmei; Zhao, Hong; Yan, Xinyan; Wang, Zhiping; Sun, Xiling; Zheng, Qiusheng

    2014-03-01

    This study evaluates antioxidative and cardioprotective effects of total flavonoids extracted from Dracocephalum moldavica L. (DML). The total flavonoids showed remarkable scavenging effects against 1,1-diphenyl-2-picrylhydrazyl, hydroxyl and superoxide anion radicals in vitro. Compared with the ischemia/reperfusion (I/R) group as demonstrated by the use of improved Langendorff retrograde perfusion technology, the total flavonoids (5 μg/mL) pretreatment improved the heart rate and coronary flow, rised left ventricular developed pressure and decreased creatine kinase, lactate dehydrogenase levels in coronary flow. The infarct size/ischemic area at risk of DML-treated hearts was smaller than that of I/R group; the superoxide dismutase activity and glutathione/glutathione disulfide ratio increased and malondialdehyde content reduced obviously (P total flavonoids treatment groups. In conclusion, the total flavonoids possess obvious protective effects on myocardial I/R injury, which may be related to the improvement of myocardial oxidative stress states.

  18. Comparative effect of grape seed extract (Vitis vinifera) and ascorbic acid in oxidative stress induced by on-pump coronary artery bypass surgery.

    Science.gov (United States)

    Safaei, Naser; Babaei, Hossein; Azarfarin, Rasoul; Jodati, Ahmad-Reza; Yaghoubi, Alireza; Sheikhalizadeh, Mohammad-Ali

    2017-01-01

    This study aimed to test the beneficial effect of grape seed extract (GSE) (Vitis vinifera) and Vitamin C in oxidative stress and reperfusion injury induced by cardiopulmonary bypass (CPB) in coronary artery bypass surgery. In this randomized trial, 87 patients undergoing elective and isolated coronary bypass surgery included. The patients were randomly assigned into three groups (n = 29 each): (1) Control group with no treatment, (2) GSE group who received the extract 24 h before operation, 100 mg every 6 h, orally, (3) Vitamin C group who received 25 mg/kg Vitamin C through CPB during surgery. Blood samples were taken from coronary sinus at (T1) just before aortic cross clamp; (T2) just before starting controlled aortic root reperfusion; and (T3) 10 min after root reperfusion. Some clinical parameters and biochemical markers were compared among the groups. There were significant differences in tracheal intubation times, sinus rhythm return, and left ventricular function between treatment groups compared with control (P 0.05 in all cases). In our patients, GSE and Vitamin C had antioxidative effects and reduced deleterious effects of CPB during coronary artery bypass grafting surgery.

  19. Comparative effect of grape seed extract (Vitis vinifera and ascorbic acid in oxidative stress induced by on-pump coronary artery bypass surgery

    Directory of Open Access Journals (Sweden)

    Naser Safaei

    2017-01-01

    Full Text Available Background: This study aimed to test the beneficial effect of grape seed extract (GSE (Vitis vinifera and Vitamin C in oxidative stress and reperfusion injury induced by cardiopulmonary bypass (CPB in coronary artery bypass surgery. Patients and Methods: In this randomized trial, 87 patients undergoing elective and isolated coronary bypass surgery included. The patients were randomly assigned into three groups (n = 29 each: (1 Control group with no treatment, (2 GSE group who received the extract 24 h before operation, 100 mg every 6 h, orally, (3 Vitamin C group who received 25 mg/kg Vitamin C through CPB during surgery. Blood samples were taken from coronary sinus at (T1 just before aortic cross clamp; (T2 just before starting controlled aortic root reperfusion; and (T3 10 min after root reperfusion. Some clinical parameters and biochemical markers were compared among the groups. Results: There were significant differences in tracheal intubation times, sinus rhythm return, and left ventricular function between treatment groups compared with control (P 0.05 in all cases. Conclusions: In our patients, GSE and Vitamin C had antioxidative effects and reduced deleterious effects of CPB during coronary artery bypass grafting surgery.

  20. Reperfusion promotes mitochondrial dysfunction following focal cerebral ischemia in rats.

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    Jun Li

    Full Text Available BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been implicated in the cell death observed after cerebral ischemia, and several mechanisms for this dysfunction have been proposed. Reperfusion after transient cerebral ischemia may cause continued and even more severe damage to the brain. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. The purpose of this study was to observe the features of mitochondrial dysfunction in isolated mitochondria during the reperfusion period following focal cerebral ischemia. METHODS: Male Wistar rats were subjected to focal cerebral ischemia. Mitochondria were isolated using Percoll density gradient centrifugation. The isolated mitochondria were fixed for electron microscopic examination; calcium-induced mitochondrial swelling was quantified using spectrophotometry. Cyclophilin D was detected by Western blotting. Fluorescent probes were used to selectively stain mitochondria to measure their membrane potential and to measure reactive oxidative species production using flow cytometric analysis. RESULTS: Signs of damage were observed in the mitochondrial morphology after exposure to reperfusion. The mitochondrial swelling induced by Ca(2+ increased gradually with the increasing calcium concentration, and this tendency was exacerbated as the reperfusion time was extended. Cyclophilin D protein expression peaked after 24 hours of reperfusion. The mitochondrial membrane potential was decreased significantly during the reperfusion period, with the greatest decrease observed after 24 hours of reperfusion. The surge in mitochondrial reactive oxidative species occurred after 2 hours of reperfusion and was maintained at a high level during the reperfusion period. CONCLUSIONS: Reperfusion following focal cerebral ischemia induced significant mitochondrial morphological damage and Ca(2+-induced mitochondrial swelling. The mechanism of this swelling may be mediated by

  1. Rosmarinic acid attenuates hepatic ischemia and reperfusion injury in rats.

    Science.gov (United States)

    Ramalho, Leandra Naira Z; Pasta, Ângelo Augusto C; Terra, Vânia Aparecida; Augusto, Marlei Josiele; Sanches, Sheila Cristina; Souza-Neto, Fernando P; Cecchini, Rubens; Gulin, Francine; Ramalho, Fernando Silva

    2014-12-01

    Rosmarinic acid (RosmA) demonstrates antioxidant and anti-inflammatory properties. We investigated the effect of RosmA on liver ischemia/reperfusion injury. Rats were submitted to 60 min of ischemia plus saline or RosmA treatment (150 mg/kg BW intraperitoneally) followed by 6 h of reperfusion. Hepatocellular injury was evaluated according to aminotransferase activity and histological damage. Hepatic neutrophil accumulation was also evaluated. Oxidative/nitrosative stress was estimated by measuring the reduced glutathione, lipid hydroperoxide and nitrotyrosine levels. Endothelial and inducible nitric oxide synthase (eNOS/iNOS) and nitric oxide (NO) were assessed with immunoblotting and chemiluminescence assays. Hepatic tumor necrosis factor-alpha (TNF-α) and interleukin-1beta mRNA were assessed using real-time PCR, and nuclear factor-kappaB (NF-κB) activation was estimated by immunostaining. RosmA treatment reduced hepatocellular damage, neutrophil infiltration and all oxidative/nitrosative stress parameters. RosmA decreased the liver content of eNOS/iNOS and NO, attenuated NF-κB activation, and down-regulated TNF-α and interleukin-1beta gene expression. These data indicate that RosmA exerts anti-inflammatory and antioxidant effects in the ischemic liver, thereby protecting hepatocytes against ischemia/reperfusion injury. The mechanisms underlying these effects may be related to the inhibitory potential of RosmA on the NF-κB signaling pathway and the reduction of iNOS and eNOS expressions and NO levels, in addition to its natural antioxidant capability.

  2. 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.

  3. Recovery of renal function after administration of adipose-tissue-derived stromal vascular fraction in rat model of acute kidney injury induced by ischemia/reperfusion injury.

    Science.gov (United States)

    Lee, Chunwoo; Jang, Myoung Jin; Kim, Bo Hyun; Park, Jin Young; You, Dalsan; Jeong, In Gab; Hong, Jun Hyuk; Kim, Choung-Soo

    2017-03-10

    Acute kidney injury (AKI) induced by ischemia/reperfusion (I/R) injury is a major challenge in critical care medicine. The purpose of this study is to determine the therapeutic effects of the adipose-tissue-derived stromal vascular fraction (SVF) and the optimal route for SVF delivery in a rat model of AKI induced by I/R injury. Fifty male Sprague-Dawley rats were randomly divided into five groups (10 animals per group): sham, nephrectomy control, I/R injury control, renal arterial SVF infusion and subcapsular SVF injection. To induce AKI by I/R injury, the left renal artery was clamped with a nontraumatic vascular clamp for 40 min, and the right kidney was removed. Rats receiving renal arterial infusion of SVF had a significantly reduced increase in serum creatinine compared with the I/R injury control group at 4 days after I/R injury. The glomerular filtration rate of the renal arterial SVF infusion group was maintained at a level similar to that of the sham and nephrectomy control groups at 14 days after I/R injury. Masson's trichrome staining showed significantly less fibrosis in the renal arterial SVF infusion group compared with that in the I/R injury control group in the outer stripe (P renal arterial SVF infusion and subcapsular SVF injection groups compared with the I/R injury control group in the outer stripe (P renal function is effectively rescued from AKI induced by I/R injury through the renal arterial administration of SVF in a rat model.

  4. Red propolis ameliorates ischemic-reperfusion acute kidney injury.

    Science.gov (United States)

    da Costa, Marcus Felipe Bezerra; Libório, Alexandre Braga; Teles, Flávio; Martins, Conceição da Silva; Soares, Pedro Marcos Gomes; Meneses, Gdayllon C; Rodrigues, Francisco Adelvane de Paulo; Leal, Luzia Kalyne Almeida Moreira; Miron, Diogo; Silva, Aline Holanda; Martins, Alice Maria Costa

    2015-08-15

    Acute kidney injury (AKI) remains a great problem in clinical practice. Renal ischemia/reperfusion (I/R) injury is a complex pathophysiological process. Propolis is a natural polyphenol-rich resinous substance collected by honeybees from a variety of plant sources that has anti-inflammatory and anti-oxidative properties. Red propolis (RP) protection in renal I/R injury was investigated. Male Wistar rats underwent unilateral nephrectomy and contralateral renal I/R (60 min). Rats were divided into four groups: (1) sham group, (2) RP group (sham-operated rats treated with RP), 3) IR group (rats submitted to ischemia) and (4) IR-RP (rats treated with RP before ischemia). At 48 h after reperfusion, renal function was assessed and kidneys were removed for analysis. I/R increased plasma levels of creatinine and reduced creatinine clearance (CrCl), and RP provided protection against this renal injury. Red propolis significantly improves oxidative stress parameters when compared with the IR group. Semiquantitative assessment of the histological lesions showed marked structural damage in I/R rats compared with the IR-RP rats. RP attenuates I/R-induced endothelial nitric oxide-synthase down regulation and increased heme-oxygenase expression in renal tissue. Red propolis protects kidney against acute ischemic renal failure and this protection is associated with reduced oxidative stress and eNOS and heme-oxygenase up regulation. Copyright © 2015 Elsevier GmbH. All rights reserved.

