Science.gov

Sample records for 4-methoxyestradiol-induced oxidative injuries

  1. 4-Methoxyestradiol-induced oxidative injuries in human lung epithelial cells

    SciTech Connect

    Cheng Yahsin; Chang, Louis W.; Cheng Lichuan; Tsai, M.-H.; Lin Pinpin . E-mail: pplin@nhri.org.tw

    2007-05-01

    Epidemiological studies indicated that people exposed to dioxins were prone to the development of lung diseases including lung cancer. Animal studies demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased liver tumors and promoted lung metaplasia in females. Metabolic changes in 17{beta}-estradiol (E{sub 2}) resulted from an interaction between TCDD and E{sub 2} could be associated with gender difference. Previously, we reported that methoxylestradiols (MeOE{sub 2}), especially 4-MeOE{sub 2}, accumulated in human lung cells (BEAS-2B) co-treated with TCDD and E{sub 2}. In the present study, we demonstrate unique accumulation of 4-MeOE{sub 2}, as a result of TCDD/E{sub 2} interaction and revealed its bioactivity in human lung epithelial cell line (H1355). 4-Methoxyestradiol treatment significantly decreased cell growth and increased mitotic index. Elevation of ROS and SOD activity, with a concomitant decrease in the intracellular GSH/GSSG ratio, was also detected in 4-MeOE{sub 2}-treated cells. Quantitative comet assay showed increased oxidative DNA damage in the 4-MeOE{sub 2}-treated H1355 cells, which could be significantly reduced by the anti-oxidant N-acetylcysteine (NAC). However, inhibition of cell growth and increase in mitotic arrest induced by 4-MeOE{sub 2} were unaffected by NAC. We concluded that 4-MeOE{sub 2} accumulation resulting from TCDD and E{sub 2} interaction would contribute to the higher vulnerability on lung pathogenesis in females when exposed to TCDD.

  2. Oxidant Mechanisms in Renal Injury and Disease

    PubMed Central

    Ratliff, Brian B.; Abdulmahdi, Wasan; Pawar, Rahul

    2016-01-01

    Abstract Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones. Antioxid. Redox Signal. 25, 119–146. PMID:26906267

  3. Nitric oxide and hyperoxic acute lung injury

    PubMed Central

    Liu, Wen-wu; Han, Cui-hong; Zhang, Pei-xi; Zheng, Juan; Liu, Kan; Sun, Xue-jun

    2016-01-01

    Hyperoxic acute lung injury (HALI) refers to the damage to the lungs secondary to exposure to elevated oxygen partial pressure. HALI has been a concern in clinical practice with the development of deep diving and the use of normobaric as well as hyperbaric oxygen in clinical practice. Although the pathogenesis of HALI has been extensively studied, the findings are still controversial. Nitric oxide (NO) is an intercellular messenger and has been considered as a signaling molecule involved in many physiological and pathological processes. Although the role of NO in the occurrence and development of pulmonary diseases including HALI has been extensively studied, the findings on the role of NO in HALI are conflicting. Moreover, inhalation of NO has been approved as a therapeutic strategy for several diseases. In this paper, we briefly summarize the role of NO in the pathogenesis of HALI and the therapeutic potential of inhaled NO in HALI. PMID:27867474

  4. Nitric Oxide as a Mediator of Oxidant Lung Injury Due to Paraquat

    NASA Astrophysics Data System (ADS)

    Berisha, Hasan I.; Pakbaz, Hedayatollah; Absood, Afaf; Said, Sami I.

    1994-08-01

    At low concentrations, nitric oxide is a physiological transmitter, but in excessive concentrations it may cause cell and tissue injury. We report that in acute oxidant injury induced by the herbicide paraquat in isolated guinea pig lungs, nitric oxide synthesis was markedly stimulated, as evidenced by increased levels of cyclic GMP in lung perfusate and of nitrite and L-citrulline production in lung tissue. All signs of injury, including increased airway and perfusion pressures, pulmonary edema, and protein leakage into the airspaces, were dose-dependently attenuated or totally prevented by either N^G-nitro-L-arginine methyl ester or N^ω-nitro-L-arginine, selective and competitive inhibitors of nitric oxide synthase. Protection was reversed by excess L-arginine but not by its enantiomer D-arginine. When blood was added to the lung perfusate, the paraquat injury was moderated or delayed as it was when paraquat was given to anesthetized guinea pigs. The rapid onset of injury and its failure to occur in the absence of Ca2+ suggest that constitutive rather than inducible nitric oxide synthase was responsible for the stimulated nitric oxide synthesis. The findings indicate that nitric oxide plays a critical role in the production of lung tissue injury due to paraquat, and it may be a pathogenetic factor in other forms of oxidant tissue injury.

  5. Protein methionine oxidation augments reperfusion injury in acute ischemic stroke

    PubMed Central

    Gu, Sean X.; Blokhin, Ilya O.; Wilson, Katina M.; Dhanesha, Nirav; Doddapattar, Prakash; Grumbach, Isabella M.; Chauhan, Anil K.; Lentz, Steven R.

    2016-01-01

    Reperfusion injury can exacerbate tissue damage in ischemic stroke, but little is known about the mechanisms linking ROS to stroke severity. Here, we tested the hypothesis that protein methionine oxidation potentiates NF-κB activation and contributes to cerebral ischemia/reperfusion injury. We found that overexpression of methionine sulfoxide reductase A (MsrA), an antioxidant enzyme that reverses protein methionine oxidation, attenuated ROS-augmented NF-κB activation in endothelial cells, in part, by protecting against the oxidation of methionine residues in the regulatory domain of calcium/calmodulin-dependent protein kinase II (CaMKII). In a murine model, MsrA deficiency resulted in increased NF-κB activation and neutrophil infiltration, larger infarct volumes, and more severe neurological impairment after transient cerebral ischemia/reperfusion injury. This phenotype was prevented by inhibition of NF-κB or CaMKII. MsrA-deficient mice also exhibited enhanced leukocyte rolling and upregulation of E-selectin, an endothelial NF-κB–dependent adhesion molecule known to contribute to neurovascular inflammation in ischemic stroke. Finally, bone marrow transplantation experiments demonstrated that the neuroprotective effect was mediated by MsrA expressed in nonhematopoietic cells. These findings suggest that protein methionine oxidation in nonmyeloid cells is a key mechanism of postischemic oxidative injury mediated by NF-κB activation, leading to neutrophil recruitment and neurovascular inflammation in acute ischemic stroke. PMID:27294204

  6. OXIDATIVE STRESS PARTICIPATES IN PARTICULATE MATTER (PM) INDUCED LUNG INJURY

    EPA Science Inventory

    Oxidative stress participates in particulate matter (PM) induced acute lung injury.
    Elizabeth S. Roberts1, Judy L. Richards2, Kevin L. Dreher2. 1College of Veterinary Medicine, NC State University, Raleigh, NC, 2US Environmental Protection Agency, NHEERL, RTP, NC.
    Epidemiol...

  7. Stimuli-responsive electrodes detect oxidative stress and liver injury.

    PubMed

    Aran, Kiana; Parades, Jacobo; Rafi, Mohammad; Yau, Jennifer F; Acharya, Abhinav P; Zibinsky, Mikhail; Liepmann, Dorian; Murthy, Niren

    2015-02-25

    A digital point-of-care biosensor for measuring reactive oxygen species is presented based on novel reactive oxygen species responsive polymer-based electrodes. The biosensor is able to detect a drug-induced liver injury by monitoring the oxidative stress in the blood.

  8. Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity.

    PubMed

    Choe, Chi-un; Lewerenz, Jan; Fischer, Gerry; Uliasz, Tracy F; Espey, Michael Graham; Hummel, Friedhelm C; King, Stephen Bruce; Schwedhelm, Edzard; Böger, Rainer H; Gerloff, Christian; Hewett, Sandra J; Magnus, Tim; Donzelli, Sonia

    2009-09-01

    Nitroxyl (HNO) donor compounds function as potent vasorelaxants, improve myocardial contractility and reduce ischemia-reperfusion injury in the cardiovascular system. With respect to the nervous system, HNO donors have been shown to attenuate NMDA receptor activity and neuronal injury, suggesting that its production may be protective against cerebral ischemic damage. Hence, we studied the effect of the classical HNO-donor, Angeli's salt (AS), on a cerebral ischemia/reperfusion injury in a mouse model of experimental stroke and on related in vitro paradigms of neurotoxicity. I.p. injection of AS (40 mumol/kg) in mice prior to middle cerebral artery occlusion exacerbated cortical infarct size and worsened the persistent neurological deficit. AS not only decreased systolic blood pressure, but also induced systemic oxidative stress in vivo indicated by increased isoprostane levels in urine and serum. In vitro, neuronal damage induced by oxygen-glucose-deprivation of mature neuronal cultures was exacerbated by AS, although there was no direct effect on glutamate excitotoxicity. Finally, AS exacerbated oxidative glutamate toxicity - that is, cell death propagated via oxidative stress in immature neurons devoid of ionotropic glutamate receptors. Taken together, our data indicate that HNO might worsen cerebral ischemia-reperfusion injury by increasing oxidative stress and decreasing brain perfusion at concentrations shown to be cardioprotective in vivo.

  9. Role of Oxidative Stress in Drug-Induced Kidney Injury

    PubMed Central

    Hosohata, Keiko

    2016-01-01

    The kidney plays a primary role in maintaining homeostasis and detoxification of numerous hydrophilic xenobiotics as well as endogenous compounds. Because the kidney is exposed to a larger proportion and higher concentration of drugs and toxins than other organs through the secretion of ionic drugs by tubular organic ion transporters across the luminal membranes of renal tubular epithelial cells, and through the reabsorption of filtered toxins into the lumen of the tubule, these cells are at greater risk for injury. In fact, drug-induced kidney injury is a serious problem in clinical practice and accounts for roughly 20% of cases of acute kidney injury (AKI) among hospitalized patients. Therefore, its early detection is becoming more important. Usually, drug-induced AKI consists of two patterns of renal injury: acute tubular necrosis (ATN) and acute interstitial nephritis (AIN). Whereas AIN develops from medications that incite an allergic reaction, ATN develops from direct toxicity on tubular epithelial cells. Among several cellular mechanisms underlying ATN, oxidative stress plays an important role in progression to ATN by activation of inflammatory response via proinflammatory cytokine release and inflammatory cell accumulation in tissues. This review provides an overview of drugs associated with AKI, the role of oxidative stress in drug-induced AKI, and a biomarker for drug-induced AKI focusing on oxidative stress. PMID:27809280

  10. Anti-oxidative aspect of inhaled anesthetic gases against acute brain injury

    PubMed Central

    Yang, Tuo; Sun, Yang; Zhang, Feng

    2016-01-01

    Acute brain injury is a critical and emergent condition in clinical settings, which needs to be addressed urgently. Commonly acute brain injuries include traumatic brain injury, ischemic and hemorrhagic strokes. Oxidative stress is a key contributor to the subsequent injuries and impedes the reparative process after acute brain injury; therefore, facilitating an anti-oxidative approach is important in the care of those diseases. Readiness to deliver and permeability to blood brain barrier are essential for the use of this purpose. Inhaled anesthetic gases are a group of such agents. In this article, we discuss the anti-oxidative roles of anesthetic gases against acute brain injury. PMID:28217295

  11. Involvement of nitric oxide system in experimental muscle crush injury.

    PubMed Central

    Rubinstein, I; Abassi, Z; Coleman, R; Milman, F; Winaver, J; Better, O S

    1998-01-01

    Muscle crush injury is often complicated by hemodynamic shock, electrolyte disorders, and myoglobinuric renal failure. In this study, we examined the involvement of the nitric oxide (NO) system in the development of muscle damage in an experimental model of crush injury induced by exertion of standardized mechanical pressure on tibialis muscle of rat. The intact limb served as a control. Four days after injury, the crushed muscle was characterized by extreme capillary vasodilatation as demonstrated by histological morphometric analysis. These changes were accompanied by muscle hyperperfusion as evaluated by measurements of femoral blood flow (ultrasonic flowmetry) and capillary blood flow (laser-doppler flowmetry). Treatment with Nomega-nitro-L-arginine methyl ester, a NO synthase (NOS) inhibitor, largely decreased the hyperperfusion. Furthermore, the expression of the different NOS isoforms, assessed by reverse transcription-PCR and immunoreactive levels, determined by Western blot, revealed a remarkable induction of the inducible NOS in the crushed limb. Similarly, endothelial NOS mRNA increased gradually after the induction of muscle damage. In contrast, the major muscular NOS, i.e., neuronal isoform remained unchanged. In line with the alterations in the mRNA levels, Western blot analysis revealed parallel changes in the immunoreactive levels of the various NOS. These findings indicate that muscle crush is associated with activation of the NO system mainly due to enhancement of iNOS. This may contribute to NO-dependent extreme vasodilatation in the injured muscle and aggravate the hypovolemic shock after crush injury. PMID:9502774

  12. Salvianolate Protects Hepatocytes from Oxidative Stress by Attenuating Mitochondrial Injury

    PubMed Central

    Zhao, Qiang; Peng, Yuan; Huang, Kai; Lei, Yang; Liu, Hong-Liang; Tao, Yan-Yan

    2016-01-01

    Salvianolate is widely used to treat angiocardiopathy in clinic in China, but its application in liver diseases remains unclear. Our study aims to investigate the effect of Salvianolate on rat hepatic injury by protecting hepatocyte mitochondria. To evaluate the effects of Salvianolate on injured hepatocytes, alpha mouse liver 12 (AML-12) cells were induced with hydrogen peroxide (H2O2) and treated with Salvianolate. Cell viability and MitoTracker Green for mitochondria and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazole-carbocyanide iodine (JC-1) levels and cytochrome C (Cyto-C) expressions were detected in vitro. To identify the effect of Salvianolate on protecting against mitochondria injury, male Wistar rats were injected with carbon tetrachloride (CCl4) and treated with Salvianolate (40 mg·kg−1). Serum liver function, parameters for peroxidative damage, hematoxylin and eosin (H&E) staining, and transmission electron microscope (TEM) of hepatocyte mitochondria were assayed. Our results showed that Salvianolate effectively protected hepatocytes, increased mitochondria vitality, and decreased Cyto-C expressions in vitro. Besides, Salvianolate alleviated the liver function, attenuated the indicators of peroxidation, and relieved the mitochondria injury in vivo. In conclusion, Salvianolate is effective in protecting hepatocytes from injury in vitro and in vivo, and the mechanism might be related to its protective effect on hepatocyte mitochondria against oxidative stress. PMID:27340417

  13. Oxidative stress and autophagy: Crucial modulators of kidney injury

    PubMed Central

    Sureshbabu, Angara; Ryter, Stefan W.; Choi, Mary E.

    2015-01-01

    Both acute kidney injury (AKI) and chronic kidney disease (CKD) that lead to diminished kidney function are interdependent risk factors for increased mortality. If untreated over time, end stage renal disease (ESRD) is an inevitable outcome. Acute and chronic kidney diseases occur partly due to imbalance between the molecular mechanisms that govern oxidative stress, inflammation, autophagy and cell death. Oxidative stress refers to the cumulative effects of highly reactive oxidizing molecules that cause cellular damage. Autophagy removes damaged organelles, protein aggregates and pathogens by recruiting these substrates into double membrane vesicles called autophagosomes which subsequently fuse with lysosomes. Mounting evidence suggests that both oxidative stress and autophagy are significantly involved in kidney health and disease. However, very little is known about the signaling processes that link them. This review is focused on understanding the role of oxidative stress and autophagy in kidney diseases. In this review, we also discuss the potential relationships between oxidative stress and autophagy that may enable the development of better therapeutic intervention to halt the progression of kidney disease and promote its repair and resolution. PMID:25613291

  14. Role of mitofusin 2 in cardiovascular oxidative injury.

    PubMed

    Zheng, Ming; Xiao, Rui-Ping

    2010-10-01

    Mitochondria are highly dynamic organelles with constant shape changes regulated by fusion and fission events. In addition to regulating mitochondrial morphology, mitochondrial fusion/fission is involved in fundamental mitochondrial biological processes, including mitochondrial metabolism, energization, respiration, mitochondrial membrane potential, and mtDNA stability. Dysfunction of mitochondrial dynamics has been implicated in various human diseases, especially in neurodegenerative diseases. Emerging evidence indicates that impaired expression of mitochondrial fusion proteins or their malfunction participates in oxidative stress-induced cardiovascular injury. This review will focus on recent advances of mitochondrial fusion in regulating various cellular processes in cardiovascular system.

