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  1. Prdx6 Upregulation by Curcumin Attenuates Ischemic Oxidative Damage via SP1 in Rats after Stroke

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    Gongwei Jia

    2017-01-01

    Full Text Available Background. The role of Peroxiredoxin 6 (Prdx6 in brain ischemia remains unclear. Curcumin (Cur treatment elicits neuroprotective effects against cerebral ischemic injury, and the associated mechanisms may involve Prdx6. In this study, we investigated whether Prdx6 and the transcription factor specific protein 1 (SP1 were involved in the antioxidant effect of Cur after stoke. Methods. Focal cerebral ischemic injury was induced by transient middle cerebral artery occlusion for 2 hours in male Sprague-Dawley rats treated with or without Prdx6 siRNA. Expression of Prdx6 in the penumbra was assessed by Real-Time PCR (RT-PCR, Western blot analysis, and immunoflourescent staining. In addition, infarct volume, neurological deficit score, and oxidative stress were evaluated. Prdx6 levels were also determined in the presence and absence of SP1 antagonist mithramycin A (MTM-A. Results. Cur treatment upregulated Prdx6 protein expression and the number of Prdx6-positive neuronal cells 24 hours after reperfusion. Cur treatment also attenuated oxidative stress and induced neuroprotective effects against ischemic damage, whereas the beneficial effects of Cur treatment were lost in animals treated with Prdx6-siRNA. Prdx6 upregulation by Cur treatment was abolished by SP1 antagonists MTM. Conclusions. Prdx6 upregulation by Cur treatment attenuates ischemic oxidative damage through SP1 induction in rats after stroke. This represents a novel mechanism of Cur-induced neuroprotection against cerebral ischemia.

  2. Isoflurane anesthesia initiated at the onset of reperfusion attenuates oxidative and hypoxic-ischemic brain injury.

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    Sergey A Sosunov

    Full Text Available This study demonstrates that in mice subjected to hypoxia-ischemia (HI brain injury isoflurane anesthesia initiated upon reperfusion limits a release of mitochondrial oxidative radicals by inhibiting a recovery of complex-I dependent mitochondrial respiration. This significantly attenuates an oxidative stress and reduces the extent of HI brain injury. Neonatal mice were subjected to HI, and at the initiation of reperfusion were exposed to isoflurane with or without mechanical ventilation. At the end of HI and isoflurane exposure cerebral mitochondrial respiration, H2O2 emission rates were measured followed by an assessment of cerebral oxidative damage and infarct volumes. At 8 weeks after HI navigational memory and brain atrophy were assessed. In vitro, direct effect of isoflurane on mitochondrial H2O2 emission was compared to that of complex-I inhibitor, rotenone. Compared to controls, 15 minutes of isoflurane anesthesia inhibited recovery of the compex I-dependent mitochondrial respiration and decreased H2O2 production in mitochondria supported with succinate. This was associated with reduced oxidative brain injury, superior navigational memory and decreased cerebral atrophy compared to the vehicle-treated HI-mice. Extended isoflurane anesthesia was associated with sluggish recovery of cerebral blood flow (CBF and the neuroprotection was lost. However, when isoflurane anesthesia was supported with mechanical ventilation the CBF recovery improved, the event associated with further reduction of infarct volume compared to HI-mice exposed to isoflurane without respiratory support. Thus, in neonatal mice brief isoflurane anesthesia initiated at the onset of reperfusion limits mitochondrial release of oxidative radicals and attenuates an oxidative stress. This novel mechanism contributes to neuroprotective action of isoflurane. The use of mechanical ventilation during isoflurane anesthesia counterbalances negative effect of isoflurane anesthesia on

  3. Extracts of Crataegus oxyacantha and Rosmarinus officinalis Attenuate Ischemic Myocardial Damage by Decreasing Oxidative Stress and Regulating the Production of Cardiac Vasoactive Agents

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    Raúl Enrique Cuevas-Durán

    2017-11-01

    Full Text Available Numerous studies have supported a role for oxidative stress in the development of ischemic damage and endothelial dysfunction. Crataegus oxyacantha (Co and Rosmarinus officinalis (Ro extracts are polyphenolic-rich compounds that have proven to be efficient in the treatment of cardiovascular diseases. We studied the effect of extracts from Co and Ro on the myocardial damage associated with the oxidative status and to the production of different vasoactive agents. Rats were assigned to the following groups: (a sham; (b vehicle-treated myocardial infarction (MI (MI-V; (c Ro extract-treated myocardial infarction (MI-Ro; (d Co extract-treated myocardial infarction (MI-Co; or (e Ro+Co-treated myocardial infarction (MI-Ro+Co. Ro and Co treatments increased total antioxidant capacity, the expression of superoxide dismutase (SOD-Cu2+/Zn2+, SOD-Mn2+, and catalase, with the subsequent decline of malondialdehyde and 8-hydroxy-2′-deoxyguanosine levels. The extracts diminished vasoconstrictor peptide levels (angiotensin II and endothelin-1, increased vasodilators agents (angiotensin 1–7 and bradikinin and improved nitric oxide metabolism. Polyphenol treatment restored the left intraventricular pressure and cardiac mechanical work. We conclude that Ro and Co treatment attenuate morphological and functional ischemic-related changes by both an oxidant load reduction and improvement of the balance between vasoconstrictors and vasodilators.

  4. NOSH-NBP, a Novel Nitric Oxide and Hydrogen Sulfide- Releasing Hybrid, Attenuates Ischemic Stroke-Induced Neuroinflammatory Injury by Modulating Microglia Polarization

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    Jing Ji

    2017-05-01

    Full Text Available NOSH-NBP, a novel nitric oxide (NO and hydrogen sulfide (H2S-releasing hybrid, protects brain from ischemic stroke. This study mainly aimed to investigate the therapeutic effect of NOSH-NBP on ischemic stroke and the underlying mechanisms. In vivo, transient middle cerebral artery occlusion (tMCAO was performed in C57BL/6 mice, with NO-NBP and H2S-NBP as controls. NO and H2S scavengers, carboxy-PTIO and BSS, respectively, were used to quench NO and H2S of NOSH-NBP. In vitro, BV2 microglia/BMDM were induced to the M1/2 phenotype, and conditioned medium (CM experiments in BV2 microglia, neurons and b.End3 cerebral microvascular endothelial cells (ECs were performed. Microglial/macrophage activation/polarization was assessed by flow cytometry, Western blot, RT-qPCR, and ELISA. Neuronal and EC survival was measured by TUNEL, flow cytometry, MTT and LDH assays. Transmission electron microscopy, EB extravasation, brain water content, TEER measurement and Western blot were used to detect blood–brain barrier (BBB integrity and function. Interestingly, NOSH-NBP significantly reduced cerebral infarct volume and ameliorated neurological deficit, with superior effects compared with NO-NBP and/or H2S-NBP in mice after tMCAO. Both NO and H2S-releasing groups contributed to protection by NOSH-NBP. Additionally, NOSH-NBP decreased neuronal death and attenuated BBB dysfunction in tMCAO-treated mice. Furthermore, NOSH-NBP promoted microglia/macrophage switch from an inflammatory M1 phenotype to the protective M2 phenotype in vivo and in vitro. Moreover, the TLR4/MyD88/NF-κB pathway and NLRP3 inflammasome were involved in the inhibitory effects of NOSH-NBP on M1 polarization, while peroxisome proliferator activated receptor gamma signaling contributed to NOSH-NBP induced M2 polarization. These findings indicated that NOSH-NBP is a potential therapeutic agent that preferentially promotes microglial/macrophage M1–M2 switch in ischemic stroke.

  5. Simvastatin Attenuates the Oxidative Stress, Endothelial Thrombogenicity and the Inducibility of Atrial Fibrillation in a Rat Model of Ischemic Heart Failure

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    Kyoung-Im Cho

    2014-08-01

    Full Text Available Increased atrial oxidative stress has an important role in inducing and maintaining atrial fibrillation (AF, and the activation of the small GTPase Rac1 contributes to the oxidative stress. We investigated the relationship of Rac1, atrial endothelial thromboprotective markers and AF inducibility and if simvastatin has a potential beneficial effect on a myocardial infarction (MI-induced heart failure (HF rat model. Rats were randomized into three groups (shams, MI group and simvastatin treatment group and underwent echocardiography, AF induction studies and left atrial (LA fibrosis analysis. Atrial Rac 1, sodium calcium exchanger (INCX, sarcoplasmic reticulum calcium ATPase (SERCA, endothelial nitric oxide synthase (eNOS and induced nitric oxide synthase (iNOS were measured. AF inducibility, AF duration and LA fibrosis were significantly higher in the MI group (p < 0.001 vs. sham, which were significantly reduced by simvastatin (p < 0.05 vs. MI. The reduced expressions of atrial eNOS, SERCA, thrombomodulin, tissue factor pathway inhibitor and tissue plasminogen activator in the MI group were significantly improved by simvastatin. Furthermore, the increased expression of atrial iNOS, INCX and Rac1 activity were significantly decreased by the simvastatin. Oxidative stress, endothelial dysfunction and thrombogenicity are associated with the promotion of AF in a rat model of ischemic HF. These were associated with increased Rac1 activity, and simvastatin treatment prevents these changes.

  6. Intermittent fasting attenuates inflammasome activity in ischemic stroke.

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    Fann, David Yang-Wei; Santro, Tomislav; Manzanero, Silvia; Widiapradja, Alexander; Cheng, Yi-Lin; Lee, Seung-Yoon; Chunduri, Prasad; Jo, Dong-Gyu; Stranahan, Alexis M; Mattson, Mark P; Arumugam, Thiruma V

    2014-07-01

    Recent findings have revealed a novel inflammatory mechanism that contributes to tissue injury in cerebral ischemia mediated by multi-protein complexes termed inflammasomes. Intermittent fasting (IF) can decrease the levels of pro-inflammatory cytokines in the periphery and brain. Here we investigated the impact of IF (16h of food deprivation daily) for 4months on NLRP1 and NLRP3 inflammasome activities following cerebral ischemia. Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion (I/R). IF decreased the activation of NF-κB and MAPK signaling pathways, the expression of NLRP1 and NLRP3 inflammasome proteins, and both IL-1β and IL-18 in the ischemic brain tissue. These findings demonstrate that IF can attenuate the inflammatory response and tissue damage following ischemic stroke by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Copyright © 2014 Elsevier Inc. All rights reserved.

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

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    Jiangwei Ma

    2012-03-01

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

  8. Novel resveratrol analogues attenuate renal ischemic injury in rats

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    Khader, Adam; Yang, Weng-Lang; Kuncewitch, Michael; Prince, Jose M.; Marambaud, Philippe; Nicastro, Jeffrey; Coppa, Gene F.; Wang, Ping

    2014-01-01

    Background Renal ischemia-reperfusion (I/R) is a severe clinical complication with no specific treatment. Resveratrol has been shown as a promising experimental agent in renal I/R due to its effect on cellular energy metabolism, oxidative stress, and inflammation. Recently, we identified two biologically active resveratrol analogues (RSVAs), RSVA405 and RSVA314. We hypothesized that both RSAVs would attenuate I/R-induced renal injury. Methods Adult male rats were subjected to renal I/R through bilateral renal pedicle clamping for 60 min, followed by reperfusion. RSVA405 (3 mg/kg BW), RSVA314 (3 mg/kg BW), or vehicle (10% DMSO and 33% Solutol in PBS) was administered by intraperitoneal injection 1 h prior to ischemia. Blood and renal tissues were collected 24 h after I/R for evaluation. Results Administration of RSVA405 and RSVA314 significantly reduced the serum levels of renal dysfunction and injury markers, including creatinine, blood urea nitrogen, aspartate aminotransferase, and lactate dehydrogenase, compared to vehicle. The protective effect of RSVA405 and RSVA314 was also reflected on histologic evaluation. Both RSVAs reduced the number of apoptotic cells by more than 60% as determined by TUNEL assay, compared to vehicle. The renal ATP levels of the vehicle group was decreased to 52.4% of control, while those of the RSVA405 and RSVA314 groups were restored to 72.3% and 79.6% of control, respectively. Both RSVAs significantly reduced the protein expression of inducible nitric oxide synthase and nitrotyrosine, and the mRNA levels of TNF-α, IL-6 and IL-1β. Conclusions RSVA405 and RSVA314 attenuate I/R-induced renal injury through the modulation of energy metabolism, oxidative stress, and inflammation. PMID:25214260

  9. Attenuation of Cerebral Ischemic Injury in Smad1 Deficient Mice.

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    Jamie K Wong

    Full Text Available Stroke results in brain tissue damage from ischemia and oxidative stress. Molecular regulators of the protective versus deleterious cellular responses after cerebral ischemia remain to be identified. Here, we show that deletion of Smad1, a conserved transcription factor that mediates canonical bone morphogenetic protein (BMP signaling, results in neuroprotection in an ischemia-reperfusion (I/R stroke model. Uninjured mice with conditional deletion of Smad1 in the CNS (Smad1 cKO displayed upregulation of the reactive astrocyte marker GFAP and hypertrophic morphological changes in astrocytes compared to littermate controls. Additionally, cultured Smad1(-/- astrocytes exhibited an enhanced antioxidant capacity. When subjected to I/R injury by transient middle cerebral artery occlusion (tMCAO, Smad1 cKO mice showed enhanced neuronal survival and improved neurological recovery at 7 days post-stroke. This neuroprotective phenotype is associated with attenuated reactive astrocytosis and neuroinflammation, along with reductions in oxidative stress, p53 induction, and apoptosis. Our data suggest that Smad1-mediated signaling pathway is involved in stroke pathophysiology and may present a new potential target for stroke therapy.

  10. Fermented Chinese formula Shuan-Tong-Ling attenuates ischemic stroke by inhibiting inflammation and apoptosis

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    Zhi-gang Mei

    2017-01-01

    Full Text Available The fermented Chinese formula Shuan-Tong-Ling is composed of radix puerariae (Gegen, salvia miltiorrhiza (Danshen, radix curcuma (Jianghuang, hawthorn (Shanzha, salvia chinensis (Shijianchuan, sinapis alba (Baijiezi, astragalus (Huangqi, panax japonicas (Zhujieshen, atractylodes macrocephala koidz (Baizhu, radix paeoniae alba (Baishao, bupleurum (Chaihu, chrysanthemum (Juhua, rhizoma cyperi (Xiangfu and gastrodin (Tianma, whose aqueous extract was fermented with lactobacillus, bacillus aceticus and saccharomycetes. Shuan-Tong-Ling is a formula used to treat brain diseases including ischemic stroke, migraine, and vascular dementia. Shuan-Tong-Ling attenuated H2O2-induced oxidative stress in rat microvascular endothelial cells. However, the potential mechanism involved in these effects is poorly understood. Rats were intragastrically treated with 5.7 or 17.2 mL/kg Shuan-Tong-Ling for 7 days before middle cerebral artery occlusion was induced. The results indicated Shuan-Tong-Ling had a cerebral protective effect by reducing infarct volume and increasing neurological scores. Shuan-Tong-Ling also decreased tumor necrosis factor-α and interleukin-1β levels in the hippocampus on the ischemic side. In addition, Shuan-Tong-Ling upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of acetylated-protein 53 and Bax. Injection of 5 mg/kg silent information regulator 1 (SIRT1 inhibitor EX527 into the subarachnoid space once every 2 days, four times, reversed the above changes. These results demonstrate that Shuan-Tong-Ling might benefit cerebral ischemia/reperfusion injury by reducing inflammation and apoptosis through activation of the SIRT1 signaling pathway.

  11. Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart

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    Singh Manjeet

    2011-07-01

    Full Text Available Abstract Background Nitric oxide (NO has been noted to produce ischemic preconditioning (IPC-mediated cardioprotection. Caveolin is a negative regulator of NO, which inhibits endothelial nitric oxide synthase (eNOS by making caveolin-eNOS complex. The expression of caveolin is increased during diabetes mellitus (DM. The present study was designed to investigate the involvement of caveolin in attenuation of the cardioprotective effect of IPC during DM in rat. Methods Experimental DM was induced by single dose of streptozotocin (50 mg/Kg, i.p, and animals were used for experiments four weeks later. Isolated heart was mounted on Langendorff's apparatus, and was subjected to 30 min of global ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Kreb's-Henseleit solution (K-H. Extent of injury was measured in terms of infarct size by triphenyltetrazolium chloride (TTC staining, and release of lactate dehydrogenase (LDH and creatin kinase-MB (CK-MB in coronary effluent. The cardiac release of NO was noted by measuring the level of nitrite in coronary effluent. Results IPC- induced cardioprotection and release of NO was significantly decreased in diabetic rat heart. Pre-treatment of diabetic rat with daidzein (DDZ a caveolin inhibitor (0.2 mg/Kg/s.c, for one week, significantly increased the release of NO and restored the attenuated cardioprotective effect of IPC. Also perfusion of sodium nitrite (10 μM/L, a precursor of NO, significantly restored the lost effect of IPC, similar to daidzein in diabetic rat. Administration of 5-hydroxy deaconate (5-HD, a mito KATP channel blocker, significantly abolished the observed IPC-induced cardioprotection in normal rat or daidzein and sodium nitrite perfused diabetic rat heart alone or in combination. Conclusions Thus, it is suggested that attenuation of the cardioprotection in diabetic heart may be due to decrease the IPC mediated release of NO in

  12. Ceftriaxone attenuates hypoxic-ischemic brain injury in neonatal rats

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    Huang Yen

    2011-09-01

    Full Text Available Abstract Background Perinatal brain injury is the leading cause of subsequent neurological disability in both term and preterm baby. Glutamate excitotoxicity is one of the major factors involved in perinatal hypoxic-ischemic encephalopathy (HIE. Glutamate transporter GLT1, expressed mainly in mature astrocytes, is the major glutamate transporter in the brain. HIE induced excessive glutamate release which is not reuptaked by immature astrocytes may induce neuronal damage. Compounds, such as ceftriaxone, that enhance the expression of GLT1 may exert neuroprotective effect in HIE. Methods We used a neonatal rat model of HIE by unilateral ligation of carotid artery and subsequent exposure to 8% oxygen for 2 hrs on postnatal day 7 (P7 rats. Neonatal rats were administered three dosages of an antibiotic, ceftriaxone, 48 hrs prior to experimental HIE. Neurobehavioral tests of treated rats were assessed. Brain sections from P14 rats were examined with Nissl and immunohistochemical stain, and TUNEL assay. GLT1 protein expression was evaluated by Western blot and immunohistochemistry. Results Pre-treatment with 200 mg/kg ceftriaxone significantly reduced the brain injury scores and apoptotic cells in the hippocampus, restored myelination in the external capsule of P14 rats, and improved the hypoxia-ischemia induced learning and memory deficit of P23-24 rats. GLT1 expression was observed in the cortical neurons of ceftriaxone treated rats. Conclusion These results suggest that pre-treatment of infants at risk for HIE with ceftriaxone may reduce subsequent brain injury.

  13. Attenuation changes of the normal and ischemic canine kidney

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    Jaschke, W.; Lipton, M.J.; Boyd, D.P.; Cann, C.; Strauss, L.; Sievers, R.S.; California Univ., San Francisco

    1985-01-01

    The potential of CT scanning to explore total and regional renal blood flow was evaluated in a dog model with unilateral renal artery stenosis (n=7, reduction of renal blood flow: 32-75% of base line flow). Attenuation versus time curves were generated for the renal cortex and medulla, as well as for the aorta and renal vein. A fast CT scanner was used which allowed for up to 24 scans/minute at the same level (slice thickness: 10 mm). A total of 10 ml contrast medim was injected into a peripheral vein for each scan series taken. During baseline conditions, the curve of the renal cortex and medulla demonstrated 2 peaks. The first peak was mainly related to early vascular enhancement, whereas the second peak corresponded mainly to the appearance of contrast medium in the distal convolutes and collecting ducts. Ischemia of the kidney resulted in a reduction of the first peak and a flattening of the leading edge slope. Transport of contrast medium through the extravascular compartments of the kidney was delayed during ischemia. Relative renal blood flow was obtained from the CT data by dividing peak enhancement by rise-time as assessed from the cortical curve. All measurements were related to baseline flow and validated by flow measurements using radioactive labeled microspheres (n=5). Correlation was found to be r=0.97. (orig.)

  14. Alpha-2 agonist attenuates ischemic injury in spinal cord neurons.

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    Freeman, Kirsten A; Puskas, Ferenc; Bell, Marshall T; Mares, Joshua M; Foley, Lisa S; Weyant, Michael J; Cleveland, Joseph C; Fullerton, David A; Meng, Xianzhong; Herson, Paco S; Reece, T Brett

    2015-05-01

    Paraplegia secondary to spinal cord ischemia-reperfusion injury remains a devastating complication of thoracoabdominal aortic intervention. The complex interactions between injured neurons and activated leukocytes have limited the understanding of neuron-specific injury. We hypothesize that spinal cord neuron cell cultures subjected to oxygen-glucose deprivation (OGD) would simulate ischemia-reperfusion injury, which could be attenuated by specific alpha-2a agonism in an Akt-dependent fashion. Spinal cords from perinatal mice were harvested, and neurons cultured in vitro for 7-10 d. Cells were pretreated with 1 μM dexmedetomidine (Dex) and subjected to OGD in an anoxic chamber. Viability was determined by MTT assay. Deoxyuridine-triphosphate nick-end labeling staining and lactate dehydrogenase (LDH) assay were used for apoptosis and necrosis identification, respectively. Western blot was used for protein analysis. Vehicle control cells were only 59% viable after 1 h of OGD. Pretreatment with Dex significantly preserves neuronal viability with 88% viable (P control cells by 50% (P neuron cell culture, OGD mimics neuronal metabolic derangement responsible for paraplegia after aortic surgery. Dex preserves neuronal viability and decreases apoptosis in an Akt-dependent fashion. Dex demonstrates clinical promise for reducing the risk of paraplegia after high-risk aortic surgery. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Ischemic preconditioning of the lower extremity attenuates the normal hypoxic increase in pulmonary artery systolic pressure.

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    Foster, Gary P; Westerdahl, Daniel E; Foster, Laura A; Hsu, Jeffrey V; Anholm, James D

    2011-12-15

    Ischemic pre-condition of an extremity (IPC) induces effects on local and remote tissues that are protective against ischemic injury. To test the effects of IPC on the normal hypoxic increase in pulmonary pressures and exercise performance, 8 amateur cyclists were evaluated under normoxia and hypoxia (13% F(I)O(2)) in a randomized cross-over trial. IPC was induced using an arterial occlusive cuff to one thigh for 5 min followed by deflation for 5 min for 4 cycles. In the control condition, the resting pulmonary artery systolic pressure (PASP) increased from a normoxic value of 25.6±2.3 mmHg to 41.8±7.2 mmHg following 90 min of hypoxia. In the IPC condition, the PASP increased to only 32.4±3.1 mmHg following hypoxia, representing a 72.8% attenuation (p=0.003). No significant difference was detected in cycle ergometer time trial duration between control and IPC conditions with either normoxia or hypoxia. IPC administered prior to hypoxic exposure was associated with profound attenuation of the normal hypoxic increase of pulmonary artery systolic pressure. Published by Elsevier B.V.

  16. Hyper-attenuating brain lesions on CT after ischemic stroke and thrombectomy are associated with final brain infarction.

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    Cabral, F B; Castro-Afonso, L H; Nakiri, G S; Monsignore, L M; Fábio, Src; Dos Santos, A C; Pontes-Neto, O M; Abud, D G

    2017-12-01

    Purpose Hyper-attenuating lesions, or contrast staining, on a non-contrast brain computed tomography (NCCT) scan have been investigated as a predictor for hemorrhagic transformation after endovascular treatment of acute ischemic stroke (AIS). However, the association of hyper-attenuating lesions and final ischemic areas are poorly investigated in this setting. The aim of the present study was to assess correlations between hyper-attenuating lesions and final brain infarcted areas after thrombectomy for AIS. Methods Data from patients with AIS of the anterior circulation who underwent endovascular treatment were retrospectively assessed. Images of the brain NCCT scans were analyzed in the first hours and late after treatment. The hyper-attenuating areas were compared to the final ischemic areas using the Alberta Stroke Program Early CT Score (ASPECTS). Results Seventy-one of the 123 patients (65.13%) treated were included. The association between the hyper-attenuating region in the post-thrombectomy CT scan and final brain ischemic area were sensitivity (58.3% to 96.9%), specificity (42.9% to 95.6%), positive predictive values (71.4% to 97.7%), negative predictive values (53.8% to 79.5%), and accuracy values (68% to 91%). The highest sensitivity values were found for the lentiform (96.9%) and caudate nuclei (80.4%) and for the internal capsule (87.5%), and the lowest values were found for the M1 (58.3%) and M6 (66.7%) cortices. Conclusions Hyper-attenuating lesions on head NCCT scans performed after endovascular treatment of AIS may predict final brain infarcted areas. The prediction appears to be higher in the deep brain regions compared with the cortical regions.

  17. Effect of X-Ray Attenuation of Arterial Obstructions on Intravenous Thrombolysis and Outcome after Ischemic Stroke.

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    Grant Mair

    Full Text Available To assess whether the x-ray attenuation of intra-arterial obstruction measured on non-contrast CT in ischemic stroke can predict response to thrombolysis and subsequent functional outcome.The Third International Stroke Trial (IST-3 was a multicenter randomized-controlled trial of intravenous thrombolysis (rt-PA given within six hours of ischemic stroke. Ethical approval and informed consent were obtained. In a subgroup of 109 IST-3 patients (38 men, median age 82 years, a single reader, masked to all clinical and other imaging data, manually measured x-ray attenuation (Hounsfield Units, HU on non-contrast CT at the location of angiographically-proven intra-arterial obstructions, pre-randomization and at 24-48 hour follow-up. We calculated change in attenuation between scans. We assessed the impact of pre-randomization arterial obstruction attenuation on six-month functional outcome.Most arterial obstructions (64/109, 59% were hyperattenuating (mean 51.0 HU. Compared with control, treatment with rt-PA was associated with a greater, but non-significant, reduction in obstruction attenuation at follow-up (-8.0 HU versus -1.4 HU in patients allocated control, p = 0.117. In multivariable ordinal regression analysis controlled for patient age, stroke severity, location and extent of obstruction, time from stroke onset to baseline scan and rt-PA treatment allocation, the attenuation of pre-randomization arterial obstruction was not independently associated with six-month outcome (odds ratio = 0.99, 95% confidence interval = 0.94-1.03, p = 0.516.In ischemic stroke, the x-ray attenuation of the arterial obstruction may decline more rapidly from baseline to 24-48 hours following treatment with thrombolysis but we found no evidence that baseline arterial obstruction attenuation predicts six-month outcome.

  18. Altering CO2 during reperfusion of ischemic cardiomyocytes modifies mitochondrial oxidant injury.

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    Lavani, Romeen; Chang, Wei-Tien; Anderson, Travis; Shao, Zuo-Hui; Wojcik, Kimberly R; Li, Chang-Qing; Pietrowski, Robert; Beiser, David G; Idris, Ahamed H; Hamann, Kimm J; Becker, Lance B; Vanden Hoek, Terry L

    2007-07-01

    Acute changes in tissue CO2 and pH during reperfusion of the ischemic heart may affect ischemia/reperfusion injury. We tested whether gradual vs. acute decreases in CO2 after cardiomyocyte ischemia affect reperfusion oxidants and injury. Comparative laboratory investigation. Institutional laboratory. Embryonic chick cardiomyocytes. Microscope fields of approximately 500 chick cardiomyocytes were monitored throughout 1 hr of simulated ischemia (PO2 of 3-5 torr, PCO2 of 144 torr, pH 6.8), followed by 3 hrs of reperfusion (PO2 of 149 torr, PCO2 of 36 torr, pH 7.4), and compared with cells reperfused with relative hypercarbia (PCO2 of 71 torr, pH 6.8) or hypocarbia (PCO2 of 7 torr, pH 7.9). The measured outcomes included cell viability (via propidium iodide) and oxidant generation (reactive oxygen species via 2',7'-dichlorofluorescin oxidation and nitric oxide [NO] via 4,5-diaminofluorescein diacetate oxidation). Compared with normocarbic reperfusion, hypercarbia significantly reduced cell death from 54.8% +/- 4.0% to 26.3% +/- 2.8% (p < .001), significantly decreased reperfusion reactive oxygen species (p < .05), and increased NO at a later phase of reperfusion (p < .01). The NO synthase inhibitor N-nitro-L-arginine methyl ester (200 microM) reversed this oxidant attenuation (p < .05), NO increase (p < .05), and the cardioprotection conferred by hypercarbic reperfusion (increasing death to 54.3% +/- 6.0% [p < .05]). Conversely, hypocarbic reperfusion increased cell death to 80.4% +/- 4.5% (p < .01). It also increased reactive oxygen species by almost two-fold (p = .052), without affecting the NO level thereafter. Increased reactive oxygen species was attenuated by the mitochondrial complex III inhibitor stigmatellin (20 nM) when given at reperfusion (p < .05). Cell death also decreased from 85.9% +/- 4.5% to 52.2% +/- 6.5% (p < .01). The nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin (300 microM) had no effect on reperfusion reactive oxygen

  19. Edaravone attenuates neuronal apoptosis in hypoxic-ischemic brain damage rat model via suppression of TRAIL signaling pathway.

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    Li, Chunyi; Mo, Zhihuai; Lei, Junjie; Li, Huiqing; Fu, Ruying; Huang, Yanxia; Luo, Shijian; Zhang, Lei

    2018-06-01

    Edaravone is a new type of oxygen free radical scavenger and able to attenuate various brain damage including hypoxic-ischemic brain damage (HIBD). This study was aimed at investigating the neuroprotective mechanism of edaravone in rat hypoxic-ischemic brain damage model and its correlation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway. 75 seven-day-old Sprague-Dawley neonatal rats were equally divided into three groups: sham-operated group (sham), HIBD group and HIBD rats injected with edaravone (HIBD + EDA) group. Neurological severity and space cognitive ability of rats in each group were evaluated using Longa neurological severity score and Morris water maze testing. TUNEL assay and flow cytometry were used to determine brain cell apoptosis. Western blot was used to estimate the expression level of death receptor-5 (DR5), Fas-associated protein with death domain (FADD), caspase 8, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax). In addition, immunofluorescence was performed to detect caspase 3. Edaravone reduced neurofunctional damage caused by HIBD and improved the cognitive capability of rats. The above experiment results suggested that edaravone could down-regulate the expression of active caspase 3 protein, thereby relieving neuronal apoptosis. Taken together, edaravone could attenuate neuronal apoptosis in rat hypoxic-ischemic brain damage model via suppression of TRAIL signaling pathway, which also suggested that edaravone might be an effective therapeutic strategy for HIBD clinical treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Role of phosphoinositide 3-kinase in ischemic postconditioning-induced attenuation of cerebral ischemia-evoked behavioral deficits in mice.

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    Rehni, Ashish K; Singh, Nirmal

    2007-01-01

    The present study has been designed to pharmacologically investigate the role of phosphoinositide 3-kinase in ischemic postconditioning-induced reversal of global cerebral ischemia and reperfusion-induced behavioral dysfunction in mice. Bilateral carotid artery occlusion for 10 min followed by reperfusion for 24 h was employed in the present study to produce ischemia and reperfusion-induced cerebral injury in mice. Short-term memory was evaluated using the elevated plus maze test. The inclined beam walking test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced impaired short-term memory, motor co-ordination and lateral push response. Three episodes of carotid artery occlusion for a period of 10 s and reperfusion of 10 s (ischemic postconditioning) significantly prevented ischemia-reperfusion-induced behavioral deficit measured in terms of loss of short-term memory, motor coordination and lateral push response. Wortmannin (2 mg/kg, iv), a phosphoinositide 3-kinase inhibitor given 10 min before ischemia attenuated the beneficial effects of ischemic postconditioning. It may be concluded that beneficial effects of ischemic postconditioning on global cerebral ischemia and reperfusion-induced behavioral deficits may involve activation of phosphoinositide 3-kinase-linked pathway.

  1. Ischemic preconditioning effect of prodromal angina is attenuated in acute myocardial infarction patients with hypertensive left ventricular hypertrophy

    International Nuclear Information System (INIS)

    Takeuchi, Toshiharu; Kikuchi, Kenjiro; Hasebe, Naoyuki; Ishii, Yoshinao

    2011-01-01

    Several animal experiments on acute myocardial infarction (AMI) have shown that the cardioprotective effects of ischemic preconditioning are more significant in hypertensive subjects. However, because there are no clinical data on the impact of hypertension on ischemic preconditioning in patients with AMI, whether clinical ischemic preconditioning of prodromal angina was beneficial in AMI patients with hypertension was investigated in the present study. 125 patients with a first anterior AMI who had undergone successful reperfusion therapy were divided into 2 groups, with or without hypertension, and into 2 further subgroups based on the presence or absence of prodromal angina. Dual-isotope (thallium-201(TL)/Tc-99m pyrophosphate) single-photon emission computed tomography (SPECT) was performed within 1 week of reperfusion therapy. Left ventricular (LV) function and LV mass index (LVMI) were measured by left ventriculography and echocardiography, respectively. In patients without hypertension, prodromal angina resulted in significantly less myocardial damage on TL-SPECT, better LV ejection fraction and a greater myocardial blush grade compared to patients without prodromal angina. However, these cardioprotective effects of prodromal angina were significantly diminished in hypertensive patients. Importantly, the myocardial salvage effects of prodromal angina showed a significant negative correlation with LVMI, which was significantly greater in hypertensive patients. The cardioprotective effects of prodromal angina were attenuated in patients with hypertension. Hypertensive LV hypertrophy may crucially limit the effects of ischemic preconditioning in AMI. (author)

  2. Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress.

    Science.gov (United States)

    Klumpe, Inga; Savvatis, Konstantinos; Westermann, Dirk; Tschöpe, Carsten; Rauch, Ursula; Landmesser, Ulf; Schultheiss, Heinz-Peter; Dörner, Andrea

    2016-06-01

    Ischemia impairs the adenine nucleotide translocase (ANT), which transports ADP and ATP across the inner mitochondrial membrane. We investigated whether ANT1 overexpression has protective effects on ischemic hearts. Myocardial infarction was induced in wild-type (WT) and heart-specific ANT1-transgenic (ANT1-TG) rats, and hypoxia was set in isolated cardiomyocytes. ANT1 overexpression reduced the myocardial infarct area and increased the survival rate of infarcted rats. Reduced ANT1 expression and increased 4-hydroxynonenal modification of ANT paralleled to impaired ANT function in infarcted WT hearts. ANT1 overexpression improved ANT expression and function. This was accompanied by reduced mitochondrial cytochrome C release and caspase-3 activation. ANT1-TG hearts suffered less from oxidative stress, as shown by lower protein carbonylation and 4-hydroxynonenal modification of ANT. ANT1 overexpression also increased cell survival of hypoxic cardiomyocytes and attenuated reactive oxygen species (ROS) production. This was linked to higher stability of mitochondrial membrane potential and lower activity of ROS detoxifying catalase. ANT1-TG cardiomyocytes also showed higher resistance against H2O2 treatment, which was independent of catalase activity. In conclusion, ANT1 overexpression compensates impaired ANT activity under oxygen-restricted conditions. It reduces ROS production and oxidative stress, stabilizes mitochondrial integrity, and increases survival, making ANT1 a component in ROS management and heart protection during ischemia. ANT1 overexpression reduces infarct size and increases survival after infarction. ANT1 overexpression compensates restricted ANT expression and function in infarcted hearts. Increased ANT1 expression enhances mitochondrial integrity. ANT1-overexpressing hearts reduce oxidative stress by decreasing ROS generation. ANT1 is a component in ROS management and heart protection.

  3. Electroacupuncture acutely improves cerebral blood flow and attenuates moderate ischemic injury via an endothelial mechanism in mice.

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    Ji Hyun Kim

    Full Text Available Electroacupuncture (EA is a novel therapy based on traditional acupuncture combined with modern eletrotherapy that is currently being investigated as a treatment for acute ischemic stroke. Here, we studied whether acute EA stimulation improves tissue and functional outcome following experimentally induced cerebral ischemia in mice. We hypothesized that endothelial nitric oxide synthase (eNOS-mediated perfusion augmentation was related to the beneficial effects of EA by interventions in acute ischemic injury. EA stimulation at Baihui (GV20 and Dazhui (GV14 increased cerebral perfusion in the cerebral cortex, which was suppressed in eNOS KO, but there was no mean arterial blood pressure (MABP response. The increased perfusion elicited by EA were completely abolished by a muscarinic acetylcholine receptor (mAChR blocker (atropine, but not a β-adrenergic receptor blocker (propranolol, an α-adrenergic receptor blocker (phentolamine, or a nicotinic acetylcholine receptor (nAChR blocker (mecamylamine. In addition, EA increased acetylcholine (ACh release and mAChR M3 expression in the cerebral cortex. Acute EA stimulation after occlusion significantly reduced infarct volume by 34.5% when compared to a control group of mice at 24 h after 60 min-middle cerebral artery occlusion (MCAO (moderate ischemic injury, but not 90-min MCAO (severe ischemic injury. Furthermore, the impact of EA on moderate ischemic injury was totally abolished in eNOS KO. Consistent with a smaller infarct size, acute EA stimulation led to prominent improvement of neurological function and vestibule-motor function. Our results suggest that acute EA stimulation after moderate focal cerebral ischemia, but not severe ischemia improves tissue and functional recovery and ACh/eNOS-mediated perfusion augmentation might be related to these beneficial effects of EA by interventions in acute ischemic injury.

  4. Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein.

    Science.gov (United States)

    Li, Zhijuan; Cheng, Jianxin; Wang, Liping

    2015-10-30

    Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation. Copyright © 2015. Published by Elsevier Inc.

  5. A novel therapy to attenuate acute kidney injury and ischemic allograft damage after allogenic kidney transplantation in mice.

    Directory of Open Access Journals (Sweden)

    Faikah Gueler

    Full Text Available Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx. In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV, might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20-50mg/kg twice daily i.p. for four consecutive days was initiated 24 hours after IRI when acute kidney injury (AKI was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF and glomerular filtration rate (GFR at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

  6. Impaired cardiac ischemic tolerance in spontaneously hypertensive rats is attenuated by adaptation to chronic and acute stress.

    Science.gov (United States)

    Ravingerová, T; Bernátová, I; Matejíková, J; Ledvényiová, V; Nemčeková, M; Pecháňová, O; Tribulová, N; Slezák, J

    2011-01-01

    Chronic hypertension may have a negative impact on the myocardial response to ischemia. On the other hand, intrinsic ischemic tolerance may persist even in the pathologically altered hearts of hypertensive animals, and may be modified by short- or long-term adaptation to different stressful conditions. The effects of long-term limitation of living space (ie, crowding stress [CS]) and brief ischemia-induced stress on cardiac response to ischemia/reperfusion (I/R) injury are not yet fully characterized in hypertensive subjects. The present study was designed to test the influence of chronic and acute stress on the myocardial response to I/R in spontaneously hypertensive rats (SHR) compared with their effects in normotensive counterparts. In both groups, chronic, eight-week CS was induced by caging five rats per cage in cages designed for two rats (200 cm(2)/rat), while controls (C) were housed four to a cage in cages designed for six animals (480 cm(2)/rat). Acute stress was evoked by one cycle of I/R (5 min each, ischemic preconditioning) before sustained I/R in isolated Langendorff-perfused hearts of normotensive and SHR rats. At baseline conditions, the effects of CS were manifested only as a further increase in blood pressure in SHR, and by marked limitation of coronary perfusion in normotensive animals, while no changes in heart mechanical function were observed in any of the groups. Postischemic recovery of contractile function, severity of ventricular arrhythmias and lethal injury (infarction size) were worsened in the hypertrophied hearts of C-SHR compared with normotensive C. However, myo-cardial stunning and reperfusion-induced ventricular arrhythmias were attenuated by CS in SHR, which was different from deterioration of I/R injury in the hearts of normotensive animals. In contrast, ischemic preconditioning conferred an effective protection against I/R in both groups, although the extent of anti-infarct and anti-arrhythmic effects was lower in SHR. Both

  7. Attenuating brain inflammation, ischemia, and oxidative damage by hyperbaric oxygen in diabetic rats after heat stroke

    Directory of Open Access Journals (Sweden)

    Kai-Li Lee

    2013-08-01

    Conclusion: Our results suggest that, in diabetic animals, HBO2 therapy may improve outcomes of HS in part by reducing heat-induced activated inflammation and ischemic and oxidative damage in the hypothalamus and other brain regions.

  8. Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein

    International Nuclear Information System (INIS)

    Li, Zhijuan; Cheng, Jianxin; Wang, Liping

    2015-01-01

    Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation. - Highlights: • Edaravone reduces oxLDL-induced monocyte adhesion to HUVECs. • Edaravone attenuates oxLDL-induced expression of MCP-1, VCAM-1, and ICAM-1. • Edaravone reduces NF-κB transcriptional activity and p65 nuclear translocation.

  9. Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zhijuan, E-mail: zjlee038@163.com; Cheng, Jianxin; Wang, Liping

    2015-10-30

    Oxidized low-density lipoprotein (oxLDL) plays a vital role in recruitment of monocytes to endothelial cells, which is important during early stages of atherosclerosis development. Edaravone, a potent and novel scavenger of free radicals inhibiting hydroxyl radicals, has been clinically used to reduce the neuronal damage following ischemic stroke. In the present study, Edaravone was revealed to markedly reduce oxLDL-induced monocyte adhesion to human umbilical vein endothelial cells (HUVECs). The inhibitory mechanism of Edaravone was associated with suppression of the chemokine MCP-1 and adhesion molecule VCAM-1 and ICAM-1 expression. In addition, luciferase reporter assay results revealed that administration of Edaravone attenuated the increase in NF-κB transcriptional activity induced by oxLDL. Notably, it's also shown that Edaravone treatment blocked oxLDL induced p65 nuclear translocation in HUVECs. Results indicate that Edaravone negatively regulates endothelial inflammation. - Highlights: • Edaravone reduces oxLDL-induced monocyte adhesion to HUVECs. • Edaravone attenuates oxLDL-induced expression of MCP-1, VCAM-1, and ICAM-1. • Edaravone reduces NF-κB transcriptional activity and p65 nuclear translocation.

  10. Association between oxidized low-density lipoprotein and cognitive impairment in patients with ischemic stroke.

    Science.gov (United States)

    Wang, A; Liu, J; Meng, X; Li, J; Wang, H; Wang, Y; Su, Z; Zhang, N; Dai, L; Wang, Y; Wang, Y

    2018-01-01

    The association between oxidized low-density lipoprotein (oxLDL) and cognitive impairment is unclear. This study aimed to investigate the potential association between oxLDL and cognitive impairment among patients with acute ischemic stroke. We measured the levels of oxLDL and recorded the Mini-Mental State Examination (MMSE) score in patients with acute ischemic stroke who were recruited from the Study of Oxidative Stress in Patients with Acute Ischemic Stroke. Cognitive impairment was defined as an MMSE score of impairment was assessed by multivariate logistic or linear regression analysis. Other clinical variables of interest were also studied. A total of 3726 patients [1287 (34.54%) female] were included in this study, with a mean age of 63.62 ± 11.96 years. After adjusting for potential confounders in our logistic regression model, each SD increase in oxLDL was associated with a 26% increase in the prevalence of cognitive impairment (odds radio, 1.26; 95% confidence interval, 1.13-1.39; P impairment (all interactions, P > 0.05). Elevated levels of oxLDL were associated with a higher prevalence of cognitive impairment in patients with ischemic stroke. © 2017 EAN.

  11. Arctigenin attenuates ischemic stroke via SIRT1-dependent inhibition of NLRP3 inflammasome.

    Science.gov (United States)

    Zhang, Shimeng; Jiang, Liangjun; Che, Fengyuan; Lu, Yucheng; Xie, Zhongxiang; Wang, Hao

    2017-11-04

    Arctigenin (ARC), a phenylpropanoid dibenzylbutyrolactone lignan derived from Arctium lappa L, has been reported to protect against cerebral ischemia injury in rats, but the underlying mechanism is unclear. In this study, we investigated whether ARC ameliorated ischemic stroke by inhibiting NLRP3 inflammasome-derived neuroinflammation and whether SIRT1 signaling was involved in this process. ARC (20 mg/kg) or vehicle were intraperitoneally injected to Sprague-Dawley rats for 3 days before middle cerebral artery occlusion (MCAO) surgery performed. The infarct volume, neurological score, brain water content, neuroinflammation, NLRP3 inflammasome activation and SIRT1 protein expression were assessed. Furthermore, we also investigated whether ARC protected against cerebral ischemia via SIRT1-dependent inhibition of NLRP3 inflammasome by administrating EX527, a specific SIRT1 inhibitor, under oxygen-glucose deprivation (OGD) condition. We found that ARC pretreatment decreased infarct volume, neurological score and brain water content. Moreover, ARC treatment effectively inhibited cerebral ischemia induced NLRP3 inflammasome activation and IL-1β, IL-18 secretion both in vivo and in vitro. Futhermore, ARC treatment activated Silent information regulator 1 (SIRT1) singnaling in the brain. Importantly, suppress of SIRT1 reversed the inhibitory effect of ARC on NLRP3 inflammasome activation. Taken together our results demonstrated that ARC may confer protection against ischemic stroke by inhibiting NLRP3 inflammasome activation. The activation of SIRT1 signaling pathway may contribute to the neuroprotection of ARC in MCAO. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Severe pain as a possible cause of dropped head syndrome that was attenuated after amputation of an ischemic lower limb.

    Science.gov (United States)

    Maki, Satoshi; Koda, Masao; Furuya, Takeo; Takahashi, Kazuhisa; Yamazaki, Masashi

    2016-03-02

    Dropped head syndrome (DHS) is defined as weakness of the neck extensor muscles causing a correctable chin-on-the-chest deformity. Here we report the case of a patient with severe pain from lower leg ischemia showing DHS whose symptoms were attenuated by pain relief after amputation of the severely ischemic lower leg. To our knowledge this is the first report indicating that severe pain can cause DHS. A 64-year-old Asian woman was referred to our department with a 1-month history of DHS. She also suffered from severe right foot pain because of limb ischemia. She began to complain of DHS as her gangrenous foot pain worsened. She had neck pain and difficulty with forward gaze. We found no clinical or laboratory findings of neuromuscular disorder or isolated neck extensor myopathy. We amputated her leg below the knee because of progressive foot gangrene. Her severe foot pain resolved after the surgery and her DHS was attenuated. Severe pain can cause DHS. If a patient with DHS has severe pain in another part of the body, we recommend considering aggressive pain relief as a treatment option.

  13. Probucol plus cilostazol attenuate hypercholesterolemia‑induced exacerbation in ischemic brain injury via anti-inflammatory effects.

    Science.gov (United States)

    Kim, Ji Hyun; Hong, Ki Whan; Bae, Sun Sik; Shin, Yong-Il; Choi, Byung Tae; Shin, Hwa Kyoung

    2014-09-01

    Probucol, a lipid-lowering agent with anti-oxidant properties, is involved in protection against atherosclerosis, while cilostazol, an antiplatelet agent, has diverse neuroprotective properties. In this study, we investigated the anti-inflammatory effects of probucol and cilostazol on focal cerebral ischemia with hypercholesterolemia. Apolipoprotein E (ApoE) knockout (KO) mice were fed a high-fat diet (HFD) with or without 0.3% probucol and/or 0.2% cilostazol for 10 weeks. To assess the protective effects of the combined therapy of probucol and cilostazol on ischemic injury, the mice received 40 min of middle cerebral artery occlusion (MCAO). Infarct volumes, neurobehavioral deficits and neuroinflammatory mediators were subsequently evaluated 48 h after reperfusion. Probucol alone and probucol plus cilostazol significantly decreased total- and low-density lipoprotein (LDL)-cholesterol in ApoE KO with HFD. MCAO resulted in significantly larger infarct volumes in ApoE KO mice provided with HFD compared to those fed a regular diet, although these volumes were significantly reduced in the probucol plus cilostazol group. Consistent with a smaller infarct size, probucol alone and the combined treatment of probucol and cilostazol improved neurological and motor function. In addition, probucol alone and probucol plus cilostazol decreased MCP-1 expression and CD11b and GFAP immuno-reactivity in the ischemic cortex. These findings suggested that the inhibitory effects of probucol plus cilostazol in MCP-1 expression in the ischemic brain with hypercholesterolemia allowed the identification of one of the mechanisms responsible for anti-inflammatory action. Probucol plus cilostazol may therefore serve as a therapeutic strategy for reducing the impact of stroke in hypercholesterolemic subjects.

  14. Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs.

    Science.gov (United States)

    Zhang, Hai-Tao; Zhang, Ping; Gao, Yi; Li, Chen-Long; Wang, Hong-Jun; Chen, Ling-Chao; Feng, Yan; Li, Rui-Yan; Li, Yong-Li; Jiang, Chuan-Lu

    2017-01-01

    Vascular endothelial growth factor (VEGF) inhibition has been demonstrated to be an effective strategy in preserving the integrity of the blood-brain barrier (BBB) in patients with acute ischemic stroke. Loss of the BBB is the key event associated with morbidity and mortality in these patients. However, the underlying mechanisms remain poorly understood. In the present study, the effects of VEGF inhibition and the possible mechanism that underlies acute cerebral ischemia in rats was investigated. Following the induction of transient middle cerebral artery occlusion for a 90‑min period, either an anti‑VEGF neutralizing antibody (RB‑222; 5 or 10 µg), or IgG (control), was administered by intracerebroventricular injection at 1 h following reperfusion. Functional outcomes, BBB leakage, brain edema, microvessel numbers and the relative protein levels of VEGF, matrix metalloproteinase (MMP)-2, MMP-9, occludin and collagen-IV were then determined using neurological assessments, Evans Blue staining, brain water content, CD31 staining and western blotting. Treatment with RB‑222 at a dose of 5 and 10 µg significantly improved neurological functional outcomes and diminished infarct size, BBB leakage and brain edema compared with the MCAO and IgG groups at 24 h following reperfusion; 10 µg RB‑222 was more effective than a 5 µg dose of the antibody. In addition, RB‑222 reduced the number of immature microvessels, which subsequently attenuated BBB permeability. RB‑222 significantly repressed VEGF expression as well as decreased MMP‑2 and MMP‑9 expression. However, it enhanced occludin and collagen‑IV levels in the ischemic rat brain compared with the MCAO and IgG groups. Taken together, the results indicate that early inhibition of VEGF may have significant potential against cerebral ischemia, partly by regulating the expression of MMPs.

  15. Huperzine A attenuates hepatic ischemia reperfusion injury via anti-oxidative and anti-apoptotic pathways.

    Science.gov (United States)

    Xu, Zhe; Wang, Yang

    2014-08-01

    Hepatic ischemia reperfusion (HI/R) injury may occur during liver transplantation and remains a serious concern in clinical practice. Huperzine A (HupA), an alkaloid isolated from the Chinese traditional medicine Huperzia serrata, has been demonstrated to possess anti‑oxidative and anti‑apoptotic properties. In the present study, a rat model of HI/R was established by clamping the hepatic artery, the hepatoportal vein and the bile duct with a vascular clamp for 30 min followed by reperfusion for 6 h under anesthesia. HupA was injected into the tail vein 5 min prior to the induction of HI/R at doses of 167 and 500 µg/kg. The histopathological assessment of the liver was performed using hematoxylin and eosin staining. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assayed in the serum samples. The tissue levels of superoxide dismutase (SOD), catalase (CAT), malondiadehyde (MDA) and glutathione (GSH) were also measured spectrophotometrically. Furthermore, the protein expression of caspase‑3, Bcl‑2 and Bax in hepatic tissues was detected via western blot analysis. Treatment of Wistar rats with HupA at doses of 167 and 500 µg/kg markedly attenuated HI/R injury as observed histologically. In addition, the significant reductions of serum ALT and AST were observed in HupA‑treated ischemic rats. Furthermore, HupA treatment enhanced the activity of hepatic tissue SOD, CAT and GSH, but decreased the MDA tissue content. Western blot analysis revealed elevated levels of Bcl‑2 expression but decreased Bax and caspase‑3 tissue expression at the protein level in the HupA‑treated group. The present data suggest that HupA attenuates the HI/R injury of rats through its anti‑oxidative and anti‑apoptotic signaling pathways.

  16. Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats.

    Science.gov (United States)

    Li, Jing; He, Jiaojun; Du, Yuanhao; Cui, Jingjun; Ma, Ying; Zhang, Xuezhu

    2014-11-11

    To investigate the effects and potential mechanism of electroacupuncture intervention on expressions of Angiotensin II and its receptors-mediated signaling pathway in experimentally induced cerebral ischemia. Totally 126 male Wistar rats were randomly divided into control group, model group and EA group. The latter two were further divided into ten subgroups (n = 6) following Middle Cerebral Artery Occlusion (MCAO). Changes in regional cerebral blood flow (rCBF) and expressions of Angiotensin II and its receptors (AT1R, AT2R), as well as effector proteins in phosphatidyl inositol signal pathway were monitored before and at different times after MCAO. MCAO-induced decline of ipsilateral rCBF was partially suppressed by electroacupuncture, and contralateral blood flow was also superior to that of model group. Angiotensin II level was remarkably elevated immediately after MCAO, while electroacupuncture group exhibited significantly lower levels at 1 to 3 h and the value was significantly increased thereafter. The enhanced expression of AT1R was partially inhibited by electroacupuncture, while increased AT2R level was further induced. Electroacupuncture stimulation attenuated and postponed the upregulated-expressions of Gq and CaM these upregulations. ELISA results showed sharply increased expressions of DAG and IP3, which were remarkably neutralized by electroacupuncture. MCAO induced significant increases in expression of Angiotensin II and its receptor-mediated signal pathway. These enhanced expressions were significantly attenuated by electroacupuncture intervention, followed by reduced vasoconstriction and improved blood supply in ischemic region, and ultimately conferred beneficial effects on cerebral ischemia.

  17. An engineered S1P chaperone attenuates hypertension and ischemic injury.

    Science.gov (United States)

    Swendeman, Steven L; Xiong, Yuquan; Cantalupo, Anna; Yuan, Hui; Burg, Nathalie; Hisano, Yu; Cartier, Andreane; Liu, Catherine H; Engelbrecht, Eric; Blaho, Victoria; Zhang, Yi; Yanagida, Keisuke; Galvani, Sylvain; Obinata, Hideru; Salmon, Jane E; Sanchez, Teresa; Di Lorenzo, Annarita; Hla, Timothy

    2017-08-15

    Endothelial dysfunction, a hallmark of vascular disease, is restored by plasma high-density lipoprotein (HDL). However, a generalized increase in HDL abundance is not beneficial, suggesting that specific HDL species mediate protective effects. Apolipoprotein M-containing HDL (ApoM + HDL), which carries the bioactive lipid sphingosine 1-phosphate (S1P), promotes endothelial function by activating G protein-coupled S1P receptors. Moreover, HDL-bound S1P is limiting in several inflammatory, metabolic, and vascular diseases. We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function. In contrast, ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors. ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke. Our proof-of-concept study suggests that selective and sustained targeting of endothelial S1P receptors by ApoM-Fc could be a viable therapeutic strategy in vascular diseases. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  18. Real-Time Fluorescence Measurements of ROS and [Ca2+] in Ischemic / Reperfused Rat Hearts: Detectable Increases Occur only after Mitochondrial Pore Opening and Are Attenuated by Ischemic Preconditioning.

    Directory of Open Access Journals (Sweden)

    Tatyana Andrienko

    Full Text Available Mitochondrial permeability transition pore (mPTP opening is critical for ischemia / reperfusion (I/R injury and is associated with increased [Ca2+] and reactive oxygen species (ROS. Here we employ surface fluorescence to establish the temporal sequence of these events in beating perfused hearts subject to global I/R. A bespoke fluorimeter was used to synchronously monitor surface fluorescence and reflectance of Langendorff-perfused rat hearts at multiple wavelengths, with simultaneous measurements of hemodynamic function. Potential interference by motion artefacts and internal filtering was assessed and minimised. Re-oxidation of NAD(PH and flavoproteins on reperfusion (detected using autofluorescence was rapid (t0.5 < 15 s and significantly slower following ischemic preconditioning (IP. This argues against superoxide production from reduced Complex 1 being a critical mediator of initial mPTP opening during early reperfusion. Furthermore, MitoPY1 (a mitochondria-targeted H2O2-sensitive fluorescent probe and aconitase activity measurements failed to detect matrix ROS increases during early reperfusion. However, two different fluorescent cytosolic ROS probes did detect ROS increases after 2-3 min of reperfusion, which was shown to be after initiation of mPTP opening. Cyclosporin A (CsA and IP attenuated these responses and reduced infarct size. [Ca2+]i (monitored with Indo-1 increased progressively during ischemia, but dropped rapidly within 90 s of reperfusion when total mitochondrial [Ca2+] was shown to be increased. These early changes in [Ca2+] were not attenuated by IP, but substantial [Ca2+] increases were observed after 2-3 min reperfusion and these were prevented by both IP and CsA. Our data suggest that the major increases in ROS and [Ca2+] detected later in reperfusion are secondary to mPTP opening. If earlier IP-sensitive changes occur that might trigger initial mPTP opening they are below our limit of detection. Rather, we suggest that

  19. Tadalafil enhances the neuroprotective effects of ischemic postconditioning in mice, probably in a nitric oxide associated manner.

    Science.gov (United States)

    Gulati, Puja; Singh, Nirmal

    2014-05-01

    This study investigates the modulatory effect of tadalafil, a selective phosphodiesterase (PDE-5) inhibitor, on the neuroprotective effects of ischemic postconditioning (iPoCo) in mice. Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion induced cerebral injury. Cerebral infarct size was measured using TTC staining. Memory was assessed using the Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walking, rota-rod, and lateral push tests. Brain nitrite/nitrate, acetylcholinesterase activity, TBARS, and glutathione levels were also estimated. BCAO followed by reperfusion produced a significant increase in cerebral infarct size, brain nitrite/nitrate and TBARS levels, and acetylcholinesterase activity along with a reduction in glutathione. Marked impairment of memory and motor coordination was also noted. iPoCo consisting of 3 episodes of 10 s carotid artery occlusion and reperfusion instituted immediately after BCAO significantly decreased infarct size, memory impairment, motor incoordination, and altered biochemistry. Pretreatment with tadalafil mimicked the neuroprotective effects of iPoCo. The tadalafil-induced neuroprotective effects were significantly attenuated by l-NAME, a nonselective NOS inhibitor. We concluded that tadalafil mimics the neuroprotective effects of iPoCo, probably through a nitric oxide dependent pathway, and PDE-5 could be a target of interest with respect to the neuroprotective mechanism of iPoCo.

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Kapil Suchal

    2016-01-01

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

  2. Attenuation of oxidative neuronal cell death by coffee phenolic phytochemicals

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Eun Sun; Jang, Young Jin [Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921 (Korea, Republic of); Hwang, Mun Kyung; Kang, Nam Joo [Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921 (Korea, Republic of); Department of Bioscience and Biotechnology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701 (Korea, Republic of); Lee, Ki Won [Department of Bioscience and Biotechnology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701 (Korea, Republic of)], E-mail: kiwon@konkuk.ac.kr; Lee, Hyong Joo [Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921 (Korea, Republic of)], E-mail: leehyjo@snu.ac.kr

    2009-02-10

    Neurodegenerative disorders such as Alzheimer's disease (AD) are strongly associated with oxidative stress, which is induced by reactive oxygen species (ROS) including hydrogen peroxide (H{sub 2}O{sub 2}). Recent studies suggest that moderate coffee consumption may reduce the risk of neurodegenerative diseases such as AD, but the molecular mechanisms underlying this effect remain to be clarified. In this study, we investigated the protective effects of chlorogenic acid (5-O-caffeoylquinic acid; CGA), a major phenolic phytochemical found in instant decaffeinated coffee (IDC), and IDC against oxidative PC12 neuronal cell death. IDC (1 and 5 {mu}g/ml) or CGA (1 and 5 {mu}M) attenuated H{sub 2}O{sub 2}-induced PC12 cell death. H{sub 2}O{sub 2}-induced nuclear condensation and DNA fragmentation were strongly inhibited by pretreatment with IDC or CGA. Pretreatment with IDC or CGA also inhibited the H{sub 2}O{sub 2}-induced cleavage of poly(ADP-ribose) polymerase (PARP), and downregulation of Bcl-X{sub L} and caspase-3. The accumulation of intracellular ROS in H{sub 2}O{sub 2}-treated PC12 cells was dose-dependently diminished by IDC or CGA. The activation of c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) by H{sub 2}O{sub 2} in PC12 cells was also inhibited by IDC or CGA. Collectively, these results indicate that IDC and CGA protect PC12 cells from H{sub 2}O{sub 2}-induced apoptosis by blocking the accumulation of intracellular ROS and the activation of MAPKs.

  3. Attenuation of oxidative neuronal cell death by coffee phenolic phytochemicals

    International Nuclear Information System (INIS)

    Cho, Eun Sun; Jang, Young Jin; Hwang, Mun Kyung; Kang, Nam Joo; Lee, Ki Won; Lee, Hyong Joo

    2009-01-01

    Neurodegenerative disorders such as Alzheimer's disease (AD) are strongly associated with oxidative stress, which is induced by reactive oxygen species (ROS) including hydrogen peroxide (H 2 O 2 ). Recent studies suggest that moderate coffee consumption may reduce the risk of neurodegenerative diseases such as AD, but the molecular mechanisms underlying this effect remain to be clarified. In this study, we investigated the protective effects of chlorogenic acid (5-O-caffeoylquinic acid; CGA), a major phenolic phytochemical found in instant decaffeinated coffee (IDC), and IDC against oxidative PC12 neuronal cell death. IDC (1 and 5 μg/ml) or CGA (1 and 5 μM) attenuated H 2 O 2 -induced PC12 cell death. H 2 O 2 -induced nuclear condensation and DNA fragmentation were strongly inhibited by pretreatment with IDC or CGA. Pretreatment with IDC or CGA also inhibited the H 2 O 2 -induced cleavage of poly(ADP-ribose) polymerase (PARP), and downregulation of Bcl-X L and caspase-3. The accumulation of intracellular ROS in H 2 O 2 -treated PC12 cells was dose-dependently diminished by IDC or CGA. The activation of c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) by H 2 O 2 in PC12 cells was also inhibited by IDC or CGA. Collectively, these results indicate that IDC and CGA protect PC12 cells from H 2 O 2 -induced apoptosis by blocking the accumulation of intracellular ROS and the activation of MAPKs

  4. The Traditional Herbal Medicine, Dangkwisoo-San, Prevents Cerebral Ischemic Injury through Nitric Oxide-Dependent Mechanisms

    Directory of Open Access Journals (Sweden)

    Ji Hyun Kim

    2011-01-01

    Full Text Available Dangkwisoo-San (DS is an herbal extract that is widely used in traditional Korean medicine to treat traumatic ecchymosis and pain by promoting blood circulation and relieving blood stasis. However, the effect of DS in cerebrovascular disease has not been examined experimentally. The protective effects of DS on focal ischemic brain were investigated in a mouse model. DS stimulated nitric oxide (NO production in human brain microvascular endothelial cells (HBMECs. DS (10–300 μg/mL produced a concentration-dependent relaxation in mouse aorta, which was significantly attenuated by the nitric oxide synthase (NOS inhibitor L-NAME, suggesting that DS causes vasodilation via a NO-dependent mechanism. DS increased resting cerebral blood flow (CBF, although it caused mild hypotension. To investigate the effect of DS on the acute cerebral injury, C57/BL6J mice received 90 min of middle cerebral artery occlusion followed by 22.5 h of reperfusion. DS administered 3 days before arterial occlusion significantly reduced cerebral infarct size by 53.7% compared with vehicle treatment. However, DS did not reduce brain infarction in mice treated with the relatively specific endothelial NOS (eNOS inhibitor, N5-(1-iminoethyl-L-ornithine, suggesting that the neuroprotective effect of DS is primarily endothelium-dependent. This correlated with increased phosphorylation of eNOS in the brains of DS-treated mice. DS acutely improves CBF in eNOS-dependent vasodilation and reduces infarct size in focal cerebral ischemia. These data provide causal evidence that DS is cerebroprotective via the eNOS-dependent production of NO, which ameliorates blood circulation.

  5. Dynamin-Related Protein 1 Inhibitors Protect against Ischemic Toxicity through Attenuating Mitochondrial Ca2+ Uptake from Endoplasmic Reticulum Store in PC12 Cells

    Directory of Open Access Journals (Sweden)

    Ye Tian

    2014-02-01

    Full Text Available Intracellular calcium homeostasis disorder and mitochondrial dysfunction are involved in many acute and chronic brain diseases, including ischemic brain injury. An imbalance in mitochondrial fission and fusion is one of the most important structural abnormalities found in a large number of mitochondrial dysfunction related diseases. Here, we investigated the effects of mitochondrial division inhibitor A (mdivi A and mdivi B, two small molecule inhibitors of mitochondrial fission protein dunamin-related protein 1 (Drp-1, in neuronal injury induced by oxygen-glucose deprivation (OGD in PC12 cells. We found that mdivi A and mdivi B inhibited OGD-induced neuronal injury through attenuating apoptotic cell death. These two inhibitors also preserved mitochondrial function, as evidenced by reduced reactive oxygen species (ROS generation and cytochrome c release, as well as prevented loss of mitochondrial membrane potential (MMP. Moreover, mdivi A and mdivi B significantly suppressed mitochondrial Ca2+ uptake, but had no effect on cytoplasmic Ca2+ after OGD injury. The results of calcium imaging and immunofluorescence staining showed that Drp-1 inhibitors attenuated endoplasmic reticulum (ER Ca2+ release and prevented ER morphological changes induced by OGD. These results demonstrate that Drp-1 inhibitors protect against ischemic neuronal injury through inhibiting mitochondrial Ca2+ uptake from the ER store and attenuating mitochondrial dysfunction.

  6. Curcumin Attenuates Hepatotoxicity Induced by Zinc Oxide Nanoparticles in Rats

    Directory of Open Access Journals (Sweden)

    Layasadat Khorsandi

    2016-06-01

    Full Text Available Background: Zinc oxide nanoparticles (NZnO are increasingly used in modern life. Most metal nanoparticles have adverse effects on the liver. Aims: To explore the protective action of curcumin (Cur against hepatotoxicity induced by NZnO in rats. Study Design: Animal experimentation. Methods: Control group animals received normal saline, while the Cur group animals were treated with 200 mg/kg of Cur orally for 21 days. NZnO-intoxicated rats received 50 mg/kg of NZnO for 14 days by gavage method. In the NZnO+Cur group, rats were pretreated with Cur for 7 days before NZnO administration. Plasma activities of Alanine aminotransferase (ALT, aspartate aminotransferase (AST and alkaline phosphatase (ALP were measured as biomarkers of hepatotoxicity. Hepatic levels of malondialdehyde (MDA and superoxide dismutase (SOD and glutathione peroxidase (GPx activities were measured for detection of oxidative stress in liver tissue. Histological changes and apoptosis in liver tissue were studied by using Hematoxylin-eosin staining and the transferase dUTP nick end labeling (TUNEL method. Results: NZnO induced a significant increase in plasma AST (2.8-fold, ALT (2.7-fold and ALP (1.97-fold activity in comparison to the control group (p<0.01. NZnO increased MDA content and reduced SOD and GPx activities. NZnO caused liver damage including centrilobular necrosis and microvesicular steatosis. The percentage of apoptosis in hepatocytes was increased in NZnO-treated rats (p<0.01. Pre-treatment of Cur significantly reduced lipid peroxidation (39%, increased SOD (156% and GPx (26% activities, and attenuated ALT (47%, AST (41% and ALP (30% activities. Pre-treatment with Cur also decreased the histology changes and apoptotic index of hepatocytes (p<0.05. Conclusion: These findings indicate that Cur effectively protects against NZnO-induced hepatotoxicity in rats. However, future studies are required to propose Cur as a potential protective agent against hepatotoxicity

  7. Arginase attenuates inhibitory nonadrenergic noncholinergic nerve-induced nitric oxide generation and airway smooth muscle relaxation

    NARCIS (Netherlands)

    Maarsingh, H; Tio, MA; Zaagsma, J; Meurs, H

    2005-01-01

    Background: Recent evidence suggests that endogenous arginase activity potentiates airway responsiveness to methacholine by attenuation of agonist-induced nitric oxide (NO) production, presumably by competition with epithelial constitutive NO synthase for the common substrate, L-arginine. Using

  8. Association between Polymorphism of Endothelial Nitric Oxide Synthase Gene (Glu298Asp) and Chronic Heart Failure in Patients with Ischemic Heart Disease and Obesity

    OpenAIRE

    O.I. Kadykova; P.P. Kravchun

    2016-01-01

    The article reviewed the links between polymorphism of endothelial nitric oxide synthase gene (Glu298Asp) and the development and progression of chronic heart failure in patients with ischemic heart disease and obesity. There has been a comprehensive survey of 222 patients with ischemic heart disease. Comparison group consisted of 115 patients with ischemic heart disease with normal body weight. The control group included 35 healthy individuals. G allele and genotype G/G polymorphism of the g...

  9. Polyphenols and Oxidative Stress in Atherosclerosis-Related Ischemic Heart Disease and Stroke

    Directory of Open Access Journals (Sweden)

    Yu-Chen Cheng

    2017-01-01

    Full Text Available Good nutrition could maintain health and life. Polyphenols are common nutrient mainly derived from fruits, vegetables, tea, coffee, cocoa, mushrooms, beverages, and traditional medicinal herbs. They are potential substances against oxidative-related diseases, for example, cardiovascular disease, specifically, atherosclerosis-related ischemic heart disease and stroke, which are health and economic problems recognized worldwide. In this study, we reviewed the risk factors for atherosclerosis, including hypertension, diabetes mellitus, hyperlipidemia, obesity, and cigarette smoking as well as the antioxidative activity of polyphenols, which could prevent the pathology of atherosclerosis, including endothelial dysfunction, low-density lipoprotein oxidation, vascular smooth muscle cell proliferation, inflammatory process by monocytes, macrophages or T lymphocytes, and platelet aggregation. The strong radical-scavenging properties of polyphenols would exhibit antioxidative and anti-inflammation effects. Polyphenols reduce ROS production by inhibiting oxidases, reducing the production of superoxide, inhibiting OxLDL formation, suppressing VSMC proliferation and migration, reducing platelet aggregation, and improving mitochondrial oxidative stress. Polyphenol consumption also inhibits the development of hypertension, diabetes mellitus, hyperlipidemia, and obesity. Despite the numerous in vivo and in vitro studies, more advanced clinical trials are necessary to confirm the efficacy of polyphenols in the treatment of atherosclerosis-related vascular diseases.

  10. Simvastatin Attenuates Contrast-Induced Nephropathy through Modulation of Oxidative Stress, Proinflammatory Myeloperoxidase, and Nitric Oxide

    Directory of Open Access Journals (Sweden)

    Ketab E. Al-Otaibi

    2012-01-01

    Full Text Available Contrast media- (CM- induced nephropathy is a serious complication of radiodiagnostic procedures. Available data suggests that the development of prophylaxis strategies is limited by poor understanding of pathophysiology of CM-induced nephropathy. Present study was designed to determine the role of oxidative stress, myeloperoxidase, and nitric oxide in the pathogenesis of iohexol model of nephropathy and its modification with simvastatin (SSTN. Adult Sprague Dawley rats were divided into seven groups. After 24 h of water deprivation, all the rats except in control and SSTN-only groups were injected (10 ml/kg with 25% glycerol. After 30 min, SSTN (15, 30, and 60 mg/kg was administered orally, daily for 4 days. Twenty-four hours after the glycerol injection, iohexol was infused (8 ml/kg through femoral vein over a period of 2 min. All the animals were sacrificed on day 5 and blood and kidneys were collected for biochemical and histological studies. The results showed that SSTN dose dependently attenuated CM-induced rise of creatinine, urea, and structural abnormalities suggesting its nephroprotective effect. A significant increase in oxidative stress (increased lipid hydroperoxides and reduced glutathione levels and myeloperoxidase (MPO and decreased nitric oxide in CM group were reversed by SSTN. These findings support the use of SSTN to combat CM-induced nephrotoxicity.

  11. Effects of Ischemic Postconditioning on the Hemodynamic Parameters and Heart Nitric Oxide Levels of Hypothyroid Rats

    International Nuclear Information System (INIS)

    Jeddi, Sajad; Zaman, Jalal; Ghasemi, Asghar

    2015-01-01

    Ischemic postconditioning (IPost) is a method of protecting the heart against ischemia-reperfusion (IR) injury. However, the effectiveness of IPost in cases of ischemic heart disease accompanied by co-morbidities such as hypothyroidism remains unclear. The aim of this study was to determine the effect of IPost on myocardial IR injury in hypothyroid male rats. Propylthiouracil in drinking water (500 mg/L) was administered to male rats for 21 days to induce hypothyroidism. The hearts from control and hypothyroid rats were perfused in a Langendorff apparatus and exposed to 30 min of global ischemia, followed by 120 min of reperfusion. IPost was induced immediately following ischemia. Hypothyroidism and IPost significantly improved the left ventricular developed pressure (LVDP) and peak rates of positive and negative changes in left ventricular pressure (±dp/dt) during reperfusion in control rats (p < 0.05). However, IPost had no add-on effect on the recovery of LVDP and ±dp/dt in hypothyroid rats. Furthermore, hypothyroidism significantly decreased the basal NO metabolite (NO x ) levels of the serum (72.5 ± 4.2 vs. 102.8 ± 3.7 μmol/L; p < 0.05) and heart (7.9 ± 1.6 vs. 18.8 ± 3.2 μmol/L; p < 0.05). Heart NO x concentration in the hypothyroid groups did not change after IR and IPost, whereas these were significantly (p < 0.05) higher and lower after IR and IPost, respectively, in the control groups. Hypothyroidism protects the heart from IR injury, which may be due to a decrease in basal nitric oxide (NO) levels in the serum and heart and a decrease in NO after IR. IPost did not decrease the NO level and did not provide further cardioprotection in the hypothyroid group

  12. Effects of Ischemic Postconditioning on the Hemodynamic Parameters and Heart Nitric Oxide Levels of Hypothyroid Rats

    Energy Technology Data Exchange (ETDEWEB)

    Jeddi, Sajad; Zaman, Jalal; Ghasemi, Asghar, E-mail: ghasemi@endocrine.ac.ir [Endocrine Physiology Research Center - Research Institute for Endocrine Sciences - Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of); Endocrine Research Center - Research Institute for Endocrine Sciences - Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of)

    2015-02-15

    Ischemic postconditioning (IPost) is a method of protecting the heart against ischemia-reperfusion (IR) injury. However, the effectiveness of IPost in cases of ischemic heart disease accompanied by co-morbidities such as hypothyroidism remains unclear. The aim of this study was to determine the effect of IPost on myocardial IR injury in hypothyroid male rats. Propylthiouracil in drinking water (500 mg/L) was administered to male rats for 21 days to induce hypothyroidism. The hearts from control and hypothyroid rats were perfused in a Langendorff apparatus and exposed to 30 min of global ischemia, followed by 120 min of reperfusion. IPost was induced immediately following ischemia. Hypothyroidism and IPost significantly improved the left ventricular developed pressure (LVDP) and peak rates of positive and negative changes in left ventricular pressure (±dp/dt) during reperfusion in control rats (p < 0.05). However, IPost had no add-on effect on the recovery of LVDP and ±dp/dt in hypothyroid rats. Furthermore, hypothyroidism significantly decreased the basal NO metabolite (NO{sub x}) levels of the serum (72.5 ± 4.2 vs. 102.8 ± 3.7 μmol/L; p < 0.05) and heart (7.9 ± 1.6 vs. 18.8 ± 3.2 μmol/L; p < 0.05). Heart NO{sub x} concentration in the hypothyroid groups did not change after IR and IPost, whereas these were significantly (p < 0.05) higher and lower after IR and IPost, respectively, in the control groups. Hypothyroidism protects the heart from IR injury, which may be due to a decrease in basal nitric oxide (NO) levels in the serum and heart and a decrease in NO after IR. IPost did not decrease the NO level and did not provide further cardioprotection in the hypothyroid group.

  13. Association between Oxidative Stress and Outcome in Different Subtypes of Acute Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Nai-Wen Tsai

    2014-01-01

    Full Text Available Objectives. This study investigated serum thiobarbituric acid-reactive substances (TBARS and free thiol levels in different subtypes of acute ischemic stroke (AIS and evaluated their association with clinical outcomes. Methods. This prospective study evaluated 100 AIS patients, including 75 with small-vessel and 25 with large-vessel diseases. Serum oxidative stress (TBARS and antioxidant (thiol were determined within 48 hours and days 7 and 30 after stroke. For comparison, 80 age- and sex-matched participants were evaluated as controls. Results. Serum TBARS was significantly higher and free thiol was lower in stroke patients than in the controls on days 1 and 7 after AIS. The level of free thiol was significantly lower in the large-vessel disease than in the small-vessel disease on day 7 after stroke. Using the stepwise logistic regression model for potential variables, only stroke subtype, NIHSS score, and serum TBARS level were independently associated with three-month outcome. Higher TBARS and lower thiol levels in the acute phase of stroke were associated with poor outcome. Conclusions. Patients with large-vessel disease have higher oxidative stress but lower antioxidant defense compared to those with small-vessel disease after AIS. Serum TBARS level at the acute phase of stroke is a potential predictor for three-month outcome.

  14. GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats.

    Science.gov (United States)

    Wang, Wei; Li, Mingchang; Wang, Yuefei; Li, Qian; Deng, Gang; Wan, Jieru; Yang, Qingwu; Chen, Qianxue; Wang, Jian

    2016-12-01

    Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke who are treated with tissue plasminogen activator (tPA). It is associated with high morbidity and mortality, but no effective treatments are currently available to reduce HT risk. Therefore, methods to prevent HT are urgently needed. In this study, we used TWS119, an inhibitor of glycogen synthase kinase 3β (GSK-3β), to evaluate the role of the Wnt/β-catenin signaling pathway in recombinant tPA (rtPA)-induced HT. Sprague-Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) model of ischemic stroke and then were administered rtPA, rtPA combined with TWS119, or vehicle at 4 h. The animals were sacrificed 24 h after infarct induction. Rats treated with rtPA showed evident HT, had more severe neurologic deficit, brain edema, and blood-brain barrier breakdown, and had larger infarction volume than did the vehicle group. Rats treated with TWS119 had significantly improved outcomes compared with those of rats treated with rtPA alone. In addition, Western blot analysis showed that TWS119 increased the protein expression of β-catenin, claudin-3, and ZO-1 while suppressing the expression of GSK-3β. These results suggest that TWS119 reduces rtPA-induced HT and attenuates blood-brain barrier disruption, possibly through activation of the Wnt/β-catenin signaling pathway. This study provides a potential therapeutic strategy to prevent tPA-induced HT after acute ischemic stroke.