  5. Vascular relaxation of canine visceral arteries after ischemia by means of supraceliac aortic cross-clamping followed by reperfusion

    OpenAIRE

    Dalio Marcelo B; Evora Paulo RB; Joviliano Edwaldo E; Baldo Caroline F; Celotto Andrea C; Capellini Verena K; Ciscato José G; Piccinato Carlos E

    2010-01-01

    Abstract Background The supraceliac aortic cross-clamping can be an option to save patients with hipovolemic shock due to abdominal trauma. However, this maneuver is associated with ischemia/reperfusion (I/R) injury strongly related to oxidative stress and reduction of nitric oxide bioavailability. Moreover, several studies demonstrated impairment in relaxation after I/R, but the time course of I/R necessary to induce vascular dysfunctio...

  6. Temperature Induced Stress Dependent Photoluminescence Properties of Nanocrystallite Zinc Oxide

    Directory of Open Access Journals (Sweden)

    V. Kumar

    2011-01-01

    Full Text Available In this paper, Temperature induced stress dependent structural, optical and photoluminescence properties of nanoscrysllites ZnO (nc-ZnO films are reported. It is seen that crystallite size, band gap and PL intensity of nc-ZnO are strongly dependent on stress. Large compressive stress has been observed at temperature 350-400 °C while minimum stress obtained at temperature 450 °C. A small amount of expensive stress is obtained at temperature 500 and 500 °C. The surface topography of the nc-ZnO films has been studied using atomic force microscopy. The optical band gap of nc-ZnO has been decreased from 3.25 to 3.23 eV as a function of temperature induced stress. The luminescence property is dependent on stress of nc-ZnO films.

  7. Sertraline induces endoplasmic reticulum stress in hepatic cells.

    Science.gov (United States)

    Chen, Si; Xuan, Jiekun; Couch, Letha; Iyer, Advait; Wu, Yuanfeng; Li, Quan-Zhen; Guo, Lei

    2014-08-01

    Sertraline is used for the treatment of depression, and is also used for the treatment of panic, obsessive-compulsive, and post-traumatic stress disorders. Previously, we have demonstrated that sertraline caused hepatic cytotoxicity, with mitochondrial dysfunction and apoptosis being underlying mechanisms. In this study, we used microarray and other biochemical and molecular analyses to identify endoplasmic reticulum (ER) stress as a novel molecular mechanism. HepG2 cells were exposed to sertraline and subjected to whole genome gene expression microarray analysis. Pathway analysis revealed that ER stress is among the significantly affected biological changes. We confirmed the increased expression of ER stress makers by real-time PCR and Western blots. The expression of typical ER stress markers such as PERK, IRE1α, and CHOP was significantly increased. To study better ER stress-mediated drug-induced liver toxicity; we established in vitro systems for monitoring ER stress quantitatively and efficiently, using Gaussia luciferase (Gluc) and secreted alkaline phosphatase (SEAP) as ER stress reporters. These in vitro systems were validated using well-known ER stress inducers. In these two reporter assays, sertraline inhibited the secretion of Gluc and SEAP. Moreover, we demonstrated that sertraline-induced apoptosis was coupled to ER stress and that the apoptotic effect was attenuated by 4-phenylbutyrate, a potent ER stress inhibitor. In addition, we showed that the MAP4K4-JNK signaling pathway contributed to the process of sertraline-induced ER stress. In summary, we demonstrated that ER stress is a mechanism of sertraline-induced liver toxicity.

  8. 20(R)-Ginsenoside Rg3 protects SH-SY5Y cells against apoptosis induced by oxygen and glucose deprivation/reperfusion.

    Science.gov (United States)

    He, Bo; Chen, Peng; Xie, Yu; Li, Shude; Zhang, Xiaochao; Yang, Renhua; Wang, Guihua; Shen, Zhiqiang; Wang, Hui

    2017-08-15

    As shown in our previous studies, 20(R)-ginsenoside Rg3 [20(R)-Rg3] exerts a neuroprotective effect on a rat model of transient focal cerebral ischemia, and the mechanism through which it decreases the mRNA expression of calpain I and caspase-3 has been delineated. However, researchers do not know whether 20(R)-Rg3 exhibits a neuroprotective effect following oxygen-glucose deprivation and reperfusion (OGD/R) injury in vitro. In the present study, 20(R)-Rg3 increased cell viability, decreased the LDH leakage rate, and inhibited the apoptosis rate in a concentration-dependent manner. In addition, 20(R)-Rg3 markedly decreased cleaved caspase-3 protein expression. Furthermore, 20(R)-Rg3 significantly decreased the Bax mRNA and protein levels and increased the levels of Bcl-2 mRNA and protein, subsequently decreasing the Bax/Bcl-2 protein ratio. Based on these findings, 20(R)-Rg3 exerts a neuroprotective effect against OGD/R-induced apoptosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. A new gastric ulcer model induced by ischemia-reperfusion in the rat: role of leukocytes on ulceration in rat stomach.

    Science.gov (United States)

    Wada, K; Kamisaki, Y; Kitano, M; Kishimoto, Y; Nakamoto, K; Itoh, T

    1996-01-01

    A new model of gastric ulcer involving damage to the muscularis mucosae was developed by clamping the celiac artery in rat to induce ischemia-reperfusion (I-R) injury. Although erosions with falling off of the gastric mucosa were observed immediately, 24 and 36 hours after the I-R, gastric ulcers involving the injury of muscularis mucosae were observed in the area of gastric glands at 48 and 72 hours after initiation of injury. Administration of omeprazol, a proton pump inhibitor, or pentoxifylline, an anti-leukocyte drug, just after the initiation of injury significantly decreased the total area of ulcers at 72 hours. A combination of omeprazol and pentoxifylline was more effective than either drug alone. An anti-leukocyte adhesion molecule (anti-CD18 antibody) also showed significant inhibitory effect on the development of ulcers at 72 hours and the infiltration of leukocytes into both submucosa and mucosa. These results indicate that in our model, gastric acid together with leukocytes contribute to the development of ulcers following erosions. This model may be used to investigate the mechanisms of the development of gastric ulcer and evaluate antiulcer drugs in a preclinical setting.

  10. Cardioprotective effects of salidroside on myocardial ischemia-reperfusion injury in coronary artery occlusion-induced rats and Langendorff-perfused rat hearts.

    Science.gov (United States)

    Chang, Xiayun; Zhang, Kai; Zhou, Rui; Luo, Fen; Zhu, Lingpeng; Gao, Jin; He, He; Wei, Tingting; Yan, Tianhua; Ma, Chunhua

    2016-07-15

    The current study was designed to investigate the protective role of salisroside on rats through the study of energy metabolism homeostasis and inflammation both in ex vivo and in vivo. Energy metabolism homeostasis and inflammation injury were respectively assessed in global ischemia of isolated hearts and coronary artery ligated rats. Excessive release of cardiac enzymes and pro-inflammatory cytokines was inhibited by salidroside in coronary artery occlusion-induced rats. ST segment was also restored with the treatment of salidroside. Triphenyltetrazolium chloride staining (TTC) staining and pathological analysis showed that salidroside could significantly alleviate myocardial injury in vivo. Accumulated data in ex vivo indicated that salidroside improved heart function recovery, which was reflected by enhanced myocardial contractility and coronary flow in isolated hearts. The contents of ATP and glycogen both in ex vivo and in vivo were restored by salidroside compared with those in the model group. Besides, the expressions of p-AMPK, PPAR-α and PGC-1α in rats and isolated hearts subjected to salidroside were significantly elevated, while the levels of p-NF-κBp65, p-IκBα, p-IKKα and p-IKKβ were dramatically reduced by salidroside. The present study comprehensively elaborated the protective effects of salidroside on myocardial injury and demonstrated that AMPK/PGC-1α and AMPK/NF-κB signaling cascades were implicated in the myocardial ischemia-reperfusion injury (I/R) model. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. 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.

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    Meihua He

    Full Text Available 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.

  12. The novel H2S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoKATP channels and reduction of oxidative stress.

    Science.gov (United States)

    Testai, Lara; Marino, Alice; Piano, Ilaria; Brancaleone, Vincenzo; Tomita, Kengo; Di Cesare Mannelli, Lorenzo; Martelli, Alma; Citi, Valentina; Breschi, Maria C; Levi, Roberto; Gargini, Claudia; Bucci, Mariarosaria; Cirino, Giuseppe; Ghelardini, Carla; Calderone, Vincenzo

    2016-11-01

    The endogenous gasotransmitter hydrogen sulphide (H2S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H2S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury, and is considered an important mediator of "ischemic preconditioning", through activation of mitochondrial potassium channels, reduction of oxidative stress, activation of the endogenous "anti-oxidant machinery" and limitation of inflammatory responses. Accordingly, H2S-donors, i.e. pro-drugs able to generate exogenous H2S, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel H2S-donor 4-carboxy phenyl-isothiocyanate (4CPI), whose vasorelaxing effects were recently reported, was tested here in different experimental models of myocardial I/R. In Langendorff-perfused rat hearts subjected to I/R, 4CPI significantly improved the post-ischemic recovery of myocardial functional parameters and limited tissue injury. These effects were antagonized by 5-hydroxydecanoic acid (a blocker of mitoKATP channels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of H2S-producing enzymes to be present in myocardial tissue: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST). Notably, 4CPI down-regulated the post-ischemic expression of CSE. In Langendorff-perfused mouse hearts, 4CPI reduced the post-ischemic release of norepinephrine and the incidence of ventricular arrhythmias. In both rat and mouse hearts, 4CPI did not affect the degranulation of resident mast cells. In isolated rat cardiac mitochondria, 4CPI partially depolarized the mitochondrial membrane potential; this effect was antagonized by ATP (i.e., the physiological inhibitor of KATP channels). Moreover, 4CPI abrogated calcium uptake in the mitochondrial matrix. Finally, in an in vivo model of acute myocardial infarction in rats, 4

  13. Stress-induced changes in wheat grain composition and quality.

    Science.gov (United States)

    Ashraf, M

    2014-01-01

    Abiotic stresses such as drought, salinity, waterlogging, and high temperature cause a myriad of changes in the metabolism of plants, and there is a lot of overlap in these changes in plants in response to different stresses such as drought and salinity. These stress-induced metabolic changes cause impaired crop growth thereby resulting in poor yield. The metabolic changes taking place in several plant species due to a particular abiotic stress have been revealed from the whole plant to the molecular level by researchers, but most studies have focused on organs such as leaf, stem, and root. Information on such stress-induced changes in seed or grains is infrequent in the literature. From the information that is available, it is now evident that abiotic stress can induce considerable changes in the composition and quality of cereal grains including those of wheat, the premier staple food crop in the world. Thus, the present review discusses how far different types of stresses, mainly salinity, drought, high temperature, and waterlogging, can alter the wheat grain composition and quality. By fully uncovering the stress-induced changes in the nutritional values of wheat grains it would be possible to establish whether balanced supplies of essential nutrients are available to the human population from the wheat crop grown on stress-affected areas.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. ER stress induced by ionising radiation in IEC-6 cells.