  15. Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury

    PubMed Central

    Lazrak, Ahmed; Creighton, Judy; Yu, Zhihong; Komarova, Svetlana; Doran, Stephen F.; Aggarwal, Saurabh; Emala, Charles W.; Stober, Vandy P.; Trempus, Carol S.; Garantziotis, Stavros

    2015-01-01

    Chlorine (Cl2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular-weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-α-trypsin-inhibitor (IαI), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against IαI post-Cl2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl2 (100 ppm, 10 min) or incubation with Cl2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca2+, and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca2+, blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca2+ channels of airway smooth muscle cells, increasing their contractility and thus causing AHR. PMID:25747964

  16. Alveolar Epithelial Cell Injury Due to Zinc Oxide Nanoparticle Exposure

    PubMed Central

    Kim, Yong Ho; Fazlollahi, Farnoosh; Kennedy, Ian M.; Yacobi, Nazanin R.; Hamm-Alvarez, Sarah F.; Borok, Zea; Kim, Kwang-Jin; Crandall, Edward D.

    2010-01-01

    Rationale: Although inhalation of zinc oxide (ZnO) nanoparticles (NPs) is known to cause systemic disease (i.e., metal fume fever), little is known about mechanisms underlying injury to alveolar epithelium. Objectives: Investigate ZnO NP–induced injury to alveolar epithelium by exposing primary cultured rat alveolar epithelial cell monolayers (RAECMs) to ZnO NPs. Methods: RAECMs were exposed apically to ZnO NPs or, in some experiments, to culture fluid containing ZnCl2 or free Zn released from ZnO NPs. Transepithelial electrical resistance (RT) and equivalent short-circuit current (IEQ) were assessed as functions of concentration and time. Morphologic changes, lactate dehydrogenase release, cell membrane integrity, intracellular reactive oxygen species (ROS), and mitochondrial activity were measured. Measurements and Main Results: Apical exposure to 176 μg/ml ZnO NPs decreased RT and IEQ of RAECMs by 100% over 24 hours, whereas exposure to 11 μg/ml ZnO NPs had little effect. Changes in RT and IEQ caused by 176 μg/ml ZnO NPs were irreversible. ZnO NP effects on RT yielded half-maximal concentrations of approximately 20 μg/ml. Apical exposure for 24 hours to 176 μg/ml ZnO NPs induced decreases in mitochondrial activity and increases in lactate dehydrogenase release, permeability to fluorescein sulfonic acid, increased intracellular ROS, and translocation of ZnO NPs from apical to basolateral fluid (most likely across injured cells and/or damaged paracellular pathways). Conclusions: ZnO NPs cause severe injury to RAECMs in a dose- and time-dependent manner, mediated, at least in part, by free Zn released from ZnO NPs, mitochondrial dysfunction, and increased intracellular ROS. PMID:20639441

  17. Green tea protects cytoskeleton from oxidative injury in cardiomyocytes.

    PubMed

    Pagnotta, Eleonora; Calonghi, Natalia; Hrelia, Silvana; Masotti, Lanfranco; Biagi, Pierluigi; Angeloni, Cristina

    2006-12-27

    Cardiac ischemia/reperfusion injury results in oxidative stress and poor physiological recovery. Episodes of hypoxia/reoxygenation (H/R) cause some subtle functional and structural alterations in sarcolemma, mithocondria, sarcoplasmic reticulum, nucleus, as well as cytoskeleton. In this report, by using cultured rat cardiomyocytes and laser confocal microscopy we have verified the possibility to counteract cytoskeleton alterations induced by H/R with the supplementation of an antioxidant agent, a green tea extract (GTE), and compared its effects to those of alpha-tocopherol. Moreover the effects of GTE on cell viability and cytosolic antioxidant activity have been evaluated. H/R induced myocardial damage occurs as histological alterations such as degeneration and disorganization of the cytoskeleton and loss of structural integrity of the nucleus. GTE supplementation increases cytosolic antioxidant activity and shows protective effects on cardiomyocyte cytoarchitecture and viability.

  18. [Oxidative injury and its defense system in vivo].

    PubMed

    Niwa, Y

    1999-03-01

    We and other researchers verified that excessively produced free radicals by neutrophils induce various diseases such as Behçet's disease, MCLS, SLE (neutrophil-stimulated lymphocytes), RA (synovial fluid neutrophils), Crohn's disease, colitis ulcerosa, and dermatitis herpetiformis (Dühring). Recently, it was reported that environmental toxic agents including herbicides such as paraquat, insecticides, nitrogen oxide, and ultraviolet radiation produce free radicals. Nitrogen oxide, a main product of the combustion of petroleum, is a prominent component of exhaust from automobiles. Generation of 1O2 by ultraviolet radiation has also increased by breaks in the earth's ozone layer induced by halogenated hydrocarbon gas. Various diseases have been induced by these agents such as malignancies, severe adult atopic dermatitis, complication of cataract and retinolysis with atopic dermatitis, skin cancer, male infertility, severe collagen diseases, and lung fibrosis. It was also found that PCB, methyl-Hg and Mn, Cd induce neuropathic diseases through the increase in free radical production. On the other hand, a self-defense system exists against oxidative injuries; high-molecular-weight antioxidants such as SOD, catalase, and GSH-Px, and low-molecular-weight antioxidants such as vitamin C, E, A, polyphenols, flavonoids, and catechin. As protection from oxidative injury, various antioxidant products have been developed, however, the development of SOD injection was given up by all the pharmaceutical companies in the world on account of ineffectiveness due to rapid excretion from the kidney, low affinity to the receptor and weak penetration into the cell. A.M. Michelson, a French biochemist succeeded in developing an effective bovine liposomal-encapsulated SOD solving these problems, however, he also gave it up since French government prohibited bovine products due to the prion virus. Regarding low-molecular-weight antioxidants, synthetic products generally show low affinity

  19. Protective effect of thymoquinone against testicular torsion induced oxidative injury.

    PubMed

    Ayan, M; Tas, U; Sogut, E; Caylı, S; Kaya, H; Esen, M; Erdemir, F; Uysal, M

    2016-03-01

    We aimed to determine the protective effects of thymoquinone (TQ), against ischaemia-reperfusion (I/R) injury in the testis tissue of rats. Twenty-seven male Wistar albino rats were randomly divided into three equal groups as follows: Group I, sham group; Group II, torsion group; and Group III, torsion + thymoquinone group. The ischaemia period was 2 h, and orchiectomy was performed after 30 min of detorsion. Testis tissue sections were analysed with the terminal transferase mediated dUTP-nick end labelling (TUNEL) assay to determine in situ apoptotic DNA fragmentation. Additionally, Caspase 3 and Bax proteins were analysed immunohistochemically. The superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) activity levels in the testis tissue were also measured. The superoxide dismutase activity and malondialdehyde levels in the torsion group were significantly higher than those of the sham group (P < 0.05). Thymoquinone administration significantly reduced these levels. Torsion significantly increased active-Caspase 3 and Bax expression, which was decreased by thymoquinone. The apoptotic index of the torsion group was significantly higher than that of the control group. However, thymoquinone significantly reduced the apoptotic index (P < 0.05). Our results indicate that thymoquinone plays a protective role in oxidative stress induced ischaemia-reperfusion in the testis tissue of rats.

  20. Indium oxide (In2O3) nanoparticles induce progressive lung injury distinct from lung injuries by copper oxide (CuO) and nickel oxide (NiO) nanoparticles.

    PubMed

    Jeong, Jiyoung; Kim, Jeongeun; Seok, Seung Hyeok; Cho, Wan-Seob

    2016-04-01

    Indium is an essential element in the manufacture of liquid crystal displays and other electronic devices, and several forms of indium compounds have been developed, including nanopowders, films, nanowires, and indium metal complexes. Although there are several reports on lung injury caused by indium-containing compounds, the toxicity of nanoscale indium oxide (In2O3) particles has not been reported. Here, we compared lung injury induced by a single exposure to In2O3 nanoparticles (NPs) to that caused by benchmark high-toxicity nickel oxide (NiO) and copper oxide (CuO) NPs. In2O3 NPs at doses of 7.5, 30, and 90 cm(2)/rat (50, 200, and 600 µg/rat) were administered to 6-week-old female Wistar rats via pharyngeal aspiration, and lung inflammation was evaluated 1, 3, 14, and 28 days after treatment. Neutrophilic inflammation was observed on day 1 and worsened until day 28, and severe pulmonary alveolar proteinosis (PAP) was observed on post-aspiration days 14 and 28. In contrast, pharyngeal aspiration of NiO NPs showed severe neutrophilic inflammation on day 1 and lymphocytic inflammation with PAP on day 28. Pharyngeal aspiration of CuO NPs showed severe neutrophilic inflammation on day 1, but symptoms were completely resolved after 14 days and no PAP was observed. The dose of In2O3 NPs that produced progressive neutrophilic inflammation and PAP was much less than the doses of other toxic particles that produced this effect, including crystalline silica and NiO NPs. These results suggest that occupational exposure to In2O3 NPs can cause severe lung injury.

  1. [Hydrogen and oxidative stress injury--from an inert gas to a medical gas].

    PubMed

    Zhang, Qiao-li; Du, Jun-bao; Tang, Chao-shu

    2011-04-18

    Oxidative stress is intensive cellular oxidation caused by redundant reactive oxygen species (ROS) or free radicals. Redundant ROS causes DNA fracture, lipid peroxidation and protein inactivation, thus leading to severe cell damage. Recent studies have shown that hydrogen is a good anti-oxidant. It selectively reduces the hydroxyl radical, the most cytotoxic of ROS; however, it does not react with other ROS, which play physiological roles. As a result, it could protect tissues against oxidative stress injuries, such as ischemia/reperfusion injury of the heart, liver and intestine, cisplatin nephrotoxicity, sepsis and colon inflammation. As a medical gas, hydrogen may have a prospect for far-reaching clinical application.

  2. Oxidative Stress and Lung Ischemia-Reperfusion Injury

    PubMed Central

    Ferrari, Renata Salatti; Andrade, Cristiano Feijó

    2015-01-01

    Ischemia-reperfusion (IR) injury is directly related to the formation of reactive oxygen species (ROS), endothelial cell injury, increased vascular permeability, and the activation of neutrophils and platelets, cytokines, and the complement system. Several studies have confirmed the destructiveness of the toxic oxygen metabolites produced and their role in the pathophysiology of different processes, such as oxygen poisoning, inflammation, and ischemic injury. Due to the different degrees of tissue damage resulting from the process of ischemia and subsequent reperfusion, several studies in animal models have focused on the prevention of IR injury and methods of lung protection. Lung IR injury has clinical relevance in the setting of lung transplantation and cardiopulmonary bypass, for which the consequences of IR injury may be devastating in critically ill patients. PMID:26161240

  3. Salidroside Suppresses HUVECs Cell Injury Induced by Oxidative Stress through Activating the Nrf2 Signaling Pathway.

    PubMed

    Zhu, Yao; Zhang, Ya-Jie; Liu, Wei-Wei; Shi, Ai-Wu; Gu, Ning

    2016-08-09

    Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Salidroside (SAL), one of the main effective constituents of Rhodiola rosea, has been reported to suppress oxidative stress-induced cardiomyocyte injury and necrosis by promoting transcription of nuclear factor E2-related factor 2 (Nrf2)-regulated genes such as heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase (quinone1) (NQO1). However, it has not been indicated whether SAL might ameliorate endothelial injury induced by oxidative stress. Here, our study demonstrated that SAL might suppress HUVEC cell injury induced by oxidative stress through activating the Nrf2 signaling pathway. The results of our study indicated that SAL decreased the levels of intercellular reactive oxygen species (ROS) and malondialdehyde (MDA), and improved the activities of superoxide dismutase (SOD) and catalase (CAT), resulting in protective effects against oxidative stress-induced cell damage in HUVECs. It suppressed oxidative stress damage by inducing Nrf2 nuclear translocation and activating the expression of Nrf2-regulated antioxidant enzyme genes such as HO-1 and NQO1 in HUVECs. Knockdown of Nrf2 with siRNA abolished the cytoprotective effects against oxidative stress, decreased the expression of Nrf2, HO-1, and NQO1, and inhibited the nucleus translocation of Nrf2 in HUVECs. This study is the first to demonstrate that SAL suppresses HUVECs cell injury induced by oxidative stress through activating the Nrf2 signaling pathway.

  4. Oxidation-Reduction Potential as a Biomarker for Severity and Acute Outcome in Traumatic Brain Injury

    PubMed Central

    Levy, Stewart; Carrick, Matthew; Mains, Charles W.; Slone, Denetta S.

    2016-01-01

    There are few reliable markers for assessing traumatic brain injury (TBI). Elevated levels of oxidative stress have been observed in TBI patients. We hypothesized that oxidation-reduction potential (ORP) could be a potent biomarker in TBI. Two types of ORP were measured in patient plasma samples: the static state of oxidative stress (sORP) and capacity for induced oxidative stress (icORP). Differences in ORP values as a function of time after injury, severity, and hospital discharge were compared using ANOVAs with significance at p ≤ 0.05. Logit regression analyses were used to predict acute outcome comparing ORP, Injury Severity Score (ISS), Abbreviated Injury Scale (AIS), and Glasgow Coma Scale (GCS). Antioxidant capacity (icORP) on day 4 was prognostic for acute outcomes (p < 0.05). An odds ratio of 4.08 was associated with poor acute outcome when icORP > 7.25 μC. IcORP was a better predictor than ISS, AIS, or GCS scores. sORP increased in those with the highest ISS values (p < 0.05). Based on these findings ORP is useful biomarker for severity and acute outcome in TBI patients. Changes in ORP values on day 4 after injury were the most prognostic, suggesting that patients' response to brain injury over time is a factor that determines outcome. PMID:27642494

  5. TMIGD1 is a novel adhesion molecule that protects epithelial cells from oxidative cell injury.

    PubMed

    Arafa, Emad; Bondzie, Philip A; Rezazadeh, Kobra; Meyer, Rosana D; Hartsough, Edward; Henderson, Joel M; Schwartz, John H; Chitalia, Vipul; Rahimi, Nader

    2015-10-01

    Oxidative damage to renal tubular epithelial cells is a fundamental pathogenic mechanism implicated in both acute kidney injury and chronic kidney diseases. Because epithelial cell survival influences the outcome of acute kidney injury and chronic kidney diseases, identifying its molecular regulators could provide new insight into pathobiology and possible new therapeutic strategies for these diseases. We have identified transmembrane and immunoglobulin domain-containing 1 (TMIGD1) as a novel adhesion molecule, which is highly conserved in humans and other species. TMIGD1 is expressed in renal tubular epithelial cells and promotes cell survival. The extracellular domain of TMIGD1 contains two putative immunoglobulin domains and mediates self-dimerization. Our data suggest that TMIGD1 regulates transepithelial electric resistance and permeability of renal epithelial cells. TMIGD1 controls cell migration, cell morphology, and protects renal epithelial cells from oxidative- and nutrient-deprivation-induced cell injury. Hydrogen peroxide-induced oxidative cell injury downregulates TMIGD1 expression and targets it for ubiquitination. Moreover, TMIGD1 expression is significantly affected in both acute kidney injury and in deoxy-corticosterone acetate and sodium chloride (deoxy-corticosterone acetate salt)-induced chronic hypertensive kidney disease mouse models. Taken together, we have identified TMIGD1 as a novel cell adhesion molecule expressed in kidney epithelial cells that protects kidney epithelial cells from oxidative cell injury to promote cell survival.