  15. Evidence that OGG1 glycosylase protects neurons against oxidative DNA damage and cell death under ischemic conditions

    DEFF Research Database (Denmark)

    Liu, Dong; Croteau, Deborah L; Souza-Pinto, Nadja

    2011-01-01

    to ischemic and oxidative stress. After exposure of cultured neurons to oxidative and metabolic stress levels of OGG1 in the nucleus were elevated and mitochondria exhibited fragmentation and increased levels of the mitochondrial fission protein dynamin-related protein 1 (Drp1) and reduced membrane potential......7,8-Dihydro-8-oxoguanine DNA glycosylase (OGG1) is a major DNA glycosylase involved in base-excision repair (BER) of oxidative DNA damage to nuclear and mitochondrial DNA (mtDNA). We used OGG1-deficient (OGG1(-/-)) mice to examine the possible roles of OGG1 in the vulnerability of neurons....... Cortical neurons isolated from OGG1(-/-) mice were more vulnerable to oxidative insults than were OGG1(+/+) neurons, and OGG1(-/-) mice developed larger cortical infarcts and behavioral deficits after permanent middle cerebral artery occlusion compared with OGG1(+/+) mice. Accumulations of oxidative DNA...

  16. extract attenuates MPTP-induced oxidative stress and behavioral

    African Journals Online (AJOL)

    on oxidative stress levels were assessed by estimating enzyme status, including superoxide dismutase. (SOD), catalase ... in both non-human primates and mice models. [12,13]. ..... Polyphenol composition and antioxidant activity of cumin.

  17. Medroxyprogesterone acetate attenuates estrogen-induced nitric oxide production in human umbilical vein endothelial cells

    International Nuclear Information System (INIS)

    Oishi, Akira; Ohmichi, Masahide; Takahashi, Kazuhiro; Takahashi, Toshifumi; Mori-Abe, Akiko; Kawagoe, Jun; Otsu, Reiko; Mochizuki, Yoshiko; Inaba, Noriyuki; Kurachi, Hirohisa

    2004-01-01

    We report the novel observation that medroxyprogesterone acetate (MPA) attenuates the induction by 17β estradiol (E2) of both nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) activity in human umbilical vein endothelial cells. Although MPA had no effect on basal NO production or basal eNOS phosphorylation or activity, it attenuated the E2-induced NO production and eNOS phosphorylation and activity. Moreover, we examined the mechanism by which MPA attenuated the E2-induced NO production and eNOS phosphorylation. MPA attenuated the E2-induced phosphorylation of Akt, a kinase that phosphorylates eNOS. Treatment with pure progesterone receptor (PR) antagonist RU486 completely abolished the inhibitory effect of MPA on E2-induced Akt phosphorylation and eNOS phosphorylation. In addition, the effects of actinomycin D were tested to rule out the influence of genomic events mediated by nuclear PRs. Actinomycin D did not affect the inhibitory effect of MPA on E2-induced Akt phosphorylation. Furthermore, the potential roles of PRA and PRB were evaluated. In COS cells transfected with either PRA or PRB, MPA attenuated E2-induced Akt phosphorylation. These results indicate that MPA attenuated E2-induced NO production via an Akt cascade through PRA or PRB in a non-genomic manner

  18. Chronic exposure to zinc oxide nanoparticles increases ischemic-reperfusion injuries in isolated rat hearts

    Energy Technology Data Exchange (ETDEWEB)

    Milivojević, Tamara; Drobne, Damjana; Romih, Tea; Mali, Lilijana Bizjak [University of Ljubljana, Department of Biology, Biotechnical Faculty (Slovenia); Marin, Irena; Lunder, Mojca; Drevenšek, Gorazd, E-mail: gorazd.drevensek@mf.uni-lj.si [University of Ljubljana, Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine (Slovenia)

    2016-10-15

    The use of zinc oxide nanoparticles (ZnO NPs) in numerous products is increasing, although possible negative implications of their long-term consumption are not known yet. Our aim was to evaluate the chronic, 6-week oral exposure to two different concentrations of ZnO NPs on isolated rat hearts exposed to ischemic-reperfusion injury and on small intestine morphology. Wistar rats of both sexes (n = 18) were randomly divided into three groups: (1) 4 mg/kg ZnO NPs, (2) 40 mg/kg ZnO NPs, and (3) control. After 6 weeks of treatment, the hearts were isolated, the left ventricular pressure (LVP), the coronary flow (CF), the duration of arrhythmias and the lactate dehydrogenase release rate (LDH) were measured. A histological investigation of the small intestine was performed. Chronic exposure to ZnO NPs acted cardiotoxic dose-dependently. ZnO NPs in dosage 40 mg/kg maximally decreased LVP (3.3-fold) and CF (2.5-fold) and increased the duration of ventricular tachycardia (all P < 0.01) compared to control, whereas ZnO NPs in dosage 4 mg/kg acted less cardiotoxic. Goblet cells in the small intestine epithelium of rats, treated with 40 mg ZnO NPs/kg, were enlarged, swollen and numerous, the intestinal epithelium width was increased. Unexpectedly, ZnO NPs in both dosages significantly decreased LDH. A 6-week oral exposure to ZnO NPs dose-dependently increased heart injuries and caused irritation of the intestinal mucosa. A prolonged exposure to ZnO NPs might cause functional damage to the heart even with exposures to the recommended daily doses, which should be tested in future studies.

  19. Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor κB p65 activation

    International Nuclear Information System (INIS)

    Xue, Xia; Qu, Xian-Jun; Yang, Ying; Sheng, Xie-Huang; Cheng, Fang; Jiang, E-Nang; Wang, Jian-hua; Bu, Wen; Liu, Zhao-Ping

    2010-01-01

    Research highlights: → Permanent NF-κB p65 activation contributes to the infarction after ischemia-reperfusion injury in rats. → Baicalin can markedly inhibit the nuclear NF-κB p65 expression and m RNA levels after ischemia-reperfusion injury in rats. → Baicalin decreased the cerebral infarction area via inhibiting the activation of nuclear NF-κB p65. -- Abstract: Baicalin is a flavonoid compound purified from plant Scutellaria baicalensis Georgi. We aimed to evaluate the neuroprotective effects of baicalin against cerebral ischemic reperfusion injury. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. Baicalin at doses of 50, 100 and 200 mg/kg was intravenously injected after ischemia onset. Twenty-four hours after reperfusion, the neurological deficit was scored and infarct volume was measured. Hematoxylin and eosin (HE) staining was performed to analyze the histopathological changes of cortex and hippocampus neurons. We examined the levels of NF-κB p65 in ischemic cortexes by Western blot analysis and RT-PCR assay. The results showed that the neurological deficit scores were significantly decreased from 2.0 ± 0.7 to 1.2 ± 0.4 and the volume of infarction was reduced by 25% after baicalin injection. Histopathological examination showed that the increase of neurons with pycnotic shape and condensed nuclear in cortex and hippocampus were not observed in baicalin treated animals. Further examination showed that NF-κB p65 in cortex was increased after ischemia reperfusion injury, indicating the molecular mechanism of ischemia reperfusion injury. The level of NF-κB p65 was decreased by 73% after baicalin treatment. These results suggest that baicalin might be useful as a potential neuroprotective agent in stroke therapy. The neuroprotective effects of baicalin may relate to inhibition of NF-κB p65.

  20. Statins attenuate but do not eliminate the reverse epidemiology of total serum cholesterol in patients with non-ischemic chronic heart failure.

    Science.gov (United States)

    Fröhlich, Hanna; Raman, Nandita; Täger, Tobias; Schellberg, Dieter; Goode, Kevin M; Kazmi, Syed; Grundtvig, Morten; Hole, Torstein; Cleland, John G F; Katus, Hugo A; Agewall, Stefan; Clark, Andrew L; Atar, Dan; Frankenstein, Lutz

    2017-07-01

    In patients with chronic heart failure (CHF) increasing levels of total serum cholesterol are associated with improved survival - while statin usage is not. The impact of statin treatment on the "reverse epidemiology" of cholesterol is unclear. 2992 consecutive patients with non-ischemic CHF due to left ventricular systolic dysfunction from the Norwegian CHF Registry and the CHF Registries of the Universities of Hull, UK, and Heidelberg, Germany, were studied. 1736 patients were individually double-matched on both cholesterol levels and the individual propensity scores for statin treatment. All-cause mortality was analyzed as a function of baseline cholesterol and statin use in both the general and the matched sample. 1209 patients (40.4%) received a statin. During a follow-up of 13,740 patient-years, 360 statin users (29.8%) and 573 (32.1%) statin non-users died. When grouped according to total cholesterol levels as low (≤3.6mmol/L), moderate (3.7-4.9mmol/L), high (4.8-6.2mmol/L), and very high (>6.2mmol/L), we found improved survival with very high as compared with low cholesterol levels. This association was present in statin users and non-users in both the general and matched sample (p<0.05 for each group comparison). The negative association of total cholesterol and mortality persisted when cholesterol was treated as a continuous variable (HR 0.83, 95%CI 0.77-0.90, p<0.001 for matched patients), but it was less pronounced in statin users than in non-users (F-test p<0.001). Statins attenuate but do not eliminate the reverse epidemiological association between increasing total serum cholesterol and improved survival in patients with non-ischemic CHF. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Curcumin Attenuates Methotrexate-Induced Hepatic Oxidative Damage in Rats

    International Nuclear Information System (INIS)

    HEMEIDA, R.A.M.; MOHAFEZ, O.M.

    2008-01-01

    In the present study, we have addressed the ability of curcumin to suppress MTX-induced liver damage. Hepatotoxicity was induced by injection of a single dose of MTX (20 mg/kg I.P.). MTX challenge induced liver damage that was well characterized histopathologically and biochemically. MTX increased relative liver/body weight ratio. Histologically, MTX produced fatty changes in hepatocytes and sinusoidal lining cells, mild necrosis and inflammation. Biochemically, the test battery entailed elevated activities of serum ALT and AST. Liver activities of superoxide dismutase (SOD), catalase (CAT) and level of reduced glutathione (GSH), were notably reduced, while lipid peroxidation, expressed as malondialdhyde (MDA) level was significantly increased. Administration of curcumin (100mg/kg, I.P.) once daily for 5 consecutive days after MTX challenge mitigated the injurious effects of MTX and ameliorated all the altered biochemical parameters. These results showed that administration of curcumin decreases MTX-induced liver damage probably via regulation of oxidant/anti-oxidant balance. In conclusion, the present study indicates that curcumin may be of therapeutic benefit against MTX-cytotoxicity.

  2. 4-Phenylbutyrate Benefits Traumatic Hemorrhagic Shock in Rats by Attenuating Oxidative Stress, Not by Attenuating Endoplasmic Reticulum Stress.

    Science.gov (United States)

    Yang, Guangming; Peng, Xiaoyong; Hu, Yi; Lan, Dan; Wu, Yue; Li, Tao; Liu, Liangming

    2016-07-01

    -phenylbutyrate increased the nuclear levels of nuclear factor-E2-related factor 2, and decreased the nuclear levels of nuclear factor κB in hypoxic vascular smooth muscle cells. 4-phenylbutyrate has beneficial effects for traumatic hemorrhagic shock including improving animal survival and protecting organ function. These beneficial effects of 4-phenylbutyrate in traumatic hemorrhagic shock result from its vascular function protection via attenuation of the oxidative stress and mitochondrial permeability transition pore opening. Nuclear factor-E2-related factor 2 and nuclear factor-κB may be involved in 4-phenylbutyrate-mediated inhibition of oxidative stress.

  3. Tanshinone IIA attenuates the cerebral ischemic injury-induced increase in levels of GFAP and of caspases-3 and -8.

    Science.gov (United States)

    Zhou, L; Bondy, S C; Jian, L; Wen, P; Yang, F; Luo, H; Li, W; Zhou, Jun

    2015-03-12

    Tanshinone IIA (TSA) is a lipid soluble agent derived from the root of Salvia miltiorrhiza (Danshen). This plant is a traditional Chinese herb, which has been used widely in China especially for enhancing circulation. However mechanisms underlying its efficacy remain poorly understood. The present study was designed to illuminate events that may underlie the apparently neuroprotective effects of TSA following ischemic insult. Adult Sprague-Dawley rats were subjected to transient focal cerebral ischemia by use of a middle cerebral artery occlusion model. They were then randomly divided into a sham-operated control group, and cerebral ischemia/reperfusion groups receiving a two-hour occlusion. Further subsets of groups received the same durations of occlusion or were sham-operated but then received daily i.p. injections of high or low doses of TSA, for seven or 15days. Hematoxylin and eosin staining revealed lesions in the entorhinal cortex of both rats subject to ischemia and to a lesser extent to those receiving TSA after surgery. Levels of glial fibrillary acidic protein (GFAP), caspase-3 and caspase-8, were quantified by both immunohistochemistry and Western blotting. TSA treatment after middle cerebral artery occlusion, markedly reduced infarct size, and reduced the expression of caspase-3 and caspase-8. These changes were considered protective and were generally proportional to the dose of TSA used. These results suggest that TSA may effect neuroprotection by way of reduction of the extent of cell inflammation and death within affected regions. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Promoter polymorphisms in the nitric oxide synthase 3 gene are associated with ischemic stroke susceptibility in young black women.

    Science.gov (United States)

    Howard, Timothy D; Giles, Wayne H; Xu, Jianfeng; Wozniak, Marcella A; Malarcher, Ann M; Lange, Leslie A; Macko, Richard F; Basehore, Monica J; Meyers, Deborah A; Cole, John W; Kittner, Steven J

    2005-09-01

    Endothelial nitric oxide exerts a variety of protective effects on endothelial cells and blood vessels, and therefore the nitric oxide synthase 3 gene (NOS3) is a logical candidate gene for stroke susceptibility. We used the population-based Stroke Prevention in Young Women case-control study to assess the association of five NOS3 polymorphisms in 110 cases (46% black) with ischemic stroke and 206 controls (38% black), 15 to 44 years of age. Polymorphisms included 3 single nucleotide polymorphisms (SNPs) in the promoter region (-1468 T>A, -922 G>A, -786 T>C), 1 SNP in exon 7 (G894T), and 1 insertion/deletion polymorphism within intron 4. Significant associations with both the -922 G>A and -786 T>C SNPs with ischemic stroke were observed in the black, but not the white, population. This association was attributable to an increased prevalence of the -922 A allele (OR=3.0, 95% CI=1.3 to 6.8; P=0.005) and the -786 T allele (OR=2.9, 95% CI=1.3 to 6.4; P=0.005) in cases versus controls. These 2 SNPs were in strong linkage disequilibrium (D'=1.0), making it impossible to determine, within the confines of this genetic study, whether 1 or both of these polymorphisms are functionally related to NOS3 expression. Two sets of haplotypes were also identified, 1 of which may confer an increased susceptibility to stroke in blacks, whereas the other appears to be protective. Promoter variants in NOS3 may be associated with ischemic stroke susceptibility among young black women.

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

    Science.gov (United States)

    Gauthaman, Karunakaran K; Saleem, Mohamed TS; Thanislas, Peter T; Prabhu, Vinoth V; Krishnamoorthy, Karthikeyan K; Devaraj, Niranjali S; Somasundaram, Jayaprakash S

    2006-01-01

    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. PMID:16987414

  6. The effects of annealing temperature on the permittivity and electromagnetic attenuation performance of reduced graphene oxide

    Science.gov (United States)

    Wu, Fan; Zeng, Qiao; Xia, Yilu; Sun, Mengxiao; Xie, Aming

    2018-05-01

    Reduced graphene oxide (RGO) has been prepared through the thermal reduction method with different annealing temperatures to explore the effects of temperature on the permittivity and electromagnetic attenuation performance. The real and imaginary parts of permittivity increase along with the decrease in the oxygen functional group and the increase in the filler loading ratio. A composite only loaded with 1 wt. % of RGO can possess an effective electromagnetic absorption bandwidth of 7.60 GHz, when graphene oxide was reduced under 300 °C for 2 h. With the annealing temperature increased to 700 °C and the well reduced RGO loaded 7 wt. % in the composite, the electromagnetic interference shielding efficiency can get higher than 35 dB from 2 to 18 GHz. This study shows that controlling the oxygen functional groups on the RGO surface can also obtain an ideal electromagnetic attenuation performance without any other decorated nanomaterials.

  7. Attenuation changes of the normal and ischemic canine kidney. Dynamic CT scanning after intravenous contrast medium bolus

    Energy Technology Data Exchange (ETDEWEB)

    Jaschke, W.; Lipton, M.J.; Boyd, D.P.; Cann, C.; Strauss, L.; Sievers, R.S.

    The potential of CT scanning to explore total and regional renal blood flow was evaluated in a dog model with unilateral renal artery stenosis (n=7, reduction of renal blood flow: 32-75% of base line flow). Attenuation versus time curves were generated for the renal cortex and medulla, as well as for the aorta and renal vein. A fast CT scanner was used which allowed for up to 24 scans/minute at the same level (slice thickness: 10 mm). A total of 10 ml contrast medim was injected into a peripheral vein for each scan series taken. During baseline conditions, the curve of the renal cortex and medulla demonstrated 2 peaks. The first peak was mainly related to early vascular enhancement, whereas the second peak corresponded mainly to the appearance of contrast medium in the distal convolutes and collecting ducts. Ischemia of the kidney resulted in a reduction of the first peak and a flattening of the leading edge slope. Transport of contrast medium through the extravascular compartments of the kidney was delayed during ischemia. Relative renal blood flow was obtained from the CT data by dividing peak enhancement by rise-time as assessed from the cortical curve. All measurements were related to baseline flow and validated by flow measurements using radioactive labeled microspheres (n=5). Correlation was found to be r=0.97. (orig.).

  8. Anti-oxidant activity and attenuation of bladder hyperactivity by the flavonoid compound kaempferol.

    Science.gov (United States)

    Huang, Yaw-Bin; Lin, Ming-Wei; Chao, Yun; Huang, Chi-Te; Tsai, Yi-Hung; Wu, Pao-Chu

    2014-01-01

    To evaluate the anti-oxidant activity of the flavonoid compound, kaempferol, and to examine its role in the suppression of oxidative stress and attenuation of bladder hyperactivity in a rat model of bladder injury. The anti-oxidative activity of kaempferol was examined in lipopolysaccharide-treated RAW264.7 macrophages by using flow cytometry. For in vivo studies, rats were pretreated with kaempferol or vehicle for 24 h. The rat urothelium was injured by the administration of protamine sulfate for 1.5 h and irritated by the subsequent infusion of potassium chloride for 4 h. Oxidative stress in the bladder tissue was assessed using chemiluminescence assay, and the bladder pressure was determination by cystomertrogram. Kaempferol significantly suppressed lipopolysaccharide-induced reactive oxygen species production in RAW264.7 rat macrophages. Exposure of the rat bladder to sequential infusion of protamine sulfate and potassium chloride induced bladder hyperactivity. Pretreatment with kaempferol, prevented the formation of reactive oxygen species and prolonged the intercontraction interval. Kaempferol suppresses oxidative stress and attenuates bladder hyperactivity caused by potassium chloride after protamine sulfate-induced bladder injury. © 2013 The Japanese Urological Association.

  9. Exercise training attenuates sympathetic activation and oxidative stress in diet-induced obesity.

    Science.gov (United States)

    Li, G; Liu, J-Y; Zhang, H-X; Li, Q; Zhang, S-W

    2015-01-01

    It is known that excessive sympathetic activity and oxidative stress are enhanced in obesity. This study aimed to clarify whether exercise training (ET) attenuates sympathetic activation and oxidative stress in obesity. The obesity was induced by high-fat diet (HFD) for 12 weeks. Male Sprague-Dawley rats were assigned to four groups: regular diet (RD) plus sedentary (RD-S), RD plus ET (RD-ET), HFD plus sedentary (HFD-S), and HFD plus ET (HFD-ET). The rats in RD-ET and HFD-ET groups were trained on a motorized treadmill for 60 min/day, five days/week for 8 weeks. The sympathetic activity was evaluated by the plasma norepinephrine (NE) level. The superoxide anion, malondialdehyde and F2-isoprostanes levels in serum and muscles were measured to evaluate oxidative stress. The ET prevented the increases in the body weight, arterial pressure and white adipose tissue mass in HFD rats. The NE level in plasma and oxidative stress related parameters got lower in HFD-ET group compared with HFD-S group. We have found decreased mRNA and protein levels of toll-like receptor (TLR)-2 and TLR-4 by ET in HFD rats. These findings suggest that ET may be effective for attenuating sympathetic activation and oxidative stress in diet-induced obesity.

  10. Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model.

    Science.gov (United States)

    Goto, Tatenobu; Hussein, Mohamed Hamed; Kato, Shin; Daoud, Ghada Abdel-Hamid; Kato, Takenori; Sugiura, Takahiro; Kakita, Hiroki; Nobata, Masanori; Kamei, Michi; Mizuno, Haruo; Imai, Masaki; Ito, Tetsuya; Kato, Ineko; Suzuki, Satoshi; Okada, Noriko; Togari, Hajime; Okada, Hidechika

    2012-12-01

    Oxidative stress (oxidant-antioxidant imbalance) plays an important role in the pathophysiology of neonatal sepsis. This study evaluated whether an antisense peptide endothelin receptor antagonist, ETR-P1/fl, could attenuate oxidative stress in a neonatal sepsis model. A total of 18 3-d-old piglets were anesthetized and mechanically ventilated. Six piglets received cecal ligation and perforation (CLP group) for induction of sepsis. Six piglets also received continuous infusion (0.05 mg/kg/h) of ETR-P1/fl 30 min after CLP (ETR-P1/fl group). Six piglets received a sham operation. Serum total hydroperoxide (TH), biological antioxidant potentials (BAPs), oxidative stress index (OSI, calculated as TH/BAP), interleukin (IL)-6, serum glutamic oxaloacetic transaminase (GOT), and creatinine were measured before CLP and at 1, 3, and 6 h after CLP. CLP evoked a state of shock resulting in elevated TH, OSI, and IL-6 levels. ETR-P1/fl administration after CLP resulted in lower serum TH at 1 and 3 h after CLP, OSI at 1 and 3 h after CLP, IL-6 at 1 and 3 h after CLP, and GOT at 3 and 6 h after CLP as compared with the CLP group. ETR-P1/fl treatment significantly attenuated the elevation of serum oxidative stress markers (TH and OSI), IL-6, and GOT in a progressive neonatal sepsis CLP model.

  11. Natural attenuation process via microbial oxidation of arsenic in a high Andean watershed.

    Science.gov (United States)

    Leiva, Eduardo D; Rámila, Consuelo d P; Vargas, Ignacio T; Escauriaza, Cristian R; Bonilla, Carlos A; Pizarro, Gonzalo E; Regan, John M; Pasten, Pablo A

    2014-01-01

    Rivers in northern Chile have arsenic (As) concentrations at levels that are toxic for humans and other organisms. Microorganism-mediated redox reactions have a crucial role in the As cycle; the microbial oxidation of As (As(III) to As(V)) is a critical transformation because it favors the immobilization of As in the solid phase. We studied the role of microbial As oxidation for controlling the mobility of As in the extreme environment found in the Chilean Altiplano (i.e., > 4000 meters above sea level (masl) and Azufre River sub-basin, where the natural attenuation of As from hydrothermal discharge (pH 4-6) was observed. As(III) was actively oxidized by a microbial consortium, leading to a significant decrease in the dissolved As concentrations and a corresponding increase in the sediment's As concentration downstream of the hydrothermal source. In-situ oxidation experiments demonstrated that the As oxidation required biological activity, and microbiological molecular analysis confirmed the presence of As(III)-oxidizing groups (aroA-like genes) in the system. In addition, the pH measurements and solid phase analysis strongly suggested that the As removal mechanism involved adsorption or coprecipitation with Fe-oxyhydroxides. Taken together, these results indicate that the microorganism-mediated As oxidation contributed to the attenuation of As concentrations and the stabilization of As in the solid phase, therefore controlling the amount of As transported downstream. This study is the first to demonstrate the microbial oxidation of As in Altiplano basins and its relevance in the immobilization of As. © 2013.

  12. Role of heat shock protein 90 and endothelial nitric oxide synthase during early anesthetic and ischemic preconditioning.

    Science.gov (United States)

    Amour, Julien; Brzezinska, Anna K; Weihrauch, Dorothee; Billstrom, Amie R; Zielonka, Jacek; Krolikowski, John G; Bienengraeber, Martin W; Warltier, David C; Pratt, Philip F; Kersten, Judy R

    2009-02-01

    Nitric oxide is known to be essential for early anesthetic preconditioning (APC) and ischemic preconditioning (IPC) of myocardium. Heat shock protein 90 (Hsp90) regulates endothelial nitric oxide synthase (eNOS) activity. In this study, the authors tested the hypothesis that Hsp90-eNOS interactions modulate APC and IPC. Myocardial infarct size was measured in rabbits after coronary occlusion and reperfusion in the absence or presence of preconditioning within 30 min of isoflurane (APC) or 5 min of coronary artery occlusion (IPC), and with or without pretreatment with geldanamycin or radicicol, two chemically distinct Hsp90 inhibitors, or N-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase NOS inhibitor. Isoflurane-dependent nitric oxide production was measured (ozone chemiluminescence) in human coronary artery endothelial cells or mouse cardiomyocytes, in the absence or presence of Hsp90 inhibitors or N-nitro-L-arginine methyl ester. Interactions between Hsp90 and eNOS, and eNOS activation, were assessed with immunoprecipitation, immunoblotting, and confocal microscopy. APC and IPC decreased infarct size (by 50% and 59%, respectively), and this action was abolished by Hsp90 inhibitors. N-nitro-L-arginine methyl ester blocked APC but not IPC. Isoflurane increased nitric oxide production in human coronary artery endothelial cells concomitantly with an increase in Hsp90-eNOS interaction (immunoprecipitation, immunoblotting, and immunohistochemistry). Pretreatment with Hsp90 inhibitors abolished isoflurane-dependent nitric oxide production and decreased Hsp90-eNOS interactions. Isoflurane did not increase nitric oxide production in mouse cardiomyocytes, and eNOS was below the level of detection. The results indicate that Hsp90 plays a critical role in mediating APC and IPC through protein-protein interactions, and suggest that endothelial cells are important contributors to nitric oxide-mediated signaling during APC.

  13. Lebetin 2, a Snake Venom-Derived Natriuretic Peptide, Attenuates Acute Myocardial Ischemic Injury through the Modulation of Mitochondrial Permeability Transition Pore at the Time of Reperfusion.

    Directory of Open Access Journals (Sweden)

    Bochra Tourki

    Full Text Available Cardiac ischemia is one of the leading causes of death worldwide. It is now well established that natriuretic peptides can attenuate the development of irreversible ischemic injury during myocardial infarction. Lebetin 2 (L2 is a new discovered peptide isolated from Macrovipera lebetina venom with structural similarity to B-type natriuretic peptide (BNP. Our objectives were to define the acute cardioprotective actions of L2 in isolated Langendorff-perfused rat hearts after regional or global ischemia-reperfusion (IR. We studied infarct size, left ventricular contractile recovery, survival protein kinases and mitochondrial permeability transition pore (mPTP opening in injured myocardium. L2 dosage was determined by preliminary experiments at its ability to induce cyclic guanosine monophosphate (cGMP release without changing hemodynamic effects in normoxic hearts. L2 was found to be as effective as BNP in reducing infarct size after the induction of either regional or global IR. Both peptides equally improved contractile recovery after regional IR, but only L2 increased coronary flow and reduced severe contractile dysfunction after global ischemia. Cardioprotection afforded by L2 was abolished after isatin or 5-hydroxydecanote pretreatment suggesting the involvement of natriuretic peptide receptors and mitochondrial KATP (mitoKATP channels in the L2-induced effects. L2 also increased survival protein expression in the reperfused myocardium as evidenced by phosphorylation of signaling pathways PKCε/ERK/GSK3β and PI3K/Akt/eNOS. IR induced mitochondrial pore opening, but this effect was markedly prevented by L2 treatment. These data show that L2 has strong cardioprotective effect in acute ischemia through stimulation of natriuretic peptide receptors. These beneficial effects are mediated, at least in part, by mitoKATP channel opening and downstream activated survival kinases, thus delaying mPTP opening and improving IR-induced mitochondrial

  14. Redox regulation of ischemic limb neovascularization – What we have learned from animal studies

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    Reiko Matsui

    2017-08-01

    Full Text Available Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice with diabetes or atherosclerosis may have higher deleterious levels of oxidants. Therefore, fine control of oxidants is required to stimulate vascularization in the limb muscle. Oxidants transduce cellular signaling through oxidative modifications of redox sensitive cysteine thiols. Of particular importance, the reversible modification with abundant glutathione, called S-glutathionylation (or GSH adducts, is relatively stable and alters protein function including signaling, transcription, and cytoskeletal arrangement. Glutaredoxin-1 (Glrx is an enzyme which catalyzes reversal of GSH adducts, and does not scavenge oxidants itself. Glrx may control redox signaling under fluctuation of oxidants levels. In ischemic muscle increased GSH adducts through Glrx deletion improves in vivo limb revascularization, indicating endogenous Glrx has anti-angiogenic roles. In accordance, Glrx overexpression attenuates VEGF signaling in vitro and ischemic vascularization in vivo. There are several Glrx targets including HIF-1α which may contribute to inhibition of vascularization by reducing GSH adducts. These animal studies provide a caution that excess antioxidants may be counter-productive for treatment of ischemic limbs, and highlights Glrx as a potential therapeutic target to improve ischemic limb vascularization. Keywords: Ischemic limb, Angiogenesis, Oxidants, GSH adducts, Glutaredoxin

  15. N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Gangduo; Wang, Jianling; Ma, Huaxian; Ansari, G.A.S.; Khan, M. Firoze, E-mail: mfkhan@utmb.edu

    2013-11-15

    Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, is known to induce autoimmunity both in humans and animal models. However, mechanisms underlying TCE-mediated autoimmunity remain largely unknown. Previous studies from our laboratory in MRL +/+ mice suggest that oxidative stress may contribute to TCE-induced autoimmune response. The current study was undertaken to further assess the role of oxidative stress in TCE-induced autoimmunity by supplementing with an antioxidant N-acetylcysteine (NAC). Groups of female MRL +/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, 250 mg/kg/day through drinking water). TCE exposure led to significant increases in serum levels of anti-nuclear, anti-dsDNA and anti-Sm antibodies. TCE exposure also led to significant induction of anti-malondiadelhyde (MDA)- and anti-hydroxynonenal (HNE)-protein adduct antibodies which were associated with increased ANA in the sera along with increased MDA-/HNE-protein adducts in the livers and kidneys, and increases in protein oxidation (carbonylation) in the sera, livers and kidneys, suggesting an overall increase in oxidative stress. Moreover, TCE exposure also resulted in increased release of IL-17 from splenocytes and increases in IL-17 mRNA expression. Remarkably, NAC supplementation attenuated not only the TCE-induced oxidative stress, IL-17 release and mRNA expression, but also the markers of autoimmunity, as evident from decreased levels of ANA, anti-dsDNA and anti-Sm antibodies in the sera. These results provide further support to a role of oxidative stress in TCE-induced autoimmune response. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for preventive and/or therapeutic strategies. - Highlights: • TCE led to increased autoantibodies, supporting its potential to induce autoimmunity. • TCE exposure led to increases in lipid perioxidation and protein carbonyls. • TCE exposure resulted in

  16. N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress

    International Nuclear Information System (INIS)

    Wang, Gangduo; Wang, Jianling; Ma, Huaxian; Ansari, G.A.S.; Khan, M. Firoze

    2013-01-01

    Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, is known to induce autoimmunity both in humans and animal models. However, mechanisms underlying TCE-mediated autoimmunity remain largely unknown. Previous studies from our laboratory in MRL +/+ mice suggest that oxidative stress may contribute to TCE-induced autoimmune response. The current study was undertaken to further assess the role of oxidative stress in TCE-induced autoimmunity by supplementing with an antioxidant N-acetylcysteine (NAC). Groups of female MRL +/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, 250 mg/kg/day through drinking water). TCE exposure led to significant increases in serum levels of anti-nuclear, anti-dsDNA and anti-Sm antibodies. TCE exposure also led to significant induction of anti-malondiadelhyde (MDA)- and anti-hydroxynonenal (HNE)-protein adduct antibodies which were associated with increased ANA in the sera along with increased MDA-/HNE-protein adducts in the livers and kidneys, and increases in protein oxidation (carbonylation) in the sera, livers and kidneys, suggesting an overall increase in oxidative stress. Moreover, TCE exposure also resulted in increased release of IL-17 from splenocytes and increases in IL-17 mRNA expression. Remarkably, NAC supplementation attenuated not only the TCE-induced oxidative stress, IL-17 release and mRNA expression, but also the markers of autoimmunity, as evident from decreased levels of ANA, anti-dsDNA and anti-Sm antibodies in the sera. These results provide further support to a role of oxidative stress in TCE-induced autoimmune response. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for preventive and/or therapeutic strategies. - Highlights: • TCE led to increased autoantibodies, supporting its potential to induce autoimmunity. • TCE exposure led to increases in lipid perioxidation and protein carbonyls. • TCE exposure resulted in

  17. Puerarin attenuates learning and memory impairments and inhibits oxidative stress in STZ-induced SAD mice.

    Science.gov (United States)

    Zhao, Shan-shan; Yang, Wei-na; Jin, Hui; Ma, Kai-ge; Feng, Gai-feng

    2015-12-01

    Puerarin (PUE), an isoflavone purified from the root of Pueraria lobata (Chinese herb), has been reported to attenuate learning and memory impairments in the transgenic mouse model of Alzheimer's disease (AD). In the present study, we tested PUE in a sporadic AD (SAD) mouse model which was induced by the intracerebroventricular injection of streptozotocin (STZ). The mice were administrated PUE (25, 50, or 100mg/kg/d) for 28 days. Learning and memory abilities were assessed by the Morris water maze test. After behavioral test, the biochemical parameters of oxidative stress (glutathione peroxidase (GSH-Px), superoxide dismutases (SOD), and malondialdehyde (MDA)) were measured in the cerebral cortex and hippocampus. The SAD mice exhibited significantly decreased learning and memory ability, while PUE attenuated these impairments. The activities of GSH-Px and SOD were decreased while MDA was increased in the SAD animals. After PUE treatment, the activities of GSH-Px and SOD were elevated, and the level of MDA was decreased. The middle dose PUE was more effective than others. These results indicate that PUE attenuates learning and memory impairments and inhibits oxidative stress in STZ-induced SAD mice. PUE may be a promising therapeutic agent for SAD. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Linking Mn(II)-oxidizing bacteria to natural attenuation at a former U mining site

    Science.gov (United States)

    Akob, D.; Bohu, T.; Beyer, A.; Schäffner, F.; Händel, M.; Johnson, C.; Merten, D.; Büchel, G.; Totsche, K.; Küsel, K.

    2012-04-01

    Uranium mining near Ronneburg, Germany resulted in widespread environmental contamination with acid mine drainage (AMD) and high concentrations of heavy metals and radionuclides. Despite physical remediation of the area, groundwater is still a source of heavy metal contaminants, e.g., Cd, Ni, Co, Cu and Zn, to nearby ecosystems. However, natural attenuation of heavy metals is occurring in Mn oxide rich soils and sediments ranging in pH from 5 to 7. While microorganisms readily oxidize Mn(II) and precipitate Mn oxides at pH ~7 under oxic conditions, few studies describe Mn(II)-oxidizing bacteria (MOB) at pH ~5 and/or in the presence of heavy metals. In this study we (1) isolated MOB from the contaminated Ronneburg area at pH 5.5 and 7 and (2) evaluated the biological formation of Mn oxides. We isolated nine MOB strains at pH 7 (members of the Proteobacteria, Actinobacteria, Bacteroidetes, and Firmicutes phyla) and a single isolate at pH 5.5 (Oxalobacteraceae isolate AB_14, within the β-Proteobacteria). LA-ICP-MS showed that all isolates accumulated Mn and Fe in their biomass. However, the Oxalobacteraceae isolate AB_14 oxidizes more Mn without additional Fe in the medium. Preliminary FTIR analysis indicated that all isolates formed precipitates, which showed absorption bands that were characteristic for birnessite. High resolution TEM showed variable morphology of precipitates and EDS confirmed the presence of Mn oxides. Isolate AB_14 was not surrounded with precipitates whereas our Actinobacteria isolate AB_18 was encrusted with Mn oxides. Electron diffraction is currently being used to confirm the presence of birnessite and other Mn oxide phases. This, the first known report of any organism capable of Mn oxidation at low pH, demonstrated that MOB can be involved in the natural attenuation of both moderately acidic and neutral pH soils and sediments via the formation of biogenic Mn oxides. Future work will fully evaluate the minerals formed in this process as well

  19. Exercise Training Attenuates the Dysregulated Expression of Adipokines and Oxidative Stress in White Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Takuya Sakurai

    2017-01-01

    Full Text Available Obesity-induced inflammatory changes in white adipose tissue (WAT, which caused dysregulated expression of inflammation-related adipokines involving tumor necrosis factor-α and monocyte chemoattractant protein-1, contribute to the development of insulin resistance. Moreover, current literature reports state that WAT generates reactive oxygen species (ROS, and the enhanced production of ROS in obese WAT has been closely associated with the dysregulated expression of adipokines in WAT. Therefore, the reduction in excess WAT and oxidative stress that results from obesity is thought to be one of the important strategies in preventing and improving lifestyle-related diseases. Exercise training (TR not only brings about a decrease in WAT mass but also attenuates obesity-induced dysregulated expression of the adipokines in WAT. Furthermore, some reports indicate that TR affects the generation of oxidative stress in WAT. This review outlines the impact of TR on the expression of inflammation-related adipokines and oxidative stress in WAT.

  20. Chitosan oligosaccharides attenuates oxidative-stress related retinal degeneration in rats.

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    I-Mo Fang

    Full Text Available This study investigated the therapeutic potential and mechanisms of chitosan oligosaccharides (COS for oxidative stress-induced retinal diseases. Retinal oxidative damage was induced in Sprague-Dawley rats by intravitreal injection of paraquat (PQ. Low-dose (5 mg/kg or high-dose (10 mg/kg COS or PBS was intragastrically given for 14 days after PQ injection. Electroretinograms were performed to determine the functionality of the retinas. The surviving neurons in the retinal ganglion cell layer and retinal apoptosis were determined by counting Neu N-positive cells in whole-mounted retinas and TUNEL staining, respectively. The generation of reactive oxygen species (ROS was determined by lucigenin- and luminol-enhanced chemiluminescence. Retinal oxidative damages were assessed by staining with nitrotyrosine, acrolein, and 8-hydroxy-2'-deoxyguanosine (8-OHdG. Immunohistochemical studies were used to demonstrate the expression of nuclear factor-kappa B (NF-κB p65 in retinas. An in vitro study using RGC-5 cells was performed to verify the results. We demonstrated COS significantly enhanced the recovery of retinal function, preserved inner retinal thickness, and decreased retinal neurons loss in a dose-dependent manner. COS administration demonstrated anti-oxidative effects by reducing luminol- and lucigenin-dependent chemiluminenscense levels and activating superoxide dismutase and catalase, leading to decreased retinal apoptosis. COS markedly reduced retinal NF-κB p65. An in vitro study demonstrated COS increased IκB expression, attenuated the increase of p65 and thus decreased NF-κB/DNA binding activity in PQ-stimulated RGC-5 cells. In conclusion, COS attenuates oxidative stress-induced retinal damages, probably by decreasing free radicals, maintaining the activities of anti-oxidative enzymes, and inhibiting the activation of NF-κB.

  1. Enhanced Local Skeletal Muscle Oxidative Capacity and Microvascular Blood Flow Following 7-Day Ischemic Preconditioning in Healthy Humans

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    Owen Jeffries

    2018-05-01

    Full Text Available Ischemic preconditioning (IPC, which involves intermittent periods of ischemia followed by reperfusion, is an effective clinical intervention that reduces the risk of myocardial injury and confers ischemic tolerance to skeletal muscle. Repeated bouts of IPC have been shown to stimulate long-term changes vascular function, however, it is unclear what metabolic adaptations may occur locally in the muscle. Therefore, we investigated 7 days of bilateral lower limb IPC (4 × 5 min above limb occlusion pressure (220 mmHg; n = 10, or sham (20 mmHg; n = 10, on local muscle oxidative capacity and microvascular blood flow. Oxidative capacity was measured using near-infrared spectroscopy (NIRS during repeated short duration arterial occlusions (300 mmHg. Microvascular blood flow was assessed during the recovery from submaximal isometric plantar flexion exercises at 40 and 60% of maximal voluntary contraction (MVC. Following the intervention period, beyond the late phase of protection (72 h, muscle oxidative recovery kinetics were speeded by 13% (rate constant pre 2.89 ± 0.47 min-1 vs. post 3.32 ± 0.69 min-1; P < 0.05 and resting muscle oxygen consumption (mO2 was reduced by 16.4% (pre 0.39 ± 0.16%.s-1 vs. post 0.33 ± 0.14%.s-1; P < 0.05. During exercise, changes in deoxygenated hemoglobin (HHb from rest to steady state were reduced at 40 and 60% MVC (16 and 12%, respectively, P < 0.05 despite similar measures of total hemoglobin (tHb. At the cessation of exercise, the time constant for recovery in oxygenated hemoglobin (O2Hb was accelerated at 40 and 60% MVC (by 33 and 43%, respectively suggesting enhanced reoxygenation in the muscle. No changes were reported for systemic measures of resting heart rate or blood pressure. In conclusion, repeated bouts of IPC over 7 consecutive days increased skeletal muscle oxidative capacity and microvascular muscle blood flow. These findings are consistent with enhanced mitochondrial and vascular function following

  2. Real-Time Fluorescence Measurements of ROS and [Ca2+] in Ischemic / Reperfused Rat Hearts: Detectable Increases Occur only after Mitochondrial Pore Opening and Are Attenuated by Ischemic Preconditioning.

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    Andrienko, Tatyana; Pasdois, Philippe; Rossbach, Andreas; Halestrap, Andrew P

    2016-01-01

    Mitochondrial permeability transition pore (mPTP) opening is critical for ischemia / reperfusion (I/R) injury and is associated with increased [Ca2+] and reactive oxygen species (ROS). Here we employ surface fluorescence to establish the temporal sequence of these events in beating perfused hearts subject to global I/R. A bespoke fluorimeter was used to synchronously monitor surface fluorescence and reflectance of Langendorff-perfused rat hearts at multiple wavelengths, with simultaneous measurements of hemodynamic function. Potential interference by motion artefacts and internal filtering was assessed and minimised. Re-oxidation of NAD(P)H and flavoproteins on reperfusion (detected using autofluorescence) was rapid (t0.5 ROS increases during early reperfusion. However, two different fluorescent cytosolic ROS probes did detect ROS increases after 2-3 min of reperfusion, which was shown to be after initiation of mPTP opening. Cyclosporin A (CsA) and IP attenuated these responses and reduced infarct size. [Ca2+]i (monitored with Indo-1) increased progressively during ischemia, but dropped rapidly within 90 s of reperfusion when total mitochondrial [Ca2+] was shown to be increased. These early changes in [Ca2+] were not attenuated by IP, but substantial [Ca2+] increases were observed after 2-3 min reperfusion and these were prevented by both IP and CsA. Our data suggest that the major increases in ROS and [Ca2+] detected later in reperfusion are secondary to mPTP opening. If earlier IP-sensitive changes occur that might trigger initial mPTP opening they are below our limit of detection. Rather, we suggest that IP may inhibit initial mPTP opening by alternative mechanisms such as prevention of hexokinase 2 dissociation from mitochondria during ischemia.

  3. Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

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    Yu, Xiao-Jing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Jia, Lin-Lin; Qi, Jie; Song, Xin-Ai; Tan, Hong [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Cui, Wei [Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Chen, Wensheng [Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China)

    2015-05-01

    We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines

  4. Propofol attenuates oxidant-induced acute lung injury in an isolated perfused rabbit-lung model.

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    Yumoto, Masato; Nishida, Osamu; Nakamura, Fujio; Katsuya, Hirotada

    2005-01-01

    Reactive oxygen species have been strongly implicated in the pathogenesis of acute lung injury (ALI). Some animal studies suggest that free radical scavengers inhibit the onset of oxidant-induced ALI. Propofol (2,6-diisopropylphenol) is chemically similar to phenol-based free radical scavengers such as the endogenous antioxidant vitamin E. Both in vivo and in vitro studies have suggested that propofol has antioxidant potential. We hypothesized that propofol may attenuate ALI by acting as a free-radical scavenger. We investigated the effects of propofol on oxidant-induced ALI induced by purine and xanthine oxidase (XO), in isolated perfused rabbit lung, in two series of experiments. In series 1, we examined the relationship between the severity of ALI and the presence of hydrogen peroxide (H2O2). In series 2, we evaluated the effects of propofol on attenuating ALI and the dose dependence of these effects. The lungs were perfused for 90 min, and we evaluated the effects on the severity of ALI by monitoring the pulmonary capillary filtration coefficient (Kfc), pulmonary arterial pressure (Ppa), and the pulmonary capillary hydrostatic pressure (Ppc). In series 1, treatment with catalase (an H2O2 scavenger) prior to the addition of purine and XO resulted in complete prevention of ALI, suggesting that H2O2 may be involved closely in the pathogenesis of ALI. In series 2, pretreatment with propofol at concentrations in excess of 0.5 mM significantly inhibited the increases in the Kfc values, and that in excess of 0.75 mM significantly inhibited the increase in the Ppa values. Propofol attenuates oxidant-induced ALI in an isolated perfused rabbit lung model, probably due to its antioxidant action.

  5. Mulberry Leaf Extract Attenuates Oxidative Stress-Mediated Testosterone Depletion in Streptozotocin-Induced Diabetic Rats

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    Mohammad Reza Hajizadeh

    2014-03-01

    Full Text Available Background: It has been proposed that oxidative stress may contribute to the development of testicular abnormalities in diabetes. Morus alba leaf extract (MAE has hypoglycemic and antioxidant properties. We, therefore, explored the impact of the administration of MAE on steroidogenesis in diabetic rats. Methods: To address this hypothesis, we measured the serum level of glucose, insulin, and free testosterone (Ts as well as oxidative stress parameters (including glutathione peroxidase, glutathione reductase, total antioxidant capacity, and malondialdehyde in the testis of control, untreated and MAE-treated (1 g/day/kg diabetic rats. In order to determine the likely mechanism of MAE action on Ts levels, we analyzed the quantitative mRNA expression level of the two key steroidogenic proteins, namely steroid acute regulatory protein (StAR and P450 cholesterol side-chain cleavage enzyme (P450scc, by real-time PCR. Results: The MAE-treated diabetic rats had significantly decreased glucose levels and on the other hand increased insulin and free Ts levels than the untreated diabetic rats. In addition, the administration of MAE to the diabetic rats restored the oxidative stress parameters toward control. Induction of diabetes decreased testicular StAR mRNA expression by 66% and MAE treatment enhanced mRNA expression to the same level of the control group. However, the expression of P540scc was not significantly decreased in the diabetic group as compared to the control group. Conclusion: Our findings indicated that MAE significantly increased Ts production in the diabetic rats, probably through the induction of StAR mRNA expression levels. Administration of MAE to experimental models of diabetes can effectively attenuate oxidative stress-mediated testosterone depletion. Please cite this article as: Hajizadeh MR, Eftekhar E, Zal F, Jaffarian A, Mostafavi-Pour Z. Mulberry Leaf Extract Attenuates Oxidative Stress-Mediated Testosterone Depletion in

  6. Mild Oxidative Damage in the Diabetic Rat Heart Is Attenuated by Glyoxalase-1 Overexpression

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    Casper G. Schalkwijk

    2013-07-01

    Full Text Available Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of the current study was to investigate if a reduction of AGEs by overexpression of the glycation precursor detoxifying enzyme glyoxalase-I (GLO-I can prevent diabetes-induced oxidative damage, inflammation and fibrosis in the heart. Diabetes was induced in wild-type and GLO-I transgenic rats by streptozotocin. After 24-weeks of diabetes, cardiac function was monitored with ultrasound under isoflurane anesthesia. Blood was drawn and heart tissue was collected for further analysis. Analysis with UPLC-MSMS showed that the AGE Nε-(1-carboxymethyllysine and its precursor 3-deoxyglucosone were significantly elevated in the diabetic hearts. Markers of oxidative damage, inflammation, and fibrosis were mildly up-regulated in the heart of the diabetic rats and were attenuated by GLO-I overexpression. In this model of diabetes, these processes were not accompanied by significant changes in systolic heart function, i.e., stroke volume, fractional shortening and ejection fraction. This study shows that 24-weeks of diabetes in rats induce early signs of mild cardiac alterations as indicated by an increase of oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation.

  7. Crocin attenuates hemorrhagic shock-induced oxidative stress and organ injuries in rats.

    Science.gov (United States)

    Yang, Long; Dong, Xiujuan

    2017-06-01

    We aimed to evaluate the effect of natural antioxidant crocin in alleviating hemorrhagic shock (HS)-induced organ damages. HS rats were treated with crocin during resuscitation. Mortality at 12h and 24h post resuscitation was documented. HS and resuscitation induced organ injuries, as characterized by elevated wet/dry ratio, quantitative assessment ratio, blood urea nitrogen, creatinine, aspartate aminotransferase and alanine aminotransferase, whereas rats received crocin treatment demonstrated improvements in all the above characteristics. This protective effect coincided with reduced malondialdehyde and increased glutathione in both serum and lung tissues, indicating attenuated oxidative stress in crocin-treated rats. Myeloperoxide levels in lung, kidney and liver were also reduced. Crocin can potentially be used to protect organs from HS-induced damages during resuscitation due to its anti-oxidative role. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Sinomenine attenuates renal fibrosis through Nrf2-mediated inhibition of oxidative stress and TGFβ signaling

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    Qin, Tian [School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009 (China); Yin, Shasha; Yang, Jun; Zhang, Qin; Liu, Yangyang [Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093 (China); Huang, Fengjie, E-mail: hfj@cpu.edu.cn [School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009 (China); Cao, Wangsen, E-mail: wangsencao@nju.edu.cn [Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing 210093 (China)

    2016-08-01

    Renal fibrosis is the common feature of chronic kidney disease and mainly mediated by TGFβ-associated pro-fibrogenic signaling, which causes excessive extracellular matrix accumulation and successive loss of kidney functions. Sinomenine (SIN), an alkaloid derived from medicinal herb extensively used in treatment of rheumatoid arthritis and various inflammatory disorders, displays renal protective properties in experimental animals; however its pharmacological potency against renal fibrosis is not explored. In this study we report that SIN possesses strong anti-renal fibrosis functions in kidney cell and in mouse fibrotic kidney. SIN beneficially modulated the pro-fibrogenic protein expression in TGFβ-treated kidney cells and attenuated the renal fibrotic pathogenesis incurred by unilateral ureteral obstruction (UUO), which correlated with its activation of Nrf2 signaling - the key defender against oxidative stress with anti-fibrotic potentials. Further investigation on its regulation of Nrf2 downstream events revealed that SIN significantly balanced oxidative stress via improving the expression and activity of anti-oxidant and detoxifying enzymes, and interrupted the pro-fibrogenic signaling of TGFβ/Smad and Wnt/β-catenin. Even more impressively SIN achieved its anti-fibrotic activities in an Nrf2-dependent manner, suggesting that SIN regulation of Nrf2-associated anti-fibrotic activities constitutes a critical component of SIN's renoprotective functions. Collectively our studies have demonstrated a novel anti-fibrotic property of SIN and its upstream events and provided a molecular basis for SIN's potential applications in treatment of renal fibrosis-associated kidney disorders. - Highlights: • Sinomenine has strong potency of inhibiting renal fibrosis in UUO mouse kidney. • Sinomenine attenuates the expression of profibrogenic proteins. • Sinomenine balances renal fibrosis-associated oxidative stress. • Sinomenine mitigates profibrogenic

  9. The metabolic enhancer piracetam attenuates mitochondrion-specific endonuclease G translocation and oxidative DNA fragmentation.

    Science.gov (United States)

    Gupta, Sonam; Verma, Dinesh Kumar; Biswas, Joyshree; Rama Raju, K Siva; Joshi, Neeraj; Wahajuddin; Singh, Sarika

    2014-08-01

    This study was performed to investigate the involvement of mitochondrion-specific endonuclease G in piracetam (P)-induced protective mechanisms. Studies have shown the antiapoptotic effects of piracetam but the mechanism of action of piracetam is still an enigma. To assess the involvement of endonuclease G in piracetam-induced protective effects, astrocyte glial cells were treated with lipopolysaccharide (LPS) and piracetam. LPS treatment caused significantly decreased viability, mitochondrial activity, oxidative stress, chromatin condensation, and DNA fragmentation, which were attenuated by piracetam cotreatment. Cotreatment of astrocytes with piracetam showed its significantly time-dependent absorption as observed with high-performance liquid chromatography. Astrocytes treated with piracetam alone showed enhanced mitochondrial membrane potential (MMP) in comparison to control astrocytes. However, in LPS-treated cells no significant alteration in MMP was observed in comparison to control cells. Protein and mRNA levels of the terminal executor of the caspase-mediated pathway, caspase-3, were not altered significantly in LPS or LPS + piracetam-treated astrocytes, whereas endonuclease G was significantly translocated to the nucleus in LPS-treated astrocytes. Piracetam cotreatment attenuated the LPS-induced endonuclease G translocation. In conclusion this study indicates that LPS treatment of astrocytes caused decreased viability, oxidative stress, mitochondrial dysfunction, chromatin condensation, DNA damage, and translocation of endonuclease G to the nucleus, which was inhibited by piracetam cotreatment, confirming that the mitochondrion-specific endonuclease G is one of the factors involved in piracetam-induced protective mechanisms. Copyright © 2014 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    1997-04-01

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

  11. Sildenafil Attenuates Inflammation and Oxidative Stress in Pelvic Ganglia Neurons after Bilateral Cavernosal Nerve Damage

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    Leah A. Garcia

    2014-09-01

    Full Text Available Erectile dysfunction is a common complication for patients undergoing surgeries for prostate, bladder, and colorectal cancers, due to damage of the nerves associated with the major pelvic ganglia (MPG. Functional re-innervation of target organs depends on the capacity of the neurons to survive and switch towards a regenerative phenotype. PDE5 inhibitors (PDE5i have been successfully used in promoting the recovery of erectile function after cavernosal nerve damage (BCNR by up-regulating the expression of neurotrophic factors in MPG. However, little is known about the effects of PDE5i on markers of neuronal damage and oxidative stress after BCNR. This study aimed to investigate the changes in gene and protein expression profiles of inflammatory, anti-inflammatory cytokines and oxidative stress related-pathways in MPG neurons after BCNR and subsequent treatment with sildenafil. Our results showed that BCNR in Fisher-344 rats promoted up-regulation of cytokines (interleukin- 1 (IL-1 β, IL-6, IL-10, transforming growth factor β 1 (TGFβ1, and oxidative stress factors (Nicotinamide adenine dinucleotide phosphate (NADPH oxidase, Myeloperoxidase (MPO, inducible nitric oxide synthase (iNOS, TNF receptor superfamily member 5 (CD40 that were normalized by sildenafil treatment given in the drinking water. In summary, PDE5i can attenuate the production of damaging factors and can up-regulate the expression of beneficial factors in the MPG that may ameliorate neuropathic pain, promote neuroprotection, and favor nerve regeneration.

  12. Thymoquinone Attenuates Brain Injury via an Anti-oxidative Pathway in a Status Epilepticus Rat Model.

    Science.gov (United States)

    Shao, Yi-Ye; Li, Bing; Huang, Yong-Mei; Luo, Qiong; Xie, Yang-Mei; Chen, Ying-Hui

    2017-01-01

    Status epilepticus (SE) results in the generation of reactive oxygen species (ROS), which contribute to seizure-induced brain injury. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE). Thymoquinone (TQ) is a bioactive monomer extracted from black cumin (Nigella sativa) seed oil that has anti-inflammatory, anti-cancer, and antioxidant activity in various diseases. This study evaluated the protective effects of TQ on brain injury in a lithium-pilocarpine rat model of SE and investigated the underlying mechanism related to antioxidative pathway. Electroencephalogram and Racine scale were used to value seizure severity. Passive-avoidance test was used to determine learning and memory function. Moreover, anti-oxidative activity of TQ was observed using Western blot and super oxide dismutase (SOD) activity assay. Latency to SE increased in the TQ-pretreated group compared with rats in the model group, while the total power was significantly lower. Seizure severity measured on the Racine scale was significantly lower in the TQ group compared with the model group. Results of behavioral experiments suggest that TQ may also have a protective effect on learning and memory function. Investigation of the protective mechanism of TQ showed that TQ-pretreatment significantly increased the expression of Nrf2, HO-1 proteins and SOD in the hippocampus. These findings showed that TQ attenuated brain injury induced by SE via an anti-oxidative pathway.

  13. Omega-3 Polyunsaturated Fatty Acids Attenuate Radiation-induced Oxidative Stress and Organ Dysfunctions in Rats

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    Abdel Aziz, N.; Yacoub, S.F.

    2013-01-01

    The Aim of the present study was to determine the possible protective effect of omega-3 polyunsaturated fatty acids (omega-3 PUFA) against radiation-induced oxidative stress associated with organ dysfunctions. Omega-3 PUFA was administered by oral gavages to male albino rats at a dose of 0.4 g/ kg body wt daily for 4 weeks before whole body γ-irradiation with 4Gy. Significant increase of serum lipid peroxidation end product as malondialdehyde (MDA) along with the reduction in blood glutathione (GSH) content, superoxide dismutase (SOD) and glutathione peroxidase (GPX) enzyme activities were recorded on 3rd and 8th days post-irradiation. Oxidative stress was associated with a significant increase in lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) enzyme activities, markers of heart damage, significant increases in uric acid, urea and creatinine levels, markers of kidney damage, significant increases of alkaline phosphatase (ALP) and transaminases (ALT and AST) activities, markers of liver damage. Moreover significant increases in total cholesterol and triglycerides levels were recorded. Omega-3 PUFA administration pre-irradiation significantly attenuated the radiation-induced oxidative stress and organ dysfunctions tested in this study. It could be concluded that oral supplementation of omega-3 PUFA before irradiation may afford protection against radiation-induced oxidative stress and might preserve the integrity of tissue functions of the organs under investigations.

  14. Linoleic acid participates in the response to ischemic brain injury through oxidized metabolites that regulate neurotransmission.

    Science.gov (United States)

    Hennebelle, Marie; Zhang, Zhichao; Metherel, Adam H; Kitson, Alex P; Otoki, Yurika; Richardson, Christine E; Yang, Jun; Lee, Kin Sing Stephen; Hammock, Bruce D; Zhang, Liang; Bazinet, Richard P; Taha, Ameer Y

    2017-06-28

    Linoleic acid (LA; 18:2 n-6), the most abundant polyunsaturated fatty acid in the US diet, is a precursor to oxidized metabolites that have unknown roles in the brain. Here, we show that oxidized LA-derived metabolites accumulate in several rat brain regions during CO 2 -induced ischemia and that LA-derived 13-hydroxyoctadecadienoic acid, but not LA, increase somatic paired-pulse facilitation in rat hippocampus by 80%, suggesting bioactivity. This study provides new evidence that LA participates in the response to ischemia-induced brain injury through oxidized metabolites that regulate neurotransmission. Targeting this pathway may be therapeutically relevant for ischemia-related conditions such as stroke.

  15. Propolis attenuates oxidative injury in brain and lung of nitric oxide synthase inhibited rats

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    Zeliha Selamoglu-Talas

    2015-10-01

    Full Text Available Background: The blocking of nitric oxide synthase (NOS activity may reason vasoconstriction with formation of reactive oxygen species. Propolis has biological and pharmacological properties, such as antioxidant. The aim of this study was to examine the antioxidant effects of propolis which natural product on biochemical parameters in brain and lung tissues of acute nitric oxide synthase inhibited rats by Nω-nitro-L-arginine methyl ester (L-NAME.Methods: Rats have been received L-NAME (40 mg/kg, intraperitoneally, NOS inhibitor for 15 days to produce hypertension and propolis (200mg/kg, by gavage the lastest 5 of 15 days.Results: There  were  the  increase  (P<0.001  in  the  malondialdehyde  levels  in  the  L-NAME treatment groups when compared to control rats, but the decrease (P<0.001 in the catalase activities in both brain and lung tissues. There were statistically changes (P<0.001 in these parameters of L-NAME+propolis treated rats as compared with L-NAME-treated group.Conclusion: The application of L-NAME to the Wistar rats resulted in well developed oxidative stress. Also, propolis may influence endothelial NO production. Identification of such compounds and characterisation of their cellular actions may increase our knowledge of the regulation of endothelial NO production and could provide valuable clues for the prevention or treatment of hypertensive diseases and oxidative stress.

  16. Agmatine attenuates intestinal ischemia and reperfusion injury by reducing oxidative stress and inflammatory reaction in rats.

    Science.gov (United States)

    Turan, Inci; Ozacmak, Hale Sayan; Ozacmak, V Haktan; Barut, Figen; Araslı, Mehmet

    2017-11-15

    Oxidative stress and inflammatory response are major factors causing several tissue injuries in intestinal ischemia and reperfusion (I/R). Agmatine has been reported to attenuate I/R injury of various organs. The present study aims to analyze the possible protective effects of agmatine on intestinal I/R injury in rats. Four groups were designed: sham control, agmatine-treated control, I/R control, and agmatine-treated I/R groups. IR injury of small intestine was induced by the occlusion of the superior mesenteric artery for half an hour to be followed by a 3-hour-long reperfusion. Agmatine (10mg/kg) was administered intraperitoneally before reperfusion period. After 180min of reperfusion period, the contractile responses to both carbachol and potassium chloride (KCl) were subsequently examined in an isolated-organ bath. Malondialdehyde (MDA), reduced glutathione (GSH), and the activity of myeloperoxidase (MPO) were measured in intestinal tissue. Plasma cytokine levels were determined. The expression of the intestinal inducible nitric oxide synthase (iNOS) was also assessed by immunohistochemistry. The treatment with agmatine appeared to be significantly effective in reducing the MDA content and MPO activity besides restoring the content of GSH. The treatment also attenuated the histological injury. The increases in the I/R induced expressions of iNOS, IFN-γ, and IL-1α were brought back to the sham control levels by the treatment as well. Our findings indicate that the agmatine pretreatment may ameliorate reperfusion induced injury in small intestine mainly due to reducing inflammatory response and oxidative stress. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Acute Ethanol Gavage Attenuates Hemorrhage/Resuscitation-Induced Hepatic Oxidative Stress in Rats

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    B. Relja

    2012-01-01

    Full Text Available Acute ethanol intoxication increases the production of reactive oxygen species (ROS. Hemorrhagic shock with subsequent resuscitation (H/R also induces ROS resulting in cellular and hepatic damage in vivo. We examined the role of acute ethanol intoxication upon oxidative stress and subsequent hepatic cell death after H/R. 14 h before H/R, rats were gavaged with single dose of ethanol or saline (5 g/kg, EtOH and ctrl; H/R_EtOH or H/R_ctrl, resp.. Then, rats were hemorrhaged to a mean arterial blood pressure of 30±2 mmHg for 60 min and resuscitated. Two control groups underwent surgical procedures without H/R (sham_ctrl and sham_EtOH, resp.. Liver tissues were harvested at 2, 24, and 72 h after resuscitation. EtOH-gavage induced histological picture of acute fatty liver. Hepatic oxidative (4-hydroxynonenal, 4-HNE and nitrosative (3-nitrotyrosine, 3-NT stress were significantly reduced in EtOH-gavaged rats compared to controls after H/R. Proapoptotic caspase-8 and Bax expressions were markedly diminished in EtOH-gavaged animals compared with controls 2 h after resuscitation. EtOH-gavage increased antiapoptotic Bcl-2 gene expression compared with controls 2 h after resuscitation. iNOS protein expression increased following H/R but was attenuated in EtOH-gavaged animals after H/R. Taken together, the data suggest that acute EtOH-gavage may attenuate H/R-induced oxidative stress thereby reducing cellular injury in rat liver.

  18. 5-HMF attenuates striatum oxidative damage via Nrf2/ARE signaling pathway following transient global cerebral ischemia.

    Science.gov (United States)

    Ya, Bai-Liu; Li, Hong-Fang; Wang, Hai-Ying; Wu, Fei; Xin, Qing; Cheng, Hong-Ju; Li, Wen-Juan; Lin, Na; Ba, Zai-Hua; Zhang, Ru-Juan; Liu, Qian; Li, Ya-Nan; Bai, Bo; Ge, Feng

    2017-01-01

    Recent studies have shown 5-hydroxymethyl-2-furfural (5-HMF) has favorable biological effects, and its neuroprotection in a variety of neurological diseases has been noted. Our previous study showed that treatment of 5-HMF led to protection against permanent global cerebral ischemia. However, the underlying mechanisms in cerebral ischemic injury are not fully understood. This study was conducted to investigate the neuroprotective effect of 5-HMF and elucidate the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway mechanism in the striatum after transient global cerebral ischemia. C57BL/6 mice were subjected to bilateral common carotid artery occlusion for 20 min and sacrificed 24 h after reperfusion. 5-HMF (12 mg/kg) or an equal volume of vehicle was intraperitoneally injected 30 min before ischemia and 5 min after the onset of reperfusion. At 24 h after reperfusion, neurological function was evaluated by neurological disability status scale, locomotor activity test and inclined beam walking test. Histological injury of the striatum was observed by cresyl violet staining and terminal deoxynucleotidyl transferase (TdT)-mediated dNTP nick end labeling (TUNEL) staining. Oxidative stress was evaluated by the carbonyl groups introduced into proteins, and malondialdehyde (MDA) levels. An enzyme-linked immunosorbent assay (ELISA)-based measurement was used to detect Nrf2 DNA binding activity. Nrf2 and its downstream ARE pathway protein expression such as heme oxygenase-1, NAD (P)H:quinone oxidoreductase 1, glutamate-cysteine ligase catalytic subunit and glutamate-cysteine ligase modulatory subunit were detected by western blot. Our results showed that 5-HMF treatment significantly ameliorated neurological deficits, reduced brain water content, attenuated striatum neuronal damage, decreased the carbonyl groups and MDA levels, and activated Nrf2/ARE signaling pathway. Taken together, these results demonstrated that

  19. Quercetin Attenuates Vascular Calcification through Suppressed Oxidative Stress in Adenine-Induced Chronic Renal Failure Rats

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    Xue-ying Chang

    2017-01-01

    Full Text Available Background. This study investigated whether quercetin could alleviate vascular calcification in experimental chronic renal failure rats induced by adenine. Methods. 32 adult male Wistar rats were randomly divided into 4 groups fed normal diet, normal diet with quercetin supplementation (25 mg/kg·BW/d, 0.75% adenine diet, or adenine diet with quercetin supplementation. All rats were sacrificed after 6 weeks of intervention. Serum renal functions biomarkers and oxidative stress biomarkers were measured and status of vascular calcification in aorta was assessed. Furthermore, the induced nitric oxide synthase (iNOS/p38 mitogen activated protein kinase (p38MAPK pathway was determined to explore the potential mechanism. Results. Adenine successfully induced renal failure and vascular calcification in rat model. Quercetin supplementation reversed unfavorable changes of phosphorous, uric acid (UA and creatinine levels, malonaldehyde (MDA content, and superoxide dismutase (SOD activity in serum and the increases of calcium and alkaline phosphatase (ALP activity in the aorta (P<0.05 and attenuated calcification and calcium accumulation in the medial layer of vasculature in histopathology. Western blot analysis showed that iNOS/p38MAPK pathway was normalized by the quercetin supplementation. Conclusions. Quercetin exerted a protective effect on vascular calcification in adenine-induced chronic renal failure rats, possibly through the modulation of oxidative stress and iNOs/p38MAPK pathway.

  20. Arginase attenuates inhibitory nonadrenergic noncholinergic nerve-induced nitric oxide generation and airway smooth muscle relaxation

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    Meurs Herman

    2005-03-01

    Full Text Available Abstract Background Recent evidence suggests that endogenous arginase activity potentiates airway responsiveness to methacholine by attenuation of agonist-induced nitric oxide (NO production, presumably by competition with epithelial constitutive NO synthase for the common substrate, L-arginine. Using guinea pig tracheal open-ring preparations, we now investigated the involvement of arginase in the modulation of neuronal nitric oxide synthase (nNOS-mediated relaxation induced by inhibitory nonadrenergic noncholinergic (iNANC nerve stimulation. Methods Electrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5 – 16 Hz-induced relaxation was measured in tracheal preparations precontracted to 30% with histamine, in the presence of 1 μM atropine and 3 μM indomethacin. The contribution of NO to the EFS-induced relaxation was assessed by the nonselective NOS inhibitor L-NNA (0.1 mM, while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor nor-NOHA (10 μM. Furthermore, the role of substrate availability to nNOS in EFS-induced relaxation was measured in the presence of various concentrations of exogenous L-arginine. Results EFS induced a frequency-dependent relaxation, ranging from 6.6 ± 0.8% at 0.5 Hz to 74.6 ± 1.2% at 16 Hz, which was inhibited with the NOS inhibitor L-NNA by 78.0 ± 10.5% at 0.5 Hz to 26.7 ± 7.7% at 8 Hz (P Conclusion The results indicate that endogenous arginase activity attenuates iNANC nerve-mediated airway relaxation by inhibition of NO generation, presumably by limiting L-arginine availability to nNOS.

  1. Low Intensity Physical Exercise Attenuates Cardiac Remodeling and Myocardial Oxidative Stress and Dysfunction in Diabetic Rats

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    C. Gimenes

    2015-01-01

    Full Text Available We evaluated the effects of a low intensity aerobic exercise protocol on cardiac remodeling and myocardial function in diabetic rats. Wistar rats were assigned into four groups: sedentary control (C-Sed, exercised control (C-Ex, sedentary diabetes (DM-Sed, and exercised diabetes (DM-Ex. Diabetes was induced by intraperitoneal injection of streptozotocin. Rats exercised for 9 weeks in treadmill at 11 m/min, 18 min/day. Myocardial function was evaluated in left ventricular (LV papillary muscles and oxidative stress in LV tissue. Statistical analysis was given by ANOVA or Kruskal-Wallis. Echocardiogram showed diabetic groups with higher LV diastolic diameter-to-body weight ratio and lower posterior wall shortening velocity than controls. Left atrium diameter was lower in DM-Ex than DM-Sed (C-Sed: 5.73±0.49; C-Ex: 5.67±0.53; DM-Sed: 6.41±0.54; DM-Ex: 5.81±0.50 mm; P<0.05 DM-Sed vs C-Sed and DM-Ex. Papillary muscle function was depressed in DM-Sed compared to C-Sed. Exercise attenuated this change in DM-Ex. Lipid hydroperoxide concentration was higher in DM-Sed than C-Sed and DM-Ex. Catalase and superoxide dismutase activities were lower in diabetics than controls and higher in DM-Ex than DM-Sed. Glutathione peroxidase activity was lower in DM-Sed than C-Sed and DM-Ex. Conclusion. Low intensity exercise attenuates left atrium dilation and myocardial oxidative stress and dysfunction in type 1 diabetic rats.

  2. Attenuation of iron-binding proteins in ARPE-19 cells reduces their resistance to oxidative stress.

    Science.gov (United States)

    Karlsson, Markus; Kurz, Tino

    2016-09-01

    Oxidative stress-related damage to retinal pigment epithelial (RPE) cells is an important feature in the development of age-related macular degeneration. Iron-catalysed intralysosomal production of hydroxyl radicals is considered a major pathogenic factor, leading to lipofuscin formation with ensuing depressed cellular autophagic capacity, lysosomal membrane permeabilization and apoptosis. Previously, we have shown that cultured immortalized human RPE (ARPE-19) cells are extremely resistant to exposure to bolus doses of hydrogen peroxide and contain considerable amounts of the iron-binding proteins metallothionein (MT), heat-shock protein 70 (HSP70) and ferritin (FT). According to previous findings, autophagy of these proteins depresses lysosomal redox-active iron. The aim of this study was to investigate whether up- or downregulation of these proteins would affect the resistance of ARPE-19 cells to oxidative stress. The sensitivity of ARPE-19 cells to H2 O2 exposure was tested following upregulation of MT, HSP70 and/or FT by pretreatment with ZnSO4 , heat shock or FeCl3 , as well as siRNA-mediated downregulation of the same proteins. Upregulation of MT, HSP70 and FT did not improve survival following exposure to H2 O2 . This was interpreted as existence of an already maximal protection. Combined siRNA-mediated attenuation of both FT chains (H and L), or simultaneous downregulation of all three proteins, made the cells significantly more susceptible to oxidative stress confirming the importance of iron-binding proteins. The findings support our hypothesis that the oxidative stress resistance exhibited by RPE cells may be explained by a high autophagic influx of iron-binding proteins that would keep levels of redox-active lysosomal iron low. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  3. CO Adsorption and Oxidation at the Catalyst-Water Interface: An Investigation by Attenuated Total Reflection Infrared Spectroscopy.

    NARCIS (Netherlands)

    Ebbesen, S.D.; Mojet, Barbara; Lefferts, Leonardus

    2006-01-01

    Adsorption of carbon monoxide and oxidation of preadsorbed carbon monoxide from gas and aqueous phases were studied on a platinum catalyst deposited on a ZnSe internal reflection element (IRE) using attenuated total reflection infrared (ATR-IR) spectroscopy. The results of this study convincingly

  4. Melatonin attenuates oxidative stress, liver damage and hepatocyte apoptosis after bile-duct ligation in rats.

    Science.gov (United States)

    Aktas, Cevat; Kanter, Mehmet; Erboga, Mustafa; Mete, Rafet; Oran, Mustafa

    2014-10-01

    The goal of this study was to evaluate the possible protective effects of melatonin against cholestatic oxidative stress, liver damage and hepatocyte apoptosis in the common rats with bile duct ligation (BDL). A total of 24 male Wistar albino rats were divided into three groups: control, BDL and BDL + received melatonin; each group contains eight animals. Melatonin-treated BDL rats received daily melatonin 100 mg/kg/day via intraperitoneal injection. The application of BDL clearly increased the malondialdehyde (MDA) levels and decreased the superoxide dismutase (SOD) and glutathione (GSH) activities. Melatonin treatment significantly decreased the elevated tissue MDA levels and increased the reduced SOD and GSH enzyme levels in the tissues. The changes demonstrate that the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules, mononuclear cells and neutrophil infiltration into the widened portal areas as observed in the BDL group. The data indicate that melatonin attenuates BDL-induced cholestatic liver injury, bile duct proliferation and fibrosis. The α-smooth muscle actin (α-SMA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the BDL were observed to be reduced with the melatonin treatment. These results suggest that administration of melatonin is a potentially beneficial agent to reduce liver damage in BDL by decreasing oxidative stress. © The Author(s) 2012.

  5. Polydatin Attenuates H2O2-Induced Oxidative Stress via PKC Pathway

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    Huilian Qiao

    2016-01-01

    Full Text Available Oxidative stress plays an important role in the pathogenesis of endothelial dysfunction, which is found to precede the development of diverse cardiovascular diseases (CVDs. The aim of this study was to observe the protective effects of PD against H2O2-induced oxidative stress injury (OSI in human umbilical vein endothelial cells (HUVECs and the possible mechanism of PD in OSI treatment. HUVECs were subjected to H2O2 in the absence or presence of PD. It turned out that PD improved cell viability and adhesive and migratory abilities, inhibited the release of lactate dehydrogenase (LDH and reactive oxygen species (ROS, and elevated the content of glutathione peroxidase (GSH-Px and superoxide dismutase (SOD. TUNEL, fluorometric assays, and Western blotting showed that OSI upregulated the apoptosis ratio, the activity of caspase-3 and the level of proapoptotic protein Bax and decreased the level of antiapoptotic protein Bcl-2. However, PD treatment partially reversed these damage effects and Protein Kinase C (PKC activation by thymeleatoxin (THX in turn eliminated the antiapoptotic effect of PD. Furthermore, PD attenuated the H2O2-induced phosphorylation of PKCs α and δ and increased the phosphorylation of PKC ε. Our results indicated that PD might exert protective effects against OSI through various interactions with PKC pathway.

  6. Narciclasine attenuates diet-induced obesity by promoting oxidative metabolism in skeletal muscle.

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    Sofi G Julien

    2017-02-01

    Full Text Available Obesity develops when caloric intake exceeds metabolic needs. Promoting energy expenditure represents an attractive approach in the prevention of this fast-spreading epidemic. Here, we report a novel pharmacological strategy in which a natural compound, narciclasine (ncls, attenuates diet-induced obesity (DIO in mice by promoting energy expenditure. Moreover, ncls promotes fat clearance from peripheral metabolic tissues, improves blood metabolic parameters in DIO mice, and protects these mice from the loss of voluntary physical activity. Further investigation suggested that ncls achieves these beneficial effects by promoting a shift from glycolytic to oxidative muscle fibers in the DIO mice thereby enhancing mitochondrial respiration and fatty acid oxidation (FAO in the skeletal muscle. Moreover, ncls strongly activates AMPK signaling specifically in the skeletal muscle. The beneficial effects of ncls treatment in fat clearance and AMPK activation were faithfully reproduced in vitro in cultured murine and human primary myotubes. Mechanistically, ncls increases cellular cAMP concentration and ADP/ATP ratio, which further lead to the activation of AMPK signaling. Blocking AMPK signaling through a specific inhibitor significantly reduces FAO in myotubes. Finally, ncls also enhances mitochondrial membrane potential and reduces the formation of reactive oxygen species in cultured myotubes.

  7. Metabolic enhancer piracetam attenuates rotenone induced oxidative stress: a study in different rat brain regions.

    Science.gov (United States)

    Verma, Dinesh Kumar; Joshi, Neeraj; Raju, Kunumuri Sivarama; Wahajuddin, Muhammad; Singh, Rama Kant; Singh, Sarika

    2015-01-01

    Piracetam is clinically being used nootropic drug but the details of its neuroprotective mechanism are not well studied. The present study was conducted to assess the effects of piracetam on rotenone induced oxidative stress by using both ex vivo and in vivo test systems. Rats were treated with piracetam (600 mg/kg b.w. oral) for seven constitutive days prior to rotenone administration (intracerebroventricular, 12 µg) in rat brain. Rotenone induced oxidative stress was assessed after 1 h and 24 h of rotenone administration. Ex vivo estimations were performed by using two experimental designs. In one experimental design the rat brain homogenate was treated with rotenone (1 mM, 2 mM and 4 mM) and rotenone+piracetam (10 mM) for 1 h. While in second experimental design the rats were pretreated with piracetam for seven consecutive days. On eighth day the rats were sacrificed, brain homogenate was prepared and treated with rotenone (1 mM, 2 mM and 4mM) for 1h. After treatment the glutathione (GSH) and malondialdehyde (MDA) levels were estimated in brain homogenate. In vivo study showed that pretreatment of piracetam offered significant protection against rotenone induced decreased GSH and increased MDA level though the protection was region specific. But the co-treatment of piracetam with rotenone did not offer significant protection against rotenone induced oxidative stress in ex vivo study. Whereas ex vivo experiments in rat brain homogenate of piracetam pretreated rats, showed the significant protection against rotenone induced oxidative stress. Findings indicated that pretreatment of piracetam significantly attenuated the rotenone induced oxidative stress though the protection was region specific. Piracetam treatment to rats led to its absorption and accumulation in different brain regions as assessed by liquid chromatography mass spectrometry/mass spectrometry. In conclusion, study indicates the piracetam is able to enhance the antioxidant capacity in brain cells

  8. Nano lead oxide and epdm composite for development of polymer based radiation shielding material: Gamma irradiation and attenuation tests

    Science.gov (United States)

    Özdemir, T.; Güngör, A.; Akbay, I. K.; Uzun, H.; Babucçuoglu, Y.