    Science.gov (United States)

    Zhang, Bo; Wang, Yan; Pang, Xueli; Su, Yongping; Ai, Guoping; Wang, Tao

    2010-06-01

    Ionising radiation (IR) can evoke a series of biochemical events inside the cell. However, whether IR can directly induce endoplasmic reticulum (ER) stress is not clear. In our previous study, we found that there might be a causative link between IR and ER stress. In this study, we further characterised the type of ER stress induced by IR. Rat intestinal epithelial cells IEC-6 were irradiated at a dose of 10 Gy, and total RNA and proteins were harvested at indicated time points. The mRNA and protein expression of immunoglobulin heavy chain binding protein (BiP) and glucose regulated protein 94 (GRP94) was detected along with proteins associated with ER stress signal pathways. Our results indicated that IR induced up-regulation of ER stress marker including BiP and GRP94 at protein and mRNA levels in IEC-6 cells. Increased phosphorylation of eukaryotic translation initiation factor 2 (eIF2alpha) and induced mRNA splicing of X-box binding protein 1 (XBP1) suggested that PERK (interferon-induced double-stranded RNA-activated protein kinase (PRKR) -like endoplasmic reticulum kinase) and IRE1 (inositol requirement 1) signal transduction pathways were involved in this kind of ER stress. However, the active form of activating transcription factor 6 (ATF6) did not change significantly in irradiated cells, which suggested that the ATF6 pathway was not involved. Thus, we concluded that IR could induce moderate ER stress directly in IEC-6 cells.

  16. Neurobiology of Stress-Induced Reproductive Dysfunction In Female Macaques

    Science.gov (United States)

    Bethea, Cynthia L.; Centeno, Maria Luisa; Cameron, Judy L.

    2012-01-01

    It is now well accepted that stress can precipitate mental and physical illness. However, it is becoming clear that given the same stress, some individuals are very vulnerable and will succumb to illness while others are more resilient and cope effectively, rather than becoming ill. This difference between individuals is called stress sensitivity. Stress-sensitivity of an individual appears to be influenced by genetically inherited factors, early life (even prenatal) stress, and by the presence or absence of factors that provide protection from stress. In comparison to other stress-related diseases, the concept of sensitivity versus resilience to stress-induced reproductive dysfunction has received relatively little attention. The studies presented herein were undertaken to begin to identify stable characteristics and the neural underpinnings of individuals with sensitivity to stress-induced reproductive dysfunction. Female cynomolgus macaques with normal menstrual cycles either stop ovulating (Stress Sensitive) or to continue to ovulate (Stress Resilient) upon exposure to a combined metabolic and psychosocial stress. However, even in the absence of stress, the stress sensitive animals have lower secretion of the ovarian steroids, estrogen and progesterone, have higher heart rates, have lower serotonin function, have fewer serotonin neurons and lower expression of pivotal serotonin-related genes, have lower expression of 5HT2A and 2C genes in the hypothalamus, have higher gene expression of GAD67 and CRH in the hypothalamus and have reduced GnRH transport to the anterior pituitary. Altogether, the results suggest that the neurobiology of reproductive circuits in stress sensitive individuals is compromised. We speculate that with the application of stress, the dysfunction of these neural systems becomes exacerbated and reproductive function ceases. PMID:18931961

  17. E2-25K SUMOylation inhibits proteasome for cell death during cerebral ischemia/reperfusion

    Science.gov (United States)

    Jeong, Eun Il; Chung, Hae Won; Lee, Won Jea; Kim, Seo-Hyun; Kim, Hyunjoo; Choi, Seon-Guk; Jung, Yong-Keun

    2016-01-01

    Cerebral ischemia/reperfusion (I/R) causes brain damage accompanied by ubiquitin accumulation and impairment of proteasome activity. In this study, we report that E2-25K, an E2-conjugating enzyme, is SUMOylated during oxidative stress and regulates cerebral I/R-induced damage. Knockdown of E2-25K expression protects against oxygen/glucose deprivation and reoxygenation (OGD/R)-induced neuronal cell death, whereas ectopic expression of E2-25K stimulates it. Compared with the control mice, cerebral infarction lesions and behavioral/neurological disorders are ameliorated in E2-25K knockout mice during middle cerebral artery occlusion and reperfusion. In particular, E2-25K is SUMOylated at Lys14 under oxidative stress, OGD/R and I/R to prompt cell death. Further, E2-25K downregulates the proteasome subunit S5a to impair proteasome complex and thus restrain proteasome activity under oxidative stress. This proteasome inhibitory activity of E2-25K is dependent on its SUMOylation. These results suggest that E2-25K has a crucial role in oxidative stress and cerebral I/R-induced damage through inhibiting proteasome via its SUMOylation. PMID:28032866

  18. Vertical variations of wave-induced radiation stress tensor

    Institute of Scientific and Technical Information of China (English)

    Zheng Jinhai; Yan Yixin

    2001-01-01

    The distributions of the wave-induced radiation stress tensor over depth are studied by using the linear wave theory, which are divided into three regions, i.e., above the mean water level, below the wave trough level, and between these two levels. The computational expressions of the wave-induced radiation stress tensor at the arbitrary wave angle are established by means of the Eulerian coordinate transformation, and the asymptotic forms for deep and shallow water are also presented. The vertical variations of a 30° incident wave-induced radiation stress tensor in deep water, intermediate water and shallow water are calculated respectively. The following conclusions are obtained from computations.The wave-induced radiation stress tensor below the wave trough level is induced by the water wave particle velocities only, whereas both the water wave particle velocities and the wave pressure contribute to the tensor above the wave trough level. The vertical variations of the wave-induced radiation stress tensor are influenced substantially by the velocity component in the direction of wave propagation. The distributions of the wave-induced radiation stress tensor over depth are nonuniform and the proportion of the tensor below the wave trough level becomes considerable in the shallow water. From the water surface to the seabed, the reversed variations occur for the predominant tensor components.

  19. Exogenous and Endogenous Hydrogen Sulfide Protects Gastric Mucosa against the Formation and Time-Dependent Development of Ischemia/Reperfusion-Induced Acute Lesions Progressing into Deeper Ulcerations

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    Marcin Magierowski

    2017-02-01

    Full Text Available Hydrogen sulfide (H2S is an endogenous mediator, synthesized from l-cysteine by cystathionine γ-lyase (CSE, cystathionine β-synthase (CBS or 3-mercaptopyruvate sulfurtransferase (3-MST. The mechanism(s involved in H2S-gastroprotection against ischemia/reperfusion (I/R lesions and their time-dependent progression into deeper gastric ulcerations have been little studied. We determined the effect of l-cysteine, H2S-releasing NaHS or slow H2S releasing compound GYY4137 on gastric blood flow (GBF and gastric lesions induced by 30 min of I followed by 3, 6, 24 and 48 h of R. Role of endogenous prostaglandins (PGs, afferent sensory nerves releasing calcitonin gene-related peptide (CGRP, the gastric expression of hypoxia inducible factor (HIF-1α and anti-oxidative enzymes were examined. Rats with or without capsaicin deactivation of sensory nerves were pretreated i.g. with vehicle, NaHS (18–180 μmol/kg GYY4137 (90 μmol/kg or l-cysteine (0.8–80 μmol/kg alone or in combination with (1 indomethacin (14 μmol/kg i.p., SC-560 (14 μmol/kg, celecoxib (26 μmol/kg; (2 capsazepine (13 μmol/kg i.p.; and (3 CGRP (2.5 nmol/kg i.p.. The area of I/R-induced gastric lesions and GBF were measured by planimetry and H2-gas clearance, respectively. Expression of mRNA for CSE, CBS, 3-MST, HIF-1α, glutathione peroxidase (GPx-1, superoxide dismutase (SOD-2 and sulfide production in gastric mucosa compromised by I/R were determined by real-time PCR and methylene blue method, respectively. NaHS and l-cysteine dose-dependently attenuated I/R-induced lesions while increasing the GBF, similarly to GYY4137 (90 μmol/kg. Capsaicin denervation and capsazepine but not COX-1 and COX-2 inhibitors reduced NaHS- and l-cysteine-induced protection and hyperemia. NaHS increased mRNA expression for SOD-2 and GPx-1 but not that for HIF-1α. NaHS which increased gastric mucosal sulfide release, prevented further progression of acute I/R injury into deeper gastric ulcers at 6, 24

  20. The effects of gallic acid on pain and memory following transient global ischemia/reperfusion in Wistar rats

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    Yaghoob Farbood

    2013-07-01

    Full Text Available Objective: It is generally agreed that most of the phenomena observed during brain ischemia and reperfusion can be explained by the damage to membrane structure. Oxidative stress is resulted in an imbalance between high consumption of oxygen and low levels of endogenous antioxidants. It is known that gallic acid (GA is a strong antioxidant. The present study was carried out to evaluate the effect of GA on ischemia/reperfusion (I/R-induced brain injury in rats.  Materials and Methods: Wistar adult male rats weighing 200–250 g were divided into six groups as sham operated (Sh, ischemia/reperfusion (I/R received normal saline (I+Veh, I/R groups treated with gallic acid (I+GA, 50, 100, or 200 mg/kg, orally, respectively, or with 100 mg /kg phenytoin (I+Phen. The global cerebral I/R injury was induced by occluding bilateral common carotid arteries (BCCA for 20 min, followed by 5 days reperfusion in adult male rats. Results: It was found that administration of 100 mg/kg GA for 5 days before and 5 days after I/R induction reversed gait performance, sensorimotor disorders (p

  1. Cardioprotective Effects of Salvianolic Acid A on Myocardial Ischemia-Reperfusion Injury In Vivo and In Vitro

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    Huaying Fan

    2012-01-01

    Full Text Available Salvianolic acid A (SAA, one of the major active components of Danshen that is a traditional Chinese medicine, has been reported to possess protective effect in cardiac diseases and antioxidative activity. This study aims to investigate the cardioprotection of SAA in vivo and in vitro using the model of myocardial ischemia-reperfusion in rat and hydrogen peroxide (H2O2-induced H9c2 rat cardiomyoblasts apoptosis. It was found that SAA significantly limited infarct size of ischemic myocardium when given immediately prior to reperfusion. SAA also significantly suppressed cellular injury and apoptotic cell death. Additionally, the results of western blot and phospho-specific antibody microarray analysis showed that SAA could up-regulate Bcl-2 expression and increase the phosphorylation of proteins such as Akt, p42/p44 extracellular signal-related kinases (Erk1/2, and their related effectors. The phosphorylation of those points was related to suppress apoptosis. In summary, SAA possesses marked protective effect on myocardial ischemia-reperfusion injury, which is related to its ability to reduce myocardial cell apoptosis and damage induced by oxidative stress. The protection is achieved via up-regulation of Bcl-2 expression and affecting protein phosphorylation. These findings indicate that SAA may be of value in cardioprotection during myocardial ischemia-reperfusion injury, which provide pharmacological evidence for clinical application.