  6. Nitric oxide protects carbon assimilation process of watermelon from boron-induced oxidative injury.

    PubMed

    Farag, Mohamed; Najeeb, Ullah; Yang, Jinghua; Hu, Zhongyuan; Fang, Zhang Ming

    2017-02-01

    Nitric oxide (NO) mediates plant response to a variety of abiotic stresses; however, limited information is available on its effect on boron (B)-stressed watermelon plants. The present study investigates the mechanism through which NO protects watermelon seedlings from B deficiency and toxicity stresses. Five days old watermelon seedlings were exposed to B (0, 0.5 and 10 mg L(-1)) alone or with 75 μmole of NO donor sodium nitroprusside (SNP) for 30 days. Both low and high B concentrations in the media altered nutrient accumulation and impaired various physiological processes of watermelon seedlings, leading to a significant reduction in biomass production. The plants exposed to B deficient or toxic concentrations had 66 and 69% lower shoot dry weight, respectively compared with optimum B levels. B toxicity-induced growth inhibition of watermelon seedlings was associated with high B translocation to shoot tissues, which caused lipid membrane peroxidation (12% increase) and chlorophyll destruction (25% reduction). In contrast, B deficiency accelerated generation of reactive oxygen species (ROS), specifically OH(-1) and induced cellular oxidative injury. Exogenously applied SNP promoted leaf chlorophyll, photosynthesis and consequently biomass production in B-stressed watermelon seedlings by reducing B accumulation, lipid membrane peroxidation and ROS generation. It also activated antioxidant enzymes such as SOD, POD and APX, and protected the seedlings from ROS-induced cellular burst.

  7. Daily sesame oil supplementation mitigates ketoconazole-induced oxidative stress-mediated apoptosis and hepatic injury.

    PubMed

    Periasamy, Srinivasan; Liu, Chuan-Teng; Chien, Se-Ping; Chen, Ying-Chien; Liu, Ming-Yie

    2016-11-01

    Ketoconazole (KCZ) is the most commonly used systemic antifungal drug. However, long-term treatment of KCZ induces hepatic injury. Oxidative stress is involved in KCZ-induced hepatic injury. Oxidative stress plays an important role in apoptosis-associated hepatic damage. Sesame oil is rich in potent antioxidants and antifungal constituents. It attenuates hepatic injury by inhibiting oxidative stress. Thus, sesame oil may protect against KCZ-induced oxidative stress, apoptosis and hepatic damage. The aim of the present study was to investigate the protective effect of sesame oil as a nutritional supplement on KCZ-induced hepatic injury in mice. KCZ (300 mg/kg/day) was administered by gastric intubation; 30 min later, sesame oil (0, 0.0625, 0.125, 0.25 or 0.5 ml/kg/day; p.o.) was administered to mice for 14 days. Blood and liver tissue were collected. Hepatic injury was evaluated by serum biochemistry and histology. Oxidative stress was evaluated by myeloperoxidase activity, p47-phox, reactive oxygen species generation, lipid peroxidation and glutathione level. Apoptosis was evaluated by p53, caspase-3, Bcl-2, Bax and Cyto-C expression. Osteopontin was measured to assess liver healing. Sesame oil attenuated hepatic injury; it also decreased oxidative stress and apoptosis in KCZ-treated mice. Sesame oil may be used as a nutritional supplement with existing antifungal therapies to neutralize the adverse hepatotoxic nature of antifungal drugs by attenuating hepatic apoptosis through redox system to protect and heal liver injury in KCZ-treated mice.

  8. Effects of phonophoresis with gold nanoparticles on oxidative stress parameters in a traumatic muscle injury model.

    PubMed

    Silveira, Paulo Cesar Lock; Victor, Eduardo Ghisi; Notoya, Frederico de Souza; Scheffer, Debora da Luz; Silva, Luciano da; Cantú, Roberto Benavides; Martínez, Virginia Hidolina Collins; de Pinho, Ricardo Aurino; Paula, Marcos Marques da Silva

    2016-01-01

    The aim of this study was to evaluate the effects of therapeutic pulsed ultrasound with gold nanoparticles on oxidative stress parameters after traumatic muscle injury in Wistar rats. The animals were randomly divided into nine groups (n = 6 each): sham (uninjured muscle); muscle injury without treatment; muscle injury and treatment with dimethyl sulfoxide (15 mg/kg); muscle injury and treatment with gold nanoparticles (27 µg); muscle injury and treatment with dimethyl sulfoxide + gold nanoparticles (Plus); muscle injury and therapeutic pulsed ultrasound; muscle injury and therapeutic pulsed ultrasound + dimethyl sulfoxide; muscle injury and therapeutic pulsed ultrasound + gold nanoparticles; and muscle injury and therapeutic pulsed ultrasound + Plus. Gastrocnemius injury was induced by a single-impact blunt trauma. Therapeutic pulsed ultrasound (6-min application, frequency 1.0 MHz, intensity 0.8 W/cm(2)) was used 2, 12, 24, and 48 h after trauma. Mitochondrial superoxide generation, lipid peroxidation, and protein carbonylation, and the activities of superoxide dismutase, glutathione peroxidase, and catalase were evaluated. The increase in the superoxide production and TBARS and carbonyl levels observed in the control group after muscle damage were reduced in animals exposed to therapeutic pulsed ultrasound plus nanoparticles. Similarly, antioxidants enzymes showed a decreased activity with the same treatment. Our work suggest that therapeutic pulsed ultrasound + dimethyl sulfoxide + gold nanoparticles has beneficial effects on the muscle healing process by inducing a decrease in oxidative stress parameters and most likely decreasing the deleterious effects of the inflammatory response.

  9. Pulmonary expression of nitric oxide synthase isoforms in sheep with smoke inhalation and burn injury.

    PubMed

    Cox, Robert A; Jacob, Sam; Oliveras, Gloria; Murakami, Kazunori; Enkhbaatar, Perenlei; Traber, Lillian; Schmalstieg, Frank C; Herndon, David N; Traber, Daniel L; Hawkins, Hal K

    2009-03-01

    Previous studies have indicated increased plasma levels of inducible nitric oxide synthase in lung. This study further examines the pulmonary expression of nitric oxide synthase (NOS) isoforms in an ovine model of acute lung injury induced by smoke inhalation and burn injury (S+B injury). Female range bred sheep (4 per group) were sacrificed at 4, 8, 12, 24, and 48 hours after injury and immunohistochemistry was performed in tissues for various NOS isoforms. The study indicates that in uninjured sheep lung, endothelial (eNOS) is constitutively expressed in the endothelial cells associated with the airways and parenchyma, and in macrophages. Similarly, neuronal (nNOS) is constitutively present in the mucous cells of the epithelium and in neurons of airway ganglia. In uninjured lung, inducible (iNOS) was present in bronchial secretory cells and macrophages. In tissue after S+B injury, new expression of iNOS was evident in bronchial ciliated cells, basal cells, and mucus gland cells. In the parenchyma, a slight increase in iNOS immunostaining was seen in type I cells at 12 and 24 hours after injury only. Virtually no change in eNOS or nNOS was seen after injury.

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

    PubMed

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

    2016-06-01

    Curcumin and dexmedetomidine have been shown to have protective effects in ischemia-reperfusion injury on various organs. However, their protective effects on kidney tissue against ischemia-reperfusion injury remain unclear. We aimed to determine whether curcumin or dexmedetomidine prevents renal tissue from injury that was induced by hind limb ischemia-reperfusion in rats. Fifty rats were divided into five groups: sham, control, curcumin (CUR) group (200 mg/kg curcumin, n = 10), dexmedetomidine (DEX) group (25 μg/kg dexmedetomidine, n = 10), and curcumin-dexmedetomidine (CUR-DEX) group (200 mg/kg curcumin and 25 μg/kg dexmedetomidine). Curcumin and dexmedetomidine were administered intraperitoneally immediately after the end of 4 h ischemia, just 5 min before reperfusion. The extremity re-perfused for 2 h and then blood samples were taken and total antioxidant capacity (TAC), total oxidative status (TOS) levels, and oxidative stress index (OSI) were measured, and renal tissue samples were histopathologically examined. The TAC activity levels in blood samples were significantly lower in the control than the other groups (p < 0.01 for all comparisons). The TOS activity levels in blood samples were significantly higher in Control group and than the other groups (p <  0.01 for all comparison). The OSI were found to be significantly increased in the control group compared to others groups (p < 0.001 for all comparisons). Histopathological examination revealed less severe lesions in the sham, CUR, DEX, and CUR-DEX groups, compared with the control group (p < 0.01). Rat hind limb ischemia-reperfusion causes histopathological changes in the kidneys. Curcumin and dexmedetomidine administered intraperitoneally was effective in reducing oxidative stress and renal histopathologic injury in an acute hind limb I/R rat model.

  11. Nanoparticles, Lung Injury, and the Role of Oxidant Stress

    PubMed Central

    Madl, Amy K.; Plummer, Laurel E.; Carosino, Christopher; Pinkerton, Kent E.

    2015-01-01

    The emergence of engineered nanoscale materials has provided significant advancements in electronic, biomedical, and material science applications. Both engineered nanoparticles and nanoparticles derived from combustion or incidental processes exhibit a range of physical and chemical properties, which have been shown to induce inflammation and oxidative stress in biologic systems. Oxidative stress reflects the imbalance between the generation of reaction oxygen species (ROS) and the biochemical mechanisms to detoxify and repair resulting damage of reactive intermediates. This review examines current research incidental and engineered nanoparticles in terms of their health effects on the lungs and mechanisms by which oxidative stress via physicochemical characteristics influence toxicity or biocompatibility. Although oxidative stress has generally been thought of as an adverse biological outcome, this review will also briefly discuss some of the potential emerging technologies to use nanoparticle-induced oxidative stress to treat disease in a site specific fashion. PMID:24215442

  12. Biomarkers for oxidative stress in acute lung injury induced in rabbits submitted to different strategies of mechanical ventilation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxidative damage has been said to play an important role in pulmonary injury, which is associated with the development and progression of acute respiratory distress syndrome (ARDS). We aimed to identify biomarkers to determine the oxidative stress in an animal model of acute lung injury (ALI) using ...

  13. ARSENIC METHYLATION AND OXIDANT INJURY BY ESR IN VIVO AND IN VITRO

    EPA Science Inventory

    Arsenic Methylation and Oxidant Injury by ESR In Vivo and In Vitro.

    Although arsenic is naturally occurring and present in the environment, it is a serious environmental concern worldwide, because of the large number of known contaminated sites and millions of people at ri...

  14. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications.

    PubMed

    Zhao, Weiling; Robbins, Mike E C

    2009-01-01

    The threat of radiation-induced late normal tissue injury limits the dose of radiation that can be delivered safely to cancer patients presenting with solid tumors. Tissue dysfunction and failure, associated with atrophy, fibrosis and/or necrosis, as well as vascular injury, have been reported in late responding normal tissues, including the central nervous system, gut, kidney, liver, lung, and skin. The precise mechanisms involved in the pathogenesis of radiation-induced late normal tissue injury have not been fully elucidated. It has been proposed recently that the radiation-induced late effects are caused, in part, by chronic oxidative stress and inflammation. Increased production of reactive oxygen species, which leads to lipid peroxidation, oxidation of DNA and proteins, as well as activation of pro-inflammatory factors has been observed in vitro and in vivo. In this review, we will present direct and indirect evidence to support this hypothesis. To improve the long-term survival and quality of life for radiotherapy patients, new approaches have been examined in preclinical models for their efficacy in preventing or mitigating the radiation-induced chronic normal tissue injury. We and others have tested drugs that can either attenuate inflammation or reduce chronic oxidative stress in animal models of late radiation-induced normal tissue injury. The effectiveness of renin-angiotensin system blockers, peroxisome proliferator-activated receptor (PPAR) gamma agonists, and antioxidants/antioxidant enzymes in preventing or mitigating the severity of radiation-induced late effects indicates that radiation-induced chronic injury can be prevented and/or treated. This provides a rationale for the design and development of anti-inflammatory-based interventional approaches for the treatment of radiation-induced late normal tissue injury.

  15. Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury.

    PubMed

    Genis, Laura; Dávila, David; Fernandez, Silvia; Pozo-Rodrigálvarez, Andrea; Martínez-Murillo, Ricardo; Torres-Aleman, Ignacio

    2014-01-01

    Oxidative stress is a proposed mechanism in brain aging, making the study of its regulatory processes an important aspect of current neurobiological research. In this regard, the role of the aging regulator insulin-like growth factor I (IGF-I) in brain responses to oxidative stress remains elusive as both beneficial and detrimental actions have been ascribed to this growth factor. Because astrocytes protect neurons against oxidative injury, we explored whether IGF-I participates in astrocyte neuroprotection and found that blockade of the IGF-I receptor in astrocytes abrogated their rescuing effect on neurons. We found that IGF-I directly protects astrocytes against oxidative stress (H 2O 2). Indeed, in astrocytes but not in neurons, IGF-I decreases the pro-oxidant protein thioredoxin-interacting protein 1 and normalizes the levels of reactive oxygen species. Furthermore, IGF-I cooperates with trophic signals produced by astrocytes in response to H 2O 2 such as stem cell factor (SCF) to protect neurons against oxidative insult. After stroke, a condition associated with brain aging where oxidative injury affects peri-infarcted regions, a simultaneous increase in SCF and IGF-I expression was found in the cortex, suggesting that a similar cooperative response takes place in vivo. Cell-specific modulation by IGF-I of brain responses to oxidative stress may contribute in clarifying the role of IGF-I in brain aging.

  16. Ozone protects rat heart against ischemia-reperfusion injury: A role for oxidative preconditioning in attenuating mitochondrial injury.

    PubMed

    Meng, Weixin; Xu, Ying; Li, Dandan; Zhu, Erjun; Deng, Li; Liu, Zonghong; Zhang, Guowei; Liu, Hongyu

    2017-04-01

    Ischemia-reperfusion injury (IRI) is a major cause of cardiac dysfunction during cardiovascular surgery, heart transplantation and cardiopulmonary bypass procedures. The purpose of the present study was to explore, firstly, whether ozone induces oxidative preconditioning by activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and, secondly, whether ozone oxidative preconditioning (OzoneOP) can protect the heart against IRI by attenuating mitochondrial damage. Rats were subjected to 30min of cardiac ischemia followed by 2h of reperfusion, with or without prior OzoneOP (100μg/kg/day) for 5 days. Antioxidant capacity, myocardial apoptosis and mitochondrial damage were evaluated and compared at the end of reperfusion. OzoneOP was found to increase antioxidant capacity and to protect the myocardium against IRI by attenuating mitochondrial damage and myocardial apoptosis. The study suggests a potential role for OzoneOP in protecting the heart against IRI during cardiovascular surgery, cardiopulmonary bypass procedures or transplantation.

  17. Schisandrin B protects against solar irradiation-induced oxidative injury in BJ human fibroblasts.

    PubMed

    Chiu, Po Yee; Lam, Philip Y; Yan, Chung Wai; Ko, Kam Ming

    2011-06-01

    The effects of schisandrin B (Sch B) and its analogs on solar irradiation-induced oxidative injury were examined in BJ human fibroblasts. Sch B and schisandrin C (Sch C) increased cellular reduced glutathione (GSH) level and protected against solar irradiation-induced oxidative injury. The photoprotection was paralleled by decreases in the elastases-type protease activity and matrix-metalloproteinases-1 expression in solar-irradiated fibroblasts. The cytochrome P-450-mediated metabolism of Sch B or Sch C caused ROS production. The results suggest that by virtue of its pro-oxidant action and the subsequent glutathione antioxidant response, Sch B or Sch C may offer the prospect of preventing skin photo-aging.