    2018-03-01

    It is important to have a shielding material that is not easily breaking in order to have a robust product that guarantee the radiation protection of the patients and radiation workers especially during the medical exposure. In this study, nano sized lead oxide (PbO) particles were used, for the first time, to obtain an elastomeric composite material in which lead oxide nanoparticles, after the surface modification with silane binding agent, was used as functional material for radiation shielding. In addition, the composite material including 1%, 5%, 10%, 15% and 20% weight percent nano sized lead oxide was irradiated with doses of 81, 100 and 120 kGy up to an irradiation period of 248 days in a gamma ray source with an initial dose rate of 21.1 Gy/h. Mechanical, thermal properties of the irradiated materials were investigated using DSC, DMA, TGA and tensile testing and modifications in thermal and mechanical properties of the nano lead oxide containing composite material via gamma irradiation were reported. Moreover, effect of bismuth-III oxide addition on radiation attenuation of the composite material was investigated. Nano lead oxide and bismuth-III oxide particles were mixed with different weight ratios. Attenuation tests have been conducted to determine lead equivalent values for the developed composite material. Lead equivalent thickness values from 0.07 to 0.65 (2-6 mm sample thickness) were obtained.

  9. Kaempferol Attenuates Cardiac Hypertrophy via Regulation of ASK1/MAPK Signaling Pathway and Oxidative Stress.

    Science.gov (United States)

    Feng, Hong; Cao, Jianlei; Zhang, Guangyu; Wang, Yanggan

    2017-07-01

    Kaempferol has been demonstrated to provide benefits for the treatment of atherosclerosis, coronary heart disease, hyperlipidemia, and diabetes through its antioxidant and anti-inflammatory properties. However, its role in cardiac hypertrophy remains to be elucidated. The aim of our study was to investigate the effects of kaempferol on cardiac hypertrophy and the underlying mechanism. Mice subjected to aorta banding were treated with or without kaempferol (100 mg/kg/d, p. o.) for 6 weeks. Echocardiography was performed to evaluate cardiac function. Mice hearts were collected for pathological observation and molecular mechanism investigation. H9c2 cardiomyocytes were stimulated with or without phenylephrine for in vitro study. Kaempferol significantly attenuated cardiac hypertrophy induced by aorta banding as evidenced by decreased cardiomyocyte areas and interstitial fibrosis, accompanied with improved cardiac functions and decreased apoptosis. The ASK1/MAPK signaling pathways (JNK1/2 and p38) were markedly activated in the aorta banding mouse heart but inhibited by kaempferol treatment. In in vitro experiments, kaempferol also inhibited the activity of ASK1/JNK1/2/p38 signaling pathway and the enlargement of H9c2 cardiomyocytes. Furthermore, our study revealed that kaempferol could protect the mouse heart and H9c2 cells from pathological oxidative stress. Our investigation indicated that treatment with kaempferol protects against cardiac hypertrophy, and its cardioprotection may be partially explained by the inhibition of the ASK1/MAPK signaling pathway and the regulation of oxidative stress. Georg Thieme Verlag KG Stuttgart · New York.

  10. Secoisolariciresinol diglucoside attenuates cardiac hypertrophy and oxidative stress in monocrotaline-induced right heart dysfunction.

    Science.gov (United States)

    Puukila, Stephanie; Fernandes, Rafael Oliveira; Türck, Patrick; Carraro, Cristina Campos; Bonetto, Jéssica Hellen Poletto; de Lima-Seolin, Bruna Gazzi; da Rosa Araujo, Alex Sander; Belló-Klein, Adriane; Boreham, Douglas; Khaper, Neelam

    2017-08-01

    Pulmonary arterial hypertension (PAH) occurs when remodeling of pulmonary vessels leads to increased pulmonary vascular resistance resulting in increased pulmonary arterial pressure. Increased pulmonary arterial pressure results in right ventricle hypertrophy and eventually heart failure. Oxidative stress has been implicated in the pathogenesis of PAH and may play a role in the regulation of cellular signaling involved in cardiac response to pressure overload. Secoisolariciresinol diglucoside (SDG), a component from flaxseed, has been shown to reduce cardiac oxidative stress in various pathophysiological conditions. We investigated the potential protective effects of SDG in a monocrotaline-induced model of PAH. Five- to six-week-old male Wistar rats were given a single intraperitoneal injection of monocrotaline (60 mg/kg) and sacrificed 21 days later where heart, lung, and plasma were collected. SDG (25 mg/kg) was given via gavage as either a 21-day co-treatment or pre-treatment of 14 days before monocrotaline administration and continued for 21 days. Monocrotaline led to right ventricle hypertrophy, increased lipid peroxidation, and elevated plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST). Co-treatment with SDG did not attenuate hypertrophy or ALT and AST levels but decreased reactive oxygen species (ROS) levels and catalase and superoxide dismutase activity compared to the monocrotaline-treated group. Pre-treatment with SDG decreased right ventricle hypertrophy, ROS levels, lipid peroxidation, catalase, superoxide dismutase, and glutathione peroxidase activity and plasma levels of ALT and AST when compared to the monocrotaline group. These findings indicate that pre-treatment with SDG provided better protection than co-treatment in this model of right heart dysfunction, suggesting an important role for SDG in PAH and right ventricular remodeling.

  11. Astragaloside IV attenuates experimental autoimmune encephalomyelitis of mice by counteracting oxidative stress at multiple levels.

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    Yixin He

    Full Text Available Multiple sclerosis (MS is a chronic autoimmune neuroinflammatory disease found mostly in young adults in the western world. Oxidative stress induced neuronal apoptosis plays an important role in the pathogenesis of MS. In current study, astragaloside IV (ASI, a natural saponin molecule isolated from Astragalus membranceus, given at 20 mg/kg daily attenuated the severity of experimental autoimmune encephalomyelitis (EAE in mice significantly. Further studies disclosed that ASI treatment inhibited the increase of ROS and pro-inflammatory cytokine levels, down-regulation of SOD and GSH-Px activities, and elevation of iNOS, p53 and phosphorylated tau in central nervous system (CNS as well as the leakage of BBB of EAE mice. Meanwhile, the decreased ratio of Bcl-2/Bax was reversed by ASI. Moreover, ASI regulated T-cell differentiation and infiltration into CNS. In neuroblast SH-SY5Y cells, ASI dose-dependently reduced cellular ROS level and phosphorylation of tau in response to hydrogen peroxide challenge by modulation of Bcl-2/Bax ratio. ASI also inhibited activation of microglia both in vivo and in vitro. iNOS up-regulation induced by IFNγ stimulation was abolished by ASI dose-dependently in BV-2 cells. In summary, ASI prevented the severity of EAE progression possibly by counterbalancing oxidative stress and its effects via reduction of cellular ROS level, enhancement of antioxidant defense system, increase of anti-apoptotic and anti-inflammatory pathways, as well as modulation of T-cell differentiation and infiltration into CNS. The study suggested ASI may be effective for clinical therapy/prevention of MS.

  12. Astragaloside IV attenuates experimental autoimmune encephalomyelitis of mice by counteracting oxidative stress at multiple levels.

    Science.gov (United States)

    He, Yixin; Du, Min; Gao, Yan; Liu, Hongshuai; Wang, Hongwei; Wu, Xiaojun; Wang, Zhengtao

    2013-01-01

    Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory disease found mostly in young adults in the western world. Oxidative stress induced neuronal apoptosis plays an important role in the pathogenesis of MS. In current study, astragaloside IV (ASI), a natural saponin molecule isolated from Astragalus membranceus, given at 20 mg/kg daily attenuated the severity of experimental autoimmune encephalomyelitis (EAE) in mice significantly. Further studies disclosed that ASI treatment inhibited the increase of ROS and pro-inflammatory cytokine levels, down-regulation of SOD and GSH-Px activities, and elevation of iNOS, p53 and phosphorylated tau in central nervous system (CNS) as well as the leakage of BBB of EAE mice. Meanwhile, the decreased ratio of Bcl-2/Bax was reversed by ASI. Moreover, ASI regulated T-cell differentiation and infiltration into CNS. In neuroblast SH-SY5Y cells, ASI dose-dependently reduced cellular ROS level and phosphorylation of tau in response to hydrogen peroxide challenge by modulation of Bcl-2/Bax ratio. ASI also inhibited activation of microglia both in vivo and in vitro. iNOS up-regulation induced by IFNγ stimulation was abolished by ASI dose-dependently in BV-2 cells. In summary, ASI prevented the severity of EAE progression possibly by counterbalancing oxidative stress and its effects via reduction of cellular ROS level, enhancement of antioxidant defense system, increase of anti-apoptotic and anti-inflammatory pathways, as well as modulation of T-cell differentiation and infiltration into CNS. The study suggested ASI may be effective for clinical therapy/prevention of MS.

  13. Gallic Acid Protects 6-OHDA Induced Neurotoxicity by Attenuating Oxidative Stress in Human Dopaminergic Cell Line.

    Science.gov (United States)

    Chandrasekhar, Y; Phani Kumar, G; Ramya, E M; Anilakumar, K R

    2018-04-18

    Gallic acid is one of the most important polyphenolic compounds, which is considered an excellent free radical scavenger. 6-Hydroxydopamine (6-OHDA) is a neurotoxin, which has been implicated in mainly Parkinson's disease (PD). In this study, we investigated the molecular mechanism of the neuroprotective effects of gallic acid on 6-OHDA induced apoptosis in human dopaminergic cells, SH-SY5Y. Our results showed that 6-OHDA induced cytotoxicity in SH-SY5Y cells was suppressed by pre-treatment with gallic acid. The percentage of live cells (90%) was high in the pre-treatment of gallic acid when compared with 6-OHDA alone treated cell line. Moreover, gallic acid was very effective in attenuating the disruption of mitochondrial membrane potential, elevated levels of intracellular ROS and apoptotic cell death induced by 6-OHDA. Gallic acid also lowered the ratio of the pro-apoptotic Bax protein and the anti-apoptotic Bcl-2 protein in SH-SY5Y cells. 6-OHDA exposure was up-regulated caspase-3 and Keap-1 and, down-regulated Nrf2, BDNF and p-CREB, which were sufficiently reverted by gallic acid pre-treatment. These findings indicate that gallic acid is able to protect the neuronal cells against 6-OHDA induced injury and proved that gallic acid might potentially serve as an agent for prevention of several human neurodegenerative diseases caused by oxidative stress and apoptosis.

  14. Edaravone attenuates brain damage in rats after acute CO poisoning through inhibiting apoptosis and oxidative stress.

    Science.gov (United States)

    Li, Qin; Bi, Ming Jun; Bi, Wei Kang; Kang, Hai; Yan, Le Jing; Guo, Yun-Liang

    2016-03-01

    Acute carbon monoxide (CO) poisoning is the most common cause of death from poisoning all over the world and may result in neuropathologic and neurophysiologic changes. Acute brain damage and delayed encephalopathy are the most serious complication, yet their pathogenesis is poorly understood. The present study aimed to evaluate the neuroprotective effects of Edaravone against apoptosis and oxidative stress after acute CO poisoning. The rat model of CO poisoning was established in a hyperbaric oxygen chamber by exposed to CO. Ultrastructure changes were observed by transmission electron microscopy (TEM). TUNEL stain was used to assess apoptosis. Immunohistochemistry and immunofluorescence double stain were used to evaluate the expression levels of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) protein and their relationship. By dynamically monitored the carboxyhemoglobin (HbCO) level in blood, we successfully established rat model of severe CO poisoning. Ultrastructure changes, including chromatin condensation, cytoplasm dissolution, vacuoles formation, nucleus membrane and cell organelles decomposition, could be observed after CO poisoning. Edaravone could improve the ultrastructure damage. CO poisoning could induce apoptosis. Apoptotic cells were widely distributed in cortex, striatum and hippocampus. Edaravone treatment attenuated neuronal apoptosis as compared with the poisoning group (P Edaravone, the expression of HO-1 and Nrf-2 significantly increased (P Edaravone may inhibit apoptosis, activate the Keapl-Nrf/ARE pathway, and thus improve the ultrastructure damage and neurophysiologic changes following acute CO poisoning. © 2014 Wiley Periodicals, Inc.

  15. By Improving Regional Cortical Blood Flow, Attenuating Mitochondrial Dysfunction and Sequential Apoptosis Galangin Acts as a Potential Neuroprotective Agent after Acute Ischemic Stroke

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    Ming Cheng

    2012-11-01

    Full Text Available Ischemic stroke is a devastating disease with a complex pathophysiology. Galangin is a natural flavonoid isolated from the rhizome of Alpina officinarum Hance, which has been widely used as an antioxidant agent. However, its effects against ischemic stroke have not been reported and its related neuroprotective mechanism has not really been explored. In this study, neurological behavior, cerebral infarct volumes and the improvement of the regional cortical blood flow (rCBF were used to evaluate the therapeutic effect of galangin in rats impaired by middle cerebral artery occlusion (MCAO-induced focal cerebral ischemia. Furthermore, the determination of mitochondrial function and Western blot of apoptosis-related proteins were performed to interpret the neuroprotective mechanism of galangin. The results showed that galangin alleviated the neurologic impairments, reduced cerebral infarct at 24 h after MCAO and exerted a protective effect on the mitochondria with decreased production of mitochondrial reactive oxygen species (ROS. These effects were consistent with improvements in the membrane potential level (Dym, membrane fluidity, and degree of mitochondrial swelling in a dose-dependent manner. Moreover, galangin significantly improved the reduced rCBF after MCAO. Western blot analysis revealed that galangin also inhibited apoptosis in a dose-dependent manner concomitant with the up-regulation of Bcl-2 expression, down-regulation of Bax expression and the Bax/Bcl-2 ratio, a reduction in cytochrome c release from the mitochondria to the cytosol, the reduced expression of activated caspase-3 and the cleavage of poly(ADP-ribose polymerase (PARP. All these data in this study demonstrated that galangin might have therapeutic potential for ischemic stroke and play its protective role through the improvement in rCBF, mitochondrial protection and inhibiting caspase-dependent mitochondrial cell death pathway for the first time.

  16. By improving regional cortical blood flow, attenuating mitochondrial dysfunction and sequential apoptosis galangin acts as a potential neuroprotective agent after acute ischemic stroke.

    Science.gov (United States)

    Li, Shaojing; Wu, Chuanhong; Zhu, Li; Gao, Jian; Fang, Jing; Li, Defeng; Fu, Meihong; Liang, Rixin; Wang, Lan; Cheng, Ming; Yang, Hongjun

    2012-11-09

    Ischemic stroke is a devastating disease with a complex pathophysiology. Galangin is a natural flavonoid isolated from the rhizome of Alpina officinarum Hance, which has been widely used as an antioxidant agent. However, its effects against ischemic stroke have not been reported and its related neuroprotective mechanism has not really been explored. In this study, neurological behavior, cerebral infarct volumes and the improvement of the regional cortical blood flow (rCBF) were used to evaluate the therapeutic effect of galangin in rats impaired by middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia. Furthermore, the determination of mitochondrial function and Western blot of apoptosis-related proteins were performed to interpret the neuroprotective mechanism of galangin. The results showed that galangin alleviated the neurologic impairments, reduced cerebral infarct at 24 h after MCAO and exerted a protective effect on the mitochondria with decreased production of mitochondrial reactive oxygen species (ROS). These effects were consistent with improvements in the membrane potential level (Dym), membrane fluidity, and degree of mitochondrial swelling in a dose-dependent manner. Moreover, galangin significantly improved the reduced rCBF after MCAO. Western blot analysis revealed that galangin also inhibited apoptosis in a dose-dependent manner concomitant with the up-regulation of Bcl-2 expression, down-regulation of Bax expression and the Bax/Bcl-2 ratio, a reduction in cytochrome c release from the mitochondria to the cytosol, the reduced expression of activated caspase-3 and the cleavage of poly(ADP-ribose) polymerase (PARP). All these data in this study demonstrated that galangin might have therapeutic potential for ischemic stroke and play its protective role through the improvement in rCBF, mitochondrial protection and inhibiting caspase-dependent mitochondrial cell death pathway for the first time.

  17. Green Tea Extract Ameliorates Learning and Memory Deficits in Ischemic Rats via Its Active Component Polyphenol Epigallocatechin-3-gallate by Modulation of Oxidative Stress and Neuroinflammation

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    Kuo-Jen Wu

    2012-01-01

    Full Text Available Ischemic stroke results in brain damage and behavioral deficits including memory impairment. Protective effects of green tea extract (GTex and its major functional polyphenol (−-epigallocatechin gallate (EGCG on memory were examined in cerebral ischemic rats. GTex and EGCG were administered 1 hr before middle cerebral artery ligation in rats. GTex, EGCG, and pentoxifylline (PTX significantly improved ishemic-induced memory impairment in a Morris water maze test. Malondialdehyde (MDA levels, glutathione (GSH, and superoxide dismutase (SOD activity in the cerebral cortex and hippocampus were increased by long-term treatment with GTex and EGCG. Both compounds were also associated with reduced cerebral infraction breakdown of MDA and GSH in the hippocampus. In in vitro experiments, EGCG had anti-inflammatory effects in BV-2 microglia cells. EGCG inhibited lipopolysaccharide- (LPS- induced nitric oxide production and reduced cyclooxygenase-2 and inducible nitric oxide synthase expression in BV-2 cells. GTex and its active polyphenol EGCG improved learning and memory deficits in a cerebral ischemia animal model and such protection may be due to the reduction of oxidative stress and neuroinflammation.

  18. PKA Inhibitor H89 (N-[2-p-bromocinnamylamino-ethyl]-5-isoquinolinesulfonamide Attenuates Synaptic Dysfunction and Neuronal Cell Death following Ischemic Injury

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    Juhyun Song

    2015-01-01

    Full Text Available The cyclic AMP-dependent protein kinase (PKA, which activates prosurvival signaling proteins, has been implicated in the expression of long-term potentiation and hippocampal long-term memory. It has come to light that H89 commonly known as the PKA inhibitor have diverse roles in the nervous system that are unrelated to its role as a PKA inhibitor. We have investigated the role of H89 in ischemic and reperfusion injury. First, we examined the expression of postsynaptic density protein 95 (PSD95, microtubule-associated protein 2 (MAP2, and synaptophysin in mouse brain after middle cerebral artery occlusion injury. Next, we examined the role of H89 pretreatment on the expression of brain-derived neurotrophic factor (BDNF, PSD95, MAP2, and the apoptosis regulators Bcl2 and cleaved caspase-3 in cultured neuroblastoma cells exposed to hypoxia and reperfusion injury. In addition, we investigated the alteration of AKT activation in H89 pretreated neuroblastoma cells under hypoxia and reperfusion injury. The data suggest that H89 may contribute to brain recovery after ischemic stroke by regulating neuronal death and proteins related to synaptic plasticity.

  19. Renal denervation attenuates NADPH oxidase-mediated oxidative stress and hypertension in rats with hydronephrosis.

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    Peleli, Maria; Al-Mashhadi, Ammar; Yang, Ting; Larsson, Erik; Wåhlin, Nils; Jensen, Boye L; G Persson, A Erik; Carlström, Mattias

    2016-01-01

    Hydronephrosis is associated with the development of salt-sensitive hypertension. Studies have suggested that increased sympathetic nerve activity and oxidative stress play important roles in hypertension and the modulation of salt sensitivity. The present study primarily aimed to examine the role of renal sympathetic nerve activity in the development of hypertension in rats with hydronephrosis. In addition, we aimed to investigate if NADPH oxidase (NOX) function could be affected by renal denervation. Partial unilateral ureteral obstruction (PUUO) was created in 3-wk-old rats to induce hydronephrosis. Sham surgery or renal denervation was performed at the same time. Blood pressure was measured during normal, high-, and low-salt diets. The renal excretion pattern, NOX activity, and expression as well as components of the renin-angiotensin-aldosterone system were characterized after treatment with the normal salt diet. On the normal salt diet, rats in the PUUO group had elevated blood pressure compared with control rats (115 ± 3 vs. 87 ± 1 mmHg, P < 0.05) and displayed increased urine production and lower urine osmolality. The blood pressure change in response to salt loading (salt sensitivity) was more pronounced in the PUUO group compared with the control group (15 ± 2 vs. 5 ± 1 mmHg, P < 0.05). Renal denervation in PUUO rats attenuated both hypertension (97 ± 3 mmHg) and salt sensitivity (5 ± 1 mmHg, P < 0.05) and normalized the renal excretion pattern, whereas the degree of renal fibrosis and inflammation was not changed. NOX activity and expression as well as renin and ANG II type 1A receptor expression were increased in the renal cortex from PUUO rats and normalized by denervation. Plasma Na(+) and K(+) levels were elevated in PUUO rats and normalized after renal denervation. Finally, denervation in PUUO rats was also associated with reduced NOX expression, superoxide production, and fibrosis in the heart. In conclusion, renal denervation attenuates

  20. RAGE-Specific Inhibitor FPS-ZM1 Attenuates AGEs-Induced Neuroinflammation and Oxidative Stress in Rat Primary Microglia.

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    Shen, Chao; Ma, Yingjuan; Zeng, Ziling; Yin, Qingqing; Hong, Yan; Hou, Xunyao; Liu, Xueping

    2017-10-01

    Advanced glycation end products (AGEs) enhance microglial activation and intensify the inflammatory response and oxidative stress in the brain. This process may occur due to direct cytotoxicity or interacting with AGEs receptors (RAGE), which are expressed on the surface of microglia. FPS-ZM1 is a high-affinity but nontoxic RAGE-specific inhibitor that has been recently shown to attenuate the Aβ-induced inflammatory response by blocking the ligation of Aβ to RAGE. In this study, we further investigated the effect of FPS-ZM1 on the AGEs/RAGE interaction and downstream elevation of neuroinflammation and oxidative stress in primary microglia cells. The results suggested that FPS-ZM1 significantly suppressed AGEs-induced RAGE overexpression, RAGE-dependent microglial activation, nuclear translocation of nuclear factor kappaB p65 (NF-κB p65), and the expression of downstream inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS)/nitric oxide (NO). Furthermore, FPS-ZM1 attenuated AGEs-stimulated NADPH oxidase (NOX) activation and reactive oxygen species (ROS) expression. Finally, FPS-ZM1 elevated the levels of transcription factors nuclear-factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), as well as decreased antioxidant capacity and increased production of oxidative species. Our results suggest that FPS-ZM1 may be neuroprotective through attenuating microglial activation, oxidative stress and inflammation by blocking RAGE.

  1. Formoterol attenuates increased oxidative stress and myosin protein loss in respiratory and limb muscles of cancer cachectic rats

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    Anna Salazar-Degracia

    2017-12-01

    Full Text Available Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Therapeutic options are still scarce. We hypothesized that cachexia-induced muscle oxidative stress may be attenuated in response to treatment with beta2-adrenoceptor-selective agonist formoterol in rats. In diaphragm and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally with and without treatment with formoterol (0.3 mg/kg body weight/day for seven days, daily subcutaneous injection, redox balance (protein oxidation and nitration and antioxidants and muscle proteins (1-dimensional immunoblots, carbonylated proteins (2-dimensional immunoblots, inflammatory cells (immunohistochemistry, and mitochondrial respiratory chain (MRC complex activities were explored. In the gastrocnemius, but not the diaphragm, of cancer cachectic rats compared to the controls, protein oxidation and nitration levels were increased, several functional and structural proteins were carbonylated, and in both study muscles, myosin content was reduced, inflammatory cell counts were greater, while no significant differences were seen in MRC complex activities (I, II, and IV. Treatment of cachectic rats with formoterol attenuated all the events in both respiratory and limb muscles. In this in vivo model of cancer-cachectic rats, the diaphragm is more resistant to oxidative stress. Formoterol treatment attenuated the rise in oxidative stress in the limb muscles, inflammatory cell infiltration, and the loss of myosin content seen in both study muscles, whereas no effects were observed in the MRC complex activities. These findings have therapeutic implications as they demonstrate beneficial effects of the beta2 agonist through decreased protein oxidation and inflammation in cachectic muscles, especially the gastrocnemius.

  2. Silibinin attenuates sulfur mustard analog-induced skin injury by targeting multiple pathways connecting oxidative stress and inflammation.

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    Neera Tewari-Singh

    Full Text Available Chemical warfare agent sulfur mustard (HD inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD-induced skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES-induced injury biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 µM treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p90%, and activation of transcription factors NF-κB and AP-1 (complete reversal. Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants.

  3. Exercise through a cardiac rehabilitation program attenuates oxidative stress in patients submitted to coronary artery bypass grafting.

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    Taty Zau, José Francisco; Costa Zeferino, Rodrigo; Sandrine Mota, Nádia; Fernandes Martins, Gerez; Manoel Serra, Salvador; Bonates da Cunha, Therezil; Medeiros Lima, Daniel; Bragança Pereira, Basilio de; Matos do Nascimento, Emília; Filho, Danilo Wilhelm; Curi Pedrosa, Rozangela; Pedrosa, Roberto Coury

    2018-12-01

    Cardiovascular disease is the main cause of morbidity and mortality in the world and oxidative stress has been implicated in the pathogenesis. Cardiac rehabilitation in patients with coronary artery disease submitted to coronary artery bypass grafting may prevent cardiovascular events probably through the attenuation of oxidative stress. The aim of this study was to evaluate the benefits of a cardiac rehabilitation program in the control of the systemic oxidative stress. The studied population consisted of 40 patients, with chronic stable coronary artery disease submitted to coronary artery bypass grafting, who attended a cardiac rehabilitation program. Biomarkers of oxidative stress were evaluated in the blood of these patients at different moments. After the onset of cardiac rehabilitation, there was a significant and progressive decrease in thiobarbituric acid reactive substances levels and protein carbonyls, an initial increase and subsequent decrease in superoxide dismutase, catalase and glutathione peroxidase activities. Also, a progressive increase of uric acid, while ferric reducing antioxidant power levels increased only at the end of the cardiac rehabilitation and a tendency to increase of glutathione contents. The results suggest that regular exercise through a cardiac rehabilitation program can attenuate oxidative stress in chronic coronary artery disease patients submitted to coronary artery bypass grafting.

  4. Attenuated response of L-type calcium current to nitric oxide in atrial fibrillation.

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    Rozmaritsa, Nadiia; Christ, Torsten; Van Wagoner, David R; Haase, Hannelore; Stasch, Johannes-Peter; Matschke, Klaus; Ravens, Ursula

    2014-03-01

    Nitric oxide (NO) synthesized by cardiomyocytes plays an important role in the regulation of cardiac function. Here, we studied the impact of NO signalling on calcium influx in human right atrial myocytes and its relation to atrial fibrillation (AF). Right atrial appendages (RAAs) were obtained from patients in sinus rhythm (SR) and AF. The biotin-switch technique was used to evaluate endogenous S-nitrosylation of the α1C subunit of L-type calcium channels. Comparing SR to AF, S-nitrosylation of Ca(2+) channels was similar. Direct effects of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) on L-type calcium current (ICa,L) were studied in cardiomyocytes with standard voltage-clamp techniques. In SR, ICa,L increased with SNAP (100 µM) by 48%, n/N = 117/56, P < 0.001. The SNAP effect on ICa,L involved activation of soluble guanylate cyclase and protein kinase A. Specific inhibition of phosphodiesterase (PDE)3 with cilostamide (1 µM) enhanced ICa,L to a similar extent as SNAP. However, when cAMP was elevated by PDE3 inhibition or β-adrenoceptor stimulation, SNAP reduced ICa,L, pointing to cGMP-cAMP cross-regulation. In AF, the stimulatory effect of SNAP on ICa,L was attenuated, while its inhibitory effect on isoprenaline- or cilostamide-stimulated current was preserved. cGMP elevation with SNAP was comparable between the SR and AF group. Moreover, the expression of PDE3 and soluble guanylate cyclase was not reduced in AF. NO exerts dual effects on ICa,L in SR with an increase of basal and inhibition of cAMP-stimulated current, and in AF NO inhibits only stimulated ICa,L. We conclude that in AF, cGMP regulation of PDE2 is preserved, but regulation of PDE3 is lost.

  5. Supplementation of α-Tocopherol Attenuates Minerals Disturbance, Oxidative Stress and Apoptosis Occurring in Favism.

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    Koriem, Khaled M M; Arbid, Mahmoud S; Gomaa, Nawal E

    2017-10-01

    The favism is a metabolic disease that characterized with an acute hemolytic anemia where α-tocopherol is a type of tocopherol accumulated inside the human body. The objective of such a study was established to evaluate the effect of α-tocopherol in favism disorders. A total of 75 human cases were divided into 5 groups as follow; group 1 normal cases without any treatment and group 2 normal cases orally administrated α-tocopherol (200 mg/kg) once a day over 30 days period. Group 3 favism patients without any treatment. Groups 4 and 5 favism patients orally administrated 100 and 200 mg α-tocopherol/kg, respectively once a day over 30 days period. The results obtained revealed that oral administration of α-tocopherol into normal cases over 30 days period did not induce any biological change. In favism, hemoglobin, hematocrit, red and white blood cells, serum glucose, glucose-6-phosphate dehydrogenase, total protein, albumin, globulin, aspartate and alanine aminotransferases, blood glutathione, superoxide dismutase, glutathione peroxidase and serum calcium, phosphorous, sodium, potassium and chloride levels were significantly decreased. On the other hand, serum alkaline phosphatase, bilirubin, selenium, zinc, manganese, copper and iron, malondialdehyde levels showed significant increase in favism. Supplementation with α-tocopherol into favism restores all the above mentioned parameters to approach the normal levels. Also, α-tocopherol has anti-apoptotic effect in favism. In conclusion, α-tocopherol attenuates minerals disturbance, oxidative stress and apoptosis occurring in favism.

  6. Morin Attenuates Ovalbumin-Induced Airway Inflammation by Modulating Oxidative Stress-Responsive MAPK Signaling

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    Yuan Ma

    2016-01-01

    Full Text Available Asthma is one of the most common inflammatory diseases characterized by airway hyperresponsiveness, inflammation, and remodeling. Morin, an active ingredient obtained from Moraceae plants, has been demonstrated to have promising anti-inflammatory activities in a range of disorders. However, its impacts on pulmonary diseases, particularly on asthma, have not been clarified. This study was designed to investigate whether morin alleviates airway inflammation in chronic asthma with an emphasis on oxidative stress modulation. In vivo, ovalbumin- (OVA- sensitized mice were administered with morin or dexamethasone before challenge. Bronchoalveolar lavage fluid (BALF and lung tissues were obtained to perform cell counts, histological analysis, and enzyme-linked immunosorbent assay. In vitro, human bronchial epithelial cells (BECs were challenged by tumor necrosis factor alpha (TNF-α. The supernatant was collected for the detection of the proinflammatory proteins, and the cells were collected for reactive oxygen species (ROS/mitogen-activated protein kinase (MAPK evaluations. Severe inflammatory responses and remodeling were observed in the airways of the OVA-sensitized mice. Treatment with morin dramatically attenuated the extensive trafficking of inflammatory cells into the BALF and inhibited their infiltration around the respiratory tracts and vessels. Morin administration also significantly suppressed goblet cell hyperplasia and collagen deposition/fibrosis and dose-dependently inhibited the OVA-induced increases in IgE, TNF-α, interleukin- (IL- 4, IL-13, matrix metalloproteinase-9, and malondialdehyde. In human BECs challenged by TNF-α, the levels of proteins such as eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1, were consistently significantly decreased by morin. Western blotting and the 2′,7′-dichlorofluorescein assay revealed that the increases in intracellular ROS and MAPK phosphorylation were

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

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    Nandini D.P.K. Manne

    2017-07-01

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

  8. P2X7 Receptor Antagonism Attenuates the Intermittent Hypoxia-induced Spatial Deficits in a Murine Model of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress

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    Yan Deng

    2015-01-01

    Conclusions: The P2X7R antagonism attenuates the CIH-induced neuroinflammation, oxidative stress, and spatial deficits, demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.

  9. Activation of α-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress.

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    Zhenying Han

    Full Text Available Activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR has a neuro-protective effect on ischemic and hemorrhagic stroke. However, the underlying mechanism is not completely understood. We hypothesized that α-7 nAchR agonist protects brain injury after ischemic stroke through reduction of pro-inflammatory macrophages (M1 and oxidative stress. C57BL/6 mice were treated with PHA568487 (PHA, α-7 nAchR agonist, methyllycaconitine (MLA, nAchR antagonist, or saline immediately and 24 hours after permanent occlusion of the distal middle cerebral artery (pMCAO. Behavior test, lesion volume, CD68(+, M1 (CD11b(+/Iba1(+ and M2 (CD206/Iba1+ microglia/macrophages, and phosphorylated p65 component of NF-kB in microglia/macrophages were quantified using histological stained sections. The expression of M1 and M2 marker genes, anti-oxidant genes and nicotinamide adenine dinucleotide phosphate (NADPH oxidase were quantified using real-time RT-PCR. Compared to the saline-treated mice, PHA mice had fewer behavior deficits 3 and 7 days after pMCAO, and smaller lesion volume, fewer CD68(+ and M1 macrophages, and more M2 macrophages 3 and 14 days after pMCAO, whereas MLA's effects were mostly the opposite in several analyses. PHA increased anti-oxidant genes and NADPH oxidase expression associated with decreased phosphorylation of NF-kB p65 in microglia/macrophages. Thus, reduction of inflammatory response and oxidative stress play roles in α-7 nAchR neuro-protective effect.

  10. Oral administration of Bifidobacterium breve attenuates UV-induced barrier perturbation and oxidative stress in hairless mice skin.

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    Ishii, Yuki; Sugimoto, Saho; Izawa, Naoki; Sone, Toshiro; Chiba, Katsuyoshi; Miyazaki, Kouji

    2014-07-01

    Recent studies have shown that some probiotics affect not only the gut but also the skin. However, the effects of probiotics on ultraviolet (UV)-induced skin damage are poorly understood. In this study, we aim to examine whether oral administration of live Bifidobacterium breve strain Yakult (BBY), a typical probiotic, can attenuate skin barrier perturbation caused by UV and reactive oxygen species (ROS) in hairless mice. The mice were orally supplemented with a vehicle only or BBY once a day for nine successive days. Mouse dorsal skin was irradiated with UV from days 6 to 9. The day after the final irradiation, the transepidermal water loss (TEWL), stratum corneum hydration, and oxidation-related factors of the skin were evaluated. We elucidated that BBY prevented the UV-induced increase in TEWL and decrease in stratum corneum hydration. In addition, BBY significantly suppressed the UV-induced increase in hydrogen peroxide levels, oxidation of proteins and lipids, and xanthine oxidase activity in the skin. Conversely, antioxidant capacity did not change regardless of whether BBY was administered or not. In parameters we evaluated, there was a positive correlation between the increase in TEWL and the oxidation levels of proteins and lipids. Our results suggest that oral administration of BBY attenuates UV-induced barrier perturbation and oxidative stress of the skin, and this antioxidative effect is not attributed to enhancement of antioxidant capacity but to the prevention of ROS generation.

  11. Rutin improves spatial memory in Alzheimer's disease transgenic mice by reducing Aβ oligomer level and attenuating oxidative stress and neuroinflammation.

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    Xu, Peng-Xin; Wang, Shao-Wei; Yu, Xiao-Lin; Su, Ya-Jing; Wang, Teng; Zhou, Wei-Wei; Zhang, He; Wang, Yu-Jiong; Liu, Rui-Tian

    2014-05-01

    Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles in the brain. Aβ aggregation is closely associated with neurotoxicity, oxidative stress, and neuronal inflammation. The soluble Aβ oligomers are believed to be the most neurotoxic form among all forms of Aβ aggregates. We have previously reported a polyphenol compound rutin that could inhibit Aβ aggregation and cytotoxicity, attenuate oxidative stress, and decrease the production of nitric oxide and proinflammatory cytokines in vitro. In the current study, we investigated the effect of rutin on APPswe/PS1dE9 transgenic mice. Results demonstrated that orally administered rutin significantly attenuated memory deficits in AD transgenic mice, decreased oligomeric Aβ level, increased super oxide dismutase (SOD) activity and glutathione (GSH)/glutathione disulfide (GSSG) ratio, reduced GSSG and malondialdehyde (MDA) levels, downregulated microgliosis and astrocytosis, and decreased interleukin (IL)-1β and IL-6 levels in the brain. These results indicated that rutin is a promising agent for AD treatment because of its antioxidant, anti-inflammatory, and reducing Aβ oligomer activities. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Total Glucosides of Danggui Buxue Tang Attenuate BLM-Induced Pulmonary Fibrosis via Regulating Oxidative Stress by Inhibiting NOX4

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    Zhao, Ping; Zhou, Wen-Cheng; Li, De-Lin; Mo, Xiao-Ting; Xu, Liang; Li, Liu-Cheng; Cui, Wen-Hui; Gao, Jian

    2015-01-01

    Pulmonary fibrosis (PF) is a serious chronic lung disease with unknown pathogenesis. Researches have confirmed that oxidative stress which is regulated by NADPH oxidase-4 (NOX4), a main source of reactive oxygen species (ROS), is an important molecular mechanism underlying PF. Previous studies showed that total glucosides of Danggui Buxue Tang (DBTG), an extract from a classical traditional Chinese herbal formula, Danggui Buxue Tang (DBT), attenuated bleomycin-induced PF in rats. However, the mechanisms of DBTG are still not clear. We hypothesize that DBTG attenuates PF through regulating the level of oxidative stress by inhibiting NOX4. And we found that fibrosis indexes hydroxyproline (HYP) and type I collagen (Col-I) were lower in DBTG groups compared with the model group. In addition, the expression of transforming growth factor-β1 (TGF-β1) and expression of alpha smooth muscle actin (α-SMA) were also much more decreased than the model group. For oxidative stress indicators, DBTG blunted the decrease of superoxide dismutase (SOD) activity, total antioxidant capacity (T-AOC), and the increase in malondialdehyde (MDA), 8-iso-prostaglandin in lung homogenates. Treatment with DBTG restrained the expression of NOX4 compared to the model group. Present study confirms that DBTG inhibits BLM-induced PF by modulating the level of oxidative stress via suppressing NOX4. PMID:26347805

  13. Attenuation of oxidative stress and inflammation by gravinol in high glucose-exposed renal tubular epithelial cells

    International Nuclear Information System (INIS)

    Kim, You Jung; Kim, Young Ae; Yokozawa, Takako

    2010-01-01

    Gravinol, a proanthocyanidin from grape seeds, has polyphenolic properties with powerful anti-oxidative effects. Although, increasing evidence strongly suggests that polyphenolic antioxidants suppress diabetic nephropathy that is causally associated with oxidative stress and inflammation, gravinol's protective action against diabetic nephropathy has not been fully explored to date. In the current study, we investigated the protective action of gravinol against oxidative stress and inflammation using the experimental diabetic nephropathy cell model, high glucose-exposed renal tubular epithelial cells. To elucidate the underlying actions of gravinol, several oxidative and inflammatory markers were estimated. Included are measurements of lipid peroxidation, total reactive species (RS), superoxide (·O 2 ), nitric oxide (NO·), and peroxynitrite (ONOO - ), as well as nuclear factor-kappa B (NF-κB) nuclear translocation. Results indicate that gravinol had a potent inhibitory action against lipid peroxidation, total RS, ·O 2 , NO·, ONOO - , the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio and more importantly, against NF-κB nuclear translocation. We propose that gravinol's strong protective effect against high glucose-induced renal tubular epithelial cell damage attenuates diabetic nephropathy by suppressing oxidative stress and inflammation.

  14. Vanillin Attenuated Behavioural Impairments, Neurochemical Deficts, Oxidative Stress and Apoptosis Against Rotenone Induced Rat Model of Parkinson's Disease.

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    Dhanalakshmi, Chinnasamy; Janakiraman, Udaiyappan; Manivasagam, Thamilarasan; Justin Thenmozhi, Arokiasamy; Essa, Musthafa Mohamed; Kalandar, Ameer; Khan, Mohammed Abdul Sattar; Guillemin, Gilles J

    2016-08-01

    Vanillin (4-hydroxy-3-methoxybenzaldehyde), a pleasant smelling organic aromatic compound, is widely used as a flavoring additive in food, beverage, cosmetic and drug industries. It is reported to cross the blood brain barrier and also displayed antioxidant and neuroprotective activities. We previously reported the neuroprotective effect of vanillin against rotenone induced in in vitro model of PD. The present experiment was aimed to analyze the neuroprotective effect of vanillin on the motor and non-motor deficits, neurochemical variables, oxidative, anti-oxidative indices and the expression of apoptotic markers against rotenone induced rat model of Parkinson's disease (PD). Rotenone treatment exhibited motor and non-motor impairments, neurochemical deficits, oxidative stress and apoptosis, whereas oral administration of vanillin attenuated the above-said indices. However further studies are needed to explore the mitochondrial protective and anti-inflammatory properties of vanillin, as these processes play a vital role in the cause and progression of PD.

  15. Intravenous grafts of amniotic fluid-derived stem cells induce endogenous cell proliferation and attenuate behavioral deficits in ischemic stroke rats.

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    Naoki Tajiri

    Full Text Available We recently reported isolation of viable rat amniotic fluid-derived stem (AFS cells [1]. Here, we tested the therapeutic benefits of AFS cells in a rodent model of ischemic stroke. Adult male Sprague-Dawley rats received a 60-minute middle cerebral artery occlusion (MCAo. Thirty-five days later, animals exhibiting significant motor deficits received intravenous transplants of rat AFS cells or vehicle. At days 60-63 post-MCAo, significant recovery of motor and cognitive function was seen in stroke animals transplanted with AFS cells compared to vehicle-infused stroke animals. Infarct volume, as revealed by hematoxylin and eosin (H&E staining, was significantly reduced, coupled with significant increments in the cell proliferation marker, Ki67, and the neuronal marker, MAP2, in the dentate gyrus (DG [2] and the subventricular zone (SVZ of AFS cell-transplanted stroke animals compared to vehicle-infused stroke animals. A significantly higher number of double-labeled Ki67/MAP2-positive cells and a similar trend towards increased Ki67/MAP2 double-labeling were observed in the DG and SVZ of AFS cell-transplanted stroke animals, respectively, compared to vehicle-infused stroke animals. This study reports the therapeutic potential of AFS cell transplantation in stroke animals, possibly via enhancement of endogenous repair mechanisms.

  16. Minocycline attenuates both OGD-induced HMGB1 release and HMGB1-induced cell death in ischemic neuronal injury in PC12 cells

    Energy Technology Data Exchange (ETDEWEB)

    Kikuchi, Kiyoshi [Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Department of Neurosurgery, Omuta City General Hospital, 2-19-1 Takarazaka, Omuta-City, Fukuoka 836-8567 (Japan); Kawahara, Ko-ichi; Biswas, Kamal Krishna; Ito, Takashi [Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Tancharoen, Salunya [Department of Pharmacology, Faculty of Dentistry, Mahidol University, 6 Yothe Rd., Rajthevee Bangkok 10400 (Thailand); Morimoto, Yoko [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Matsuda, Fumiyo [Division of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8560 (Japan); Oyama, Yoko; Takenouchi, Kazunori [Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Miura, Naoki [Laboratory of Veterinary Diagnostic Imaging, Department of Veterinary Medicine, Faculty of Agriculture, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065 (Japan); Arimura, Noboru; Nawa, Yuko; Meng, Xiaojie; Shrestha, Binita; Arimura, Shinichiro [Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); and others

    2009-07-24

    High mobility group box-1 (HMGB1), a non-histone DNA-binding protein, is massively released into the extracellular space from neuronal cells after ischemic insult and exacerbates brain tissue damage in rats. Minocycline is a semisynthetic second-generation tetracycline antibiotic which has recently been shown to be a promising neuroprotective agent. In this study, we found that minocycline inhibited HMGB1 release in oxygen-glucose deprivation (OGD)-treated PC12 cells and triggered the activation of p38mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK1/2). The ERK kinase (MEK)1/2 inhibitor U-0126 and p38MAPK inhibitor SB203580 blocked HMGB1 release in response to OGD. Furthermore, HMGB1 triggered cell death in a dose-dependent fashion. Minocycline significantly rescued HMGB1-induced cell death in a dose-dependent manner. In light of recent observations as well as the good safety profile of minocycline in humans, we propose that minocycline might play a potent neuroprotective role through the inhibition of HMGB1-induced neuronal cell death in cerebral infarction.

  17. Minocycline attenuates both OGD-induced HMGB1 release and HMGB1-induced cell death in ischemic neuronal injury in PC12 cells

    International Nuclear Information System (INIS)

    Kikuchi, Kiyoshi; Kawahara, Ko-ichi; Biswas, Kamal Krishna; Ito, Takashi; Tancharoen, Salunya; Morimoto, Yoko; Matsuda, Fumiyo; Oyama, Yoko; Takenouchi, Kazunori; Miura, Naoki; Arimura, Noboru; Nawa, Yuko; Meng, Xiaojie; Shrestha, Binita; Arimura, Shinichiro

    2009-01-01

    High mobility group box-1 (HMGB1), a non-histone DNA-binding protein, is massively released into the extracellular space from neuronal cells after ischemic insult and exacerbates brain tissue damage in rats. Minocycline is a semisynthetic second-generation tetracycline antibiotic which has recently been shown to be a promising neuroprotective agent. In this study, we found that minocycline inhibited HMGB1 release in oxygen-glucose deprivation (OGD)-treated PC12 cells and triggered the activation of p38mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK1/2). The ERK kinase (MEK)1/2 inhibitor U-0126 and p38MAPK inhibitor SB203580 blocked HMGB1 release in response to OGD. Furthermore, HMGB1 triggered cell death in a dose-dependent fashion. Minocycline significantly rescued HMGB1-induced cell death in a dose-dependent manner. In light of recent observations as well as the good safety profile of minocycline in humans, we propose that minocycline might play a potent neuroprotective role through the inhibition of HMGB1-induced neuronal cell death in cerebral infarction.

  18. Tanshinol Attenuates the Deleterious Effects of Oxidative Stress on Osteoblastic Differentiation via Wnt/FoxO3a Signaling

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    Yajun Yang

    2013-01-01

    Full Text Available There is now increasing evidence which suggests a pivotal role for oxidative stress in the development and progression of osteoporosis. We confirm herein the protective effects of natural antioxidant Tanshinol against oxidative stress in osteoblastic differentiation and the underlying mechanism. Our results show that hydrogen peroxide (H2O2 leads to accumulation of reactive oxygen species (ROS, decrease in cell viability, cell cycle arrest and apoptosis in a caspase-3-dependent manner, and inhibition of osteoblastic differentiation. Tanshinol reverses these deleterious consequence triggered by oxidative stress. Moreover, under the condition of oxidative stress, Tanshinol suppresses the activation of FoxO3a transcription factor and expressions of its target genes Gadd45a and catalase (CAT and simultaneously counteracts the inhibition of Wnt signalling and expressions of target genes Axin2, alkaline phosphatase (ALP, and Osteoprotegerin (OPG. The findings are further consolidated using FoxO3a siRNA interference and overexpression of Tcf4. The results illustrate that Tanshinol attenuates oxidative stress via down-regulation of FoxO3a signaling, and rescues the decrease of osteoblastic differentiation through upregulation of Wnt signal under oxidative stress. The present findings suggest that the beneficial effects of Tanshinol may be adopted as a novel therapeutic approach in recently recognized conditions of niche targeting osteoporosis.

  19. Chronic infusion of lisinopril into hypothalamic paraventricular nucleus modulates cytokines and attenuates oxidative stress in rostral ventrolateral medulla in hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Li, Hong-Bao [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Ma, Le [Department of Public Health, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Miao, Yu-Wang [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Lu, Yan [Department of Clinical Laboratory, Sanaitang Hospital, Lanzhou 730030 (China); Song, Xin-Ai [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China)

    2014-09-01

    The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play a critical role in the generation and maintenance of sympathetic nerve activity. The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. This study was designed to determine whether inhibition of the angiotensin-converting enzyme (ACE) in the PVN modulates cytokines and attenuates oxidative stress (ROS) in the RVLM, and decreases the blood pressure and sympathetic activity in renovascular hypertensive rats. Renovascular hypertension was induced in male Sprague–Dawley rats by the two-kidney one-clip (2K1C) method. Renovascular hypertensive rats received bilateral PVN infusion with ACE inhibitor lisinopril (LSP, 10 μg/h) or vehicle via osmotic minipump for 4 weeks. Mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma proinflammatory cytokines (PICs) were significantly increased in renovascular hypertensive rats. The renovascular hypertensive rats also had higher levels of ACE in the PVN, and lower level of interleukin-10 (IL-10) in the RVLM. In addition, the levels of PICs, the chemokine MCP-1, the subunit of NAD(P)H oxidase (gp91{sup phox}) and ROS in the RVLM were increased in hypertensive rats. PVN treatment with LSP attenuated those changes occurring in renovascular hypertensive rats. Our findings suggest that the beneficial effects of ACE inhibition in the PVN in renovascular hypertension are partly due to modulation cytokines and attenuation oxidative stress in the RVLM. - Highlights: • Chronic ACE inhibition in PVN on renovascular hypertension was investigated. • 2K1C resulted in sympathoexcitation, increased plasma PICs and hypertension. • 2K1C rats had higher levels of cytokines and reactive oxygen species (ROS) in RVLM. • Chronic inhibiting PVN ACE attenuates cytokines and ROS in RVLM in hypertension.

  20. Chronic infusion of lisinopril into hypothalamic paraventricular nucleus modulates cytokines and attenuates oxidative stress in rostral ventrolateral medulla in hypertension

    International Nuclear Information System (INIS)

    Li, Hong-Bao; Qin, Da-Nian; Ma, Le; Miao, Yu-Wang; Zhang, Dong-Mei; Lu, Yan; Song, Xin-Ai; Zhu, Guo-Qing; Kang, Yu-Ming

    2014-01-01

    The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play a critical role in the generation and maintenance of sympathetic nerve activity. The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. This study was designed to determine whether inhibition of the angiotensin-converting enzyme (ACE) in the PVN modulates cytokines and attenuates oxidative stress (ROS) in the RVLM, and decreases the blood pressure and sympathetic activity in renovascular hypertensive rats. Renovascular hypertension was induced in male Sprague–Dawley rats by the two-kidney one-clip (2K1C) method. Renovascular hypertensive rats received bilateral PVN infusion with ACE inhibitor lisinopril (LSP, 10 μg/h) or vehicle via osmotic minipump for 4 weeks. Mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma proinflammatory cytokines (PICs) were significantly increased in renovascular hypertensive rats. The renovascular hypertensive rats also had higher levels of ACE in the PVN, and lower level of interleukin-10 (IL-10) in the RVLM. In addition, the levels of PICs, the chemokine MCP-1, the subunit of NAD(P)H oxidase (gp91 phox ) and ROS in the RVLM were increased in hypertensive rats. PVN treatment with LSP attenuated those changes occurring in renovascular hypertensive rats. Our findings suggest that the beneficial effects of ACE inhibition in the PVN in renovascular hypertension are partly due to modulation cytokines and attenuation oxidative stress in the RVLM. - Highlights: • Chronic ACE inhibition in PVN on renovascular hypertension was investigated. • 2K1C resulted in sympathoexcitation, increased plasma PICs and hypertension. • 2K1C rats had higher levels of cytokines and reactive oxygen species (ROS) in RVLM. • Chronic inhibiting PVN ACE attenuates cytokines and ROS in RVLM in hypertension

  1. Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease.

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    Hany H Arab

    Full Text Available Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD via its proinflammatory features. Telmisartan (TLM is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o. attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI, colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α, prostaglandin E2 (PGE2 and myeloperoxidase (MPO activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10. TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB p65 and mRNA of cyclo-oxygenase-2 (COX-2 and inducible nitric oxide synthase (iNOS proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO besides boosting glutathione (GSH, total anti-oxidant capacity (TAC and the activities of superoxide dismutase (SOD and glutathione peroxidase (GPx. With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.

  2. Opuntia ficus indica (nopal) attenuates hepatic steatosis and oxidative stress in obese Zucker (fa/fa) rats.

    Science.gov (United States)

    Morán-Ramos, Sofía; Avila-Nava, Azalia; Tovar, Armando R; Pedraza-Chaverri, José; López-Romero, Patricia; Torres, Nimbe

    2012-11-01

    Nonalcoholic fatty liver disease (NAFLD) is associated with multiple factors such as obesity, insulin resistance, and oxidative stress. Nopal, a cactus plant widely consumed in the Mexican diet, is considered a functional food because of its antioxidant activity and ability to improve biomarkers of metabolic syndrome. The aim of this study was to assess the effect of nopal consumption on the development of hepatic steatosis and hepatic oxidative stress and on the regulation of genes involved in hepatic lipid metabolism. Obese Zucker (fa/fa) rats were fed a control diet or a diet containing 4% nopal for 7 wk. Rats fed the nopal-containing diet had ∼50% lower hepatic TG than the control group as well as a reduction in hepatomegaly and biomarkers of hepatocyte injury such as alanine and aspartate aminotransferases. Attenuation of hepatic steatosis by nopal consumption was accompanied by a higher serum concentration of adiponectin and a greater abundance of mRNA for genes involved in lipid oxidation and lipid export and production of carnitine palmitoyltransferase-1 and microsomal TG transfer proteins in liver. Hepatic reactive oxygen species and lipid peroxidation biomarkers were significantly lower in rats fed nopal compared with the control rats. Furthermore, rats fed the nopal diet had a lower postprandial serum insulin concentration and a greater liver phosphorylated protein kinase B (pAKT):AKT ratio in the postprandial state. This study suggests that nopal consumption attenuates hepatic steatosis by increasing fatty acid oxidation and VLDL synthesis, decreasing oxidative stress, and improving liver insulin signaling in obese Zucker (fa/fa) rats.

  3. Sesame oil mitigates nutritional steatohepatitis via attenuation of oxidative stress and inflammation: a tale of two-hit hypothesis.

    Science.gov (United States)

    Periasamy, Srinivasan; Chien, Se-Ping; Chang, Po-Cheng; Hsu, Dur-Zong; Liu, Ming-Yie

    2014-02-01

    Nonalcoholic fatty liver disease, the most common chronic liver disorder worldwide, comprises conditions from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is associated with an increased risk of hepatocellular carcinoma. Sesame oil, a healthful food, increases resistance to oxidative stress, inflammation and protects against multiple organ injury in various animal models. We investigated the protective effect of sesame oil against nutritional steatohepatitis in mice. C57BL/6 J mice were fed with methionine-choline deficient (MCD) diet for 28 days to induce NASH. Sesame oil (1 and 2 ml/kg) was treated from 22nd to 28th day. Body weight, steatosis, triglycerides, aspartate transaminase, alanine transaminase, nitric oxide, malondialdehyde, tumor necrosis factor-α, interlukin-6, interleukin-1β, leptin, and transforming growth factor-β1 (TGF-β1) were assessed after 28 days. All tested parameters were higher in MCD-fed mice than in normal control mice. Mice fed with MCD diet for 4 weeks showed severe liver injury with steatosis, oxidative stress, and necrotic inflammation. In sesame-oil-treated mice, all tested parameters were significantly attenuated compared with MCD-alone mice. Sesame oil inhibited oxidative stress, inflammatory cytokines, leptin, and TGF-β1 in MCD-fed mice. In addition, histological analysis showed that sesame oil provided significant protection against fibrotic collagen. We conclude that sesame oil protects against steatohepatitic fibrosis by decreasing oxidative stress, inflammatory cytokines, leptin and TGF-β1. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Opioid Use Disorder Induces Oxidative Stress and Inflammation: The Attenuating Effect of Methadone Maintenance Treatment

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    Ali Salarian

    2018-02-01

    Full Text Available Objective: Frequent use of opioids produces reactive oxygen species, upregulates inflammatory factors, and contributes to opiate dependence. In this study, we examined perturbations of plasma oxidative and inflammatory markers in patients with opioid use disorder in two phases. In the first phase, we compared the oxidative status in patients with opioid use disorders and in healthy controls; and in the second phase, we examined oxidative changes before and after methadone maintenance treatment.Method: To explore whether oxidative changes were associated with opioid use disorder, we compared plasma oxidative and inflammatory markers in patients with opioid use disorder and in smoking and non-smoking healthy participants. All participants completed measures of catalase (CAT, glutathione (GSH, malondialdehyde (MDA, superoxide dismutase (SOD, matrix metalloproteinase (MMP-9, and TNF-α at baseline. Baseline measures were compared using Kruskal-Wallis test. In the second phase, to explore oxidative changes during transition from opium use to methadone, blood and urine samples of patients with opioid use disorder were re-evaluated on Days 3, 7, and 14 after methadone therapy. Repeated measures analysis was used to determine the relative contribution of intervention to changes in CAT, GSH, MDA, SOD, MMP-9, and TNF-α level over time.Results: We observed lower SOD and catalase activities, and higher TNF-α and MMP-9 level in patients compared to the two comparison groups. Opioids exacerbated the oxidative imbalance and superimposed the underlying oxidative injury in smoker comparison group. Methadone therapy was associated with lower MMP-9 and TNF-α level, and higher SOD and catalase activities two weeks after therapy; showing an improvement in oxidative profile.Conclusion: This was an investigation indicating an oxidative imbalance before methadone therapy and during early days of transition from opium use to methadone. Being aware of redox status is

  5. Shark Cartilage Attenuates Oxidative Stress in the liver of Guinea Pigs Exposed to Carbon Tetrachloride and/or Gamma Irradiation

    International Nuclear Information System (INIS)

    Ibrahim, N.K.; Abd El Aziz, N.

    2009-01-01

    There is overwhelming evidence to indicate that oxidative stress is involved in the pathogenesis of several diseases. Carbon tetrachloride (CCl 4 ) and ionizing radiations are environmental pollutants well known to induce free radicals formation and oxidative stress. The objective of this work was to evaluate the effect of shark cartilage administration on CCl 4 and/or gamma radiation-induced oxidative damage in the liver. CCl 4 (1 ml/kg body wt) was subcutaneously administered to guinea pigs twice a week for four weeks. Gamma irradiation (RAD) was applied by whole body exposure of guinea pigs to 1.0 Gy/week up to a total dose of 4.0 Gy. Shark cartilage (ShC) was given to animals at a concentration of 1.0 g/kg body wt daily, one week before exposure to CCl 4 and/or gamma irradiation and during the experimental period. Animals sacrificed at the end of the experimental period showed that administration of shark cartilage has significantly attenuated the increase in liver malonaldehyde (MDA) observed in CCl 4 and/or irradiated guinea pigs. Furthermore, shark cartilage treatment has significantly increased the activity of antioxidant enzymes: superoxide dismutase (SOD) and catalase (CAT) and the content of reduced glutathione (GSH). The amelioration of oxidative stress induced in liver tissues of CCL 4 and/or irradiated guinea pigs treated with shark cartilage was associated with significant improvement in the activity of serum alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP), as well as, bilirubin, albumin, and iron contents. It could be concluded that shark cartilage might protect liver tissues from oxidative injury induced by environmental pro-oxidants pollutants via modulating the antioxidant status and decreasing the process of lipid peroxidation

  6. Attenuation of Diabetic Nephropathy by Carvacrol through Anti-oxidative Effects in Alloxan-Induced Diabetic Rats

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    Hamid Reza Jamshidi

    2018-03-01

    Full Text Available Background and Objectives: Diabetes, a common metabolic disorder, is prevalent in many countries. Nephropathy is a main debate’s side effect. Role of oxidative stress is well known in induction of diabetic nephropathy while carvacrol is a potent anti-oxidant that might attenuate oxidative stress. The aim of this study was to explore the effect of carvacrol in decreasing nephropathy-induced oxidative damage in diabetic rats. Methods: Thirty five Wistar rats (200-250 g were divided to 7 groups. The rats received alloxan (i.p., 200 mg/kg for induction of diabetes. After one week, fasting blood sugar (FBS was assessed and the rats with FBS>250 mg/dL were considered as diabetic. Three weeks after alloxan injection, the blood urea (BUN and creatinine (Cr were determined for confirmation of inducing nephropathy. Then, the animals were treated with carvacrol for one week. Finally, they were anesthetized and blood was collected from animal’s heart for calculation of BUN and Cr. Furthermore, the kidneys were for oxidative stress markers such as glutathione capacity, protein carbonyl, lipid peroxidation and catalase activity. Results: Our results showed that glutathione level and catalase activity significantly increased after treatment with carvacrol. Same results were found in rats that received vitamin E. Also, lipid peroxidation, protein carbonyl content, BUN and Cr levels significantly decreased after treatment with carvacrol in comparison with diabetic rats. Conclusion: Our results showed that carvacrol improved nephropathy-induced oxidative damage similar to vitamin E. Therefore, it may be suggested that carvacrol can be suggested as a useful supplement in decreasing diabetic complaints along with anti-diabetic drugs.

  7. DHEA supplementation to dexamethasone-treated rabbits alleviates oxidative stress in kidney-cortex and attenuates albuminuria.

    Science.gov (United States)

    Kiersztan, Anna; Trojan, Nina; Tempes, Aleksandra; Nalepa, Paweł; Sitek, Joanna; Winiarska, Katarzyna; Usarek, Michał

    2017-11-01

    Our recent study has shown that dehydroepiandrosterone (DHEA) administered to rabbits partially ameliorated several dexamethasone (dexP) effects on hepatic and renal gluconeogenesis, insulin resistance and plasma lipid disorders. In the current investigation, we present the data on DHEA protective action against dexP-induced oxidative stress and albuminuria in rabbits. Four groups of adult male rabbits were used in the in vivo experiment: (1) control, (2) dexP-treated, (3) DHEA-treated and (4) both dexP- and DHEA-treated. Administration of dexP resulted in accelerated generation of renal hydroxyl free radicals (HFR) and malondialdehyde (MDA), accompanied by diminished superoxide dismutase (SOD) and catalase activities and a dramatic rise in urinary albumin/creatinine ratio. Treatment with DHEA markedly reduced dexP-induced oxidative stress in kidney-cortex due to a decline in NADPH oxidase activity and enhancement of catalase activity. Moreover, DHEA effectively attenuated dexP-evoked albuminuria. Surprisingly, dexP-treated rabbits exhibited elevation of GSH/GSSG ratio, accompanied by a decrease in glutathione peroxidase (GPx) and glutathione-S-transferase (GST) activities as well as an increase in glucose-6-phosphate dehydrogenase (G6PDH) activity. Treatment with DHEA resulted in a decline in GSH/GSSG ratio and glutathione reductase (GR) activity, accompanied by an elevation of GPx activity. Interestingly, rabbits treated with both dexP and DHEA remained the control values of GSH/GSSG ratio. As the co-administration of DHEA with dexP resulted in (i) reduction of oxidative stress in kidney-cortex, (ii) attenuation of albuminuria and (iii) normalization of glutathione redox state, DHEA might limit several undesirable renal side effects during chronic GC treatment of patients suffering from allergies, asthma, rheumatoid arthritis and lupus. Moreover, its supplementation might be particularly beneficial for the therapy of patients with glucocorticoid-induced diabetes

  8. Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes*

    Science.gov (United States)

    Collins, John A.; Wood, Scott T.; Nelson, Kimberly J.; Rowe, Meredith A.; Carlson, Cathy S.; Chubinskaya, Susan; Poole, Leslie B.; Furdui, Cristina M.; Loeser, Richard F.

    2016-01-01

    Oxidative stress-mediated post-translational modifications of redox-sensitive proteins are postulated as a key mechanism underlying age-related cellular dysfunction and disease progression. Peroxiredoxins (PRX) are critical intracellular antioxidants that also regulate redox signaling events. Age-related osteoarthritis is a common form of arthritis that has been associated with mitochondrial dysfunction and oxidative stress. The objective of this study was to determine the effect of aging and oxidative stress on chondrocyte intracellular signaling, with a specific focus on oxidation of cytosolic PRX2 and mitochondrial PRX3. Menadione was used as a model to induce cellular oxidative stress. Compared with chondrocytes isolated from young adult humans, chondrocytes from older adults exhibited higher levels of PRX1–3 hyperoxidation basally and under conditions of oxidative stress. Peroxiredoxin hyperoxidation was associated with inhibition of pro-survival Akt signaling and stimulation of pro-death p38 signaling. These changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) and in cartilage explants from MCAT transgenic mice. Peroxiredoxin hyperoxidation was observed in situ in human cartilage sections from older adults and in osteoarthritic cartilage. MCAT transgenic mice exhibited less age-related osteoarthritis. These findings demonstrate that age-related oxidative stress can disrupt normal physiological signaling and contribute to osteoarthritis and suggest peroxiredoxin hyperoxidation as a potential mechanism. PMID:26797130

  9. Treatment with glial derived neurotropic factor (GDNF attenuates oxidative damages of spinal

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    Tao Li

    2016-05-01

    Full Text Available Spinal cord injury (SCI is a serious and debilitating issue being suffered by wide population worldwide. Extensive treatment approaches have been tested and being verified for their efficacy. Owing to the nature of central nervous system (CNS, the resident stem cells would be triggered in response to any sort of trauma with nerve factors as their communication signals. Apart from physical injuries, damages due to oxidative stress also need to be addressed while CNS repair mechanism takes place. This study looks at the potential of glial derived nerve factor (GDNF in addressing the SCI in regard to oxidative damages. A total of 60 Wistar rats were clustered into five groups and GDNF at various concentrations was tested in each group. Assessments in terms of oxidative stress parameters were noted and analyzed accordingly. It was noted that GDNF had reduced oxidative damages and increased the levels of anti-oxidants in dose-dependent manner (p < 0.05. Though treatment with 10 mg/mL and 20 mg/mL showed significant changes as compared to control group, these treatment modalities remained insignificant among each other. In conclusion, we demonstrated that GDNF exerted a neuro-protective effect on CNS by inducing anti-oxidants and reducing the levels of oxidative stress in SCI induced rat models.

  10. Low-density lipoprotein subfraction, carotid artery intima-media thickness, nitric oxide, and tumor necrosis factor alpha are associated with newly diagnosed ischemic stroke

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    Medine Cumhur Cure

    2013-01-01

    Full Text Available Objectives: Small dense (sd low-density lipoprotein (LDL, tumor necrosis factor (TNF alpha (a, and nitric oxide (NO have recently emerged as important stroke risk factors. The aim of the study was to investigate the effects of increased levels of small LDL particle size, TNF-a and NO on the developed ischemic stroke and increased carotid artery intima-media thickness (CIMT. Materials and Methods: A total of 29 women and 25 men (a total of 54 ischemic stroke patients and a similar age group of 50 controls (29 females and 21 males were included in the study. CIMT, C-reactive protein (CRP, TNF-a, NO, and lipid subfraction test of the two groups were measured. Results: The mean LDL particle size was smaller in patients with stroke than in the controls (26.8 ± 0.31 nm vs. 27.0 ± 0.31 nm, P = 0.003. sd-LDL, TNF-a, NO, CRP, right CIMT, and left CIMT were higher in patients with stroke than in the controls (respectively; 8.2 ± 7.8 mg/dL vs. 3.3 ± 3.5 mg/dL, P < 0.001;75.6 ± 25.0 pg/mL vs. 65.4 ± 9.1 pg/mL, P = 0.009;76.4 ± 53.3 mmol/L vs. 41.5 ± 27.0 mmol/L, P < 0.001;1.9 ± 2.6 mm vs. 0.4 ± 0.3 mm P < 0.001;0.97 ± 0.38 mm vs. 0.83 ± 0.15 mm, P = 0.007;1.04 ± 0.44 mm vs. 0.87 ± 0.19 mm, P = 0.010. Conclusion: These results show that sd-LDL is independently associated with the incidence of stroke and may be a risk factor in the development of stroke. In addition, TNF-a, NO, right CIMT, and left CIMT may be a risk factor in the development of ischemic stroke.

  11. Cluster Differentiating 36 (CD36) Deficiency Attenuates Obesity-Associated Oxidative Stress in the Heart.

    Science.gov (United States)

    Gharib, Mohamed; Tao, Huan; Fungwe, Thomas V; Hajri, Tahar

    2016-01-01

    Obesity is often associated with a state of oxidative stress and increased lipid deposition in the heart. More importantly, obesity increases lipid influx into the heart and induces excessive production of reactive oxygen species (ROS) leading to cell toxicity and metabolic dysfunction. Cluster differentiating 36 (CD36) protein is highly expressed in the heart and regulates lipid utilization but its role in obesity-associated oxidative stress is still not clear. The aim of this study was to determine the impact of CD36 deficiency on cardiac steatosis, oxidative stress and lipotoxicity associated with obesity. Studies were conducted in control (Lean), obese leptin-deficient (Lepob/ob) and leptin-CD36 double null (Lepob/obCD36-/-) mice. Compared to lean mice, cardiac steatosis, and fatty acid (FA) uptake and oxidation were increased in Lepob/ob mice, while glucose uptake and oxidation was reduced. Moreover, insulin resistance, oxidative stress markers and NADPH oxidase-dependent ROS production were markedly enhanced. This was associated with the induction of NADPH oxidase expression, and increased membrane-associated p47phox, p67phox and protein kinase C. Silencing CD36 in Lepob/ob mice prevented cardiac steatosis, increased insulin sensitivity and glucose utilization, but reduced FA uptake and oxidation. Moreover, CD36 deficiency reduced NADPH oxidase activity and decreased NADPH oxidase-dependent ROS production. In isolated cardiomyocytes, CD36 deficiency reduced palmitate-induced ROS production and normalized NADPH oxidase activity. CD36 deficiency prevented obesity-associated cardiac steatosis and insulin resistance, and reduced NADPH oxidase-dependent ROS production. The study demonstrates that CD36 regulates NADPH oxidase activity and mediates FA-induced oxidative stress.

  12. Treadmill Exercise Attenuates Retinal Oxidative Stress in Naturally-Aged Mice: An Immunohistochemical Study

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    Chan-Sik Kim

    2015-09-01

    Full Text Available In the retina, a number of degenerative diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration, may occur as a result of aging. Oxidative damage is believed to contribute to the pathogenesis of aging as well as to age-related retinal disease. Although physiological exercise has been shown to reduce oxidative stress in rats and mice, it is not known whether it has a similar effect in retinal tissues. The aim of this study was to evaluate retinal oxidative stress in naturally-aged mice. In addition, we evaluated the effects of aerobic training on retinal oxidative stress by immunohistochemically evaluating oxidative stress markers. A group of twelve-week-old male mice were not exercised (young control. Two groups of twenty-two-month-old male mice were created: an old control group and a treadmill exercise group. The old control group mice were not exercised. The treadmill exercise group mice ran on a treadmill (5 to 12 m/min, 30 to 60 min/day, 3 days/week for 12 weeks. The retinal thickness and number of cells in the ganglion cell layer of the naturally-aged mice were reduced compared to those in the young control mice. However, treadmill exercise reversed these morphological changes in the retinas. We evaluated retinal expression of carboxymethyllysine (CML, 8-hydroxy-2′-deoxyguanosine (8-OHdG and nitrotyrosine. The retinas from the aged mice showed increased CML, 8-OHdG, and nitrotyrosine immunostaining intensities compared to young control mice. The exercise group exhibited significantly lower CML levels and nitro-oxidative stress than the old control group. These results suggest that regular exercise can reduce retinal oxidative stress and that physiological exercise may be distinctly advantageous in reducing retinal oxidative stress.

  13. Attenuation of phosphamidon-induced oxidative stress and immune dysfunction in rats treated with N-acetylcysteine

    Directory of Open Access Journals (Sweden)

    S.G. Suke

    2008-09-01

    Full Text Available The effect of N-acetylcysteine, a thiolic antioxidant, on attenuation of phosphamidon-induced oxidative stress and immune dysfunction was evaluated in adult male Wistar rats weighing 200-250 g. Rats were divided into four groups, 8 animals/group, and treated with phosphamidon, N-acetylcysteine or the combination of both for 28 days. Oral administration of phosphamidon (1.74 mg/kg, an organophosphate insecticide, increased serum malondialdehyde (3.83 ± 0.18 vs 2.91 ± 0.24 nmol/mL; P < 0.05 and decreased erythrocyte superoxide dismutase (567.8 ± 24.36 vs 749.16 ± 102.61 U/gHb; P < 0.05, catalase activity (1.86 ± 0.18 vs 2.43 ± 0.08 U/gHb; P < 0.05 and whole blood glutathione levels (1.25 ± 0.21 vs 2.28 ± 0.08 mg/gHb; P < 0.05 showing phosphamidon-induced oxidative stress. Phosphamidon exposure markedly suppressed humoral immune response as assessed by antibody titer to ovalbumin (4.71 ± 0.51 vs 8.00 ± 0.12 -log2; P < 0.05, and cell-mediated immune response as assessed by leukocyte migration inhibition (25.24 ± 1.04 vs 70.8 ± 1.09%; P < 0.05 and macrophage migration inhibition (20.38 ± 0.99 vs 67.16 ± 5.30%; P < 0.05 response. Phosphamidon exposure decreased IFN-у levels (40.7 ± 3.21 vs 55.84 ± 3.02 pg/mL; P < 0.05 suggesting a profound effect of phosphamidon on cell-mediated immune response. A phosphamidon-induced increase in TNF-α level (64.19 ± 6.0 vs 23.16 ± 4.0 pg/mL; P < 0.05 suggests a contributory role of immunocytes in oxidative stress. Co-administration of N-acetylcysteine (3.5 mmol/kg, orally with phosphamidon attenuated the adverse effects of phosphamidon. These findings suggest that oral N-acetylcysteine treatment exerts protective effect and attenuates free radical injury and immune dysfunction caused by subchronic phosphamidon exposure.

  14. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Malaviya, Rama; Venosa, Alessandro [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Hall, LeRoy [Drug Safety Sciences, Johnson and Johnson, Raritan, NJ 08869 (United States); Gow, Andrew J. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sinko, Patrick J. [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, 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)

    2012-12-15

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute

  15. Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress.

    Science.gov (United States)

    Yang, Ting; Zhang, Xing-Mei; Tarnawski, Laura; Peleli, Maria; Zhuge, Zhengbing; Terrando, Niccolo; Harris, Robert A; Olofsson, Peder S; Larsson, Erik; Persson, A Erik G; Lundberg, Jon O; Weitzberg, Eddie; Carlstrom, Mattias

    2017-10-01

    Ischemia-reperfusion (IR) injury involves complex pathological processes in which reduction of nitric oxide (NO) bioavailability is suggested as a key factor. Inorganic nitrate can form NO in vivo via NO synthase-independent pathways and may thus provide beneficial effects during IR. Herein we evaluated the effects of dietary nitrate supplementation in a renal IR model. Male mice (C57BL/6J) were fed nitrate-supplemented chow (1.0mmol/kg/day) or standard chow for two weeks prior to 30min ischemia and during the reperfusion period. Unilateral renal IR caused profound tubular and glomerular damage in the ischemic kidney. Renal function, assessed by plasma creatinine levels, glomerular filtration rate and renal plasma flow, was also impaired after IR. All these pathologies were significantly improved by nitrate. Mechanistically, nitrate treatment reduced renal superoxide generation, pro-inflammatory cytokines (IL-1β, IL-6 and IL-12 p70) and macrophage infiltration in the kidney. Moreover, nitrate reduced mRNA expression of pro-inflammatory cytokines and chemo attractors, while increasing anti-inflammatory cytokines in the injured kidney. In another cohort of mice, two weeks of nitrate supplementation lowered superoxide generation and IL-6 expression in bone marrow-derived macrophages. Our study demonstrates protective effect of dietary nitrate in renal IR injury that may be mediated via modulation of oxidative stress and inflammatory responses. These novel findings suggest that nitrate supplementation deserve further exploration as a potential treatment in patients at high risk of renal IR injury. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  16. In vivo toxicity of copper oxide, lead oxide and zinc oxide nanoparticles acting in different combinations and its attenuation with a complex of innocuous bio-protectors.

    Science.gov (United States)

    Minigalieva, Ilzira A; Katsnelson, Boris A; Panov, Vladimir G; Privalova, Larisa I; Varaksin, Anatoly N; Gurvich, Vladimir B; Sutunkova, Marina P; Shur, Vladimir Ya; Shishkina, Ekaterina V; Valamina, Irene E; Zubarev, Ilya V; Makeyev, Oleg H; Meshtcheryakova, Ekaterina Y; Klinova, Svetlana V

    2017-04-01

    Stable suspensions of metal oxide nanoparticles (Me-NPs) obtained by laser ablation of 99.99% pure copper, zinc or lead under a layer of deionized water were used separately, in three binary combinations and a triple combination in two independent experiments on rats. In one of the experiments the rats were instilled with Me-NPs intratracheally (i.t.) (for performing a broncho-alveolar lavage in 24h to estimate the cytological and biochemical indices of the response of the lower airways), while in the other, Me-NPs were repeatedly injected intraperitoneally (i.p.) 18 times during 6 weeks (for estimating the accumulation of corresponding metals in the blood and their excretion with urine and feces and for assessing subchronic intoxication by a large number of functional and morphological indices). Mathematical description of the results from both experiments with the help of the Response Surface Methodology has shown that, as well as in the case of any other binary toxic combinations previously investigated by us, the response of the organism to a simultaneous exposure to any two of the Me-NPs under study is characterized by complex interactions between all possible types of combined toxicity (additivity, subadditivity or superadditivity of unidirectional action and different variants of opposite effects) depending on which effect it is estimated for as well as on the levels of the effect and dose. With any third Me-NP species acting in the background, the type of combined toxicity displayed by the other two may change significantly (as in the earlier described case of a triple combination of soluble metal salts). It is shown that various harmful effects produced by CuO-NP+ZnO-NP+PbO-NP combination may be substantially attenuated by giving rats per os a complex of innocuous bioactive substances theoretically expected to provide a protective integral and/or metal-specific effect during one month before i.t. instillation or during the entire period of i.p. injections

  17. Antenatal betamethasone attenuates the angiotensin-(1-7)-Mas receptor-nitric oxide axis in isolated proximal tubule cells.