  2. Cardioprotective Effects of Salvianolic Acid A on Myocardial Ischemia-Reperfusion Injury In Vivo and In Vitro

    Science.gov (United States)

    Fan, Huaying; Yang, Liu; Fu, Fenghua; Xu, Hui; Meng, Qinggang; Zhu, Haibo; Teng, Lirong; Yang, Mingyan; Zhang, Leiming; Zhang, Ziliang; Liu, Ke

    2012-01-01

    Salvianolic acid A (SAA), one of the major active components of Danshen that is a traditional Chinese medicine, has been reported to possess protective effect in cardiac diseases and antioxidative activity. This study aims to investigate the cardioprotection of SAA in vivo and in vitro using the model of myocardial ischemia-reperfusion in rat and hydrogen peroxide (H2O2)-induced H9c2 rat cardiomyoblasts apoptosis. It was found that SAA significantly limited infarct size of ischemic myocardium when given immediately prior to reperfusion. SAA also significantly suppressed cellular injury and apoptotic cell death. Additionally, the results of western blot and phospho-specific antibody microarray analysis showed that SAA could up-regulate Bcl-2 expression and increase the phosphorylation of proteins such as Akt, p42/p44 extracellular signal-related kinases (Erk1/2), and their related effectors. The phosphorylation of those points was related to suppress apoptosis. In summary, SAA possesses marked protective effect on myocardial ischemia-reperfusion injury, which is related to its ability to reduce myocardial cell apoptosis and damage induced by oxidative stress. The protection is achieved via up-regulation of Bcl-2 expression and affecting protein phosphorylation. These findings indicate that SAA may be of value in cardioprotection during myocardial ischemia-reperfusion injury, which provide pharmacological evidence for clinical application. PMID:21789047

  3. Effect of drought stress induced by polyethylene glycol (PEG) on ...

    African Journals Online (AJOL)

    Effect of drought stress induced by polyethylene glycol (PEG) on germination indices in corn ( Zea mays L.) hybrids. ... African Journal of Biotechnology ... and success in this stage is dependent on moisture content of soil at time of planting.

  4. Dipropionylcysteine ethyl ester compensates for loss of citric acid cycle intermediates during post ischemia reperfusion in the pig heart.

    Science.gov (United States)

    Kasumov, Takhar; Sharma, Naveen; Huang, Hazel; Kombu, Rajan S; Cendrowski, Andrea; Stanley, William C; Brunengraber, Henri

    2009-12-01

    During reperfusion, following myocardial ischemia, uncompensated loss of citric acid cycle (CAC) intermediates may impair CAC flux and energy transduction. Propionate has an anaplerotic effect when converted to the CAC intermediate succinyl-CoA, and may improve contractile recovery during reperfusion. Antioxidant therapy with N-acetylcysteine decreases reperfusion injury. To synergize the antioxidant effects of cysteine with the anaplerotic effects of propionate, we synthesized a novel bi-functional compound, N,S-dipropionyl cysteine ethyl ester (DPNCE) and tested its anaplerotic and anti-oxidative capacity in anesthetized pigs. Ischemia was induced by a 70% reduction in left anterior descending coronary artery flow for one hour, followed by 1 h of reperfusion. After 30 min of ischemia and throughout reperfusion animals were treated with saline or intravenous DPNCE (1.5 mg x kg(-1) x min(-1), n = 8/group). Arterial concentrations and myocardial propionate, cysteine, free fatty acids, glucose and lactate uptakes, cardiac mechanical functions, myocardial content of CAC intermediates and oxidative stress were assessed. Ischemia resulted in reduction in myocardial tissue concentration of CAC intermediates. DPNCE treatment elevated arterial propionate and cysteine concentrations and myocardial propionate uptake, and increased myocardial concentrations of citrate, succinate, fumarate, and malate compared to saline treated animals. DPNCE treatment did not affect blood pressure or myocardial contractile function, but increased arterial free fatty acid concentration and myocardial fatty acid uptake. Arterial cysteine concentration was elevated by DPNCE, but there was negligible myocardial cysteine uptake, and no change in markers of oxidative stress. DPNCE elevated arterial cysteine and propionate, and increased myocardial concentration of CAC intermediates, but did not affect mechanical function or oxidative stress.

  5. Possible Biomarkers of Chronic Stress Induced Exhaustion - A Longitudinal Study.

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    Johanna Wallensten

    Full Text Available Vascular endothelial growth factor (VEGF, epidermal growth factor (EGF and monocyte chemotactic protein-1 (MCP-1 have previously been suggested to be potential biomarkers for chronic stress induced exhaustion. The knowledge about VEGF has increased during the last decades and supports the contention that VEGF plays an important role in stress and depression. There is scarce knowledge on the possible relationship of EGF and MCP-1 in chronic stress and depression. This study further examines the role of VEGF, EGF and MCP-1 in women with chronic stress induced exhaustion and healthy women during a follow-up period of two years.Blood samples were collected from 105 women with chronic stress induced exhaustion on at least 50% sick leave for at least three months, at inclusion (T0, after 12 months (T12 and after 24 months (T24. Blood samples were collected at inclusion (T0 in 116 physically and psychiatrically healthy women. The plasma levels of VEGF, EGF and MCP-1 were analyzed using Biochip Array Technology. Women with chronic stress induced exhaustion had significantly higher plasma levels of VEGF and EGF compared to healthy women at baseline, T12 and at T24. There was no significant difference in plasma levels of MCP-1. Plasma levels of VEGF and EGF decreased significantly in women with chronic stress induced exhaustion during the two years follow-up.The replicated findings of elevated levels of VEGF and EGF in women with chronic stress induced exhaustion and decreasing plasma levels of VEGF and EGF during the two years follow-up add important knowledge to the pathophysiology of chronic stress induced exhaustion.

  6. N-acetylcysteine attenuates ischemia-reperfusion-induced apoptosis and autophagy in mouse liver via regulation of the ROS/JNK/Bcl-2 pathway.

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    Chengfen Wang

    Full Text Available BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI remains a pivotal clinical problem after hemorrhagic shock, transplantation, and some types of toxic hepatic injury. Apoptosis and autophagy play important roles in cell death during HIRI. It is also known that N-acetylcysteine (NAC has significant pharmacologic effects on HIRI including elimination of reactive oxygen species (ROS and attenuation of hepatic apoptosis. However, the effects of NAC on HIRI-induced autophagy have not been reported. In this study, we evaluated the effects of NAC on autophagy and apoptosis in HIRI, and explored the possible mechanism involved. METHODS: A mouse model of segmental (70% hepatic warm ischemia was adopted to determine hepatic injury. NAC (150 mg/kg, a hepatoprotection agent, was administered before surgery. We hypothesized that the mechanism of NAC may involve the ROS/JNK/Bcl-2 pathway. We evaluated the expression of JNK, P-JNK, Bcl-2, Beclin 1 and LC3 by western blotting and immunohistochemical staining. Autophagosomes were evaluated by transmission electron microscopy (TEM. RESULTS: We found that ALT, AST and pathological changes were significantly improved in the NAC group. Western blotting analysis showed that the expression levels of Beclin 1 and LC3 were significantly decreased in NAC-treated mice. In addition, JNK, p-JNK, Bax, TNF-α, NF-κB, IL2, IL6 and levels were also decreased in NAC-treated mice. CONCLUSION: NAC can prevent HIRI-induced autophagy and apoptosis by influencing the JNK signal pathway. The mechanism is likely to involve attenuation of JNK and p-JNK via scavenged ROS, an indirect increase in Bcl-2 level, and finally an alteration in the balance of Beclin 1 and Bcl-2.

  7. Altered Gravity Induces Oxidative Stress in Drosophila Melanogaster

    Science.gov (United States)

    Bhattacharya, Sharmila; Hosamani, Ravikumar

    2015-01-01

    Altered gravity environments can induce increased oxidative stress in biological systems. Microarray data from our previous spaceflight experiment (FIT experiment on STS-121) indicated significant changes in the expression of oxidative stress genes in adult fruit flies after spaceflight. Currently, our lab is focused on elucidating the role of hypergravity-induced oxidative stress and its impact on the nervous system in Drosophila melanogaster. Biochemical, molecular, and genetic approaches were combined to study this effect on the ground. Adult flies (2-3 days old) exposed to acute hypergravity (3g, for 1 hour and 2 hours) showed significantly elevated levels of Reactive Oxygen Species (ROS) in fly brains compared to control samples. This data was supported by significant changes in mRNA expression of specific oxidative stress and antioxidant defense related genes. As anticipated, a stress-resistant mutant line, Indy302, was less vulnerable to hypergravity-induced oxidative stress compared to wild-type flies. Survival curves were generated to study the combined effect of hypergravity and pro-oxidant treatment. Interestingly, many of the oxidative stress changes that were measured in flies showed sex specific differences. Collectively, our data demonstrate that altered gravity significantly induces oxidative stress in Drosophila, and that one of the organs where this effect is evident is the brain.

  8. Serotonergic involvement in stress-induced vasopressin and oxytocin secretion

    DEFF Research Database (Denmark)

    Jørgensen, Henrik; Knigge, Ulrich; Kjaer, Andreas

    2002-01-01

    OBJECTIVE: To investigate the involvement of serotonin (5-hydroxytryptamine - 5-HT) receptors in mediation of stress-induced arginine vasopressin (AVP) and oxytocin (OT) secretion in male rats. DESIGN: Experiments on laboratory rats with control groups. METHODS: Different stress paradigms were ap...