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

    PubMed

    Sosunov, Sergey A; Ameer, Xavier; Niatsetskaya, Zoya V; Utkina-Sosunova, Irina; Ratner, Veniamin I; Ten, Vadim S

    2015-01-01

    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 recovery of

  19. Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injury

    SciTech Connect

    Eto, Hideyuki; Miyata, Masaaki . E-mail: miyatam@m3.kufm.kagoshima-u.ac.jp; Kume, Noriaki; Minami, Manabu; Itabe, Hiroyuki; Orihara, Koji; Hamasaki, Shuichi; Biro, Sadatoshi; Otsuji, Yutaka; Kita, Toru; Tei, Chuwa

    2006-03-10

    Lectin-like oxidized LDL receptor-1 (LOX-1) is an oxidized LDL receptor, and its role in restenosis after angioplasty remains unknown. We used a balloon-injury model of rabbit aorta, and reverse transcription-polymerase chain reaction revealed that LOX-1 mRNA expression was modest in the non-injured aorta, reached a peak level 2 days after injury, and remained elevated until 24 weeks after injury. Immunohistochemistry and in situ hybridization showed that LOX-1 was not detected in the media of non-injured aorta but expressed in both medial and neointimal smooth muscle cells (SMC) at 2 and 24 weeks after injury. Low concentrations of ox-LDL (10 {mu}g/mL) stimulated the cultured SMC proliferation, which was inhibited by antisense oligonucleotides of LOX-1 mRNA. Double immunofluorescense staining showed the colocalization of LOX-1 and proliferating cell nuclear antigen in human restenotic lesion. These results suggest that LOX-1 mediates ox-LDL-induced SMC proliferation and plays a role in neointimal formation after vascular injury.

  20. Effect of Pulsed Electric Field on Membrane Lipids and Oxidative Injury of Salmonella typhimurium

    PubMed Central

    Yun, Ou; Zeng, Xin-An; Brennan, Charles S.; Han, Zhong

    2016-01-01

    Salmonella typhimurium cells were subjected to pulsed electric field (PEF) treatment at 25 kV/cm for 0–4 ms to investigate the effect of PEF on the cytoplasmic membrane lipids and oxidative injury of cells. Results indicated that PEF treatment induced a decrease of membrane fluidity of Salmonella typhimurium (S. typhimuriumi), possibly due to the alterations of fatty acid biosynthesis-associated gene expressions (down-regulation of cfa and fabA gene expressions and the up-regulation of fabD gene expression), which, in turn, modified the composition of membrane lipid (decrease in the content ratio of unsaturated fatty acids to saturated fatty acids). In addition, oxidative injury induced by PEF treatment was associated with an increase in the content of malondialdehyde. The up-regulation of cytochrome bo oxidase gene expressions (cyoA, cyoB, and cyoC) indicated that membrane damage was induced by PEF treatment, which was related to the repairing mechanism of alleviating the oxidative injury caused by PEF treatment. Based on these results, we achieved better understanding of microbial injury induced by PEF, suggesting that micro-organisms tend to decrease membrane fluidity in response to PEF treatment and, thus, a greater membrane fluidity might improve the efficiency of PEF treatment to inactivate micro-organisms. PMID:27556460

  1. Nitric oxide as a mediator of gastrointestinal mucosal injury?—Say it ain't so

    PubMed Central

    Kubes, Paul

    1995-01-01

    Nitric oxide has been suggested as a contributor to tissue injury in various experimental models of gastrointestinal inflammation. However, there is overwhelming evidence that nitric oxide is one of the most important mediators of mucosal defence, influencing such factors as mucus secretion, mucosal blood flow, ulcer repair and the activity of a variety of mucosal immunocytes. Nitric oxide has the capacity to down-regulate inflammatory responses in the gastrointestinal tract, to scavenge various free radical species and to protect the mucosa from injury induced by topical irritants. Moreover, questions can be raised regarding the evidence purported to support a role for nitric oxide in producing tissue injury. In this review, we provide an overview of the evidence supporting a role for nitric oxide in protecting the gastrointestinal tract from injury. PMID:18475671

  2. CHRONIC FETAL HYPOXIA PRODUCES SELECTIVE BRAIN INJURY ASSOCIATED WITH ALTERED NITRIC OXIDE SYNTHASES

    PubMed Central

    DONG, Yafeng; YU, Zhiyong; SUN, Yan; ZHOU, Hui; STITES, Josh; NEWELL, Katherine; WEINER, Carl P.

    2011-01-01

    OBJECTIVE The impact of chronic hypoxia on the nitric oxide synthase isoenzymes (NOSs) in specific brain structures is unknown. STUDY DESIGN Time-mated pregnant guinea pigs were exposed to 10.5% O2 for 14d (HPX) or room air (NMX); L-NIL (an iNOS inhibitor, 1mg/kg/day) was administered to HPX animals for 14d (L-NIL+HPX). Fetal brains were harvested at term. Multi-labeled immunofluorescence was used to generate a brain injury map. Laser capture microdissection and quantitative PCR were applied and cell injury markers, apoptosis activation, neuron loss, total NO, and the levels of individual NOSs quantified. RESULTS Chronic hypoxia causes selective fetal brain injury rather than globally. Injury is associated with differentially affected NO synthases in both neurons and glial cells, with iNOS up regulated at all injury sites. L-NIL attenuated the injury despite continued hypoxia. CONCLUSIONS These studies demonstrate chronic hypoxia selectively injures the fetal brain in part by the differential regulation of NOSs in an anatomic and cell specific manner. PMID:21272843

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

    PubMed Central

    Shao, Yi-ye; Li, Bing; Huang, Yong-mei; Luo, Qiong; Xie, Yang-mei; Chen, Ying-hui

    2017-01-01

    Abstract Aim 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. Methods 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. Results 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. Conclusion These findings showed that TQ attenuated brain injury induced by SE via an anti-oxidative pathway.

  4. L-carnitine attenuates oxidant injury in HK-2 cells via ROS-mitochondria pathway.

    PubMed

    Ye, Junsheng; Li, Juan; Yu, Yuming; Wei, Qiang; Deng, Wenfeng; Yu, Lixin

    2010-04-09

    Oxidative stress has been considered as the possible mechanism of renal ischemia/reperfusion injury. L-carnitine is an endogenous mitochondrial membrane compound and could effectively protect ischemia-reperfusion injury in the kidney. To elucidate the nephroprotective effects of L-carnitine, here we assessed the effect of L-carnitine on hydrogen peroxide (H(2)O(2))-mediated oxidative stress in the human proximal tubule epithelial cell line, HK-2 cells. The results showed that pretreatment with L-carnitine 12h inhibited H(2)O(2)-induced cell viability loss, intracellular reactive oxygen species generation and lipid peroxidation in a concentration-dependent manner. Also L-carnitine promoted endogenous antioxidant defense components including total antioxidative capacity, glutathione peroxidase, catalase and superoxide dismutase. In parallel, cell apoptosis triggered by H(2)O(2) characterized with the DNA fragment and caspase-3 activity were also inhibited by L-carnitine. Furthermore, mitochondrial dysfunction associated with cell apoptosis including membrane potential loss, down-regulation of Bcl-2 and up-regulation of Bax and the release of cytochrome c were abrogated in the presence of L-carnitine. These results suggested that L-carnitine could protect HK-2 cells from H(2)O(2)-induced injury through the inhibition of oxidative damage, mitochondria dysfunction and ultimately inhibition of cell apoptosis, which indicates that L-carnitine may be a promising approach for the treatment of oxidative stress in renal diseases.

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

    PubMed

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

    2013-04-17

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

  6. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    SciTech Connect

    Salama, Samir A.; Omar, Hany A.; Maghrabi, Ibrahim A.; AlSaeed, Mohammed S.; EL-Tarras, Adel E.

    2014-01-01

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  7. Recombinant erythropoietin is neuroprotective in a novel mouse oxidative injury model.

    PubMed

    Juul, Sandra E; McPherson, Ronald J; Bammler, Theodor K; Wilkerson, Jasmine; Beyer, Richard P; Farin, Federico M

    2008-01-01

    To identify neuroprotective changes in gene expression, we developed a neonatal mouse model of moderate to severe oxidative brain injury and hypothesized that recombinant erythropoietin (rEpo) would decrease the expression of proapoptotic and proinflammatory genes 24 and 48 h, respectively, after injury and increase the expression of neurogenic and angiogenic genes 168 h after injury. Postnatal day 10 BALB-c mice underwent sham surgery or right common carotid artery occlusion followed by alternating hypoxia and hyperoxia and were then treated with rEpo (5,000 U/kg s.c.) or saline (vehicle) daily for up to three doses. At death, gross brain injury was assessed, then hippocampus, cortex, and thalamus were isolated for RNA or protein extraction. Microarray analysis, real-time polymerase chain reaction, and Bio-Plex suspension array system validation were performed. rEpo decreased both incidence and severity of brain injury (median injury score 3 vs. 0, p < 0.0001) and reduced the injury-induced increases in interleukin-1alpha and interleukin-6 gene expression (p < 0.001), with corresponding effects on protein translation. Similarly, the expression of caspase-1, caspase-4, and caspase-6 and of p53 was increased by brain injury at 24 h, but mitigated by rEpo (p < 0.01). The interleukin-10 expression was higher in the rEpo-treated animals. Apoptotic and proinflammatory gene expression persisted for 168 h. There was no increase in angiogenic gene expression at the time points studied.

  8. Oxidative Lung Injury in Virus-Induced Wheezing

    DTIC Science & Technology

    2012-05-01

    acid , 0.5 µg/mL triiodothyronine, 50 mg/mL gentamicin and 50 mg/mL bovine serum albumin (BSA) for SAEC medium. When SAE were used for RSV...cytokines by human respiratory syncytial virus requires activation of NF-kB and is inhibited by sodium salicylate and aspirin. Virology 232: 369-378...8217, prepared from a small number of cells. Nucleic Acids Res 17: 6419, 1989. 32. Schwarz KB. Oxidative stress during viral infection: A review. Free Rad

  9. Erythropoietin, forkhead proteins, and oxidative injury: biomarkers and biology.

    PubMed

    Maiese, Kenneth; Hou, Jinling; Chong, Zhao Zhong; Shang, Yan Chen

    2009-10-02

    Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO), and members of the mammalian forkhead transcription factors of the O class (FoxOs), may offer the greatest promise for new treatment regimens, since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. Yet, EPO and FoxOs may sometimes have unexpected and undesirable effects that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as the complex role that EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation.

  10. Melatonin protects rat liver against irradiation-induced oxidative injury.

    PubMed

    Koc, Mehmet; Taysi, Seyithan; Buyukokuroglu, Mehmet Emin; Bakan, Nuri

    2003-09-01

    The aim of this study was to investigate the antioxidant roles of different doses of melatonin (5 and 10 mg x kg (-1) ) against gamma-irradiation-caused oxidative damage in liver tissue after total body irradiation (TBI) with a single dose of 6.0 Gy. Fifty adult rats were divided into 5 equal groups, 10 rats each. Groups I and II were injected with 5 and 10 mg x kg (-1) of melatonin, and group III was injected with an isotonic NaCl solution. Group IV was injected with only 5 mg x kg (-1) of melatonin. Group V was reserved as a sham control. Following a 30-min-period, 6.0 Gy TBI was given to groups 1, 2 and 3 in a single fraction. The liver malondialdehyde (MDA) levels, super oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were measured in all groups. TBI resulted in a significant increase in the liver tissue MDA levels and a decrease of SOD and GSH-Px activities. The results demonstrated that the liver tissue MDA levels in irradiated rats that were pretreated with melatonin (5 or 10 mg x kg (-1) ) were significantly decreased, while the SOD and GSH-Px activities were significantly increased. Decreasing the MDA levels by melatonin was dose dependent, but the liver tissue SOD and GSH activities were not. The data obtained in this study suggest that melatonin administration prior to irradiation may prevent liver damage by irradiation.

  11. Erythropoietin, Forkhead Proteins, and Oxidative Injury: Biomarkers and Biology

    PubMed Central

    Maiese, Kenneth; Hou, Jinling; Chong, Zhao Zhong; Shang, Yan Chen

    2009-01-01

    Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO), and members of the mammalian forkhead transcription factors of the O class (FoxOs), may offer the greatest promise for new treatment regimens, since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. Yet, EPO and FoxOs may sometimes have unexpected and undesirable effects that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as the complex role that EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation. PMID:19802503

  12. Oxidative Stress Mediates Radiation Lung Injury by Inducing Apoptosis

    SciTech Connect

    Zhang Yu; Zhang Xiuwu; Rabbani, Zahid N.; Jackson, Isabel L.; Vujaskovic, Zeljko

    2012-06-01

    Purpose: Apoptosis in irradiated normal lung tissue has been observed several weeks after radiation. However, the signaling pathway propagating cell death after radiation remains unknown. Methods and Materials: C57BL/6J mice were irradiated with 15 Gy to the whole thorax. Pro-apoptotic signaling was evaluated 6 weeks after radiation with or without administration of AEOL10150, a potent catalytic scavenger of reactive oxygen and nitrogen species. Results: Apoptosis was observed primarily in type I and type II pneumocytes and endothelium. Apoptosis correlated with increased PTEN expression, inhibition of downstream PI3K/AKT signaling, and increased p53 and Bax protein levels. Transforming growth factor-{beta}1, Nox4, and oxidative stress were also increased 6 weeks after radiation. Therapeutic administration of AEOL10150 suppressed pro-apoptotic signaling and dramatically reduced the number of apoptotic cells. Conclusion: Increased PTEN signaling after radiation results in apoptosis of lung parenchymal cells. We hypothesize that upregulation of PTEN is influenced by Nox4-derived oxidative stress. To our knowledge, this is the first study to highlight the role of PTEN in radiation-induced pulmonary toxicity.

  13. Resveratrol ameliorates oxidative stress and inhibits aquaporin 4 expression following rat cerebral ischemia-reperfusion injury.

    PubMed

    Li, Weina; Tan, Changhong; Liu, Yi; Liu, Xi; Wang, Xin; Gui, Yuejiang; Qin, Lu; Deng, Fen; Yu, Zhen; Hu, Changlin; Chen, Lifen

    2015-11-01

    Cerebral ischemia-reperfusion (I/R) is associated with increased levels of reactive oxygen species (ROS) and brain edema, which lead to the deterioration of patient prognosis. Resveratrol serves a neuroprotective role in I/R injury, and this role may be associated with its anti‑oxidative effects. However, resveratrol's mechanism of action in cerebral I/R injury remains to be fully understood. In order to investigate the effect of resveratrol in cerebral I/R‑induced injury, male Sprague‑Dawley rats were randomly assigned to four groups: The sham‑operation group, the I/R group and the edaravone and resveratrol groups (I/R + E and I/R + R groups). Infarct volume was evaluated by 2,3,5‑tripenyltetrazolium chloride staining, brain edema was evaluated by the water content in the reperfused brain and malondialdehyde (MDA) was measured by the thiobarbituric acid method. Superoxide dismutase (SOD) levels were measured using the Total Superoxide Dismutase Assay kit. Inducible nitric oxide synthase (iNOS) levels in the hippocampus and cortex were measured by ELISA, and aquaporin 4 (AQP4) expression was measured by immunohistochemical staining and western blot analysis. The results demonstrated that resveratrol reduced the infarct volume and the incidence of brain edema and reduced neurological deficits. These outcomes were accompanied by reduced levels of MDA, iNOS and AQP4, and increased SOD levels in cerebral I/R injury. In conclusion, resveratrol protected against cerebral I/R injury by ameliorating oxidative stress and reducing AQP4 expression.

  14. Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation.

    PubMed

    Sunil, Vasanthi R; Vayas, Kinal N; Cervelli, Jessica A; Malaviya, Rama; Hall, LeRoy; Massa, Christopher B; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L

    2014-08-01

    Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (150-174 g; 8-10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histopathological changes in the lung within 3d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2(+) and MMP-9(+)), and anti-inflammatory/wound repair (CD163+ and Gal-3(+)) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3(+) macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants.