    Science.gov (United States)

    Su, Yixin; Bi, Jianli; Pulgar, Victor M; Chappell, Mark C; Rose, James C

    2017-06-01

    We previously reported a sex-specific effect of antenatal treatment with betamethasone (Beta) on sodium (Na + ) excretion in adult sheep whereby treated males but not females had an attenuated natriuretic response to angiotensin-(1-7) [Ang-(1-7)]. The present study determined the Na + uptake and nitric oxide (NO) response to low-dose Ang-(1-7) (1 pM) in renal proximal tubule cells (RPTC) from adult male and female sheep antenatally exposed to Beta or vehicle. Data were expressed as percentage of basal uptake or area under the curve for Na + or percentage of control for NO. Male Beta RPTC exhibited greater Na + uptake than male vehicle cells (433 ± 28 vs. 330 ± 26%; P 0.05). Ang-(1-7) significantly inhibited Na + uptake in RPTC from vehicle male (214 ± 11%) and from both vehicle (190 ± 14%) and Beta (209 ± 11%) females but failed to attenuate Na + uptake in Beta male cells. Beta exposure also abolished stimulation of NO by Ang-(1-7) in male but not female RPTC. Both the Na + and NO responses to Ang-(1-7) were blocked by Mas receptor antagonist d-Ala 7 -Ang-(1-7). We conclude that the tubular Ang-(1-7)-Mas-NO pathway is attenuated in males and not females by antenatal Beta exposure. Moreover, since primary cultures of RPTC retain both the sex and Beta-induced phenotype of the adult kidney in vivo they appear to be an appropriate cell model to examine the effects of fetal programming on Na + handling by the renal tubules. Copyright © 2017 the American Physiological Society.

  18. Gamma-ray mass attenuation coefficient and half value layer factor of some oxide glass shielding materials

    International Nuclear Information System (INIS)

    Waly, El-Sayed A.; Fusco, Michael A.; Bourham, Mohamed A.

    2016-01-01

    The variation in dosimetric parameters such as mass attenuation coefficient, half value layer factor, exposure buildup factor, and the photon mean free path for different oxide glasses for the incident gamma energy range 0.015–15 MeV has been studied using MicroShield code. It has been inferred that the addition of PbO and Bi 2 O 3 improves the gamma ray shielding properties. Thus, the effect of chemical composition on these parameters is investigated in the form of six different glass compositions, which are compared with specialty concrete for nuclear radiation shielding. The composition termed ‘Glass 6’ in this paper has the highest mass attenuation and the smallest half value layer and may have potential applications in radiation shielding. An example dry storage cask utilizing an additional layer of Glass 6 as an intermediate shielding layer, simulated in MicroShield, is capable of reducing the exposure rate at the cask surface by over 20 orders of magnitude compared to the case without a glass layer. Based on this study, Glass 6 shows promise as a gamma-ray shielding material, particularly for dry cask storage.

  19. Impaired mitochondrial function in chronically ischemic human heart

    DEFF Research Database (Denmark)

    Stride, Nis Ottesen; Larsen, Steen; Hey-Mogensen, Martin

    2013-01-01

    , and finally to assess myocardial antioxidant levels. Mitochondrial respiration in biopsies from ischemic and nonischemic regions from the left ventricle of the same heart was compared in nine human subjects. Maximal oxidative phosphorylation capacity in fresh muscle fibers was lower in ischemic compared.......05), and the levels of antioxidant protein expression was lower. Diminished mitochondrial respiration capacity and excessive ROS production demonstrate an impaired mitochondrial function in ischemic human heart muscle. No chronic ischemic preconditioning effect was found....

  20. H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation

    Directory of Open Access Journals (Sweden)

    Hong-Xia Zhang

    2016-12-01

    Full Text Available Background: Hydrogen sulfide (H2S, known as the third endogenous gaseous transmitter, has received increasing attention because of its diverse effects, including angiogenesis, vascular relaxation and myocardial protection.We aimed to investigate the role of H2S in oxidative/nitrative stress and inflammation in acute lung injury (ALI induced by endotoxemia. Methods: Male ICR mice were divided in six groups: (1 Control group; (2 GYY4137treatment group; (3 L-NAME treatment group; (4 lipopolysaccharide (LPS treatment group; (5 LPS with GYY4137 treatment group; and (6 LPS with L-NAME treatment group. The lungs were analysed by histology, NO production in the mouse lungs determined by modified Griess (Sigma-Aldrich reaction, cytokine levels utilizing commercialkits, and protein abundance by Western blotting. Results: GYY4137, a slowly-releasing H2S donor, improved the histopathological changes in the lungs of endotoxemic mice. Treatment with NG-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase (NOS inhibitor, increased anti-oxidant biomarkers such as thetotal antioxidant capacity (T-AOC and theactivities of catalase (CAT and superoxide dismutase (SOD but decreased a marker of peroxynitrite (ONOO- action and 3-nitrotyrosine (3-NT in endotoxemic lung. L-NAME administration also suppressed inflammation in endotoxemic lung, as evidenced by the decreased pulmonary levels of interleukin (IL-6, IL-8, and myeloperoxidase (MPO and the increased level of anti-inflammatory cytokine IL-10. GYY4137 treatment reversed endotoxin-induced oxidative/nitrative stress, as evidenced by a decrease in malondialdehyde (MDA, hydrogenperoxide (H2O2 and 3-NT and an increase in the antioxidant biomarker ratio of reduced/oxidized glutathione(GSH/GSSG ratio and T-AOC, CAT and SOD activity. GYY4137 also attenuated endotoxin-induced lung inflammation. Moreover, treatment with GYY4137 inhibited inducible NOS (iNOS expression and nitric oxide (NO production in the

  1. Maltol, a Food Flavoring Agent, Attenuates Acute Alcohol-Induced Oxidative Damage in Mice

    Directory of Open Access Journals (Sweden)

    Ye Han

    2015-01-01

    Full Text Available The purpose of this study was to evaluate the hepatoprotective effect of maltol, a food-flavoring agent, on alcohol-induced acute oxidative damage in mice. Maltol used in this study was isolated from red ginseng (Panax ginseng C.A Meyer and analyzed by high performance liquid chromatography (HPLC and mass spectrometry. For hepatoprotective activity in vivo, pretreatment with maltol (12.5, 25 and 50 mg/kg; 15 days drastically prevented the elevated activities of aspartate transaminase (AST, alanine transaminase (ALT, alkaline phosphatase (ALP and triglyceride (TG in serum and the levels of malondialdehyde (MDA, tumor necrosis factor-α (TNF-α, interleukin-1β (IL-1β in liver tissue (p < 0.05. Meanwhile, the levels of hepatic antioxidant, such as catalase (CAT, superoxide dismutase (SOD, glutathione peroxidase (GSH-Px were elevated by maltol pretreatment, compared to the alcohol group (p < 0.05. Histopathological examination revealed that maltol pretreatment significantly inhibited alcohol-induced hepatocyte apoptosis and fatty degeneration. Interestingly, pretreatment of maltol effectively relieved alcohol-induced oxidative damage in a dose-dependent manner. Maltol appeared to possess promising anti-oxidative and anti-inflammatory capacities. It was suggested that the hepatoprotective effect exhibited by maltol on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.

  2. Piroxicam attenuates 3-nitropropionic acid-induced brain oxidative stress and behavioral alteration in mice.

    Science.gov (United States)

    C, Jadiswami; H M, Megha; Dhadde, Shivsharan B; Durg, Sharanbasappa; Potadar, Pandharinath P; B S, Thippeswamy; V P, Veerapur

    2014-12-01

    3-Nitropropionic acid (3-NP) is a fungal toxin that produces Huntington's disease like symptoms in both animals and humans. Piroxicam, a non-selective cyclooxygenase (COX) inhibitor, used as anti-inflammatory agent and also known to decrease free oxygen radical production. In this study, the effect of piroxicam was evaluated against 3-NP-induced brain oxidative stress and behavioral alteration in mice. Adult male Swiss albino mice were injected with vehicle/piroxicam (10 and 20 mg/kg, i.p.) 30 min before 3-NP challenge (15 mg/kg, i.p.) regularly for 14 days. Body weights of the mice were measured on alternative days of the experiment. At the end of the treatment schedule, mice were evaluated for behavioral alterations (movement analysis, locomotor test, beam walking test and hanging wire test) and brain homogenates were used for the estimation of oxidative stress markers (lipid peroxidation, reduced glutathione and catalase). Administration of 3-NP significantly altered the behavioral activities and brain antioxidant status in mice. Piroxicam, at both the tested doses, caused a significant reversal of 3-NP-induced behavioral alterations and oxidative stress in mice. These findings suggest piroxicam protects the mice against 3-NP-induced brain oxidative stress and behavioral alteration. The antioxidant properties of piroxicam may be responsible for the observed beneficial actions.

  3. Attenuation of Oxidative Damage by Boerhaavia diffusa L. Against Different Neurotoxic Agents in Rat Brain Homogenate.

    Science.gov (United States)

    Ayyappan, Prathapan; Palayyan, Salin Raj; Kozhiparambil Gopalan, Raghu

    2016-01-01

    Due to a high rate of oxidative metabolic activity in the brain, intense production of reactive oxygen metabolite occurs, and the subsequent generation of free radicals is implicated in the pathogenesis of traumatic brain injury, epilepsy, and ischemia as well as chronic neurodegenerative diseases. In the present study, protective effects of polyphenol rich ethanolic extract of Boerhaavia diffusa (BDE), a neuroprotective edible medicinal plant against oxidative stress induced by different neurotoxic agents, were evaluated. BDE was tested against quinolinic acid (QA), 3-nitropropionic acid (NPA), sodium nitroprusside (SNP), and Fe (II)/EDTA complex induced oxidative stress in rat brain homogenates. QA, NPA, SNP, and Fe (II)/EDTA treatment caused an increased level of thiobarbituric acid reactive substances (TBARS) in brain homogenates along with a decline in the activities of antioxidant enzymes. BDE treatment significantly decreased the production of TBARS (p cerebral cortex. Inhibitory potential of BDE against deoxyribose degradation (IC50 value 38.91 ± 0.12 μg/ml) shows that BDE can protect hydroxyl radical induced DNA damage in the tissues. Therefore, B. diffusa had high antioxidant potential that could inhibit the oxidative stress induced by different neurotoxic agents in brain. Since many of the neurological disorders are associated with free radical injury, these data may imply that B. diffusa, functioning as an antioxidant agent, may be beneficial for reducing various neurodegenerative complications.

  4. L-arginine increases nitric oxide and attenuates pressor and heart ...

    African Journals Online (AJOL)

    olayemitoyin

    heart rate responses to change in posture in sickle cell anemia subjects. 1 .... the standing position and measurements made immediately. Arterial ... pressure was the difference between systolic and diastolic ... Table 3. Effect of L-Arginine Supplementation on Blood Pressure Parameters, Plasma L-Arginine and Nitric Oxide.

  5. Astaxanthin Attenuates Homocysteine-Induced Cardiotoxicity in Vitro and in Vivo by Inhibiting Mitochondrial Dysfunction and Oxidative Damage

    Directory of Open Access Journals (Sweden)

    Cun-dong Fan

    2017-12-01

    Full Text Available Homocysteine (Hcy as an independent risk factor contributes to the occurrence and development of human cardiovascular diseases (CVD. Induction of oxidative stress and apoptosis was commonly accepted as the major mechanism in Hcy-induced cardiotoxicity. Astaxanthin (ATX as one of the most powerful antioxidants exhibits novel cardioprotective potential against Hcy-induced endothelial dysfunction. However, the protective effect and mechanism of ATX against Hcy-induced cardiotoxicity in cardiomyocytes have not been elucidated yet. Herein, H9c2 rat cardiomyocytes and Hcy-injured animal model were employed in the present study. The MTT, flow cytometry analysis (FCM, TUNEL-DAPI and western blotting results all demonstrated that ATX significantly alleviated Hcy-induced cytotoxicity in H9c2 cells through inhibition of mitochondria-mediated apoptosis. The JC-1 and Mito-tracker staining both revealed that ATX pre-treatment blocked Hcy-induced mitochondrial dysfunction by regulating Bcl-2 family expression. Moreover, DCFH-DA and Mito-SOX staining showed that ATX effectively attenuated Hcy-induced oxidative damage via scavenging intracellular reactive oxygen species (ROS. Importantly, the ELISA and immunohistochemical results indicated that Hcy-induced cardiotoxicity in vivo was also significantly inhibited by ATX through inhibition of oxidative damage and apoptosis, and improvement of the angiogenesis. Taken together, our results demonstrated that ATX suppressed Hcy-induced cardiotoxicity in vitro and in vivo by inhibiting mitochondrial dysfunction and oxidative damage. Our findings validated the strategy of using ATX may be a highly efficient way to combat Hcy-mediated human CVD.

  6. Astaxanthin Attenuates Homocysteine-Induced Cardiotoxicity in Vitro and in Vivo by Inhibiting Mitochondrial Dysfunction and Oxidative Damage.

    Science.gov (United States)

    Fan, Cun-Dong; Sun, Jing-Yi; Fu, Xiao-Ting; Hou, Ya-Jun; Li, Yuan; Yang, Ming-Feng; Fu, Xiao-Yan; Sun, Bao-Liang

    2017-01-01

    Homocysteine (Hcy) as an independent risk factor contributes to the occurrence and development of human cardiovascular diseases (CVD). Induction of oxidative stress and apoptosis was commonly accepted as the major mechanism in Hcy-induced cardiotoxicity. Astaxanthin (ATX) as one of the most powerful antioxidants exhibits novel cardioprotective potential against Hcy-induced endothelial dysfunction. However, the protective effect and mechanism of ATX against Hcy-induced cardiotoxicity in cardiomyocytes have not been elucidated yet. Herein, H9c2 rat cardiomyocytes and Hcy-injured animal model were employed in the present study. The MTT, flow cytometry analysis (FCM), TUNEL-DAPI and western blotting results all demonstrated that ATX significantly alleviated Hcy-induced cytotoxicity in H9c2 cells through inhibition of mitochondria-mediated apoptosis. The JC-1 and Mito-tracker staining both revealed that ATX pre-treatment blocked Hcy-induced mitochondrial dysfunction by regulating Bcl-2 family expression. Moreover, DCFH-DA and Mito-SOX staining showed that ATX effectively attenuated Hcy-induced oxidative damage via scavenging intracellular reactive oxygen species (ROS). Importantly, the ELISA and immunohistochemical results indicated that Hcy-induced cardiotoxicity in vivo was also significantly inhibited by ATX through inhibition of oxidative damage and apoptosis, and improvement of the angiogenesis. Taken together, our results demonstrated that ATX suppressed Hcy-induced cardiotoxicity in vitro and in vivo by inhibiting mitochondrial dysfunction and oxidative damage. Our findings validated the strategy of using ATX may be a highly efficient way to combat Hcy-mediated human CVD.

  7. D-Methionine attenuated cisplatin-induced vestibulotoxicity through altering ATPase activities and oxidative stress in guinea pigs

    International Nuclear Information System (INIS)

    Cheng, P.-W.; Liu, S.-H.; Young, Y.-H.; Lin-Shiau, Shoei-Yn

    2006-01-01

    Cisplatin has been used as a chemotherapeutic agent to treat many kinds of malignancies. Its damage to the vestibulo-ocular reflex (VOR) system has been reported. However, the underlying biochemical change in the inner ear or central vestibular nervous system is not fully understood. In this study, we attempted to examine whether cisplatin-induced vestibulotoxicity and D-methionine protection were correlated with the changes of ATPase activities and oxidative stress of ampullary tissue of vestibules as well as cerebellar cortex (the inhibitory center of VOR system) of guinea pigs. By means of a caloric test coupled with electronystagmographic recordings, we found that cisplatin exposure caused a dose-dependent (1, 3, or 5 mg/kg) vestibular dysfunction as revealed by a decrease of slow phase velocity (SPV). In addition, cisplatin significantly inhibited the Na + , K + -ATPase and Ca 2+ -ATPase activities in the ampullary tissue with a good dose-response relationship but not those of cerebellar cortex. Regression analysis indicated that a decrease of SPV was well correlated with the reduction of Na + , K + -ATPase and Ca 2+ -ATPase activities of the ampullary tissue. D-Methionine (300 mg/kg) reduced both abnormalities of SPV and ATPase activities in a correlated manner. Moreover, cisplatin exposure led to a significant dose-dependent increase of lipid peroxidation and nitric oxide concentrations of the vestibules, which could be significantly suppressed by D-methionine. However, cisplatin did not alter the levels of lipid peroxidation and nitric oxide of the cerebellum. In conclusion, cisplatin inhibited ATPase activities and increased oxidative stress in guinea pig vestibular labyrinths. D-Methionine attenuated cisplatin-induced vestibulotoxicity associated with ionic disturbance through its antioxidative property

  8. Virgin coconut oil supplementation attenuates acute chemotherapy hepatotoxicity induced by anticancer drug methotrexate via inhibition of oxidative stress in rats.

    Science.gov (United States)

    Famurewa, Ademola C; Ufebe, Odomero G; Egedigwe, Chima A; Nwankwo, Onyebuchi E; Obaje, Godwin S

    2017-03-01

    The emerging health benefit of virgin coconut oil (VCO) has been associated with its potent natural antioxidants; however, the antioxidant and hepatoprotective effect of VCO against methotrexate-induced liver damage and oxidative stress remains unexplored. The study explored the antioxidant and hepatoprotective effects of VCO against oxidative stress and liver damage induced by anticancer drug methotrexate (MTX) in rats. Liver damage was induced in Wistar rats pretreated with dietary supplementation of VCO (5% and 15%) by intraperitoneal administration of MTX (20mg/kg bw) on day 10 only. After 12days of treatment, assays for serum liver biomarkers (aminotransferases), alkaline phosphatase, albumin and total protein as well as hepatic content of malondialdehyde, reduced glutathione and antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were carried out. Liver was used to examine histopathological changes. MTX administration induced significant increase in serum liver enzymes along with marked decrease in albumin and total protein compared to control group. Hepatic activities of antioxidant enzymes were significantly decreased, while malondialdehyde increased significantly. Treatment with VCO supplemented diet prior to MTX administration attenuated MTX-induced liver injury and oxidative stress evidenced by significant improvements in serum liver markers, hepatic antioxidant enzymes and malondialdehyde comparable to control group. Histopathological alterations were prevented and correlated well with the biochemical indices. The study suggests antioxidant and hepatoprotective effects of VCO supplementation against hepatotoxicity and oxidative damage via improving antioxidant defense system in rats. Our findings may have beneficial application in the management of hepatotoxicity associated with MTX cancer chemotherapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors.

    Science.gov (United States)

    Cunha, Andréia S; Matheus, Filipe C; Moretti, Morgana; Sampaio, Tuane B; Poli, Anicleto; Santos, Danúbia B; Colle, Dirleise; Cunha, Mauricio P; Blum-Silva, Carlos H; Sandjo, Louis P; Reginatto, Flávio H; Rodrigues, Ana Lúcia S; Farina, Marcelo; Prediger, Rui D

    2016-10-01

    Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice

  10. Attenuation of Oxidative Stress and Inflammation by Portulaca oleracea in Streptozotocin-Induced Diabetic Rats.

    Science.gov (United States)

    Samarghandian, Saeed; Borji, Abasalt; Farkhondeh, Tahereh

    2017-10-01

    The present study was designed to investigate the protective effect of the aqueous extract of Portulaca oleracea against hyperglycemic, oxidative damage and inflammation in the serum of streptozotocin (STZ)-induced diabetic rats. In the present study, the rats were divided into the following groups of 8 animals each: control, untreated diabetic, 3 Portulaca oleracea (100, 200, 400 mg/kg/d)-treated diabetic groups. At the end of the 4-week period, glucose, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), glutathione (GSH), and total antioxidant status (TAS) levels were measured. STZ caused an elevation in the serum levels of glucose, MDA, IL-6, and TNF-α with reduction in the levels of GSH and TAS ( P Portulaca oleracea ameliorated glucose, MDA, IL-6, TNF-α, GSH, and TAS levels in diabetic groups versus to the untreated groups ( P Portulaca oleracea prevented hyperglycemia by preventing the oxidative stress and inflammation.

  11. Nilotinib counteracts thioacetamide-induced hepatic oxidative stress and attenuates liver fibrosis progression.

    Science.gov (United States)

    Shaker, Mohamed E; Salem, Hatem A; Shiha, Gamal E; Ibrahim, Tarek M

    2011-04-01

    The aim of this study was to evaluate and compare the effects of imatinib and nilotinib to that of silymarin on established liver fibrosis and oxidative stress in a thioacetamide (TAA) rat model. Male Wistar rats received intraperitoneal (i.p.) injections of TAA (150mg/kg, twice weekly) for 12weeks. Daily treatments with imatinib (10mg/kg), nilotinib (10mg/kg), and silymarin (100mg/kg) were administered orally during the last 4weeks of TAA-administration. At the end of the study, hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis. Hepatic oxidative stress was assessed by measuring malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), total nitrate/nitrite (NOx), and reduced glutathione (GSH) contents, as well as myeloperoxidase (MPO) and superoxide dismutase (SOD) activities. Nilotinib, silymarin and, to a lesser extent, imatinib treatments ameliorated TAA-induced hepatic oxidative stress and damage as indicated by hepatic MDA, 4-HNE, NOx, GSH, MPO and SOD levels, as well as liver function tests. Hepatic histopathology results revealed that nilotinib, imatinib, and silymarin treatments decreased the mean score of fibrosis in TAA-treated rats by 24, 14, and 3%, respectively. However, nilotinib and silymarin, but not imatinib, treatments decreased hepatic collagen content in TAA-treated rats by 17 and 36%, respectively. In conclusion, we demonstrated for the first time that nilotinib not only protected against hepatic oxidative stress, but also slowed down liver fibrosis progression. Thus, we provide the first evidence that nilotinib might be a promising anti-fibrotic drug. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

  12. Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage

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    Jie Deng

    2018-04-01

    Full Text Available Oxidative DNA damage in bone marrow cells is the main side effect of chemotherapy drugs including cyclophosphamide (CTX. However, not all antioxidants are effective in inhibiting oxidative DNA damage. In this study, we report the beneficial effect of carnosine (β-alanyl-l-histidine, a special antioxidant with acrolein-sequestering ability, on CTX-induced bone marrow cell suppression. Our results show that carnosine treatment (100 and 200 mg/kg, i.p. significantly inhibited the generation of reactive oxygen species (ROS and 8-hydroxy-2′-deoxyguanosine (8-oxo-dG, and decreased chromosomal abnormalities in the bone marrow cells of mice treated with CTX (20 mg/kg, i.v., 24 h. Furthermore, carnosine evidently mitigated CTX-induced G2/M arrest in murine bone marrow cells, accompanied by reduced ratios of p-Chk1/Chk1 and p-p53/p53 as well as decreased p21 expression. In addition, cell apoptosis caused by CTX was also suppressed by carnosine treatment, as assessed by decreased TUNEL-positive cell counts, down-regulated expressions of Bax and Cyt c, and reduced ratios of cleaved Caspase-3/Caspase-3. These results together suggest that carnosine can protect murine bone marrow cells from CTX-induced DNA damage via its antioxidant activity. Keywords: Carnosine, Cyclophosphamide, Oxidative DNA damage, Sister chromatid exchange, Apoptosis, Cell cycle arrest

  13. Quercetin Attenuates Vascular Calcification through Suppressed Oxidative Stress in Adenine-Induced Chronic Renal Failure Rats.

    Science.gov (United States)

    Chang, Xue-Ying; Cui, Lei; Wang, Xing-Zhi; Zhang, Lei; Zhu, Dan; Zhou, Xiao-Rong; Hao, Li-Rong

    2017-01-01

    This study investigated whether quercetin could alleviate vascular calcification in experimental chronic renal failure rats induced by adenine. 32 adult male Wistar rats were randomly divided into 4 groups fed normal diet, normal diet with quercetin supplementation (25 mg/kg·BW/d), 0.75% adenine diet, or adenine diet with quercetin supplementation. All rats were sacrificed after 6 weeks of intervention. Serum renal functions biomarkers and oxidative stress biomarkers were measured and status of vascular calcification in aorta was assessed. Furthermore, the induced nitric oxide synthase (iNOS)/p38 mitogen activated protein kinase (p38MAPK) pathway was determined to explore the potential mechanism. Adenine successfully induced renal failure and vascular calcification in rat model. Quercetin supplementation reversed unfavorable changes of phosphorous, uric acid (UA) and creatinine levels, malonaldehyde (MDA) content, and superoxide dismutase (SOD) activity in serum and the increases of calcium and alkaline phosphatase (ALP) activity in the aorta ( P chronic renal failure rats, possibly through the modulation of oxidative stress and iNOs/p38MAPK pathway.

  14. Quercetin Attenuates Vascular Calcification through Suppressed Oxidative Stress in Adenine-Induced Chronic Renal Failure Rats

    Science.gov (United States)

    Chang, Xue-ying; Cui, Lei; Wang, Xing-zhi; Zhang, Lei; Zhu, Dan

    2017-01-01

    Background This study investigated whether quercetin could alleviate vascular calcification in experimental chronic renal failure rats induced by adenine. Methods 32 adult male Wistar rats were randomly divided into 4 groups fed normal diet, normal diet with quercetin supplementation (25 mg/kg·BW/d), 0.75% adenine diet, or adenine diet with quercetin supplementation. All rats were sacrificed after 6 weeks of intervention. Serum renal functions biomarkers and oxidative stress biomarkers were measured and status of vascular calcification in aorta was assessed. Furthermore, the induced nitric oxide synthase (iNOS)/p38 mitogen activated protein kinase (p38MAPK) pathway was determined to explore the potential mechanism. Results Adenine successfully induced renal failure and vascular calcification in rat model. Quercetin supplementation reversed unfavorable changes of phosphorous, uric acid (UA) and creatinine levels, malonaldehyde (MDA) content, and superoxide dismutase (SOD) activity in serum and the increases of calcium and alkaline phosphatase (ALP) activity in the aorta (P chronic renal failure rats, possibly through the modulation of oxidative stress and iNOs/p38MAPK pathway. PMID:28691026

  15. Natriuretic peptide receptor-C activation attenuates angiotensin II-induced enhanced oxidative stress and hyperproliferation of aortic vascular smooth muscle cells.

    Science.gov (United States)

    Madiraju, Padma; Hossain, Ekhtear; Anand-Srivastava, Madhu B

    2018-02-07

    We showed previously that natriuretic peptide receptor-C (NPR-C) agonist, C-ANP 4-23 , attenuated the enhanced expression of Giα proteins in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) through the inhibition of enhanced oxidative stress. Since the enhanced levels of endogenous angiotensin II (Ang II) contribute to the overexpression of Giα proteins and augmented oxidative stress in VSMC from SHR, the present study was undertaken to investigate if C-ANP 4-23 could also attenuate angiotensin II (Ang II)-induced oxidative stress and associated signaling. Ang II treatment of aortic VSMC augmented the levels of superoxide anion (O 2 - ), NADPH oxidase activity, and the expression of NADPH oxidase subunits and C-ANP 4-23 treatment attenuated all these to control levels. In addition, Ang II-induced enhanced levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyl content were also attenuated toward control levels by C-ANP 4-23 treatment. On the other hand, Ang II inhibited the levels of nitric oxide (NO) and augmented the levels of peroxynitrite (OONO - ) in VSMC which were restored to control levels by C-ANP 4-23 treatment. Furthermore, C-ANP 4-23 treatment attenuated Ang II-induced enhanced expression of Giα proteins, phosphorylation of p38, JNK, and ERK 1,2 as well as hyperproliferation of VSMC as determined by DNA synthesis, and metabolic activity. These results indicate that C-ANP 4-23 , via the activation of NPR-C, attenuates Ang II-induced enhanced nitroxidative stress, overexpression of Giα proteins, increased activation of the p38/JNK/ERK 1,2 signaling pathways, and hyperproliferation of VSMC. It may be suggested that C-ANP 4-23 could be used as a therapeutic agent in the treatment of vascular remodeling associated with hypertension and atherosclerosis.

  16. The aqueous extract of Albizia adianthifolia leaves attenuates 6-hydroxydopamine-induced anxiety, depression and oxidative stress in rat amygdala.

    Science.gov (United States)

    Beppe, Galba Jean; Dongmo, Alain Bertrand; Foyet, Harquin Simplice; Dimo, Théophile; Mihasan, Marius; Hritcu, Lucian

    2015-10-19

    While the Albizia adianthifolia (Schumach.) W. Wright (Fabaceae) is a traditional herb largely used in the African traditional medicine as analgesic, purgative, antiinflammatory, antioxidant, antimicrobial, memory-enhancer, anxiolytic and antidepressant drug, there are no scientific data that clarify the anxiolytic and antidepressant-like effects in 6-hydroxydopamine (6-OHDA)-lesioned animal model of Parkinson's disease. This study was undertaken in order to identify the effects of aqueous extract of A. adianthifolia leaves on 6-hydroxydopamine-induced anxiety, depression and oxidative stress in the rat amygdala. The effect of the aqueous extract of A. adianthifolia leaves (150 and 300 mg/kg, orally, daily, for 21 days) on anxiety and depression was assessed using elevated plus-maze and forced swimming tests, as animal models of anxiety and depression. Also, the antioxidant activity in the rat amygdala was assessed using assessed using superoxide dismutase, glutathione peroxidase and catalase specific activities, the total content of the reduced glutathione, protein carbonyl and malondialdehyde levels. Statistical analyses were performed using by one-way analysis of variance (ANOVA). Significant differences were determined by Tukey's post hoc test. F values for which p amygdala. Our results suggest that the aqueous extract ameliorates 6-OHDA-induced anxiety and depression by attenuation of the oxidative stress in the rat amygdala. These pieces of evidence accentuate its use in traditional medicine.

  17. Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases

    International Nuclear Information System (INIS)

    Huang, T.-Y.; Chu, H.-C.; Lin, Y.-L.; Lin, C.-K.; Hsieh, T.-Y.; Chang, W.-K.; Chao, Y.-C.; Liao, C.-L.

    2009-01-01

    In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases.

  18. Heme oxygenase-2 gene deletion attenuates oxidative stress in neurons exposed to extracellular hemin

    Directory of Open Access Journals (Sweden)

    Benvenisti-Zarom Luna

    2004-09-01

    Full Text Available Abstract Background Hemin, the oxidized form of heme, accumulates in intracranial hematomas and is a potent oxidant. Growing evidence suggests that it contributes to delayed injury to surrounding tissue, and that this process is affected by the heme oxygenase enzymes. In a prior study, heme oxygenase-2 gene deletion increased the vulnerability of cultured cortical astrocytes to hemin. The present study tested the effect of HO-2 gene deletion on protein oxidation, reactive oxygen species formation, and cell viability after mixed cortical neuron/astrocyte cultures were incubated with neurotoxic concentrations of hemin. Results Continuous exposure of wild-type cultures to 1–10 μM hemin for 14 h produced concentration-dependent neuronal death, as detected by both LDH release and fluorescence intensity after propidium iodide staining, with an EC50 of 1–2 μM; astrocytes were not injured by these low hemin concentrations. Cell death was consistently reduced by at least 60% in knockout cultures. Exposure to hemin for 4 hours, a time point that preceded cell lysis, increased protein oxidation in wild-type cultures, as detected by staining of immunoblots for protein carbonyl groups. At 10 μM hemin, carbonylation was increased 2.3-fold compared with control sister cultures subjected to medium exchanges only; this effect was reduced by about two-thirds in knockout cultures. Cellular reactive oxygen species, detected by fluorescence intensity after dihydrorhodamine 123 (DHR staining, was markedly increased by hemin in wild-type cultures and was localized to neuronal cell bodies and processes. In contrast, DHR fluorescence intensity in knockout cultures did not differ from that of sham-washed controls. Neuronal death in wild-type cultures was almost completely prevented by the lipid-soluble iron chelator phenanthroline; deferoxamine had a weaker but significant effect. Conclusions These results suggest that HO-2 gene deletion protects neurons in mixed

  19. The expression of endothelial and inducible nitric oxide synthase and apoptosis in intestinal ischemia and reperfusion injury under the action of ischemic preconditioning and pentoxifylline.

    Science.gov (United States)

    Oliveira, Teresinha Regina Ribeiro de; Oliveira, Geraldo Ferreira de; Simões, Ricardo Santos; Feitosa, Suellen Maurim; Tikazawa, Eduardo Hiroshi; Monteiro, Hugo Pequeno; Fagundes, Djalma José; Taha, Murched Omar

    2017-11-01

    To investigate the expression of nitric oxide synthase (NOS) and apoptosis associated with ischemic preconditioning (IPC) and pentoxifylline (PTX) in intestinal ischemia (I) and reperfusion (R) injury. Thirty male rats were assigned to 5 groups: (CG), no clamping of the superior mesenteric artery (90 minutes); (IR-SS) saline + ischemia (30 minutes) + reperfusion (60 minutes); (IR-PTX) PTX + ischemia (30 minutes) + reperfusion (60 minutes); (IPC-IR-SS) 5 minutes of ischemia + 5 minutes of reperfusion (IPC) + saline + I(30 minutes)+R(60 minutes); and (IPC-IR-PTX) IPC + PTX + I(30 minutes)+ R(60 minutes). The application of IPC and PTX showed a significantly lower immunohistochemistry reaction for active caspase-3 (P0.05). The NOS-2 expression (qRTPCR) in the IR-PTX group (P<0.05) was higher than the values for the IPC+IR-SS and IPC-IR-PTX groups. The NOS-3 expression was significantly upper in the IPC-IR-PTX group than in the CG (P<0.05), the IR-SS (P<0.05) and the IR-PTX (P<0.05) groups. The BCL-2 and active caspase-3 showed beneficial effects on PTX and IPC. The expression of NOS-2 and NOS-3 in the IPC and IPC-PTX groups showed no synergistic effect.

  20. Interactions of silica nanoparticles with therapeutics for oxidative stress attenuation in neurons

    Science.gov (United States)

    White-Schenk, Desiree; Shi, Riyi; Leary, James F.

    2015-03-01

    Oxidative stress plays a major role in many disease pathologies, notably in the central nervous system (CNS). For instance, after initial spinal cord injury, the injury site tends to increase during a secondary chemical injury process based on oxidative stress from necrotic cells and the inflammatory response. Prevention of this secondary chemical injury would represent a major advance in the treatment of people with spinal cord injuries. Few therapeutics are useful in combating such stress in the CNS due to side effects, low efficacy, or half-life. Mesoporous silica nanoparticles show promise for delivering therapeutics based on the formation of a porous network during synthesis. Ideally, they increase the circulation time of loaded therapeutics to increase the half-life while reducing overall concentrations to avoid side effects. The current study explored the use of silica nanoparticles for therapeutic delivery of anti-oxidants, in particular, the neutralization of acrolein which can lead to extensive tissue damage due to its ability to generate more and more copies of itself when it interacts with normal tissue. Both an FDA-approved therapeutic, hydralazine, and natural product, epigallocatechin gallate, were explored as antioxidants for acrolein with nanoparticles for increased efficacy and stability in neuronal cell cultures. Not only were the nanoparticles explored in neuronal cells, but also in a co-cultured in vitro model with microglial cells to study potential immune responses to near-infrared (NIRF)-labeled nanoparticles and uptake. Studies included nanoparticle toxicity, uptake, and therapeutic response using fluorescence-based techniques with both dormant and activated immune microglia co-cultured with neuronal cells.

  1. Diphenylmethyl selenocyanate attenuates malachite green induced oxidative injury through antioxidation & inhibition of DNA damage in mice

    Science.gov (United States)

    Das, Jayanta Kumar; Sarkar, Sibani; Hossain, Sk Ugir; Chakraborty, Pramita; Das, Rajat Kumar; Bhattacharya, Sudin

    2013-01-01

    Background & objectives: Malachite green (MG), an environmentally hazardous material, is used as a non permitted food colouring agent, especially in India. Selenium (Se) is an essential nutritional trace element required for animals and humans to guard against oxidative stress induced by xenobiotic compounds of diverse nature. In the present study, the role of the selenium compound diphenylmethyl selenocyanate (DMSE) was assessed on the oxidative stress (OS) induced by a food colouring agent, malachite green (MG) in vivo in mice. Methods: Swiss albino mice (Mus musculus) were intraperitoneally injected with MG at a standardized dose of 100 μg/ mouse for 30 days. DMSE was given orally at an optimum dose of 3 mg/kg b.w. in pre (15 days) and concomitant treatment schedule throughout the experimental period. The parameters viz. ALT, AST, LPO, GSH, GST, SOD, CAT, GPx, TrxR, CA, MN, MI and DNA damage have been evaluated. Results: The DMSE showed its potential to protect against MG induced hepatotoxicity by controlling the serum alanine aminotransferase and aspartate amino transferase (ALT and AST) levels and also ameliorated oxidative stress by modulating hepatic lipid peroxidation and different detoxifying and antioxidative enzymes such as glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and also the selenoenzymes such as glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) and reduced glutathione level which in turn reduced DNA damage. Interpretation & conclusions: The organo-selenium compound DMSE showed significant protection against MG induced heptotoxicity and DNA damage in murine model. Better protection was observed in pretreatment group than in the concomitant group. Further studies need to be done to understand the mechanism of action. PMID:23852297

  2. Oleuropein attenuates cognitive dysfunction and oxidative stress induced by some anesthetic drugs in the hippocampal area of rats.

    Science.gov (United States)

    Alirezaei, Masoud; Rezaei, Maryam; Hajighahramani, Shahin; Sookhtehzari, Ali; Kiani, Katayoun

    2017-01-01

    The present study was designed to evaluate the antioxidant effects of oleuropein against oxidative stress in the hippocampal area of rats. We used seven experimental groups as follows: Control, Propofol, Propofol-Ketamine (Pro.-Ket.), Xylazine-Ketamine (Xyl.-Ket.), and three oleuropein-pretreated groups (Ole.-Pro., Ole.-Pro.-Ket. and Ole.-Xyl.-Ket.). The oleuropein-pretreated groups received oleuropein (15 mg/kg body weight as orally) for 10 consecutive days. Propofol 100 mg/kg, xylazine 3 mg/kg, and ketamine 75 mg/kg once as ip was used on the 11th day of treatment. Spatial memory impairment and antioxidant status of hippocampus were measured via Morris water maze, lipid peroxidation marker, and antioxidant enzyme activities. Spatial memory impairment and lipid peroxidation significantly increased in Xyl.-Ket.-treated rats in comparison to the control, propofol, Ole.-Pro. and Ole.-Pro.-Ket. groups. Oleuropein pretreatment significantly reversed spatial memory impairment and lipid peroxidation in the Ole.-Xyl.-Ket. group as compared to the Xyl.-Ket.-treated rats. There was no significant difference between the control and the propofol group in lipid peroxidation and spatial memory status. Superoxide dismutase and catalase activities both significantly decreased in Xyl.-Ket.-treated rats when compared to the control, propofol, Ole.-Pro., Ole.-Pro.-Ket., and Ole.-Xyl.-Ket. groups. In contrast, glutathione peroxidase activity in Xyl.-Ket.-treated rats significantly increased as compared to the control, propofol, Pro.-Ket., Ole.-Pro., and Ole.-Pro.-Ket. groups. We concluded that xylazine in combination with ketamine is an oxidative anesthetic drug and oleuropein pretreatment attenuates cognitive dysfunction and oxidative stress induced by anesthesia in the hippocampal area of rats. We also confirmed the antioxidant properties of propofol as a promising antioxidant anesthetic agent.

  3. Protocatechuic aldehyde attenuates cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation

    Directory of Open Access Journals (Sweden)

    Li Gao

    2016-12-01

    Full Text Available Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress and programmed cell death of renal tubular epithelial cells. All of which lead to higher mortality rates in patients. In this study we examined the protective effect of protocatechuic aldehyde (PA in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza. Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA largely blocked cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients with cisplatin treatment.

  4. Attenuation of Ca2+ homeostasis, oxidative stress, and mitochondrial dysfunctions in diabetic rat heart: insulin therapy or aerobic exercise?

    Science.gov (United States)

    da Silva, Márcia F; Natali, Antônio J; da Silva, Edson; Gomes, Gilton J; Teodoro, Bruno G; Cunha, Daise N Q; Drummond, Lucas R; Drummond, Filipe R; Moura, Anselmo G; Belfort, Felipe G; de Oliveira, Alessandro; Maldonado, Izabel R S C; Alberici, Luciane C

    2015-07-15

    We tested the effects of swimming training and insulin therapy, either alone or in combination, on the intracellular calcium ([Ca(2+)]i) homeostasis, oxidative stress, and mitochondrial functions in diabetic rat hearts. Male Wistar rats were separated into control, diabetic, or diabetic plus insulin groups. Type 1 diabetes mellitus was induced by streptozotocin (STZ). Insulin-treated groups received 1 to 4 UI of insulin daily for 8 wk. Each group was divided into sedentary or exercised rats. Trained groups were submitted to swimming (90 min/day, 5 days/wk, 8 wk). [Ca(2+)]i transient in left ventricular myocytes (LVM), oxidative stress in LV tissue, and mitochondrial functions in the heart were assessed. Diabetes reduced the amplitude and prolonged the times to peak and to half decay of the [Ca(2+)]i transient in LVM, increased NADPH oxidase-4 (Nox-4) expression, decreased superoxide dismutase (SOD), and increased carbonyl protein contents in LV tissue. In isolated mitochondria, diabetes increased Ca(2+) uptake, susceptibility to permeability transition pore (MPTP) opening, uncoupling protein-2 (UCP-2) expression, and oxygen consumption but reduced H2O2 release. Swimming training corrected the time course of the [Ca(2+)]i transient, UCP-2 expression, and mitochondrial Ca(2+) uptake. Insulin replacement further normalized [Ca(2+)]i transient amplitude, Nox-4 expression, and carbonyl content. Alongside these benefits, the combination of both therapies restored the LV tissue SOD and mitochondrial O2 consumption, H2O2 release, and MPTP opening. In conclusion, the combination of swimming training with insulin replacement was more effective in attenuating intracellular Ca(2+) disruptions, oxidative stress, and mitochondrial dysfunctions in STZ-induced diabetic rat hearts. Copyright © 2015 the American Physiological Society.

  5. Renal denervation attenuates NADPH oxidase-mediated oxidative stress and hypertension in rats with hydronephrosis

    DEFF Research Database (Denmark)

    Peleli, Maria; Al-Mashhadi, Ammar; Yang, Ting

    2016-01-01

    Hydronephrosis is associated with development of salt-sensitive hypertension. Studies suggest that increased sympathetic nerve activity (SNA) and oxidative stress play important roles in renovascular hypertension. This study aimed to investigate the link between renal SNA and NADPH oxidase (NOX......) regulation in the development of hypertension in rats with hydronephrosis. Hydronephrosis was induced by partial unilateral ureteral obstruction (PUUO) in young rats. Sham surgery or renal denervation was performed at the same time. Blood pressure was measured during normal, high and low salt diets. Renal...

  6. Antioxidants Attenuate Oxidative Stress-Induced Hidden Blood Loss in Rats

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    Hong Qian

    2017-12-01

    Full Text Available Objective: Hidden blood loss (HBL, commonly seen after total knee or hip arthroplasty, causes postoperative anemia even after reinfusion or blood transfusion based on the visible blood loss volume. Recent studies demonstrated that oxidative stress might be involved in HBL. However, whether the antioxidants proanthocyanidin (PA or hydrogen water (HW can ameliorate HBL remains poorly understood. The aim of this study was to evaluate the effects of PA and HW on HBL. Materials and Methods: A rat HBL model was established through administration of linoleic acid with or without treatment with PA or HW. The levels of hemoglobin (Hb, red blood cell (RBC count, superoxide dismutase (SOD activity, glutathione peroxidase (GSH-PX activity, malondialdehyde (MDA, and ferryl Hb were measured. Results: RBC and Hb values as well as the activity of SOD and GSH-PX were reduced after administration of linoleic acid, which was ameliorated by treatment with PA or HW. In addition, the quantity of MDA was significantly decreased with the administration of PA or HW. Conclusion: PA and HW could ameliorate HBL in a rat model by reducing oxidative stress, suggesting that they might be used as a novel therapeutic approach in the prophylaxis or treatment of HBL in clinics.

  7. Attenuation of CCl4-Induced Oxidative Stress and Hepatonephrotoxicity by Saudi Sidr Honey in Rats

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    Mohammed Al-Yahya

    2013-01-01

    Full Text Available The present study was undertaken to investigate the possible protective effect of Saudi Sidr honey (SSH on carbon tetrachloride (CCl4 induced oxidative stress and liver and kidney damage in rat. Moreover, the antioxidant activity and the phenolic and flavonoidal contents were determined. The hepatorenal protective activity of the SSH was determined by assessing biochemical, hematological, and histological parameters. Serum transaminases, ALP, GGT, creatinine, bilirubin urea, uric acid, and MDA level in liver and kidney tissues were significantly elevated, and the antioxidant status of nonprotein sulfhydryls, albumin, and total protein levels in liver and kidney were declined significantly in CCl4 alone treated animals. Pretreatment with SSH and silymarin prior to the administration of CCl4 significantly prevented the increase of the serum levels of enzyme markers and reduced oxidative stress. SSH also exhibited a significant lipid-lowering effect and caused an HDL-C enhanced level in serum. The histopathological evaluation of the liver and kidney also revealed that honey protected incidence of both liver and kidney lesions. Moreover, SSH showed a strong antioxidant activity in DPPH and β-carotene-linoleic acid assays. SSH was found to contain phenolic compounds. Additionally, the SSH supplementation restored the hepatocytes viability against 2′,7′-dichlorofluorescein (DCF toxicity in ex vivo test.

  8. Diphenyl diselenide attenuates oxidative stress and inflammatory parameters in ulcerative colitis: A comparison with ebselen.

    Science.gov (United States)

    Petronilho, Fabricia; Michels, Monique; Danielski, Lucinéia G; Goldim, Mariana Pereira; Florentino, Drielly; Vieira, Andriele; Mendonça, Mariana G; Tournier, Moema; Piacentini, Bárbara; Giustina, Amanda Della; Leffa, Daniela D; Pereira, Gregório W; Pereira, Volnei D; Rocha, João Batista Teixeira Da

    2016-09-01

    The aim of this study was to evaluate the effects of diphenyl diselenide (PhSe)2 and ebselen (EB) in ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in rats. The effects of (PhSe)2 and EB in rats submitted to DSS-induced colitis were determined by measurement of oxidative stress parameters, inflammatory response and bowel histopathological alterations. Animals developed moderate to severe neutrophil infiltration in histopathology assay in DSS rats and (PhSe)2 improved this response. Moreover, the treatment with (PhSe)2 decreased the oxidative damage in lipids and proteins, as well as reversed the superoxide dismutase (SOD) and catalase (CAT) levels in rats treated with DSS. EB was able only to reverse damage in lipids and the low levels of SOD in this animal model. The organoselenium compounds tested demonstrated an anti-inflammatory and antioxidant activity reducing the colon damage, being (PhSe)2 more effective than EB. Copyright © 2016 Elsevier GmbH. All rights reserved.

  9. Silybum marianum oil attenuates oxidative stress and ameliorates mitochondrial dysfunction in mice treated with D-galactose

    Science.gov (United States)

    Zhu, Shu Yun; Dong, Ying; Tu, Jie; Zhou, Yue; Zhou, Xing Hua; Xu, Bin

    2014-01-01

    Background: Silybum marianum has been used as herbal medicine for the treatment of liver disease, liver cirrhosis, and to prevent liver cancer in Europe and Asia since ancient times. Silybum marianum oil (SMO), a by-product of silymarin production, is rich in essential fatty acids, phospholipids, sterols, and vitamin E. However, it has not been very good development and use. Objective: In the present study, we used olive oil as a control to investigate the antioxidant and anti-aging effect of SMO in D-galactose (D-gal)-induced aging mice. Materials and Methods: D-gal was injected intraperitoneally (500 mg/kg body weight daily) for 7 weeks while SMO was simultaneously administered orally. The triglycerides (TRIG) and cholesterol (CHOL) levels were estimated in the serum. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), monoamine oxidase (MAO), malondialdehyde (MDA), caspase-3, and Bcl-2 were determined in the liver and brain. The activities of Na+-K+-adenosine triphosphatase (ATPase), Ca2+-Mg2+-ATPase, membrane potential (ΔΨm), and membrane fluidity of the liver mitochondrial were estimated. Results: SMO decreased levels of TRIG and CHOL in aging mice. SMO administration elevated the activities of SOD, GSH-Px, and T-AOC, which are suppressed by aging. The levels of MAO and MDA in the liver and brain were reduced by SMO administration in aging mice. Enzyme linked immunosorbent assay showed that SMO significantly decreased the concentration of caspase-3 and improved the activity of Bcl-2 in the liver and brain of aging mice. Furthermore, SMO significantly attenuated the D-gal induced liver mitochondrial dysfunction by improving the activities of Na+-K+-ATPase, Ca2+-Mg2+-ATPase, membrane potential (ΔΨm), and membrane fluidity. Conclusion: These results indicate that SMO effectively attenuated oxidative damage and improved apoptosis related factors as well as liver mitochondrial dysfunction in aging mice. PMID:24914315

  10. A blueberry-enriched diet attenuates nephropathy in a rat model of hypertension via reduction in oxidative stress.

    Directory of Open Access Journals (Sweden)

    Carrie M Elks

    Full Text Available To assess renoprotective effects of a blueberry-enriched diet in a rat model of hypertension. Oxidative stress (OS appears to be involved in the development of hypertension and related renal injury. Pharmacological antioxidants can attenuate hypertension and hypertension-induced renal injury; however, attention has shifted recently to the therapeutic potential of natural products as antioxidants. Blueberries (BB have among the highest antioxidant capacities of fruits and vegetables.Male spontaneously hypertensive rats received a BB-enriched diet (2% w/w or an isocaloric control diet for 6 or 12 weeks or 2 days. Compared to controls, rats fed BB-enriched diet for 6 or 12 weeks exhibited lower blood pressure, improved glomerular filtration rate, and decreased renovascular resistance. As measured by electron paramagnetic resonance spectroscopy, significant decreases in total reactive oxygen species (ROS, peroxynitrite, and superoxide production rates were observed in kidney tissues in rats on long-term dietary treatment, consistent with reduced pathology and improved function. Additionally, measures of antioxidant status improved; specifically, renal glutathione and catalase activities increased markedly. Contrasted to these observations indicating reduced OS in the BB group after long-term feeding, similar measurements made in rats fed the same diet for only 2 days yielded evidence of increased OS; specifically, significant increases in total ROS, peroxynitrite, and superoxide production rates in all tissues (kidney, brain, and liver assayed in BB-fed rats. These results were evidence of "hormesis" during brief exposure, which dissipated with time as indicated by enhanced levels of catalase in heart and liver of BB group.Long-term feeding of BB-enriched diet lowered blood pressure, preserved renal hemodynamics, and improved redox status in kidneys of hypertensive rats and concomitantly demonstrated the potential to delay or attenuate development

  11. α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: role of nitric oxide.

    Science.gov (United States)

    Parvardeh, Siavash; Moghimi, Mahsa; Eslami, Pegah; Masoudi, Alireza

    2016-02-01

    Dependence and tolerance to opioid analgesics are major problems limiting their clinical application. α-Terpineol is a monoterpenoid alcohol with neuroprotective effects which is found in several medicinal plants such as Myrtus communis, Laurus nobilis, and Stachys byzantina. It has been shown that some of these medicinal plants such as S. byzantina attenuate dependence and tolerance to morphine. Since α-terpineol is one of the bioactive phytochemical constituent of these medicinal plants, the present study was conducted to investigate the effects of α-terpineol on morphine-induced dependence and tolerance in mice. The mice were rendered dependent or tolerant to morphine by a 3-day administration schedule. The hot-plate test and naloxone-induced withdrawal syndrome were used to evaluate tolerance and dependence on morphine, respectively. To investigate a possible role for nitric oxide (NO) in the protective effect of α-terpineol, the NO synthase inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) and NO precursor, L-arginine, were used. Administration of α-terpineol (5, 10, and 20 mg/kg, IP) significantly decreased the number of jumps in morphine dependent animals. Moreover, α-terpineol (20 and 40 mg/kg, IP) attenuated tolerance to the analgesic effect of morphine. The inhibitory effects of α-terpineol on morphine-induced dependence and tolerance were enhanced by pretreatment with L-NAME (10 mg/kg, IP). However, L-arginine (300 mg/kg, IP) antagonized the protective effects of α-terpineol on dependence and tolerance to morphine. These findings indicate that α-terpineol prevents the development of dependence and tolerance to morphine probably through the influence on NO production.

  12. HSL Attenuates the Follicular Oxidative Stress and Enhances the Hair Growth in ob/ob Mice

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    Takeo Minematsu, PhD

    2013-10-01

    Full Text Available Summary: We demonstrated enhanced hair regeneration following topical administration of N-(3-oxododecanoyl-L-homoserine lactone (HSL in ob/ob mice. The ob/ob mice showed delayed hair regeneration (more than 6 wk after depilation, which rapidly induced transition to anagen in the hair cycle in wild-type mice. Vehicle and HSL solutions were applied to the depilated dorsal skin of ob/ob mice. The depilated skin of the HSL-treated mice was fully covered with hair, whereas no macroscopic alteration was observed in vehicle-treated group by the fourth week after depilation. Oxidative stress was drastically decreased and the expression of the antioxidative enzymes PON1 and PON3 was increased in the HSL-treated skin with highly proliferative anagen follicles. These results suggest that HSL is a candidate therapeutic agent for alopecia in metabolic syndrome.

  13. Attenuation of Methotrexate-Induced Embryotoxicity and Oxidative Stress by Ethyl Pyruvate

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    Najafi Gholamreza

    2016-07-01

    Full Text Available Background Methotrexate (MTX, as an anti-folate agent, is widely used in the treatment of rheumatic disorders and malignant tumors, however it damages reproductive sys- tem in mice. The aim of this research was to study the effects of ethyl pyruvate (EP on embryo development and oxidative stress changes in the testis of mice treated with MTX. Materials and Methods In this experimental study, thirty-two adult male Naval Medical Research Institute mice, with average weight of 26 ± 2 g, were divided into four groups. The first group (control received distilled water (0.1 ml/mice/day, while the second group was intraperitoneally (IP treated with 20 mg/kg MTX once per week. The third group was IP treated with 40 mg/kg/day EP, and the fourth group was IP treated with both 20 mg/kg MTX and 40 mg/kg/day EP for 30 days. At the end of treatment fertilization rate and embryonic development were evaluated. Differences between these groups were assessed by ANOVA using the SPSS software package for Windows with a Tukey-Kramer multiple post-hoc comparison test. Results MTX treatment caused significant (P<0.05 increase in malondialdehyde (MDA and reduced catalase (CAT, as well as leading to in vitro fertilization (IVF and embryonic development. The improved effects of EP on the IVF were determined by the reduced level of MDA (index of oxidative stress and significant increased level of CAT (a key antioxidant. We observed significant increase in fertilization rate and embryonic development in the treated group with both MTX and EP. Conclusion It is suggested that EP can be useful in ameliorating testicular damages and embryotoxicity induced by MTX. These effects could be attributed to its antioxidant properties.

  14. Methane oxidation and attenuation of sulphur compounds in landfill top cover systems: Lab-scale tests.

    Science.gov (United States)

    Raga, Roberto; Pivato, Alberto; Lavagnolo, Maria Cristina; Megido, Laura; Cossu, Raffaello

    2018-03-01

    In this study, a top cover system is investigated as a control for emissions during the aftercare of new landfills and for old landfills where biogas energy production might not be profitable. Different materials were studied as landfill cover system in lab-scale columns: mechanical-biological pretreated municipal solid waste (MBP); mechanical-biological pretreated biowaste (PB); fine (PBS f ) and coarse (PBS c ) mechanical-biological pretreated mixtures of biowaste and sewage sludge, and natural soil (NS). The effectiveness of these materials in removing methane and sulphur compounds from a gas stream was tested, even coupled with activated carbon membranes. Concentrations of CO 2 , CH 4 , O 2 , N 2 , H 2 S and mercaptans were analysed at different depths along the columns. Methane degradation was assessed using mass balance and the results were expressed in terms of methane oxidation rate (MOR). The highest maximum and mean MOR were observed for MBP (17.2gCH 4 /m 2 /hr and 10.3gCH 4 /m 2 /hr, respectively). Similar values were obtained with PB and PBS c . The lowest values of MOR were obtained for NS (6.7gCH 4 /m 2 /hr) and PBS f (3.6gCH 4 /m 2 /hr), which may be due to their low organic content and void index, respectively. Activated membranes with high load capacity did not seem to have an influence on the methane oxidation process: MBP coupled with 220g/m 2 and 360g/m 2 membranes gave maximum MOR of 16.5gCH 4 /m 2 /hr and 17.4gCH 4 /m 2 /hr, respectively. Activated carbon membranes proved to be very effective on H 2 S adsorption. Furthermore, carbonyl sulphide, ethyl mercaptan and isopropyl mercaptan seemed to be easily absorbed by the filling materials. Copyright © 2017. Published by Elsevier B.V.

  15. Salix alba attenuated oxidative stress in the heart and kidney of hypercholesterolemic rabbits

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    Narges Amel Zabihi

    2017-12-01

    Full Text Available Objective: Oxidative stress plays a critical role in the development of hypercholesterolemia-induced complications. This study evaluated the effects of aspirin and Salix alba hydroethanolic extract on oxidative stress in the heart and kidney of hypercholesterolemic rabbits. Materials and Methods: The antioxidant activity, as well as total phenolic and salicin content of S. alba (Sa extract were assessed by DPPH radical scavenging activity, Folin-Ciocalteu and HPLC methods, respectively. Animals were divided into two groups of control (fed with normal chow, and HD (fed with high cholesterol diet for 6 weeks. Then, hypercholesterolemic animals allocated to the following treatment groups: CHO (received HD, Sa extract (HD plus extract 60 and 120 mg/kg, and aspirin (HD plus aspirin 120 mg/kg and received the treatments on a daily basis for 6 weeks. MDA, GSH, and nitrite concentrations as well as the activities of SOD and CAT were evaluated in cardiac and kidney tissues. Results: The scavenging activity, total phenolic content and salicin were 19.1 µg/ml (IC50, 153.75 ± 3.6 mg of gallic acid/g, and 18.03 µg/mg, respectively. In comparison to CHO group, MDA levels were diminished in Sa and ASA groups but GSH levels were improved. NO metabolites increased in the heart of Sa 120 mg/kg group and in the kidney of all Sa and ASA treated groups. SOD activity increased only in the heart of Sa groups and in the kidney of Sa and ASA groups. CAT activity increased in the heart and kidney tissues of all Sa and ASA treated groups. Conclusion: The results showed S. alba extract improved redox homeostasis in heart and kidney tissues of hypercholesterolemic rabbits. The extract antioxidant property may be related to its phenolic content.

  16. Water extract of Vitis coignetiae Pulliat leaves attenuates oxidative stress and inflammation in progressive NASH rats.

    Science.gov (United States)

    Pak, Wing; Takayama, Fusako; Hasegawa, Azusa; Mankura, Mitsumasa; Egashira, Toru; Ueki, Keiji; Nakamoto, Kazuo; Kawasaki, Hiromu; Mori, Akitane

    2012-01-01

    This study aimed to investigate the therapeutic effects of the water extract of leaves of Vitis coignetiae Pulliat (VCPL) on nonalcoholic steatohepatitis (NASH) with advanced fibrosis, as our previous study exhibited its preventive effect on NASH. The NASH animal model [PCT/JP2007/52477] was prepared by loading recurrent and intermittent hypoxemia stress to a rat with fatty liver, which resembled the condition occurring in patients with obstructive sleep apnea (OSA) and fatty liver, who have a high incidence of NASH. Intermittent hypoxemia stress is regarded as a condition similar to warm ischemia followed by re-oxygenation, which induces oxidative stress (OS). The daily 100 or 300 mg/kg VCPL administrations were performed for 3 weeks perorally beginning at the time of detection of advanced liver fibrosis. The therapeutic efficacy of VCPL on NASH was demonstrated by the reduction of the leakage of hepato-biliary enzymes and the amelioration of liver fibrosis. The OS elevation in NASH rats was measured based on the derivation of reactive oxygen species from liver mitochondrial energy metabolism and on the decrease in plasma SOD-like activity. The aggravation of inflammatory responses was demonstrated by the neutrophil infiltration (elevated myeloperoxidase activity) and the progression of fibrosis in the livers of NASH rats. In addition, the NASH rats without VCPL treatment also exhibited activation of nuclear factor-κB, a key factor in the link between oxidative stress and inflammation. All of these changes were reduced dose-dependently by the VCPL administration. These findings indicate that VCPL may improve hepatic fibrosis or at least suppress the progression of NASH, by breaking the crosstalk between OS and inflammation.

  17. Oxidative stress evoked damages on rat sperm and attenuated antioxidant status on consumption of aspartame.

    Science.gov (United States)

    Ashok, I; Poornima, P S; Wankhar, D; Ravindran, R; Sheeladevi, R

    2017-07-01

    Although several studies on toxic effect of aspartame metabolite have been studied, controversial reports over the use of aspartame owing to the fact that it releases methanol as one of its metabolite during metabolism exist. This present study is proposed to investigate whether aspartame (40 mg kg -1 b.wt) administration for 90 days could induce oxidative stress and alter antioxidant status of epididymal sperm in Wistar strain male albino rats. To mimic the human methanol metabolism, methotrexate (MTX)-treated rats were included to study the effects of aspartame. Oral intubations of FDA approved 40 mg kg -1 b.wt aspartame were given daily for 90 days to Wistar strain male albino rats and studied along with controls and MTX-treated controls. Sperm count, viability, morphology, morphometry and motility were assessed. A significant decrease in sperm function of aspartame treated animals was observed when compared with the control and MTX control. The free radical generation were observed in epididymal sperm by assessing the scavenging enzymes, enzymatic and non-enzymatic antioxidants. Result suggest that there was a significant increase glutathione-s-transferase (GST), with a significant decrease in reduced glutathione (GSH), superoxide dismutase activity (SOD), glutathione peroxidase levels (GPx), catalase activity (CAT) and glutathione reductase concentration. The increase in free radicals generation could have ultimately caused the lipid peroxidation mediated damages on the testis. Aspartame treated animals also revealed the reduced space in seminiferous tubules, which resulted in reduced Leydig cells when compared with control in histopathology. These findings demonstrate that aspartame metabolites could be a contributing factor for development of oxidative stress in the epididymal sperm.

  18. Alpha B-crystallin prevents the arrhythmogenic effects of particulate matter isolated from ambient air by attenuating oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hyelim [The Division of Cardiology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Science, Yonsei University, Seoul (Korea, Republic of); Park, Sanghoon; Jeon, Hyunju [The Division of Cardiology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Song, Byeong-Wook [The Division of Cardiology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Science, Yonsei University, Seoul (Korea, Republic of); Kim, Jin-Bae [Division of Cardiology, Kyung Hee University College of Medicine, Seoul (Korea, Republic of); Kim, Chang-Soo [The Department of Preventive Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Pak, Hui-Nam [The Division of Cardiology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Hwang, Ki-Chul [The Division of Cardiology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Science, Yonsei University, Seoul (Korea, Republic of); Lee, Moon-Hyoung [The Division of Cardiology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Chung, Ji Hyung, E-mail: jhchung@yuhs.ac [The Division of Cardiology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Joung, Boyoung, E-mail: cby6908@yuhs.ac [The Division of Cardiology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Science, Yonsei University, Seoul (Korea, Republic of)

    2013-01-15

    Ca{sup 2+}/calmodulin-dependent protein kinase II (CaMKII) is activated by particulate matter (PM) isolated from ambient air and linked to prolonged repolarization and cardiac arrhythmia. We evaluated whether alpha B-crystallin (CryAB), a heat shock protein, could prevent the arrhythmogenic effects of PM by preventing CaMKII activation. CryAB was delivered into cardiac cells using a TAT-protein transduction domain (TAT-CryAB). ECGs were measured before and after tracheal exposure of diesel exhaust particles (DEP) and each intervention in adult Sprague–Dawley rats. After endotracheal exposure of DEP (200 μg/mL for 30 minutes, n = 11), QT intervals were prolonged from 115 ± 14 ms to 144 ± 20 ms (p = 0.03), and premature ventricular contractions were observed more frequently (0% vs. 44%) than control (n = 5) and TAT-Cry (n = 5). However, DEP-induced arrhythmia was not observed in TAT-CryAB (1 mg/kg) pretreated rats (n = 5). In optical mapping of Langendorff-perfused rat heats, compared with baseline, DEP infusion of 12.5 μg/mL (n = 12) increased apicobasal action potential duration (APD) differences from 2 ± 6 ms to 36 ± 15 ms (p < 0.001), APD restitution slope from 0.26 ± 0.07 to 1.19 ± 0.11 (p < 0.001) and ventricular tachycardia (VT) from 0% to 75% (p < 0.001). DEP infusion easily induced spatially discordant alternans. However, the effects of DEP were prevented by TAT-CryAB (1 mg/kg, n = 9). In rat myocytes, while DEP increased reactive oxygen species (ROS) generation and phosphated CaMKII, TAT-CryAB prevented these effects. In conclusion, CryAB, a small heat shock protein, might prevent the arrhythmogenic effects of PM by attenuating ROS generation and CaMKII activation. -- Highlights: ► Particulate matter (PM) increases arrhythmia. ► PM induced arrhythmias are related with oxidative stress and CaMKII activation. ► Alpha B-crystallin (CryAB) could attenuate the arrhythmogenic effect of PM. ► CryAB decreases oxidative stress and CaMKII activation

  19. Use of an internal sample attenuator in radioimmunoassay. Assay of triiodothyronine (T3) using starch particles containing entrapped charcoal and bismuth oxide in combination with free antibodies

    International Nuclear Information System (INIS)

    Eriksson, H.; Mattiasson, B.; Thorell, J.I.

    1981-01-01

    A radioimmunoassay for triiodothyronine involving no separate washing or separation steps is described. By using an internal sample attenuator, bismuth oxide, co-immobilized with the sorbent, charcoal, for the non-bound fraction of T 3 , a system was designed in which a suspension of starch spheres containing the sorbent and the attenuator was added after the immunological reaction had taken place. The particles sedimented and the whole test tube was counted in a gamma-counter. The coefficient of correlation between the results obtained with the present method and those from conventional procedures was 0.993. (Auth.)

  20. Tat-PRAS40 prevent hippocampal HT-22 cell death and oxidative stress induced animal brain ischemic insults.

    Science.gov (United States)

    Shin, Min Jea; Kim, Dae Won; Jo, Hyo Sang; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Yeo, Eun Ji; Choi, Yeon Joo; Kim, Ji An; Hwang, Jung Soon; Sohn, Eun Jeong; Jeong, Ji-Heon; Kim, Duk-Soo; Kwon, Hyeok Yil; Cho, Yong-Jun; Lee, Keunwook; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2016-08-01

    Proline rich Akt substrate (PRAS40) is a component of mammalian target of rapamycin complex 1 (mTORC1) and is known to play an important role against reactive oxygen species-induced cell death. However, the precise function of PRAS40 in ischemia remains unclear. Thus, we investigated whether Tat-PRAS40, a cell-permeable fusion protein, has a protective function against oxidative stress-induced hippocampal neuronal (HT-22) cell death in an animal model of ischemia. We showed that Tat-PRAS40 transduced into HT-22 cells, and significantly protected against cell death by reducing the levels of H2O2 and derived reactive species, and DNA fragmentation as well as via the regulation of Bcl-2, Bax, and caspase 3 expression levels in H2O2 treated cells. Also, we showed that transduced Tat-PARS40 protein markedly increased phosphorylated RRAS40 expression levels and 14-3-3σ complex via the Akt signaling pathway. In an animal ischemia model, Tat-PRAS40 effectively transduced into the hippocampus in animal brain and significantly protected against neuronal cell death in the CA1 region. We showed that Tat-PRAS40 protein effectively transduced into hippocampal neuronal cells and markedly protected against neuronal cell damage. Therefore, we suggest that Tat-PRAS40 protein may be used as a therapeutic protein for ischemia and oxidative stress-induced brain disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Ursolic acid attenuates oxidative stress-mediated hepatocellular carcinoma induction by diethylnitrosamine in male Wistar rats.

    Science.gov (United States)

    Gayathri, Renganathan; Priya, D Kalpana Deepa; Gunassekaran, G R; Sakthisekaran, Dhanapal

    2009-01-01

    Hepatocellular carcinoma is the most common primary cancer of the liver in Asian countries. For more than a decade natural dietary agents including fruits, vegetables and spices have drawn a great deal of attention in the prevention of diseases, preferably cancer. Ursolic acid is a natural triterpenoid widely found in food, medicinal herbs, apple peel and other products it has been extensively studied for its anticancer and antioxidant properties. The purpose of this study was to evaluate the effect of ursolic acid in diethylnitrosamine (DEN) induced and phenobarbital promoted hepatocarcinogenesis in male Wistar rats. Antioxidant status was assessed by alterations in level of lipid peroxides and protein carbonyls. Damage to plasma membranes was assessed by levels of membrane and tissue ATPases. Liver tissue was homogenized and utilized for estimation of lipid peroxides, protein carbonyls and glycoproteins. Anticoagulated blood was utilized for erythrocyte membrane isolation. Oral administration of UA 20 mg/kg bodyweight for 6 weeks decreased the levels of lipid peroxides and protein carbonyls at a significance of pmembrane and tissue ATPases returned to normal after UA administration. Levels of glycoproteins were also restored after treatment. Histopathological observations were recorded. The findings from the above study suggest the effectiveness of UA in reducing the oxidative stress mediated changes in liver of rats. Since UA has been found to be a potent antioxidant, it can be suggested as an excellent chemopreventive agent in overcoming diseases like cancer which are mediated by free radicals.

  2. Resveratrol attenuates radiation damage in Caenorhabditis elegans by preventing oxidative stress

    International Nuclear Information System (INIS)

    Ye Kan; Gu Guixiong; Ji Chenbo; Ni Yuhui; Chen Xiaohui; Guo Xirong; Lu Xiaowei; Gao Chunlin; Zhao Yaping

    2010-01-01

    Resveratrol, a member of a class of polyphenolic compounds known as flavonols, has been extensively studied for its anticancer, antiviral, anti-inflammatory, and neuroprotective roles. Caenorhabidits elegans is a well-established animal for investigating responses to radiation. We found that resveratrol may provide protection against hazardous radiation. Pre-treatment with resveratrol extended both the maximum and mean life span of irradiated C. elegans. Resveratrol acted as a strong radical scavenger and regulated superoxide dismutase (SOD) expression. In addition, resveratrol was shown to be capable of alleviating γ-ray radiation exposure-induced reduction in mitochondrial SOD expression. Ultimately, a correlation may exist between dietary intake of trace amounts of resveratrol and anti-aging effects. A specific response mechanism may be activated after the administration of resveratrol in irradiated animals. Our results suggest the protective effect of resveratrol is due to its strong ability to protect from oxidative stress and protective effects in mitochondria. Therefore, resveratrol is potentially an effective protecting agent against irradiative damage. (author)

  3. Saikosaponin-a Attenuates Oxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cells.

    Science.gov (United States)

    He, Dan; Wang, Hongyan; Xu, Ling; Wang, Xiaoqing; Peng, Kuang; Wang, Lili; Liu, Pixu; Qu, Peng

    2016-06-01

    Saikosaponins-a (Ssa) is a major bioactive extract of Radix Bupleuri which is a traditional Chinese medicine. The roles of inflammatory response and lipid transportation in the process of atherosclerosis have drawn increasing attention. We explored the regulation of lipid transportation and immune-inflammatory role of Ssa in early atherosclerosis. The antiatherogenic actions and possible molecular mechanisms of Ssa were texted in THP-1 cells. We examined the effect of Ssa on oxidized low-density lipoprotein (ox-LDL)-induced lipid uptake, cholesterol efflux, immune-inflammatory response. THP-1 macrophages were treated with Ssa followed by ox-LDL for 24 hours. Results from western blot showed that Ssa obviously reduced lipoprotein uptake to block foam cell formation and the expression of Density Lipoprotein Receptor-1 and CD36. Ssa also significantly boosted cholesterol efflux and the expression of ATP binding cassettetransporter A1 and peroxisome proliferator-activated receptor γ. The results also indicated that Ssa inhibited ox-LDL-induced activation of AKT and nuclear factor-κB, assembly of NLRP3 inflammasome and production of proinflammatory cytokines. It is suggested that the ability against immune inflammatory response of Ssa is due to modulation of the PI3K/AKT/NF-κB/NLRP3 pathway. In conclusion, this study provides new insight into Ssa's molecular mechanism and its therapeutic potential in the treatment of atherosclerosis.

  4. Cofilin Knockdown Attenuates Hemorrhagic Brain Injury-induced Oxidative Stress and Microglial Activation in Mice.

    Science.gov (United States)

    Alhadidi, Qasim; Nash, Kevin M; Alaqel, Saleh; Sayeed, Muhammad Shahdaat Bin; Shah, Zahoor A

    2018-05-08

    Intracerebral hemorrhage (ICH) resulting from the rupture of the blood vessels in the brain is associated with significantly higher mortality and morbidity. Clinical studies focused on alleviating the primary injury, hematoma formation and expansion, were largely ineffective, suggesting that secondary injury-induced inflammation and the formation of reactive species also contribute to the overall injury process. In this study, we explored the effects of cofilin knockdown in a mouse model of ICH. Animals given stereotaxic injections of cofilin siRNA, 72-h prior to induction of ICH by collagenase injection within the area of siRNA administration showed significantly decreased cofilin expression levels and lower hemorrhage volume and edema, and the animals performed significantly better in neurobehavioral tasks i.e., rotarod, grip strength and neurologic deficit scores. Cofilin siRNA knocked-down mice had reduced ICH-induced DNA fragmentation, blood-brain barrier disruption and microglial activation, with a concomitant increase in astrocyte activation. Increased expression of pro-survival proteins and decreased markers of oxidative stress were also observed in cofilin siRNA-treated mice possibly due to the reduced levels of cofilin. Our results suggest that cofilin plays a major role in ICH-induced secondary injury, and could become a potential therapeutic target. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Dexmedetomidine Attenuates Oxidative Stress Induced Lung Alveolar Epithelial Cell Apoptosis In Vitro

    Directory of Open Access Journals (Sweden)

    Jian Cui

    2015-01-01

    Full Text Available Background. Oxidative stress plays a pivotal role in the lung injuries of critical ill patients. This study investigates the protection conferred by α2 adrenoceptor agonist dexmedetomidine (Dex from lung alveolar epithelial cell injury induced by hydrogen peroxide (H2O2 and the underlying mechanisms. Methods. The lung alveolar epithelial cell line, A549, was cultured and then treated with 500 μM H2O2 with or without Dex (1 nM or Dex in combination with atipamezole (10 nM, an antagonist of α2 receptors. Their effect on mitochondrial membrane potential (Δψm, reactive oxygen species (ROS, and the cell cycle was assessed by flow cytometry. Cleaved-caspases 3 and 9, BAX, Bcl-2, phospho-mTOR (p-mTOR, ERK1/2, and E-cadherin expression were also determined with immunocytochemistry. Results. Upregulation of cleaved-caspases 3 and 9 and BAX and downregulation of Bcl-2, p-mTOR, and E-cadherin were found following H2O2 treatment, and all of these were reversed by Dex. Dex also prevented the ROS generation, cytochrome C release, and cell cycle arrest induced by H2O2. The effects of Dex were partially reversed by atipamezole. Conclusion. Our study demonstrated that Dex protected lung alveolar epithelial cells from apoptotic injury, cell cycle arrest, and loss of cell adhesion induced by H2O2 through enhancing the cell survival and proliferation.

  6. Specificity protein 1-zinc finger protein 179 pathway is involved in the attenuation of oxidative stress following brain injury

    Directory of Open Access Journals (Sweden)

    Jian-Ying Chuang

    2017-04-01

    Full Text Available After sudden traumatic brain injuries, secondary injuries may occur during the following days or weeks, which leads to the accumulation of reactive oxygen species (ROS. Since ROS exacerbate brain damage, it is important to protect neurons against their activity. Zinc finger protein 179 (Znf179 was shown to act as a neuroprotective factor, but the regulation of gene expression under oxidative stress remains unknown. In this study, we demonstrated an increase in Znf179 protein levels in both in vitro model of hydrogen peroxide (H2O2-induced ROS accumulation and animal models of traumatic brain injury. Additionally, we examined the sub-cellular localization of Znf179, and demonstrated that oxidative stress increases Znf179 nuclear shuttling and its interaction with specificity protein 1 (Sp1. Subsequently, the positive autoregulation of Znf179 expression, which is Sp1-dependent, was further demonstrated using luciferase reporter assay and green fluorescent protein (GFP-Znf179-expressing cells and transgenic mice. The upregulation of Sp1 transcriptional activity induced by the treatment with nerve growth factor (NGF led to an increase in Znf179 levels, which further protected cells against H2O2-induced damage. However, Sp1 inhibitor, mithramycin A, was shown to inhibit NGF effects, leading to a decrease in Znf179 expression and lower cellular protection. In conclusion, the results obtained in this study show that Znf179 autoregulation through Sp1-dependent mechanism plays an important role in neuroprotection, and NGF-induced Sp1 signaling may help attenuate more extensive (ROS-induced damage following brain injury.

  7. SEAWEED EXTRACTS AS A POTENTIAL TOOL FOR THE ATTENUATION OF OXIDATIVE DAMAGE IN OBESITY-RELATED PATHOLOGIES1.

    Science.gov (United States)

    Lee, Ok-Hwan; Yoon, Kye-Yoon; Kim, Kui-Jin; You, SangGuan; Lee, Boo-Yong

    2011-06-01

    Recent studies suggest that seaweed extracts are a significant source of bioactive compounds comparable to the dietary phytochemicals such as onion and tea extracts. The exploration of natural antioxidants that attenuate oxidative damage is important for developing strategies to treat obesity-related pathologies. The objective of this study was to screen the effects of seaweed extracts of 49 species on adipocyte differentiation and reactive oxygen species (ROS) production during the adipogenesis in 3T3-L1 adipocytes, and to investigate their total phenol contents and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities. Our results show that high total phenol contents were observed in the extracts of Ecklonia cava (see Table 1 for taxonomic authors) (681.1 ± 16.0 μg gallic acid equivalents [GAE] · g -1 ), Dictyopteris undulata (641.3 ± 70.7 μg GAE · g -1 ), and Laurencia intermedia (560.9 ± 48.1 μg GAE · g -1 ). In addition, DPPH radical scavenging activities were markedly higher in Sargassum macrocarpum (60.2%), Polysiphonia morrowii (55.0%), and Ishige okamurae (52.9%) than those of other seaweed extracts (P Gelidium amansii, Gracilaria verrucosa, and Grateloupia lanceolata significantly inhibited adipocyte differentiation and ROS production during differentiation of 3T3-L1 preadipocytes. Furthermore, the production of ROS was positively correlated with lipid accumulation (R 2  = 0.8149). According to these preliminary results, some of the seaweed extracts can inhibit ROS generation, which may protect against oxidative stress that is linked to obesity. Further studies are required to determine the molecular mechanism between the verified seaweeds and ROS, and the resulting effects on obesity. [Table: see text]. © 2011 Phycological Society of America.