  9. Histone deacetylase inhibition abolishes stress-induced spatial memory impairment.

    Science.gov (United States)

    Vargas-López, Viviana; Lamprea, Marisol R; Múnera, Alejandro

    2016-10-01

    Acute stress induced before spatial training impairs memory consolidation. Although non-epigenetic underpinning of such effect has been described, the epigenetic mechanisms involved have not yet been studied. Since spatial training and intense stress have opposite effects on histone acetylation balance, it is conceivable that disruption of such balance may underlie acute stress-induced spatial memory consolidation impairment and that inhibiting histone deacetylases prevents such effect. Trichostatin-A (TSA, a histone deacetylase inhibitor) was used to test its effectiveness in preventing stress' deleterious effect on memory. Male Wistar rats were trained in a spatial task in the Barnes maze; 1-h movement restraint was applied to half of them before training. Immediately after training, stressed and non-stressed animals were randomly assigned to receive either TSA (1mg/kg) or vehicle intraperitoneal injection. Twenty-four hours after training, long-term spatial memory was tested; plasma and brain tissue were collected immediately after the memory test to evaluate corticosterone levels and histone H3 acetylation in several brain areas. Stressed animals receiving vehicle displayed memory impairment, increased plasma corticosterone levels and markedly reduced histone H3 acetylation in prelimbic cortex and hippocampus. Such effects did not occur in stressed animals treated with TSA. The aforementioned results support the hypothesis that acute stress induced-memory impairment is related to histone deacetylation. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. SOD1 aggregation in astrocytes following ischemia/reperfusion injury: a role of NO-mediated S-nitrosylation of protein disulfide isomerase (PDI

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    Chen Xueping

    2012-10-01

    Full Text Available Abstract Background Ubiquitinated-protein aggregates are implicated in cerebral ischemia/reperfusion injury. The very presence of these ubiquitinated-protein aggregates is abnormal and seems to be disease-related. However, it is not clear what leads to aggregate formation and whether the aggregations represent a reaction to aggregate-mediated neurodegeneration. Methods To study the nitrosative stress-induced protein aggregation in cerebral ischemia/reperfusion injury, we used primary astrocyte cultures as a cell model, and systematically examined their iNOS expression and consequent NO generation following oxygen glucose deprivation and reperfusion. The expression of protein disulfide isomerase (PDI and copper-zinc superoxide dismutase (SOD1 were also examined, and the biochemical interaction between PDI and SOD1 was determined by immunoprecipitation. In addition, the levels of S-nitrosylated PDI in cultured astrocytes after oxygen glucose deprivation and reperfusion treatment were measured using the biotin-switch assay. The formation of ubiquitinated-protein aggregates was detected by immunoblot and immunofluorescence staining. Results Our data showed that the up-regulation of iNOS expression after oxygen glucose deprivation and reperfusion treatment led to excessive NO generation. Up-regulation of PDI and SOD1 was also identified in cultured astrocytes following oxygen glucose deprivation and reperfusion, and these two proteins were found to bind to each other. Furthermore, the increased nitrosative stress due to ischemia/reperfusion injury was highly associated with NO-induced S-nitrosylation of PDI, and this S-nitrosylation of PDI was correlated with the formation of ubiquitinated-protein aggregates; the levels of S-nitrosylated PDI increased in parallel with the formation of aggregates. When NO generation was pharmacologically inhibited by iNOS specific inhibitor 1400W, S-nitrosylation of PDI was significantly blocked. In addition, the

  11. Breath Pentane as a Potential Biomarker for Survival in Hepatic Ischemia and Reperfusion Injury—A Pilot Study

    Science.gov (United States)

    Sun, Bo; Liu, Desheng; Li, Peng; Gong, Yulei; He, Ying; Liu, Shujuan; Xu, Guowang; Li, Jianyi; Luo, Ailin; Li, Enyou

    2012-01-01

    Background Exhaled pentane, which is produced as a consequence of reactive oxygen species-mediated lipid peroxidation, is a marker of oxidative stress. Propofol is widely used as a hypnotic agent in intensive care units and the operating room. Moreover, this agent has been reported to inhibit lipid peroxidation by directly scavenging reactive oxygen species. In this study, using a porcine liver ischemia-reperfusion injury model, we have evaluated the hypothesis that high concentrations of breath pentane are related to adverse outcome and that propofol could reduce breath pentane and improve liver injury and outcome in swine in this situation. Methodology/Principal Findings Twenty male swine were assigned to two groups: propofol (n = 10) and chloral hydrate groups (n = 10). Hepatic ischemia was induced by occluding the portal inflow vessels. Ischemia lasted for 30 min, followed by reperfusion for 360 min. Exhaled and blood pentane concentrations in the chloral hydrate group markedly increased 1 min after reperfusion and then decreased to baseline. Breath and blood pentane concentrations in the propofol group increased 1 min after reperfusion but were significantly lower than in the chloral hydrate group. A negative correlation was found between breath pentane levels and survival in the chloral hydrate group. The median overall survival was 251 min after reperfusion (range 150–360 min) in the chloral hydrate group. All of the swine were alive in the propofol group. Conclusions Monitoring of exhaled pentane may be useful for evaluating the severity of hepatic ischemia-reperfusion injury and aid in predicting the outcome; propofol may improve the outcome in this situation. PMID:22984587

  12. Breath pentane as a potential biomarker for survival in hepatic ischemia and reperfusion injury--a pilot study.

    Science.gov (United States)

    Wang, Changsong; Shi, Jinghui; Sun, Bo; Liu, Desheng; Li, Peng; Gong, Yulei; He, Ying; Liu, Shujuan; Xu, Guowang; Li, Jianyi; Luo, Ailin; Li, Enyou

    2012-01-01

    Exhaled pentane, which is produced as a consequence of reactive oxygen species-mediated lipid peroxidation, is a marker of oxidative stress. Propofol is widely used as a hypnotic agent in intensive care units and the operating room. Moreover, this agent has been reported to inhibit lipid peroxidation by directly scavenging reactive oxygen species. In this study, using a porcine liver ischemia-reperfusion injury model, we have evaluated the hypothesis that high concentrations of breath pentane are related to adverse outcome and that propofol could reduce breath pentane and improve liver injury and outcome in swine in this situation. Twenty male swine were assigned to two groups: propofol (n = 10) and chloral hydrate groups (n = 10). Hepatic ischemia was induced by occluding the portal inflow vessels. Ischemia lasted for 30 min, followed by reperfusion for 360 min. Exhaled and blood pentane concentrations in the chloral hydrate group markedly increased 1 min after reperfusion and then decreased to baseline. Breath and blood pentane concentrations in the propofol group increased 1 min after reperfusion but were significantly lower than in the chloral hydrate group. A negative correlation was found between breath pentane levels and survival in the chloral hydrate group. The median overall survival was 251 min after reperfusion (range 150-360 min) in the chloral hydrate group. All of the swine were alive in the propofol group. Monitoring of exhaled pentane may be useful for evaluating the severity of hepatic ischemia-reperfusion injury and aid in predicting the outcome; propofol may improve the outcome in this situation.

  13. Breath pentane as a potential biomarker for survival in hepatic ischemia and reperfusion injury--a pilot study.

    Directory of Open Access Journals (Sweden)

    Changsong Wang

    Full Text Available BACKGROUND: Exhaled pentane, which is produced as a consequence of reactive oxygen species-mediated lipid peroxidation, is a marker of oxidative stress. Propofol is widely used as a hypnotic agent in intensive care units and the operating room. Moreover, this agent has been reported to inhibit lipid peroxidation by directly scavenging reactive oxygen species. In this study, using a porcine liver ischemia-reperfusion injury model, we have evaluated the hypothesis that high concentrations of breath pentane are related to adverse outcome and that propofol could reduce breath pentane and improve liver injury and outcome in swine in this situation. METHODOLOGY/PRINCIPAL FINDINGS: Twenty male swine were assigned to two groups: propofol (n = 10 and chloral hydrate groups (n = 10. Hepatic ischemia was induced by occluding the portal inflow vessels. Ischemia lasted for 30 min, followed by reperfusion for 360 min. Exhaled and blood pentane concentrations in the chloral hydrate group markedly increased 1 min after reperfusion and then decreased to baseline. Breath and blood pentane concentrations in the propofol group increased 1 min after reperfusion but were significantly lower than in the chloral hydrate group. A negative correlation was found between breath pentane levels and survival in the chloral hydrate group. The median overall survival was 251 min after reperfusion (range 150-360 min in the chloral hydrate group. All of the swine were alive in the propofol group. CONCLUSIONS: Monitoring of exhaled pentane may be useful for evaluating the severity of hepatic ischemia-reperfusion injury and aid in predicting the outcome; propofol may improve the outcome in this situation.

  14. Potential role of punicalagin against oxidative stress induced testicular damage

    Directory of Open Access Journals (Sweden)

    Faiza Rao

    2016-01-01

    Full Text Available Punicalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin (purity ≥98% on oxidative stress induced testicular damage and its effect on fertility. We detected the antioxidant potential of punicalagin in lipopolysaccharide (LPS induced oxidative stress damage in testes, also tried to uncover the boosting fertility effect of Punicalagin (PU against oxidative stress-induced infertility. Results demonstrated that 9 mg kg−1 for 7 days treatment significantly decreases LPS induced oxidative damage in testes and nitric oxide production. The administration of oxidative stress resulted in a significant reduction in testes antioxidants GSH, T-SOD, and CAT raised LPO, but treatment with punicalagin for 7 days increased antioxidant defense GSH, T-SOD, and CAT by the end of the experiment and reduced LPO level as well. PU also significantly activates Nrf2, which is involved in regulation of antioxidant defense systems. Hence, the present research categorically elucidates the protective effect of punicalagin against LPS induced oxidative stress induced perturbation in the process of spermatogenesis and significantly increased sperm health and number. Moreover, fertility success significantly decreased in LPS-injected mice compared to controls. Mice injected with LPS had fertility indices of 12.5%, while others treated with a combination of PU + LPS exhibited 75% indices. By promoting fertility and eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of infertility.

  15. Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway.

    Science.gov (United States)

    Gong, Juanjuan; Sun, Fumou; Li, Yihang; Zhou, Xiaoling; Duan, Zhenzhen; Duan, Fugang; Zhao, Lei; Chen, Hansen; Qi, Suhua; Shen, Jiangang

    2015-04-01

    Momordica charantia (MC) is a medicinal plant for stroke treatment in Traditional Chinese Medicine, but its active compounds and molecular targets are unknown yet. M. charantia polysaccharide (MCP) is one of the important bioactive components in MC. In the present study, we tested the hypothesis that MCP has neuroprotective effects against cerebral ischemia/reperfusion injury through scavenging superoxide (O2(-)), nitric oxide (NO) and peroxynitrite (ONOO(-)) and inhibiting c-Jun N-terminal protein kinase (JNK3) signaling cascades. We conducted experiments with in vivo global and focal cerebral ischemia/reperfusion rat models and in vitro oxygen glucose deprivation (OGD) neural cells. The effects of MCP on apoptotic cell death and infarction volume, the bioactivities of scavenging O2(-), NO and ONOO(-), inhibiting lipid peroxidation and modulating JNK3 signaling pathway were investigated. Major results are summarized as below: (1) MCP dose-dependently attenuated apoptotic cell death in neural cells under OGD condition in vitro and reduced infarction volume in ischemic brains in vivo; (2) MCP had directing scavenging effects on NO, O2(-) and ONOO(-) and inhibited lipid peroxidation; (3) MCP inhibited the activations of JNK3/c-Jun/Fas-L and JNK3/cytochrome C/caspases-3 signaling cascades in ischemic brains in vivo. Taken together, we conclude that MCP could be a promising neuroprotective ingredient of M. charantia and its mechanisms could be at least in part attributed to its antioxidant activities and inhibiting JNK3 signaling cascades during cerebral ischemia/reperfusion injury. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. A new paradigm to induce mental stress: The Sing-a-Song Stress Test (SSST

    Directory of Open Access Journals (Sweden)

    Anne-Marie eBrouwer

    2014-07-01

    Full Text Available We here introduce a new experimental paradigm to induce mental stress in a quick and easy way while adhering to ethical standards and controlling for potential confounds resulting from sensory input and body movements. In our Sing-a-Song Stress Test, participants are presented with neutral messages on a screen, interleaved with 1-minute time intervals. The final message is that the participant should sing a song aloud after the interval has elapsed. Participants sit still during the whole procedure. We found that heart rate and skin conductance during the 1-minute intervals following the sing-a-song stress message are substantially higher than during intervals following neutral messages. The order of magnitude of the rise is comparable to that achieved by the Trier Social Stress Test. Skin conductance increase correlates positively with experienced stress level as reported by participants. We also simulated stress detection in real time. When using both skin conductance and heart rate, stress is detected for 18 out of 20 participants, approximately 10s after onset of the sing-a-song message. In conclusion, the Sing-a-Song Stress Test provides a quick, easy, controlled and potent way to induce mental stress and could be helpful in studies ranging from examining physiological effects of mental stress to evaluating interventions to reduce stress.