  15. Sleep deprivation-induced multi-organ injury: role of oxidative stress and inflammation

    PubMed Central

    Periasamy, Srinivasan; Hsu, Dur-Zong; Fu, Yu-Hsuan; Liu, Ming-Yie

    2015-01-01

    Sleep deprivation affects all aspects of health. Adverse health effects by sleep deviation are still underestimated and undervalued in clinical practice and, to a much greater extent in monitoring human health. We hypothesized that sleep deprivation-induced mild organ injuries; oxidative stress and inflammation might play a crucial role in inducing multi-organ injury. Male C57BL/6J mice (n = 6-7) were sleep-deprived for 0-72 h using a modified multiple platform boxes method. Blood and tissue were collected. Liver, heart, kidney, lung, and pancreatic injuries were evaluated using biochemical and histological analyses. Glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), total billirubin (TBIL), creatine phosphokinase (CPK), creatine phosphokinase-myocardial band (CKMB), lactic dehydrogenase (LDH), creatinine (CRE), and blood urea nitrogen (BUN) were assayed in blood. Malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels were measured. Histology revealed mild-to-moderate liver and lung injury in sleep-deprived mice. Sleep-deprived mice had significantly higher GOT, GPT, TBIL, CPK, CKMB, LDH, BUN, and α-amylase (AMYL) levels, which indicated liver, heart, kidney, and pancreatic injuries. Serum IL-1β at 24 h and IL-6 at 72 h were significantly higher in sleep-deprived than in control mice. Hepatic TNF-α and IL-1β were significantly higher, but IL-6 significantly lower in mice that had been sleep-deprived for 72 h. Sleep deprivation-mediated inflammation may be associated with mild to moderate multi-organ damage in mice. The implication of this study indicates sleep deprivation in humans may induce multi-organ injury that negatively affects cardiovascular and gastrointestinal health. PMID:26648820

  16. Balance of nitric oxide and reactive oxygen species in myocardial reperfusion injury and protection.

    PubMed

    Folino, Anna; Losano, Gianni; Rastaldo, Raffaella

    2013-12-01

    Depending on their concentrations, both nitric oxide (NO) and reactive oxygen species (ROS) take part either in myocardial ischemia reperfusion injury or in protection by ischemic and pharmacological preconditioning (Ipre) and postconditioning (Ipost). At the beginning of reperfusion, a transient release of NO is promptly scavenged by ROS to form the highly toxic peroxynitrite, which is responsible for a further increase of ROS through endothelial nitric oxide synthase uncoupling. The protective role of NO has suggested the use of NO donors to mimic Ipre and Ipost. However, NO donors have not always given the expected protection, possibly because they are responsible for the production of different amounts of ROS that depend on the amount of released NO. This review is focused on the role of the balance of NO and ROS in myocardial injury and its prevention by Ipre and Ipost and after the use of NO donors given with or without antioxidant compounds to mimic Ipre and Ipost.

  17. Regulation of Injury-Induced Neurogenesis by Nitric Oxide

    PubMed Central

    Carreira, Bruno P.; Carvalho, Caetana M.; Araújo, Inês M.

    2012-01-01

    The finding that neural stem cells (NSCs) are able to divide, migrate, and differentiate into several cellular types in the adult brain raised a new hope for restorative neurology. Nitric oxide (NO), a pleiotropic signaling molecule in the central nervous system (CNS), has been described to be able to modulate neurogenesis, acting as a pro- or antineurogenic agent. Some authors suggest that NO is a physiological inhibitor of neurogenesis, while others described NO to favor neurogenesis, particularly under inflammatory conditions. Thus, targeting the NO system may be a powerful strategy to control the formation of new neurons. However, the exact mechanisms by which NO regulates neural proliferation and differentiation are not yet completely clarified. In this paper we will discuss the potential interest of the modulation of the NO system for the treatment of neurodegenerative diseases or other pathological conditions that may affect the CNS. PMID:22997523

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

    PubMed Central

    Kurian, Gino A.; Rajagopal, Rashmi; Vedantham, Srinivasan; Rajesh, Mohanraj

    2016-01-01

    Oxidative and reductive stress are dual dynamic phases experienced by the cells undergoing adaptation towards endogenous or exogenous noxious stimulus. The former arises due to the imbalance between the reactive oxygen species production and antioxidant defenses, while the latter is due to the aberrant increase in the reducing equivalents. Mitochondrial malfunction is the common denominator arising from the aberrant functioning of the rheostat that maintains the homeostasis between oxidative and reductive stress. Recent experimental evidences suggest that the maladaptation during oxidative stress could play a pivotal role in the pathophysiology of major cardiovascular diseases such as myocardial infraction, atherosclerosis, and diabetic cardiovascular complications. In this review we have discussed the role of oxidative and reductive stress pathways in the pathogenesis of myocardial ischemia/reperfusion injury and diabetic cardiomyopathy (DCM). Furthermore, we have provided impetus for the development of subcellular organelle targeted antioxidant drug therapy for thwarting the deterioration of the failing myocardium in the aforementioned cardiovascular conditions. PMID:27313825

  19. Nitrogen Substituent Polarity Influences Dithiocarbamate-Mediated Lipid Oxidation, Nerve Copper Accumulation, and Myelin Injury

    PubMed Central

    Valentine, Holly L.; Viquez, Olga M.; Amarnath, Kalyani; Amarnath, Venkataraman; Zyskowski, Justin; Kassa, Endalkachew N.; Valentine, William M.

    2009-01-01

    Dithiocarbamates have a wide spectrum of applications in industry, agriculture, and medicine, with new applications being investigated. Past studies have suggested that the neurotoxicity of some dithiocarbamates may result from copper accumulation, protein oxidative damage, and lipid oxidation. The polarity of a dithiocarbamate’s nitrogen substituents influences the lipophilicity of the copper complexes it generates and thus potentially determines its ability to promote copper accumulation within nerve and induce myelin injury. In the current study, a series of dithiocarbamate-copper complexes differing in their lipophilicity were evaluated for their relative abilities to promote lipid peroxidation determined by malondialdehyde levels generated in an ethyl arachidonate oil-in-water emulsion. In a second component of this study, rats were exposed to either N,N-diethyldithiocarbamate or sarcosine dithiocarbamate; both generate dithiocarbamate-copper complexes that are lipid and water soluble, respectively. Following the exposures, brain, tibial nerve, spinal cord and liver tissue copper levels were measured by inductively coupled mass spectroscopy to assess the relative abilities of these two dithiocarbamates to promote copper accumulation. Peripheral nerve injury was evaluated using grip strengths, nerve conduction velocities and morphologic changes at the light microscope level. Additionally, the protein expression levels of glutathione transferase alpha and heme-oxygenase-1 in nerve were determined and the quantity of protein carbonyls measured to assess levels of oxidative stress and injury. The data provide evidence that dithiocarbamate-copper complexes are redox active; and that the ability of dithiocarbamate complexes to promote lipid peroxidation is correlated to the lipophilicity of the complex. Consistent with neurotoxicity requiring the formation of a lipid soluble copper complex, significant increases in copper accumulation, oxidative stress and myelin

  20. Nitrogen substituent polarity influences dithiocarbamate-mediated lipid oxidation, nerve copper accumulation, and myelin injury.

    PubMed

    Valentine, Holly L; Viquez, Olga M; Amarnath, Kalyani; Amarnath, Venkataraman; Zyskowski, Justin; Kassa, Endalkachew N; Valentine, William M

    2009-01-01

    Dithiocarbamates have a wide spectrum of applications in industry, agriculture, and medicine, with new applications being investigated. Past studies have suggested that the neurotoxicity of some dithiocarbamates may result from copper accumulation, protein oxidative damage, and lipid oxidation. The polarity of a dithiocarbamate's nitrogen substituents influences the lipophilicity of the copper complexes that it generates and thus potentially determines its ability to promote copper accumulation within nerve and induce myelin injury. In the current study, a series of dithiocarbamate-copper complexes differing in their lipophilicity were evaluated for their relative abilities to promote lipid peroxidation determined by malondialdehyde levels generated in an ethyl arachidonate oil-in-water emulsion. In a second component of this study, rats were exposed to either N,N-diethyldithiocarbamate or sarcosine dithiocarbamate; both generated dithiocarbamate-copper complexes that were lipid- and water-soluble, respectively. Following the exposures, brain, tibial nerve, spinal cord, and liver tissue copper levels were measured by inductively coupled mass spectroscopy to assess the relative abilities of these two dithiocarbamates to promote copper accumulation. Peripheral nerve injury was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. Additionally, the protein expression levels of glutathione transferase alpha and heme-oxygenase-1 in nerve were determined, and the quantity of protein carbonyls was measured to assess levels of oxidative stress and injury. The data provided evidence that dithiocarbamate-copper complexes are redox active and that the ability of dithiocarbamate complexes to promote lipid peroxidation is correlated to the lipophilicity of the complex. Consistent with neurotoxicity requiring the formation of a lipid-soluble copper complex, significant increases in copper accumulation, oxidative

  1. An immunohistochemical panel to assess ultraviolet radiation-associated oxidative skin injury.

    PubMed

    Mamalis, Andrew; Fiadorchanka, Natallia; Adams, Lauren; Serravallo, Melissa; Heilman, Edward; Siegel, Daniel; Brody, Neil; Jagdeo, Jared

    2014-05-01

    Ultraviolet (UV) radiation results in a significant loss in years of healthy life, approximately 1.5 million disability-adjusted life years (DALYs), and is associated with greater than 60,000 deaths annually worldwide that are attributed to melanoma and other skin cancers. Currently, there are no standardized biomarkers or assay panels to assess oxidative stress skin injury patterns in human skin exposed to ionizing radiation. Using biopsy specimens from chronic solar UV-exposed and UV-protected skin, we demonstrate that UV radiation-induced oxidative skin injury can be evaluated by an immunohistochemical panel that stains 8-hydroxydeoxyguanosine (8-OH-dG) to assess DNA adducts, 4-hydroxy-2-nonenal (HNE) to assess lipid peroxidation, and advanced glycation end products (AGEs) to assess protein damage. We believe this panel contains the necessary cellular biomarkers to evaluate topical agents, such as sunscreens and anti-oxidants that are designed to prevent oxidative skin damage and may reduce UV-associated skin aging, carcinogenesis, and inflammatory skin diseases. We envision that this panel will become an important tool for researchers developing topical agents to protect against UV radiation and other oxidants and ultimately lead to reductions in lost years of healthy life, DALYs, and annual deaths associated with UV radiation.

  2. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition.

    PubMed

    Wu, Aiguo; Ying, Zhe; Gomez-Pinilla, Fernando

    2006-02-01

    The pervasive action of oxidative stress on neuronal function and plasticity after traumatic brain injury (TBI) is becoming increasingly recognized. Here, we evaluated the capacity of the powerful antioxidant curry spice curcumin ingested in the diet to counteract the oxidative damage encountered in the injured brain. In addition, we have examined the possibility that dietary curcumin may favor the injured brain by interacting with molecular mechanisms that maintain synaptic plasticity and cognition. The analysis was focused on the BDNF system based on its action on synaptic plasticity and cognition by modulating synapsin I and CREB. Rats were exposed to a regular diet or a diet high in saturated fat, with or without 500 ppm curcumin for 4 weeks (n = 8/group), before a mild fluid percussion injury (FPI) was performed. The high-fat diet has been shown to exacerbate the effects of TBI on synaptic plasticity and cognitive function. Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of BDNF, synapsin I, and CREB that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. These results are in agreement with previous evidence, showing that oxidative stress can affect the injured brain by acting through the BDNF system to affect synaptic plasticity and cognition. The fact that oxidative stress is an intrinsic component of the neurological sequel of TBI and other insults indicates that dietary antioxidant therapy is a realistic approach to promote protective mechanisms in the injured brain.

  3. Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury.

    PubMed

    Ansari, Mubeen A; Roberts, Kelly N; Scheff, Stephen W

    2008-08-15

    Oxidative stress, an imbalance between oxidants and antioxidants, contributes to the pathogenesis of traumatic brain injury (TBI). Oxidative neurodegeneration is a key mediator of exacerbated morphological responses and deficits in behavioral recoveries. The present study assessed early hippocampal sequential imbalance to possibly enhance antioxidant therapy. Young adult male Sprague-Dawley rats were subjected to a unilateral moderate cortical contusion. At various times post-TBI, animals were killed and the hippocampus was analyzed for antioxidants (GSH, GSSG, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase, superoxide dismutase, and catalase) and oxidants (acrolein, 4-hydroxynonenal, protein carbonyl, and 3-nitrotyrosine). Synaptic markers (synapsin I, postsynaptic density protein 95, synapse-associated protein 97, growth-associated protein 43) were also analyzed. All values were compared with those for sham-operated animals. Significant time-dependent changes in antioxidants were observed as early as 3 h posttrauma and paralleled increases in oxidants (4-hydroxynonenal, acrolein, and protein carbonyl), with peak values obtained at 24-48 h. Time-dependent changes in synaptic proteins (synapsin I, postsynaptic density protein 95, and synapse-associated protein 97) occurred well after levels of oxidants peaked. These results indicate that depletion of antioxidant systems following trauma could adversely affect synaptic function and plasticity. Early onset of oxidative stress suggests that the initial therapeutic window following TBI appears to be relatively short, and it may be necessary to stagger selective types of antioxidant therapy to target specific oxidative components.

  4. Nitric oxide and its role in ischaemic brain injury.

    PubMed

    Keynes, Robert G; Garthwaite, John

    2004-03-01

    The role of the neural messenger nitric oxide (NO) in cerebral ischaemia has been investigated extensively in the past decade. NO may play either a protective or destructive role in ischaemia and the literature is plagued with contradictory findings. Working with NO presents many unique difficulties and here we review the potential artifacts that may have contributed to discrepancies and cause future problems for the unwary investigator. Recent evidence challenges the idea that NO from neurones builds up to levels (micromolar) sufficient to directly elicit cell death during the post-ischaemic period. Concomitantly, the case is strengthened for a role of NO in delayed death mediated post-ischaemia by the inducible NO synthase. Mechanistically it seems unlikely that NO is released in high enough quantities to inhibit respiration in vivo; the formation of reactive nitrogen species, such as peroxynitrite, represents the more likely pathway to cell death. The protective and restorative properties of NO have become of increasing interest. NO from endothelial cells may, via stimulating cGMP production, protect the ischaemic brain by acutely augmenting blood flow, and by helping to form new blood vessels in the longer term (angiogenesis). Elevated cGMP production may also stop cells dying by inhibiting apoptosis and help repair damage by stimulating neurogenesis. In addition NO may act as a direct antioxidant and participate in the triggering of protective gene expression programmes that underlie cerebral ischaemic preconditioning. Better understanding of the molecular mechanisms by which NO is protective may ultimately identify new potential therapeutic targets.