  8. Ghrelin Pre-treatment Attenuates Local Oxidative Stress and End Organ Damage During Cardiopulmonary Bypass in Anesthetized Rats

    Science.gov (United States)

    Sukumaran, Vijayakumar; Tsuchimochi, Hirotsugu; Fujii, Yutaka; Hosoda, Hiroshi; Kangawa, Kenji; Akiyama, Tsuyoshi; Shirai, Mikiyasu; Tatsumi, Eisuke; Pearson, James T.

    2018-01-01

    Cardiopulmonary bypass (CPB) induced systemic inflammation significantly contributes to the development of postoperative complications, including respiratory failure, myocardial, renal and neurological dysfunction and ultimately can lead to failure of multiple organs. Ghrelin is a small endogenous peptide with wide ranging physiological effects on metabolism and cardiovascular regulation. Herein, we investigated the protective effects of ghrelin against CPB-induced inflammatory reactions, oxidative stress and acute organ damage. Adult male Sprague Dawley rats randomly received vehicle (n = 5) or a bolus of ghrelin (150 μg/kg, sc, n = 5) and were subjected to CPB for 4 h (protocol 1). In separate rats, ghrelin pre-treatment (protocol 2) was compared to two doses of ghrelin (protocol 3) before and after CPB for 2 h followed by recovery for 2 h. Blood samples were taken prior to CPB, and following CPB at 2 h and 4 h. Organ nitrosative stress (3-nitrotyrosine) was measured by Western blotting. CPB induced leukocytosis with increased plasma levels of tumor necrosis factor-α and interleukin-6 indicating a potent inflammatory response. Ghrelin treatment significantly reduced plasma organ damage markers (lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase) and protein levels of 3-nitrotyrosine, particularly in the brain, lung and liver, but only partly suppressed inflammatory cell invasion and did not reduce proinflammatory cytokine production. Ghrelin partially attenuated the CPB-induced elevation of epinephrine and to a lesser extent norepinephrine when compared to the CPB saline group, while dopamine levels were completely suppressed. Ghrelin treatment sustained plasma levels of reduced glutathione and decreased glutathione disulphide when compared to CPB saline rats. These results suggest that even though ghrelin only partially inhibited the large CPB induced increase in catecholamines and organ macrophage infiltration, it reduced oxidative

  9. Punica granatum improves renal function in gentamicin-induced nephropathy in rats via attenuation of oxidative stress.

    Science.gov (United States)

    Mestry, Snehal N; Gawali, Nitin B; Pai, Sarayu A; Gursahani, Malvika S; Dhodi, Jayesh B; Munshi, Renuka; Juvekar, Archana R

    2018-03-16

    Gentamicin is widely used as an antibiotic for the treatment of gram negative infections. Evidences indicates that oxidative stress is involved in gentamicin-induced nephrotoxicity. In Ayurvedic medicine, Punica granatum Linn. is considered as 'a pharmacy unto itself". It has been claimed in traditional literature, to treat various kidney ailments due to its antioxidant potential. To explore the possible mechanism of action of methanolic extract of P.granatum leaves (MPGL) in exerting a protective effect on gentamicin-induced nephropathy. Animals were administered with gentamicin (80 mg/kg/day i.m.) and simultaneously with MPGL (100, 200 and 400 mg/kg p.o.) or metformin (100 mg/kg p.o.) for 8 days. A satellite group was employed in order to check for reversibility of nephrotoxic effects post discontinuation of gentamicin administration. At the end of the study, all the rats were sacrificed and serum-urine parameters were investigated. Antioxidant enzymes and tumor necrosis factor alpha (TNF-α) levels were determined in the kidney tissues along with histopathological examination of kidneys. Increase in serum creatinine, urea, TNF-α, lipid peroxidation along with fall in the antioxidant enzymes activity and degeneration of tubules, arterioles as revealed by histopathological examination confirmed the manifestation of nephrotoxicity caused due to gentamicin. Simultaneous administration of MPGL and gentamicin protected kidneys against nephrotoxic effects of gentamicin as evidenced from normalization of renal function parameters and amelioration of histopathological changes. Data suggests that MPGL attenuated oxidative stress associated renal injury by preserving antioxidant enzymes, reducing lipid peroxidation and inhibiting inflammatory mediators such as TNF-α. Copyright © 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

  10. Ischemic preconditioning protects against ischemic brain injury

    Directory of Open Access Journals (Sweden)

    Xiao-meng Ma

    2016-01-01

    Full Text Available In this study, we hypothesized that an increase in integrin αv ß 3 and its co-activator vascular endothelial growth factor play important neuroprotective roles in ischemic injury. We performed ischemic preconditioning with bilateral common carotid artery occlusion for 5 minutes in C57BL/6J mice. This was followed by ischemic injury with bilateral common carotid artery occlusion for 30 minutes. The time interval between ischemic preconditioning and lethal ischemia was 48 hours. Histopathological analysis showed that ischemic preconditioning substantially diminished damage to neurons in the hippocampus 7 days after ischemia. Evans Blue dye assay showed that ischemic preconditioning reduced damage to the blood-brain barrier 24 hours after ischemia. This demonstrates the neuroprotective effect of ischemic preconditioning. Western blot assay revealed a significant reduction in protein levels of integrin αv ß 3, vascular endothelial growth factor and its receptor in mice given ischemic preconditioning compared with mice not given ischemic preconditioning 24 hours after ischemia. These findings suggest that the neuroprotective effect of ischemic preconditioning is associated with lower integrin αv ß 3 and vascular endothelial growth factor levels in the brain following ischemia.

  11. Minocycline attenuates colistin-induced neurotoxicity via suppression of apoptosis, mitochondrial dysfunction and oxidative stress.

    Science.gov (United States)

    Dai, Chongshan; Ciccotosto, Giuseppe D; Cappai, Roberto; Wang, Yang; Tang, Shusheng; Xiao, Xilong; Velkov, Tony

    2017-06-01

    Neurotoxicity is an adverse effect patients experience during colistin therapy. The development of effective neuroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy. The present study investigates the neuroprotective effect of the synergistic tetracycline antibiotic minocycline against colistin-induced neurotoxicity. The impact of minocycline pretreatment on colistin-induced apoptosis, caspase activation, oxidative stress and mitochondrial dysfunction were investigated using cultured mouse neuroblastoma-2a (N2a) and primary cortical neuronal cells. Colistin-induced neurotoxicity in mouse N2a and primary cortical cells gives rise to the generation of reactive oxygen species (ROS) and subsequent cell death via apoptosis. Pretreatment of the neuronal cells with minocycline at 5, 10 and 20 μM for 2 h prior to colistin (200 μM) exposure (24 h), had an neuroprotective effect by significantly decreasing intracellular ROS production and by upregulating the activities of the anti-ROS enzymes superoxide dismutase and catalase. Minocycline pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation and subsequent apoptosis. Immunohistochemical imaging studies revealed colistin accumulates within the dendrite projections and cell body of primary cortical neuronal cells. To our knowledge, this is first study demonstrating the protective effect of minocycline on colistin-induced neurotoxicity by scavenging of ROS and suppression of apoptosis. Our study highlights that co-administration of minocycline kills two birds with one stone: in addition to its synergistic antimicrobial activity, minocycline could potentially ameliorate unwanted neurotoxicity in patients undergoing polymyxin therapy. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions

  12. Lycopene attenuates dichlorvos-induced oxidative damage and hepatotoxicity in rats.

    Science.gov (United States)

    El-Saad, Am Abu; Ibrahim, M M; Hazani, A A; El-Gaaly, G A

    2016-06-01

    Because of the widespread use of dichlorvos (DDVP) for domestic applications, evaluation of their toxic effects is of major concern to public health. Lycopene may lower oxidative stress by a mechanism that is not fully elucidated. The present study was undertaken to evaluate the protective efficacy of lycopene in terms of normalization of altered biochemical parameters following DDVP treatment in rats. Animals were divided into four groups. The first group was used as control, while groups 2, 3, and 4 were orally treated with lycopene (10 mg kg(-1) body weight (b.w.)), DDVP (1.6 mg kg(-1) b.w.), and DDVP plus lycopene, respectively. Results showed that oral administration of DDVP for 30 days increased the levels of lipid peroxidation markers such as malondialdehyde, 4-hydroxynonanal, and protein carbonyl content in liver. Also, a decrease in levels of vitamin C, vitamin E, and reduced glutathione was detected due to DDVP administration. These were accompanied by a decrease in the activities of antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase in the liver tissue. Moreover, DDVP increased the activities of serum transaminases, alkaline phosphatase, lactate dehydrogenase, and lipoxygenase, and the levels of bilirubin, total cholesterol, low-density lipoprotein cholesterol, triglyceride and DNA-protein crosslinks, and 8-hydroxy-2-deoxyguanosine, while decreased the level of high-density lipoprotein cholesterol. Our results provide new insights into the biochemical studies of relation between DDVP hepatotoxicity and lycopene treatment. Administration of lycopene to DDVP-treated rats reverted the status of hepatic markers to near-normal levels. These data suggest that lycopene can protect against the liver damage induced by DDVP. © The Author(s) 2015.

  13. QSYQ Attenuates Oxidative Stress and Apoptosis Induced Heart Remodeling Rats through Different Subtypes of NADPH-Oxidase

    Directory of Open Access Journals (Sweden)

    Yong Wang

    2013-01-01

    Full Text Available We aim to investigate the therapeutic effects of QSYQ, a drug of heart failure (HF in clinical practice in China, on a rat heart failure (HF model. 3 groups were divided: HF model group (LAD ligation, QSYQ group (LAD ligation and treated with QSYQ, and sham-operated group. After 4 weeks, rats were sacrificed for cardiac injury measurements. Rats with HF showed obvious histological changes including necrosis and inflammation foci, elevated ventricular remodeling markers levels(matrix metalloproteinases-2, MMP-2, deregulated ejection fraction (EF value, increased formation of oxidative stress (Malondialdehyde, MDA, and up-regulated levels of apoptotic cells (caspase-3, p53 and tunnel in myocardial tissue. Treatment of QSYQ improved cardiac remodeling through counter-acting those events. The improvement of QSYQ was accompanied with a restoration of NADPH oxidase 4 (NOX4 and NADPH oxidase 2 (NOX2 pathways in different patterns. Administration of QSYQ could attenuate LAD-induced HF, and AngII-NOX2-ROS-MMPs pathway seemed to be the critical potential targets for QSYQ to reduce the remodeling. Moreover, NOX4 was another key targets to inhibit the p53 and Caspase3, thus to reduce the hypertrophy and apoptosis, and eventually provide a synergetic cardiac protective effect.

  14. Spirulina vesicolor Improves Insulin Sensitivity and Attenuates Hyperglycemia-Mediated Oxidative Stress in Fructose-Fed Rats

    Directory of Open Access Journals (Sweden)

    Walaa Hozayen

    2016-03-01

    Full Text Available Aim: The current study aimed to investigate the anti-hyperglycemic, anti-hyperlipidemic and insulin sensitizing effects of the cyanobacterium Spirulina vesicolor extract in fructose-fed rats. Materials and Methods: Rats were fed 30% fructose solution in drinking water for 4 weeks. Animals exhibited hyperglycemia and hyperinsulinemia were selected for further investigations. Diabetic and control rats were orally supplemented with 50 mg/kg body weight S. vesicolor extract for 4 weeks. Results: At the end of 8 weeks, fructose-fed rats showed significant increase in serum glucose, insulin, cholesterol, triglycerides, cardiovascular risk indices and insulin resistance. Treatment of the fructose-fed rats with S. vesicolor extract improved this metabolic profile. Fructose feeding produced a significant increase in serum tumor necrosis factor alpha (TNF-α and a decrease in adiponectin levels. In addition, fructose-fed rats exhibited a significant increase in liver, kidney and heart lipid peroxidation levels, and declined antioxidant defenses. Supplementation of the fructose-fed rats with S. vesicolor extract reversed these alterations. Conclusion: S. vesicolor attenuates hyperglycemia-mediated oxidative stress and inflammation, and is thus effective in improving insulin sensitivity in fructose-fed rats. [J Complement Med Res 2016; 5(1.000: 57-64

  15. Food restriction attenuates oxidative stress in brown adipose tissue of striped hamsters acclimated to a warm temperature.

    Science.gov (United States)

    Zhang, Ji-Ying; Zhao, Xiao-Ya; Wang, Gui-Ying; Wang, Chun-Ming; Zhao, Zhi-Jun

    2016-05-01

    It has been suggested that the up-regulation of uncoupling proteins (UCPs) decreases reactive oxygen species (ROS) production, in which case there should be a negative relationship between UCPs expression and ROS levels. In this study, the effects of temperature and food restriction on ROS levels and metabolic rate, UCP1 mRNA expression and antioxidant levels were examined in the brown adipose tissue (BAT) of the striped hamsters (Cricetulus barabensis). The metabolic rate and food intake of hamsters which had been restricted to 80% of ad libitum food intake, and acclimated to a warm temperature (30°C), decreased significantly compared to a control group. Hydrogen peroxide (H2O2) levels were 42.9% lower in food restricted hamsters than in the control. Malonadialdehyde (MDA) levels of hamsters acclimated to 30°C that were fed ad libitum were significantly higher than those of the control group, but 60.1% lower than hamsters that had been acclimated to the same temperature but subject to food restriction. There were significantly positive correlations between H2O2 and, MDA levels, catalase activity, and total antioxidant capacity. Cytochrome c oxidase activity and UCP1 mRNA expression significantly decreased in food restricted hamsters compared to the control. These results suggest that warmer temperatures increase oxidative stress in BAT by causing the down-regulation of UCP1 expression and decreased antioxidant activity, but food restriction may attenuate the effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Real-time monitoring of nitric oxide (NO) and pO2 levels under ischemic conditions associated with small bowel ischemia/reperfusion injury using selective electrodes for NO and oxygen molecules.

    Science.gov (United States)

    Watanabe, T; Owada, S; Kobayashi, H; Ishiuchi, A; Nakano, H; Asakuta, T; Shimamura, T; Asano, T; Koizumi, S; Jinnouchi, Y; Katayama, M; Kamibayasi, M; Murakami, E; Otsubo, T

    2007-12-01

    The present study demonstrated the feasibility of monitoring nitric oxide (NO) and pO2 levels under ischemic conditions associated with small bowel ischemia/reperfusion (I/R) injury through the use of selective electrodes for NO and oxygen molecules. NO levels gradually increased during ischemia. When reperfusion was started, the NO level decreased suddenly and returned to pre-ischemia values within 10 minutes. After clamping, pO2 decreased rapidly. When reperfusion was started, pO2 increased suddenly, returning to pre-ischemia values within 10 minutes. We concluded that it is feasible to monitor NO and pO2 levels under ischemic conditions of small bowel I/R injury through the use of electrodes selective for NO and oxygen molecules.

  17. Attenuation of the in vitro neurotoxicity of 316L SS by graphene oxide surface coating

    International Nuclear Information System (INIS)

    Tasnim, Nishat; Kumar, Alok; Joddar, Binata

    2017-01-01

    A persistent theme in biomaterials research comprises of surface engineering and modification of bare metallic substrates for improved cellular response and biocompatibility. Graphene Oxide (GO), a derivative of graphene, has outstanding chemical and mechanical properties; its large surface to volume ratio, ease of surface modification and processing make GO an attractive coating material. GO-coatings have been extensively studied as biosensors. Further owing to its surface nano-architecture, GO-coated surfaces promote cell adhesion and growth, making it suitable for tissue engineering applications. The need to improve the long-term durability and therapeutic effectiveness of commercially available bare 316L stainless steel (SS) surfaces led us to adopt a polymer-free approach which is cost-effective and scalable. GO was immobilized on to 316L SS utilizing amide linkage, to generate a strongly adherent uniform coating with surface roughness. GO-coated 316L SS surfaces showed increased hydrophilicity and biocompatibility with SHSY-5Y neuronal cells, which proliferated well and showed decreased reactive oxygen species (ROS) expression. In contrast, cells did not adhere to bare uncoated 316L SS meshes nor maintain viability when cultured in the vicinity of bare meshes. Therefore the combination of the improved surface properties and biocompatibility implies that GO-coating can be utilized to overcome pertinent limitations of bare metallic 316L SS implant surfaces, especially SS neural electrodes. Also, the procedure for making GO-based protective coatings can be applied to numerous other implants where the development of such protective films is necessary. - Highlights: • GO was immobilized on to 316L SS utilizing carbodiimide chemistry to generate a strong adherent uniform nano coating. • GO-modified surfaces showed increased hydrophilicity and biocompatibility with SH5YSY cells cultured atop these surfaces. • Proliferation and alignment of the cells with the

  18. Attenuation of the in vitro neurotoxicity of 316L SS by graphene oxide surface coating

    Energy Technology Data Exchange (ETDEWEB)

    Tasnim, Nishat; Kumar, Alok; Joddar, Binata, E-mail: bjoddar@utep.edu

    2017-04-01

    A persistent theme in biomaterials research comprises of surface engineering and modification of bare metallic substrates for improved cellular response and biocompatibility. Graphene Oxide (GO), a derivative of graphene, has outstanding chemical and mechanical properties; its large surface to volume ratio, ease of surface modification and processing make GO an attractive coating material. GO-coatings have been extensively studied as biosensors. Further owing to its surface nano-architecture, GO-coated surfaces promote cell adhesion and growth, making it suitable for tissue engineering applications. The need to improve the long-term durability and therapeutic effectiveness of commercially available bare 316L stainless steel (SS) surfaces led us to adopt a polymer-free approach which is cost-effective and scalable. GO was immobilized on to 316L SS utilizing amide linkage, to generate a strongly adherent uniform coating with surface roughness. GO-coated 316L SS surfaces showed increased hydrophilicity and biocompatibility with SHSY-5Y neuronal cells, which proliferated well and showed decreased reactive oxygen species (ROS) expression. In contrast, cells did not adhere to bare uncoated 316L SS meshes nor maintain viability when cultured in the vicinity of bare meshes. Therefore the combination of the improved surface properties and biocompatibility implies that GO-coating can be utilized to overcome pertinent limitations of bare metallic 316L SS implant surfaces, especially SS neural electrodes. Also, the procedure for making GO-based protective coatings can be applied to numerous other implants where the development of such protective films is necessary. - Highlights: • GO was immobilized on to 316L SS utilizing carbodiimide chemistry to generate a strong adherent uniform nano coating. • GO-modified surfaces showed increased hydrophilicity and biocompatibility with SH5YSY cells cultured atop these surfaces. • Proliferation and alignment of the cells with the

  19. Momordica charantia (bitter melon attenuates high-fat diet-associated oxidative stress and neuroinflammation

    Directory of Open Access Journals (Sweden)

    Feher Domonkos

    2011-06-01

    . Similarly, HFD-induced brain oxidative stress was significantly reduced by BM supplementation with a concomitant reduction in FoxO, normalization of Sirt1 protein expression and up-regulation of Sirt3 mRNA expression. Furthermore, plasma antioxidant enzymes and pro-inflammatory cytokines were also normalized in mice fed HFD with BM as compared to HFD-fed mice. Conclusions Functional foods such as BM offer a unique therapeutic strategy to improve obesity-associated peripheral inflammation and neuroinflammation.

  20. Nitric oxide induces hypoxia ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism.

    Science.gov (United States)

    Lu, Qing; Harris, Valerie A; Rafikov, Ruslan; Sun, Xutong; Kumar, Sanjiv; Black, Stephen M

    2015-12-01

    We have recently shown that increased hydrogen peroxide (H2O2) generation is involved in hypoxia-ischemia (HI)-mediated neonatal brain injury. H2O2 can react with free iron to form the hydroxyl radical, through Fenton Chemistry. Thus, the objective of this study was to determine if there was a role for the hydroxyl radical in neonatal HI brain injury and to elucidate the underlying mechanisms. Our data demonstrate that HI increases the deposition of free iron and hydroxyl radical formation, in both P7 hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD), and the neonatal rat exposed to HI. Both these processes were found to be nitric oxide (NO) dependent. Further analysis demonstrated that the NO-dependent increase in iron deposition was mediated through increased transferrin receptor expression and a decrease in ferritin expression. This was correlated with a reduction in aconitase activity. Both NO inhibition and iron scavenging, using deferoxamine administration, reduced hydroxyl radical levels and neuronal cell death. In conclusion, our results suggest that increased NO generation leads to neuronal cell death during neonatal HI, at least in part, by altering iron homeostasis and hydroxyl radical generation. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Multiple low-dose radiation prevents type 2 diabetes-induced renal damage through attenuation of dyslipidemia and insulin resistance and subsequent renal inflammation and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Minglong Shao

    Full Text Available Dyslipidemia and lipotoxicity-induced insulin resistance, inflammation and oxidative stress are the key pathogeneses of renal damage in type 2 diabetes. Increasing evidence shows that whole-body low dose radiation (LDR plays a critical role in attenuating insulin resistance, inflammation and oxidative stress.The aims of the present study were to investigate whether LDR can prevent type 2 diabetes-induced renal damage and the underlying mechanisms.Mice were fed with a high-fat diet (HFD, 40% of calories from fat for 12 weeks to induce obesity followed by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg to develop a type 2 diabetic mouse model. The mice were exposed to LDR at different doses (25, 50 and 75 mGy for 4 or 8 weeks along with HFD treatment. At each time-point, the kidney weight, renal function, blood glucose level and insulin resistance were examined. The pathological changes, renal lipid profiles, inflammation, oxidative stress and fibrosis were also measured.HFD/STZ-induced type 2 diabetic mice exhibited severe pathological changes in the kidney and renal dysfunction. Exposure of the mice to LDR for 4 weeks, especially at 50 and 75 mGy, significantly improved lipid profiles, insulin sensitivity and protein kinase B activation, meanwhile, attenuated inflammation and oxidative stress in the diabetic kidney. The LDR-induced anti-oxidative effect was associated with up-regulation of renal nuclear factor E2-related factor-2 (Nrf-2 expression and function. However, the above beneficial effects were weakened once LDR treatment was extended to 8 weeks.These results suggest that LDR exposure significantly prevented type 2 diabetes-induced kidney injury characterized by renal dysfunction and pathological changes. The protective mechanisms of LDR are complicated but may be mainly attributed to the attenuation of dyslipidemia and the subsequent lipotoxicity-induced insulin resistance, inflammation and oxidative stress.

  2. Muscle-derived expression of the chemokine CXCL1 attenuates diet-induced obesity and improves fatty acid oxidation in the muscle

    DEFF Research Database (Denmark)

    Pedersen, Line; Holkmann Olsen, Caroline; Pedersen, Bente Klarlund

    2012-01-01

    Serum levels and muscle expression of the chemokine CXCL1 increase markedly in response to exercise in mice. Because several studies have established muscle-derived factors as important contributors of metabolic effects of exercise, this study aimed at investigating the effect of increased expres...... in muscle angiogenesis. In conclusion, our data show that overexpression of CXCL1 within a physiological range attenuates diet-induced obesity, likely mediated through a CXCL1-induced improvement of fatty acid oxidation and oxidative capacity in skeletal muscle tissue....

  3. Assessment of Radiation-Attenuated Vaccine or Thyme Oil Treatment on Controlling DNA Damage and Nitric Oxide Synthesis in Brain of Rat Infected with Toxocara canis

    International Nuclear Information System (INIS)

    Amin, M.M.; Hafez, E.N.; Abd Raboo, M.A.

    2016-01-01

    Toxocara canis is a worldwide zoonotic roundworm that infects a number of hosts including humans. It exhibits marked affinity to the nervous tissues. This study deals with the changes in the brain of Toxocara canis infected rats regarding parasitological, nitric oxide (NO) level and DNA damage compared to the effect of vaccination with gamma radiation-attenuated embryonated egg or thyme oil treatment. Eighty rats were classified into four groups (twenty each): GI (normal control); GII infected with 2500 T. canis infective eggs/ml/rat (infected control); GIII vaccinated with 800 Gy gamma-attenuated embryonated eggs (vaccinated group) and GIV infected with 2500 T. canis eggs and treated with thyme oil (thyme treated group). At the 14th day post-infection, ten rats from each group were sacrificed and the remaining were re-infected (challenged) with the same number of eggs. At the 14th days post challenge, brain tissues were taken for larval recovery, nitric oxide level evaluation and DNA damage using fragmentation and comet assay. The results exhibited a significant decrease in larval count and nitric oxide level with less damage in brain cells in thyme treated and gamma radiation-attenuated vaccinated groups compared to control infected group. It is also, concluded that vaccination using γ- rays is more effective in protection compared to using thyme oil.

  4. Chronic Administration of Oil Palm (Elaeis guineensis Leaves Extract Attenuates Hyperglycaemic-Induced Oxidative Stress and Improves Renal Histopathology and Function in Experimental Diabetes

    Directory of Open Access Journals (Sweden)

    Varatharajan Rajavel

    2012-01-01

    Full Text Available Oil palm (Elaeis guineensis leaves extract (OPLE has antioxidant properties and because oxidative stress contributes to the pathogenesis of diabetic nephropathy (DN, we tested the hypothesis that OPLE prevents diabetes renal oxidative stress, attenuating injury. Sprague-Dawley rats received OPLE (200 and 500 mg kg−1 for 4 and 12 weeks after diabetes induction (streptozotocin 60 mg kg−1. Blood glucose level, body and kidney weights, urine flow rate (UFR, glomerular filtration rate (GFR, and proteinuria were assessed. Oxidative stress variables such as 8-hydroxy-2′-deoxyguanosine (8-OHdG, glutathione (GSH, and lipid peroxides (LPO were quantified. Renal morphology was analysed, and plasma transforming growth factor-beta1 (TGF-β1 was measured. Diabetic rats demonstrated increase in blood glucose and decreased body and increased kidney weights. Renal dysfunction (proteinuria, elevations in UFR and GFR was observed in association with increases in LPO, 8-OHdG, and TGF-β1 and a decrease in GSH. Histological evaluation of diabetic kidney demonstrated glomerulosclerosis and tubulointerstitial fibrosis. OPLE attenuated renal dysfunction, improved oxidative stress markers, and reduced renal pathology in diabetic animals. These results suggest OPLE improves renal dysfunction and pathology in diabetes by reducing oxidative stress; furthermore, the protective effect of OPLE against renal damage in diabetes depends on the dose of OPLE as well as progression of DN.

  5. Attenuating brain edema, hippocampal oxidative stress, and cognitive dysfunction in rats using hyperbaric oxygen preconditioning during simulated high-altitude exposure.

    Science.gov (United States)

    Lin, Hung; Chang, Ching-Ping; Lin, Hung-Jung; Lin, Mao-Tsun; Tsai, Cheng-Chia

    2012-05-01

    We assessed whether hyperbaric oxygen preconditioning (HBO2P) in rats induced heat shock protein (HSP)-70 and whether HSP-70 antibody (Ab) preconditioning attenuates high altitude exposure (HAE)-induced brain edema, hippocampal oxidative stress, and cognitive dysfunction. Rats were randomly divided into five groups: the non-HBO2P + non-HAE group, the HBO2P + non-HAE group, the non-HBO2P + HAE group, the HBO2P + HAE group, and the HBO2P + HSP-70 Abs + HAE group. The HBO2P groups were given 100% O2 at 2.0 absolute atmospheres for 1 hour per day for 5 consecutive days. The HAE groups were exposed to simulated HAE (9.7% O2 at 0.47 absolute atmospheres of 6,000 m) in a hypobaric chamber for 3 days. Polyclonal rabbit anti-mouse HSP-70-neutralizing Abs were intravenously injected 24 hours before the HAE experiments. Immediately after returning to normal atmosphere, the rats were given cognitive performance tests, overdosed with a general anesthetic, and then their brains were excised en bloc for water content measurements and biochemical evaluation and analysis. Non-HBO2P group rats displayed cognitive deficits, brain edema, and hippocampal oxidative stress (evidenced by increased toxic oxidizing radicals [e.g., nitric oxide metabolites and hydroxyl radicals], increased pro-oxidant enzymes [e.g., malondialdehyde and oxidized glutathione] but decreased antioxidant enzymes [e.g., reduced glutathione, glutathione peroxide, glutathione reductase, and superoxide dismutase]) in HAE. HBO2P induced HSP-70 overexpression in the hippocampus and significantly attenuated HAE-induced brain edema, cognitive deficits, and hippocampal oxidative stress. The beneficial effects of HBO2P were significantly reduced by HSP-70 Ab preconditioning. Our results suggest that high-altitude cerebral edema, cognitive deficit, and hippocampal oxidative stress can be prevented by HSP-70-mediated HBO2P in rats.

  6. Remote Ischemic Conditioning

    Science.gov (United States)

    Heusch, Gerd; Bøtker, Hans Erik; Przyklenk, Karin; Redington, Andrew; Yellon, Derek

    2014-01-01

    In remote ischemic conditioning (RIC) brief, reversible episodes of ischemia with reperfusion in one vascular bed, tissue or organ confer a global protective phenotype and render remote tissues and organs resistant to ischemia/reperfusion injury. The peripheral stimulus can be chemical, mechanical or electrical and involves activation of peripheral sensory nerves. The signal transfer to the heart or other organs is through neuronal and humoral communications. Protection can be transferred, even across species, with plasma-derived dialysate and involves nitric oxide, stromal derived factor-1α, microRNA-144, but also other, not yet identified factors. Intracardiac signal transduction involves: adenosine, bradykinin, cytokines, and chemokines, which activate specific receptors; intracellular kinases; and mitochondrial function. RIC by repeated brief inflation/deflation of a blood pressure cuff protects against endothelial dysfunction and myocardial injury in percutaneous coronary interventions, coronary artery bypass grafting and reperfused acute myocardial infarction. RIC is safe and effective, noninvasive, easily feasible and inexpensive. PMID:25593060

  7. Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression.

    Science.gov (United States)

    Stanquini, Laura Alves; Biojone, Caroline; Guimarães, Francisco Silveira; Joca, Sâmia Regiane

    2017-11-20

    Nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects in animal models sensitive to acute drug treatment such as the forced swimming test. However, it is not yet clear if repeated treatment with these drugs is required to induce antidepressant-like effects in preclinical models. The aim of this study was to test the effect induced by acute or repeated (7 days) treatment with 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS, in rats submitted to the learned helplessness (LH) model. In addition, we aimed at investigating if 7-NI treatment would increase brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus, similarly to the effect of prototype antidepressants. Animals were submitted to a pre-test (PT) session with inescapable footshocks or habituation (no shocks) to the experimental shuttle box. Six days later they were exposed to a test with escapable footshocks. Independent groups received acute (a single injection after PT or before test) or repeated (once a day for 7 days) treatment with vehicle or 7-NI (30 mg/kg). Repeated, but not acute, treatment with 7-NI attenuated LH development. The effect was similar to repeated imipramine treatment. Moreover, in an independent experimental group, only repeated treatment with 7-NI and imipramine increased BDNF protein levels in the hippocampus. The results suggest the nitrergic system could be a target for the treatment of depressive-like conditions. They also indicate that, similar to the positive control imipramine, the antidepressant-like effects of NOS inhibition could involve an increase in hippocampal BDNF levels.

  8. Tangshen formula attenuates hepatic steatosis by inhibiting hepatic lipogenesis and augmenting fatty acid oxidation in db/db mice.

    Science.gov (United States)

    Kong, Qin; Zhang, Haojun; Zhao, Tingting; Zhang, Weiku; Yan, Meihua; Dong, Xi; Li, Ping

    2016-12-01

    Tangshen formula (TSF), a well-prescribed traditional Chinese formula, has been used in the treatment of diabetic nephropathy. However, whether TSF ameliorates dyslipidemia and liver injury associated with diabetes remains unclear. In this study, we examined the effects of TSF on lipid profiles and hepatic steatosis in db/db mice. For this purpose, 8‑week-old db/db mice were treated with TSF or saline for 12 weeks via gavage and db/m mice were used as controls. Body weight and blood glucose levels were monitored weekly and bi-weekly, respectively. Blood samples were obtained for the analysis of lipids and enzymes related to hepatic function, and liver tissues were analyzed by histology, immunohistochemistry and molecular examination. The results revealed that TSF markedly reduced body weight, liver index [liver/body weight (LW/BW)] and improved lipid profiles, hepatic function and steatosis in db/db mice. TSF induced the phosphoralation of AMP-activated protein kinase and inhibited the activity of sterol regulatory element-binding protein 1 together with the inhibition of the expression of genes involved in de novo lipogenesis (DNL) and gluconeogenesis, such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), stearoyl CoA desaturase 1 (SCD1), glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase 1 (Pck1). Additionally, the silent mating type information regulation 2 homolog 1 (Sirt1)/peroxisome proliferator-activated receptor α (PPARα)/malonyl-CoA decarboxylase (MLYCD) cascade was potently activated by TSF in the liver and skeletal muscle of db/db mice, which led to enhanced fatty acid oxidation. These findings demonstrated that TSF attenuated hepatic fat accumulation and steatosis in db/db mice by inhibiting lipogenesis and augmenting fatty acid oxidation.

  9. Klotho upregulation contributes to the neuroprotection of ligustilide against cerebral ischemic injury in mice.

    Science.gov (United States)

    Long, Fang-Yi; Shi, Meng-Qi; Zhou, Hong-Jing; Liu, Dong-Ling; Sang, Na; Du, Jun-Rong

    2018-02-05

    Klotho, an aging-suppressor gene, encodes a protein that potentially acts as a neuroprotective factor. Our previous studies showed that ligustilide minimizes the cognitive dysfunction and brain damage induced by cerebral ischemia; however, the underlying mechanisms remain unclear. This study aims to investigate whether klotho is involved in the protective effects of ligustilide against cerebral ischemic injury in mice. Cerebral ischemia was induced by bilateral common carotid arterial occlusion. Neurobehavioral tests as well as Nissl and Fluoro-Jade B staining were used to evaluate the protective effects of ligustilide in cerebral ischemia, and Western blotting and ELISA approaches were used to investigate the underlying mechanisms. Administration of ligustilide prevented the development of neurological deficits and reduced neuronal loss in the hippocampal CA1 region and the caudate putamen after cerebral ischemia. The protective effects were associated with inhibition of the RIG-I/NF-κB p65 and Akt/FoxO1 pathways and with prevention of inflammation and oxidative stress in the brain. Further, downregulation of klotho could attenuate the neuroprotection of ligustilide against cerebral ischemic injury. Ligustilide exerted neuroprotective effects in mice after cerebral ischemia by regulating anti-inflammatory and anti-oxidant signaling pathways. Furthermore, klotho upregulation contributes to the neuroprotection of LIG against cerebral ischemic injury. These results indicated that ligustilide may be a promising therapeutic agent for the treatment of cerebral ischemia. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Tranexamic Acid Does Not Influence Cardioprotection by Ischemic Preconditioning and Remote Ischemic Preconditioning

    NARCIS (Netherlands)

    van Caster, Patrick; Eiling, Sandra; Boekholt, Yvonne; Behmenburg, Friederike; Dorsch, Marianne; Heinen, André; Hollmann, Markus W.; Huhn, Ragnar

    2018-01-01

    Prior studies have suggested that the antifibrinolytic drug aprotinin increases the infarct size after ischemia and reperfusion (I/R) and attenuates the effect of ischemic preconditioning (IPC). Aprotinin was replaced by tranexamic acid (TXA) in clinical practice. Here, we investigated whether TXA

  11. Dual Gas Treatment With Hydrogen and Carbon Monoxide Attenuates Oxidative Stress and Protects From Renal Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Nishida, T; Hayashi, T; Inamoto, T; Kato, R; Ibuki, N; Takahara, K; Takai, T; Yoshikawa, Y; Uchimoto, T; Saito, K; Tanda, N; Kouno, J; Minami, K; Uehara, H; Hirano, H; Nomi, H; Okada, Y; Azuma, H

    Hydrogen (H 2 ) and carbon monoxide (CO) gas are both reported to reduce reactive oxygen species and alleviate tissue ischemia-reperfusion (I-R) injury. The present study was conducted to evaluate the effects of a mixture of H 2 gas and CO gas (dual gas) in comparison with hydrogen gas (H 2 : 2%) alone on I-R renal injury (composition of dual gas; N 2 : 77.8%; O 2 : 20.9%; H 2 : 1.30%; CO: 250 parts per million). Adult male Sprague-Dawley rats (body weight 250-280 g) were divided into 5 groups: (1) sham operation control, (2) dual gas inhalation (dual treatment) without I-R treatment, (3) I-R renal injury, (4) H 2 gas alone inhalation (H 2 treatment) with I-R renal injury, and (5) dual treatment with I-R renal injury. I-R renal injury was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, and then contralateral nephrectomy was performed 2 weeks later. Renal function was markedly decreased at 24 hours after reperfusion, and thereafter the effects of dual gas were assessed by histologic examination and determination of the superoxide radical, together with functional and molecular analyses. Pathologic examination of the kidney of I-R rats revealed severe renal damage. Importantly, cytoprotective effects of the dual treatment in comparison with H 2 treatment and I-R renal injury were observed in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment and I-R renal injury showed significant decreases in blood urea nitrogen. Increased expression of several inflammatory cytokines (tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, nuclear factor-κB, hypoxia inducible factor-1α, and heme oxygenase-1) was attenuated by the dual treatment. Dual gas inhalation decreases oxidative stress and markedly improves I-R-induced renal injury. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Neuroprotection by curcumin in ischemic brain injury involves the Akt/Nrf2 pathway.

    Directory of Open Access Journals (Sweden)

    Jingxian Wu

    Full Text Available Oxidative damage plays a critical role in many diseases of the central nervous system. This study was conducted to determine the molecular mechanisms involved in the putative anti-oxidative effects of curcumin against experimental stroke. Oxygen and glucose deprivation/reoxygenation (OGD/R was used to mimic ischemic insult in primary cultured cortical neurons. A rapid increase in the intracellular expression of NAD(PH: quinone oxidoreductase1 (NQO1 induced by OGD was counteracted by curcumin post-treatment, which paralleled attenuated cell injury. The reduction of phosphorylation Akt induced by OGD was restored by curcumin. Consequently, NQO1 expression and the binding activity of nuclear factor-erythroid 2-related factor 2 (Nrf2 to antioxidant response element (ARE were increased. LY294002 blocked the increase in phospho-Akt evoked by curcumin and abolished the associated protective effect. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion for 60 minutes. Curcumin administration significantly reduced infarct size. Curcumin also markedly reduced oxidative stress levels in middle cerebral artery occlusion (MCAO rats; hence, these effects were all suppressed by LY294002. Taken together, these findings provide evidence that curcumin protects neurons against ischemic injury, and this neuroprotective effect involves the Akt/Nrf2 pathway. In addition, Nrf2 is involved in the neuroprotective effects of curcumin against oxidative damage.

  13. Neuroprotection by Curcumin in Ischemic Brain Injury Involves the Akt/Nrf2 Pathway

    Science.gov (United States)

    Wu, Jingxian; Li, Qiong; Wang, Xiaoyan; Yu, Shanshan; Li, Lan; Wu, Xuemei; Chen, Yanlin; Zhao, Jing; Zhao, Yong

    2013-01-01

    Oxidative damage plays a critical role in many diseases of the central nervous system. This study was conducted to determine the molecular mechanisms involved in the putative anti-oxidative effects of curcumin against experimental stroke. Oxygen and glucose deprivation/reoxygenation (OGD/R) was used to mimic ischemic insult in primary cultured cortical neurons. A rapid increase in the intracellular expression of NAD(P)H: quinone oxidoreductase1 (NQO1) induced by OGD was counteracted by curcumin post-treatment, which paralleled attenuated cell injury. The reduction of phosphorylation Akt induced by OGD was restored by curcumin. Consequently, NQO1 expression and the binding activity of nuclear factor-erythroid 2-related factor 2 (Nrf2) to antioxidant response element (ARE) were increased. LY294002 blocked the increase in phospho-Akt evoked by curcumin and abolished the associated protective effect. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion for 60 minutes. Curcumin administration significantly reduced infarct size. Curcumin also markedly reduced oxidative stress levels in middle cerebral artery occlusion (MCAO) rats; hence, these effects were all suppressed by LY294002. Taken together, these findings provide evidence that curcumin protects neurons against ischemic injury, and this neuroprotective effect involves the Akt/Nrf2 pathway. In addition, Nrf2 is involved in the neuroprotective effects of curcumin against oxidative damage. PMID:23555802

  14. Furoxans (oxadiazole-4N-oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory.

    Science.gov (United States)

    Horton, Austin; Nash, Kevin; Tackie-Yarboi, Ethel; Kostrevski, Alexander; Novak, Adam; Raghavan, Aparna; Tulsulkar, Jatin; Alhadidi, Qasim; Wamer, Nathan; Langenderfer, Bryn; Royster, Kalee; Ducharme, Maxwell; Hagood, Katelyn; Post, Megan; Shah, Zahoor A; Schiefer, Isaac T

    2018-04-23

    Nitric oxide (NO) mimetics and other agents capable of enhancing NO/cGMP signaling have demonstrated efficacy as potential therapies for Alzheimer's disease. A group of thiol-dependent NO mimetics known as furoxans may be designed to exhibit attenuated reactivity to provide slow onset NO effects. The present study describes the design, synthesis, and evaluation of a furoxan library resulting in the identification of a prototype furoxan, 5a, which was profiled for use in the CNS. 5a demonstrated negligible reactivity toward generic cellular thiols under physiological conditions. Nonetheless, cGMP dependent neuroprotection was observed. 5a (20 mg/kg) reversed cholinergic memory deficits in a mouse model of passive avoidance fear memory. Importantly, 5a can be prepared as a pharmaceutically acceptable salt and is observed in the brain 12 hr after oral administration, suggesting potential for daily dosing and excellent metabolic stability. Continued investigation into furoxans as attenuated NO mimetics for the CNS is warranted.

  15. Flavonoid-rich fraction of the Monodora tenuifolia seed extract attenuates behavioural alterations and oxidative damage in forced-swim stressed rats.

    Science.gov (United States)

    Ekeanyanwu, Raphael Chukwuma; Njoku, Obioma Uzoma

    2015-03-01

    The antidepressant effects of the flavonoid-rich fraction of Monodora tenuifolia seed extract were examined by assessing the extent of attenuation of behavioural alterations and oxidative damage in the rats that were stressed by forced swim test. Compared with the model control group, the altered behavioural parameters were attenuated significantly (P fluoxetine (10 mg·kg(-1)). The flavonoid-rich fraction and fluoxetine improved significantly (P < 0.05) the activities of the antioxidant enzymes such as superoxide dismutase and catalase as well as other biochemical parameters such as reduced glutathione, protein, and nitrite in the brain of the stressed rats. These results suggested that the flavonoid-rich fraction of Monodora tenuifolia seed extract exerted the antidepressant-like effects which could be useful in the management of stress induced disease. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  16. Low-ω3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Karina Reyes-Gordillo

    2016-01-01

    Full Text Available Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-ω3 fatty acid (Low-ω3FA that primarily regulates PGC1α and soy protein (SP that seems to have its major regulatory effect on PGC1β were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low ω3FA fish oil and soy protein. Low-ω3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1 and PGC1α and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1β and sterol regulatory element-binding protein 1c (SREBP1c and their target lipogenic pathway genes via the phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK. Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways.

  17. Filipendula ulmaria extracts attenuate cisplatin-induced liver and kidney oxidative stress in rats: In vivo investigation and LC-MS analysis.

    Science.gov (United States)

    Katanić, Jelena; Matić, Sanja; Pferschy-Wenzig, Eva-Maria; Kretschmer, Nadine; Boroja, Tatjana; Mihailović, Vladimir; Stanković, Vesna; Stanković, Nevena; Mladenović, Milan; Stanić, Snežana; Mihailović, Mirjana; Bauer, Rudolf

    2017-01-01

    Filipendula ulmaria, known as meadowsweet, is a perennial herb found in wild and cultivated habitats in Europe and Asia. Usage of F. ulmaria in traditional medicine is based on diuretic, astringent, antirheumatic, and anti-inflammatory properties of this plant. Exposure to cisplatin at a dose of 7.5 mg/kg caused significant increase in serum parameters of liver and kidneys function and tissue oxidative stress markers along with some histopathological changes in liver and kidney tissues of experimental rats, as well as high level of genotoxicity. Administration of F. ulmaria extracts in three different concentrations (100, 200, and 400 mg/kg/day) for 10 days resulted in a reduction of oxidative stress in tissues and decrease of serum parameters. Moreover, tested extracts attenuated the genotoxicity of cisplatin in reverse dose-dependent manner. F. ulmaria extracts had no in vitro cytotoxic activity at all applied concentrations (IC 50  > 50 μg/mL). Tested extracts, rich in polyphenolic compounds, attenuate cisplatin-induced liver and kidney oxidative stress, reduce tissue damage, and enhance the antioxidative status of experimental animals during cisplatin application. Therefore, F. ulmaria extracts may be used as supportive agent for the prevention and amelioration of cisplatin side effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-β receptor-mediated ERK and p38 pathways

    International Nuclear Information System (INIS)

    Zhang, Feng; Ni, Chunyan; Kong, Desong; Zhang, Xiaoping; Zhu, Xiaojing; Chen, Li; Lu, Yin; Zheng, Shizhong

    2012-01-01

    Hepatic fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with accumulation of extracellular matrix (ECM) in the liver. Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrogenesis. Compelling evidence indicates that oxidative stress is concomitant with liver fibrosis irrespective of the underlying etiology. Natural antioxidant ligustrazine exhibits potent antifibrotic activities, but the mechanisms are poorly understood. Our studies were to investigate the ligustrazine effects on HSC activation stimulated by hydrogen peroxide (H 2 O 2 ), an in vitro model mimicking the oxidative stress in liver fibrogenesis, and to elucidate the possible mechanisms. Our results demonstrated that H 2 O 2 at 5 μM significantly stimulated HSC proliferation and expression of marker genes of HSC activation; whereas ligustrazine dose-dependently suppressed proliferation and induced apoptosis in H 2 O 2 -activated HSCs, and attenuated expression of fibrotic marker genes. Mechanistic investigations revealed that ligustrazine reduced platelet-derived growth factor-β receptor (PDGF-βR) expression and blocked the phosphorylation of extracellular regulated protein kinase (ERK) and p38 kinase, two downstream effectors of PDGF-βR. Further molecular evidence suggested that ligustrazine interruption of ERK and p38 pathways was dependent on the blockade of PDGF-βR and might be involved in ligustrazine reduction of fibrotic marker gene expression under H 2 O 2 stimulation. Furthermore, ligustrazine modulated some proteins critical for HSC activation and ECM homeostasis in H 2 O 2 -stimulated HSCs. These data collectively indicated that ligustrazine could attenuate HSC activation caused by oxidative stress, providing novel insights into ligustrazine as a therapeutic option for hepatic fibrosis. Highlights: ► Ligustrazine inhibits oxidative stress-induced HSC activation. ► Ligustrazine reduces fibrotic marker genes

  19. Gamma-ray attenuation coefficients in some heavy metal oxide borate glasses at 662 keV

    International Nuclear Information System (INIS)

    Khanna, A.; Bhatti, S.S.; Singh, K.J.; Thind, K.S.

    1996-01-01

    The linear attenuation coefficient (μ) and mass attenuation coefficients (μ/ρ) of glasses in three systems: xPbO(1-x)B 2 O 3 , 0.25PbO.xCdO(0.75-x)B 2 O 3 and xBi 2 O 3 (1-x)B 2 O 3 were measured at 662 keV. Appreciable variations were noted in the attenuation coefficients due to changes in the chemical composition of glasses. In addition to this, absorption cross-sections per atom were also calculated. A comparison of shielding properties of these glasses with standar d shielding materials like lead, lead glass and concrete has proven that these glasses have a potential application as transparent radiation shielding. (orig.)

  20. Mesenchymal stem cells attenuate adriamycin-induced nephropathy by diminishing oxidative stress and inflammation via downregulation of the NF-kB.

    Science.gov (United States)

    Song, In-Hwan; Jung, Kyong-Jin; Lee, Tae-Jin; Kim, Joo-Young; Sung, Eon-Gi; Bae, Young Chul; Park, Yong Hoon

    2018-05-01

    This study aimed to evaluate the molecular mechanism mitigating progress of chronic nephropathy by mesenchymal stem cells (MSCs). Rats were divided into normal control (Normal), adriamycin (ADR)+vehicle (CON), and ADR+MSC (MSC) groups. Nephropathy was induced by ADR (4 mg/kg) and MSCs (2 × 10 6 ) were injected. Rats were euthanized 1 or 6 weeks after ADR injection. NF-kB, MAPKs, inflammation, oxidative stress, profibrotic molecules, and nephrin expression were evaluated. Electron and light microscopy were used for structural analysis. MSCs were co-cultured with renal tubular epithelial cells or splenocytes to evaluate relation with oxidative stress and inflammatory molecules RESULTS: Adriamycin treatment upregulated inflammation, oxidative stress, and profibrotic molecules; this was mitigated by MSCs. Glomerulosclerosis and interstitial fibrosis were observed in ADR-treated groups, and were more prominent in the CON group than in the MSC group. Fusion of foot processes and loss of slit diaphragms were also more prominent in the CON group than in the MSC group. In vitro, MSCs reduced oxidative stress related molecules, inflammatory cytokines, and NF-kB transcription. MSC- or ADR-induced regulation of NF-kB transcriptional activity was confirmed by a luciferase reporter assay. Mesenchymal stem cells attenuate ADR-induced nephropathy by diminishing oxidative stress and inflammation via downregulation of NF-kB. © 2017 Asian Pacific Society of Nephrology.

  1. Suppressive effects of 17β-estradiol on tributyltin-induced neuronal injury via Akt activation and subsequent attenuation of oxidative stress.

    Science.gov (United States)

    Ishihara, Yasuhiro; Fujitani, Noriko; Kawami, Tomohito; Adachi, Chika; Ishida, Atsuhiko; Yamazaki, Takeshi

    2014-03-18

    Neuroactive steroids are reported to protect neurons from various harmful compounds; however, the protective mechanisms remain largely unclear. In this study, we examined the suppressive effects of 17β-estradiol (E2) on tributyltin (TBT)-induced neurotoxicity. Organotypic hippocampal slices were prepared from neonatal rats and then cultured. Cell death was assayed by propidium iodide uptake. Levels of reactive oxygen species (ROS) were determined by dihydroethidium staining. Protein phosphorylation was evaluated by immunoblotting. Pretreatment of the slices with E2 dose-dependently attenuated the neuronal injury induced by TBT. An estrogen receptor antagonist, ICI182,780 abrogated these neuroprotective effects. The de novo protein synthesis inhibitors actinomycin D and cycloheximide showed no effects on the neuroprotective mechanism, indicating that a nongenomic pathway acting via the estrogen receptor may be involved in the neuroprotection conferred by E2. E2 suppressed the ROS production and lipid peroxidation induced by TBT, and these effects were almost completely canceled by ICI182,780. TBT decreased Akt phosphorylation, and this reduction was suppressed by E2. An Akt inhibitor, triciribine, attenuated the decreases in both the ROS production and neuronal injury mediated by E2. E2 enhances the phosphorylation of Akt, thereby attenuating the oxidative stress and subsequent neuronal injury induced by TBT. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. 3H-1,2-Dithiole-3-thione as a novel therapeutic agent for the treatment of ischemic stroke through Nrf2 defense pathway.

    Science.gov (United States)

    Kuo, Ping-Chang; Yu, I-Chen; Scofield, Barbara A; Brown, Dennis A; Curfman, Eric T; Paraiso, Hallel C; Chang, Fen-Lei; Yen, Jui-Hung

    2017-05-01

    Cerebral ischemic stroke accounts for more than 80% of all stroke cases. During cerebral ischemia, reactive oxygen species produced in brain tissue induce oxidative stress and inflammatory responses. D3T, the simplest compound of the cyclic, sulfur-containing dithiolethiones, is found in cruciferous vegetables and has been reported to induce antioxidant genes and glutathione biosynthesis through activation of Nrf2. In addition to antioxidant activity, D3T was also reported to possess anti-inflammatory effects. In this study, we evaluated the therapeutic potential of D3T for the treatment of ischemic stroke and investigated the mechanisms underlying the protective effects of D3T in ischemic stroke. Mice subjected to transient middle cerebral artery occlusion/reperfusion (tMCAO/R) were administered with vehicle or D3T to evaluate the effect of D3T in cerebral brain injury. We observed D3T reduced infarct size, decreased brain edema, lessened blood-brain barrier disruption, and ameliorated neurological deficits. Further investigation revealed D3T suppressed microglia (MG) activation and inhibited peripheral inflammatory immune cell infiltration of CNS in the ischemic brain. The protective effect of D3T in ischemic stroke is mediated through Nrf2 induction as D3T-attenuated brain injury was abolished in Nrf2 deficient mice subjected to tMCAO/R. In addition, in vitro results indicate the induction of Nrf2 by D3T is required for its suppressive effect on MG activation and cytokine production. In summary, we demonstrate for the first time that D3T confers protection against ischemic stroke, which is mediated through suppression of MG activation and inhibition of CNS peripheral cell infiltration, and that the protective effect of D3T in ischemic stroke is dependent on the activation of Nrf2. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Resistance exercise attenuates skeletal muscle oxidative stress, systemic pro-inflammatory state, and cachexia in Walker-256 tumor-bearing rats.

    Science.gov (United States)

    Padilha, Camila Souza; Borges, Fernando Henrique; Costa Mendes da Silva, Lilian Eslaine; Frajacomo, Fernando Tadeu Trevisan; Jordao, Alceu Afonso; Duarte, José Alberto; Cecchini, Rubens; Guarnier, Flávia Alessandra; Deminice, Rafael

    2017-09-01

    The aim of this study was to investigate the effects of resistance exercise training (RET) on oxidative stress, systemic inflammatory markers, and muscle wasting in Walker-256 tumor-bearing rats. Male (Wistar) rats were divided into 4 groups: sedentary controls (n = 9), tumor-bearing (n = 9), exercised (n = 9), and tumor-bearing exercised (n = 10). Exercised and tumor-bearing exercised rats were exposed to resistance exercise of climbing a ladder apparatus with weights tied to their tails for 6 weeks. The physical activity of control and tumor-bearing rats was confined to the space of the cage. After this period, tumor-bearing and tumor-bearing exercised animals were inoculated subcutaneously with Walker-256 tumor cells (11.0 × 10 7 cells in 0.5 mL of phosphate-buffered saline) while control and exercised rats were injected with vehicle. Following inoculation, rats maintained resistance exercise training (exercised and tumor-bearing exercised) or sedentary behavior (control and tumor-bearing) for 12 more days, after which they were euthanized. Results showed muscle wasting in the tumor-bearing group, with body weight loss, increased systemic leukocytes, and inflammatory interleukins as well as muscular oxidative stress and reduced mTOR signaling. In contrast, RET in the tumor-bearing exercised group was able to mitigate the reduced body weight and muscle wasting with the attenuation of muscle oxidative stress and systemic inflammatory markers. RET also prevented loss of muscle strength associated with tumor development. RET, however, did not prevent the muscle proteolysis signaling via FBXO32 gene messenger RNA expression in the tumor-bearing group. In conclusion, RET performed prior tumor implantation prevents cachexia development by attenuating tumor-induced systemic pro-inflammatory condition with muscle oxidative stress and muscle damage.

  4. Overview of Experimental and Clinical Findings regarding the Neuroprotective Effects of Cerebral Ischemic Postconditioning

    OpenAIRE

    Ma, Di; Feng, Liangshu; Deng, Fang; Feng, Jia-Chun

    2017-01-01

    Research on attenuating the structural and functional deficits observed following ischemia-reperfusion has become increasingly focused on the therapeutic potential of ischemic postconditioning. In recent years, various methods and animal models of ischemic postconditioning have been utilized. The results of these numerous studies have indicated that the mechanisms underlying the neuroprotective effects of ischemic postconditioning may involve reductions in the generation of free radicals and ...

  5. Edaravone attenuates lipopolysaccharide-induced acute respiratory distress syndrome associated early pulmonary fibrosis via amelioration of oxidative stress and transforming growth factor-β1/Smad3 signaling.

    Science.gov (United States)

    Wang, Xida; Lai, Rongde; Su, Xiangfen; Chen, Guibin; Liang, Zijing

    2018-01-01

    Pulmonary fibrosis is responsible for the both short-term and long-term outcomes in patients with acute respiratory distress syndrome (ARDS). There is still no effective cure to improve prognosis. The purpose of this study was to investigate whether edaravone, a free radical scavenger, have anti-fibrosis effects in the rat model of ARDS associated early pulmonary fibrosis by lipopolysaccharide (LPS) administration. Rats were subjected to intravenous injection of LPS, and edaravone was given intraperitoneally after LPS administration daily for 7 consecutive days. LPS treatment rapidly increased lung histopathology abnormalities, coefficient of lung, hydroxyproline and collagen I levels, stimulated myofibroblast differentiation and induced expression of TGF-β1 and activation of TGF-β1/Smad3 signaling as early as day 7 after LPS injection. Moreover, LPS intoxication significantly increased the contents of malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), whereas it dramatically decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities from day 1 after LPS treatment. On the contrary, edaravone treatment ameliorated LPS-induced myofibroblast differentiation and pulmonary fibrosis, simultaneously, and attenuated LPS-stimulated oxidative stress and activation of TGF-β1/Smad3 signaling. Collectively, edaravone may attenuate ARDS associated early pulmonary fibrosis through amelioration of oxidative stress and TGF-β1/Smad3 signaling pathway. Edaravone may be a promising drug candidate for the treatment of ARDS-related pulmonary fibrosis in early period. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD).

    Science.gov (United States)

    Ni, Xunjun; Wang, Haiyan

    2016-01-01

    Silymarin, which derived from the milk thistle plant (silybum marianum), has been used for centuries as a natural remedy for diseases of the liver and biliary tract. Considering the therapeutic potential to liver disease, we tested efficacy of silymarin on hepatic steatosis with a high fat diet (HFD)-induced mouse model of non-alcoholic fatty liver disease (NAFLD), and investigated possible effects on lipid metabolic pathways. In our study, silymarin could attenuate the hepatic steatosis, which was proved by both Oil Red O staining and hepatic triglyceride (TG) level determination. Furthermore, compared with INT-747, a potent and selective FXR agonist, silymarin could preserve plasmatic high-density lipoprotein cholesterol (HDL-C) to a higher level and low-density lipoprotein cholesterol (LDL-C) to a lower level, which benefited more to the circulation system. Through real-time PCR analysis, we clarified a vital protective role of silymarin in mRNA regulation of genes involved in lipid metabolism and oxidative stress. It was also shown that silymarin had no effects on body weight, food intake, and liver transaminase. Taken together, silymarin could attenuate hepatic steatosis in a mouse model of NAFLD through regulation of lipid metabolism and oxidative stress, and benefit to the circulation system. All these findings shed new light on NAFLD treatment.

  7. S-Allylmercaptocysteine Attenuates  Cisplatin-Induced Nephrotoxicity through  Suppression of Apoptosis, Oxidative Stress, and  Inflammation.

    Science.gov (United States)

    Zhu, Xiaosong; Jiang, Xiaoyan; Li, Ang; Zhao, Zhongxi; Li, Siying

    2017-02-20

    Cisplatin is a potent chemotherapeutic agent, but its clinical usage is limited by nephrotoxicity. S-allylmercaptocysteine (SAMC), one of the water-soluble organosulfur garlic derivatives, has antioxidant and anti-inflammatory properties and plays an important role in protecting cells from apoptosis. This study aims to examine the protective effects of SAMC on cisplatin nephrotoxicity and to explore the mechanism of its renoprotection. Rats were treated with cisplatin with or without pre-treatment with SAMC. Renal function, histological change, oxidative stress markers and antioxidant enzyme activities were investigated. Apoptotic marker, nuclearfactor (NF)-κB activity, expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (NQO1) and inflammatory cytokines were also examined. The effect of SAMC on cell viability and apoptosis was examined in cultured human kidney (HK-2) cells. SAMC was confirmed to significantly attenuate cisplatin-induced renal damage by using histological pathology and molecular biological method. Pre-treatment with SAMC reduced NF-κB activity, up-regulated Nrf2 and NQO1 expression and down-regulated inflammatory cytokine levels after cisplatin administration. Cisplatin-induced apoptosis in HK-2 cells was significantly attenuated by SAMC. Thus our results suggest that SAMC could be a potential therapeutic agent in the treatment of the cisplatin-induced nephrotoxicity through its anti-apoptotic, anti-oxidant and anti-inflammatory effects.

  8. Possible role of oxidative stress and immunological activation in mouse model of chronic fatigue syndrome and its attenuation by olive extract.

    Science.gov (United States)

    Gupta, Amit; Vij, Garima; Chopra, Kanwaljit

    2010-09-14

    Various putative theories involved in the development of chronic fatigue syndrome revolve around the role of stress, infection and oxidative stress. Scientific evidence highlighting the protective role of nutritional supplements in chronic fatigue syndrome is lacking. Based on these assumptions, the present study was designed to evaluate the effect of olive extract in a mouse model of immunologically-induced fatigue, wherein purified lipopolysaccharide (LPS) and Brucella abortus (BA) antigen were used as immunogens. The assessment of chronic fatigue syndrome was based on immobility period during chronic water-immersion stress test for 10 min daily. The stress-induced hyperalgesia was measured by tail withdrawal latency. Mice challenged with LPS or BA for 19 days showed significant increase in the immobility time, hyperalgesia and oxidative stress on the 19th day. Serum tumor necrosis factor-alpha (TNF-α) levels were also markedly increased with LPS or BA challenge. Concurrent treatment with olive extract resulted in a significant decrease in the immobility time as well as hyperalgesia. There was significant attenuation of oxidative stress as well as serum TNF-α levels. The results of the present study strongly indicate the role of oxidative stress and immunological activation in the pathophysiology of chronic fatigue syndrome and highlight the valuable role of olive extract in combating chronic fatigue syndrome. Copyright © 2010 Elsevier B.V. All rights reserved.

  9. Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin-induced diabetic osteopenia: a novel role of oxidative stress and therapeutic implications.

    Science.gov (United States)

    Hamada, Yasuhiro; Fujii, Hideki; Kitazawa, Riko; Yodoi, Junji; Kitazawa, Sohei; Fukagawa, Masafumi

    2009-05-01

    Diabetes mellitus is associated with increased risk of osteopenia and bone fracture. However, the mechanisms accounting for diabetic bone disorder are unclear. We have previously reported that streptozotocin-induced diabetic mice develop low turnover osteopenia associated with increased oxidative stress in the diabetic condition. To determine the role of oxidative stress in the development of diabetic osteopenia, we presently investigated the effect of overexpression of thioredoxin-1 (TRX), a major intracellular antioxidant, on the development of diabetic osteopenia, using TRX transgenic mice (TRX-Tg). TRX-Tg are C57BL/6 mice that carry the human TRX transgene under the control of beta-actin promoter. Eight-week-old male TRX-Tg mice and wild type (WT) littermates were intraperitoneally injected with either streptozotocin or vehicle. Mice were grouped as 1) non-diabetic WT, 2) non-diabetic TRX-Tg, 3) diabetic WT, and 4) diabetic TRX-Tg. After 12 weeks of streptozotocin treatment, oxidative stress on the whole body and bone was evaluated, and the physical properties of the femora, and histomorphometry parameters of the tibiae were assessed. TRX overexpression did not affect either body weight or hemoglobin A1c levels. There were no significant differences in renal function and in serum levels of calcium, phosphate, and intact parathyroid hormone among the four groups. On the other hand, urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, was significantly elevated in diabetic WT and attenuated in diabetic TRX-Tg. Immunohistochemical staining for 8-OHdG revealed marked intensity in the bone tissue of diabetic WT compared with non-diabetic WT, while staining was attenuated in diabetic TRX-Tg. TRX overexpression partially restored reduced bone mineral density and prevented the suppression of bone formation observed in diabetic WT. Increased oxidative stress in diabetic condition contributes to the development of diabetic osteopenia

  10. Protective effect of thymoquinone improves cardiovascular function, and attenuates oxidative stress, inflammation and apoptosis by mediating the PI3K/Akt pathway in diabetic rats.

    Science.gov (United States)

    Liu, Hui; Liu, Hong-Yang; Jiang, Yi-Nong; Li, Nan

    2016-03-01

    Thymoquinone is the main active monomer extracted from black cumin and has anti‑inflammatory, antioxidant and anti‑apoptotic functions. However, the protective effects of thymoquinone on cardiovascular function in diabetes remain to be fully elucidated. The present study aimed to investigate the molecular mechanisms underling the beneficial effects of thymoquinone on the cardiovascular function in streptozotocin‑induced diabetes mellitus (DM) rats. Supplement thymoquinone may recover the insulin levels and body weight, inhibit blood glucose levels and reduce the heart rate in DM‑induced rats. The results indicated that the heart, liver and lung to body weight ratios, in addition to the blood pressure levels, were similar for each experimental group. Treatment with thymoquinone significantly reduced oxidative stress damage, inhibited the increased endothelial nitric oxide synthase protein expression and suppressed the elevation of cyclooxygenase‑2 levels in DM‑induced rats. In addition, thymoquinone significantly suppressed the promotion of tumor necrosis factor‑α and interleukin‑6 levels in the DM‑induced rats. Furthermore, administration of thymoquinone significantly reduced caspase‑3 activity and the promotion of phosphorylated‑protein kinase B (Akt) protein expression levels in DM‑induced rats. These results suggest that the protective effect of thymoquinone improves cardiovascular function and attenuates oxidative stress, inflammation and apoptosis by mediating the phosphatidylinositol 3‑kinase/Akt pathway in DM‑induced rats.

  11. Astragalus membranaceus Extract Attenuates Inflammation and Oxidative Stress in Intestinal Epithelial Cells via NF-κB Activation and Nrf2 Response

    Directory of Open Access Journals (Sweden)

    Simona Adesso

    2018-03-01

    Full Text Available Astragalus membranaceus, dried root extract, also known as Astragali radix, is used in traditional Chinese medicine as a tonic remedy. Moreover, it has been reported that Astragalus membranaceus could attenuate intestinal inflammation; however, the underlying mechanism for its anti-inflammatory activity in intestinal epithelial cells (IECs remains unclear. In this study, we evaluated Astragalus membranaceus extract (5–100 µg/mL in a model of inflammation and oxidative stress for IECs. We showed that Astragalus membranaceus extract reduced the inflammatory response induced by lipopolysaccharide from E. coli (LPS plus interferon-γ (IFN, decreasing tumor necrosis factor-α (TNF-α release, cycloxygenase-2 (COX-2 and inducible nitric oxide synthase (iNOS expression, nitrotyrosine formation, nuclear factor-κB (NF-κB activation, and reactive oxygen species (ROS release in the non-tumorigenic intestinal epithelial cell line (IEC-6. The antioxidant potential of Astragalus membranaceus extract was also evaluated in a model of hydrogen peroxide (H2O2-induced oxidative stress in IEC-6, indicating that this extract reduced ROS release and increased nuclear factor (erythroid-derived 2-like 2 (Nrf2 activation and the expression of antioxidant cytoprotective factors in these cells. The results contributed to clarify the mechanisms involved in Astragalus membranaceus extract-reduced inflammation and highlighted the potential use of this extract as an anti-inflammatory and antioxidant remedy for intestinal diseases.

  12. Magnetic resonance imaging in acute ischemic stroke

    Energy Technology Data Exchange (ETDEWEB)

    Ohta, Kouichi [Mito Red Cross Hospital (Japan)

    2000-01-01

    This paper summarizes current MRI technology used in the diagnosis of acute cerebral infarction and discusses tasks for further improvement of MRI technology. First, the principles and methods of MRI imaging are described in terms of 1) diffusion-weighted imaging (DWI) and ADC maps, 2) perfusion imaging, 3) the fluid-attenuated inversion recovery (FLAIR) method, and 4) MR angiography (MRA). Then, the actual use of MRI in the early phase of ischemic cerebrovascular disorders is discussed focusing on general MRI procedures, cases in which an ischemic lesion dose not yield a high signal with DWI in the acute phase, and chronological changes in DWI signal strength and ADC. Third, chronological changes in acute cerebrovascular disorder in an animal model of local cerebral ischemia are summarized in terms of expansion of reduced ADC areas and ischemic penumbras in the acute phase of cerebral ischemia. Finally, chronological changes in acute ischemic disorders in patients with cerebrovascular disorders are assessed by reviewing the development of reduced ADC and expansion of DWI lesions. Whether MRI can identify cerebral tissues that can be rescued by the reperfusion method by examining the mismatchs between perfusion images and DWI, relative CBV, and ADC is also discussed. (K.H.)

  13. Pomegranate juice and punicalagin attenuate oxidative stress and apoptosis in human placenta and in human placental trophoblasts

    Science.gov (United States)

    Tuuli, Methodius G.; Longtine, Mark S.; Shin, Joong Sik; Lawrence, Russell; Inder, Terrie; Michael Nelson, D.

    2012-01-01

    The human placenta is key to pregnancy outcome, and the elevated oxidative stress present in many complicated pregnancies contributes to placental dysfunction and suboptimal pregnancy outcomes. We tested the hypothesis that pomegranate juice, which is rich in polyphenolic antioxidants, limits placental trophoblast injury in vivo and in vitro. Pregnant women with singleton pregnancies were randomized at 35∼38 wk gestation to 8 oz/day of pomegranate juice or apple juice (placebo) until the time of delivery. Placental tissues from 12 patients (4 in the pomegranate group and 8 in the control group) were collected for analysis of oxidative stress. The preliminary in vivo results were extended to oxidative stress and cell death assays in vitro. Placental explants and cultured primary human trophoblasts were exposed to pomegranate juice or glucose (control) under defined oxygen tensions and chemical stimuli. We found decreased oxidative stress in term human placentas from women who labored after prenatal ingestion of pomegranate juice compared with apple juice as control. Moreover, pomegranate juice reduced in vitro oxidative stress, apoptosis, and global cell death in term villous explants and primary trophoblast cultures exposed to hypoxia, the hypoxia mimetic cobalt chloride, and the kinase inhibitor staurosporine. Punicalagin, but not ellagic acid, both prominent polyphenols in pomegranate juice, reduced oxidative stress and stimulus-induced apoptosis in cultured syncytiotrophoblasts. We conclude that pomegranate juice reduces placental oxidative stress in vivo and in vitro while limiting stimulus-induced death of human trophoblasts in culture. The polyphenol punicalagin mimics this protective effect. We speculate that antenatal intake of pomegranate may limit placental injury and thereby may confer protection to the exposed fetus. PMID:22374759

  14. Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent

    Directory of Open Access Journals (Sweden)

    Lan Z

    2015-06-01

    Full Text Available Zujian Lan, Xiaoyu Xu, Wenkai Xu, Jin Li, Zengrong Liang, Xuefei Zhang, Ming Lei, Chunshun Zhao School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China Abstract: To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a–i derivatives, one of which (3d exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke. Keywords: stroke, platelet aggregation, ischemia/reperfusion, middle cerebral artery occlusion, 3-alkyl-2,3-dihydro-1H-isoindol-1-ones

  15. Anoxic nitrate reduction coupled with iron oxidation and attenuation of dissolved arsenic and phosphate in a sand and gravel aquifer

    Science.gov (United States)

    Smith, Richard L.; Kent, Douglas B.; Repert, Deborah A.; Böhlke, J.K.

    2017-01-01

    Nitrate has become an increasingly abundant potential electron acceptor for Fe(II) oxidation in groundwater, but this redox couple has not been well characterized within aquifer settings. To investigate this reaction and some of its implications for redox-sensitive groundwater contaminants, we conducted an in situ field study in a wastewater-contaminated aquifer on Cape Cod. Long-term (15 year) geochemical monitoring within the contaminant plume indicated interacting zones with variable nitrate-, Fe(II)-, phosphate-, As(V)-, and As(III)-containing groundwater. Nitrate and phosphate were derived predominantly from wastewater disposal, whereas Fe(II), As(III), and As(V) were mobilized from the aquifer sediments. Multiple natural gradient, anoxic tracer tests were conducted in which nitrate and bromide were injected into nitrate-free, Fe(II)-containing groundwater. Prior to injection, aqueous Fe(II) concentrations were approximately 175 μM, but sorbed Fe(II) accounted for greater than 90% of the total reactive Fe(II) in the aquifer. Nitrate reduction was stimulated within 1 m of transport for 100 μM and 1000 μM nitrate additions, initially producing stoichiometric quantities of nitrous oxide (>300 μM N). In subsequent injections at the same site, nitrate was reduced even more rapidly and produced less nitrous oxide, especially over longer transport distances. Fe(II) and nitrate concentrations decreased together and were accompanied by Fe(III) oxyhydroxide precipitation and decreases in dissolved phosphate, As(III), and As(V) concentrations. Nitrate N and O isotope fractionation effects during nitrate reduction were approximately equal (ε15N/ε18O = 1.11) and were similar to those reported for laboratory studies of biological nitrate reduction, including denitrification, but unlike some reported effects on nitrate by denitrification in aquifers. All constituents affected by the in situ tracer experiments returned to pre-injection levels after several

  16. Synergism effects of pioglitazone and Urtica dioica extract in streptozotocin-induced nephropathy via attenuation of oxidative stress

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    Mohammad Shokrzadeh

    2017-05-01

    Full Text Available Objective(s: Hyperglycemia promotes oxidative stress that plays a crucial role in the pathogenesis of Diabetic nephropathy (DN. In this study, we investigated the synergism effects of hydroalcoholic extract of Urtica dioica and pioglitazone (PIO on the prevention of DN in streptozotocin induced-diabetic mice. Materials and Methods: Forty-two mice were divided into six groups as follows: non-diabetic control group, DMSO group (as solvent, diabetic group and four treatment groups which received U. dioica, pioglitazone, U. dioica plus pioglitazone and vitE. Diabetes was induced by a single dose of streptozotocin (STZ (200 mg/kg body wt, IP diluted in citrate buffer (pH= 4.6. After 4 weeks treatment, all animals were anaesthetized and blood was collected for serum urea and creatinine levels assessment in plasma and kidney tissue were excised for evaluation of oxidative stress markers. Results: Treatment with U. dioica significantly inhibited increase in serum urea and creatinine in plasma that were observed in diabetic mice. Furthermore, the elevated level of oxidative stress markers (glutathione oxidation, lipid peroxidation (LPO, protein carbonyl in renal supernatant of diabetic mice was inhibited by U. dioica treatment.  Interestingly, U. dioica promoted beneficial effects of PIO in reducing STZ-induced hyperglycemia, renal damage and oxidative stress markers. Conclusion: Our findings showed that PIO plus U. dioica have synergism protective effects against STZ-induced nephropathy that can be a candidate as a therapeutic approach in order to treatment of DN.

  17. Synergism effects of pioglitazone and Urtica dioica extract in streptozotocin-induced nephropathy via attenuation of oxidative stress.

    Science.gov (United States)

    Shokrzadeh, Mohammad; Sadat-Hosseini, Sara; Fallah, Marjan; Shaki, Fatemeh

    2017-05-01

    Hyperglycemia promotes oxidative stress that plays a crucial role in the pathogenesis of Diabetic nephropathy (DN). In this study, we investigated the synergism effects of hydroalcoholic extract of Urtica dioica and pioglitazone (PIO) on the prevention of DN in streptozotocin induced-diabetic mice. Forty-two mice were divided into six groups as follows: non-diabetic control group, DMSO group (as solvent), diabetic group and four treatment groups which received U. dioica , pioglitazone, U. dioica plus pioglitazone and vitE. Diabetes was induced by a single dose of streptozotocin (STZ) (200 mg/kg body wt, IP) diluted in citrate buffer (pH= 4.6). After 4 weeks treatment, all animals were anaesthetized and blood was collected for serum urea and creatinine levels assessment in plasma and kidney tissue were excised for evaluation of oxidative stress markers. Treatment with U. dioica significantly inhibited increase in serum urea and creatinine in plasma that were observed in diabetic mice. Furthermore, the elevated level of oxidative stress markers (glutathione oxidation, lipid peroxidation (LPO), protein carbonyl) in renal supernatant of diabetic mice was inhibited by U. dioica treatment. Interestingly, U. dioica promoted beneficial effects of PIO in reducing STZ-induced hyperglycemia, renal damage and oxidative stress markers. Our findings showed that PIO plus U. dioica have synergism protective effects against STZ-induced nephropathy that can be a candidate as a therapeutic approach in order to treatment of DN.

  18. Dicranostiga leptopodu (Maxim.) Fedde extracts attenuated CCl4-induced acute liver damage in mice through increasing anti-oxidative enzyme activity to improve mitochondrial function.

    Science.gov (United States)

    Tang, Deping; Wang, Fang; Tang, Jinzhou; Mao, Aihong; Liao, Shiqi; Wang, Qin

    2017-01-01

    Dicranostiga Leptodu (Maxim.) fedde (DLF), a poppy plant, has been reported have many benefits and medicinal properties, including free radicals scavenging and detoxifying. However, the protective effect of DLF extracts against carbon tetrachloride (CCl 4 )-induced damage in mice liver has not been elucidated. Here, we demonstrated that DLF extracts attenuated CCl 4 -induced liver damage in mice through increasing anti-oxidative enzyme activity to improve mitochondrial function. In this study, the mice liver damage evoked by CCl 4 was marked by morphology changes, significant rise in lipid peroxidation, as well as alterations of mitochondrial respiratory function. Interestingly, pretreatment with DLF extracts attenuated CCl 4 -induced morphological damage and increasing of lipid peroxidation in mice liver. Additionally, DLF extracts improved mitochondrial function by preventing the disruption of respiratory chain and suppression of mitochondrial Na + K + -ATPase and Ca 2+ -ATPase activity. Furthermore, administration with DLF extracts elevated superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels and maintained the balance of redox status. This results showed that toxic protection effect of DLF extracts on mice liver is mediated by improving mitochondrial respiratory function and keeping the balance of redox status, which suggesting that DLF extracts could be used as potential toxic protection agent for the liver against hepatotoxic agent. Copyright © 2016. Published by Elsevier Masson SAS.

  19. Physical exercise prevents short and long-term deficits on aversive and recognition memory and attenuates brain oxidative damage induced by maternal deprivation.

    Science.gov (United States)

    Neves, Ben-Hur; Menezes, Jefferson; Souza, Mauren Assis; Mello-Carpes, Pâmela B

    2015-12-01

    It is known from previous research that physical exercise prevents long-term memory deficits induced by maternal deprivation in rats. But we could not assume similar effects of physical exercise on short-term memory, as short- and long-term memories are known to result from some different memory consolidation processes. Here we demonstrated that, in addition to long-term memory deficit, the short-term memory deficit resultant from maternal deprivation in object recognition and aversive memory tasks is also prevented by physical exercise. Additionally, one of the mechanisms by which the physical exercise influences the memory processes involves its effects attenuating the oxidative damage in the maternal deprived rats' hippocampus and prefrontal cortex.