  17. Melatonin attenuates stress-induced defecation: lesson from a rat model of stress-induced gut dysfunction.

    Science.gov (United States)

    Song, G H; Gwee, K A; Moochhala, S M; Ho, K Y

    2005-10-01

    Melatonin is known to alleviate stress and modulate gut motility. We investigated the modulating effects of melatonin on stress-induced gut dysfunction. One hundred Wistar rats were randomly assigned to five equal groups, receiving intraperitoneal injections of 0, 1, 10, 100 or 1000 microg kg(-1) melatonin, respectively. Fifteen minutes later, each group was divided again into four subgroups receiving no treatment, 0.25 mg luzindole (a non-selective melatonin receptor antagonist) intraperitoneally, wrap-restraint stress, and 10 mg kg(-1) serotonin intraperitoneally, respectively. Two hours later, serum serotonin, corticotropin-releasing factor (CRF) and melatonin levels, and faecal output were recorded. Results showed that intraperitoneal melatonin increased faecal output, but this effect was abolished by luzindole. In wrap-restraint group, prior intraperitoneal melatonin at doses of 100 or 1000 microg kg(-1) significantly inhibited stress-induced defecation. This effect was associated with corresponding reductions in serum serotonin and CRF concentrations. In serotonin-treated group, serotonin-induced defecation was also inhibited by melatonin. In conclusion, melatonin exhibited an excitatory effect on bowel output in rats placed under resting state, while attenuated defecation in those subjected to wrap-restraint stress or serotonin treatment. The inhibitory effects of melatonin on stress-induced defecation may stem from its antagonistic effect on stress-induced enhancement of serotonin and CRF secretion.

  18. Modeling Threshold of Stress Intensity Factor in Iodine Induced Stress Corrosion Crack of Zirconium

    Institute of Scientific and Technical Information of China (English)

    SHANG; Xin-yuan; CHEN; Peng

    2013-01-01

    KISCC,which is the threshold of stress intensity factor of iodine induced stress corrosion crack(ISCC)of Zirconium,reflects the susceptibility of ISCC of zirconium.Once the stress intensity factor surpasses the threshold,the cracking propagation modality in material will transform to transgranular from intergranular immediately and the velocity of the cracking will increase rapidly.Four key factors that’s

  19. A new paradigm to induce mental stress : the Sing-a-Song Stress Test(SSST)

    NARCIS (Netherlands)

    Brouwer, A.M.; Hogervorst, M.A.

    2014-01-01

    We here introduce a new experimental paradigm to induce mental stress in a quick and easy way while adhering to ethical standards and controlling for potential confounds resulting from sensory input and body movements. In our Sing-a-Song Stress Test, participants are presented with neutral messages

  20. A new paradigm to induce mental stress : the Sing-a-Song Stress Test(SSST)

    NARCIS (Netherlands)

    Brouwer, A.M.; Hogervorst, M.A.

    2014-01-01

    We here introduce a new experimental paradigm to induce mental stress in a quick and easy way while adhering to ethical standards and controlling for potential confounds resulting from sensory input and body movements. In our Sing-a-Song Stress Test, participants are presented with neutral messages

  1. Oxidative stress-induced autophagy: Role in pulmonary toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Malaviya, Rama [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2014-03-01

    Autophagy is an evolutionarily conserved catabolic process important in regulating the turnover of essential proteins and in elimination of damaged organelles and protein aggregates. Autophagy is observed in the lung in response to oxidative stress generated as a consequence of exposure to environmental toxicants. Whether autophagy plays role in promoting cell survival or cytotoxicity is unclear. In this article recent findings on oxidative stress-induced autophagy in the lung are reviewed; potential mechanisms initiating autophagy are also discussed. A better understanding of autophagy and its role in pulmonary toxicity may lead to the development of new strategies to treat lung injury associated with oxidative stress. - Highlights: • Exposure to pulmonary toxicants is associated with oxidative stress. • Oxidative stress is known to induce autophagy. • Autophagy is upregulated in the lung following exposure to pulmonary toxicants. • Autophagy may be protective or pathogenic.

  2. Stress-induced obesity and the emotional nervous system.

    Science.gov (United States)

    Dallman, Mary F

    2010-03-01

    Stress and emotional brain networks foster eating behaviors that can lead to obesity. The neural networks underlying the complex interactions among stressors, body, brain and food intake are now better understood. Stressors, by activating a neural stress-response network, bias cognition toward increased emotional activity and degraded executive function. This causes formed habits to be used rather than a cognitive appraisal of responses. Stress also induces secretion of glucocorticoids, which increases motivation for food, and insulin, which promotes food intake and obesity. Pleasurable feeding then reduces activity in the stress-response network, reinforcing the feeding habit. These effects of stressors emphasize the importance of teaching mental reappraisal techniques to restore responses from habitual to thoughtful, thus battling stress-induced obesity.

  3. HCV-Induced Oxidative Stress: Battlefield-Winning Strategy

    Science.gov (United States)

    Rebbani, Khadija; Tsukiyama-Kohara, Kyoko

    2016-01-01

    About 150 million people worldwide are chronically infected with hepatitis C virus (HCV). The persistence of the infection is controlled by several mechanisms including the induction of oxidative stress. HCV relies on this strategy to redirect lipid metabolism machinery and escape immune response. The 3β-hydroxysterol Δ24-reductase (DHCR24) is one of the newly discovered host markers of oxidative stress. This protein, as HCV-induced oxidative stress responsive protein, may play a critical role in the pathogenesis of HCV chronic infection and associated liver diseases, when aberrantly expressed. The sustained expression of DHCR24 in response to HCV-induced oxidative stress results in suppression of nuclear p53 activity by blocking its acetylation and increasing its interaction with MDM2 in the cytoplasm leading to its degradation, which may induce hepatocarcinogenesis. PMID:27293514

  4. Overlay degradation induced by film stress

    Science.gov (United States)

    Huang, Chi-hao; Liu, Yu-Lin; Luo, Shing-Ann; Yang, Mars; Yang, Elvis; Hung, Yung-Tai; Luoh, Tuung; Yang, T. H.; Chen, K. C.

    2017-03-01

    The semiconductor industry has continually sought the approaches to produce memory devices with increased memory cells per memory die. One way to meet the increasing storage capacity demand and reduce bit cost of NAND flash memories is 3D stacked flash cell array. In constructing 3D NAND flash memories, increasing the number of stacked layers to build more memory cell number per unit area necessitates many high-aspect-ratio etching processes accordingly the incorporation of thick and unique etching hard-mask scheme has been indispensable. However, the ever increasingly thick requirement on etching hard-mask has made the hard-mask film stress control extremely important for maintaining good process qualities. The residual film stress alters the wafer shape consequently several process impacts have been readily observed across wafer, such as wafer chucking error on scanner, film peeling, materials coating and baking defects, critical dimension (CD) non-uniformity and overlay degradation. This work investigates the overlay and residual order performance indicator (ROPI) degradation coupling with increasingly thick advanced patterning film (APF) etching hard-mask. Various APF films deposited by plasma enhanced chemical vapor deposition (PECVD) method under different deposition temperatures, chemicals combinations, radio frequency powers and chamber pressures were carried out. And -342MPa to +80MPa film stress with different film thicknesses were generated for the overlay performance study. The results revealed the overlay degradation doesn't directly correlate with convex or concave wafer shapes but the magnitude of residual APF film stress, while increasing the APF thickness will worsen the overlay performance and ROPI strongly. High-stress APF film was also observed to enhance the scanner chucking difference and lead to more serious wafer to wafer overlay variation. To reduce the overlay degradation from ever increasingly thick APF etching hard-mask, optimizing the

  5. Residual Stress Induced by Nitriding and Nitrocarburizing

    DEFF Research Database (Denmark)

    Somers, Marcel A.J.

    2005-01-01

    The present chapter is devoted to the various mechanisms involved in the buildup and relief of residual stress in nitrided and nitrocarburized cases. The work presented is an overview of model studies on iron and iron-based alloys. Subdivision is made between the compound (or white) layer......, developing at the surfce and consisting of iron-based (carbo)nitrides, and the diffusion zone underneath, consisting of iron and alloying element nitrides dispersed in af ferritic matrix. Microstructural features are related directly to the origins of stress buildup and stres relief....

  6. Residual Stress Induced by Nitriding and Nitrocarburizing

    DEFF Research Database (Denmark)

    Somers, Marcel A.J.

    2005-01-01

    The present chapter is devoted to the various mechanisms involved in the buildup and relief of residual stress in nitrided and nitrocarburized cases. The work presented is an overview of model studies on iron and iron-based alloys. Subdivision is made between the compound (or white) layer......, developing at the surfce and consisting of iron-based (carbo)nitrides, and the diffusion zone underneath, consisting of iron and alloying element nitrides dispersed in af ferritic matrix. Microstructural features are related directly to the origins of stress buildup and stres relief....

  7. Stress-induced neuroinflammation: mechanisms and new pharmacological targets

    Directory of Open Access Journals (Sweden)

    C.D. Munhoz

    2008-12-01

    Full Text Available Stress is triggered by numerous unexpected environmental, social or pathological stimuli occurring during the life of animals, including humans, which determine changes in all of their systems. Although acute stress is essential for survival, chronic, long-lasting stress can be detrimental. In this review, we present data supporting the hypothesis that stress-related events are characterized by modifications of oxidative/nitrosative pathways in the brain in response to the activation of inflammatory mediators. Recent findings indicate a key role for nitric oxide (NO and an excess of pro-oxidants in various brain areas as responsible for both neuronal functional impairment and structural damage. Similarly, cyclooxygenase-2 (COX-2, another known source of oxidants, may account for stress-induced brain damage. Interestingly, some of the COX-2-derived mediators, such as the prostaglandin 15d-PGJ2 and its peroxisome proliferator-activated nuclear receptor PPARγ, are activated in the brain in response to stress, constituting a possible endogenous anti-inflammatory mechanism of defense against excessive inflammation. The stress-induced activation of both biochemical pathways depends on the activation of the N-methyl-D-aspartate (NMDA glutamate receptor and on the activation of the transcription factor nuclear factor kappa B (NFκB. In the case of inducible NO synthase (iNOS, release of the cytokine TNF-α also accounts for its expression. Different pharmacological strategies directed towards different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNF-α activation and release, inhibitors of NFκB, specific inhibitors of iNOS and COX-2 activities and PPARγ agonists. This article reviews recent contributions to this area addressing possible new pharmacological targets for the treatment of stress-induced neuropsychiatric disorders.