  5. Vitamin D3 pretreatment alleviates renal oxidative stress in lipopolysaccharide-induced acute kidney injury.

    PubMed

    Xu, Shen; Chen, Yuan-Hua; Tan, Zhu-Xia; Xie, Dong-Dong; Zhang, Cheng; Xia, Mi-Zhen; Wang, Hua; Zhao, Hui; Xu, De-Xiang; Yu, De-Xin

    2015-08-01

    Increasing evidence demonstrates that reactive oxygen species plays important roles in sepsis-induced acute kidney injury. This study investigated the effects of VitD3 pretreatment on renal oxidative stress in sepsis-induced acute kidney injury. Mice were intraperitoneally injected with lipopolysaccharide (LPS, 2.0mg/kg) to establish an animal model of sepsis-induced acute kidney injury. In VitD3+LPS group, mice were orally pretreated with three doses of VitD3 (25 μg/kg) at 1, 24 and 48 h before LPS injection. As expected, oral pretreatment with three daily recommended doses of VitD3 markedly elevated serum 25(OH)D concentration and efficiently activated renal VDR signaling. Interestingly, LPS-induced renal GSH depletion and lipid peroxidation were markedly alleviated in VitD3-pretreated mice. LPS-induced serum and renal nitric oxide (NO) production was obviously suppressed by VitD3 pretreatment. In addition, LPS-induced renal protein nitration, as determined by 3-nitrotyrosine residue, was obviously attenuated by VitD3 pretreatment. Further analysis showed that LPS-induced up-regulation of renal inducible nitric oxide synthase (inos) was repressed in VitD3-pretreated mice. LPS-induced up-regulation of renal p47phox and gp91phox, two NADPH oxidase subunits, were normalized by VitD3 pretreatment. In addition, LPS-induced down-regulation of renal superoxide dismutase (sod) 1 and sod2, two antioxidant enzyme genes, was reversed in VitD3-pretreated mice. Finally, LPS-induced tubular epithelial cell apoptosis, as determined by TUNEL, was alleviated by VitD3 pretreatment. Taken together, these results suggest that VitD3 pretreatment alleviates LPS-induced renal oxidative stress through regulating oxidant and antioxidant enzyme genes.

  6. Treadmill Exercise Protects Against Pentylenetetrazol-Induced Seizures and Oxidative Stress after Traumatic Brain Injury

    PubMed Central

    Silva, Luiz Fernando Almeida; Hoffmann, Maurício Scopel; Gerbatin, Rogério da Rosa; Fiorin, Fernando da Silva; Dobrachinski, Fernando; Mota, Bibiana Castagna; Wouters, Angelica Terezinha Barth; Pavarini, Saulo Petinatti; Soares, Félix Alexandre Antunes; Fighera, Michele Rechia

    2013-01-01

    Abstract Traumatic brain injury (TBI) is a major cause of acquired epilepsy, and significant resources are required to develop a better understanding of the pathologic mechanism as targets for potential therapies. Thus, we decided to investigate whether physical exercise after fluid percussion injury (FPI) protects from oxidative and neurochemical alterations as well as from behavioral electroencephalographic (EEG) seizures induced by subeffective convulsive doses of pentylenetetrazol (PTZ; 35 mg/kg). Behavioral and EEG recordings revealed that treadmill physical training increased latency to first clonic and tonic-clonic seizures, attenuated the duration of generalized seizures, and protected against the increase of PTZ-induced Racine scale 5 weeks after neuronal injury. EEG recordings also revealed that physical exercise prevented PTZ-induced amplitude increase in TBI animals. Neurochemical analysis showed that exercise training increased glutathione/oxidized glutathione ratio and glutathione levels per se. Exercise training was also effective against alterations in the redox status, herein characterized by lipid peroxidation (thiobarbituric acid reactive substances), protein carbonyl increase, as well as the inhibition of superoxide dismutase and Na+,K+-ATPase activities after FPI. On the other hand, histologic analysis with hematoxylin and eosin revealed that FPI induced moderate neuronal damage in cerebral cortex 4 weeks after injury and that physical exercise did not protect against neuronal injury. These data suggest that the ability of physical exercise to reduce FPI-induced seizures is not related to its protection against neuronal damage; however, the effective protection of selected targets, such as Na+/K+-ATPase elicited by physical exercise, may represent a new line of treatment for post-traumatic seizure susceptibility. PMID:23530735

  7. Elevation of oxidative stress indicators in a pilot study of plasma following traumatic brain injury.

    PubMed

    Halstrom, Alison; MacDonald, Ellen; Neil, Claire; Arendts, Glenn; Fatovich, Daniel; Fitzgerald, Melinda

    2017-01-01

    Traumatic brain injury (TBI) encompasses a broad range of injury mechanisms and severity. A detailed determination of TBI severity can be a complex challenge, with current clinical tools sometimes insufficient to tailor a clinical response to a spectrum of patient needs. Blood biomarkers of TBI may supplement clinical assessments but currently available biomarkers have limited sensitivity and specificity. While oxidative stress is known to feature in damage mechanisms following TBI, investigation of blood biomarkers of oxidative stress has been limited. This exploratory pilot study of a subset of 18 trauma patients with TBI of varying severity, quantifies circulating concentrations of the structural damage indicators S100b, and myelin basic protein (MBP), and the biomarkers of oxidative stress hydroxynonenal (HNE), malondialdehyde (MDA), carboxy-methyl-lysine (CML), and 8-hydroxy-2'-deoxy-guanosine (8-OHDG). Significant increases in circulating S100b, MBP, and HNE were observed in TBI patient samples compared to 8 uninjured controls, and there was a significant decrease in CML. This small exploratory study supports the current literature on S100b and MBP elevation in TBI, and reveals potential for the use of peripheral oxidative stress markers to assist in determination of TBI severity. Further investigation is required to validate results and confirm trends.

  8. Influence of PACAP on oxidative stress and tissue injury following small-bowel autotransplantation.

    PubMed

    Ferencz, Andrea; Racz, Boglarka; Tamas, Andrea; Reglodi, Dora; Lubics, Andrea; Nemeth, Jozsef; Nedvig, Klara; Kalmar-Nagy, Karoly; Horvath, Ors Peter; Weber, Gyorgy; Roth, Erzsebet

    2009-02-01

    Tissue injury caused by cold preservation and reperfusion remains an unsolved problem during small-bowel transplantation. Pituitary adenylate cyclase-activating polypeptide (PACAP) is present and plays a central role in the intestinal physiology. This study investigated effect of PACAP-38 on the oxidative stress and tissue damage in autotransplanted intestine. Sham-operated, ischemia/reperfusion, and autotransplanted groups were established in Wistar rats. In ischemia/reperfusion groups, 1 h (group A), 2 h (group B), and 3 h (group C) ischemia followed by 3 h of reperfusion was applied. In autotransplanted groups, total orthotopic intestinal autotransplantation was performed. Grafts were preserved in University of Wisconsin (UW) solution and in UW containing 30 microg PACAP-38 for 1, 2, 3, and 6 h. Reperfusion lasted 3 h in all groups. Endogenous PACAP-38 concentration was measured by radioimmunoassay. To determine oxidative stress parameters, malondialdehyde, reduced glutathione, and superoxide dismutase were measured in tissue samples. Tissue damage was analyzed by qualitative and quantitative methods on hematoxylin/eosin-stained sections. Concentration of endogenous PACAP-38 significantly decreased in groups B and C compared to sham-operated group. Preservation solution containing PACAP-38 ameliorated bowel tissue oxidative injury induced by cold ischemia and reperfusion. Histological results showed that preservation caused destruction of the mucous, submucous, and muscular layers, which were further deteriorated by the end of reperfusion. In contrast, PACAP-38 significantly protected the intestinal structure. Ischemia/reperfusion decreased the endogenous PACAP-38 concentration in the intestinal tissue. Administration of PACAP-38 mitigated the oxidative injury and histological lesions in small-bowel autotransplantation model.

  9. Pathophysiology and Treatments of Oxidative Injury in Ischemic Stroke: Focus on the Phagocytic NADPH Oxidase 2

    PubMed Central

    Carbone, Federico; Teixeira, Priscila Camillo; Braunersreuther, Vincent; Mach, François; Vuilleumier, Nicolas

    2015-01-01

    Abstract Significance: Phagocytes play a key role in promoting the oxidative stress after ischemic stroke occurrence. The phagocytic NADPH oxidase (NOX) 2 is a membrane-bound enzyme complex involved in the antimicrobial respiratory burst and free radical production in these cells. Recent Advances: Different oxidants have been shown to induce opposite effects on neuronal homeostasis after a stroke. However, several experimental models support the detrimental effects of NOX activity (especially the phagocytic isoform) on brain recovery after stroke. Therapeutic strategies selectively targeting the neurotoxic ROS and increasing neuroprotective oxidants have recently produced promising results. Critical Issues: NOX2 might promote carotid plaque rupture and stroke occurrence. In addition, NOX2-derived reactive oxygen species (ROS) released by resident and recruited phagocytes enhance cerebral ischemic injury, activating the inflammatory apoptotic pathways. The aim of this review is to update evidence on phagocyte-related oxidative stress, focusing on the role of NOX2 as a potential therapeutic target to reduce ROS-related cerebral injury after stroke. Future Directions: Radical scavenger compounds (such as Ebselen and Edaravone) are under clinical investigation as a therapeutic approach against stroke. On the other hand, NOX inhibition might represent a promising strategy to prevent the stroke-related injury. Although selective NOX inhibitors are not yet available, nonselective compounds (such as apocynin and fasudil) provided encouraging results in preclinical studies. Whereas additional studies are needed to better evaluate this therapeutic potential in human beings, the development of specific NOX inhibitors (such as monoclonal antibodies, small-molecule inhibitors, or aptamers) might further improve brain recovery after stroke. Antioxid. Redox Signal. 23, 460–489. PMID:24635113

  10. Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial alteration in ischemic retinal injury.

    PubMed

    Lee, Dongwook; Kim, Keun-Young; Shim, Myoung Sup; Kim, Sang Yeop; Ellisman, Mark H; Weinreb, Robert N; Ju, Won-Kyu

    2014-04-01

    Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species for protecting neuronal cells against oxidative stress in neurodegenerative diseases. We tested whether a diet supplemented with CoQ10 ameliorates oxidative stress and mitochondrial alteration, as well as promotes retinal ganglion cell (RGC) survival in ischemic retina induced by intraocular pressure elevation. A CoQ10 significantly promoted RGC survival at 2 weeks after ischemia. Superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) expression were significantly increased at 12 h after ischemic injury. In contrast, the CoQ10 significantly prevented the upregulation of SOD2 and HO-1 protein expression in ischemic retina. In addition, the CoQ10 significantly blocked activation of astroglial and microglial cells in ischemic retina. Interestingly, the CoQ10 blocked apoptosis by decreasing caspase-3 protein expression in ischemic retina. Bax and phosphorylated Bad (pBad) protein expression were significantly increased in ischemic retina at 12 h. Interestingly, while CoQ10 significantly decreased Bax protein expression in ischemic retina, CoQ10 showed greater increase of pBad protein expression. Of interest, ischemic injury significantly increased mitochondrial transcription factor A (Tfam) protein expression in the retina at 12 h, however, CoQ10 significantly preserved Tfam protein expression in ischemic retina. Interestingly, there were no differences in mitochondrial DNA content among control- or CoQ10-treated groups. Our findings demonstrate that CoQ10 protects RGCs against oxidative stress by modulating the Bax/Bad-mediated mitochondrial apoptotic pathway as well as prevents mitochondrial alteration by preserving Tfam protein expression in ischemic retina. Our results suggest that CoQ10 may provide neuroprotection against oxidative stress-mediated mitochondrial alterations in ischemic retinal injury.

  11. Selective phosphodiesterase 3 inhibitor olprinone attenuates meconium-induced oxidative lung injury.

    PubMed

    Mokra, Daniela; Drgova, Anna; Pullmann, Rudolf; Calkovska, Andrea

    2012-06-01

    Since inflammation and oxidation play a key role in the pathophysiology of neonatal meconium aspiration syndrome, various anti-inflammatory drugs have been tested in the treatment. This study evaluated whether the phosphodiesterase (PDE) 3 inhibitor olprinone can alleviate meconium-induced inflammation and oxidative lung injury. Oxygen-ventilated rabbits intratracheally received 4 ml/kg of meconium (25 mg/ml) or saline. Thirty minutes after meconium/saline instillation, meconium-instilled animals were treated by intravenous olprinone (0.2 mg/kg) or were left without treatment. All animals were oxygen-ventilated for an additional 5 h. A bronchoalveolar lavage (BAL) of the left lungs was performed and differential leukocyte count in the sediment was estimated. The right lungs were used to determine lung edema by wet/dry weight ratio, as well as to detect oxidative damage to the lungs. In the lung tissue homogenate, total antioxidant status (TAS) was determined. In isolated lung mitochondria, the thiol group content, conjugated dienes, thiobarbituric acid-reactive substances (TBARS), dityrosine, lysine-lipid peroxidation products, and activity of cytochrome c oxidase (COX) were estimated. To evaluate the effects of meconium instillation and olprinone treatment on the systemic level, TBARS and TAS were determined in the blood plasma, as well. Meconium instillation increased the relative numbers of neutrophils and eosinophils in the BAL fluid, increased edema formation and concentrations of oxidation markers, and decreased TAS. Treatment with olprinone reduced the numbers of polymorphonuclears in the BAL fluid, decreased the formation of most oxidation markers in the lungs, reduced lung edema and prevented a decrease in TAS in the lung homogenate compared to non-treated animals. In the blood plasma, olprinone decreased TBARS and increased TAS compared to the non-treated group. Conclusion, the selective PDE3 inhibitor olprinone has shown potent antioxidative and anti

  12. Dioscin alleviates dimethylnitrosamine-induced acute liver injury through regulating apoptosis, oxidative stress and inflammation.

    PubMed

    Zhang, Weixin; Yin, Lianhong; Tao, Xufeng; Xu, Lina; Zheng, Lingli; Han, Xu; Xu, Youwei; Wang, Changyuan; Peng, Jinyong

    2016-07-01

    In our previous study, the effects of dioscin against alcohol-, carbon tetrachloride- and acetaminophen-induced liver damage have been found. However, the activity of it against dimethylnitrosamine (DMN)-induced acute liver injury remained unknown. In the present study, dioscin markedly decreased serum ALT and AST levels, significantly increased the levels of SOD, GSH-Px, GSH, and decreased the levels of MDA, iNOS and NO. Mechanism study showed that dioscin significantly decreased the expression levels of IL-1β, IL-6, TNF-α, IκBα, p50 and p65 through regulating TLR4/MyD88 pathway to rehabilitate inflammation. In addition, dioscin markedly up-regulated the expression levels of SIRT1, HO-1, NQO1, GST and GCLM through increasing nuclear translocation of Nrf2 against oxidative stress. Furthermore, dioscin significantly decreased the expression levels of FasL, Fas, p53, Bak, Caspase-3/9, and upregulated Bcl-2 level through decreasing IRF9 level against apoptosis. In conclusion, dioscin showed protective effect against DMN-induced acute liver injury via ameliorating apoptosis, oxidative stress and inflammation, which should be developed as a new candidate for the treatment of acute liver injury in the future.

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

    PubMed Central

    Liu, Fu-Chao; Tsai, Hsin-I; Yu, Huang-Ping

    2015-01-01

    Resveratrol, a polyphenol extracted from red wine, possesses potential antioxidative and anti-inflammatory effects, including the reduction of free radicals and proinflammatory mediators overproduction, the alteration of the expression of adhesion molecules, and the inhibition of neutrophil function. A growing body of evidence indicates that resveratrol plays an important role in reducing organ damage following ischemia- and hemorrhage-induced reperfusion injury. Such protective phenomenon is reported to be implicated in decreasing the formation and reaction of reactive oxygen species and pro-nflammatory cytokines, as well as the mediation of a variety of intracellular signaling pathways, including the nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, deacetylase sirtuin 1, mitogen-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, hemeoxygenase-1, and estrogen receptor-related pathways. Reperfusion injury is a complex pathophysiological process that involves multiple factors and pathways. The resveratrol is an effective reactive oxygen species scavenger that exhibits an antioxidative property. In this review, the organ-protective effects of resveratrol in oxidative stress-related reperfusion injury will be discussed. PMID:26161238

  14. Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

    PubMed Central

    Siow, Yaw L.; Isaak, Cara K.