  20. Enhanced Microwave Absorption and Surface Wave Attenuation Properties of Co0.5Ni0.5Fe2O4 Fibers/Reduced Graphene Oxide Composites

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    Yinrui Li

    2018-03-01

    Full Text Available Co0.5Ni0.5Fe2O4 fibers with a diameter of about 270 nm and a length of about 10 μm were synthesized by a microemulsion-mediated solvothermal method with subsequent heat treatment. The Co0.5Ni0.5Fe2O4 fibers/reduced graphene oxide (RGO composite was prepared by a facile in-situ chemical reduction method. The crystalline structures and morphologies were investigated based on X-ray diffraction patterns and scanning electron microscopy. Magnetization measurements were carried out using a vibrating sample magnetometer at room temperature. Co0.5Ni0.5Fe2O4 fibers/RGO composites achieve both a wider and stronger absorption and an adjustable surface wave attenuation compared with Co0.5Ni0.5Fe2O4 fibers, indicating the potential for application as advanced microwave absorbers.

  1. Imaging of cerebral ischemic edema and neuronal death

    Energy Technology Data Exchange (ETDEWEB)

    Kummer, Ruediger von [Universitaetsklinikum Carl Gustav Carus, Institut fuer Diagnostische und Interventionelle Neuroradiologie, Dresden (Germany); Dzialowski, Imanuel [Elblandklinikum Meissen, Neurologische Rehabilitationsklinik Grossenhain, Meissen (Germany)

    2017-06-15

    In acute cerebral ischemia, the assessment of irreversible injury is crucial for treatment decisions and the patient's prognosis. There is still uncertainty how imaging can safely differentiate reversible from irreversible ischemic brain tissue in the acute phase of stroke. We have searched PubMed and Google Scholar for experimental and clinical papers describing the pathology and pathophysiology of cerebral ischemia under controlled conditions. Within the first 6 h of stroke onset, ischemic cell injury is subtle and hard to recognize under the microscope. Functional impairment is obvious, but can be induced by ischemic blood flow allowing recovery with flow restoration. The critical cerebral blood flow (CBF) threshold for irreversible injury is ∝15 ml/100 g x min. Below this threshold, ischemic brain tissue takes up water in case of any residual capillary flow (ionic edema). Because tissue water content is linearly related to X-ray attenuation, computed tomography (CT) can detect and measure ionic edema and, thus, determine ischemic brain infarction. In contrast, diffusion-weighted magnetic resonance imaging (DWI) detects cytotoxic edema that develops at higher thresholds of ischemic CBF and is thus highly sensitive for milder levels of brain ischemia, but not specific for irreversible brain tissue injury. CT and MRI are complimentary in the detection of ischemic stroke pathology and are valuable for treatment decisions. (orig.)

  2. Polydatin attenuates d-galactose-induced liver and brain damage through its anti-oxidative, anti-inflammatory and anti-apoptotic effects in mice.

    Science.gov (United States)

    Xu, Lie-Qiang; Xie, You-Liang; Gui, Shu-Hua; Zhang, Xie; Mo, Zhi-Zhun; Sun, Chao-Yue; Li, Cai-Lan; Luo, Dan-Dan; Zhang, Zhen-Biao; Su, Zi-Ren; Xie, Jian-Hui

    2016-11-09

    Accumulating evidence has shown that chronic injection of d-galactose (d-gal) can mimic natural aging, with accompanying liver and brain injury. Oxidative stress and apoptosis play a vital role in the aging process. In this study, the antioxidant ability of polydatin (PD) was investigated using four established in vitro systems. An in vivo study was also conducted to investigate the possible protective effect of PD on d-gal-induced liver and brain damage. The results showed that PD had remarkable in vitro free radical scavenging activity on 2,2-diphenyl-1-picryl-hydrazyl (DPPH˙), 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) (ABTS + ˙) radical ions, and hydroxyl and superoxide anions. Results in vivo indicated that, in a group treated with d-gal plus PD, PD remarkably decreased the depression of body weight and organ indexes, reduced the levels of the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and alleviated alterations in liver and brain histopathology. PD also significantly decreased the level of MDA and elevated SOD, GSH-Px, CAT activity and T-AOC levels in the liver and brain. In addition, the levels of inflammatory mediators, such as TNF-α, IL-1β and IL-6 in serum were markedly reduced after PD treatment. Western blotting results revealed that PD treatment noticeably attenuated the d-gal-induced elevation of Bcl-2/Bax ratio and caspase-3 protein expression in liver and brain. Overall, our findings indicate that PD treatment could effectively attenuate d-gal-induced liver and brain damage, and the mechanism might be associated with decreasing the oxidative stress, inflammation and apoptosis caused by d-gal. PD holds good potential for further development into a promising pharmaceutical candidate for the treatment of age-associated diseases.

  3. Alcohol Dehydrogenase Protects against Endoplasmic Reticulum Stress-Induced Myocardial Contractile Dysfunction via Attenuation of Oxidative Stress and Autophagy: Role of PTEN-Akt-mTOR Signaling.

    Directory of Open Access Journals (Sweden)

    Jiaojiao Pang

    Full Text Available The endoplasmic reticulum (ER plays an essential role in ensuring proper folding of the newly synthesized proteins. Aberrant ER homeostasis triggers ER stress and development of cardiovascular diseases. ADH is involved in catalyzing ethanol to acetaldehyde although its role in cardiovascular diseases other than ethanol metabolism still remains elusive. This study was designed to examine the impact of ADH on ER stress-induced cardiac anomalies and underlying mechanisms involved using cardiac-specific overexpression of alcohol dehydrogenase (ADH.ADH and wild-type FVB mice were subjected to the ER stress inducer tunicamycin (1 mg/kg, i.p., for 48 hrs. Myocardial mechanical and intracellular Ca(2+ properties, ER stress, autophagy and associated cell signaling molecules were evaluated.ER stress compromised cardiac contractile function (evidenced as reduced fractional shortening, peak shortening, maximal velocity of shortening/relengthening, prolonged relengthening duration and impaired intracellular Ca(2+ homeostasis, oxidative stress and upregulated autophagy (increased LC3B, Atg5, Atg7 and p62, along with dephosphorylation of PTEN, Akt and mTOR, all of which were attenuated by ADH. In vitro study revealed that ER stress-induced cardiomyocyte anomaly was abrogated by ADH overexpression or autophagy inhibition using 3-MA. Interestingly, the beneficial effect of ADH was obliterated by autophagy induction, inhibition of Akt and mTOR. ER stress also promoted phosphorylation of the stress signaling ERK and JNK, the effect of which was unaffected by ADH transgene.Taken together, these findings suggested that ADH protects against ER stress-induced cardiac anomalies possibly via attenuation of oxidative stress and PTEN/Akt/mTOR pathway-regulated autophagy.

  4. Utility of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) in the postmortem diagnosis of ischemic heart disease.

    Science.gov (United States)

    Takasu, Shojiro; Matsumoto, Sari; Kanto, Yuko; Iwadate, Kimiharu

    2018-04-01

    Ischemic heart disease (IHD) is a major cause of death in developed countries. Postmortem IHD diagnosis using biochemical markers is difficult because of the postmortem changes. In the present study, we investigated the utility of soluble lectin-like low-density lipoprotein receptor-1 (sLOX-1) in body fluids obtained from forensic autopsy cases. We measured pericardial fluid, urine, and serum sLOX-1 levels; these samples were obtained from medicolegal autopsy cases (n = 149, postmortem interval fluid and urine of patients with acute IHD had higher sLOX-1 levels (p fluid and urine samples obtained postmortem are useful markers of acute IHD. Copyright © 2018 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  5. MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism.

    Science.gov (United States)

    Liao, Weitang; Fu, Zongjie; Zou, Yanfang; Wen, Dan; Ma, Hongkun; Zhou, Fangfang; Chen, Yongxi; Zhang, Mingjun; Zhang, Wen

    2017-11-15

    Oxidative stress was predominantly involved in the pathogenesis of acute kidney injury (AKI). Recent studies had reported the protective role of specific microRNAs (miRNAs) against oxidative stress. Hence, we investigated the levels of miR140-5p and its functional role in the pathogenesis of Cisplatin induced AKI. A mice Cisplatin induced-AKI model was established. We found that miR-140-5p expression was markedly increased in mice kidney. Bioinformatics analysis revealed nuclear factor erythroid 2-related factor (Nrf2) was a potential target of miR-140-5p, We demonstrated that miR-140-5p did not affect Kelch-like ECH-associated protein 1 (Keap1) level but directly targeted the 3'-UTR of Nrf2 mRNA and played a positive role in the regulation of Nrf2 expression which was confirmed by luciferase activity assay and western blot. What was more, consistent with miR140-5p expression, the mRNA and protein levels of Nrf2, as well as antioxidant response element (ARE)-driven genes Heme Oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase l (NQO1) were significantly increased in mice kidney tissues. In vitro study, Enforced expression of miR-140-5p in HK2 cells significantly attenuated oxidative stress by decreasing ROS level and increasing the expression of manganese superoxide dismutase (MnSOD). Simultaneously, miR-140-5p decreased lactate dehydrogenase (LDH) leakage and improved cell vitality in HK2 cells under Cisplatin-induced oxidative stress. However, HK2 cells transfected with a siRNA targeting Nrf2 abrogated the protective effects of miR-140-5p against oxidative stress. These results indicated that miR-140-5p might exert its anti-oxidative stress function via targeting Nrf2. Our findings showed the novel transcriptional role of miR140-5p in the expression of Nrf2 and miR-140-5p protected against Cisplatin induced oxidative stress by activating Nrf2-dependent antioxidant pathway, providing a potentially therapeutic target in acute kidney injury. Copyright © 2017

  6. Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation

    Czech Academy of Sciences Publication Activity Database

    Cahová, M.; Páleníčková, E.; Danková, H.; Sticová, E.; Burian, M.; Drahota, Zdeněk; Červinková, Z.; Kučera, O.; Gladkova, Ch.; Stopka, Pavel; Křížová, Jana; Papáčková, Z.; Oliyarnyk, O.; Kazdová, L.

    2015-01-01

    Roč. 309, č. 2 (2015), G100-G111 ISSN 0193-1857 R&D Projects: GA MŠk(CZ) LL1204 Institutional support: RVO:67985823 ; RVO:61388980 Keywords : metformin * oxidative stress * mitochondrial respiration * liver injury * 31P MR spectroscopy Subject RIV: EB - Genetics ; Molecular Biology; CA - Inorganic Chemistry (UACH-T) Impact factor: 3.297, year: 2015

  7. Ropivacaine-Induced Contraction Is Attenuated by Both Endothelial Nitric Oxide and Voltage-Dependent Potassium Channels in Isolated Rat Aortae

    Directory of Open Access Journals (Sweden)

    Seong-Ho Ok

    2013-01-01

    Full Text Available This study investigated endothelium-derived vasodilators and potassium channels involved in the modulation of ropivacaine-induced contraction. In endothelium-intact rat aortae, ropivacaine concentration-response curves were generated in the presence or absence of the following inhibitors: the nonspecific nitric oxide synthase (NOS inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, the neuronal NOS inhibitor Nω-propyl-L-arginine hydrochloride, the inducible NOS inhibitor 1400W dihydrochloride, the nitric oxide-sensitive guanylyl cyclase (GC inhibitor ODQ, the NOS and GC inhibitor methylene blue, the phosphoinositide-3 kinase inhibitor wortmannin, the cytochrome p450 epoxygenase inhibitor fluconazole, the voltage-dependent potassium channel inhibitor 4-aminopyridine (4-AP, the calcium-activated potassium channel inhibitor tetraethylammonium (TEA, the inward-rectifying potassium channel inhibitor barium chloride, and the ATP-sensitive potassium channel inhibitor glibenclamide. The effect of ropivacaine on endothelial nitric oxide synthase (eNOS phosphorylation in human umbilical vein endothelial cells was examined by western blotting. Ropivacaine-induced contraction was weaker in endothelium-intact aortae than in endothelium-denuded aortae. L-NAME, ODQ, and methylene blue enhanced ropivacaine-induced contraction, whereas wortmannin, Nω-propyl-L-arginine hydrochloride, 1400W dihydrochloride, and fluconazole had no effect. 4-AP and TEA enhanced ropivacaine-induced contraction; however, barium chloride and glibenclamide had no effect. eNOS phosphorylation was induced by ropivacaine. These results suggest that ropivacaine-induced contraction is attenuated primarily by both endothelial nitric oxide and voltage-dependent potassium channels.

  8. Troxerutin attenuates diet-induced oxidative stress, impairment of mitochondrial biogenesis and respiratory chain complexes in mice heart.

    Science.gov (United States)

    Rajagopalan, Geetha; Chandrasekaran, Sathiya Priya; Carani Venkatraman, Anuradha

    2017-01-01

    Mitochondrial abnormality is thought to play a key role in cardiac disease originating from the metabolic syndrome (MS). We evaluated the effect of troxerutin (TX), a semi-synthetic derivative of the natural bioflavanoid rutin, on the respiratory chain complex activity, oxidative stress, mitochondrial biogenesis and dynamics in heart of high fat, high fructose diet (HFFD) -induced mouse model of MS. Adult male Mus musculus mice of body weight 25-30 g were fed either control diet or HFFD for 60 days. Mice from each dietary regimen were divided into two groups on the 16th day and were treated or untreated with TX (150 mg/kg body weight [bw], per oral) for the next 45 days. At the end of experimental period, respiratory chain complex activity, uncoupling proteins (UCP)-2 and -3, mtDNA content, mitochondrial biogenesis and dynamics, oxidative stress markers and reactive oxygen species (ROS) generation were analyzed. Reduced mtDNA abundance with alterations in the expression of genes related to mitochondrial biogenesis and fission and fusion processes were observed in HFFD-fed mice. Disorganized and smaller mitochondria, reduction in complexes I, III and IV activities (by about 55%) and protein levels of UCP-2 (52%) and UCP-3 (46%) were noted in these mice. TX administration suppressed oxidative stress, improved the oxidative capacity and biogenesis and restored fission/fusion imbalance in the cardiac mitochondria of HFFD-fed mice. TX protects the myocardium by modulating the putative molecules of mitochondrial biogenesis and dynamics and by its anti-oxidant function in a mouse model of MS. © 2016 John Wiley & Sons Australia, Ltd.

  9. Erythropoietin Attenuates the Memory Deficits in Aging Rats by Rescuing the Oxidative Stress and Inflammation and Promoting BDNF Releasing.

    Science.gov (United States)

    Jia, Zhankui; Xue, Rui; Ma, Shengli; Xu, Jingjing; Guo, Si; Li, Songchao; Zhang, Erwei; Wang, Jun; Yang, Jinjian

    2016-10-01

    Aging is a natural process accompanied with many disorders, including the memory decline. The underlying mechanisms for the age-related memory decline are complicated. Previous work suggested that oxidative stress, inflammatory disturbance, and the neurotropic absence play important roles in the age-related disorders. Thus, to seek a drug to target those abnormalities might be a possible protective approach for aging. Here, we reported that supplements with exogenous erythropoietin (EPO) for 4 weeks could partially rescue the spatial and fear memory impairments in aged rats. The EPO treatment also suppresses the oxidative stress and inflammatory response. Most importantly, EPO supplement restores the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), the critical neurotropic factor for synaptic plasticity and memory. Our study strongly suggests the potential usage of EPO in an anti-aging agent clinically.

  10. The Effect of Rebadioside A on Attenuation of Oxidative Stress in Kidney of Mice under Acetaminophen Toxicity

    Directory of Open Access Journals (Sweden)

    Seyed Ali Hashemi

    2014-11-01

    Full Text Available Background: Acetaminophen (APAP overdose causes renal and hepatic injury. It is also believed that oxidative stress has a pivotal role in APAP-induced renal injury. Therefore, protective effects of different antioxidants have been examined in APAP-induced renal and hepatic toxicity models. Stevia rebadiana is a plant with a high degree of natural antioxidant activity in its leaf extract. The aim of this study was to investigate the possible protective effects of rebadioside A; one of the main components of stevia extract, on APAP-induced oxidative stress in kidney of mice. Methods: Oxidative stress was induced in kidney of BALB/c mice by the intraperitoneal (i.p. administration of a single dose of 300 mg/kg APAP. Some of these mice also received rebadioside A (700 mg/kg (i.p. 30 minutes after APAP injection. Two and six hours after APAP injection, all mice were sacrificed and malondialdehyde (MDA, glutathione (GSH, free APAP, and glutathione conjugated of APAP (APAP-GSH were determined in the kidney tissue. Results: GSH depletion and MDA levels significantly (P<0.05 increased in mice treated with either APAP or APAP plus Rebadioside A, respectively in 2 and 6 hours intervals after APAP administration. Significantly (P<0.05 higher levels of free APAP and APAP-GSH levels detected in kidney of mice administrated with APAP plus rebadioside A compared to APAP treated ones. Conclusion: Rebadioside A may be a potential compound in alleviation of APAP-induced oxidative stress in kidney of mice after APAP overdoses.

  11. Saponins from Panax japonicus attenuate D-galactose-induced cognitive impairment through its anti-oxidative and anti-apoptotic effects in rats.

    Science.gov (United States)

    Wang, Ting; Di, Guojie; Yang, Li; Dun, Yaoyan; Sun, Zhiwei; Wan, Jingzhi; Peng, Ben; Liu, Chaoqi; Xiong, Guangrun; Zhang, Changcheng; Yuan, Ding

    2015-09-01

    To investigate the neuroprotective effects of saponins from Panax japonicus (SPJ) on D-galactose (D-gal)-induced brain ageing, and further explore the underlying mechanisms. SPJ were analysed using high-pressure liquid chromatography. Male Wistar rats weighing 200 ± 20 g were randomly divided into four groups: control group (saline), D-gal-treated group (400 mg/kg, subcutaneously), D-gal + SPJ groups (50, 100 and 200 mg/kg, orally) and vitamin E group (100 mg/kg). Rats were injected corresponding drugs once daily for 8 weeks. Neuroprotective effects of SPJ were evaluated by Morris water maze, histopathological observations, biochemical assays, western blot analysis and quantitative real-time polymerase chain reaction (PCR) analysis in vivo as well as reactive oxygen species (ROS) measurement and apoptosis assay in vitro. Our present study showed that D-gal had a neurotoxic effect in rats and in SH-SY5Y cells due to oxidative stress induction, including decreased total anti-oxidant capacity, superoxide dismutase (SOD) and glutathione peroxidase activity, ultimately leading to spatial learning and memory impairment in rats and ROS accumulation in SH-SY5Y cells. SPJ improved spatial learning and memory deficits, attenuated hippocampus histopathological injury and restored impaired anti-oxidative as well as anti-apoptotic capacities in D-gal-induced ageing rats. In addition, SPJ remarkably decreased lipofuscin levels, increased hippocampus nuclear factor erythroid 2-related factor 2 (Nrf2) and silent mating type information regulation 2 homologue (SIRT1) protein levels and anti-oxidant genes expression such as manganese superoxide dismutase (Mn-SOD), heme oxygenase (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1) and cysteine ligase catalytic (GCLC) in D-gal-induced brain ageing. Our data suggested that D-gal induced multiple molecular and functional changes in brain similar to natural ageing process. SPJ protected brain from D-gal-induced neuronal

  12. Argan Oil-Mediated Attenuation of Organelle Dysfunction, Oxidative Stress and Cell Death Induced by 7-Ketocholesterol in Murine Oligodendrocytes 158N

    Directory of Open Access Journals (Sweden)

    Asmaa Badreddine

    2017-10-01

    Full Text Available Argan oil is widely used in Morocco in traditional medicine. Its ability to treat cardiovascular diseases is well-established. However, nothing is known about its effects on neurodegenerative diseases, which are often associated with increased oxidative stress leading to lipid peroxidation and the formation of 7-ketocholesterol (7KC resulting from cholesterol auto-oxidation. As 7KC induces oxidative stress, inflammation and cell death, it is important to identify compounds able to impair its harmful effects. These compounds may be either natural or synthetic molecules or mixtures of molecules such as oils. In this context: (i the lipid profiles of dietary argan oils from Berkane and Agadir (Morocco in fatty acids, phytosterols, tocopherols and polyphenols were determined by different chromatographic techniques; and (ii their anti-oxidant and cytoprotective effects in 158N murine oligodendrocytes cultured with 7KC (25–50 µM; 24 h without and with argan oil (0.1% v/v or α-tocopherol (400 µM, positive control were evaluated with complementary techniques of cellular and molecular biology. Among the unsaturated fatty acids present in argan oils, oleate (C18:1 n-9 and linoleate (C18:1 n-6 were the most abundant; the highest quantities of saturated fatty acids were palmitate (C16:0 and stearate (C18:0. Several phytosterols were found, mainly schottenol and spinasterol (specific to argan oil, cycloartenol, β-amyrin and citrostadienol. α- and γ-tocopherols were also present. Tyrosol and protocatechic acid were the only polyphenols detected. Argan and extra virgin olive oils have many compounds in common, principally oleate and linoleate, and tocopherols. Kit Radicaux Libres (KRL and ferric reducing antioxidant power (FRAP tests showed that argan and extra virgin olive oils have anti-oxidant properties. Argan oils were able to attenuate the cytotoxic effects of 7KC on 158N cells: loss of cell adhesion, cell growth inhibition, increased plasma

  13. Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling

    Directory of Open Access Journals (Sweden)

    Marcondes Alves Barbosa Da Silva

    2015-10-01

    Full Text Available Type 2 diabetes (DM2 increases the risk of cardiovascular disease. Aldosterone, which has pro-oxidative and pro-inflammatory effects in the cardiovascular system, is positively regulated in DM2. We assessed whether blockade of mineralocorticoid receptors (MR with spironolactone decreases ROS-associated vascular dysfunction and improves vascular NO signaling in diabetes. Leptin receptor knockout [LepRdb/LepRdb (db/db] mice, a model of DM2, and their counterpart controls [LepRdb/LepR+, (db/+ mice] received spironolactone (50 mg/kg body weight/day or vehicle (ethanol 1% via oral per gavage for 6 weeks. Spironolactone treatment abolished the endothelial dysfunction and increased endothelial nitric oxide synthase (eNOS phosphorylation (Ser1177, determined by acetylcholine-induced relaxation and Western Blot analysis, respectively. MR antagonist therapy also abrogated augmented ROS-generation in aorta from diabetic mice, determined by lucigenin luminescence assay. Spironolactone treatment increased superoxide dismutase-1 (SOD1 and catalase expression, improved sodium nitroprusside (SNP and BAY 41-2272-induced relaxation, as well as increased soluble guanylyl cyclase (sGC subunit β protein expression in arteries from db/db mice. Our results demonstrate that spironolactone decreases diabetes-associated vascular oxidative stress and prevents vascular dysfunction through processes involving increased expression of antioxidant enzymes and sGC. These findings further elucidate redox-sensitive mechanisms whereby spironolactone protects against vascular injury in diabetes.

  14. Unsaponifiable fraction isolated from grape (Vitis vinifera L.) seed oil attenuates oxidative and inflammatory responses in human primary monocytes.

    Science.gov (United States)

    Millan-Linares, Maria C; Bermudez, Beatriz; Martin, Maria E; Muñoz, Ernesto; Abia, Rocio; Millan, Francisco; Muriana, Francisco J G; Montserrat-de la Paz, Sergio

    2018-04-25

    Grape (Vitis vinifera L.) seed has well-known potential for production of oil as a byproduct of winemaking and is a rich source of bioactive compounds. Herein, we report that the unsaponifiable fraction (UF) isolated from grape seed oil (GSO) possesses anti-oxidative and anti-inflammatory properties towards human primary monocytes. The UF isolated from GSO was phytochemically characterized by GC-MS and HPLC. Freshly obtained human monocytes were used to analyse the effects of GSOUF (10-100 μg mL-1) on oxidative and inflammatory responses using FACS analysis, RT-qPCR, and ELISA procedures. GSOUF skewed the monocyte plasticity towards the anti-inflammatory non-classical CD14+CD16++ monocytes and reduced the inflammatory competence of LPS-treated human primary monocytes diminishing TNF-α, IL-1β, and IL-6 gene expression and secretion. In addition, GSOUF showed a strong reactive oxygen species (ROS)-scavenging activity, reducing significantly nitrite levels with a significant decrease in Nos2 gene expression. Our results suggest that the UF isolated from GSO has significant potential for the management of inflammatory and oxidative conditions and offer novel benefits derived from the consumption of GSO in the prevention of inflammation-related diseases.

  15. Pomegranate peel extract attenuates oxidative stress by decreasing coronary angiotensin-converting enzyme (ACE) activity in hypertensive female rats.

    Science.gov (United States)

    Dos Santos, Roger L; Dellacqua, Lais O; Delgado, Nathalie T B; Rouver, Wender N; Podratz, Priscila L; Lima, Leandro C F; Piccin, Mariela P C; Meyrelles, Silvana S; Mauad, Helder; Graceli, Jones B; Moyses, Margareth R

    2016-01-01

    Based on the antioxidant properties of pomegranate, this study was designed to investigate the effects of pomegranate peel extract on damage associated with hypertension and aging in a spontaneously hypertensive rat (SHR) model. The influence of pomegranate consumption was examined on systolic blood pressure (SBP), angiotensin-converting enzyme (ACE) coronary activity, oxidative stress, and vascular morphology. Four- or 28-wk-old SHR model rats were treated for 30 d, with terminal experimental animal age being 8 and 32 wk, respectively, with either pomegranate extract (SHR-PG) or filtered water (SHR). Data showed significant reduction in SBP and coronary ACE activity in both age groups. The levels of superoxide anion, a measure of oxidative stress, were significantly lower in animals in the SHR-PG group compared to SHR alone. Coronary morphology demonstrated total increases in vascular wall areas were in the SHR group, and pomegranate peel extract diminished this effect. Pomegranate peel extract consumption conferred protection against hypertension in the SHR model. This finding was demonstrated by marked reduction in coronary ACE activity, oxidative stress, and vascular remodelling. In addition, treatment was able to reduce SBP in both groups. Evidence indicates that the use of pomegranate peel extract may prove beneficial in alleviating coronary heart disease.

  16. Troxerutin protects against 2,2',4,4'-tetrabromodiphenyl ether (BDE-47)-induced liver inflammation by attenuating oxidative stress-mediated NAD⁺-depletion.

    Science.gov (United States)

    Zhang, Zi-Feng; Zhang, Yan-Qiu; Fan, Shao-Hua; Zhuang, Juan; Zheng, Yuan-Lin; Lu, Jun; Wu, Dong-Mei; Shan, Qun; Hu, Bin

    2015-01-01

    Emerging evidence indicates that 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces liver injury through enhanced ROS production and lymphocytic infiltration, which may promote a liver inflammatory response. Antioxidants have been reported to attenuate the cellular toxicity associated with polybrominated diphenyl ethers (PBDEs). In this study, we investigated the effect of troxerutin, a trihydroxyethylated derivative of the natural bioflavonoid rutin, on BDE-47-induced liver inflammation and explored the potential mechanisms underlying this effect. Our results showed that NAD(+)-depletion was involved in the oxidative stress-mediated liver injury in a BDE-47 treated mouse model, which was confirmed by Vitamin E treatment. Furthermore, our data revealed that troxerutin effectively alleviated liver inflammation by mitigating oxidative stress-mediated NAD(+)-depletion in BDE-47 treated mice. Consequently, troxerutin remarkably restored SirT1 protein expression and activity in the livers of BDE-47-treated mice. Mechanistically, troxerutin dramatically repressed the nuclear translocation of NF-κB p65 and the acetylation of NF-κB p65 (Lys 310) and Histone H3 (Lys9) to abate the transcription of inflammatory genes in BDE-47-treated mouse livers. These inhibitory effects of troxerutin were markedly blunted by EX527 (SirT1 inhibitor) treatment. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be used in the prevention and therapy of BDE-47-induced hepatotoxicity. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Imoxin attenuates high fructose-induced oxidative stress and apoptosis in renal epithelial cells via downregulation of protein kinase R pathway.

    Science.gov (United States)

    Kalra, Jaspreet; Mangali, Suresh Babu; Bhat, Audesh; Dhar, Indu; Udumula, Mary Priyanka; Dhar, Arti

    2018-02-11

    Double-stranded RNA (dsRNA)-activated protein kinase R (PKR), a ubiquitously expressed serine/threonine kinase, is a key inducer of inflammation, insulin resistance, and glucose homeostasis in obesity. Recent studies have demonstrated that PKR can respond to metabolic stress in mice as well as in humans. However, the underlying molecular mechanism is not fully understood. The aim of this study was to examine the effect of high fructose (HF) in cultured renal tubular epithelial cells (NRK-52E) derived from rat kidney and to investigate whether inhibition of PKR could prevent any deleterious effects of HF in these cells. PKR expression was determined by immunofluorescence staining and Western blotting. Oxidative damage and apoptosis were measured by flow cytometry. HF-treated renal cells developed a significant increase in PKR expression. A significant increase in reactive oxygen species generation and apoptosis was also observed in HF-treated cultured renal epithelial cells. All these effects of HF were attenuated by a selective PKR inhibitor, imoxin (C16). In conclusion, our study demonstrates PKR induces oxidative stress and apoptosis, is a significant contributor involved in vascular complications and is a possible mediator of HF-induced hypertension. Inhibition of PKR pathway can be used as a therapeutic strategy for the treatment of cardiovascular and metabolic disorders. © 2018 Société Française de Pharmacologie et de Thérapeutique.

  18. Ketogenic Diet Provides Neuroprotective Effects against Ischemic Stroke Neuronal Damages

    Directory of Open Access Journals (Sweden)

    Sheida Shaafi

    2014-12-01

    Full Text Available Ischemic stroke is a leading cause of death and disability in the world. Many mechanisms contribute in cell death in ischemic stroke. Ketogenic diet which has been successfully used in the drug-resistant epilepsy has been shown to be effective in many other neurologic disorders. The mechanisms underlying of its effects are not well studied, but it seems that its neuroprotective ability is mediated at least through alleviation of excitotoxicity, oxidative stress and apoptosis events. On the basis of these mechanisms, it is postulated that ketogenic diet could provide benefits to treatment of cerebral ischemic injuries.

  19. Ischemic Conditioning as a Hemostatic Intervention in Surgery and Cardiac Procedures: A Systematic Review

    DEFF Research Database (Denmark)

    Krag, Andreas Engel; Hvas, Anne-Mette

    2017-01-01

    did not increase operative bleeding. In conclusion, ischemic conditioning reduced platelet activity without increasing the risk of bleeding in patients undergoing surgery or cardiac procedures. Limited evidence supports the proposal that ischemic conditioning reduces the incidence of arterial......Ischemic conditioning induced by nonlethal cycles of tissue ischemia and reperfusion attenuates ischemia–reperfusion injury. The objective of this study is to systematically review the effects of local and remote ischemic conditioning on laboratory parameters of hemostasis and the clinical outcomes......, thromboembolism, and bleeding were extracted for qualitative synthesis. In total, 69 studies were included; of these, 53 were randomized controlled trials (RCTs) and 11 were meta-analyses. Local and remote ischemic conditioning reduced platelet activation in patients undergoing cardiac procedures. Local ischemic...

  20. Drug Delivery to the Ischemic Brain

    Science.gov (United States)

    Thompson, Brandon J.; Ronaldson, Patrick T.

    2014-01-01

    Cerebral ischemia occurs when blood flow to the brain is insufficient to meet metabolic demand. This can result from cerebral artery occlusion that interrupts blood flow, limits CNS supply of oxygen and glucose, and causes an infarction/ischemic stroke. Ischemia initiates a cascade of molecular events inneurons and cerebrovascular endothelial cells including energy depletion, dissipation of ion gradients, calcium overload, excitotoxicity, oxidative stress, and accumulation of ions and fluid. Blood-brain barrier (BBB) disruption is associated with cerebral ischemia and leads to vasogenic edema, a primary cause of stroke-associated mortality. To date, only a single drug has received US Food and Drug Administration (FDA) approval for acute ischemic stroke treatment, recombinant tissue plasminogen activator (rt-PA). While rt-PA therapy restores perfusion to ischemic brain, considerable tissue damage occurs when cerebral blood flow is re-established. Therefore, there is a critical need for novel therapeutic approaches that can “rescue” salvageable brain tissue and/or protect BBB integrity during ischemic stroke. One class of drugs that may enable neural cell rescue following cerebral ischemia/reperfusion injury is the HMG-CoA reductase inhibitors (i.e., statins). Understanding potential CNS drug delivery pathways for statins is critical to their utility in ischemic stroke. Here, we review molecular pathways associated with cerebral ischemia and novel approaches for delivering drugs to treat ischemic disease. Specifically, we discuss utility of endogenous BBB drug uptake transporters such as organic anion transporting polypeptides (OATPs/Oatps) and nanotechnology-based carriers for optimization of CNS drug delivery. Overall, this chapter highlights state-of-the-art technologies that may improve pharmacotherapy of cerebral ischemia. PMID:25307217

  1. Rose oil (from Rosa × damascena Mill.) vapor attenuates depression-induced oxidative toxicity in rat brain.

    Science.gov (United States)

    Nazıroğlu, Mustafa; Kozlu, Süleyman; Yorgancıgil, Emre; Uğuz, Abdülhadi Cihangir; Karakuş, Kadir

    2013-01-01

    Oxidative stress is a critical route of damage in various physiological stress-induced disorders, including depression. Rose oil may be a useful treatment for depression because it contains flavonoids which include free radical antioxidant compounds such as rutin and quercetin. We investigated the effects of absolute rose oil (from Rosa × damascena Mill.) and experimental depression on lipid peroxidation and antioxidant levels in the cerebral cortex of rats. Thirty-two male rats were randomly divided into four groups. The first group was used as control, while depression was induced in the second group using chronic mild stress (CMS). Oral (1.5 ml/kg) and vapor (0.15 ml/kg) rose oil were given for 28 days to CMS depression-induced rats, constituting the third and fourth groups, respectively. The sucrose preference test was used weekly to identify depression-like phenotypes during the experiment. At the end of the experiment, cerebral cortex samples were taken from all groups. The lipid peroxidation levels in the cerebral cortex in the CMS group were higher than in control whereas their levels were decreased by rose oil vapor exposure. The vitamin A, vitamin E, vitamin C and β-carotene concentrations in the cerebral cortex were lower in the CMS group than in the control group whereas their concentrations were higher in the rose oil vapor plus CMS group. The CMS-induced antioxidant vitamin changes were not modulated by oral treatment. Glutathione peroxidase activity and reduced glutathione did not change statistically in the four groups following CMS or either treatment. In conclusion, experimental depression is associated with elevated oxidative stress while treatment with rose oil vapor induced protective effects on oxidative stress in depression.

  2. Curcumin attenuates oxidative stress induced NFκB mediated inflammation and endoplasmic reticulum dependent apoptosis of splenocytes in diabetes.

    Science.gov (United States)

    Rashid, Kahkashan; Chowdhury, Sayantani; Ghosh, Sumit; Sil, Parames C

    2017-11-01

    The present study was aimed to determine the curative role of curcumin against diabetes induced oxidative stress and its associated splenic complications. Diabetes was induced in the experimental rats via the intraperitoneal administration of a single dose of STZ (65mgkg -1 body weight). Increased blood glucose and intracellular ROS levels along with decreased body weight, the activity of cellular antioxidant enzymes and GSH/GSSG ratio were observed in the diabetic animals. Histological assessment showed white pulp depletion and damaged spleen anatomy in these animals. Oral administration of curcumin at a dose of 100mgkg -1 body weight daily for 8weeks, however, restored these alterations. Investigation of the mechanism of hyperglycemia induced oxidative stress mediated inflammation showed upregulation of inflammatory cytokines, chemokines, adhesion molecules and increased translocation of NFκB into the nucleus. Moreover, ER stress dependent cell death showed induction of eIF2α and CHOP mediated signalling pathways as well as increment in the expression of GRP78, Caspase-12, Calpain-1, phospho JNK, phospho p38 and phospho p53 in the diabetic group. Alteration of Bax/Bcl-2 ratio; disruption of mitochondrial membrane potential, release of cytochrome-C from mitochondria and upregulation of caspase 3 along with the formation of characteristic DNA ladder in the diabetic animals suggest the involvement of mitochondria dependent apoptotic pathway in the splenic cells. Treatment with curcumin could, however, protect cells from inflammatory damage and ER as well as mitochondrial apoptotic death by restoring the alterations of these parameters. Our results suggest that curcumin has the potential to act as an anti-diabetic, anti-oxidant, anti-inflammatory and anti-apoptotic therapeutic against diabetes mediated splenic damage. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Attenuation of pyrite oxidation with a fly ash pre-barrier: Reactive transport modelling of column experiments

    Energy Technology Data Exchange (ETDEWEB)

    Perez-Lopez, R.; Cama, J.; Nieto, J.M.; Ayora, C.; Saaltink, M.W. [University of Huelva, Huelva (Spain). Dept. of Geology

    2009-09-15

    Conventional permeable reactive barriers (PRBs) for passive treatment of groundwater contaminated by acid mine drainage (AMD) use limestone as reactive material that neutralizes water acidity. However, the limestone-alkalinity potential ceases as inevitable precipitation of secondary metal-phases on grain surfaces occurs, limiting its efficiency. In the present study, fly ash derived from coal combustion is investigated as an alternative alkalinity generating material for the passive treatment of AMD using solution-saturated column experiments. Unlike conventional systems, the utilization of fly ash in a pre-barrier to intercept the non-polluted recharge water before this water reacts with pyrite-rich wastes is proposed. Chemical variation in the columns was interpreted with the reactive transport code RETRASO. In parallel, kinetics of fly ash dissolution at alkaline pH were studied using flow-through experiments and incorporated into the model. In a saturated column filled solely with pyritic sludge-quartz sand (1: 10), oxidation took place at acidic conditions (pH 3.7). According to SO{sub 4}{sup 2-} release and pH, pyrite dissolution occurred favourably in the solution-saturated porous medium until dissolved O{sub 2} was totally consumed. In a second saturated column, pyrite oxidation took place at alkaline conditions (pH 10.45) as acidity was neutralized by fly ash dissolution in a previous level. At this pH Fe release from pyrite dissolution was immediately depleted as Fe-oxy(hydroxide) phases that precipitated on the pyrite grains, forming Fe-coatings (microencapsulation). With time, pyrite microencapsulation inhibited oxidation in practically 97% of the pyritic sludge. Rapid pyrite-surface passivation decreased its reactivity, preventing AMD production in the relatively short term.

  4. Troxerutin protects against 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47)-induced liver inflammation by attenuating oxidative stress-mediated NAD+-depletion

    International Nuclear Information System (INIS)

    Zhang, Zi-Feng; Zhang, Yan-qiu; Fan, Shao-Hua; Zhuang, Juan; Zheng, Yuan-Lin; Lu, Jun; Wu, Dong-Mei; Shan, Qun; Hu, Bin

    2015-01-01

    Highlights: • BDE-47 promotes liver inflammation by triggering oxidative stress-induced NAD + depletion. • Troxerutin inhibits BDE-47-induced liver inflammation via its antioxidant properties. • Troxerutin restores NAD + level and consequently abates SirT1 loss. • Troxerutin represses acetylation of NF-κB p65 (K310) and H3K9. • Troxerutin is a candidate for prevention and therapy of BDE-47-induced hepatotoxicity. - Abstract: Emerging evidence indicates that 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) induces liver injury through enhanced ROS production and lymphocytic infiltration, which may promote a liver inflammatory response. Antioxidants have been reported to attenuate the cellular toxicity associated with polybrominated diphenyl ethers (PBDEs). In this study, we investigated the effect of troxerutin, a trihydroxyethylated derivative of the natural bioflavonoid rutin, on BDE-47-induced liver inflammation and explored the potential mechanisms underlying this effect. Our results showed that NAD + -depletion was involved in the oxidative stress-mediated liver injury in a BDE-47 treated mouse model, which was confirmed by Vitamin E treatment. Furthermore, our data revealed that troxerutin effectively alleviated liver inflammation by mitigating oxidative stress-mediated NAD + -depletion in BDE-47 treated mice. Consequently, troxerutin remarkably restored SirT1 protein expression and activity in the livers of BDE-47-treated mice. Mechanistically, troxerutin dramatically repressed the nuclear translocation of NF-κB p65 and the acetylation of NF-κB p65 (Lys 310) and Histone H3 (Lys9) to abate the transcription of inflammatory genes in BDE-47-treated mouse livers. These inhibitory effects of troxerutin were markedly blunted by EX527 (SirT1 inhibitor) treatment. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be used in the prevention and therapy of BDE-47-induced hepatotoxicity

  5. Concomitant ingestion of lactic acid bacteria and black tea synergistically enhances flavonoid bioavailability and attenuates d-galactose-induced oxidative stress in mice via modulating glutathione antioxidant system.

    Science.gov (United States)

    Zhao, Danyue; Shah, Nagendra P

    2016-12-01

    Black tea (BT) has been positively linked to improved redox status, while its efficacy is limited due to the low bioavailability of BT flavonoids. In addition to the direct antioxidant activity, flavonoids regulate redox balance via inducing endogenous antioxidants, particularly glutathione (GSH) and GSH-dependent antioxidant enzymes. This work first examined the effect of lactic acid bacteria (LAB) and BT alone or in combination on flavonoid bioavailability and metabolism; next, the effect of LAB-fermented BT diet in attenuating oxidative stress in mice and the underlying mechanisms were studied. Phenolic profiles of plasma, urine and feces from healthy mice consuming plain yogurt, BT milk (BTM) or BT yogurt (BTY) were acquired using LC-MS/MS. Plasma antioxidant capacity, lipid peroxidation level, content of nonprotein thiols and expression of GSH-related antioxidant enzymes and Nrf2 were examined in d-galactose-treated mice. Total flavonoid content in plasma following a single dose of BTY attained 0.657 μmol/l, increased by 50% compared with the BTM group. Increased excretion of phenolic metabolite and hippuric acid in urine and feces indicated enhanced metabolism of flavonoids in BTY-fed mice. In the second study, 8-week concomitant LAB-BT treatment of oxidatively stressed mice effectively restored plasma antioxidant capacity and GSH levels, and mitigated lipid peroxidation, which were associated with significant induction of GSH-dependent antioxidant enzymes and nuclear accumulation of Nrf2. Our results demonstrated the effect of LAB fermentation in enhancing BT flavonoid bioavailability in vivo. The synergistic antioxidant efficacy of LAB-BT diet implied its therapeutic potential in enhancing antioxidant defenses and protecting organisms from oxidative damage. Copyright © 2016. Published by Elsevier Inc.

  6. Ischemic necrosis and osteochondritis

    International Nuclear Information System (INIS)

    Weissman, S.D.

    1989-01-01

    Osteonecrosis indicates that ischemic death of the cellular constituents of bone and marrow has occurred. Historically, this first was thought to be related to sepsis in the osseous segments. However, continued studies led to the use of the term aseptic necrosis. Subsequent observations indicated that the necrotic areas of bone were not only aseptic, but were also avascular. This led to the terms ischemic necrosis, vascular necrosis and bone infarction. Ischemic necrosis of bone is discussed in this chapter. It results from a significant reduction in or obliteration of blood supply to the affected area. The various bone cells, including osteocytes, osteoclasts, and osteoblasts, usually undergo anoxic death in 12 to 48 hours after blood supply is cut off. The infarct that has thus developed in three-dimensional and can be divided into a number of zones: a central zone of cell death; an area of ischemic injury, most severe near the zone of cell death, and lessening as it moves peripherally; an area of active hyperemia and the zone of normal unaffected tissue. Once ischemic necrosis has begun, the cellular damage provokes an initial inflammatory response, which typically is characterized by vasodilatation, transudation of fluid and fibrin, and local infiltration of flammatory cells. This response can be considered the first stage in repair of the necrotic area

  7. Effect of Kombucha, a fermented black tea in attenuating oxidative stress mediated tissue damage in alloxan induced diabetic rats.

    Science.gov (United States)

    Bhattacharya, Semantee; Gachhui, Ratan; Sil, Parames C

    2013-10-01

    Diabetic complications associated with increased oxidative stress can be suppressed by antioxidants. In the present study we investigated the antidiabetic and antioxidant effects of Kombucha (KT), a fermented black tea, in comparison to that of unfermented black tea (BT), in ALX-induced diabetic rats. ALX exposure lowered the body weight and plasma insulin by about 28.12% and 61.34% respectively and elevated blood glucose level and glycated Hb by about 3.79 and 3.73 folds respectively. The oxidative stress related parameters like lipid peroxidation end products (increased by 3.38, 1.7, 1.65, 1.94 folds respectively), protein carbonyl content (increased by 2.5, 2.35, 1.8, 3.26 folds respectively), glutathione content (decreased by 59.8%, 47.27%, 53.69%, 74.03% respectively), antioxidant enzyme activities were also altered in the pancreatic, hepatic, renal and cardiac tissues of diabetic animals. Results showed significant antidiabetic potential of the fermented beverage (150 mg lyophilized extract/kg bw for 14 days) as it effectively restored ALX-induced pathophysiological changes. Moreover, it could ameliorate DNA fragmentation and caspase-3 activation in the pancreatic tissue of diabetic rats. Although unfermented black tea is effective in the above pathophysiology, KT was found to be more efficient. This might be due to the formation of some antioxidant molecules during fermentation period. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Low-Dose Ribavirin Treatments Attenuate Neuroinflammatory Activation of BV-2 Cells by Interfering with Inducible Nitric Oxide Synthase

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    Iva Bozic

    2015-01-01

    Full Text Available Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation.

  9. Low-Dose Ribavirin Treatments Attenuate Neuroinflammatory Activation of BV-2 Cells by Interfering with Inducible Nitric Oxide Synthase

    Science.gov (United States)

    Bozic, Iva; Savic, Danijela; Jovanovic, Marija; Bjelobaba, Ivana; Laketa, Danijela; Nedeljkovic, Nadezda; Stojiljkovic, Mirjana; Pekovic, Sanja; Lavrnja, Irena

    2015-01-01

    Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM) modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM) to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS) stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation. PMID:26413464

  10. Minocycline through attenuation of oxidative stress and inflammatory response reduces the neuropathic pain in a rat model of chronic constriction injury

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    Abolfazl Abbaszadeh

    2018-02-01

    Full Text Available Objective(s: Several lines of evidence showed that minocycline possesses antioxidant and anti-inflammatory properties. This study aimed to demonstrate the effects of minocycline in rats subjected to chronic constriction injury (CCI. Materials and Methods: In this study four groups (n = 6–8 of rats were used as follows: Sham, CCI, CCI + minocycline (MIN 10 mg/Kg (IP and CCI + MIN 30 mg/Kg (IP. On days 3, 7, 14, and 21 post-surgery hot-plate, acetone, and von Frey tests were carried out. Finally, Motor Nerve Conduction Velocity Evaluation (MNCV assessment was performed and spinal cords were harvested in order to measure tissue concentrations of TNF_α, IL-1β, Glutathione peroxidase (GPx, Superoxide dismutase (SOD and Malondialdehyde (MDA. Extent of perineural inflammation and damage around the sciatic nerve was histopathologically evaluated. Results: Our results demonstrated that CCI significantly caused hyperalgesia and allodynia twenty-one days after CCI. MIN attenuated heat hyperalgesia, cold and mechanical allodynia and MNCV in animals. MIN also decreased the levels of TNF_α and IL-1β. Antioxidative enzymes (SOD, MDA, and GPx were restored following MIN treatment. Our findings showed that MIN decreased perineural inflammation around the sciatic nerve. According to the results, the neuropathic pain reduced in the CCI hyperalgesia model using 30 mg/kg of minocycline. Conclusion: It is suggested that antinociceptive effects of minocycline might be mediated through the inhibition of inflammatory response and attenuation of oxidative stress.

  11. Overexpression of HIPK2 attenuates spinal cord injury in rats by modulating apoptosis, oxidative stress, and inflammation.

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    Li, Renbo; Shang, Jingbo; Zhou, Wei; Jiang, Li; Xie, Donghui; Tu, Guanjun

    2018-04-09

    HIPK2 is considered to be a tumor suppressor. It also has been implicated in several functions such as apoptosis and inflammation that are linked to spinal cord injury (SCI). However, whether HIPK2 ameliorates the neurological pain of SCI remains unclear. Here, we investigated the effects of HIPK2 on neurological function, oxidative stress, levels of inflammatory cytokines and expression of Bcl-2/Bax in an SCI model. Firstly, we evaluated the therapeutic effects of HIPK2 on neurological pain in the SCI rat using the Basso, Beattie and Bresnahan scores and H & E staining. Overexpression of HIPK2 significantly elevated the levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), and reduced the mRNA expression of Nogo-A and RhoA in SCI rats. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays showed that overexpression of HIPK2 significantly reduced the number of apoptotic cells. Overexpression of HIPK2 also decreased expression of Bax and Caspase-3 and elevated expression of Bcl-2 in the SCI model, indicating that HIPK2 exhibited its protective activity by inhibiting SCI-induced apoptosis. Then, we measured the serum concentrations of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). We also determined the mRNA and protein levels of nuclear factor-κB p65 unit, tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β. HIPK2 overexpression reduced oxidative stress and the levels of inflammatory cytokines compared with SCI control animals. Additionally, acetylation of HIPK2 was reduced in SCI rats. Overexpression of HIPK2 could enhance autophagy by elevating the expression of Beclin-1 and LC3-II while autophagy is regarded as a beneficial regulator to improve spinal cord injury. Together, overexpression of HIPK2 improved contusive SCI induced pain by modulating oxidative stress, Bcl‑2 and Bax signaling, and

  12. Solanum torvum Swartz. fruit attenuates cadmium-induced liver and kidney damage through modulation of oxidative stress and glycosylation.

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    Ramamurthy, C H; Subastri, A; Suyavaran, A; Subbaiah, K C V; Valluru, L; Thirunavukkarasu, C

    2016-04-01

    Increased levels of environmental pollutants are linked to almost all human disorders; the efficient method to manage the human health is through naturally available dietary molecule. Solanum torvum (ST) Swartz (Solanaceae) commonly called Turkey Berry is found in Africa, Asia, and South America. Its fruit, part of traditional Indian cuisine, is a widely consumed nutritious herb, acclaimed for its medicinal value. ST aqueous extract (STAe) (250, 500, and 1000 mg/kg b.w., 6 days; oral) against acute Cadmium (Cd) (6.3 mg/kg b.w., single dose; oral) toxicity was evaluated in rats. Protective effect was assessed using serum markers, tissue antioxidants, oxidant derivatives, glycoprotein, and histopathological studies. The activities of serum marker enzymes were increased (40-60 %); antioxidant enzymes such as SOD and CAT, GSH, and its metabolic enzyme activities were decreased (50-80 %) in the liver and kidney upon Cd intoxication. During STAe pre-treatment, at doses of 250 and 500 mg/kg b.w., the above changes were brought to near normal (25-63 %). Tissue 4-hydroxynonenal, 3-nitrotyrosine, and protein carbonyls were increased (8-15 fold) in Cd-alone-treated rats, whereas pre-supplementation of STAe significantly decreased their levels and inhibited the protein glycosylation effectively. The pharmacological effect of STAe was confirmed by histopathological observations. Based on previous literature and present investigation, we conclude that ST may serve as a potential functional food against environmental contaminant such as heavy metal-induced oxidative stress.

  13. Nitric oxide donors attenuate clongenic potential in rat C6 glioma cells treated with alkylating chemotherapeutic agents.

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    Yang, Jir-Jei; Yin, Jiu-Haw; Yang, Ding-I

    2007-05-11

    1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) kills tumor cells via multiple actions including alkylation and carbamoylation. Previously, we have reported that formation of S-nitrosoglutathione (GSNO) in glioma cells overexpressing inducible nitric oxide synthase (iNOS) contributed to nitric oxide (NO)-dependent carbamoylating chemoresistance against BCNU. To further characterize the effects of NO on alkylating cytotoxicity, colony formation assay was applied to evaluate the effects of various NO donors on rat C6 glioma cells challenged with alkylating agents. We demonstrate that NO donors including GSNO, diethylamine NONOate (DEA/NO), and sodium nitroprusside (SNP) substantially reduced the extent of colony formation in glioma cells treated with alkylating agents, namely methyl methanesulfonate (MMS), N-methyl-N-nitrosourea (MNU), and N-ethyl-N-nitrosourea (ENU). Without alkylating agents these NO-releasing agents alone had no effects on clongenic potential of rat C6 glioma cells. Among these three NO donors used, the effectiveness in potentiating alkylating cytotoxicity is in the order of "GSNO>DEA/NO>SNP" when applied at the same dosages. GSNO also exerted similar synergistic actions reducing the extents of colony formation when co-administrated with 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-hydrazine (compound #1), another alkylating agent that mimics the chloroethylating action of BCNU. Together with our previous findings, we propose that NO donors may be used as adjunct chemotherapy with alkylating agents for such malignant brain tumors as glioblastoma multiforme (GBM). In contrast, production of NO as a result of iNOS induction, such as that occurring after surgical resection of brain tumors, may compromise the efficacy of carbamoylating chemotherapy.

  14. Lipopolysaccharide-Induced Behavioral Alterations Are Alleviated by Sodium Phenylbutyrate via Attenuation of Oxidative Stress and Neuroinflammatory Cascade.

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    Jangra, Ashok; Sriram, Chandra Shaker; Lahkar, Mangala

    2016-08-01

    Oxido-nitrosative stress, neuroinflammation, and reduced level of neurotrophins are implicated in the pathophysiology of anxiety and depressive illness. A few recent studies have revealed the role of endoplasmic reticulum (ER) stress in the pathophysiology of stress and depression. The aim of the present study is to investigate the neuroprotective potential of sodium phenylbutyrate (SPB), an ER stress inhibitor against lipopolysaccharide (LPS)-induced anxiety and depressive-like behavior in Swiss albino mice. Anxiety and depressive-like behavior was induced by LPS (0.83 mg/kg; i.p.) administration. Various behavioral tests were conducted to evaluate the anxiety and depressive-like behavior in mice. Real-time PCR was employed for the detection and expression of ER stress markers (78-kDa glucose-regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Pretreatment with SPB significantly ameliorated the LPS-induced anxiety and depressive-like behavior as revealed by behavioral paradigm results. LPS-induced oxidative stress was ameliorated by SPB pretreatment in hippocampus (HC) and prefrontal cortex (PFC) region. Neuroinflammation was significantly reduced by SPB pretreatment in LPS-treated mice as evident from reduction in proinflammatory cytokines (IL-1β and TNF-α). Importantly, LPS administration significantly up-regulated the GRP78 mRNA expression level in the HC which suggests the involvement of unfolded protein response (UPR) in LPS-evoked behavioral anomalies. These results highlight the neuroprotective potential of SPB in LPS-induced anxiety and depressive illness model which may be partially due to inhibition of oxidative stress-neuroinflammatory cascade.

  15. Lavender (Lavandula stoechas L.) essential oils attenuate hyperglycemia and protect against oxidative stress in alloxan-induced diabetic rats.

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    Sebai, Hichem; Selmi, Slimen; Rtibi, Kais; Souli, Abdelaziz; Gharbi, Najoua; Sakly, Mohsen

    2013-12-28

    The present study described the phytochemical profile of Lavandula stoechas essential oils, collected in the area of Ain-Draham (North-West of Tunisia), as well as their protective effects against alloxan-induced diabetes and oxidative stress in rat. Essential oils samples were obtained from the aerial parts of the plant by hydrodistillation and analyzed by GC-MS. Rats were divided into four groups: Healthy Control (HC); Diabetic Control (DC); Healthy + Essential Oils (H + EO) and Diabetic + Essential Oils (D + EO).Antidiabetic and antioxidant activities were evaluated after subacute intraperitoneally injection of Lavandula stoechas essential oils (50 mg/kg b.w., i.p.) to rats during 15 days. The principal compounds detected are: D-Fenchone (29.28%), α-pinene (23.18%), Camphor (15.97%), Camphene (7.83%), Eucapur (3.29%), Limonene, (2.71%) Linalool, (2.01%) Endobornyl Acetate (1.03%). The essential oils also contained smaller percentages of Tricyclene, Cymene, Delta-Cadinene, Selina-3,7(11)-diene. Furthermore, we found that Lavandula stoechas essential oils significantly protected against the increase of blood glucose as well as the decrease of antioxidant enzyme activities induced by aloxan treatment. Subacute essential oils treatment induced a decrease of lipoperoxidation as well as an increase of antioxidant enzyme activities. These findings suggested that lavandula stoechas essential oils protected against diabetes and oxidative stress induced by alloxan treatment. These effects are in partly due to its potent antioxidant properties.

  16. Osthol attenuates neutrophilic oxidative stress and hemorrhagic shock-induced lung injury via inhibition of phosphodiesterase 4.

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    Tsai, Yung-Fong; Yu, Huang-Ping; Chung, Pei-Jen; Leu, Yann-Lii; Kuo, Liang-Mou; Chen, Chun-Yu; Hwang, Tsong-Long

    2015-12-01

    Oxidative stress caused by neutrophils is an important pathogenic factor in trauma/hemorrhagic (T/H)-induced acute lung injury (ALI). Osthol, a natural coumarin found in traditional medicinal plants, has therapeutic potential in various diseases. However, the pharmacological effects of osthol in human neutrophils and its molecular mechanism of action remain elusive. In this study, our data showed that osthol potently inhibited the production of superoxide anion (O2(•-)) and reactive oxidants derived therefrom as well as expression of CD11b in N-formylmethionylleucylphenylalanine (FMLP)-activated human neutrophils. However, osthol inhibited neutrophil degranulation only slightly and it failed to inhibit the activity of subcellular NADPH oxidase. FMLP-induced phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) was inhibited by osthol. Notably, osthol increased the cAMP concentration and protein kinase A (PKA) activity in activated neutrophils. PKA inhibitors reversed the inhibitory effects of osthol, suggesting that these are mediated through cAMP/PKA-dependent inhibition of ERK and Akt activation. Furthermore, the activity of cAMP-specific phosphodiesterase (PDE) 4, but not PDE3 or PDE7, was significantly reduced by osthol. In addition, osthol reduced myeloperoxidase activity and pulmonary edema in rats subjected to T/H shock. In conclusion, our data suggest that osthol has effective anti-inflammatory activity in human neutrophils through the suppression of PDE4 and protects significantly against T/H shock-induced ALI in rats. Osthol may have potential for future clinical application as a novel adjunct therapy to treat lung inflammation caused by adverse circulatory conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Lavender (Lavandula stoechas L.) essential oils attenuate hyperglycemia and protect against oxidative stress in alloxan-induced diabetic rats

    Science.gov (United States)

    2013-01-01

    Background The present study described the phytochemical profile of Lavandula stoechas essential oils, collected in the area of Ain-Draham (North-West of Tunisia), as well as their protective effects against alloxan-induced diabetes and oxidative stress in rat. Methods Essential oils samples were obtained from the aerial parts of the plant by hydrodistillation and analyzed by GC–MS. Rats were divided into four groups: Healthy Control (HC); Diabetic Control (DC); Healthy + Essential Oils (H + EO) and Diabetic + Essential Oils (D + EO). Antidiabetic and antioxidant activities were evaluated after subacute intraperitoneally injection of Lavandula stoechas essential oils (50 mg/kg b.w., i.p.) to rats during 15 days. Results The principal compounds detected are: D-Fenchone (29.28%), α-pinene (23.18%), Camphor (15.97%), Camphene (7.83%), Eucapur (3.29%), Limonene, (2.71%) Linalool, (2.01%) Endobornyl Acetate (1.03%). The essential oils also contained smaller percentages of Tricyclene, Cymene, Delta-Cadinene, Selina-3,7(11)-diene. Furthermore, we found that Lavandula stoechas essential oils significantly protected against the increase of blood glucose as well as the decrease of antioxidant enzyme activities induced by aloxan treatment. Subacute essential oils treatment induced a decrease of lipoperoxidation as well as an increase of antioxidant enzyme activities. Conclusions These findings suggested that lavandula stoechas essential oils protected against diabetes and oxidative stress induced by alloxan treatment. These effects are in partly due to its potent antioxidant properties. PMID:24373672

  18. Positive effects of intermittent fasting in ischemic stroke.

    Science.gov (United States)

    Fann, David Yang-Wei; Ng, Gavin Yong Quan; Poh, Luting; Arumugam, Thiruma V

    2017-03-01

    Intermittent fasting (IF) is a dietary protocol where energy restriction is induced by alternate periods of ad libitum feeding and fasting. Prophylactic intermittent fasting has been shown to extend lifespan and attenuate the progress and severity of age-related diseases such as cardiovascular (e.g. stroke and myocardial infarction), neurodegenerative (e.g. Alzheimer's disease and Parkinson's disease) and cancerous diseases in animal models. Stroke is the second leading cause of death, and lifestyle risk factors such as obesity and physical inactivity have been associated with elevated risks of stroke in humans. Recent studies have shown that prophylactic IF may mitigate tissue damage and neurological deficit following ischemic stroke by a mechanism(s) involving suppression of excitotoxicity, oxidative stress, inflammation and cell death pathways in animal stroke models. This review summarizes data supporting the potential hormesis mechanisms of prophylactic IF in animal models, and with a focus on findings from animal studies of prophylactic IF in stroke in our laboratory. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Probucol Attenuates Cyclophosphamide-induced Oxidative Apoptosis, p53 and Bax Signal Expression in Rat Cardiac Tissues

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    Yousif A. Asiri

    2010-01-01

    Full Text Available Cyclophosphamide (CP is a widely used drug in cancer chemotherapy and immunosuppression, which could cause toxicity of the normal cells due to its toxic metabolites. Probucol, a cholesterol-lowering drug, acts as potential inhibitor of DNA damage and shows to protect against doxorubicin-induced cardiomyopathy by enhancing the endogenous antioxidant system including glutathione peroxidase, catalase and superoxide dismutase. This study examined the possible protective effects of probucol, a lipid-lowering compound with strong antioxidant properties, against CPinduced cardiotoxicity. This objective could be achieved through studying the gene expression-based on the possible protective effects of probucol against CP-induced cardiac failure in rats. Adult male Wistar albino rats were assigned into four treatment groups: Animals in the first (control and second (probucol groups were injected intraperitoneally with corn oil and probucol (61 mg/kg/day, respectively, for two weeks. Animals in the third (CP and fourth (probucol plus CP groups were injected with the same doses of corn oil and probucol (61 mg/kg/day, respectively, for one week before and one week after a single dose of CP (200 mg/kg, I.P.. The p53, Bax, Bcl2 and oxidative genes signal expression were measured by real time PCR. CP-induced cardiotoxicity was clearly observed by a significant increase in serum creatine phosphokinase isoenzyme (CK-MB (117%, lactate dehydrogenase (LDH (64%, free (69% and esterified cholesterol (42% and triglyceride (69% compared to control group. In cardiac tissues, CP significantly increases the mRNA expression levels of apoptotic genes, p53 with two-fold and Bax with 1.6-fold, and decreases the anti-apoptotic gene Bcl2 with 0.5-fold. Moreover, CP caused downregulation of antioxidant genes, glutathione peroxidase, catalase, and superoxide dismutase and increased the lipid peroxidation and decreased adenosine triphosphate (ATP (40% and ATP/ADP (44% in cardiac

  20. Proanthocyanidins Attenuation of Chronic Lead-Induced Liver Oxidative Damage in Kunming Mice via the Nrf2/ARE Pathway

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    Miao Long

    2016-10-01

    Full Text Available Lead is harmful for human health and animals. Proanthocyanidins (PCs, a natural antioxidant, possess a broad spectrum of pharmacological and medicinal properties. However, its protective effects against lead-induced liver damage have not been clarified. This study was aimed to evaluate the protective effect of PCs on the hepatotoxicity of male Kunming mice induced by chronic lead exposure. A total of 70 healthy male Kunming mice were averagely divided into four groups: control group, i.e., the group exposed to lead, the group treated with PCs, and the group co-treated with lead and PCs. The mice exposed to lead were given water containing 0.2% lead acetate. Mice treated in the PCs and PCs lead co-treated groups were given PC (100 mg/kg in 0.9% saline by oral gavage. Lead exposure caused a significant elevation in the liver function parameters, lead level, lipid peroxidation, and inhibition of antioxidant enzyme activities. The induction of oxidative stress and histological alterations in the liver were minimized by co-treatment with PCs. Meanwhile, the number of Transferase-Mediated Deoxyuridine Triphosphate-Biotin Nick End Labeling (TUNEL-positive cells was significantly reduced in the PCs/lead co-treated group compared to the lead group. In addition, the lead group showed an increase in the expression level of Bax, while the expression of Bcl-2 was decreased. Furthermore, the lead group showed an increase in the expression level of endoplasmic reticulum (ER stress-related genes and protein (GRP78 and CHOP. Co-treated with PCs significantly reversed these expressions in the liver. PCs were, therefore, demonstrated to have protective, antioxidant, and anti-ER stress and anti-apoptotic activities in liver damage caused by chronic lead exposure in the Kunming mouse. This may be due to the ability of PCs to enhance the ability of liver tissue to protect against oxidative stress via the Nrf2/ARE signaling pathway, resulting in decreasing ER stress

  1. Curcumin attenuates paraquat-induced cell death in human neuroblastoma cells through modulating oxidative stress and autophagy.

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    Jaroonwitchawan, Thiranut; Chaicharoenaudomrung, Nipha; Namkaew, Jirapat; Noisa, Parinya

    2017-01-01

    Paraquat is a neurotoxic agent, and oxidative stress plays an important role in neuronal cell death after paraquat exposure. In this study, we assessed the neuroprotective effect of curcumin against paraquat and explored the underlying mechanisms of curcumin in vitro. Curcumin treatment prevented paraquat-induced reactive oxygen species (ROS) and apoptotic cell death. Curcumin also exerted a neuroprotective effect by increasing the expression of anti-apoptotic and antioxidant genes. The pretreatment of curcumin significantly decreased gene expression and protein production of amyloid precursor protein. The activation of autophagy process was found defective in paraquat-induced cells, indicated by the accumulation and reduction of LC3I/II. Noteworthy, curcumin restored LC3I/II expression after the pretreatment. Collectively, curcumin demonstrated as a prominent suppressor of ROS, and could reverse autophagy induction in SH-SY5Y cells. The consequences of this were the reduction of APP production and prevention of SH-SY5Y cells from apoptosis. Altogether, curcumin potentially serves as a therapeutic agent of neurodegenerative diseases, associated with ROS overproduction and autophagy dysfunction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Carnosic Acid, a Natural Diterpene, Attenuates Arsenic-Induced Hepatotoxicity via Reducing Oxidative Stress, MAPK Activation, and Apoptotic Cell Death Pathway

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    Sonjit Das

    2018-01-01

    Full Text Available The present studies have been executed to explore the protective mechanism of carnosic acid (CA against NaAsO2-induced hepatic injury. CA exhibited a concentration dependent (1–4 μM increase in cell viability against NaAsO2 (12 μM in murine hepatocytes. NaAsO2 treatment significantly enhanced the ROS-mediated oxidative stress in the hepatic cells both in in vitro and in vivo systems. Significant activation of MAPK, NF-κB, p53, and intrinsic and extrinsic apoptotic signaling was observed in NaAsO2-exposed hepatic cells. CA could significantly counteract with redox stress and ROS-mediated signaling and thereby attenuated NaAsO2-mediated hepatotoxicity. NaAsO2 (10 mg/kg treatment caused significant increment in the As bioaccumulation, cytosolic ATP level, DNA fragmentation, and oxidation in the liver of experimental mice (n=6. The serum biochemical and haematological parameters were significantly altered in the NaAsO2-exposed mice (n=6. Simultaneous treatment with CA (10 and 20 mg/kg could significantly reinstate the NaAsO2-mediated toxicological effects in the liver. Molecular docking and dynamics predicted the possible interaction patterns and the stability of interactions between CA and signal proteins. ADME prediction anticipated the drug-likeness characteristics of CA. Hence, there would be an option to employ CA as a new therapeutic agent against As-mediated toxic manifestations in future.

  3. LEDGF/p75 Overexpression Attenuates Oxidative Stress-Induced Necrosis and Upregulates the Oxidoreductase ERP57/PDIA3/GRP58 in Prostate Cancer.

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    Anamika Basu

    Full Text Available Prostate cancer (PCa mortality is driven by highly aggressive tumors characterized by metastasis and resistance to therapy, and this aggressiveness is mediated by numerous factors, including activation of stress survival pathways in the pro-inflammatory tumor microenvironment. LEDGF/p75, also known as the DFS70 autoantigen, is a stress transcription co-activator implicated in cancer, HIV-AIDS, and autoimmunity. This protein is targeted by autoantibodies in certain subsets of patients with PCa and inflammatory conditions, as well as in some apparently healthy individuals. LEDGF/p75 is overexpressed in PCa and other cancers, and promotes resistance to chemotherapy-induced cell death via the transactivation of survival proteins. We report in this study that overexpression of LEDGF/p75 in PCa cells attenuates oxidative stress-induced necrosis but not staurosporine-induced apoptosis. This finding was consistent with the observation that while LEDGF/p75 was robustly cleaved in apoptotic cells into a p65 fragment that lacks stress survival activity, it remained relatively intact in necrotic cells. Overexpression of LEDGF/p75 in PCa cells led to the upregulation of transcript and protein levels of the thiol-oxidoreductase ERp57 (also known as GRP58 and PDIA3, whereas its depletion led to ERp57 transcript downregulation. Chromatin immunoprecipitation and transcription reporter assays showed LEDGF/p75 binding to and transactivating the ERp57 promoter, respectively. Immunohistochemical analysis revealed significantly elevated co-expression of these two proteins in clinical prostate tumor tissues. Our results suggest that LEDGF/p75 is not an inhibitor of apoptosis but rather an antagonist of oxidative stress-induced necrosis, and that its overexpression in PCa leads to ERp57 upregulation. These findings are of significance in clarifying the role of the LEDGF/p75 stress survival pathway in PCa.

  4. Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase

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    Engelmann, Alexander J.; Aparicio, Mark B.; Kim, Airee; Sobieraj, Jeffery C.; Yuan, Clara J.; Grant, Yanabel

    2013-01-01

    We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration-induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2′-deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake

  5. Licofelone Attenuates LPS-induced Depressive-like Behavior in Mice: A Possible Role for Nitric Oxide.

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    Mousavi, Seyyedeh Elaheh; Saberi, Pegah; Ghasemkhani, Naeemeh; Fakhraei, Nahid; Mokhtari, Rezvan; Dehpour, Ahmad Reza

    2018-01-01

    Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, possesses antioxidant, antiapoptotic, neuroprotective, and anti-inflammatory properties. The aim of the present study was to investigate the effect of licofelone on lipopolysaccharide (LPS)-induced depression in a mouse model and also a possible role for nitric oxide (NO). To elucidate the role of NO on this effect of licofelone (5 and 20 mg/kg, i.p.), L-NAME, a non-specific NO synthase (NOS) inhibitor; aminoguanidine (AG), a specific inducible NOS (iNOS) inhibitor; 7-nitroindazole (7-NI) a preferential neuronal NOS inhibitor (nNOS) and; L-arginine (L-Arg), as a NO donor, were used. The animal's behaviors were evaluated employing forced swimming test (FST), tail suspension test (TST) and open field test (OFT). LPS (0.83 mg/kg, i.p.) induced depressive-like behavior increasing immobility time in FST and TST. Conversely, licofelone (20 mg/kg i.p.) reversed the depressive effect of LPS and lowered the immobility time in FST and TST. On the other hand, pretreatment with L-Arg also reversed the antidepressant-like effect of licofelone (20 mg/kg) in FST and TST. On the other hand, L-NAME (10 and 30 mg/kg), AG (50 and 100 mg/kg) and 7-NI (60 mg/kg) could potentiate licofelone (5 mg/kg) and lowered the immobility duration. NO down-regulation possibly through iNOS and nNOS inhibition may involve in the antidepressant property of licofelone. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

  6. Dendrobium officinale Kimura et Migo attenuates diabetic cardiomyopathy through inhibiting oxidative stress, inflammation and fibrosis in streptozotocin-induced mice.

    Science.gov (United States)

    Zhang, Zhihao; Zhang, Duoduo; Dou, Mengmeng; Li, Zhubo; Zhang, Jie; Zhao, Xiaoyan

    2016-12-01

    Dendrobium officinale Kimura et Migo (Dendrobium catenatum Lindley), a prized traditional Chinese Medicine, has been used in China and Southeast Asian countries for centuries. The present study was aimed to investigate the effects and the possible mechanisms of the Dendrobium officinale extracts (DOE) on diabetic cardiomyopathy in mice. The diabetic model was induced by intraperitoneal injection of streptozotocin at the dose of 50mg/kg body weight for 5 consecutive days. After 8 weeks treatment of DOE, mice were sacrificed, blood sample and heart tissues were collected. Our results showed that Streptozotocin-induced diabetic model was effectively achieved and serum CK and LDH levels were significantly increased in mice with diabetic cardiomyopathy. Pretreatment with DOE decreased the heart-to-body weight ratio (HW/BW) and showed an evident hypoglycemic effect. DOE pretreatment significantly decreased CK, LDH, TC and TG levels, limited the production of MDA and increased the activities of T-SOD. The histological analysis of Oil red O staining and Sirius red staining showed an obvious amelioration of cardiac injury, inhibition of cardiac lipid accumulation and deposition of collagen when pretreatment with DOE. In addition, Western blot detection and analysis showed that DOE down-regulated the expression of TGF-β, collegan-1, fibronectin, NF-κB, TNF-α and IL-1β. In conclusion, our study suggested that DOE possesses the cardioprotective potential against diabetic cardiomyopathy, which may be due to the inhibition of oxidative stress, cardiac lipid accumulation, pro-inflammatory cytokines and cardiac fibrosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  7. Andrographolide ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated renal oxidative stress and inflammation via Akt/NF-κB pathway.

    Science.gov (United States)

    Ji, Xiaoqian; Li, Changzheng; Ou, Yitao; Li, Ning; Yuan, Kai; Yang, Guizhi; Chen, Xiaoyan; Yang, Zhicheng; Liu, Bing; Cheung, Wai W; Wang, Lijing; Huang, Ren; Lan, Tian

    2016-12-05

    Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial hypertrophy and extracellular matrix (ECM) accumulation. Our recent study found that andrographolide inhibited high glucose-induced mesangial cell proliferation and fibronectin expression through inhibition of AP-1 pathway. However, whether andrographolide has reno-protective roles in DN has not been fully elucidated. Here, we studied the pharmacological effects of andrographolide against the progression of DN and high glucose-induced mesangial dysfunction. Diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ). After 1 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Diabetic mice were intraperitoneal injected with andrographolide (2 mg/kg, twice a week). After 8 weeks, functional and histological analyses were carried out. Parallel experiments uncovering the molecular mechanism by which andrographolide prevents from DN was performed in mesangial cells. Andrographolide inhibited the increases in fasting blood glucose, triglyceride, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. Andrographolide also prevented renal hypertrophy and ECM accumulation. Furthermore, andrographolide markedly attenuated NOX1 expression, ROS production and pro-inflammatory cytokines as well. Additionally, andrographolide inhibited Akt/NF-κB signaling pathway. These results demonstrate that andrographolide is protective against the progression of experimental DN by inhibiting renal oxidative stress, inflammation and fibrosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. Active Fragment of Veronica ciliata Fisch. Attenuates t-BHP-Induced Oxidative Stress Injury in HepG2 Cells through Antioxidant and Antiapoptosis Activities

    Directory of Open Access Journals (Sweden)

    Yiran Sun

    2017-01-01

    Full Text Available Excessive amounts of reactive oxygen species (ROS in the body are a key factor in the development of hepatopathies such as hepatitis. The aim of this study was to assess the antioxidation effect in vitro and hepatoprotective activity of the active fragment of Veronica ciliata Fisch. (VCAF. Antioxidant assays (DPPH, superoxide, and hydroxyl radicals scavenging were conducted, and hepatoprotective effects through the application of tert-butyl hydroperoxide- (t-BHP- induced oxidative stress injury in HepG2 cells were evaluated. VCAF had high phenolic and flavonoid contents and strong antioxidant activity. From the perspective of hepatoprotection, VCAF exhibited a significant protective effect on t-BHP-induced HepG2 cell injury, as indicated by reductions in cytotoxicity and the levels of ROS, 8-hydroxydeoxyguanosine (8-OHdG, and protein carbonyls. Further study demonstrated that VCAF attenuated the apoptosis of t-BHP-treated HepG2 cells by suppressing the activation of caspase-3 and caspase-8. Moreover, it significantly decreased the levels of ALT and AST, increased the activities of acetyl cholinesterase (AChE, glutathione (GSH, superoxide dismutase (SOD, and catalase (CAT, and increased total antioxidative capability (T-AOC. Collectively, we concluded that VCAF may be a considerable candidate for protecting against liver injury owing to its excellent antioxidant and antiapoptosis properties.

  9. Taurine and pioglitazone attenuate diabetes-induced testicular damage by abrogation of oxidative stress and up-regulation of the pituitary-gonadal axis.

    Science.gov (United States)

    Abd El-Twab, Sanaa M; Mohamed, Hanaa M; Mahmoud, Ayman M

    2016-06-01

    Chronic hyperglycemia is associated with impairment of testicular function. The current study aimed to investigate the protective effects and the possible mechanisms of taurine and pioglitazone against diabetes-induced testicular dysfunction in rats. Diabetes was induced by streptozotocin injection. Both normal and diabetic rats received taurine (100 mg/kg) or pioglitazone (10 mg/kg) orally and daily for 6 weeks. Diabetic rats showed a significant (P Taurine and pioglitazone alleviated hyperglycemia, decreased pro-inflammatory cytokines, and increased circulating levels of insulin, testosterone, LH, and FSH. Gene and protein expression of LH and FSH receptors and cytochrome P450 17α-hydroxylase (CYP17) was significantly (P taurine and pioglitazone. In addition, taurine and pioglitazone significantly decreased lipid peroxidation and DNA damage, and enhanced activity of the antioxidant enzymes in testes of diabetic rats. In conclusion, taurine and pioglitazone exerted protective effects against diabetes-induced testicular damage through attenuation of hyperglycemia, inflammation, oxidative stress and DNA damage, and up-regulation of the pituitary/gonadal axis.

  10. Purple Sweet Potato Color Ameliorates Cognition Deficits and Attenuates Oxidative Damage and Inflammation in Aging Mouse Brain Induced by D-Galactose

    Directory of Open Access Journals (Sweden)

    Qun Shan

    2009-01-01

    Full Text Available Purple sweet potato color (PSPC, a naturally occurring anthocyanin, has a powerful antioxidant activity in vitro and in vivo. This study explores whether PSPC has the neuroprotective effect on the aging mouse brain induced by D-galactose (D-gal. The mice administrated with PSPC (100 mg/kg.day, 4 weeks, from 9th week via oral gavage showed significantly improved behavior performance in the open field and passive avoidance test compared with D-gal-treated mice (500 mg/kg.day, 8 weeks. We further investigate the mechanism involved in neuroprotective effects of PSPC on mouse brain. Interestingly, we found, PSPC decreased the expression level of glial fibrillary acidic protein (GFAP, inducible nitric oxide synthase (iNOS, and cyclooxygenase-2 (COX-2, inhibited nuclear translocation of nuclear factor-kappaB (NF-κB, increased the activity of copper/zinc superoxide dismutase (Cu/Zn-SOD and catalase (CAT, and reduced the content of malondialdehyde (MDA, respectively. Our data suggested that PSPC attenuated D-gal-induced cognitive impairment partly via enhancing the antioxidant and anti-inflammatory capacity.