  8. Danshen-Enhanced Cardioprotective Effect of Cardioplegia on Ischemia Reperfusion Injury in a Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Model.

    Science.gov (United States)

    Wei, Wei; Liu, Yiwei; Zhang, Qiang; Wang, Yangming; Zhang, Xiaoling; Zhang, Hao

    2017-05-01

    Myocardial ischemia-reperfusion (I/R) injury is unavoidable during cardioplegic arrest and open-heart surgery. Danshen is one of the most popular traditional herbal medicines in China, which has entered the Food and Drug Administration-approved phase III clinical trial. This study was aimed to develop a human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) model to mimic I/R injury and evaluate the cardioprotective effect of regular cardioplegic solution with Danshen. hiPSC-CMs were cultured with the crystalloid cardioplegic solution (Thomas group) and Thomas solution with 2 or 10 µg/mL Danshen (Thomas plus Danshen groups). The cells under normoxic culture condition served as baseline group. Then, the cells were placed in a modular incubator chamber. After 45 min hypoxia and 3 h reoxygenation, hiPSC-CMs subjected to hypoxia/reoxygenation resulted in a sharp increase of reactive oxygen species (ROS) content in Thomas group versus baseline group. Compared with the Thomas group, ROS accumulation was significant suppressed in Thomas plus Danshen groups, which might result from elevating the content of glutathione and enhanced activities of superoxide dismutase and glutathione peroxidase. The enhanced L-type Ca(2+) current in hiPSC-CMs after I/R injury was also significantly decreased by Danshen, and meanwhile intracellular Ca(2+) level was reduced and calcium overload was suppressed. Thomas plus Danshen groups also presented less irregular transients and lower apoptosis rates. As a result, Danshen could improve antioxidant and calcium handling in cardiomyocytes during I/R and lead to reduced arrhythmia events and apoptosis rates. hiPSC-CMs model offered a platform for the future translational study of the cardioplegia. © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  9. Reperfusion pulmonary edema

    Energy Technology Data Exchange (ETDEWEB)

    Klausner, J.M.; Paterson, I.S.; Mannick, J.A.; Valeri, C.R.; Shepro, D.; Hechtman, H.B. (Harvard Medical School, Boston, MA (USA))

    1989-02-17

    Reperfusion following lower-torso ischemia in humans leads to respiratory failure manifest by pulmonary hypertension, hypoxemia, and noncardiogenic pulmonary edema. The mechanism of injury has been studied in the sheep lung lymph preparation, where it has been demonstrated that the reperfusion resulting in pulmonary edema is due to an increase in microvascular permeability of the lung to protein. This respiratory failure caused by reperfusion appears to be an inflammatory reaction associated with intravascular release of the chemoattractants leukotriene B{sub 4} and thromboxane. Histological studies of the lung in experimental animals revealed significant accumulation of neutrophils but not platelets in alveolar capillaries. The authors conclude that thromboxane generated and released from the ischemic tissue is responsible for the transient pulmonary hypertension. Second, it is likely that the chemoattractants are responsible for leukosequestration, and third, neutrophils, oxygen-derived free radicals, and thromboxane moderate the altered lung permeability.

  10. 百里醌通过抑制氧化应激信号通路减轻肝缺血再灌注损伤%Thymoquinone protected hepatic ischemia reperfusion injury by suppressing oxidative stress

    Institute of Scientific and Technical Information of China (English)

    陈志则; 夏中元; 孟庆涛

    2015-01-01

    Thymoquinone could decrease the hepatic ischemia reperfusion injury by suppressing oxidative stress.

  11. Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia-reperfusion: therapeutic potential of mitochondrially-targeted antioxidants

    Science.gov (United States)

    Mukhopadhyay, Partha; Horváth, Bėla; Zsengellėr, Zsuzsanna; Bátkai, Sándor; Cao, Zongxian; Kechrid, Malek; Holovac, Eileen; Erdėlyi, Katalin; Tanchian, Galin; Liaudet, Lucas; Stillman, Isaac E.; Joseph, Joy; Kalyanaraman, Balaraman; Pacher, Pál

    2012-01-01

    Mitochondrial reactive oxygen species generation has been implicated in the pathophysiology of ischemia-reperfusion (I/R) injury, however its exact role and its spatial-temporal relationship with inflammation are elusive. Herein we explored the spatial-temporal relationship of oxidative/nitrative stress and inflammatory response during the course of hepatic I/R and the possible therapeutic potential of mitochondrial-targeted antioxidants, using a mouse model of segmental hepatic ischemia-reperfusion injury. Hepatic I/R was characterized by early (at 2 hours of reperfusion) mitochondrial injury, decreased complex I activity, increased oxidant generation in the liver or liver mitochondria, and profound hepatocellular injury/dysfunction with acute pro-inflammatory response (TNF-α, MIP-1αCCL3, MIP-2/CXCL2) without inflammatory cell infiltration, followed by marked neutrophil infiltration and more pronounced secondary wave of oxidative/nitrative stress in the liver (starting from 6 hours of reperfusion and peaking at 24 hours). Mitochondrially-targeted antioxidants, MitoQ or Mito-CP, dose-dependently attenuated I/R-induced liver dysfunction, the early and delayed oxidative and nitrative stress response (HNE/carbonyl adducts, malondialdehyde, 8-OHdG, and 3-nitrotyrosine formation), mitochondrial and histopathological injury/dysfunction, as well as delayed inflammatory cell infiltration and cell death. Mitochondrially generated oxidants play a central role in triggering the deleterious cascade of events associated with hepatic I/R, which may be targeted by novel antioxidants for therapeutic advantage. PMID:22683818

  12. Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells.

    Science.gov (United States)

    Wang, Xin; Xu, Mei; Frank, Jacqueline A; Ke, Zun-Ji; Luo, Jia

    2017-04-01

    Thiamine (vitamin B1) deficiency (TD) plays a major role in the etiology of Wernicke's encephalopathy (WE) which is a severe neurological disorder. TD induces selective neuronal cell death, neuroinflammation, endoplasmic reticulum (ER) stress and oxidative stress in the brain which are commonly observed in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and progressive supranuclear palsy (PSP). However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research is hindered due to the lack of appropriate in vitro models. The neurons derived for the human induced pluripotent stem cells (hiPSCs) provide a relevant and powerful tool for the research in pharmaceutical and environmental neurotoxicity. In this study, we for the first time used human induced pluripotent stem cells (hiPSCs)-derived neurons (iCell neurons) to investigate the mechanisms of TD-induced neurodegeneration. We showed that TD caused a concentration- and duration-dependent death of iCell neurons. TD induced ER stress which was evident by the increase in ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2α, and cleaved caspase-12. TD also triggered oxidative stress which was shown by the increase in the expression 2,4-dinitrophenyl (DNP) and 4-hydroxynonenal (HNE). ER stress inhibitors (STF-083010 and salubrinal) and antioxidant N-acetyl cysteine (NAC) were effective in alleviating TD-induced death of iCell neurons, supporting the involvement of ER stress and oxidative stress. It establishes that the iCell neurons are a novel tool to investigate cellular and molecular mechanisms for TD-induced neurodegeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. The neurobiology of stress-induced hyperthermia

    NARCIS (Netherlands)

    Vinkers, C.H.

    2009-01-01

    Everyone who has been in a stressful situation, whether it is being attacked by a wild animal, the moment right before an important presentation or just finding yourself in an awkward situation, knows the warm and aroused feeling that one can experience at that moment. This change in body temperatur

  14. Beneficial effects of thymoquinone and omega-3 on intestinal ischemia/reperfusion-induced renal dysfunction in rats

    Directory of Open Access Journals (Sweden)

    Ahmed M. Fayez

    2014-12-01

    Depending on the obtained results in the present study it could be concluded that thymoquinone and omega-3 have beneficial effects on II/R-induced renal dysfunction in rats. The protective potential could be attributed to the antioxidant, antiapoptotic and anti-inflammatory effects of test drugs.

  15. Down-Regulation of CXCL12/CXCR4 Expression Alleviates Ischemia-Reperfusion-Induced Inflammatory Pain via Inhibiting Glial TLR4 Activation in the Spinal Cord

    Science.gov (United States)

    Li, Xiao-Qian; Zhang, Zai-Li; Tan, Wen-Fei; Sun, Xi-Jia; Ma, Hong

    2016-01-01

    Toll-like receptor 4 (TLR4) is important for the pathogenesis of inflammatory reactions and the promotion of pain processing after ischemia/reperfusion (IR) in spinal cord. Recently, C-X-C chemokine ligand 12 (CXCL12) and its receptor, C-X-C chemokine receptor 4 (CXCR4), were demonstrated to be simultaneously critical for inflammatory reactions, thereby facilitating glial activation. However, whether CXCL12/CXCR4 expression can contribute to IR-induced inflammatory pain via spinal TLR4 remained unclear. A rat model was established by 8 min of aortic arch occlusion. The effects of CXCL12/CXCR4 expression and TLR4 activation on inflammatory hyperalgesia were investigated by pretreatments with CXCL12-neutralizing antibody, CXCR4 antagonist (AMD3100) and TLR4 antagonist (TAK-242) for 5 consecutive days before surgery. The results indicated that IR induced significant and sustained inflammatory pain, observed as decreases in paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), throughout the post-injury period. The increased levels of TLR4 and proinflammatory chemokine CXCL12, as well as its receptor, CXCR4, were closely correlated with the PWT and PWL trends. Double immunostaining further suggested that TLR4, which is mainly expressed on astrocytes and microglia, was closely co-localized with CXCL12 and CXCR4 in spinal dorsal horn. As expected, intrathecal pretreatment with the TLR4 antagonist, TAK-242 markedly ameliorated pain by inhibiting astrocytic and microglial activation, as shown by decreases in TLR4 immunoreactivity and the percentage of double-labeled cells. These protective effects were likely due in part to the reduced production of the downstream cytokines IL-1β and TNF-α, as well as for the recruitment of CXCL12 and CXCR4. Additionally, intrathecal pretreatment with CXCL12-neutralizing antibody and AMD3100 resulted in similar analgesic and anti-inflammatory effects as those receiving TAK-242 pretreatment. These results suggest that

  16. Temporal pore pressure induced stress changes during injection and depletion

    Science.gov (United States)

    Müller, Birgit; Heidbach, Oliver; Schilling, Frank; Fuchs, Karl; Röckel, Thomas

    2016-04-01

    Induced seismicity is observed during injection of fluids in oil, gas or geothermal wells as a rather immediate response close to the injection wells due to the often high-rate pressurization. It was recognized even earlier in connection with more moderate rate injection of fluid waste on a longer time frame but higher induced event magnitudes. Today, injection-related induced seismicity significantly increased the number of events with M>3 in the Mid U.S. However, induced seismicity is also observed during production of fluids and gas, even years after the onset of production. E.g. in the Groningen gas field production was required to be reduced due to the increase in felt and damaging seismicity after more than 50 years of exploitation of that field. Thus, injection and production induced seismicity can cause severe impact in terms of hazard but also on economic measures. In order to understand the different onset times of induced seismicity we built a generic model to quantify the role of poro-elasticity processes with special emphasis on the factors time, regional crustal stress conditions and fault parameters for three case studies (injection into a low permeable crystalline rock, hydrothermal circulation and production of fluids). With this approach we consider the spatial and temporal variation of reservoir stress paths, the "early" injection-related induced events during stimulation and the "late" production induced ones. Furthermore, in dependence of the undisturbed in situ stress field conditions the stress tensor can change significantly due to injection and long-term production with changes of the tectonic stress regime in which previously not critically stressed faults could turn to be optimally oriented for fault reactivation.