    2016-01-01

    Ischemia-reperfusion is a common cause for acute kidney injury and can lead to distant organ dysfunction. Glutathione is a major endogenous antioxidant and its depletion directly correlates to ischemia-reperfusion injury. The liver has high capacity for producing glutathione and is a key organ in modulating local and systemic redox balance. In the present study, we investigated the mechanism by which kidney ischemia-reperfusion led to glutathione depletion and oxidative stress. The left kidney of Sprague-Dawley rats was subjected to 45 min ischemia followed by 6 h reperfusion. Ischemia-reperfusion impaired kidney and liver function. This was accompanied by a decrease in glutathione levels in the liver and plasma and increased hepatic lipid peroxidation and plasma homocysteine levels. Ischemia-reperfusion caused a significant decrease in mRNA and protein levels of hepatic glutamate-cysteine ligase mediated through the inhibition of transcription factor Nrf2. Ischemia-reperfusion inhibited hepatic expression of cystathionine γ-lyase, an enzyme responsible for producing cysteine (an essential precursor for glutathione synthesis) through the transsulfuration pathway. These results suggest that inhibition of glutamate-cysteine ligase expression and downregulation of the transsulfuration pathway lead to reduced hepatic glutathione biosynthesis and elevation of plasma homocysteine levels, which, in turn, may contribute to oxidative stress and distant organ injury during renal ischemia-reperfusion. PMID:27872680

  15. Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice.

    PubMed

    Sinz, E H; Kochanek, P M; Dixon, C E; Clark, R S; Carcillo, J A; Schiding, J K; Chen, M; Wisniewski, S R; Carlos, T M; Williams, D; DeKosky, S T; Watkins, S C; Marion, D W; Billiar, T R

    1999-09-01

    Nitric oxide (NO) derived from the inducible isoform of NO synthase (iNOS) is an inflammatory product implicated both in secondary damage and in recovery from brain injury. To address the role of iNOS in experimental traumatic brain injury (TBI), we used 2 paradigms in 2 species. In a model of controlled cortical impact (CCI) with secondary hypoxemia, rats were treated with vehicle or with 1 of 2 iNOS inhibitors (aminoguanidine and L-N-iminoethyl-lysine), administered by Alzet pump for 5 days and 1. 5 days after injury, respectively. In a model of CCI, knockout mice lacking the iNOS gene (iNOS(-/-)) were compared with wild-type (iNOS(+/+)) mice. Functional outcome (motor and cognitive) during the first 20 days after injury, and histopathology at 21 days, were assessed in both studies. Treatment of rats with either of the iNOS inhibitors after TBI significantly exacerbated deficits in cognitive performance, as assessed by Morris water maze (MWM) and increased neuron loss in vulnerable regions (CA3 and CA1) of hippocampus. Uninjured iNOS(+/+) and iNOS(-/-) mice performed equally well in both motor and cognitive tasks. However, after TBI, iNOS(-/-) mice showed markedly worse performance in the MWM task than iNOS(+/+) mice. A beneficial role for iNOS in TBI is supported.

  16. NBQX treatment improves mitochondrial function and reduces oxidative events after spinal cord injury.

    PubMed

    Mu, Xiaojun; Azbill, Robert D; Springer, Joe E

    2002-08-01

    The purpose of this study was to examine the effects of inhibiting ionotropic glutamate receptor subtypes on measures of oxidative stress events at acute times following traumatic spinal cord injury (SCI). Rats received a moderate contusion injury and 15 min later were treated with one of two doses of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzol[f]quinoxaline-7-sulfonamide disodium (NBQX), MK-801, or the appropriate vehicle. At 4 h following injury, spinal cords were removed and a crude synaptosomal preparation obtained to examine mitochondrial function using the MTT assay, as well as measures of reactive oxygen species (ROS), lipid peroxidation, and glutamate and glucose uptake. We report here that intraspinal treatment with either 15 or 30 nmol of NBQX improves mitochondrial function and reduces the levels of ROS and lipid peroxidation products. In contrast, MK-801, given intravenously at doses of 1.0 or 5.0 mg/kg, was without effect on these same measures. Neither drug treatment had an effect on glutamate or glucose uptake, both of which are reduced at acute times following SCI. Previous studies have documented that drugs acting on non-N-methyl-D-aspartate (NMDA) receptors exhibit greater efficacy compared to NMDA receptor antagonists on recovery of function and tissue sparing following traumatic spinal cord injury. The results of this study provide a potential mechanism by which blockade of the non-NMDA ionotropic receptors exhibit positive effects following traumatic SCI.

  17. Resolution of experimental lung injury by Monocyte-derived inducible nitric oxide synthase (iNOS)

    PubMed Central

    D’Alessio, Franco R.; Tsushima, Kenji; Aggarwal, Neil R.; Mock, Jason R.; Eto, Yoshiki; Garibaldi, Brian T.; Files, Daniel C.; Avalos, Claudia R.; Rodriguez, Jackie V.; Waickman, Adam T.; Reddy, Sekhar P.; Pearse, David B.; Sidhaye, Venkataramana K.; Hassoun, Paul M.; Crow, Michael T.; King, Landon S.

    2012-01-01

    While early events in the pathogenesis of acute lung injury (ALI) have been defined, little is known about mechanisms mediating resolution. To search for determinants of resolution, we exposed wild type (WT) mice to intratracheal lipopolysacaccharide (i.t. LPS) and assessed the response at intervals to day 10, when injury had resolved. Inducible nitric oxide synthase (iNOS) was significantly upregulated in the lung at day 4 after LPS. When iNOS−/− mice were exposed to i.t. LPS, early lung injury was attenuated, however recovery was markedly impaired compared to wild type (WT) mice. iNOS−/− mice had increased mortality and sustained increases in markers of lung injury. Adoptive transfer of WT (iNOS+/+) bone marrow-derived monocytes or direct adenoviral gene delivery of iNOS into injured iNOS−/− mice restored resolution of ALI. Irradiated bone marrow chimeras confirmed the protective effects of myeloid-derived iNOS, but not of epithelial iNOS. Alveolar macrophages exhibited sustained expression of co-signalling molecule CD86 in iNOS−/− mice compared to WT mice. Antibody-mediated blockade of CD86 in iNOS−/− mice improved survival and enhanced resolution of lung inflammation. Our findings show that monocyte-derived iNOS plays a pivotal role in mediating resolution of ALI by modulating lung immune responses, thus facilitating clearance of alveolar inflammation and promoting lung repair. PMID:22844117

  18. Impact of exercise training on oxidative stress in individuals with a spinal cord injury

    PubMed Central

    van Duijnhoven, Noortje; Hesse, Evelyne; Janssen, Thomas; Wodzig, Will; Scheffer, Peter

    2010-01-01

    Individuals with a spinal cord injury (SCI) have an increased cardiovascular risk. We hypothesize that (anti)oxidative imbalance is associated with the increased cardiovascular risk in SCI, while exercise can reverse this status. The aim of the study is to compare baseline levels of oxidative stress and antioxidative capacity between individuals with SCI and able-bodied (AB) subjects, and to assess acute and long-term effects of functional electrical stimulation (FES) exercise on oxidative stress and antioxidative capacity in SCI. Venous blood was taken from subjects with an SCI (n = 9) and age- and gender-matched AB subjects (n = 9) to examine oxidative stress through malondialdehyde (MDA) levels, while superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme levels represented anti-oxidative capacity. Subsequently, subjects with an SCI performed an 8-week FES exercise training period. Blood was taken before and after the first exercise bout and after the last FES session to examine the acute and chronic effect of FES exercise, respectively. Baseline levels of MDA, SOD and GPx were not different between individuals with SCI and AB subjects. SCI demonstrated a correlation between initial fitness level and MDA (R = −0.83, P = 0.05). MDA, SOD and GPx levels were neither altered by a single FES exercise bout nor by 8 weeks FES training. In conclusion, although individuals with an SCI demonstrate a preserved (anti)oxidative status, the correlation between fitness level and (anti)oxidative balance suggests that higher fitness levels are related to improved (anti)oxidative status in SCI. Nonetheless, the FES exercise stimulus was insufficient to acutely or chronically change (anti)oxidative status in individuals with an SCI. PMID:20364349

  19. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat.

    PubMed

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (P<0.0001). Reduction of TBARS (P<0.01 and P<0.001) followed by enhancement of GSH., SOD and catalase (P<0.0001) in liver homogenate in sesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes.

  20. Arabidopsis mutants lacking phenolic sunscreens exhibit enhanced ultraviolet-B injury and oxidative damage

    SciTech Connect

    Landry, L.G.; Last, R.L.; Chapple, C.C.S.

    1995-12-01

    We have assessed ultraviolet-B (UV-B)-induced injury in wild-type Arabidopsis thaliana and two mutants with altered aromatic secondary product biosynthesis. Arabidopsis mutants defective in the ability to synthesize UV-B-absorbing compounds (flavonoids in transparent testa 5 [tt5] and sinapate esters in ferulic acid hydroxylase 1 [fah 1]) are more sensitive to UV-B than is the wild-type Landsberg erecta. Despite its ability to accumulate UV-absorptive flavonoid compounds, the ferulic acid hydroxylase mutant fah1 exhibits more physiological injury (growth inhibition and foliar lesions) than either wild type or tt5. The extreme UV-B sensitivity of fah1 demonstrates the importance of hydroxycinnamate esters as UV-B protectants. Consistent with the whole-plant response, the highest levels of lipid and protein oxidation products were seen in fah1. Ascorbate peroxidase enzyme activity was also increased in the leaves of UV-B-treated plants in a dose- and genotype-dependent manner. These results demonstrate that, in A. thaliana, hydryoxycinnamates are more effective UV-B protectants than flavonoids. The data also indicate that A. thaliana responds to UV-B as an oxidative stress, and sunscreen compounds reduce the oxidative damage caused by UV-B. 36 refs., 6 figs.

  1. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat

    PubMed Central

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (P<0.0001). Reduction of TBARS (P<0.01 and P<0.001) followed by enhancement of GSH., SOD and catalase (P<0.0001) in liver homogenate in sesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes. PMID:26191289

  2. Ozone-induced injury and oxidative stress in bronchiolar epithelium are associated with altered pulmonary mechanics.

    PubMed

    Sunil, Vasanthi R; Vayas, Kinal N; Massa, Christopher B; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L

    2013-06-01

    In these studies, we analyzed the effects of ozone on bronchiolar epithelium. Exposure of rats to ozone (2 ppm, 3 h) resulted in rapid (within 3 h) and persistent (up to 72 h) histological changes in the bronchiolar epithelium, including hypercellularity, loss of cilia, and necrotizing bronchiolitis. Perivascular edema and vascular congestion were also evident, along with a decrease in Clara cell secretory protein in bronchoalveolar lavage, which was maximal 24 h post-exposure. Ozone also induced the appearance of 8-hydroxy-2'-deoxyguanosine, Ym1, and heme oxygenase-1 in the bronchiolar epithelium. This was associated with increased expression of cleaved caspase-9 and beclin-1, indicating initiation of apoptosis and autophagy. A rapid and persistent increase in galectin-3, a regulator of epithelial cell apoptosis, was also observed. Following ozone exposure (3-24 h), increased expression of cyclooxygenase-2, inducible nitric oxide synthase, and arginase-1 was noted in bronchiolar epithelium. Ozone-induced injury and oxidative stress in bronchiolar epithelium were linked to methacholine-induced alterations in pulmonary mechanics. Thus, significant increases in lung resistance and elastance, along with decreases in lung compliance and end tidal volume, were observed at higher doses of methacholine. This indicates that ozone causes an increase in effective stiffness of the lung as a consequence of changes in the conducting airways. Collectively, these studies demonstrate that bronchiolar epithelium is highly susceptible to injury and oxidative stress induced by acute exposure to ozone; moreover, this is accompanied by altered lung functioning.

  3. Arabidopsis mutants lacking phenolic sunscreens exhibit enhanced ultraviolet-B injury and oxidative damage.

    PubMed Central

    Landry, L G; Chapple, C C; Last, R L

    1995-01-01

    We have assessed ultraviolet-B (UV-B)-induced injury in wild-type Arabidopsis thaliana and two mutants with altered aromatic secondary product biosynthesis. Arabidopsis mutants defective in the ability to synthesize UV-B-absorbing compounds (flavonoids in transparent testa 5 [tt5] and sinapate esters in ferulic acid hydroxylase 1 [fah1]) are more sensitive to UV-B than is the wild-type Landsberg erecta. Despite its ability to accumulate UV-absorptive flavonoid compounds, the ferulic acid hydroxylase mutant fah1 exhibits more physiological injury (growth inhibition and foliar lesions) than either wild type or tt5. The extreme UV-B sensitivity of fah1 demonstrates the importance of hydroxycinnamate esters as UV-B protectants. Consistent with the whole-plant response, the highest levels of lipid and protein oxidation products were seen in fah1. Ascorbate peroxidase enzyme activity was also increased in the leaves of UV-B-treated plants in a dose- and genotype-dependent manner. These results demonstrate that, in A. thaliana, hydroxycinnamates are more effective UV-B protectants than flavonoids. The data also indicate that A. thaliana responds to UV-B as an oxidative stress, and sunscreen compounds reduce the oxidative damage caused by UV-B. PMID:8539286

  4. Beneficial Effects of Concomitant Neuronal and Inducible Nitric Oxide Synthase Inhibition in Ovine Burn and Inhalation Injury

    PubMed Central

    Lange, Matthias; Hamahata, Atsumori; Enkhbaatar, Perenlei; Cox, Robert A.; Nakano, Yoshimitsu; Westphal, Martin; Traber, Lillian D.; Herndon, David N.; Traber, Daniel L.

    2013-01-01

    Different isoforms of nitric oxide synthase are critically involved in the development of pulmonary failure secondary to acute lung injury. Here we tested the hypothesis that simultaneous blockade of inducible and neuronal nitric oxide synthase effectively prevents the pulmonary lesions in an ovine model of acute respiratory distress syndrome (ARDS) induced by combined burn and smoke inhalation injury. Chronically instrumented sheep were allocated to a sham-injured group (n = 6), an injured and untreated group (n = 6), or an injured group treated with simultaneous infusion of selective inducible and neuronal nitric oxide synthase inhibitors (n = 5). The injury was induced by 48 breath of cotton smoke and a 3rd degree burn of 40% total body surface area. All sheep were mechanically ventilated and fluid resuscitated. The injury induced severe pulmonary dysfunction as indicated by decreases in PaO2/FiO2 ratio and increases in pulmonary shunt fraction, ventilatory pressures, lung lymph flow, and lung wet/dry weight ratio. The treatment fully prevented the elevations in lymph and plasma nitrate/nitrite levels, pulmonary shunting, ventilatory pressures, lung lymph flow, and wet/dry weight ratio and significantly attenuated the decline in PaO2/FiO2 ratio. In conclusion, simultaneous blockade of inducible and neuronal nitric oxide synthase exerts beneficial pulmonary effects in an ovine model of ARDS secondary to combined burn and smoke inhalation injury. This novel treatment strategy may represent a useful therapeutic adjunct for patients with these injuries. PMID:21263377

  5. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide.