  11. Ischemic strokes and migraine

    Energy Technology Data Exchange (ETDEWEB)

    Bousser, M.G.; Baron, J.C.; Chiras, J.

    1985-11-01

    Lasting neurological deficits, though most infrequent, do occur in migrainous subjects and are well documented by clinical angiographic computed tomographic (CT scan) and even pathological studies. However the mechanism of cerebral ischemia in migraine remains widely unknown and the precise role of migraine in the pathogenesis of ischemic strokes is still debated. (orig./MG).

  12. SCM-198 attenuates early atherosclerotic lesions in hypercholesterolemic rabbits via modulation of the inflammatory and oxidative stress pathways.

    Science.gov (United States)

    Zhang, Yanfei; Guo, Wei; Wen, Yadan; Xiong, Qinghui; Liu, Hongrui; Wu, Jian; Zou, Yunzeng; Zhu, Yizhun

    2012-09-01

    GPx in the aorta. In a rabbit atherosclerotic model, SCM-198 dose-dependently ameliorated the progression of atherosclerotic lesions and vascular dysfunction accompanied by the suppression of inflammatory factors and oxidative stress. These findings suggested that SCM-198 might be a potential agent for the treatment of atherosclerosis. Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.

  13. Role of hydrous iron oxide formation in attenuation and diel cycling of dissolved trace metals in a stream affected by acid rock drainage

    Science.gov (United States)

    Parker, S.R.; Gammons, C.H.; Jones, Clain A.; Nimick, D.A.

    2007-01-01

    Mining-impacted streams have been shown to undergo diel (24-h) fluctuations in concentrations of major and trace elements. Fisher Creek in south-central Montana, USA receives acid rock drainage (ARD) from natural and mining-related sources. A previous diel field study found substantial changes in dissolved metal concentrations at three sites with differing pH regimes during a 24-h period in August 2002. The current work discusses follow-up field sampling of Fisher Creek as well as field and laboratory experiments that examine in greater detail the underlying processes involved in the observed diel concentration changes. The field experiments employed in-stream chambers that were either transparent or opaque to light, filled with stream water and sediment (cobbles coated with hydrous Fe and Al oxides), and placed in the stream to maintain the same temperature. Three sets of laboratory experiments were performed: (1) equilibration of a Cu(II) and Zn(II) containing solution with Fisher Creek stream sediment at pH 6.9 and different temperatures; (2) titration of Fisher Creek water from pH 3.1 to 7 under four different isothermal conditions; and (3) analysis of the effects of temperature on the interaction of an Fe(II) containing solution with Fisher Creek stream sediment under non-oxidizing conditions. Results of these studies are consistent with a model in which Cu, Fe(II), and to a lesser extent Zn, are adsorbed or co-precipitated with hydrous Fe and Al oxides as the pH of Fisher Creek increases from 5.3 to 7.0. The extent of metal attenuation is strongly temperature-dependent, being more pronounced in warm vs. cold water. Furthermore, the sorption/co-precipitation process is shown to be irreversible; once the Cu, Zn, and Fe(II) are removed from solution in warm water, a decrease in temperature does not release the metals back to the water column. ?? 2006 Springer Science+Business Media B.V.

  14. Aloperine attenuated neuropathic pain induced by chronic constriction injury via anti-oxidation activity and suppression of the nuclear factor kappa B pathway

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Ya-Qiong [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Jin, Shao-Ju [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Luohe Medical College, Luohe 462002, Henan Province (China); Liu, Ning [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Li, Yu-Xiang [College of Nursing, Ningxia Medical University, Yinchuan 750004 (China); Zheng, Jie [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Ma, Lin [Ningxia Key Lab of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan 750004 (China); Du, Juan; Zhou, Ru [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Zhao, Cheng-Jun [Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan 750000 (China); Niu, Yang [Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004 (China); Sun, Tao [Ningxia Key Lab of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan 750004 (China); Yu, Jian-Qiang, E-mail: Yujq910315@163.com [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Luohe Medical College, Luohe 462002, Henan Province (China)

    2014-09-05

    Highlights: • Aloperine has anti-nociceptive effects on neuropathic pain induced CCI. • Aloperine reduces ROS in neuropathic pain mice. • Aloperine down-regulates the expression of NF-κB and its downstream pro-inflammatory cytokines in neuropathic pain mice. - Abstract: Objective: To investigate whether aloperine (ALO) has antinociceptive effects on neuropathic pain induced by chronic constriction injury, whether ALO reduces ROS against neuropathic pain, and what are the mechanisms involved in ALO attenuated neuropathic pain. Methods: Mechanical and cold allodynia, thermal and mechanical hyperalgesia and spinal thermal hyperalgesia were estimated by behavior methods such as Von Frey filaments, cold-plate, radiant heat, paw pressure and tail immersion on one day before surgery and days 7, 8, 10, 12 and 14 after surgery, respectively. In addition, T-AOC, GSH-PX, T-AOC and MDA in the spinal cord (L4/5) were measured to evaluate anti-oxidation activity of ALO on neuropathic pain. Expressions of NF-κB and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in the spinal cord (L4/5) were analyzed by using Western blot. Results: Administration of ALO (80 mg/kg and 40 mg/kg, i.p.) significantly increased paw withdrawal threshold, paw pressure, paw withdrawal latencies, tail-curling latencies, T-AOC, GSH-PX and T-SOD concentration, reduced the numbers of paw lifts and MDA concentration compared to CCI group. ALO attenuated CCI induced up-regulation of expressions of NF-κB, TNF-α, IL-6, IL-1β at the dose of 80 mg/kg (i.p.). Pregabalin produced similar effects serving as positive control at the dose of 10 mg/kg (i.p.). Conclusion: ALO has antinociceptive effects on neuropathic pain induced by CCI. The antinociceptive effects of ALO against neuropathic pain is related to reduction of ROS, via suppression of NF-κB pathway.

  15. Aloperine attenuated neuropathic pain induced by chronic constriction injury via anti-oxidation activity and suppression of the nuclear factor kappa B pathway

    International Nuclear Information System (INIS)

    Xu, Ya-Qiong; Jin, Shao-Ju; Liu, Ning; Li, Yu-Xiang; Zheng, Jie; Ma, Lin; Du, Juan; Zhou, Ru; Zhao, Cheng-Jun; Niu, Yang; Sun, Tao; Yu, Jian-Qiang

    2014-01-01

    Highlights: • Aloperine has anti-nociceptive effects on neuropathic pain induced CCI. • Aloperine reduces ROS in neuropathic pain mice. • Aloperine down-regulates the expression of NF-κB and its downstream pro-inflammatory cytokines in neuropathic pain mice. - Abstract: Objective: To investigate whether aloperine (ALO) has antinociceptive effects on neuropathic pain induced by chronic constriction injury, whether ALO reduces ROS against neuropathic pain, and what are the mechanisms involved in ALO attenuated neuropathic pain. Methods: Mechanical and cold allodynia, thermal and mechanical hyperalgesia and spinal thermal hyperalgesia were estimated by behavior methods such as Von Frey filaments, cold-plate, radiant heat, paw pressure and tail immersion on one day before surgery and days 7, 8, 10, 12 and 14 after surgery, respectively. In addition, T-AOC, GSH-PX, T-AOC and MDA in the spinal cord (L4/5) were measured to evaluate anti-oxidation activity of ALO on neuropathic pain. Expressions of NF-κB and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in the spinal cord (L4/5) were analyzed by using Western blot. Results: Administration of ALO (80 mg/kg and 40 mg/kg, i.p.) significantly increased paw withdrawal threshold, paw pressure, paw withdrawal latencies, tail-curling latencies, T-AOC, GSH-PX and T-SOD concentration, reduced the numbers of paw lifts and MDA concentration compared to CCI group. ALO attenuated CCI induced up-regulation of expressions of NF-κB, TNF-α, IL-6, IL-1β at the dose of 80 mg/kg (i.p.). Pregabalin produced similar effects serving as positive control at the dose of 10 mg/kg (i.p.). Conclusion: ALO has antinociceptive effects on neuropathic pain induced by CCI. The antinociceptive effects of ALO against neuropathic pain is related to reduction of ROS, via suppression of NF-κB pathway

  16. The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1.

    Science.gov (United States)

    Li, Tao; Qin, Juan-Juan; Yang, Xia; Ji, Yan-Xiao; Guo, Fangliang; Cheng, Wen-Lin; Wu, Xiaolin; Gong, Fu-Han; Hong, Ying; Zhu, Xue-Yong; Gong, Jun; Wang, Zhihua; Huang, Zan; She, Zhi-Gang; Li, Hongliang

    2017-12-13

    Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Rac1 pathway might be a promising target to attenuate cerebral I/R injury. SIGNIFICANCE STATEMENT Stroke is one of the most severe and devastating neurological diseases globally. The complicated pathophysiological processes restrict the translation of potential therapeutic targets into medicine. Further elucidating the molecular mechanisms underlying cerebral ischemia/reperfusion injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study revealed that ischemia-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) upregulation binds and ubiquitinates Rac1 directly, which promotes neuron death through neuroinflammation and neuro-oxidative signals. Therefore, precisely targeting

  17. Toll-like Receptor 4 Signaling Confers Cardiac Protection Against Ischemic Injury via Inducible Nitric Oxide Synthase- and Soluble Guanylate Cyclase-dependent Mechanisms

    Science.gov (United States)

    Wang, E; Feng, Yan; Zhang, Ming; Zou, Lin; Li, Yan; Buys, Emmanuel S.; Huang, Peigen; Brouckaert, Peter; Chao, Wei

    2011-01-01

    Background Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that TLR4 mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein inducing interferon-β–mediated transcription-factor (Trif), inducible nitric-oxide synthase (iNOS), and soluble guanylate cyclase (sGC). Methods Wild-type mice and the genetically modified mice, i.e., TLR4-deficient (TLR4-def), TLR2 knockout (TLR2−/−), MyD88−/−, Trif−/−, iNOS−/−, and sGCα1−/−, were treated with normal saline or 0.1 mg/kg of lipopolysaccharide, intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min of global ischemia and reperfusion for up to 60 min. Left ventricular function and myocardial infarction sizes were examined. Results Compared to saline-treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dtmax (P < 0.01) and reduced MI sizes (37.2 ± 3.4% vs. 19.8 ± 4.9%, P < 0.01) after ischemia-reperfusion. The cardiac protective effect of lipopolysaccharide was abolished in the TLR4-def and MyD88−/− mice, but remained intact in TLR2−/− or Trif−/− mice. iNOS−/− mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. While sGC 1−/− mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection. Conclusions TLR4 activation confers a potent cardiac protection against ischemia

  18. Gender and post-ischemic recovery of hypertrophied rat hearts

    Directory of Open Access Journals (Sweden)

    Popov Kirill M

    2006-03-01

    Full Text Available Abstract Background Gender influences the cardiac response to prolonged increases in workload, with differences at structural, functional, and molecular levels. However, it is unknown if post-ischemic function or metabolism of female hypertrophied hearts differ from male hypertrophied hearts. Thus, we tested the hypothesis that gender influences post-ischemic function of pressure-overload hypertrophied hearts and determined if the effect of gender on post-ischemic outcome could be explained by differences in metabolism, especially the catabolic fate of glucose. Methods Function and metabolism of isolated working hearts from sham-operated and aortic-constricted male and female Sprague-Dawley rats before and after 20 min of no-flow ischemia (N = 17 to 27 per group were compared. Parallel series of hearts were perfused with Krebs-Henseleit solution containing 5.5 mM [5-3H/U-14C]-glucose, 1.2 mM [1-14C]-palmitate, 0.5 mM [U-14C]-lactate, and 100 mU/L insulin to measure glycolysis and glucose oxidation in one series and oxidation of palmitate and lactate in the second. Statistical analysis was performed using two-way analysis of variance. The sequential rejective Bonferroni procedure was used to correct for multiple comparisons and tests. Results Female gender negatively influenced post-ischemic function of non-hypertrophied hearts, but did not significantly influence function of hypertrophied hearts after ischemia such that mass-corrected hypertrophied heart function did not differ between genders. Before ischemia, glycolysis was accelerated in hypertrophied hearts, but to a greater extent in males, and did not differ between male and female non-hypertrophied hearts. Glycolysis fell in all groups after ischemia, except in non-hypertrophied female hearts, with the reduction in glycolysis after ischemia being greatest in males. Post-ischemic glycolytic rates were, therefore, similarly accelerated in hypertrophied male and female hearts and higher in

  19. [Genetics of ischemic stroke].

    Science.gov (United States)

    Gschwendtner, A; Dichgans, M

    2013-02-01

    Stroke is one of the most widespread causes of mortality und disability worldwide. Around 80 % of strokes are ischemic and different forms of intracranial bleeding account for the remaining cases. Monogenic stroke disorders are rare but the diagnosis may lead to specific therapeutic consequences for the affected patients who are predominantly young. In common sporadic stroke, genetic factors play a role in the form of susceptibility genes. Their discovery may give rise to new therapeutic options in the future.

  20. Human recombinant factor VIIa may improve heat intolerance in mice by attenuating hypothalamic neuronal apoptosis and damage.

    Science.gov (United States)

    Hsu, Chuan-Chih; Chen, Sheng-Hsien; Lin, Cheng-Hsien; Yung, Ming-Chi

    2014-10-01

    Intolerance to heat exposure is believed to be associated with hypothalamo-pituitary-adrenocortical (HPA) axis impairment [reflected by decreases in blood concentrations of both adrenocorticotrophic-hormone (ACTH) and corticosterone]. The purpose of this study was to determine the effect of human recombinant factor VIIa (rfVIIa) on heat intolerance, HPA axis impairment, and hypothalamic inflammation, ischemic and oxidative damage, and apoptosis in mice under heat stress. Immediately after heat stress (41.2 °C for 1 h), mice were treated with vehicle (1 mL/kg of body weight) or rfVIIa (65-270 µg/kg of body weight) and then returned to room temperature (26 °C). Mice still alive on day 4 of heat exposure were considered survivors. Cellular ischemia markers (e.g., glutamate, lactate-to-pyruvate ratio), oxidative damage markers (e.g., nitric oxide metabolite, hydroxyl radials), and pro-inflammatory cytokines (e.g., interleukin-6, interleukin-1β, tumor necrosis factor-α) in hypothalamus were determined. In addition, blood concentrations of both ACTH and corticosterone were measured. Hypothalamic cell damage was assessed by determing the neuronal damage scores, whereas the hypothalamic cell apoptosis was determined by assessing the numbers of cells stained with terminal deoxynucleotidyl transferase-mediated αUTP nick-end labeling, caspase-3-positive cells, and platelet endothelial cell adhesion molecula-1-positive cells in hypothalamus. Compared with vehicle-treated heated mice, rfVIIa-treated heated mice had significantly higher fractional survival (8/10 vs 1/10), lesser thermoregulatory deficit (34.1 vs 24.8 °C), lesser extents of ischemic, oxidative, and inflammatory markers in hypothalamus, lesser neuronal damage scores and apoptosis in hypothalamus, and lesser HPA axis impairment. Human recombinant factor VIIa appears to exert a protective effect against heatstroke by attenuating hypothalamic cell apoptosis (due to ischemic, inflammatory, and oxidative damage

  1. Resveratrol Ameliorates Palmitate-Induced Inflammation in Skeletal Muscle Cells by Attenuating Oxidative Stress and JNK/NF-κB Pathway in a SIRT1-Independent Mechanism.

    Science.gov (United States)

    Sadeghi, Asie; Seyyed Ebrahimi, Shadi Sadat; Golestani, Abolfazl; Meshkani, Reza

    2017-09-01

    Resveratrol has been shown to exert anti-inflammatory and anti-oxidant effects in a variety of cell types, however, its role in prevention of inflammatory responses mediated by palmitate in skeletal muscle cells remains unexplored. In the present study, we investigated the effects of resveratrol on palmitate-induced inflammation and elucidated the underlying mechanisms in skeletal muscle cells. The results showed that palmitate significantly enhanced TNF-α and IL-6 mRNA expression and protein secretion from C2C12 cells at 12, 24, and 36 h treatments. Increased expression of cytokines was accompanied by an enhanced phosphorylation of JNK, P38, ERK1/2, and IKKα/IKKβ. In addition, JNK and P38 inhibitors could significantly attenuate palmitate-induced mRNA expression of TNF-α and IL-6, respectively, whereas NF-κB inhibitor reduced the expression of both cytokines in palmitate-treated cells. Resveratrol pretreatment significantly prevented palmitate-induced TNF-α and IL-6 mRNA expression and protein secretion in C2C12 cells. Importantly, pre-treatment of the cells with resveratrol completely abrogated the phosphorylation of ERK1/2, JNK, and IKKα/IKKβ in palmitate treated cells. The protection from palmitate-induced inflammation by resveratrol was accompanied by a decrease in the generation of reactive oxygen species (ROS). N-acetyl cysteine (NAC), a known scavenger of ROS, could protect palmitate-induced expression of TNF-α and IL-6. Furthermore, inhibition of SIRT1 by shRNA or sirtinol demonstrated that the anti-inflammatory effect of resveratrol in muscle cells is mediated through a SIRT1-independent mechanism. Taken together, these findings suggest that resveratrol may represent a promising therapy for prevention of inflammation in skeletal muscle cells. J. Cell. Biochem. 118: 2654-2663, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  2. Adiponectin attenuates angiotensin II-induced vascular smooth muscle cell remodeling through nitric oxide and the RhoA/ROCK pathway.

    Directory of Open Access Journals (Sweden)

    Wared eNour-Eldine

    2016-04-01

    Full Text Available INTRODUCTION: Adiponectin (APN, an adipocytokine, exerts protective effects on cardiac remodeling, while angiotensin II (Ang II induces hypertension and vascular remodeling. The potential protective role of APN on the vasculature during hypertension has not been fully elucidated yet. Here, we evaluate the molecular mechanisms of the protective role of APN in the physiological response of the vascular wall to Ang II.METHODS AND RESULTS: Rat aortic tissues were used to investigate the effect of APN on Ang II-induced vascular remodeling and hypertrophy. We investigated whether nitric oxide (NO, the RhoA/ROCK pathway, actin cytoskeleton remodeling, and reactive oxygen species (ROS mediate the anti-hypertrophic effect of APN. Ang II-induced protein synthesis was attenuated by pre-treatment with APN, NO donor (SNAP, or cGMP. The hypertrophic response to Ang II was associated with a significant increase in RhoA activation and vascular force production, which were prevented by APN and SNAP. NO was also associated with inhibition of Ang II-induced phosphorylation of cofilin. In addition, immunohistochemistry revealed that 24 hr Ang II treatment increased the F- to G-actin ratio, an effect that was inhibited by SNAP. Ang II-induced ROS formation and upregulation of p22phox mRNA expression were inhibited by APN and NO. Both compounds failed to inhibit Nox1 and p47phox expression. CONCLUSIONS: Our results suggest that the anti-hypertrophic effects of APN are due, in part, to NO-dependent inhibition of the RhoA/ROCK pathway and ROS formation.

  3. Natural attenuation of uranium and formation of autunite at the expense of apatite within an oxidizing environment, south Eastern Desert of Egypt

    International Nuclear Information System (INIS)

    Abd El-Naby, Hamdy H.; Dawood, Yehia H.

    2008-01-01

    X-ray diffraction (XRD), back scattered electron imaging (BSE), wavelength-dispersion spectral scan (WDS), X-ray compositional mapping and quantitative electron probe micro analyses (EPMA) have been used to examine a natural attenuation of U during low temperature alteration of the Sela granite, south Eastern Desert of Egypt. The data confirmed that a pre-existing hydroxyapatite was transformed to autunite through an unidentified intermediate phase. The boundaries between these three phases are not sharp and are generally interfering indicative of the replacement of Ca by U. The hydroxyapatite, intermediate phase and autunite show similar chondrite normalized rare earth elements (REE) patterns suggesting a genetic relationship. Alteration processes have enriched the three phases with heavy rare earth elements (HREE) and Eu and caused Ce, Dy and Yb negative anomalies. Based on the pH of the aqueous solutions, two mechanisms may explain the conversion of hydroxyapatite to autunite: (1) the dissolution of hydroxyapatite and precipitation of autunite which would happen when the uranyl bearing solutions were acidic enough (pH = 3-6.8) to be able to dissolve the pre-existing hydroxyapatite and (2) sorption of the uranyl ion on the surface of hydroxyapatite followed by substitution of (UO 2 ) 2+ at the expense of Ca 2+ . The latter mechanism would have happened if the pH of the aqueous solutions were near neutral and at low dissolved concentrations of uranyl ion. The genesis of uranyl mineralization in the Sela area supports the use of apatite-based technologies for U remediation in an oxidizing environment

  4. The methanol seed extract of Garcinia kola attenuated angiotensin II- and lipopolyssacharide-inducedvascular smooth muscle cell proliferation and nitric oxide production

    Directory of Open Access Journals (Sweden)

    Adeolu A. Adedapo

    2016-10-01

    Full Text Available All over the world, cardiovascular diseases are a risk factor for poor health and early death with predisposing factors to include age, gender, tobacco use, physical inactivity, excessive alcohol consumption, unhealthy diet, obesity, family history of cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, psychosocial factors, poverty and low educational status, and air pollution. It is envisaged that herbal products that can stem this trend would be of great benefit. Garcinia kola (GK, also known as bitter kola is one of such plants. Generally used as a social snack and offered to guests in some cultural settings, bitter kola has been indicated in the treatment of laryngitis, general inflammation, bronchitis, viral infections and diabetes. In this study, the effects of methanol seed extract of Garcinia kola on the proliferation of Vascular Smooth Muscle Cells (VSMCs in cell culture by Angiotensin II (Ang II and LPS-induced NO production were carried out. Confluent VSMCs were exposed to GK (25, 50 and 100 μg/ml before or after treatment with lipopolyssacharide (100μg/ml, and Angiotensin II (10-8-10-6M. Cellular proliferation was determined by MTT assay and NO production by Griess assay. Treatment with Angiotensin II (10-8, 10-6 or LPS significantly enhanced proliferation of VSM cells while LPS significantly increased nitric oxide (NO production. Treatment with GK (25, 50 & 100 μg/ml attenuated VSM cell proliferation. The results indicate that GK has potential to inhibit mitogen activated vascular cell growth and possibly inhibit inflammatory responses to LPS. Thus GK may be useful in condition that is characterized by cellular proliferation and inflammatory responses.

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

    Science.gov (United States)

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

    2012-01-01

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

  6. P2X7 Receptor Antagonism Attenuates the Intermittent Hypoxia-induced Spatial Deficits in a Murine Model of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress.

    Science.gov (United States)

    Deng, Yan; Guo, Xue-Ling; Yuan, Xiao; Shang, Jin; Zhu, Die; Liu, Hui-Guo

    2015-08-20

    The mechanism of the neural injury caused by chronic intermittent hypoxia (CIH) that characterizes obstructive sleep apnea syndrome (OSAS) is not clearly known. The purpose of this study was to investigate whether P2X7 receptor (P2X7R) is responsible for the CIH-induced neural injury and the possible pathway it involves. Eight-week-old male C57BL/6 mice were used. For each exposure time point, eight mice divided in room air (RA) and IH group were assigned to the study of P2X7R expression. Whereas in the 21 days-Brilliant Blue G (BBG, a selective P2X7R antagonist) study, 48 mice were randomly divided into CIH group, BBG-treated CIH group, RA group and BBG-treated RA group. The hippocampus P2X7R expression was determined by Western blotting and real-time polymerase chain reaction (PCR). The spatial learning was analyzed by Morris water maze. The nuclear factor kappa B (NFκB) and NADPH oxidase 2 (NOX2) expressions were analyzed by Western blotting. The expressions of tumor necrosis factor α, interleukin 1β (IL-β), IL-18, and IL-6 were measured by real-time PCR. The malondialdehyde and superoxide dismutase levels were detected by colorimetric method. Cell damage was evaluated by Hematoxylin and Eosin staining and Terminal Transferase dUTP Nick-end Labeling method. The P2X7R mRNA was elevated and sustained after 3-day IH exposure and the P2X7R protein was elevated and sustained after 7-day IH exposure. In the BBG study, the CIH mice showed severer neuronal cell damage and poorer performance in the behavior test. The increased NFκB and NOX2 expressions along with the inflammation injury and oxidative stress were also observed in the CIH group. BBG alleviated CIH-induced neural injury and consequent functional deficits. The P2X7R antagonism attenuates the CIH-induced neuroinflammation, oxidative stress, and spatial deficits, demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.

  7. Protective effects of incensole acetate on cerebral ischemic injury.

    Science.gov (United States)

    Moussaieff, Arieh; Yu, Jin; Zhu, Hong; Gattoni-Celli, Sebastiano; Shohami, Esther; Kindy, Mark S

    2012-03-14

    The resin of Boswellia species is a major anti-inflammatory agent that has been used for centuries to treat various conditions including injuries and inflammatory conditions. Incensole acetate (IA), a major constituent of this resin, has been shown to inhibit NF-κB activation and concomitant inflammation, as well as the neurological deficit following head trauma. Here, we show that IA protects against ischemic neuronal damage and reperfusion injury in mice, attenuating the inflammatory nature of ischemic damage. IA given post-ischemia, reduced infarct volumes and improved neurological activities in the mouse model of ischemic injury in a dose dependent fashion. The protection from damage was accompanied by inhibition of TNF-α, IL-1β and TGF-β expression, as well as NF-κB activation following injury. In addition, IA is shown to have a therapeutic window of treatment up to 6h after ischemic injury. Finally, the protective effects of IA were partially mediated by TRPV3 channels as determined by the TRPV3 deficient mice and channel blocker studies. This study suggests that the anti-inflammatory and neuroprotective activities of IA may serve as a novel therapeutic treatment for ischemic and reperfusion injury, and as a tool in the ongoing research of mechanisms for neurological damage. Published by Elsevier B.V.

  8. Extremely low frequency electromagnetic field (ELF-EMF) reduces oxidative stress and improves functional and psychological status in ischemic stroke patients.

    Science.gov (United States)

    Cichoń, Natalia; Bijak, Michał; Miller, Elżbieta; Saluk, Joanna

    2017-07-01

    As a result of ischaemia/reperfusion, massive generation of reactive oxygen species occurs, followed by decreased activity of antioxidant enzymes. Extremely low frequency electromagnetic fields (ELF-EMF) can modulate oxidative stress, but there are no clinical antioxidant studies in brain stroke patients. The aim of our study was to investigate the effect of ELF-EMF on clinical and antioxidant status in post-stroke patients. Fifty-seven patients were divided into two groups: ELF-EMF and non-ELF-EMF. Both groups underwent the same 4-week rehabilitation program. Additionally, the ELF-EMF group was exposed to an ELF-EMF field of 40 Hz, 7 mT for 15 min/day for 4 weeks (5 days a week). The activity of catalase and superoxide dismutase was measured in hemolysates, and total antioxidant status (TAS) determined in plasma. Functional status was assessed before and after the series of treatments using Activities of Daily Living (ADL), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS). Applied ELF-EMF significantly increased enzymatic antioxidant activity; however, TAS levels did not change in either group. Results show that ELF-EMF induced a significant improvement in functional (ADL) and mental (MMSE, GDS) status. Clinical parameters had positive correlation with the level of enzymatic antioxidant protection. Bioelectromagnetics. 38:386-396, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  9. The ischemic perinatal brain damage

    International Nuclear Information System (INIS)

    Crisi, G.; Mauri, C.; Canossi, G.; Della Giustina, E.

    1986-01-01

    The term ''hypoxic-ischemic encephalopathy'' covers a large part of neonatal neuropathology including the various forms of intracerebral haemorrhage. In the present work the term is confined to ischemic brain edema and actual infarction, be it diffuse or focal. Eighteen newborns with CT evidence of ischemic brain lesions and infarctual necrosis were selected. Emphasis is placed on current data on neuropathology of ischemic brain edema and its CT appearance. Particular entities such as periventricular leukomalacia and multicystic encephalopathy are discussed. Relationship between CT and temporal profile of cerebral damage is emphasized in order to predict the structural sequelae and the longterm prognosis

  10. Pathophysiology and Biomarkers in Acute Ischemic Stroke – A Review

    African Journals Online (AJOL)

    The pathophysiology of ischemic stroke is complex, and majorly involves excitotoxicity, oxidative stress, inflammation, blood-brain barrier dysfunction, apoptosis, etc. Several of the biomarkers are related to these pathophysiologic mechanisms and they may have applications in stroke prediction, diagnosis, assessment, ...

  11. Involvement of CCR-2 chemokine receptor activation in ischemic preconditioning and postconditioning of brain in mice.

    Science.gov (United States)

    Rehni, Ashish K; Singh, Thakur Gurjeet

    2012-10-01

    The present study has been designed to investigate the potential role of CCR-2 chemokine receptor in ischemic preconditioning as well as postconditioning induced reversal of ischemia-reperfusion injury in mouse brain. Bilateral carotid artery occlusion of 17 min followed by reperfusion for 24h was employed in present study to produce ischemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using elevated plus-maze test and Morris water maze test. Rota rod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor co-ordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min were employed to elicit ischemic preconditioning of brain, while three episodes of bilateral carotid artery occlusion for 10s and reperfusion of 10s immediately after the completion of were employed to elicit ischemic postconditioning of brain. Both prior ischemic preconditioning as well as ischemic postconditioning immediately after global cerebral ischemia prevented markedly ischemia-reperfusion-induced cerebral injury as measured in terms of infarct size, loss of memory and motor coordination. RS 102895, a selective CCR-2 chemokine receptor antagonist, attenuated the neuroprotective effect of both the ischemic preconditioning as well as postconditioning. It is concluded that the neuroprotective effect of both ischemic preconditioning as well as ischemic postconditioning may involve the activation of CCR-2 chemokine receptors. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Ischemic preconditioning improves mitochondrial tolerance to experimental calcium overload.

    Science.gov (United States)

    Crestanello, Juan A; Doliba, Nicolai M; Babsky, Andriy M; Doliba, Natalia M; Niibori, Koki; Whitman, Glenn J R; Osbakken, Mary D

    2002-04-01

    Ca(2+) overload leads to mitochondrial uncoupling, decreased ATP synthesis, and myocardial dysfunction. Pharmacologically opening of mitochondrial K(ATP) channels decreases mitochondrial Ca(2+) uptake, improving mitochondrial function during Ca(2+) overload. Ischemic preconditioning (IPC), by activating mitochondrial K(ATP) channels, may attenuate mitochondrial Ca(2+) overload and improve mitochondrial function during reperfusion. The purpose of these experiments was to study the effect of IPC (1) on mitochondrial function and (2) on mitochondrial tolerance to experimental Ca(2+) overload. Rat hearts (n = 6/group) were subjected to (a) 30 min of equilibration, 25 min of ischemia, and 30 min of reperfusion (Control) or (b) two 5-min episodes of ischemic preconditioning, 25 min of ischemia, and 30 min of reperfusion (IPC). Developed pressure (DP) was measured. Heart mitochondria were isolated at end-Equilibration (end-EQ) and at end-Reperfusion (end-RP). Mitochondrial respiratory function (state 2, oxygen consumption with substrate only; state 3, oxygen consumption stimulated by ADP; state 4, oxygen consumption after cessation of ADP phosphorylation; respiratory control index (RCI, state 3/state 4); rate of oxidative phosphorylation (ADP/Deltat), and ADP:O ratio) was measured with polarography using alpha-ketoglutarate as a substrate in the presence of different Ca(2+) concentrations (0 to 5 x 10(-7) M) to simulate Ca(2+) overload. IPC improved DP at end-RP. IPC did not improve preischemic mitochondrial respiratory function or preischemic mitochondrial response to Ca(2+) loading. IPC improved state 3, ADP/Deltat, and RCI during RP. Low Ca(2+) levels (0.5 and 1 x 10(-7) M) stimulated mitochondrial function in both groups predominantly in IPC. The Control group showed evidence of mitochondrial uncoupling at lower Ca(2+) concentrations (1 x 10(-7) M). IPC preserved state 3 at high Ca(2+) concentrations. The cardioprotective effect of IPC results, in part, from

  13. The inhibition of nitric oxide-activated poly(ADP-ribose) synthetase attenuates transsynaptic alteration of spinal cord dorsal horn neurons and neuropathic pain in the rat.

    Science.gov (United States)

    Mao, J; Price, D D; Zhu, J; Lu, J; Mayer, D J

    1997-09-01

    Transsynaptic alteration of spinal cord dorsal horn neurons characterized by hyperchromatosis of cytoplasm and nucleoplasm (so-called 'dark' neurons) occurs in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the common sciatic nerve. The incidence of dark neurons in CCI rats has been proposed to be mediated by glutamate-induced neurotoxicity. In the present study, we examined whether the inhibition of the nitric oxide (NO)-activated poly(ADP-ribose) synthetase (PARS), a nuclear enzyme critical to glutamate-induced neurotoxicity, would both reduce the incidence of dark neurons and attenuate behavioral manifestations of neuropathic pain in CCI rats. Dark neurons were observed bilaterally (with ipsilateral predominance) within the spinal cord dorsal horn, particularly in laminae I-II, of rats 8 days after unilateral sciatic nerve ligation as compared to sham operated rats. The number of dark neurons in the dorsal horn was dose-dependently reduced in CCI rats receiving once daily intrathecal (i.t.) treatment with the PARS inhibitor benzamide (200 or 400 nmol, but not 100 nmol benzamide or saline) for 7 days. Consistent with the histological improvement, thermal hyperalgesia, mechanical hyperalgesia, and low threshold mechano-allodynia also were reliably reduced in CCI rats treated with either 200 or 400 nmol benzamide. Neither dark neurons nor neuropathic pain behaviors were reliably affected by i.t. administration of either 800 nmol novobiocin (a mono(ADP-ribose) synthetase) or 800 nmol benzoic acid (the backbone structure of benzamide), indicating a selective effect of benzamide. Intrathecal treatment with an NO synthase inhibitor NG-nitro-L-arginine methyl ester (40 nmol, but not its inactive D-isomer) utilizing the same benzamide treatment regimen resulted in similar reductions of both dark neurons and neuropathic pain behaviors in CCI rats. These results provide, for the first time, in vivo evidence indicating that benzamide is

  14. Sulfide oxidation and the natural attenuation of arsenic and trace metals in the waste rocks of the abandoned Seobo tungsten mine, Korea

    International Nuclear Information System (INIS)

    Lee, Pyeong-koo; Kang, Min-Ju; Choi, Sang-Hoon; Touray, Jean-Claude

    2005-01-01

    Mineralogical examinations were performed to characterize the formation of secondary minerals and natural removal process of dissolved As and trace metals (Pb, Zn and Cu) from sulfide oxidation. Laboratory-based leaching tests were also conducted to determine whether the concentrations of As and trace metals in the leachates from waste-rock materials and contaminated soil could be affected by the presence acids such as acid rainwater or acid mine drainage. Waste-rock materials and contaminated soil were compared by 4-day leaching tests using HNO 3 solutions of increasing acidity (0.00001-0.1mole/L). Mineralogical studies of the waste rocks confirmed the presence of Fe-(oxy)hydroxides (e.g. goethite), jarosite, elemental S, Fe-sulfates, amorphous Fe-As phases, anglesite and covellite as secondary minerals. These secondary minerals act as mineralogical scavengers of dissolved trace metals, SO 4 2- and acidity released by sulfide oxidation. Arsenic was attenuated by the adsorption on Fe-(oxy)hydroxides and/or the formation of an amorphous Fe-As phase, with a Fe/As ratio=1 (maybe scorodite: FeAsO 4 .2H 2 O). Electron probe microanalyses data showed that the Fe-(oxy)hydroxides had high concentrations of Pb (up to 21wt%), with appreciable amounts of As (up to 7.7wt%), Zn (up to 4.6wt%) and Cu (up to 2.5wt%) indicating that dissolved metals were co-precipitated and adsorbed onto Fe-(oxy)hydroxides, Fe(Mn)-hydroxides and Fe-sulfates. The results of the leaching experiments within the pH-range 3.5-5.0 indicated that acidic rainstorms may leach minor amounts of Pb (ca. 1.7-4.0% of total), Zn (ca. 0.8-2.2% of total), Cu (ca. 0.0-0.2% of total) and As (ca. 0.02-0.1% of total) from waste rocks, including the dissolution of soluble secondary minerals previously formed during prolonged dry periods, while dissolution of these elements was negligible from the contaminated soil. In the pH-range 1.0-3.0, the leaching of Pb (ca. 2.4-31% of total) and As (ca. 0.1-5.8% of total) from

  15. Hypertension and Ischemic Heart Disease in Women.

    Science.gov (United States)

    Dorobantu, Maria; Onciul, Sebastian; Tautu, Oana Florentina; Cenko, Edina

    2016-01-01

    Ischemic heart disease (IHD) is the most important cause of mortality worldwide. Although the awareness of cardiovascular risk factors and IHD in women has increased over the last decades, mortality rates are still higher in women than in men. Among traditional cardiovascular risk factors, hypertension is associated with a greater risk for IHD in women as compared to men. In this review, discuss gender differences in epidemiology and pathophysiology of hypertension and its impact on the incidence and outcomes of IHD in women. We also, discuss some "women conditions" such as hypertensive disorders in pregnancy (HDP) and polycystic ovarian syndrome (PCOS). Even though this is not a systematic review, English-language studies on MEDLINE and the Cochrane Database of Systematic reviews were searched for consultation and analysis. Hypertension display different epidemiological patterns in men and women. Studies have shown that hypertension has a different proatherogenic effects in men and women. Hypertension has a direct effect on microcirculation, but estrogens have a protective role in this regard in premenopausal women. However, after the decline in estrogen levels, women are exposed to the same cardiovascular risk as males. Postmenopausal women exhibit a greater burden of cardiovascular risk factors, which together with microvascular dysfunction and smaller and stiffer arteries conducts to the worse prognosis observed in women with IHD. "Women specific conditions" such as HDP and PCOS affects 10% of pregnant women and women in reproductive age, respectively. These conditions are associated with increased risk of hypertension and IHD later in life. Although women are more aware of their hypertension, cardiovascular mortality is higher in hypertensive women with comorbid IHD. Yet these gender disparities in outcomes seem to be attenuated with effective therapy. The pathophysiology of IHD is gender specific, women with ischemic symptoms presenting less often with

  16. Sodium 4-phenylbutyrate protects against cerebral ischemic injury.

    Science.gov (United States)

    Qi, Xin; Hosoi, Toru; Okuma, Yasunobu; Kaneko, Masayuki; Nomura, Yasuyuki

    2004-10-01

    Sodium 4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid that has been used for treatment of urea cycle disorders in children, sickle cell disease, and thalassemia. It has been demonstrated recently that 4-PBA can act as a chemical chaperone by reducing the load of mutant or mislocated proteins retained in the endoplasmic reticulum (ER) under conditions associated with cystic fibrosis and liver injury. In the present study, we evaluated the neuroprotective effect of 4-PBA on cerebral ischemic injury. Pre- or post-treatment with 4-PBA at therapeutic doses attenuated infarction volume, hemispheric swelling, and apoptosis and improved neurological status in a mouse model of hypoxia-ischemia. Moreover, 4-PBA suppressed ER-mediated apoptosis by inhibiting eukaryotic initiation factor 2alpha phosphorylation, CCAAT/enhancer-binding protein homologous protein induction, and caspase-12 activation. In neuroblastoma neuro2a cells, 4-PBA reduced caspase-12 activation, DNA fragmentation, and cell death induced by hypoxia/reoxygenation. It protected against ER stress-induced but not mitochondria-mediated cell death. Additionally, 4-PBA inhibited the expression of inducible nitric-oxide synthase and tumor necrosis factor-alpha in primary cultured glial cells under hypoxia/reoxygenation. These results indicate that 4-PBA could protect against cerebral ischemia through inhibition of ER stress-mediated apoptosis and inflammation. Therefore, the multiple actions of 4-PBA may provide a strong effect in treatment of cerebral ischemia, and its use as a chemical chaperone would provide a novel approach for the treatment of stroke.

  17. Hemichorea after ischemic stroke

    Directory of Open Access Journals (Sweden)

    Sadullah Saglam

    2016-03-01

    Full Text Available The deterioration of the balance between direct and indirect ways in the basal ganglia causes chorea. The lesions of contralateral basal ganglia, thalamus or the connection of them all together are responsible for this. Chorea can be observed during the course of metabolic and vascular diseases, neurodegenerative or hereditary diseases. Hyperkinetic movement disorders after acute ischemic stroke are reported as rare; however, hemichorea is the most frequent developing disorder of hyperkinetic movement as a result of cerebrovascular disease. In this case report, we presented two case who applied us with choreiform movements in his left half of the body after acute thalamic stroke. [Cukurova Med J 2016; 41(0.100: 29-32

  18. Obesity increases risk of ischemic stroke in young adults.

    Science.gov (United States)

    Mitchell, Andrew B; Cole, John W; McArdle, Patrick F; Cheng, Yu-Ching; Ryan, Kathleen A; Sparks, Mary J; Mitchell, Braxton D; Kittner, Steven J

    2015-06-01

    Body mass index has been associated with ischemic stroke in older populations, but its association with stroke in younger populations is not known. In light of the current obesity epidemic in the United States, the potential impact of obesity on stroke risk in young adults deserves attention. A population-based case-control study design with 1201 cases and 1154 controls was used to investigate the relationship of obesity and young onset ischemic stroke. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between body mass index and ischemic stroke with and without adjustment for comorbid conditions associated with stroke. In analyses adjusted for age, sex, and ethnicity, obesity (body mass index >30 kg/m(2)) was associated with an increased stroke risk (odds ratio, 1.57; 95% confidence interval, 1.28-1.94) although this increased risk was highly attenuated and not statistically significant after adjustment for smoking, hypertension, and diabetes mellitus. These results indicate that obesity is a risk factor for young onset ischemic stroke and suggest that this association may be partially mediated through hypertension, diabetes mellitus, or other variables associated with these conditions. © 2015 American Heart Association, Inc.

  19. Neighborhood disadvantage and ischemic stroke: the Cardiovascular Health Study (CHS).

    Science.gov (United States)

    Brown, Arleen F; Liang, Li-Jung; Vassar, Stefanie D; Stein-Merkin, Sharon; Longstreth, W T; Ovbiagele, Bruce; Yan, Tingjian; Escarce, José J

    2011-12-01

    Neighborhood characteristics may influence the risk of stroke and contribute to socioeconomic disparities in stroke incidence. The objectives of this study were to examine the relationship between neighborhood socioeconomic status and incident ischemic stroke and examine potential mediators of these associations. We analyzed data from 3834 whites and 785 blacks enrolled in the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ages≥65 years from 4 US counties. The primary outcome was adjudicated incident ischemic stroke. Neighborhood socioeconomic status was measured using a composite of 6 census tract variables. Race-stratified multilevel Cox proportional hazard models were constructed adjusted for sociodemographic, behavioral, and biological risk factors. Among whites, in models adjusted for sociodemographic characteristics, stroke hazard was significantly higher among residents of neighborhoods in the lowest compared with the highest neighborhood socioeconomic status quartile (hazard ratio, 1.32; 95% CI, 1.01-1.72) with greater attenuation of the hazard ratio after adjustment for biological risk factors (hazard ratio, 1.16; 0.88-1.52) than for behavioral risk factors (hazard ratio, 1.30; 0.99-1.70). Among blacks, we found no significant associations between neighborhood socioeconomic status and ischemic stroke. Higher risk of incident ischemic stroke was observed in the most disadvantaged neighborhoods among whites, but not among blacks. The relationship between neighborhood socioeconomic status and stroke among whites appears to be mediated more strongly by biological than behavioral risk factors.

  20. Revisiting the slow force response: the role of the PKG signaling pathway in the normal and the ischemic heart.

    Science.gov (United States)

    Castro-Ferreira, Ricardo; Neves, João Sérgio; Ladeiras-Lopes, Ricardo; Leite-Moreira, André M; Neiva-Sousa, Manuel; Almeida-Coelho, João; Ferreira-Martins, João; F Leite-Moreira, Adelino

    2014-09-01

    The myocardial response to acute stretch consists of a two-phase increase in contractility: an acute increase by the Frank-Starling mechanism and a gradual and time-dependent increase in force generated known as the slow force response (SFR). The SFR is actively modulated by different signaling pathways, but the role of protein kinase G (PKG) signaling is unknown. In this study we aim to characterize the role of the PKG signaling pathway in the SFR under normal and ischemic conditions. Rabbit papillary muscles were stretched from 92 to 100% of maximum length (Lmax) under basal conditions, in the absence (1) or presence of: a PKG agonist (2) and a PKG inhibitor (3); under ischemic conditions in the absence (4) or presence of: a PKG agonist (5); a nitric oxide (NO) donor (6) and a phosphodiesterase 5 (PDE5) inhibitor (7). Under normoxia, the SFR was significantly attenuated by inhibition of PKG and remained unaltered with PKG activation. Ischemia induced a progressive decrease in myocardial contractility after stretch. Neither the PKG agonist nor the NO donor altered the myocardial response to stretch under ischemic conditions. However, the use of a PDE5 inhibitor in ischemia partially reversed the progressive deterioration in contractility. PKG activity is essential for the SFR. During ischemia, a progressive decline in the force is observed in response to acute myocardial stretch. This dysfunctional response can be partially reversed by the use of PDE5 inhibitors. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  1. Overview of Experimental and Clinical Findings regarding the Neuroprotective Effects of Cerebral Ischemic Postconditioning.

    Science.gov (United States)

    Ma, Di; Feng, Liangshu; Deng, Fang; Feng, Jia-Chun

    2017-01-01

    Research on attenuating the structural and functional deficits observed following ischemia-reperfusion has become increasingly focused on the therapeutic potential of ischemic postconditioning. In recent years, various methods and animal models of ischemic postconditioning have been utilized. The results of these numerous studies have indicated that the mechanisms underlying the neuroprotective effects of ischemic postconditioning may involve reductions in the generation of free radicals and inhibition of calcium overload, as well as the release of endogenous active substances, alterations in membrane channel function, and activation of protein kinases. Here we review the novel discovery, mechanism, key factors, and clinical application of ischemic postconditioning and discuss its implications for future research and problem of clinical practice.

  2. Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

    Directory of Open Access Journals (Sweden)

    Park YJ

    2012-09-01

    Full Text Available Yoon Jung Choi,1,* Jue Yeon Lee,2,* Chong Pyoung Chung,2 Yoon Jeong Park,1,21Craniomaxillofacial Reconstructive Sciences, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea; 2Research Institute, Nano Intelligent Biomedical Engineering, Seoul, Republic of Korea*These authors contributed equally to this workBackground: Human dental pulp stem cells (DPSCs have potential applications in tissue regeneration because of their convenient cell harvesting procedures and multipotent capacity. However, the tissue regenerative potential of DPSCs is known to be negatively regulated by aging in long-term culture and under oxidative stress. With an aim of reducing cellular senescence and oxidative stress in DPSCs, an intracellular delivery system for superoxide dismutase 1 (SOD1 was developed. We conjugated SOD1 with a cell-penetrating peptide known as low-molecular weight protamine (LMWP, and investigated the effect of LMWP-SOD1 conjugates on hydrogen peroxide-induced cellular senescence and osteoblastic differentiation.Results: LMWP-SOD1 significantly attenuated enlarged and flattened cell morphology and increased senescence-associated β-galactosidase activity. Under the same conditions, LMWP-SOD1 abolished activation of the cell cycle regulator proteins, p53 and p21Cip1, induced by hydrogen peroxide. In addition, LMWP-SOD1 reversed the inhibition of osteoblastic differentiation and downregulation of osteogenic gene markers induced by hydrogen peroxide. However, LMWP-SOD1 could not reverse the decrease in odontogenesis caused by hydrogen peroxide.Conclusion: Overall, cell-penetrating LMWP-SOD1 conjugates are effective for attenuation of cellular senescence and reversal of osteoblastic differentiation of DPSCs caused by oxidative stress inhibition. This result suggests potential application in the field of antiaging and tissue engineering to overcome the limitations of senescent stem cells.Keywords: superoxide

  3. DNA Protecting Activities of Nymphaea nouchali (Burm. f Flower Extract Attenuate t-BHP-Induced Oxidative Stress Cell Death through Nrf2-Mediated Induction of Heme Oxygenase-1 Expression by Activating MAP-Kinases

    Directory of Open Access Journals (Sweden)

    Md Badrul Alam

    2017-09-01

    Full Text Available This study was performed to investigate the antioxidant activities of Nymphaea nouchali flower (NNF extract and the underlying mechanism using RAW 264.7 cells. The presence of gallic acid, catechin, epicatechin, epigallocatechin, epicatechin gallate, caffeic acid, quercetin, and apigenin in the NNF was confirmed by high-performance liquid chromatography (HPLC. The extract had a very potent capacity to scavenge numerous free radicals. NNF extract was also able to prevent DNA damage and quench cellular reactive oxygen species (ROS generation induced by tert-Butyl hydroperoxide (t-BHP with no signs of toxicity. The NNF extract was able to augment the expression of both primary and phase II detoxifying enzyme, resulting in combat the oxidative stress. This is accomplished by phosphorylation of mitogen-activated protein kinase (MAP kinase (p38 kinase and extracellular signal-regulated kinase (ERK followed by enhancing the nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2. This attenuates cellular ROS generation and confers protection from cell death. Altogether, the results of current study revealed that Nymphaea nouchali flower could be a source of natural phytochemicals that could lead to the development of new therapeutic agents for preventing oxidative stress associated diseases and attenuating disease progression.

  4. Metabolic Enhancer Piracetam Attenuates the Translocation of Mitochondrion-Specific Proteins of Caspase-Independent Pathway, Poly [ADP-Ribose] Polymerase 1 Up-regulation and Oxidative DNA Fragmentation.

    Science.gov (United States)

    Verma, Dinesh Kumar; Gupta, Sonam; Biswas, Joyshree; Joshi, Neeraj; Sivarama Raju, K; Wahajuddin, Mu; Singh, Sarika

    2018-03-12

    Piracetam, a nootropic drug, has been clinically used for decades; however, its mechanism of action still remains enigmatic. The present study was undertaken to evaluate the role of mitochondrion-specific factors of caspase-independent pathway like apoptotic-inducing factor (AIF) and endonuclease-G (endo-G) in piracetam-induced neuroprotection. N2A cells treated with lipopolysaccharide (LPS) exhibited significant cytotoxicity, impaired mitochondrial activity, and reactive oxygen species generation which was significantly attenuated with piracetam co-treatment. Cells co-treated with LPS and piracetam exhibited significant uptake of piracetam in comparison to only piracetam-treated cells as estimated by liquid chromatography-mass spectrometry (LC-MSMS). LPS treatment caused significant translocation of AIF and endonuclease-G in neuronal N2A cells which were significantly attenuated with piracetam co-treatment. Significant over-expression of proinflammatory cytokines was also observed after treatment of LPS to cells which was inhibited with piracetam co-treatment demonstrating its anti-inflammatory property. LPS-treated cells exhibited significant oxidative DNA fragmentation and poly [ADP-ribose] polymerase-1 (PARP-1) up-regulation in nucleus, both of which were attenuated with piracetam treatment. Antioxidant melatonin but not z-VAD offered the inhibited LPS-induced DNA fragmentation indicating the involvement of oxidative DNA fragmentation. Further, we did not observe the altered caspase-3 level after LPS treatment initially while at a later time point, significantly augmented level of caspase-3 was observed which was not inhibited with piracetam treatment. In total, our findings indicate the interference of piracetam in mitochondrion-mediated caspase-independent pathway, as well as its anti-inflammatory and antioxidative properties. Graphical Abstract Graphical abstract indicating the novel interference of metabolic enhancer piracetam (P) in neuronal death

  5. Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration.

    Science.gov (United States)

    Romero, Juan Ignacio; Holubiec, Mariana Inés; Tornatore, Tamara Logica; Rivière, Stéphanie; Hanschmann, Eva-Maria; Kölliker-Frers, Rodolfo Alberto; Tau, Julia; Blanco, Eduardo; Galeano, Pablo; Rodríguez de Fonseca, Fernando; Lillig, Christopher Horst; Capani, Francisco

    2017-01-01

    The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

  6. Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration

    Directory of Open Access Journals (Sweden)

    Juan Ignacio Romero

    2017-01-01

    Full Text Available The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

  7. Ischemic optic neuropathy as a model of neurodegenerative disorder: A review of pathogenic mechanism of axonal degeneration and the role of neuroprotection.

    Science.gov (United States)

    Khalilpour, Saba; Latifi, Shahrzad; Behnammanesh, Ghazaleh; Majid, Amin Malik Shah Abdul; Majid, Aman Shah Abdul; Tamayol, Ali

    2017-04-15

    Optic neuropathy is a neurodegenerative disease which involves optic nerve injury. It is caused by acute or intermittent insults leading to visual dysfunction. There are number of factors, responsible for optic neuropathy, and the optic nerve axon is affected in all type which causes the loss of retinal ganglion cells. In this review we will highlight various mechanisms involved in the cell loss cascades during axonal degeneration as well as ischemic optic neuropathy. These mechanisms include oxidative stress, excitotoxicity, angiogenesis, neuroinflammation and apoptosis following retinal ischemia. We will also discuss the effect of neuroprotective agents in attenuation of the negative effect of factors involve in the disease occurrence and progression. Copyright © 2016. Published by Elsevier B.V.

  8. Local Injections of Superoxide Dismutase Attenuate the Exercise Pressor Reflex in Rats with Femoral Artery Occlusion

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    Jihong Xing

    2018-02-01

    Full Text Available The exercise pressor reflex is amplified in patients with peripheral artery disease (PAD and in an experimental PAD model of rats induced by femoral artery occlusion. Heightened blood pressure worsens the restricted blood flow directed to the limbs in this disease. The purpose of this study was to determine the role played by muscle oxidative stress in regulating the augmented pressor response to static exercise in PAD. We hypothesized that limb ischemia impairs muscle superoxide dismutase (SOD thereby leading to abnormal autonomic responsiveness observed in PAD animals, and a chronic compensation of SOD for anti-oxidation improves the exaggerated exercise pressor reflex. Our data show that femoral occlusion decreased the protein levels of SOD in ischemic muscle as compared with control muscle. Downregulation of SOD appeared to a greater degree in the oxidative (red muscle than in the glycolytic (white muscle under the condition of muscle ischemia. In addition, the exercise pressor response was assessed during electrically induced static contraction. The data demonstrates that the enhancement of the exercise pressor reflex was significantly attenuated after tempol (a mimetic of SOD, 30 mg over a period of 72 h was administered into the occluded hindlimb. In the occluded rats, mean arterial pressure (MAP response was 26 ± 3 mmHg with no tempol and 12 ± 2 mmHg with tempol application (P < 0.05 vs. group with no tempol; n = 6 in each group. There were no differences in muscle tension development (time-tension index: 12.1 ± 1.2 kgs with no tempol and 13.5 ± 1.1 kgs with tempol; P > 0.05 between groups. In conclusion, SOD is lessened in the ischemic muscles and supplement of SOD improves the amplified exercise pressor reflex, which is likely beneficial to the restricted blood flow to the limbs in PAD.

  9. Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury

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    Shelly A Cruz

    2018-01-01

    Full Text Available Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK associated with the tumor necrosis factor-alpha (TNF-α/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-α. However, subsequent lower doses (5 mg/kg/day failed to sustain this neuroprotective effect after 4 days. Dabrafenib blocked lipopolysaccharides-induced activation of TNF-α in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-α-induced necroptotic pathway after ischemic brain injury. Since Dabrafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.

  10. Curcuma longa polyphenols improve insulin-mediated lipid accumulation and attenuate proinflammatory response of 3T3-L1 adipose cells during oxidative stress through regulation of key adipokines and antioxidant enzymes.

    Science.gov (United States)

    Septembre-Malaterre, Axelle; Le Sage, Fanny; Hatia, Sarah; Catan, Aurélie; Janci, Laurent; Gonthier, Marie-Paule

    2016-07-08

    Plant polyphenols may exert beneficial action against obesity-related oxidative stress and inflammation which promote insulin resistance. This study evaluated the effect of polyphenols extracted from French Curcuma longa on 3T3-L1 adipose cells exposed to H2 O2 -mediated oxidative stress. We found that Curcuma longa extract exhibited high amounts of curcuminoids identified as curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which exerted free radical-scavenging activities. Curcuma longa polyphenols improved insulin-mediated lipid accumulation and upregulated peroxisome proliferator-activated receptor-gamma gene expression and adiponectin secretion which decreased in H2 O2 -treated cells. Curcuminoids attenuated H2 O2 -enhanced production of pro-inflammatory molecules such as interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and nuclear factor κappa B. Moreover, they reduced intracellular levels of reactive oxygen species elevated by H2 O2 and modulated the expression of genes encoding superoxide dismutase and catalase antioxidant enzymes. Collectively, these findings highlight that Curcuma longa polyphenols protect adipose cells against oxidative stress and may improve obesity-related metabolic disorders. © 2016 BioFactors, 42(4):418-430, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

  11. MRI in ischemic heart disease

    International Nuclear Information System (INIS)

    Hazirolan, T.

    2012-01-01

    Full text: The role of magnetic resonance imaging in the evaluation of ischemic heart disease has increased over the last years. Cardiac MRI is the only imaging modality that provides 'one stop shop' assessment. Information about ventricular function, myocardial ischemia and myocardial viability can be obtained in a single cardiac MRI session. Additionally, Cardiac MRI has become a gold standard method in evaluation of myocardial viability and in assessment of ventricular mass and function. As a result, cardiac MRI enable radiologist to comprehensively assess ischemic heart disease. The aim of this presentation is to provide the reader a state-of-the art on how the newest cardiac MRI techniques can be used to study ischemic heart disease patients.

  12. MR imaging of ischemic penumbra

    International Nuclear Information System (INIS)

    Abe, Osamu; Aoki, Shigeki; Shirouzu, Ichiro; Kunimatsu, Akira; Hayashi, Naoto; Masumoto, Tomohiko; Mori, Harushi; Yamada, Haruyasu; Watanabe, Makoto; Masutani, Yoshitaka; Ohtomo, Kuni

    2003-01-01

    Cerebral ischemic stroke is one of the most fatal diseases despite current advances in medical science. Recent demonstration of efficacy using intravenous and intra-arterial thrombolysis demands therapeutic intervention tailored to the physiologic state of the individual tissue and stratification of patients according to the potential risks for therapies. In such an era, the role of the neuroimaging becomes increasingly important to evaluate the extent and location of tissues at risk of infarction (ischemic penumbra), to distinguish it from unsalvageable infarcted tissues or doomed hemorrhagic parenchyma. In this review, we present briefly the current role and limitation of computed tomography and conventional magnetic resonance imaging (MRI). We also present the possible applications of advanced MR techniques, such as diffusion and perfusion imaging, concentrating on the delineation or detection of ischemic penumbra

  13. Substrate use in ischemic and reperfused canine myocardium: quantitative considerations

    International Nuclear Information System (INIS)

    Myears, D.W.; Sobel, B.E.; Bergmann, S.R.

    1987-01-01

    The patterns of use of substrate in reperfused myocardium are not yet well elucidated, and their delineation is essential for adequate interpretation of results of analyses performed after positron emission tomography with labeled substrates to differentiate normal from abnormal heart muscle. Accordingly, in open-chest, anesthetized dogs the authors measured glucose and fatty acid utilization in normal, ischemic, and reperfused myocardium and assessed the contributions of metabolism of each substrate to overall oxidative metabolism. Intracoronary [ 3 H]glucose and [ 14 C]palmitate were administered in five control dogs, eight dogs subjected to 1 h of coronary occlusion, and nine dogs subjected to reperfusion after 1 h of ischemia. Regional coronary venous blood samples were assayed sequentially. In reperfused myocardium, utilization of glucose was 103% greater than that in ischemic and 273% greater than in normal myocardium. Utilization of fatty acid during reperfusion, although greater than that in ischemic myocardium, was significantly less than that in normal myocardium despite restoration of flow to 80% of control values. Despite diminished net uptake of fatty acid, oxidation of fatty acid accounted for 63% of total oxygen consumption in reperfused myocardium. These studies indicate that canine myocardium reperfused after 1 h of ischemia exhibits enhanced uptake of glucose and impaired utilization of palmitate. Nevertheless, palmitate continues to comprise the substrate primarily utilized for oxidative metabolism

  14. The protective effect of ischemic preconditioning on rat testis

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    Ciralik Harun

    2007-12-01

    Full Text Available Abstract Background It has been demonstrated that brief episodes of sublethal ischemia-reperfusion, so-called ischemic preconditioning, provide powerful tissue protection in different tissues such as heart, brain, skeletal muscle, lung, liver, intestine, kidney, retina, and endothelial cells. Although a recent study has claimed that there are no protective effects of ischemic preconditioning in rat testis, the protective effects of ischemic preconditioning on testicular tissue have not been investigated adequately. The present study was thus planned to investigate whether ischemic preconditioning has a protective effect on testicular tissue. Methods Rats were divided into seven groups that each contained seven rats. In group 1 (control group, only unilateral testicular ischemia was performed by creating a testicular torsion by a 720 degree clockwise rotation for 180 min. In group 2, group 3, group 4, group 5, group 6, and group 7, unilateral testicular ischemia was performed for 180 min following different periods of ischemic preconditioning. The ischemic preconditioning periods were as follows: 10 minutes of ischemia with 10 minutes of reperfusion in group 2; 20 minutes of ischemia with 10 minutes of reperfusion in group 3; 30 minutes of ischemia with 10 minutes of reperfusion in group 4; multiple preconditioning periods were used (3 × 10 min early phase transient ischemia with 10 min reperfusion in all episodes in group 5; multiple preconditioning periods were used (5, 10, and 15 min early phase transient ischemia with 10 min reperfusion in all episodes in group 6; and, multiple preconditioning periods were used (10, 20, and 30 min early phase transient ischemia with 10 min reperfusion in all episodes in group 7. After the ischemic protocols were carried out, animals were sacrificed by cervical dislocation and testicular tissue samples were taken for biochemical measurements (protein, malondialdehyde, nitric oxide and histological examination

  15. Geraniol attenuates 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress and inflammation in mouse skin: possible role of p38 MAP Kinase and NF-κB.

    Science.gov (United States)

    Khan, Abdul Quaiyoom; Khan, Rehan; Qamar, Wajhul; Lateef, Abdul; Rehman, Muneeb U; Tahir, Mir; Ali, Farrah; Hamiza, Oday O; Hasan, Syed Kazim; Sultana, Sarwat

    2013-06-01

    Abnormal production of reactive oxygen species (ROS) and proinflammatory cytokines often act as trigger for development of most of the chronic human diseases including cancer via up-regulation of transcription factors and activation of MAP kinases. We investigated the protective effects of geraniol (GOH) against 12-O-tetradecanoyl phorbol-13-acetate (TPA) induced oxidative and inflammatory responses, expression of p38MAPK, NF-κB and COX-2 in mouse skin. Animals were divided into four groups I-IV (n=6). Group II and III received topical application of TPA at the dose of 10 nmol/0.2 ml of acetone/animal/day, for two days. Group III was pre-treated with GOH (250 μg) topically 30 min prior to each TPA administration. While group I and IV were given acetone (0.2 ml) and GOH respectively. Our results show that GOH significantly inhibited TPA induced lipid peroxidation (LPO), inflammatory responses, proinflammatory cytokine release, up regulates reduced glutathione (GSH) content and the activity of different antioxidant enzymes. Interestingly, GOH also inhibited TPA induced altered activity of p38MAPK. Further, TPA induced altered expression of NF-κB (p65) and COX-2 was also attenuated by GOH. Thus, our results suggest that GOH attenuates early tumor promotional changes, and it may serve as one of the various ways to prevent carcinogenesis. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Arctigenin, a Potent Ingredient of Arctium lappa L., Induces Endothelial Nitric Oxide Synthase and Attenuates Subarachnoid Hemorrhage-Induced Vasospasm through PI3K/Akt Pathway in a Rat Model.

    Science.gov (United States)

    Chang, Chih-Zen; Wu, Shu-Chuan; Chang, Chia-Mao; Lin, Chih-Lung; Kwan, Aij-Lie

    2015-01-01

    Upregulation of protein kinase B (PKB, also known as Akt) is observed within the cerebral arteries of subarachnoid hemorrhage (SAH) animals. This study is of interest to examine Arctigenin, a potent antioxidant, on endothelial nitric oxide synthase (eNOS) and Akt pathways in a SAH in vitro study. Basilar arteries (BAs) were obtained to examine phosphatidylinositol-3-kinase (PI3K), phospho-PI3K, Akt, phospho-Akt (Western blot) and morphological examination. Endothelins (ETs) and eNOS evaluation (Western blot and immunostaining) were also determined. Arctigenin treatment significantly alleviates disrupted endothelial cells and tortured internal elastic layer observed in the SAH groups (p Arctigenin (p Arctigenin might exert dural effects in preventing SAH-induced vasospasm through upregulating eNOS expression via the PI3K/Akt signaling pathway and attenuate endothelins after SAH. Arctigenin shows therapeutic promise in the treatment of cerebral vasospasm following SAH.

  17. Attenuated flow‐induced dilatation of middle cerebral arteries is related to increased vascular oxidative stress in rats on a short‐term high salt diet

    Science.gov (United States)

    Cosic, Anita; Jukic, Ivana; Stupin, Ana; Mihalj, Martina; Mihaljevic, Zrinka; Novak, Sanja; Vukovic, Rosemary

    2016-01-01

    Key points Recent studies have shown that high salt (HS) intake leads to endothelial dysfunction and impaired vascular reactivity in different vascular beds in both animal and human models, due to increased oxidative stress.The objective of this study was to assess vascular response to flow‐induced dilatation (FID) and to elucidate the role of vascular oxidative stress/antioxidative capacity in middle cerebral arteries (MCAs) of HS‐fed rats in vitro.The novelty of this study is in demonstrating impaired flow‐induced dilatation of MCAs and down‐regulation of vascular antioxidant genes with HS intake, leading to increased levels of oxidative stress in blood vessels and peripheral lymph organs, which together contribute to impaired FID.In addition, results show increased oxidative stress in leukocytes of peripheral lymph organs, suggesting the occurrence of inflammatory processes due to HS intake.Recirculation of leukocytes might additionally increase vascular oxidative stress in vivo. Abstract The aim of this study was to determine flow‐induced dilatation (FID) and the role of oxidative stress/antioxidative capacity in isolated, pressurized middle cerebral arteries (MCAs) of high salt (HS)‐fed rats. Healthy male Sprague‐Dawley rats (11 weeks old) were fed low salt (0.4% NaCl; LS group) or high salt (4% NaCl; HS group) diets for 1 week. Reactivity of MCAs in response to stepwise increases in pressure gradient (Δ10–Δ100 mmHg) was determined in the absence or presence of the superoxide dismutase (SOD) mimetic TEMPOL and/or the nitric oxide synthases (NOS) inhibitor N ω‐nitro‐l‐arginine methyl ester (l‐name). mRNA levels of antioxidative enzymes, NAPDH‐oxidase components, inducible (iNOS) and endothelial nitric oxide synthases (eNOS) were determined by quantitative real‐time PCR. Blood pressure (BP), antioxidant enzymes activity, oxidative stress in peripheral leukocytes, lipid peroxidation products and the antioxidant capacity of plasma

  18. Potent effects of alkaloid-rich extract from Huperzia selago against sodium nitroprusside-evoked PC12 cells damage via attenuation of oxidative stress and apoptosis

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    Anna Magdalena Lenkiewicz

    2016-06-01

    Full Text Available Imbalance between production and scavenging of free radicals and other reactive oxygen species (ROS is a component of many diseases, but it is especially important in aging-related diseases of the central nervous system. Oxidative stress-induced neuronal dysfunction plays an important role in the pathomechanism of neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Experimental data showed that free radical scavengers may protect the brain against oxidative modifications. The need for efficient and safe antioxidants with therapeutic potential stimulated the rise of interest in the medicinal plant products, which are a rich source of phytochemicals possessing biological activity. In our studies we focused on alkaloid fractions (AFs isolated from club moss, Huperzia selago and Diphasiastrum complanatum, due to their beneficial activity and exclusive chemical structure. Our previous study demonstrated that selected alkaloids from Huperzia selago effectively protect macromolecules from oxidative damage. Therefore, in the present study we investigated the effects and mechanisms of action of AFs isolated from Huperzia selago and Diphasiastrum complanatum against sodium nitroprusside (SNP-induced oxidative injury in PC12 cells. The results demonstrated that the selected AFs via reduction of nitric oxide (NO liberation protected cells against oxidative stress, DNA and mitochondrial damage, as well as apoptosis caused by SNP. Selected AF notably decreased SNP-evoked mitochondrial polymerase γ (Polg up-regulation. Furthermore, AF which contains Lycopodine, Serratidine, Lycoposerramine-G and (probably Cermizine B completely inhibited the SNP-induced expression of interferon-γ (Ifng and cyclooxygenase 2 (Ptgs2 as well as significantly down-regulated the expression of 12/15-lipoxygenase (Alox12 and tended to decrease the mRNA level of interleukin-6 gene (Il6. In conclusion, these results suggest that the AFs from Huperzia selago

  19. Ischemic preconditioning provides both acute and delayed protection against renal ischemia and reperfusion injury in mice.

    Science.gov (United States)

    Joo, Jin Deok; Kim, Mihwa; D'Agati, Vivette D; Lee, H Thomas

    2006-11-01

    Acute as well as delayed ischemic preconditioning (IPC) provides protection against cardiac and neuronal ischemia reperfusion (IR) injury. This study determined whether delayed preconditioning occurs in the kidney and further elucidated the mechanisms of renal IPC in mice. Mice were subjected to IPC (four cycles of 5 min of ischemia and reperfusion) and then to 30 min of renal ischemia either 15 min (acute IPC) or 24 h (delayed IPC) later. Both acute and delayed renal IPC provided powerful protection against renal IR injury. Inhibition of Akt but not extracellular signal-regulated kinase phosphorylation prevented the protection that was afforded by acute IPC. Neither extracellular signal-regulated kinase nor Akt inhibition prevented protection that was afforded by delayed renal IPC. Pretreatment with an antioxidant, N-(2-mercaptopropionyl)-glycine, to scavenge free radicals prevented the protection that was provided by acute but not delayed renal IPC. Inhibition of protein kinase C or pertussis toxin-sensitive G-proteins attenuated protection from both acute and delayed renal IPC. Delayed renal IPC increased inducible nitric oxide synthase (iNOS) as well as heat-shock protein 27 synthesis, and the renal protective effects of delayed preconditioning were attenuated by a selective inhibitor of iNOS (l-N(6)[1-iminoethyl]lysine). Moreover, delayed IPC was not observed in iNOS knockout mice. Both acute and delayed IPC were independent of A(1) adenosine receptors (AR) as a selective A(1)AR antagonist failed to block preconditioning and acute and delayed preconditioning occurred in mice that lacked A(1)AR. Therefore, this study demonstrated that acute or delayed IPC provides renal protection against IR injury in mice but involves distinct signaling pathways.

  20. Effects of Remote Ischemic Conditioning Methods on Ischemia-Reperfusion Injury in Muscle Flaps: An Experimental Study in Rats

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    Durdane Keskin

    2017-09-01

    Full Text Available Background The aim of this study was to investigate the effects of remote ischemic conditioning on ischemia-reperfusion injury in rat muscle flaps histopathologically and biochemically. Methods Thirty albino rats were divided into 5 groups. No procedure was performed in the rats in group 1, and only blood samples were taken. A gracilis muscle flap was elevated in all the other groups. Microclamps were applied to the vascular pedicle for 4 hours in order to achieve tissue ischemia. In group 2, no additional procedure was performed. In groups 3, 4, and 5, the right hind limb was used and 3 cycles of ischemia-reperfusion for 5 minutes each (total, 30 minutes was applied with a latex tourniquet (remote ischemic conditioning. In group 3, this procedure was performed before flap elevation (remote ischemic preconditoning. In group 4, the procedure was performed 4 hours after flap ischemia (remote ischemic postconditioning. In group 5, the procedure was performed after the flap was elevated, during the muscle flap ischemia episode (remote ischemic perconditioning. Results The histopathological damage score in all remote conditioning ischemia groups was lower than in the ischemic-reperfusion group. The lowest histopathological damage score was observed in group 5 (remote ischemic perconditioning. Conclusions The nitric oxide levels were higher in the blood samples obtained from the remote ischemic perconditioning group. This study showed the effectiveness of remote ischemic conditioning procedures and compared their usefulness for preventing ischemia-reperfusion injury in muscle flaps.

  1. Effects of Remote Ischemic Conditioning Methods on Ischemia-Reperfusion Injury in Muscle Flaps: An Experimental Study in Rats.

    Science.gov (United States)

    Keskin, Durdane; Unlu, Ramazan Erkin; Orhan, Erkan; Erkilinç, Gamze; Bogdaycioglu, Nihal; Yilmaz, Fatma Meric

    2017-09-01

    The aim of this study was to investigate the effects of remote ischemic conditioning on ischemia-reperfusion injury in rat muscle flaps histopathologically and biochemically. Thirty albino rats were divided into 5 groups. No procedure was performed in the rats in group 1, and only blood samples were taken. A gracilis muscle flap was elevated in all the other groups. Microclamps were applied to the vascular pedicle for 4 hours in order to achieve tissue ischemia. In group 2, no additional procedure was performed. In groups 3, 4, and 5, the right hind limb was used and 3 cycles of ischemia-reperfusion for 5 minutes each (total, 30 minutes) was applied with a latex tourniquet (remote ischemic conditioning). In group 3, this procedure was performed before flap elevation (remote ischemic preconditoning). In group 4, the procedure was performed 4 hours after flap ischemia (remote ischemic postconditioning). In group 5, the procedure was performed after the flap was elevated, during the muscle flap ischemia episode (remote ischemic perconditioning). The histopathological damage score in all remote conditioning ischemia groups was lower than in the ischemic-reperfusion group. The lowest histopathological damage score was observed in group 5 (remote ischemic perconditioning). The nitric oxide levels were higher in the blood samples obtained from the remote ischemic perconditioning group. This study showed the effectiveness of remote ischemic conditioning procedures and compared their usefulness for preventing ischemia-reperfusion injury in muscle flaps.

  2. Garlic and Resveratrol attenuate diabetic complications, loss of β-cells, pancreatic and hepatic oxidative stress in streptozotocin-induced diabetic rats

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    Gagandeep Kaur

    2016-10-01

    Full Text Available Abstract:The study was aimed at finding the effect of garlic and resveratrol on loss of β-cells and diabetic complication in streptozotocin (STZ-induced Type-I diabetic rats. Rats were injected with single dose STZ (50mg/kg, i.p. for induction of type 1 diabetes (Dia and compared with control group. Rats from third (Dia+Gar, fourth (Dia+Resv and fifth (Dia+Met groups were fed raw garlic homogenate (250 mg/kg/day, resveratrol (25 mg/kg/day and metformin (500 mg/kg/day orally, respectively for a period of 4 weeks. Diabetic group had decreased serum insulin and hydrogen sulfide levels along with increased blood glucose and glycated hemoglobin, triglyceride, uric acid and nitric oxide levels. Significant (p<0.05 increase in pancreatic and hepatic TBARS, conjugated dienes, nitric oxide, and AGE level and significant (p<0.05 decrease in SOD, catalase, H2S, GSH level were observed in diabetic group. Administration of garlic, resveratrol and metformin significantly (p<0.05 normalized most of the altered metabolic and oxidative stress parameters as well as histopathological changes. Administration of garlic, resveratrol and 9metformin in diabetic rat decreases pancreatic β-cell damage and hepatic injury. Our data concluded that administration of garlic showed more promising effect in terms of reducing oxidative stress and pathological changes when compared to resveratrol and metformin groups.

  3. Polyploidy Analysis and Attenuation of Oxidative Stress in Hepatic Tissue of STZ-Induced Diabetic Rats Treated with an Aqueous Extract of Vochysia rufa

    Directory of Open Access Journals (Sweden)

    Izabela Barbosa Moraes

    2015-01-01

    Full Text Available Diabetes mellitus (DM is characterized by hyperglycemia and alterations in the metabolism of lipids, carbohydrates, and proteins. Due to its hypoglycemic effect Vochysia rufa is frequently used in Uberlandia, Brazil, to treat DM. Despite its popularity, there is little information about its effect on hepatic tissue. Therefore, we evaluated the histoarchitecture, oxidative stress parameters, and polyploidy of liver tissue from streptozotocin- (STZ- induced diabetic rats treated with aqueous extract of Vochysia rufa (AEV. Histology was determined by fixing the livers, processing, and staining with HE. Oxidative stress was determined by evaluating CAT, GPx, and SOD activity in liver homogenates and hepatic mitochondria fraction and by measuring GST, GSH levels and lipid peroxidation (MDA. Polyploidy was determined by subjecting isolated hepatocyte nuclei to flow cytometry. In the diabetic group, GST activity and GSH rates decreased whereas liver homogenate analysis showed that GPx, SOD activity and MDA increased. AEV treatment restored all parameters to normal levels. The oxidative stress analysis of hepatic mitochondria fraction showed similar results. Lower polyploid cell populations were found in the diabetic rat livers, even after glibenclamide treatment. Thus, AEV treatment efficiently reduced hepatic oxidative stress caused by STZ-induced diabetes and produced no morphological changes in the histological analysis.

  4. Consumption of both low and high (-)-epicatechin apple puree attenuates platelet reactivity and increases plasma concentrations of nitric oxide metabolites: A randomized controlled trial

    NARCIS (Netherlands)

    Gasper, A.; Hollands, W.; Casgrain, A.; Saha, S.; Teucher, B.; Dainty, J.R.; Venema, D.P.; Hollman, P.C.H.

    2014-01-01

    We hypothesised that consumption of flavanol-containing apple puree would modulate platelet activity and increase nitric oxide metabolite status, and that high flavanol apple puree would exert a greater effect than low flavanol apple puree. 25 subjects consumed 230 g of apple puree containing 25 and

  5. An oxidative burst and its attenuation by bacterial peroxidase activity is required for optimal establishment of the Arachis hypogaea-Bradyrhizobium sp. symbiosis.