  17. Stress-Induced Premature Senescence or Stress-Induced Senescence-Like Phenotype: One In Vivo Reality, Two Possible Definitions?

    Directory of Open Access Journals (Sweden)

    Olivier Toussaint

    2002-01-01

    Full Text Available No consensus exists so far on the definition of cellular senescence. The narrowest definition of senescence is irreversible growth arrest triggered by telomere shortening counting cell generations (definition 1. Other authors gave an enlarged functional definition encompassing any kind of irreversible arrest of proliferative cell types induced by damaging agents or cell cycle deregulations after overexpression of proto-oncogenes (definition 2. As stress increases, the proportion of cells in “stress-induced premature senescence-like phenotype” according to definition 1 or “stress-induced premature senescence,” according to definition 2, should increase when a culture reaches growth arrest, and the proportion of cells that reached telomere-dependent replicative senescence due to the end-replication problem should decrease. Stress-induced premature senescence-like phenotype and telomere-dependent replicatively senescent cells share basic similarities such as irreversible growth arrest and resistance to apoptosis, which may appear through different pathways. Irreversible growth arrest after exposure to oxidative stress and generation of DNA damage could be as efficient in avoiding immortalisation as “telomere-dependent” replicative senescence. Probabilities are higher that the senescent cells (according to definition 2 appearing in vivo are in stress-induced premature senescence rather than in telomere-dependent replicative senescence. Examples are given suggesting these cells affect in vivo tissue (pathophysiology and aging.

  18. STRESS INDUCED NITROGEN DIFFUSION IN NITRITED CoCr ALLOY

    Directory of Open Access Journals (Sweden)

    AKVILĖ PETRAITIENĖ

    2015-03-01

    Full Text Available In the present study the nitrogen transport mechanism in plasma nitrited CoCr alloy at moderate temperature ( 400ºC is explained by non-Fickian diffusion model. This mechanism is considered by stress induced diffusion model. The model involves diffusion of nitrogen induced by internal stresses created during nitriding process. The model considers the diffusion of nitrogen in the presence of  internal stresses gradient induced by penetrating nitrogen as the next driving force of diffusion after concentration gradient. This model is commonly used for analysis of stainless steel nitriding, however, in this work it is shown that the same nitrogen penetration mechanism takes place in CoCr alloy. For mathematical description of stress induced diffusion process the equation of baro-diffusion is used which involves concentration dependant baro-diffusion concentration. For calculation of stress gradient it is assumed that stress depth profile linearly relates with nitrogen concentration depth profile. The fitting is done using experimental curves of nitrogen depth profiles for medical grade CoCr alloy (ISO 5831-12 nitrited at 400 ºC temperature. The experimental curves are taken from literature. The nitriding duration was 2h, 6h, 20h. Calculated nitrogen depth profiles in CoCr alloy are in good agreement with experimental nitrogen depth profiles.  The diffusion coefficient D is found from fitting of experimental data.DOI: http://dx.doi.org/10.5755/j01.ms.21.1.5711

  19. Gravity-induced stresses in stratified rock masses

    Science.gov (United States)

    Amadei, B.; Swolfs, H.S.; Savage, W.Z.

    1988-01-01

    This paper presents closed-form solutions for the stress field induced by gravity in anisotropic and stratified rock masses. These rocks are assumed to be laterally restrained. The rock mass consists of finite mechanical units, each unit being modeled as a homogeneous, transversely isotropic or isotropic linearly elastic material. The following results are found. The nature of the gravity induced stress field in a stratified rock mass depends on the elastic properties of each rock unit and how these properties vary with depth. It is thermodynamically admissible for the induced horizontal stress component in a given stratified rock mass to exceed the vertical stress component in certain units and to be smaller in other units; this is not possible for the classical unstratified isotropic solution. Examples are presented to explore the nature of the gravity induced stress field in stratified rock masses. It is found that a decrease in rock mass anisotropy and a stiffening of rock masses with depth can generate stress distributions comparable to empirical hyperbolic distributions previously proposed in the literature. ?? 1988 Springer-Verlag.

  20. Cellular and Molecular Basis for Stress-Induced Depression

    Science.gov (United States)

    Seo, Ji-Seon; Wei, Jing; Qin, Luye; Kim, Yong; Yan, Zhen

    2016-01-01

    Chronic stress plays a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2+) glutamatergic neurons. Viral expression of p11 in D2+ PrL neurons alleviates the depression-like behaviors exhibited by genetically manipulated mice with D2+ neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2+ PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses. PMID:27457815

  1. Anti-inflammatory effect of lycopene on carrageenan-induced paw oedema and hepatic ischaemia-reperfusion in the rat

    OpenAIRE

    Bignotto, L; Rocha, J.; Sepodes, B; Eduardo-Figueira, M; Pinto, R.; Chaud, M; Carvalho, J.; Moreno, H.; Mota-Filipe, H

    2009-01-01

    The regular intake of tomatoes or its products has been associated with a reduced risk of chronic diseases and these effects have been mainly attributed to lycopene. Here, we evaluated the anti-inflammatory properties of lycopene and its protective effects on organ injury in two experimental models of inflammation. In order to study the effects of lycopene in local inflammation, a carrageenan-induced paw oedema model in rats was performed. Lycopene was administered as an acute (1, 10, 25 or 5...

  2. Moisture-induced stresses in glulam frames

    DEFF Research Database (Denmark)

    Ormarsson, Sigurdur; Gislason, Oskar V

    2016-01-01

    Wood is a hygroscopic and moisture-sensitive material that seeks to achieve equilibrium moisture content (EMC) with its surrounding environment. For softwood timber structures exposed to variations in climate throughout their service life, this behaviour results in variable moisture...... by hand. Accordingly, there is a need for advanced computer tools to study how the long-term stress behaviour of timber structures is affected by creep and cyclic variations in climate. A beam model to simulate the overall hygro-mechanical and visco-elastic behaviour of (inhomogeneous) glulam structures...... is presented. A two-dimensional transient, non-linear moisture transport model for wood is also developed and linked with this beam model. The combined models are used to study the long-term deformations and stresses in a curved frame structure exposed to both mechanical loading and cyclic climate conditions...

  3. Pattern of Stress-Induced Hyperglycemia according to Type of Diabetes: A Predator Stress Model

    Directory of Open Access Journals (Sweden)

    Jin-Sun Chang

    2013-12-01

    Full Text Available BackgroundWe aimed to quantify stress-induced hyperglycemia and differentiate the glucose response between normal animals and those with diabetes. We also examined the pattern in glucose fluctuation induced by stress according to type of diabetes.MethodsTo load psychological stress on animal models, we used a predator stress model by exposing rats to a cat for 60 minutes and measured glucose level from the beginning to the end of the test to monitor glucose fluctuation. We induced type 1 diabetes model (T1D for ten Sprague-Dawley rats using streptozotocin and used five Otsuka Long-Evans Tokushima Fatty rats as obese type 2 diabetes model (OT2D and 10 Goto-Kakizaki rats as nonobese type 2 diabetes model (NOT2D. We performed the stress loading test in both the normal and diabetic states and compared patterns of glucose fluctuation among the three models. We classified the pattern of glucose fluctuation into A, B, and C types according to speed of change in glucose level.ResultsIncrease in glucose, total amount of hyperglycemic exposure, time of stress-induced hyperglycemia, and speed of glucose increase were significantly increased in all models compared to the normal state. While the early increase in glucose after exposure to stress was higher in T1D and NOT2D, it was slower in OT2D. The rate of speed of the decrease in glucose level was highest in NOT2D and lowest in OT2D.ConclusionThe diabetic state was more vulnerable to stress compared to the normal state in all models, and the pattern of glucose fluctuation differed among the three types of diabetes. The study provides basic evidence for stress-induced hyperglycemia patterns and characteristics used for the management of diabetes patients.

  4. Quercetin protects rat skeletal muscle from ischemia reperfusion injury.

    Science.gov (United States)

    Ekinci Akdemir, Fazile Nur; Gülçin, İlhami; Karagöz, Berna; Soslu, Recep

    2016-01-01

    In this study, we investigated the potential beneficial effects of quercetin on skeletal muscle ischemia reperfusion injury. Twenty-four Sprague-Dawley type rats were randomly divided into four groups. In the sham group, only gastrocnemius muscle were removed and given no quercetin. In ischemia group, all the femoral artery, vein and collaterals were occluded in the left hindlimb by applying tourniquate under general anaesthesia for three hours but reperfusion was not done. In the Quercetin + Ischemia reperfusion group, quercetin (200 mg kg(-1) dose orally) was given during one-week reoperation and later ischemia reperfusion model was done. Finally, gastrocnemius muscle samples were removed to measure biochemical parameters. The biomarkers, MDA levels, SOD, CAT and GPx activities, were evaluated related to skeletal muscle ischemia reperfusion injury. MDA levels reduced and SOD, CAT and GPx activities increased significantly in Quercetin + Ischemia reperfusion group. Results clearly showed that Quercetin have a protective role against oxidative damage induced by ischemia reperfusion in rats.

  5. Mechanical stress induces biotic and abiotic stress responses via a novel cis-element.

    Directory of Open Access Journals (Sweden)

    Justin W Walley

    2007-10-01

    Full Text Available Plants are continuously exposed to a myriad of abiotic and biotic stresses. However, the molecular mechanisms by which these stress signals are perceived and transduced are poorly understood. To begin to identify primary stress signal transduction components, we have focused on genes that respond rapidly (within 5 min to stress signals. Because it has been hypothesized that detection of physical stress is a mechanism common to mounting a response against a broad range of environmental stresses, we have utilized mechanical wounding as the stress stimulus and performed whole genome microarray analysis of Arabidopsis thaliana leaf tissue. This led to the identification of a number of rapid wound responsive (RWR genes. Comparison of RWR genes with published abiotic and biotic stress microarray datasets demonstrates a large overlap across a wide range of environmental stresses. Interestingly, RWR genes also exhibit a striking level and pattern of circadian regulation, with induced and repressed genes displaying antiphasic rhythms. Using bioinformatic analysis, we identified a novel motif overrepresented in the promoters of RWR genes, herein designat