    Science.gov (United States)

    Muñoz, V; Ibáñez, F; Figueredo, M S; Fabra, A

    2016-07-01

    The main purpose of this study was to determine whether the Arachis hypogaea L. root oxidative burst, produced at early stages of its symbiotic interaction with Bradyrhizobium sp. SEMIA 6144, and the bacterial antioxidant system are required for the successful development of this interaction. Pharmacological approaches were used to reduce both plant oxidative burst and bacterial peroxidase enzyme activity. In plants whose H2 O2 levels were decreased, a low nodule number, a reduction in the proportion of red nodules (%) and an increase in the bacteroid density were found. The symbiotic phenotype of plants inoculated with a Bradyrhizobium sp. SEMIA 6144 culture showing decreased peroxidase activity was also affected, since the biomass production, nodule number and percentage of red nodules in these plants were lower than in plants inoculated with Bradyrhizobium sp. control cultures. We demonstrated for the first time that the oxidative burst triggered at the early events of the symbiotic interaction in peanut, is a prerequisite for the efficient development of root nodules, and that the antioxidant system of bradyrhizobial peanut symbionts, particularly the activity of peroxidases, is counteracting this oxidative burst for the successful establishment of the symbiosis. Our results provide new insights into the mechanisms involved in the development of the symbiotic interaction established in A. hypogaea L. a legume infected in an intercellular way. © 2016 The Society for Applied Microbiology.

  6. Perillyl alcohol improves functional and histological outcomes against ischemia-reperfusion injury by attenuation of oxidative stress and repression of COX-2, NOS-2 and NF-κB in middle cerebral artery occlusion rats.

    Science.gov (United States)

    Tabassum, Rizwana; Vaibhav, Kumar; Shrivastava, Pallavi; Khan, Andleeb; Ahmed, Mohd Ejaz; Ashafaq, Mohammad; Khan, M Badruzzaman; Islam, Farah; Safhi, Mohammed M; Islam, Fakhrul

    2015-01-15

    Perillyl alcohol (PA) is a monoterpene found in essential oils of mints, cherries, citreous fruits and lemon grass, reported to have antioxidant and anti-inflammatory properties. However, the role of PA in stroke is still illusive. Since oxidative stress and inflammation play a pivotal role in ischemia-reperfusion (I-R) injury, this study was designed to elucidate the potential effects of PA against I-R induced pathology in rat׳s brain. Middle cerebral artery occlusion (MCAO) for 2h followed by 22h reperfusion in Wistar male rats (250-280g, 14-16 weeks old) induced the behavioral and histological alterations along with exhausted antioxidant status and enhanced inflammatory mediators. However, PA administration (25, 50 and 100mg/kg b.wt orally once daily for 7 days) prior to MCAO significantly attenuated neurological deficits related to flexion test and spontaneous motor activity, improved grip strength and motor coordination in a dose dependent manner. PA treatment also inhibited oxidative stress in MCAO rats as evident from decreased lipid peroxidation and augmented level of reduced glutathione and restored activities of catalase, glutathione peroxidase, and glutathione reductase and thus, reduced infarct volume and protected the brain histology after I-R injury. Furthermore, PA markedly suppressed the level of proinflammatory cytokines (IL-1β, TNF α and IL-6) and down regulated expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (NOS-2) and nuclear factor κB (NF-κB) in MCAO group. In conclusion, PA mediates neuroprotection against I-R injury via mitigation of oxidative stress and inflammation and thus, may be a good therapeutic approach in stroke prone patient. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Attenuation of oxidative stress in Type 1 diabetic rats supplemented with a seasoning obtained from winemaking by-products and its effect on endothelial function.

    Science.gov (United States)

    Del Pino-García, Raquel; Rivero-Pérez, María D; González-SanJosé, María L; Castilla-Camina, Pablo; Croft, Kevin D; Muñiz, Pilar

    2016-10-12

    Type 1 diabetes mellitus (DM) is characterized by hyperglycemia resulting from insulin deficiency. This is usually accompanied by a pro-oxidative environment, dyslipidemia and endothelial dysfunction, thus leading to several micro- and macro-vascular complications. This study investigated the potential benefits of a seasoning obtained from seedless red wine pomace (RWPS) in protecting against oxidative damage and preserving endothelial function in Type 1 DM, and the underlying mechanisms involved at the level of gene expression. The diet of streptozotocin (45 mg kg -1 )-induced diabetic (DB) and control (CN) male Wistar rats (n = 5 rats per group) was supplemented with RWPS (300 mg per kg per day) or vehicle for 4 weeks. Characteristic indicators of DM such as increased food and water intakes and weight loss were significantly ameliorated in DB + RWPS rats, with a notable normalization in their fasting glycemic control and cholesterol profile. Plasma total antioxidant capacity (TAC) was substantially increased, and biomarkers of oxidative damage to lipids (F 2 -isoprostanes, 24.9%; malondialdehyde, 28.4%) and proteins (carbonyl groups, 5.91%) were significantly decreased. Nitric oxide availability tended to improve in plasma of DB + RWPS compared with DB rats. Insulin levels were increased (1.51-fold) and aortic tissue antioxidant enzymes such as mitochondrial superoxide dismutase (SOD2, 1.93-fold) were up-regulated. Other important genes for endothelial function, including endothelial β-nicotinamide adenine dinucleotide phosphate oxidase (NOX4), endothelial and inducible nitric oxide synthases (eNOS, iNOS), and angiotensin-converting enzyme-I (ACE), were non-significantly modulated, although certain potentially positive trends were observed. These results indicate that RWPS supplementation might be a useful nutritional approach to manage Type 1 DM and ameliorate its vascular complications.

  8. Caffeic acid attenuates the inflammatory stress induced by glycated LDL in human endothelial cells by mechanisms involving inhibition of AGE-receptor, oxidative, and endoplasmic reticulum stress.

    Science.gov (United States)

    Toma, Laura; Sanda, Gabriela M; Niculescu, Loredan S; Deleanu, Mariana; Stancu, Camelia S; Sima, Anca V

    2017-09-10

    Type 2 diabetes mellitus is a worldwide epidemic and its atherosclerotic complications determine the high morbidity and mortality of diabetic patients. Caffeic acid (CAF), a phenolic acid present in normal diets, is known for its antioxidant properties. The aim of this study was to investigate CAF's anti-inflammatory properties and its mechanism of action, using cultured human endothelial cells (HEC) incubated with glycated low-density lipoproteins (gLDL). Levels of the receptor for advanced glycation end-products (RAGE), inflammatory stress markers (C reactive protein, CRP; vascular cell adhesion molecule-1, VCAM-1; monocyte chemoattractant protein-1, MCP-1), and oxidative stress and endoplasmic reticulum stress (ERS) markers were evaluated in gLDL-exposed HEC, in the presence/absence of CAF. RAGE silencing or blocking, specific inhibitors for oxidative stress (apocynin, N-acetyl-cysteine), and ERS (salubrinal) were used. The results showed that: (i) gLDL induced CRP synthesis and secretion through mechanisms involving NADPH oxidase-dependent oxidative stress and ERS in HEC; (ii) gLDL-RAGE interaction, oxidative stress, and ERS stimulated the secretion of VCAM-1 and MCP-1 in HEC; and (iii) CAF reduced the secretion of CRP, VCAM-1, and MCP-1 in gLDL-exposed HEC by inhibiting RAGE expression, oxidative stress, and ERS. In conclusion, CAF might be a promising alternative to ameliorate a wide spectrum of disorders due to its complex mechanisms of action resulting in anti-inflammatory and antioxidative properties. © 2017 BioFactors, 43(5):685-697, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

  9. Unilateral anterior ischemic optic neuropathy

    DEFF Research Database (Denmark)

    Herbst, Kristina; Sander, Birgit; Lund-Andersen, Henrik

    2013-01-01

    of this study was to investigate the ipRGC mediated pupil response in patients with a unilateral non-arteritic anterior ischemic optic neuropathy (NAION). Consensual pupil responses during and after exposure to continuous 20 s blue (470 nm) or red (660 nm) light of high intensity (300 cd/m(2)) were recorded...

  10. [Ischemic stroke in young women

    NARCIS (Netherlands)

    Ekker, M.S.; Wermer, M.J.; Riksen, N.P.; Klijn, C.J.; Leeuw, F.E. de

    2016-01-01

    - In virtually all age groups, the incidence of ischemic stroke is higher in men. However, in women aged between 25-49 years the prevalence is higher than in men. Female-specific risk factors and disorders may explain this peak.- Pregnancy and the post-partum period are associated with physiological

  11. Diabetes and ischemic heart disease

    DEFF Research Database (Denmark)

    Bergmann, Natasha; Ballegaard, Søren; Holmager, Pernille

    2014-01-01

    The aim of this study was to test i) whether patients having diabetes and ischemic heart disease (IHD), i.e., patients suffering from two chronic diseases, demonstrate a higher degree of chronic stress when compared with patients suffering from IHD alone, and ii) whether suffering from the two...

  12. Olanzapine-induced ischemic colitis

    Directory of Open Access Journals (Sweden)

    Esteban Sáez-González

    Full Text Available Background: Ischemic colitis (IC is an uncommon adverse event associated with antipsychotic agents, more commonly found with phenothiazine drugs and atypical neuroleptics such as clozapine. The risk of developing ischemic colitis increases when anticholinergic drugs are associated. Case report: We report the case of a 38-year-old woman with a history of schizoaffective disorder who had been on chronic quetiapine for 3 years, and presented to the ER because of diarrhea for 5 days. Four months previously, olanzapine had been added to her psychiatric drug regimen. Physical examination revealed abdominal distension with abdominal tympanic sounds and tenderness. Emergency laboratory tests were notable for increased acute phase reagents. Tomography revealed a concentric thickening of the colonic wall in the transverse, descending and sigmoid segments, with no signs of intestinal perforation. Colonoscopy demonstrated severe mucosal involvement from the sigmoid to the hepatic flexure, with ulcerations and fibrinoid exudate. Biopsies confirmed the diagnosis of ischemic colitis. The only relevant finding in her history was the newly added drug to her baseline regimen. An adverse effect was suspected because of its anticholinergic action at the intestinal level, and the drug was withdrawn. After 6 months of follow-up clinical, laboratory and endoscopic recovery was achieved. Discussion: Antipsychotic medication should be considered as a potential cause of ischemic colitis, particularly atypical antipsychotics such as clozapine and olanzapine; despite being uncommon, this adverse event may result in high morbidity and mortality.

  13. Oxidative stress evoked damages leading to attenuated memory and inhibition of NMDAR–CaMKII–ERK/CREB signalling on consumption of aspartame in rat model

    Directory of Open Access Journals (Sweden)

    Ashok Iyaswamy

    2018-04-01

    Full Text Available Many controversial reports are available on the use of aspartame as it releases methanol as one of its metabolite during metabolism. The present study proposes to investigate whether long term (90 days aspartame (40 mg/kg b.wt administration could induce oxidative stress and alter the memory in Wistar strain male albino rats. To mimic the human methanol metabolism, methotrexate (MTX-treated rats were included as a model to study the effects of aspartame. Wistar strain albino rats were administered with aspartame (40 mg/kg b.wt orally and studied along with controls and MTX-treated controls. Aspartame interfered in the body weight and corticosterone levels in the rats. A marked increase in the mRNA and protein expression of neuronal nitric oxide synthase (nNOS and induced nitric oxide synthase (iNOS which resulted in the increased nitric oxide radical's level indicating that aspartame is a stressor. These reactive nitrogen species could be responsible for the altered cell membrane integrity and even cause death of neurons by necrosis or apoptosis. The animals showed a marked decrease in learning, spatial working and spatial recognition memory deficit in the Morris water maze and Y-maze performance task which could have resulted due to reduced hippocampal acetylcholine esterase (AChE activity. The animal brain homogenate also revealed the decrease in the phosphorylation of NMDAR1–CaMKII–ERK/CREB signalling pathway, which well documents the inhibition of phosphorylation leads to the excitotoxicity of the neurons and memory decline. This effect may be due to methanol which may also activate the NOS levels, microglia and astrocytes, inducing neurodegeneration in brain. Neuronal shrinkage of hippocampal layer due to degeneration of pyramidal cells revealed the abnormal neuronal morphology of pyramidal cell layers in the aspartame treated animals. These findings demonstrate that aspartame metabolites could be a contributing factor for the

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

    Science.gov (United States)

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

    2017-02-01

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

  15. Resveratrol attenuates oxidative stress and improves behaviour in 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) challenged mice

    OpenAIRE

    Anandhan, Annadurai; Tamilselvam, Kuppusamy; Vijayraja, Dhanraj; Ashokkumar, Nataraj; Rajasankar, Srinivasagam; Manivasagam, Thamilarasan

    2010-01-01

    Background Parkinson's disease (PD) is the most common neurodegenerative disorder, characterized by loss of dopaminergic neurons in substantia nigra and depletion of dopamine in striatum due to mitochondrial dysfunction, oxidative stress, excitotoxicity, apoptosis, inflammation and proteasome failure. Purpose The present study deals with the neuroprotective effect of resveratrol, a wine polyphenol (50 mg/kg body weight) against MPTP (30mg/kg body weight as i.p. administration) induced mice mo...

  16. Resveratrol attenuates lipopolysaccharide-induced hepatitis in D-Galactosamine sensitized rats: Role of nitric oxide synthase 2 and heme oxygenase-1

    Czech Academy of Sciences Publication Activity Database

    Farghali, H.; Černý, D.; Kameníková, L.; Martínek, J.; Hořínek, A.; Kmoníčková, Eva; Zídek, Zdeněk

    2009-01-01

    Roč. 21, 3-4 (2009), s. 216-225 ISSN 1089-8603 R&D Projects: GA ČR GA305/07/0061 Grant - others:GA ČR(CZ) GA305/09/0004; GA MZd(CZ) NR9379 Institutional research plan: CEZ:AV0Z50390512 Keywords : resveratrol * lipopolysacchride * nitrix oxide Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 2.506, year: 2009

  17. Tocotrienol rich tocomin attenuates oxidative stress and improves endothelium-dependent relaxation in aortae from rats fed a high-fat western diet

    Directory of Open Access Journals (Sweden)

    Saher F Ali

    2016-10-01

    Full Text Available We have previously reported that tocomin, a mixture high in tocotrienol content and also containing tocopherol, acutely preserves endothelial function in the presence of oxidative stress. In this study we investigated whether tocomin treatment would preserve endothelial function in aortae isolated from rats fed a high fat diet known to cause oxidative stress. Wistar hooded rats were fed a western diet (WD, 21% fat or control rat chow (SD, 6% fat for 12 weeks. Tocomin (40 mg/kg/day sc or its vehicle (peanut oil was administered for the last 4 weeks of the feeding regime. Aortae from WD rats showed an impairment of endothelium-dependent relaxation that was associated with an increased expression of the NADPH oxidase Nox2 subunit and an increase in the vascular generation of superoxide measured using L-012 chemiluminescence. The increase in vascular oxidative stress was accompanied by a decrease in basal NO release and impairment of the contribution of NO to ACh-induced relaxation. The impaired relaxation is likely contributed to by a decreased expression of eNOS, calmodulin and phosphorylated Akt and an increase in caveolin-Tocotrienol rich tocomin, which prevented the diet-induced changes in vascular function, reduced vascular superoxide production and abolished the diet-induced changes in eNOS and other protein expression. Using selective inhibitors of nitric oxide synthase (NOS, soluble guanylate cyclase (sGC and calcium activated potassium (KCa channels we demonstrated that tocomin increased NO mediated relaxation, without affecting the contribution of endothelium-dependent hyperpolarization type relaxation to the endothelium-dependent relaxation. The beneficial actions of tocomin in this diet-induced model of obesity suggests that it may have potential to be used as a therapeutic agent to prevent vascular disease in obesity.

  18. Statin-induced inhibition of breast cancer proliferation and invasion involves attenuation of iron transport: intermediacy of nitric oxide and antioxidant defence mechanisms.

    Science.gov (United States)

    Kanugula, Anantha Koteswararao; Gollavilli, Paradesi Naidu; Vasamsetti, Sathish Babu; Karnewar, Santosh; Gopoju, Raja; Ummanni, Ramesh; Kotamraju, Srigiridhar

    2014-08-01

    Accumulating evidence from in vitro, in vivo, clinical and epidemiological studies shows promising results for the use of statins against many cancers including breast carcinoma. However, the molecular mechanisms responsible for the anti-proliferative and anti-invasive properties of statins still remain elusive. In this study, we investigated the involvement of nitric oxide, iron homeostasis and antioxidant defence mechanisms in mediating the anti-proliferative and anti-invasive properties of hydrophobic statins in MDA-MB-231, MDA-MB-453 and BT-549 metastatic triple negative breast cancer cells. Fluvastatin and simvastatin significantly increased cytotoxicity which was reversed with mevalonate. Interestingly, fluvastatin downregulated transferrin receptor (TfR1), with a concomitant depletion of intracellular iron levels in these cells. Statin-induced effects were mimicked by geranylgeranyl transferase inhibitor (GGTI-298) but not farnesyl transferase inhibitor (FTI-277). Further, it was observed that TfR1 downregulation is mediated by increased nitric oxide levels via inducible nitric oxide synthase (iNOS) expression. NOS inhibitors (asymmetric dimethylarginine and 1400W) counteracted and sepiapterin, a precursor of tetrahydrobiopterin, exacerbated statin-induced depletion of intracellular iron levels. Notably, fluvastatin increased manganese superoxide dismutase (by repressing the transcription factor DNA damage-binding protein 2), catalase and glutathione which, in turn, diminished H2 O2 levels. Fluvastatin-induced downregulation of TfR1, matrix metalloproteinase-2, -9 and inhibition of invasion were reversed in the presence of aminotriazole, a specific inhibitor of catalase. Finally, we conclude that fluvastatin, by altering iron homeostasis, nitric oxide generation and antioxidant defence mechanisms, induces triple negative breast cancer cell death. © 2014 FEBS.

  19. Attenuation of oxidative and nitrosative stress in cortical area associates with antidepressant-like effects of tropisetron in male mice following social isolation stress.

    Science.gov (United States)

    Haj-Mirzaian, Arya; Amiri, Shayan; Amini-Khoei, Hossein; Rahimi-Balaei, Maryam; Kordjazy, Nastaran; Olson, Carl O; Rastegar, Mojgan; Naserzadeh, Parvaneh; Marzban, Hassan; Dehpour, Ahmad Reza; Hosseini, Mir-Jamal; Samiei, Elika; Mehr, Shahram Ejtemaei

    2016-06-01

    Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, tropisetron (5mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20mg/kg) augmented the protective effects of tropisetron (1mg/kg) on SIS. Furthermore, l-arginine (nitric oxide precursor, 100mg/kg) abolished the positive effects of tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral cortex. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Grapefruit-seed extract attenuates ethanol-and stress-induced gastric lesions via activation of prostaglandin, nitric oxide and sensory nerve pathways.

    Science.gov (United States)

    Brzozowski, Tomasz; Konturek, Peter C; Drozdowicz, Danuta; Konturek, Stanislaw J; Zayachivska, Oxana; Pajdo, Robert; Kwiecien, Slawomir; Pawlik, Wieslaw W; Hahn, Eckhart G

    2005-11-07

    Grapefruit-seed extract (GSE) containing flavonoids, possesses antibacterial and antioxidative properties but whether it influences the gastric defense mechanism and gastroprotection against ethanol- and stress-induced gastric lesions remains unknown. We compared the effects of GSE on gastric mucosal lesions induced in rats by topical application of 100% ethanol or 3.5 h of water immersion and restraint stress (WRS) with or without (A) inhibition of cyclooxygenase (COX)-1 activity by indomethacin and rofecoxib, the selective COX-2 inhibitor, (B) suppression of NO-synthase with L-NNA (20 mg/kg ip), and (C) inactivation by capsaicin (125 mg/kg sc) of sensory nerves with or without intragastric (ig) pretreatment with GSE applied 30 min prior to ethanol or WRS. One hour after ethanol and 3.5 h after the end of WRS, the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was assessed by H2-gas clearance technique and plasma gastrin levels and the gastric mucosal generation of PGE2, superoxide dismutase (SOD) activity and malonyldialdehyde (MDA) concentration, as an index of lipid peroxidation were determined. Ethanol and WRS caused gastric lesions accompanied by the significant fall in the GBF and SOD activity and the rise in the mucosal MDA content. Pretreatment with GSE (8-64 mg/kg i g) dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID50) was 25 and 36 mg/kg, respectively, and this protective effect was similar to that obtained with methyl PGE2 analog (5 microg/kg i g). GSE significantly raised the GBF, mucosal generation of PGE2, SOD activity and plasma gastrin levels while attenuating MDA content. Inhibition of PGE2 generation with indomethacin or rofecoxib and suppression of NO synthase by L-NNA or capsaicin denervation reversed the GSE-induced protection and the accompanying hyperemia. Co-treatment of exogenous calcitonine gene-related peptide (CGRP) with

  1. Oxidative stress evoked damages leading to attenuated memory and inhibition of NMDAR-CaMKII-ERK/CREB signalling on consumption of aspartame in rat model.

    Science.gov (United States)

    Iyaswamy, Ashok; Kammella, Ananth Kumar; Thavasimuthu, Citarasu; Wankupar, Wankhar; Dapkupar, Wankhar; Shanmugam, Sambantham; Rajan, Ravindran; Rathinasamy, Sheeladevi

    2018-04-01

    Many controversial reports are available on the use of aspartame as it releases methanol as one of its metabolite during metabolism. The present study proposes to investigate whether long term (90 days) aspartame (40 mg/kg b.wt) administration could induce oxidative stress and alter the memory in Wistar strain male albino rats. To mimic the human methanol metabolism, methotrexate (MTX)-treated rats were included as a model to study the effects of aspartame. Wistar strain albino rats were administered with aspartame (40 mg/kg b.wt) orally and studied along with controls and MTX-treated controls. Aspartame interfered in the body weight and corticosterone levels in the rats. A marked increase in the mRNA and protein expression of neuronal nitric oxide synthase (nNOS) and induced nitric oxide synthase (iNOS) which resulted in the increased nitric oxide radical's level indicating that aspartame is a stressor. These reactive nitrogen species could be responsible for the altered cell membrane integrity and even cause death of neurons by necrosis or apoptosis. The animals showed a marked decrease in learning, spatial working and spatial recognition memory deficit in the Morris water maze and Y-maze performance task which could have resulted due to reduced hippocampal acetylcholine esterase (AChE) activity. The animal brain homogenate also revealed the decrease in the phosphorylation of NMDAR1-CaMKII-ERK/CREB signalling pathway, which well documents the inhibition of phosphorylation leads to the excitotoxicity of the neurons and memory decline. This effect may be due to methanol which may also activate the NOS levels, microglia and astrocytes, inducing neurodegeneration in brain. Neuronal shrinkage of hippocampal layer due to degeneration of pyramidal cells revealed the abnormal neuronal morphology of pyramidal cell layers in the aspartame treated animals. These findings demonstrate that aspartame metabolites could be a contributing factor for the development of oxidative

  2. Topical fentanyl stimulates healing of ischemic wounds in diabetic rats

    Science.gov (United States)

    FAROOQUI, Mariya; ERICSON, Marna E; GUPTA, Kalpna

    2016-01-01

    Background Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth-promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration. Methods We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho-PDGFR-β were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting. Results Fentanyl significantly promoted wound closure as compared to PBS. Histology scores were significantly higher in fentanyl-treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, NOS and PDGFR-β signaling as compared to PBS. Phospho PDGFR-β co-localized with CD31 co-staining for vasculature. Conclusions Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing. PMID:25266258

  3. Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Michihiro Fujiwara

    2010-07-01

    Full Text Available Cannabis contains the psychoactive component delta9-tetrahydrocannabinol (delta9-THC, and the non-psychoactive components cannabidiol (CBD, cannabinol, and cannabigerol. It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system. In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. Of the CB1 receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB1 receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.

  4. Studies of nitride- and oxide-based materials as absorptive shifters for embedded attenuated phase-shifting mask in 193 nm

    Science.gov (United States)

    Lin, Cheng-ming; Chang, Keh-wen; Lee, Ming-der; Loong, Wen-An

    1999-07-01

    Abstract-Five materials which are PdSixOy, CrAlxOy, SiNx, TiSixNy, and TiSixOyNz as absorptive shifters for attenuated phase-shifting mask in 193 nm wavelength lithography are presented. PdSixOy films were deposited by dual e-gun evaporation. CrAlxOy, TiSixNy and TiSixOyNz films were formed by plasma sputtering and SiNx films were formed with LPCVD. All of these materials are shown to be capable of achieving 4 percent - 15 percent transmittance in 193 nm with thickness that produce a 180 degrees phase shift. Under BCl3:Cl2 equals 14:70 sccm; chamber pressure 5 mtorr and RF power 1900W, the dry etching selectivity of TiSixNy over DQN positive resist and fused silica, were found to be 2:1 and 4,8:1 respectively. An embedded layer TiSixNy with 0.5 micrometers line/space was successfully patterned.

  5. Melatonin and Ischemic Stroke: Mechanistic Roles and Action

    Directory of Open Access Journals (Sweden)

    Syed Suhail Andrabi

    2015-01-01

    Full Text Available Stroke is one of the most devastating neurological disabilities and brain’s vulnerability towards it proves to be fatal and socio-economic loss of millions of people worldwide. Ischemic stroke remains at the center stage of it, because of its prevalence amongst the several other types attacking the brain. The various cascades of events that have been associated with stroke involve oxidative stress, excitotoxicity, mitochondrial dysfunction, upregulation of Ca2+ level, and so forth. Melatonin is a neurohormone secreted by pineal and extra pineal tissues responsible for various physiological processes like sleep and mood behaviour. Melatonin has been implicated in various neurological diseases because of its antioxidative, antiapoptotic, and anti-inflammatory properties. We have previously reviewed the neuroprotective effect of melatonin in various models of brain injury like traumatic brain injury and spinal cord injury. In this review, we have put together the various causes and consequence of stroke and protective role of melatonin in ischemic stroke.

  6. Melatonin and Ischemic Stroke: Mechanistic Roles and Action.

    Science.gov (United States)

    Andrabi, Syed Suhail; Parvez, Suhel; Tabassum, Heena

    2015-01-01

    Stroke is one of the most devastating neurological disabilities and brain's vulnerability towards it proves to be fatal and socio-economic loss of millions of people worldwide. Ischemic stroke remains at the center stage of it, because of its prevalence amongst the several other types attacking the brain. The various cascades of events that have been associated with stroke involve oxidative stress, excitotoxicity, mitochondrial dysfunction, upregulation of Ca(2+) level, and so forth. Melatonin is a neurohormone secreted by pineal and extra pineal tissues responsible for various physiological processes like sleep and mood behaviour. Melatonin has been implicated in various neurological diseases because of its antioxidative, antiapoptotic, and anti-inflammatory properties. We have previously reviewed the neuroprotective effect of melatonin in various models of brain injury like traumatic brain injury and spinal cord injury. In this review, we have put together the various causes and consequence of stroke and protective role of melatonin in ischemic stroke.

  7. Troxerutin protects against 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47)-induced liver inflammation by attenuating oxidative stress-mediated NAD{sup +}-depletion

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Zi-Feng [School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221008, Jiangsu Province (China); Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province (China); Zhang, Yan-qiu [School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221008, Jiangsu Province (China); Fan, Shao-Hua [Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province (China); Zhuang, Juan [School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221008, Jiangsu Province (China); Zheng, Yuan-Lin, E-mail: ylzheng@jsnu.edu.cn [Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province (China); Lu, Jun; Wu, Dong-Mei; Shan, Qun; Hu, Bin [Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, 101 Shanghai Road, Xuzhou 221116, Jiangsu Province (China)

    2015-02-11

    Highlights: • BDE-47 promotes liver inflammation by triggering oxidative stress-induced NAD{sup +} depletion. • Troxerutin inhibits BDE-47-induced liver inflammation via its antioxidant properties. • Troxerutin restores NAD{sup +} level and consequently abates SirT1 loss. • Troxerutin represses acetylation of NF-κB p65 (K310) and H3K9. • Troxerutin is a candidate for prevention and therapy of BDE-47-induced hepatotoxicity. - Abstract: Emerging evidence indicates that 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) induces liver injury through enhanced ROS production and lymphocytic infiltration, which may promote a liver inflammatory response. Antioxidants have been reported to attenuate the cellular toxicity associated with polybrominated diphenyl ethers (PBDEs). In this study, we investigated the effect of troxerutin, a trihydroxyethylated derivative of the natural bioflavonoid rutin, on BDE-47-induced liver inflammation and explored the potential mechanisms underlying this effect. Our results showed that NAD{sup +}-depletion was involved in the oxidative stress-mediated liver injury in a BDE-47 treated mouse model, which was confirmed by Vitamin E treatment. Furthermore, our data revealed that troxerutin effectively alleviated liver inflammation by mitigating oxidative stress-mediated NAD{sup +}-depletion in BDE-47 treated mice. Consequently, troxerutin remarkably restored SirT1 protein expression and activity in the livers of BDE-47-treated mice. Mechanistically, troxerutin dramatically repressed the nuclear translocation of NF-κB p65 and the acetylation of NF-κB p65 (Lys 310) and Histone H3 (Lys9) to abate the transcription of inflammatory genes in BDE-47-treated mouse livers. These inhibitory effects of troxerutin were markedly blunted by EX527 (SirT1 inhibitor) treatment. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be used in the prevention and therapy of BDE-47-induced

  8. Nutrition for brain recovery after ischemic stroke: an added value to rehabilitation.

    Science.gov (United States)

    Aquilani, Roberto; Sessarego, Paolo; Iadarola, Paolo; Barbieri, Annalisa; Boschi, Federica

    2011-06-01

    In patients who undergo rehabilitation after ischemic stroke, nutrition strategies are adopted to provide tube-fed individuals with adequate nutrition and/or to avoid the body wasting responsible for poor functional outcome and prolonged stay in the hospital. Investigations have documented that nutrition interventions can enhance the recovery of neurocognitive function in individuals with ischemic stroke. Experimental studies have shown that protein synthesis is suppressed in the ischemic penumbra. In clinical studies on rehabilitation patients designed to study the effects of counteracting or limiting this reduction of protein synthesis by providing protein supplementation, patients receiving such supplementation had enhanced recovery of neurocognitive function. Cellular damage in cerebral ischemia is also partly caused by oxidative damage secondary to free radical formation and lipid peroxidation. Increased oxidative stress negatively affects a patient's life and functional prognosis. Some studies have documented that nutrition supplementation with B-group vitamins may mitigate oxidative damage after acute ischemic stroke. Experimental investigations have also shown that cerebral ischemia changes synaptic zinc release and that acute ischemia increases zinc release, aggravating neuronal injury. In clinical practice, patients with ischemic stroke were found to have a lower than recommended dietary intake of zinc. Patients in whom daily zinc intake was normalized had better recovery of neurological deficits than subjects given a placebo. The aim of this review is to highlight those brain metabolic alterations susceptible to nutrition correction in clinical practice. The mechanisms underlying the relationship between cerebral ischemia and nutrition metabolic conditions are discussed.

  9. Effects of yam tuber protein, dioscorin, on attenuating oxidative status and learning dysfunction in d-galactose-induced BALB/c mice.

    Science.gov (United States)

    Han, Chuan-Hsiao; Lin, Yuh-Feng; Lin, Yin-Shiou; Lee, Tai-Lin; Huang, Wei-Jan; Lin, Shyr-Yi; Hou, Wen-Chi

    2014-03-01

    The yam tuber is a traditional Chinese medicine used in long-term treatment as a juvenescent substance. The purified yam tuber's major water-soluble protein, dioscorin, and its protease hydrolysates have been reported to have several biological activities. In this study, d-galactose (Gal) was subcutaneously injected into the dorsal necks of BALB/c mice daily for 10weeks (Gal group) to induce oxidative stress. By the fifth week, 20 or 80mg dioscorin/kg was orally administered daily combined with a daily Gal injection until the end of the study. The plasma malondialdehyde (MDA) level and advanced glycation end-products obtained after dioscorin oral administrations were lower compared to the Gal group. In addition, the latency and swimming distance in the mice that received dioscorin administration were significantly improved compared to the Gal group in the Morris water maze. Dioscorin administration resulted in higher GSH levels and oxygen radical antioxidant capacity (ORAC) activity and lower MDA and inducible nitric oxide synthase (iNOS) levels in the brain compared to mice in the Gal group. These elevated antioxidant activities following oral administration of yam dioscorin in vivo may reflect traditional juvenescent uses with the potential for anti-aging treatments. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. L-cysteine protects intestinal integrity, attenuates intestinal inflammation and oxidant stress, and modulates NF-κB and Nrf2 pathways in weaned piglets after LPS challenge.

    Science.gov (United States)

    Song, Ze he; Tong, Guo; Xiao, Kan; Jiao, Le fei; Ke, Ya lu; Hu, Cai hong

    2016-04-01

    In this study we investigated whetherL-cysteine (L-cys) could alleviate LPS-induced intestinal disruption and its underlying mechanism. Piglets fed with anL-cys-supplemented diet had higher average daily gain.L-cys alleviated LPS-induced structural and functional disruption of intestine in weanling piglets, as demonstrated by higher villus height, villus height (VH) to crypt depth (CD) ratio, and transepithelial electrical resistance (TER) and lower FITC-dextran 4 (FD4) kDa flux in jejunum and ileum. Supplementation withL-cys up-regulated occludin and claudin-1 expression, reduced caspase-3 activity and enhanced proliferating cell nuclear antigen expression of jejunum and ileum relative to LPS group. Additionally,L-cys suppressed the LPS-induced intestinal inflammation and oxidative stress, as demonstrated by down-regulated TNF-α, IL-6 and IL-8 mRNA levels, increased catalase, superoxide dismutase, glutathione peroxidase activity, glutathione (GSH) contents and the ratio of GSH and oxidized glutathione in jejunum and ileum. Finally, a diet supplemented withL-cys inhibited NF-κB(p65) nuclear translocation and elevated NF erythroid 2-related factor 2 (Nrf2) translocation compared with the LPS group. Collectively, our results indicated the protective function ofL-cys on intestinal mucosa barrier may closely associated with its anti-inflammation, antioxidant and regulating effect on the NF-κB and Nrf2 signaling pathways. © The Author(s) 2016.

  11. Epigallocatechin Gallate Attenuates Proliferation and Oxidative Stress in Human Vascular Smooth Muscle Cells Induced by Interleukin-1β via Heme Oxygenase-1

    Directory of Open Access Journals (Sweden)

    Po-Len Liu

    2014-01-01

    Full Text Available Proliferation of vascular smooth muscle cells (VSMCs triggered by inflammatory stimuli and oxidative stress contributes importantly to atherogenesis. The association of green tea consumption with cardiovascular protection has been well documented in epidemiological observations, however, the underlying mechanisms remain unclear. This study aimed to elucidate the effects of the most active green tea catechin derivative, (−-epigallocatechin-3-gallate (EGCG, in human aortic smooth muscle cells (HASMCs, focusing particularly on the role of a potent anti-inflammatory and antioxidative enzyme heme oxygenase-1 (HO-1. We found that pretreatment of EGCG dose- and time-dependently induced HO-1 protein levels in HASMCs. EGCG inhibited interleukin- (IL-1β-induced HASMC proliferation and oxidative stress in a dose-dependent manner. The HO-1 inducer CoPPIX decreased IL-1β-induced cell proliferation, whereas the HO-1 enzyme inhibitor ZnPPIX significantly reversed EGCG-caused growth inhibition in IL-1β-treated HASMCs. At the molecular level, EGCG treatment significantly activated nuclear factor erythroid-2-related factor (Nrf2 transcription activities. These results suggest that EGCG might serve as a complementary and alternative medicine in the treatment of these pathologies by inducing HO-1 expression and subsequently decreasing VSMC proliferation.

  12. Attenuation by methyl mercury and mercuric sulfide of pentobarbital induced hypnotic tolerance in mice through inhibition of ATPase activities and nitric oxide production in cerebral cortex

    Energy Technology Data Exchange (ETDEWEB)

    Chuu, Jiunn-Jye; Huang, Zih-Ning; Yu, Hsun-Hsin; Chang, Liang-Hao [College of Engineering, Southern Taiwan University, Institute of Biotechnology, Tainan (China); Lin-Shiau, Shoei-Yn [College of Medicine, National Taiwan University, Institute of Pharmacology, Taipei (China)

    2008-06-15

    This study is aimed at exploring the possible mechanism of hypnosis-enhancing effect of HgS or cinnabar (a traditional Chinese medicine containing more than 95% HgS) in mice treated with pentobarbital. We also examined whether the effect of HgS is different from that of the well-known methyl mercury (MeHg). After a short period (7 days) of oral administration to mice, a nontoxic dose (0.1 g/kg) of HgS not only significantly enhanced pentobarbital-induced hypnosis but also attenuated tolerance induction; while a higher dose (1 g/kg) of HgS or cinnabar exerted an almost irreversible enhancing effect on pentobarbital-hypnosis similar to that of MeHg (2 mg/kg) tested, which was still effective even after 10 or 35 days cessation of administration. To study comparatively the effects of different mercury forms from oral administration of MeHg and HgS on membrane ATPase activities of experimental mice, analysis of the Hg content in the cerebral cortex revealed that correlated with the decrease of Na{sup +}/K{sup +}-ATPase and Ca{sup 2+}-ATPase activities. Furthermore, NO levels of blood but not that of cerebral cortex were also decreased by mercuric compounds. Although pentobarbital alone enhanced cytochrome p450-2C9 in time dependent manner, all of mercurial compounds tested had no such effect. All of these findings indicated that the mercurial compounds including cinnabar, HgS and MeHg exert a long-lasting enhancing hypnotic activity without affecting pentobarbital metabolism, which provides evidence-based sedative effect of cinnabar used in Chinese traditional medicine for more than 2,000 years. The nontoxic HgS dosing (0.1 g/kg/day) for consecutive 7 days is perhaps useful for delaying or preventing pentobarbital-tolerance. (orig.)

  13. Edaravone, a potent free radical scavenger and a calcium channel blocker attenuate isoproterenol induced myocardial infarction by suppressing oxidative stress, apoptotic signaling and ultrastructural damage.

    Science.gov (United States)

    Hassan, Md Quamrul; Akhtar, Md Sayeed; Akhtar, Mohd; Ali, Javed; Haque, Syed Ehtaishamul; Najmi, Abul Kalam

    2016-08-01

    In the present study, we investigated whether combination therapy of low-dose benidipine with the potent free radical scavenger edaravone has a cardioprotective effect against isoproterenol (ISO)-induced myocardial infarction (MI) in Wistar rats. Rats were pretreated with concurrent doses of benidipine and edaravone (1 μg/kg/day + 1 mg/kg/day and 3 μg/kg/day + 3 mg/kg/day) by intravenous (i.v.) and intraperitoneal (i.p.) routes respectively for 28 days, followed by MI induction using ISO (85 mg/kg) by subcutaneous route for two days at 24 h intervals. After the treatment period, blood was withdrawn and the heart was preserved for biochemical estimations. The activities of the cardiac biomarkers (lactate dehydrogenase and creatine kinase-MB), and the level of malondialdehyde (MDA) significantly increased, while antioxidant markers (reduced glutathione, catalase, superoxidase dismutase, glutathione peroxidase, glutathione reductase) were significantly decreased in the ISO intoxicated group compared with the control group. Moreover, the level of C-reactive protein (CRP) and Caspase-3 activity significantly increased in ISO-intoxicated group. An ultrastructure study was also carried out. Pretreatment with a combination of benidipine and edaravone significantly attenuated the activities of the cardiac biomarkers and the level of MDA, and significantly increased the antioxidant markers compared with the ISO-intoxicated group. Furthermore, pretreatment with the combination of benidipine and edaravone significantly decreased the level of CRP and Caspase-3 activity as compared to the ISO-treated group. The ultrastructure study of myocardium revealed that pretreated groups preserved the mitochondrial shape, the membrane and its internal structures. Taken together these results suggest that the combination of benidipine and edaravone showed significant protective effect in ISO-induced MI. © The Author(s), 2016.

  14. Role of homocysteine in the ischemic stroke nad development of ischemic tolerance

    Directory of Open Access Journals (Sweden)

    Jan Lehotsky

    2016-11-01

    Full Text Available Homocysteine (Hcy is a toxic, sulfur-containing intermediate of methionine metabolism. Hyperhomocysteinemia (hHcy, as a consequence of impaired Hcy metabolism or defects in crucial co-factors that participate in its recycling, is assumed as an independent human stroke risk factor. Neural cells are sensitive to prolonged hHcy treatment, because Hcy cannot be metabolized either by the transsulfuration pathway or by the folate/vitamin B12 independent remethylation pathway. Its detrimental effect after ischemia-induced damage includes accumulation of reactive oxygen species (ROS and posttranslational modifications of proteins via homocysteinylation and thiolation. Ischemic preconditioning (IPC is an adaptive response of the CNS to sub-lethal ischemia, which elevates tissues tolerance to subsequent ischemia. The main focus of this review is on the recent data on homocysteine metabolism and mechanisms of its neurotoxicity. In this context, the review documents an increased oxidative stress and functional modification of enzymes involved in redox balance in experimentally induced hyperhomocysteinemia. It also gives an interpretation whether hyperhomocysteinemia alone or in combination with IPC affects the ischemia-induced neurodegenerative changes as well as intracellular signalling. Studies document that hHcy alone significantly increased Fluoro-Jade C- and TUNEL-positive cell neurodegeneration in the rat hippocampus as well as in the cortex. IPC, even if combined with hHcy, could still preserve the neuronal tissue from the lethal ischemic effects. This review also describes the changes in the mitogen-activated protein kinase (MAPK protein pathways following ischemic injury and IPC. These studies provide evidence for the interplay and tight integration between ERK and p38 MAPK signalling mechanisms in response to the hHcy and also in association of hHcy with ischemia/IPC challenge in the rat brain. Further investigations of the protective factors

  15. Resveratrol attenuates oxidative stress and improves behaviour in 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) challenged mice.

    Science.gov (United States)

    Anandhan, Annadurai; Tamilselvam, Kuppusamy; Vijayraja, Dhanraj; Ashokkumar, Nataraj; Rajasankar, Srinivasagam; Manivasagam, Thamilarasan

    2010-07-01

    Parkinson's disease (PD) is the most common neurodegenerative disorder, characterized by loss of dopaminergic neurons in substantia nigra and depletion of dopamine in striatum due to mitochondrial dysfunction, oxidative stress, excitotoxicity, apoptosis, inflammation and proteasome failure. The present study deals with the neuroprotective effect of resveratrol, a wine polyphenol (50 mg/kg body weight) against MPTP (30mg/kg body weight as i.p. administration) induced mice model of idiopathic Parkinson's disease. A combination of behaviour tasks and biochemical parameters were tested using standard molecular tools. Pretreatment of resveratrol significantly reversed toxic effects of MPTP by increasing the levels of dopamine, its metabolites, GSH and activities of GPx and reducing levels of TBARS, catalase and SOD activities along with enhanced behavior performance. The multifactorial etiology of these diseases suggests that drugs with multiple targets such as resveratrol could have therapeutic potential for these pathologies.

  16. Low dose of L-glutamic acid attenuated the neurological dysfunctions and excitotoxicity in bilateral common carotid artery occluded mice.

    Science.gov (United States)

    Ramanathan, Muthiah; Abdul, Khadar K; Justin, Antony

    2016-10-01

    Glutamate, an excitatory neurotransmitter in the brain, produces excitotoxicity through its agonistic action on postsynaptic N-methyl-D-aspartate receptor, resulting in neurodegeneration. We hypothesized that the administration of low doses of glutamate in cerebral ischemia could attenuate the excitotoxicity in neurons through its autoreceptor regulatory mechanism, and thereby control neurodegeneration. To test the hypothesis, the effect of L-glutamic acid (L-GA) 400 μmol/l/kg was evaluated in a bilateral common carotid artery occlusion-induced global ischemic mouse model. Memantine was used as a positive control. Global ischemia in mice was induced by occlusion of both the common carotid artery (bilateral common carotid artery occlusion) for 20 min, followed by reperfusion injury. L-GA was infused slowly through the tail vein 30 min before the surgery and every 24 h thereafter until the end of the experiment. The time-dependent change in cerebral blood flow was monitored using a laser Doppler image analyzer. The neurotransmitters glutamate and γ-aminobutyric acid (GABA) and the neurobiochemicals ATP, glutathione, and nitric oxide were measured in the different regions of brain at 0, 24, 48, and 72 h after reperfusion injury. L-GA increased locomotor activity, muscle coordination, and cerebral blood flow in ischemic mice at 72 h after ischemic insult. L-GA reduced glutamate levels in the cortex, striatum, and hippocampus at 72 h, whereas GABA levels were elevated in all three brain regions studied. Further, L-GA elevated glutathione levels and attenuated nitric oxide levels, but failed to restore ATP levels 72 h after ischemia-reperfusion. We conclude that the gradual reduction of glutamate along with elevation of GABA in different brain regions could have contributed toward the neuroprotective effect of L-GA. Hence, a slow infusion of a low dose of L-GA could be beneficial in controlling excitotoxicity-induced neurodegeneration following ischemia.

  17. Propofol attenuates H2O2-induced oxidative stress and apoptosis via the mitochondria- and ER-medicated pathways in neonatal rat cardiomyocytes.

    Science.gov (United States)

    Liu, Xue-Ru; Cao, Lu; Li, Tao; Chen, Lin-Lin; Yu, Yi-Yan; Huang, Wen-Jun; Liu, Li; Tan, Xiao-Qiu

    2017-05-01

    Previous studies have shown that propofol, an intravenous anesthetic commonly used in clinical practice, protects the myocardium from injury. Mitochondria- and endoplasmic reticulum (ER)-mediated oxidative stress and apoptosis are two important signaling pathways involved in myocardial injury and protection. The present study aimed to test the hypothesis that propofol could exert a cardio-protective effect via the above two pathways. Cultured neonatal rat cardiomyocytes were treated with culture medium (control group), H 2 O 2 at 500 μM (H 2 O 2 group), propofol at 50 μM (propofol group), and H 2 O 2 plus propofol (H 2 O 2  + propofol group), respectively. The oxidative stress, mitochondrial membrane potential (ΔΨm) and apoptosis of the cardiomyocytes were evaluated by a series of assays including ELISA, flow cytometry, immunofluorescence microscopy and Western blotting. Propofol significantly suppressed the H 2 O 2 -induced elevations in the activities of caspases 3, 8, 9 and 12, the ratio of Bax/Bcl-2, and cell apoptosis. Propofol also inhibited the H 2 O 2 -induced reactive oxygen species (ROS) generation, lactic dehydrogenase (LDH) release and mitochondrial transmembrane potential (ΔΨm) depolarization, and restored the H 2 O 2 -induced reductions of glutathione (GSH) and superoxide dismutase (SOD). In addition, propofol decreased the expressions of glucose-regulated protein 78 kDa (Grp78) and inositol-requiring enzyme 1α (IRE1α), two important signaling molecules in the ER-mediated apoptosis pathway. Propofol protects cardiomyocytes from H 2 O 2 -induced injury by inhibiting the mitochondria- and ER-mediated apoptosis signaling pathways.

  18. Tracer attenuation in groundwater

    Science.gov (United States)

    Cvetkovic, Vladimir

    2011-12-01

    The self-purifying capacity of aquifers strongly depends on the attenuation of waterborne contaminants, i.e., irreversible loss of contaminant mass on a given scale as a result of coupled transport and transformation processes. A general formulation of tracer attenuation in groundwater is presented. Basic sensitivities of attenuation to macrodispersion and retention are illustrated for a few typical retention mechanisms. Tracer recovery is suggested as an experimental proxy for attenuation. Unique experimental data of tracer recovery in crystalline rock compare favorably with the theoretical model that is based on diffusion-controlled retention. Non-Fickian hydrodynamic transport has potentially a large impact on field-scale attenuation of dissolved contaminants.

  19. Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection.

    Science.gov (United States)

    Kolb, Alexander L; Corridon, Peter R; Zhang, Shijun; Xu, Weimin; Witzmann, Frank A; Collett, Jason A; Rhodes, George J; Winfree, Seth; Bready, Devin; Pfeffenberger, Zechariah J; Pomerantz, Jeremy M; Hato, Takashi; Nagami, Glenn T; Molitoris, Bruce A; Basile, David P; Atkinson, Simon J; Bacallao, Robert L

    2018-04-01

    Ischemic preconditioning confers organ-wide protection against subsequent ischemic stress. A substantial body of evidence underscores the importance of mitochondria adaptation as a critical component of cell protection from ischemia. To identify changes in mitochondria protein expression in response to ischemic preconditioning, we isolated mitochondria from ischemic preconditioned kidneys and sham-treated kidneys as a basis for comparison. The proteomic screen identified highly upregulated proteins, including NADP+-dependent isocitrate dehydrogenase 2 (IDH2), and we confirmed the ability of this protein to confer cellular protection from injury in murine S3 proximal tubule cells subjected to hypoxia. To further evaluate the role of IDH2 in cell protection, we performed detailed analysis of the effects of Idh2 gene delivery on kidney susceptibility to ischemia-reperfusion injury. Gene delivery of IDH2 before injury attenuated the injury-induced rise in serum creatinine ( P <0.05) observed in controls and increased the mitochondria membrane potential ( P <0.05), maximal respiratory capacity ( P <0.05), and intracellular ATP levels ( P <0.05) above those in controls. This communication shows that gene delivery of Idh2 can confer organ-wide protection against subsequent ischemia-reperfusion injury and mimics ischemic preconditioning. Copyright © 2018 by the American Society of Nephrology.

  20. Rehabilitation Outcomes: Ischemic versus Hemorrhagic Strokes

    OpenAIRE

    Perna, Robert; Temple, Jessica

    2015-01-01

    Background. Ischemic and hemorrhagic strokes have different pathophysiologies and possibly different long-term cerebral and functional implications. Hemorrhagic strokes expose the brain to irritating effects of blood and ischemic strokes reflect localized or diffuse cerebral vascular pathology. Methods. Participants were individuals who suffered either an ischemic (n = 172) or hemorrhagic stroke (n = 112) within the past six months and were involved in a postacute neurorehabilitation program....

  1. Analogous β-Carboline Alkaloids Harmaline and Harmine Ameliorate Scopolamine-Induced Cognition Dysfunction by Attenuating Acetylcholinesterase Activity, Oxidative Stress, and Inflammation in Mice

    Science.gov (United States)

    Li, Shu-Ping; Wang, Yu-Wen; Qi, Sheng-Lan; Zhang, Yun-Peng; Deng, Gang; Ding, Wen-Zheng; Ma, Chao; Lin, Qi-Yan; Guan, Hui-Da; Liu, Wei; Cheng, Xue-Mei; Wang, Chang-Hong

    2018-01-01

    The analogous β-carboline alkaloids, harmaline (HAL) and harmine (HAR), possess a variety of biological properties, including acetylcholinesterase (AChE) inhibitory activity, antioxidant, anti-inflammatory, and many others, and have great potential for treating Alzheimer’s disease (AD). However, studies have showed that the two compounds have similar structures and in vitro AChE inhibitory activities but with significant difference in bioavailability. The objective of this study was to comparatively investigate the effects of HAL and HAR in memory deficits of scopolamine-induced mice. In the present study, mice were pretreated with HAL (2, 5, and 10 mg/kg), HAR (10, 20, and 30 mg/kg) and donepezil (5 mg/kg) by intragastrically for 7 days, and were daily intraperitoneal injected with scopolamine (1 mg/kg) to induce memory deficits and then subjected to behavioral evaluation by Morris water maze. To further elucidate the underlying mechanisms of HAL and HAR in improving learning and memory, the levels of various biochemical factors and protein expressions related to cholinergic function, oxidative stress, and inflammation were examined. The results showed that HAL and HAR could effectively ameliorate memory deficits in scopolamine-induced mice. Both of them exhibited an enhancement in cholinergic function by inhibiting AChE and inducing choline acetyltransferase (ChAT) activities, and antioxidant defense via increasing the antioxidant enzymes activities of superoxide dismutase and glutathione peroxidase, and reducing maleic diadehyde production, and anti-inflammatory effects through suppressing myeloperoxidase, tumor necrosis factor α, and nitric oxide as well as modulation of critical neurotransmitters such as acetylcholine (ACh), choline (Ch), L-tryptophan (L-Trp), 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (γ-GABA), and L-glutamic acid (L-Glu). Furthermore, the regulations of HAL on cholinergic function, inflammation, and neurotransmitters were more

  2. Consequences of age on ischemic wound healing in rats: altered antioxidant activity and delayed wound closure.

    Science.gov (United States)

    Moor, Andrea N; Tummel, Evan; Prather, Jamie L; Jung, Michelle; Lopez, Jonathan J; Connors, Sarah; Gould, Lisa J

    2014-04-01

    Advertisements targeted at the elderly population suggest that antioxidant therapy will reduce free radicals and promote wound healing, yet few scientific studies substantiate these claims. To better understand the potential utility of supplemental antioxidant therapy for wound healing, we tested the hypothesis that age and tissue ischemia alter the balance of endogenous antioxidant enzymes. Using a bipedicled skin flap model, ischemic and non-ischemic wounds were created on young and aged rats. Wound closure and the balance of the critical antioxidants superoxide dismutase and glutathione in the wound bed were determined. Ischemia delayed wound closure significantly more in aged rats. Lower superoxide dismutase 2 and glutathione in non-ischemic wounds of aged rats indicate a basal deficit due to age alone. Ischemic wounds from aged rats had lower superoxide dismutase 2 protein and activity initially, coupled with decreased ratios of reduced/oxidized glutathione and lower glutathione peroxidase activity. De novo glutathione synthesis, to restore redox balance in aged ischemic wounds, was initiated as evidenced by increased glutamate cysteine ligase. Results demonstrate deficiencies in two antioxidant pathways in aged rats that become exaggerated in ischemic tissue, culminating in profoundly impaired wound healing and prolonged inflammation.

  3. Limb Remote Ischemic Conditioning: Mechanisms, Anesthetics, and the Potential for Expanding Therapeutic Options

    Science.gov (United States)

    Chen, Gangling; Thakkar, Mrugesh; Robinson, Christopher; Doré, Sylvain

    2018-01-01

    Novel and innovative approaches are essential in developing new treatments and improving clinical outcomes in patients with ischemic stroke. Remote ischemic conditioning (RIC) is a series of mechanical interruptions in blood flow of a distal organ, following end organ reperfusion, shown to significantly reduce infarct size through inhibition of oxidation and inflammation. Ischemia/reperfusion (I/R) is what ultimately leads to the irreversible brain damage and clinical picture seen in stroke patients. There have been several reports and reviews about the potential of RIC in acute ischemic stroke; however, the focus here is a comprehensive look at the differences in the three types of RIC (remote pre-, per-, and postconditioning). There are some limited uses of preconditioning in acute ischemic stroke due to the unpredictability of the ischemic event; however, it does provide the identification of biomarkers for clinical studies. Remote limb per- and postconditioning offer a more promising treatment during patient care as they can be harnessed during or after the initial ischemic insult. Though further research is needed, it is imperative to discuss the importance of preclinical data in understanding the methods and mechanisms involved in RIC. This understanding will facilitate translation to a clinically feasible paradigm for use in the hospital setting. PMID:29467715

  4. The nitric oxide donor sodium nitroprusside attenuates recognition memory deficits and social withdrawal produced by the NMDA receptor antagonist ketamine and induces anxiolytic-like behaviour in rats.

    Science.gov (United States)

    Trevlopoulou, Aikaterini; Touzlatzi, Ntilara; Pitsikas, Nikolaos

    2016-03-01

    Experimental evidence indicates that the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine impairs cognition and can mimic certain aspects of positive and negative symptoms of schizophrenia in rodents. Nitric oxide (NO) is considered as an intracellular messenger in the brain, and its abnormalities have been linked to schizophrenia. The present study was designed to investigate the ability of the NO donor sodium nitroprusside (SNP) to counteract schizophrenia-like behavioural deficits produced by ketamine in rats. The ability of SNP to reverse ketamine-induced memory deficits and social withdrawal were assessed using the novel object recognition task (NORT) and the social interaction test, respectively. Furthermore, since anxiety disorders are noted to occur commonly in schizophrenics, the effects of SNP on anxiety-like behaviour were examined using the light/dark test. Locomotor activity was also assessed as an independent measure of the potential motoric effects of this NO donor. SNP (0.3 and 1 mg/kg) reversed ketamine (3 mg/kg)-induced short-term recognition memory deficits. SNP (1 mg/kg) counteracted the ketamine (8 mg/kg)-induced social isolation in the social interaction test. The anxiolytic-like effects in the light/dark test of SNP (1 mg/kg) cannot be attributed to changes in locomotor activity. Our findings illustrate a functional interaction between the nitrergic and glutamatergic system that may be of relevance for schizophrenia-like behavioural deficits. The data also suggest a role of NO in anxiety.

  5. Selenite and ebselen supplementation attenuates D-galactose-induced oxidative stress and increases expression of SELR and SEP15 in rat lens.

    Science.gov (United States)

    Dai, Jie; Zhou, Jun; Liu, Hongmei; Huang, Kaixun

    2016-12-01

    Selenite and ebselen supplementation has been shown to possess anti-cataract potential in some experimental animal models of cataract, however, the underlying mechanisms remain unclear. The present study was designed to evaluate the anti-cataract effects and the underlying mechanisms of selenite and ebselen supplementation on galactose induced cataract in rats, a common animal model of sugar cataract. Transmission electron microscopy images of lens fiber cells (LFC) and lens epithelial cells (LEC) were observed in D-galactose-induced experimental cataractous rats treated with or without selenite and ebselen, also redox homeostasis and expression of proteins such as selenoprotein R (SELR), 15kD selenoprotein (SEP15), superoxide dismutase 1 (SOD1), catalase (CAT), β-crystallin protein, aldose reductase (AR) and glucose-regulated protein 78 (GRP78) were estimated in the lenses. The results showed that D-galactose injection injured rat lens and resulted in cataract formation; however, selenite and ebselen supplementation markedly alleviated ultrastructural injury of LFC and LEC. Moreover, selenite and ebselen supplementation could mitigate the oxidative damage in rat lens and increase the protein expressions of SELR, SEP15, SOD1, CAT and β-crystallin, as well as decrease the protein expressions of AR and GRP78. Taken together, these findings for the first time reveal the anti-cataract potential of selenite and ebselen in galactosemic cataract, and provide important new insights into the anti-cataract mechanisms of selenite and ebselen in sugar cataract.

  6. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.

    Science.gov (United States)

    Kernan, Walter N; Viscoli, Catherine M; Furie, Karen L; Young, Lawrence H; Inzucchi, Silvio E; Gorman, Mark; Guarino, Peter D; Lovejoy, Anne M; Peduzzi, Peter N; Conwit, Robin; Brass, Lawrence M; Schwartz, Gregory G; Adams, Harold P; Berger, Leo; Carolei, Antonio; Clark, Wayne; Coull, Bruce; Ford, Gary A; Kleindorfer, Dawn; O'Leary, John R; Parsons, Mark W; Ringleb, Peter; Sen, Souvik; Spence, J David; Tanne, David; Wang, David; Winder, Toni R

    2016-04-07

    Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; Pischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

  7. Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice.

    Science.gov (United States)

    Tsai, Ming-Shiun; Wang, Ying-Han; Lai, Yan-Yun; Tsou, Hsi-Kai; Liou, Gan-Guang; Ko, Jiunn-Liang; Wang, Sue-Hong

    2018-06-15

    Acetaminophen (APAP) overdose can induce acute liver injury (ALI) with significant morbidity and mortality. Propacetamol is an APAP prodrug, which is clinically bioequivalent to APAP. Kaempferol, a dietary flavonoid, has antioxidant, anti-inflammatory, and anti-apoptotic effects. In this study, we investigated the protective effect of kaempferol on propacetamol-induced ALI and its underlying mechanism in mice. Kaempferol pretreatment (125 mg/kg) before propacetamol injection significantly decreased propacetamol-induced serum ALT and AST activities, and DNA fragmentation. Kaempferol administration also reduced propacetamol-induced oxidative stress by inhibiting thiobarbituric acid reactive substances (TBARS) and 3-nitrotyrosine (3-NT) formation partly through downregulation of cytochrome P450 2E1 (CYP2E1) expression, upregulation of UDP glucuronosyltransferase family 1 member A1 (UGT1A1) expression, restoration of the activities of antioxidant enzymes including SOD, GPx and catalase toward normal, recovery of propacetamol-suppressed Nrf2 and GCLC expressions, and maintenance of normal glutathione level. Furthermore, kaempferol markedly attenuated APAP-induced serum TNF-α and IL-6 productions, downregulated APAP-induced phosphorylations of JNK and ERK, and decreased early hepatic apoptosis via decreasing Bax/Bcl-2 ratio and caspase 3 activation. Furthermore, administration of N-acetylcysteine (NAC) and kaempferol significantly rescued more mice than a low dose of NAC only did when a lethal dose of propacetamol injected and therapized at a delayed time point. These data suggested that kaempferol protects the liver against propacetamol-induced injury through anti-oxidative, anti-inflammatory and anti-apoptotic activities. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Natural attenuation of biogas in landfill covers

    International Nuclear Information System (INIS)

    Cossu, R.; Privato, A.; Raga, R.

    2005-01-01

    In the risk evaluation of uncontrolled biogas emissions from landfills, the process of natural attenuation in landfill covers assumes a very important role. The capacity of biogas oxidation in the cover soils seems to be the most important control to mitigate the biogas emission during the aftercare period when the biogas collection system might fail. In the present paper laboratory experiences on lab columns to study the biogas oxidation are discussed [it

  9. ALA/LA ameliorates glucose toxicity on HK-2 cells by attenuating oxidative stress and apoptosis through the ROS/p38/TGF-β1 pathway.

    Science.gov (United States)

    Jiang, Mingxia; Zhang, Haifen; Zhai, Lijie; Ye, Bianliang; Cheng, Yin; Zhai, Chengkai

    2017-11-16

    Growing evidence indicates that oxidative stress (OS) plays a pivotal role in Diabetic nephropathy (DN). In a previous study we demonstrated that ALA/LA protected HK-2 cells against high glucose-induced cytotoxicity. So we aimed to establish the glucose injury model of HK-2 cells and investigate the beneficial effects of ALA/LA on high glucose-induced excessive production of TGF-β1 and the possible mechanisms mediating the effects. The expression of OS markers in high glucose-induced HK-2 cells treated with ALA/LA., including the antioxidant enzymes and reactive oxygen species (ROS) production, as well as the apoptosis rate were assayed by ELISA and flow cytometry. The p38/transforming growth factor β 1 (TGF-β 1 ) signal pathway were measured by real-time RT-PCR and western blot. The modeling condition of glucose toxicity on HK-2 cells was at the glucose concentration of 40.9 mM. ALA/LA can significantly increase the activities of antioxidant enzymes and decrease ROS production stimulated by high glucose. The study also found that ALA/LA caused a decrease in the apoptosis rate and TGF-β 1 level of HK-2 cells under high glucose stress through the ROS/p38 pathway. ALA/LA exerts protective effects in vitro through inhibition of ROS generation, down regulation of the activation of the p38MAPK pathway and the expression of TGF-β 1 in HK-2 cells.

  10. Butanolic fraction of Moringa oleifera Lam. (Moringaceae) attenuates isoprotrenol-induced cardiac necrosis and oxidative stress in rats: an EPR study

    Science.gov (United States)

    Panda, Sunanda

    2015-01-01

    The preventive effect of Moringa oleifera polyphenolic fraction (MOPF) on cardiac damage was evaluated in isoproterenol (ISO) induced cardiotoxicity model of Wistar rats. Male rats in different groups were treated with MOPF orally at the dose of 50, 100 and 150 mg/kg/day for 28 days and were subsequently administered (s.c.) with ISO (85 mg/kg body weight) for the last two days. At the end of the experiment levels of serum troponin-T, creatine kinase-MB, lactate dehydrogenase, content of malondialdehyde (MDA), activities/levels of different cellular antioxidants were estimated in control and experimental groups. Additionally, scavenging potential to the hydroxyl radical of the fraction was measured by electron paramagnetic resonance (EPR). ISO administered rats showed significant increase in the levels of serum troponin-I, creatine kinase, lactate dehydrogenase, and heart tissue MDA content. Furthermore, marked reduction in the activities of antioxidants such as superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione levels were observed. EPR study showed an increase in signal intensity in ISO-induced rats. Triphenyl tetrazolium chloride (TTC) staining of heart section revealed a marked increase in infarcted area in ISO-induced rats. Histological features of the heart also indicated a disruption in the structure of cardiac myofibrils in these animals. MOPF (100 mg/kg body weight) pretreatment prevented all these adverse effects of ISO. Present results show that the rich polyphenolic content of Moringa oleifera significantly reduced the myocardial damage and decreased the oxidative stress, possibly through hydroxyl radical scavenging activity as evidenced from the EPR spectra. PMID:26417351

  11. Arctigenin, a Potent Ingredient of Arctium lappa L., Induces Endothelial Nitric Oxide Synthase and Attenuates Subarachnoid Hemorrhage-Induced Vasospasm through PI3K/Akt Pathway in a Rat Model

    Directory of Open Access Journals (Sweden)

    Chih-Zen Chang

    2015-01-01

    Full Text Available Upregulation of protein kinase B (PKB, also known as Akt is observed within the cerebral arteries of subarachnoid hemorrhage (SAH animals. This study is of interest to examine Arctigenin, a potent antioxidant, on endothelial nitric oxide synthase (eNOS and Akt pathways in a SAH in vitro study. Basilar arteries (BAs were obtained to examine phosphatidylinositol-3-kinase (PI3K, phospho-PI3K, Akt, phospho-Akt (Western blot and morphological examination. Endothelins (ETs and eNOS evaluation (Western blot and immunostaining were also determined. Arctigenin treatment significantly alleviates disrupted endothelial cells and tortured internal elastic layer observed in the SAH groups (p<0.01. The reduced eNOS protein and phospho-Akt expression in the SAH groups were relieved by the treatment of Arctigenin (p<0.01. This result confirmed that Arctigenin might exert dural effects in preventing SAH-induced vasospasm through upregulating eNOS expression via the PI3K/Akt signaling pathway and attenuate endothelins after SAH. Arctigenin shows therapeutic promise in the treatment of cerebral vasospasm following SAH.

  12. Association of nNOS Gene Polymorphism with Ischemic Stroke in Han Chinese of North China

    Directory of Open Access Journals (Sweden)

    Yingjie Dai

    2013-01-01

    Full Text Available Nitric oxide (NO is an important messenger molecule and effector molecule. This study aimed to investigate the relation of neuronal nitric oxide synthase (nNOS gene polymorphism with ischemic stroke in Han Chinese of North China. This was a case-control study. A total of 413 patients with ischemic stroke were recruited from Han Chinese of North China. There were 201 males and 212 females. In addition, 477 healthy subjects served as controls including 224 males and 253 females. Multiplex SNaPshot was employed to detect nNOS gene polymorphism (rs2293050, rs2139733, rs7308402, and rs1483757. Results showed that the rs1483757, rs2139733, and rs2293050 genotypes and allele frequencies were comparable between patients and controls. However, ischemic stroke patients had significantly reduced AG genotype and A allele frequency when compared with controls (P=0.037, P=0.041. After adjusting confounding factors (gender, age, smoking, history of drinking, hypertension, and diabetes, AG genotype and A allele were still related to ischemic stroke (OR=0.572, 95% CI: 0.335–0.978, P=0.041; OR=0.611, 95% C: 0.378–0.985, and P=0.041 and both were found to be protective factors. Our results showed that rs7308402 gene polymorphism of nNOS is related to ischemic stroke in Han Chinese of North China.

  13. [Molecular mechanisms of ischemic-reperfusion syndrome and its personalized therapy].

    Science.gov (United States)

    Grebenchikov, O A; Likhvantsev, V V; Plotnikov, E Iu; Silachev, D N; Pevzner, I B; Zorova, L D; Zorov, D B

    2014-01-01

    Cardiovascular pathologies are the major causes of morbidity and mortality in the world. Cessation of the blood flow in large vessels, supplying tissues with oxygen and substrates, leads to ischemic conditions accompanied by unwanted shifts of oxidative metabolism and rise of the reactive oxygen species (ROS) generation. Small amounts of ROS are essential elements of the cell metabolism, however pathological elevation of ROS jeopardizes the survival of cells, organs and even organisms. Paradoxically, blood flow restoration during prolonged ischemia leads to oxidative stress that is often fatal for a live system. Oxygen paradox appears to be a limiting factor in clinical practice that intuitively seeks for immediate and complete restoration of a damaged blood flow. Mitochondrion is a major ROS source and a key element of pro-apoptotic signaling, however it is clear, that mitochondria are the main target for anti-ischemic treatment. In the present review we consider two ways of such anti-ischemic strategy, bringing ischemic tolerance to the organ through mitochondrial involvement, such as intrinsic, biological, or artificial, pharmacological adaptive systems (preconditioning). The latter is aimed to simulate elements and high efficiency of intrinsic protective system. The role of antioxidants in anti-ischemic therapy and their effects on preconditioning signaling are discussed in the review.

  14. α-lipoic acid inhibits oxidative stress in testis and attenuates testicular toxicity in rats exposed to carbimazole during embryonic period

    Directory of Open Access Journals (Sweden)

    P. Prathima

    for the suppressed reproduction in rats exposed to the carbimazole transplacentally. On the other hand, α-lipoic acid through its antioxidant and steroidogenic properties mitigated testicular toxicity which eventually restored the male reproductive health of carbimazole-exposed rats. Keywords: Carbimazole, Lipoic acid, Oxidative stress, Spermatogenesis, Testosterone, Rats

  15. Electroacupuncture attenuates liver and kidney oxidative stress in anesthetized rats Eletroacupuntura atenua o estresse oxidativo no fígado e no rim em ratos anestesiados

    Directory of Open Access Journals (Sweden)

    Agamenon Honório Silva

    2011-01-01

    Full Text Available PURPOSE: Investigate the effects of a single electroacupuncture (EA session at acupoints Zusanli (ST-36 and Zhongwan (CV-12 combined in regulating oxidative stress in liver and kidney in anesthetized rats. METHODS: Eighteen healthy rats randomly assigned to 3 groups (n=6 were anesthetized intraperitoneally with ketamine (90mg kg-1 body weight + xylazine (10mg/kg body weight: G-1: Control (anesthesia, G-2: anesthesia+EA10Hz and 10 mA, 10 Hz applied to right ST-36 and CV-12 acupoints for 30 minutes. G-3 was likewise treated, using a tenfold higher frequency (100 Hz. G6PDH activity, malondialdehyde (MDA and glutathione (GSH levels were assayed spectrophotometrically. RESULTS: Liver MDA and GSH concentrations increased significantly in rats submitted to EA 10Hz (pOBJETIVO: Investigar os efeitos de uma única sessão de eletroacupuntura (EA aplicada nos acupontos Zusanli (E-36 e Zhongwan (RM-12 simultaneamente, na regulação do estresse oxidativo no fígado e rins em ratos anestesiados. MÉTODOS: Dezoito ratos sadios, distribuídos aleatoriamente em três grupos (n = 6, foram anestesiados com cetamina (90mg/kg de peso + xilazina (10mg/kg de peso: G-1: Controle (anestesia, G-2: anestesia + EA10Hz e G-3: anestesia + EA100Hz. Os ratos do grupo G-2 foram submetidos à EA (ondas quadradas pulsadas, 10 mA, 10 Hz aplicada aos acupontos ST-36 direito e VC-12 por 30 minutos. Nos ratos do grupo G-3 utilizou-se uma freqüência dez vezes maior (100 Hz. A atividade da enzima G6PDH e as concentrações de malondialdeído (MDA e glutationa (GSH foram verificadas por espectrofotometria. RESULTADOS: As concentrações hepáticas de MDA e GSH aumentaram significativamente nos ratos submetidos à EA, utilizando 10Hz (p <0,01 e 100Hz (p <0,001, comparado com o controle. A atividade de G6GPH diminuiu significativamente no G-2 (p <0,01 e G-3 (p <0,001 no fígado e no rim em comparação ao grupo G-1 em ratos tratados com 100Hz. CONCLUSÃO: Uma única sessão de EA 10

  16. Attenuation of dermal wounds via downregulating oxidative stress and inflammatory markers by protocatechuic acid rich n-butanol fraction of Trianthema portulacastrum Linn. in wistar albino rats.

    Science.gov (United States)

    Yadav, Ekta; Singh, Deepika; Yadav, Pankajkumar; Verma, Amita

    2017-12-01

    Oxidative stress and inflammation contribute as a key factor for retarding the process of dermal wound healing. Trianthema portulcastrum Linn. (TP) leaves reported to possess antioxidant, antifungal, anti-inflammatory and antibacterial properties, which could make TP a promising wound healing agent. The current study was aimed to estimate the antioxidant potential of the fractionated hydroethanolic extract of TP leaves and evaluate wound healing activity by excision and incision wound models along with the assessment of possible underlying mechanism. Ethyl acetate, chloroform and n-butanol fractions of the hydroethanolic extract of TP leaves were examined for in vitro antioxidant ability by DPPH method. Strongest antioxidant activity bearing n-butanol fraction (nBuTP) was further analyzed quantitatively by High Performance Liquid Chromatography coupled with Diode Array Detector (HPLC-DAD). Wound healing potential of nBUTP using excision and incision wound model was studied. Wistar albino rats were randomly divided into four groups, containing six animals in each group; group I served as control treated with simple ointment base, group II was standard group, treated with povidone-iodine ointment USP (5%), group III treated with nBuTP 5% w/w ointment, and group IV treated with nBuTP 10%w/w ointment. All the groups were topically applied their respective ointments, once daily, till the complete healing achieved. Wound healing was assessed by analyzing % wound closure, hydroxyproline content, epithelialization period, tensile strength, enzymatic antioxidative status and inflammatory markers. Total phenolic and flavonoid content of the extract was estimated to be 112.32±1.12 and 84.42±0.47mg/g, respectively. HPLC-DAD of nBuTP confirmed the presence of chlorogenic acid (20.74±0.03), protocatechuic acid (34.45±0.02mg/g), caffeic acid (4.31±0.03mg/g) and ferulic acid (1.43±0.01mg/g). 5% and 10%w/w nBuTP ointment significantly accelerated the wound healing process

  17. Peripheral Mechanisms of Ischemic Myalgia

    Directory of Open Access Journals (Sweden)

    Luis F. Queme

    2017-12-01

    Full Text Available Musculoskeletal pain due to ischemia is present in a variety of clinical conditions including peripheral vascular disease (PVD, sickle cell disease (SCD, complex regional pain syndrome (CRPS, and even fibromyalgia (FM. The clinical features associated with deep tissue ischemia are unique because although the subjective description of pain is common to other forms of myalgia, patients with ischemic muscle pain often respond poorly to conventional analgesic therapies. Moreover, these patients also display increased cardiovascular responses to muscle contraction, which often leads to exercise intolerance or exacerbation of underlying cardiovascular conditions. This suggests that the mechanisms of myalgia development and the role of altered cardiovascular function under conditions of ischemia may be distinct compared to other injuries/diseases of the muscles. It is widely accepted that group III and IV muscle afferents play an important role in the development of pain due to ischemia. These same muscle afferents also form the sensory component of the exercise pressor reflex (EPR, which is the increase in heart rate and blood pressure (BP experienced after muscle contraction. Studies suggest that afferent sensitization after ischemia depends on interactions between purinergic (P2X and P2Y receptors, transient receptor potential (TRP channels, and acid sensing ion channels (ASICs in individual populations of peripheral sensory neurons. Specific alterations in primary afferent function through these receptor mechanisms correlate with increased pain related behaviors and altered EPRs. Recent evidence suggests that factors within the muscles during ischemic conditions including upregulation of growth factors and cytokines, and microvascular changes may be linked to the overexpression of these different receptor molecules in the dorsal root ganglia (DRG that in turn modulate pain and sympathetic reflexes. In this review article, we will discuss the

  18. Sex Hormones and Ischemic Stroke

    DEFF Research Database (Denmark)

    Holmegard, Haya N; Nordestgaard, Børge G; Jensen, Gorm B

    2016-01-01

    CONTEXT AND OBJECTIVE: Whether endogenous sex hormones are associated with ischemic stroke (IS) is unclear. We tested the hypothesis that extreme concentrations of endogenous sex hormones are associated with risk of IS in the general population. DESIGN, SETTING, AND PARTICIPANTS: Adult men (n...... = 4615) and women (n = 4724) with measurements of endogenous sex hormones during the 1981-1983 examination of the Copenhagen City Heart Study, Denmark, were followed for up to 29 years for incident IS, with no loss to follow-up. Mediation analyses assessed whether risk of IS was mediated through...

  19. Identification of ischemic regions in a rat model of stroke.

    Science.gov (United States)

    Popp, Anke; Jaenisch, Nadine; Witte, Otto W; Frahm, Christiane

    2009-01-01

    Investigations following stroke first of all require information about the spatio-temporal dimension of the ischemic core as well as of perilesional and remote affected tissue. Here we systematically evaluated regions differently impaired by focal ischemia. Wistar rats underwent a transient 30 or 120 min suture-occlusion of the middle cerebral artery (MCAO) followed by various reperfusion times (2 h, 1 d, 7 d, 30 d) or a permanent MCAO (1 d survival). Brains were characterized by TTC, thionine, and immunohistochemistry using MAP2, HSP72, and HSP27. TTC staining reliably identifies the infarct core at 1 d of reperfusion after 30 min MCAO and at all investigated times following 120 min and permanent MCAO. Nissl histology denotes the infarct core from 2 h up to 30 d after transient as well as permanent MCAO. Absent and attenuated MAP2 staining clearly identifies the infarct core and perilesional affected regions at all investigated times, respectively. HSP72 denotes perilesional areas in a limited post-ischemic time (1 d). HSP27 detects perilesional and remote impaired tissue from post-ischemic day 1 on. Furthermore a simultaneous expression of HSP72 and HSP27 in perilesional neurons was revealed. TTC and Nissl staining can be applied to designate the infarct core. MAP2, HSP72, and HSP27 are excellent markers not only to identify perilesional and remote areas but also to discriminate affected neuronal and glial populations. Moreover markers vary in their confinement to different reperfusion times. The extent and consistency of infarcts increase with prolonged occlusion of the MCA. Therefore interindividual infarct dimension should be precisely assessed by the combined use of different markers as described in this study.

  20. 25-Hydroxyvitamin D and symptomatic ischemic stroke

    DEFF Research Database (Denmark)

    Brøndum-Jacobsen, Peter; Nordestgaard, Børge G; Schnohr, Peter

    2013-01-01

    City Heart Study. During 21 years of follow-up, 1,256 and 164 persons developed ischemic and hemorrhagic stroke, respectively. In a meta-analysis of ischemic stroke, we included 10 studies, 58,384 participants, and 2,644 events. RESULTS: Stepwise decreasing plasma 25-hydroxyvitamin D concentrations...

  1. Cerebral ischemic stroke: is gender important?

    Science.gov (United States)

    Gibson, Claire L

    2013-09-01

    Cerebral stroke continues to be a major cause of death and the leading cause of long-term disability in developed countries. Evidence reviewed here suggests that gender influences various aspects of the clinical spectrum of ischemic stroke, in terms of influencing how a patients present with ischemic stroke through to how they respond to treatment. In addition, this review focuses on discussing the various pathologic mechanisms of ischemic stroke that may differ according to gender and compares how intrinsic and hormonal mechanisms may accou