    PubMed Central

    Beckman, J S; Beckman, T W; Chen, J; Marshall, P A; Freeman, B A

    1990-01-01

    Superoxide dismutase reduces injury in many disease processes, implicating superoxide anion radical (O2-.) as a toxic species in vivo. A critical target of superoxide may be nitric oxide (NO.) produced by endothelium, macrophages, neutrophils, and brain synaptosomes. Superoxide and NO. are known to rapidly react to form the stable peroxynitrite anion (ONOO-). We have shown that peroxynitrite has a pKa of 7.49 +/- 0.06 at 37 degrees C and rapidly decomposes once protonated with a half-life of 1.9 sec at pH 7.4. Peroxynitrite decomposition generates a strong oxidant with reactivity similar to hydroxyl radical, as assessed by the oxidation of deoxyribose or dimethyl sulfoxide. Product yields indicative of hydroxyl radical were 5.1 +/- 0.1% and 24.3 +/- 1.0%, respectively, of added peroxynitrite. Product formation was not affected by the metal chelator diethyltriaminepentaacetic acid, suggesting that iron was not required to catalyze oxidation. In contrast, desferrioxamine was a potent, competitive inhibitor of peroxynitrite-initiated oxidation because of a direct reaction between desferrioxamine and peroxynitrite rather than by iron chelation. We propose that superoxide dismutase may protect vascular tissue stimulated to produce superoxide and NO. under pathological conditions by preventing the formation of peroxynitrite. PMID:2154753

  6. Involvement of Oxidative Stress and Inflammation in Liver Injury Caused by Perfluorooctanoic Acid Exposure in Mice

    PubMed Central

    Yang, Bei; Zou, Weiying; Hu, Zhenzhen; Liu, Fangming; Zhou, Ling; Yang, Shulong; Kuang, Haibin; Wu, Lei; Wei, Jie; Wang, Jinglei; Zou, Ting; Zhang, Dalei

    2014-01-01

    Perfluorooctanoic acid (PFOA) is widely present in the environment and has been reported to induce hepatic toxicity in animals and humans. In this study, mice were orally administered different concentrations of PFOA (2.5, 5, or 10 mg/kg/day). Histological examination showed that the exposure to PFOA for 14 consecutive days led to serious hepatocellular injury and obvious inflammatory cell infiltration. In addition, malondialdehyde formation and hydrogen peroxide generation, indicators of oxidative stress, were significantly induced by PFOA treatment in the liver of mice. Furthermore, hepatic levels of interleukin-6, cyclooxygenase-2, and C-reactive protein, markers of inflammatory response, were markedly increased by exposure to PFOA in mice. These results demonstrated that PFOA-induced hepatic toxicity may be involved in oxidative stress and inflammatory response in mice. PMID:24724082

  7. Activation of glutathione peroxidase via Nrf1 mediates genistein's protection against oxidative endothelial cell injury

    SciTech Connect

    Hernandez-Montes, Eva; Pollard, Susan E.; Vauzour, David; Jofre-Montseny, Laia; Rota, Cristina; Rimbach, Gerald; Weinberg, Peter D.; Spencer, Jeremy P.E. . E-mail: j.p.e.spencer@reading.ac.uk

    2006-08-04

    Cellular actions of isoflavones may mediate the beneficial health effects associated with high soy consumption. We have investigated protection by genistein and daidzein against oxidative stress-induced endothelial injury. Genistein but not daidzein protected endothelial cells from damage induced by oxidative stress. This protection was accompanied by decreases in intracellular glutathione levels that could be explained by the generation of glutathionyl conjugates of the oxidised genistein metabolite, 5,7,3',4'-tetrahydroxyisoflavone. Both isoflavones evoked increased protein expression of {gamma}-glutamylcysteine synthetase-heavy subunit ({gamma}-GCS-HS) and increased cytosolic accumulation and nuclear translocation of Nrf2. However, only genistein led to increases in the cytosolic accumulation and nuclear translocation of Nrf1 and the increased expression of and activity of glutathione peroxidase. These results suggest that genistein-induced protective effects depend primarily on the activation of glutathione peroxidase mediated by Nrf1 activation, and not on Nrf2 activation or increases in glutathione synthesis.

  8. Acute kidney injury mediated by oxidative stress in Egyptian horses with exertional rhabdomyolysis.

    PubMed

    el-Ashker, Maged R

    2011-06-01

    The present study was carried out to evaluate the role of oxidative stress in the pathophysiologic process of acute renal failure associated with exertional rhabdomyolysis (ER) in Egyptian horses. ER was tentatively diagnosed in 31 Baladi horses based on case history, physical examination findings and confirmed by elevation of plasma creatine kinase (CK) and urine myoglobin concentrations. According to severity of the condition, the diseased horses were categorized into two main groups; the first group included 18 horses with minimal clinical signs and plasma CK <60 000 IU/L; whereas, the second group included 13 horses with overt clinical signs and plasma CK >100 000 IU/L). It was found that plasma creatol (CTL) was positively correlated (p < 0.01) with plasma malondialdehyde (MDA) (r = 0.775), nitric oxide (NO) (r = 0.768), methyguanididne (MG) (r = 0.995), CK (r = 0.768), urine glucose (r = 0.778), urine protein (r = 0.767), renal failure index (RFI) (r = 0.814) and urine sodium (r = 0.799) and negatively correlated (p < 0.01) with total antioxidant capacity (TAC) (r = -0.795), superoxide dismutase (SOD) (r = -0.815), glutathione peroxidase (GSH-Px) (r = -0.675), Vitamin C (r = -0.830), urine creatinine (r = -0.800), urine/plasma creatinine ratio (r = -0.827) and urine/plasma urea ratio (r = -0.807). The correlation between these biochemical variables might suggest a possible role of oxidative stress in renal injury associated with severe rhabdomyolysis in horses. It is suggested that exaggeration of oxidative stress associated with increased muscle membrane leakage plays a key role in acute kidney injury in Baladi horses with severe rhabdomyolysis.

  9. What are the progesterone-induced changes of the outcome and the serum markers of injury, oxidant activity and inflammation in diffuse axonal injury patients?

    PubMed

    Mofid, Behshad; Soltani, Zahra; Khaksari, Mohammad; Shahrokhi, Nader; Nakhaee, Nouzar; Karamouzian, Saeed; Ahmadinejad, Mehdi; Maiel, Masoud; Khazaeli, Payam

    2016-03-01

    To permit appropriate targeted therapy, the present clinical study was aimed to investigate the effects of progesterone on the outcome and the serum markers of injury, oxidant activity and inflammation in diffuse axonal injury (DAI). Forty-eight male DAI patients were divided into two groups (control and progesterone). Progesterone group received progesterone in dose of 1mg/kg per 12h for five days. The outcome was investigated using Extended Glasgow Outcome Scale (GOS-E) and functional independence measure (FIM). The markers of inflammation [interleukin-1β (IL-1β), IL-6, transforming growth factor-β1 (TGF-β1)], injury (brain protein of S-100B), and oxidant activity [malondialdehyde (MDA)] were evaluated in the serum of the patients. Higher GOS-E and FIM scores were observed in progesterone group at the six-month follow-up (P<0.05 and P<0.01, respectively). Meanwhile, a reduction in the serum levels of IL-1β, MDA and S-100B was noticed in progesterone group 24h after injury (P<0.05, P<0.001 and P<0.05, respectively), and there was an increase in serum levels of IL-6 and TGF-β1 (P<0.01 and P<0.05, respectively). Also, lower levels of MDA and S-100B, and higher levels of TGF-β1 were observed in progesterone group six days after injury (P<0.05). According to these findings, progesterone may improve the outcome in DAI patients probably through modulation in the levels of cytokines, and reduction in the injury and oxidant activity.

  10. Biocompatibility of reduced graphene oxide nanoscaffolds following acute spinal cord injury in rats

    PubMed Central

    Palejwala, Ali H.; Fridley, Jared S.; Mata, Javier A.; Samuel, Errol L. G.; Luerssen, Thomas G.; Perlaky, Laszlo; Kent, Thomas A.; Tour, James M.; Jea, Andrew

    2016-01-01

    Background: Graphene has unique electrical, physical, and chemical properties that may have great potential as a bioscaffold for neuronal regeneration after spinal cord injury. These nanoscaffolds have previously been shown to be biocompatible in vitro; in the present study, we wished to evaluate its biocompatibility in an in vivo spinal cord injury model. Methods: Graphene nanoscaffolds were prepared by the mild chemical reduction of graphene oxide. Twenty Wistar rats (19 male and 1 female) underwent hemispinal cord transection at approximately the T2 level. To bridge the lesion, graphene nanoscaffolds with a hydrogel were implanted immediately after spinal cord transection. Control animals were treated with hydrogel matrix alone. Histologic evaluation was performed 3 months after the spinal cord transection to assess in vivo biocompatibility of graphene and to measure the ingrowth of tissue elements adjacent to the graphene nanoscaffold. Results: The graphene nanoscaffolds adhered well to the spinal cord tissue. There was no area of pseudocyst around the scaffolds suggestive of cytotoxicity. Instead, histological evaluation showed an ingrowth of connective tissue elements, blood vessels, neurofilaments, and Schwann cells around the graphene nanoscaffolds. Conclusions: Graphene is a nanomaterial that is biocompatible with neurons and may have significant biomedical application. It may provide a scaffold for the ingrowth of regenerating axons after spinal cord injury. PMID:27625885

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

    PubMed Central

    Zhao, Dajun

    2017-01-01

    Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress. mTOR signaling presents both cardioprotective and cardiotoxic effects on the diabetic heart, which interplays with oxidative stress directly or indirectly. Antihyperglycemic agent metformin and newly found free radicals scavengers, Sirt1 and CTRP9, may serve as promising pharmacological therapeutic targets. In this review, we will focus on the role of oxidative stress and mTOR signaling in the pathophysiology of MI/R injury in diabetes and discuss potential mechanisms and their interactions in an effort to provide some evidence for cardiometabolic targeted therapies for ischemic heart disease (IHD). PMID:28298952

  12. Nitrate/Nitrite as Critical Mediators to Limit Oxidative Injury and Inflammation

    PubMed Central

    Waltz, Paul; Escobar, Daniel; Botero, Ana Maria

    2015-01-01

    Abstract Significance: Nitric oxide (NO) is a critical signaling molecule marked by complex chemistry and varied biological responses depending on the context of the redox environment. In the setting of inflammation, NO can not only contribute to tissue injury and be causative of oxidative damage but can also signal as an adaptive molecule to limit inflammatory signaling in multiple cell types and tissues. Recent Advances: An advance in our understanding of NO biology was the recognition of the nitrate-nitrite-NO axis, whereby nitrate (predominantly from dietary sources) could be converted to nitrite and nitrite could be reduced to NO. Critical Issues: Intriguingly, the recognition of multiple enzymes that serve as nitrite reductases in the setting of hypoxia or ischemia established the concept of nitrite as a circulating endocrine reservoir of NO, with the selective release of NO at sites that were primed for this reaction. This review highlights the anti-inflammatory roles of nitrite in numerous clinical conditions, including ischemia/reperfusion, transplant, cardiac arrest, and vascular injury, and in gastrointestinal inflammation. Future Directions: These preclinical and clinical investigations set up further clinical trials and studies that elucidate the endogenous role this pathway plays in protection against inflammatory signaling. Antioxid. Redox Signal. 23, 328–339. PMID:26140517

  13. Pyrrolizidine alkaloid clivorine induced oxidative injury on primary cultured rat hepatocytes.

    PubMed

    Ji, LiLi; Liu, TianYu; Wang, ZhengTao

    2010-04-01

    Clivorine is an otonecine-type hepatotoxic pyrrolizidine alkaloid (HPAs), to which humans are exposed when consuming herbs containing such components. In the present study, we investigated clivorine-induced oxidative stress injury on primary cultured rat hepatocytes. Rat hepatocytes were treated with various concentrations of clivorine (1-100 microM) for 48 hours, and then cell viability was detected by 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, while lipid peroxidation (LPO) level, glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD) activities were determined to evaluate the oxidative injury. The results of MTT assay showed that clivorine decreased cell viability in a concentration-dependent manner. Clivorine also increased LPO amounts in rat hepatocytes at the concentrations of 50 microM and 100 microM. Further results showed that clivorine decreased GPx, GST and GR activities, which are all reduced glutathione (GSH)-related antioxidant enzymes. CAT and SOD are both important antioxidant enzymes, and the results showed that clivorine increased CAT activity at the low concentration of 5 muM and decreased cellular SOD activity at all concentrations. Taken together, our results demonstrated that clivorine induced toxicity on primary cultured rat hepatocytes by causing the damage on cellular redox balance.

  14. Binge ethanol exposure causes endoplasmic reticulum stress, oxidative stress and tissue injury in the pancreas

    PubMed Central

    Ren, Zhenhua; Wang, Xin; Xu, Mei; Yang, Fanmuyi; Frank, Jacqueline A.; Ke, Zun-ji; Luo, Jia

    2016-01-01

    Alcohol abuse is associated with both acute and chronic pancreatitis. Repeated episodes of acute pancreatitis or pancreatic injury may result in chronic pancreatitis. We investigated ethanol-induced pancreatic injury using a mouse model of binge ethanol exposure. Male C57BL/6 mice were exposed to ethanol intragastrically (5 g/kg, 25% ethanol w/v) daily for 10 days. Binge ethanol exposure caused pathological changes in pancreas demonstrated by tissue edema, acinar atrophy and moderate fibrosis. Ethanol caused both apoptotic and necrotic cell death which was demonstrated by the increase in active caspase-3, caspase-8, cleaved PARP, cleaved CK-18 and the secretion of high mobility group protein B1 (HMGB1). Ethanol altered the function of the pancreas which was indicated by altered levels of alpha-amylase, glucose and insulin. Ethanol exposure stimulated cell proliferation in the acini, suggesting an acinar regeneration. Ethanol caused pancreatic inflammation which was indicated by the induction of TNF-alpha, IL-1beta, IL-6, MCP-1 and CCR2, and the increase of CD68 positive macrophages in the pancreas. Ethanol-induced endoplasmic reticulum stress was demonstrated by a significant increase in ATF6, CHOP, and the phosphorylation of PERK and eiF-2alpha. In addition, ethanol increased protein oxidation, lipid peroxidation and the expression of iNOS, indicating oxidative stress. Therefore, this paradigm of binge ethanol exposure caused a spectrum of tissue injury and cellular stress to the pancreas, offering a good model to study alcoholic pancreatitis. PMID:27527870

  15. Endothelial Nitric Oxide Synthase Deficient Mice Are Protected from Lipopolysaccharide Induced Acute Lung Injury

    PubMed Central

    Gross, Christine M.; Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh; Ham III, P. Benson; Meadows, Mary Louise; Cherian-Shaw, Mary; Kangath, Archana; Sridhar, Supriya; Lucas, Rudolf; Black, Stephen M.

    2015-01-01

    Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/-mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury. PMID:25786132

  16. Targeted Nitric Oxide Delivery by Supramolecular Nanofibers for the Prevention of Restenosis After Arterial Injury

    PubMed Central

    Bahnson, Edward S.M.; Kassam, Hussein A.; Moyer, Tyson J.; Jiang, Wulin; Morgan, Courtney E.; Vercammen, Janet M.; Jiang, Qun; Flynn, Megan E.; Stupp, Samuel I.

    2016-01-01

    Abstract Aims: Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. We sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. Results: Structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. Innovation: This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. Conclusion: We successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases. Antioxid. Redox Signal. 27, 401–418. PMID:26593400

  17. Targeted nitric oxide delivery by supramolecular nanofibers for the prevention of restenosis after arterial injury

    SciTech Connect

    Bahnson, Edward S. M.; Kassam, Hussein A.; Moyer, Tyson J.; Jiang, Wulin; Morgan, Courtney E.; Vercammen, Janet M.; Jiang, Qun; Flynn, Megan E.; Stupp, Samuel I.; Kibbe, Melina R.

    2016-01-21

    Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. Here we sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. As a result, structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. In conclusion, we successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases

  18. Targeted nitric oxide delivery by supramolecular nanofibers for the prevention of restenosis after arterial injury

    DOE PAGES

    Bahnson, Edward S. M.; Kassam, Hussein A.; Moyer, Tyson J.; ...

    2016-01-21

    Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. Here we sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. As a result, structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescentmore » detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. In conclusion, we successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases« less

  19. A link between hyperbilirubinemia, oxidative stress and injury to neocortical synaptosomes.

    PubMed

    Brito, Maria Alexandra; Brites, Dora; Butterfield, D Allan

    2004-11-05

    Cytotoxicity by unconjugated bilirubin involves disturbances of membrane structure, excitotoxicity and cell death. These events were reported to trigger elevated free radicals production and impairment of calcium homeostasis, and to result in loss of cell membrane integrity. Therefore, this study was designed to investigate whether interaction of clinically relevant concentrations of free unconjugated bilirubin with synaptosomal membrane vesicles could be linked to oxidative stress, cytosolic calcium accumulation and perturbation of membrane function. Synaptosomal vesicles were prepared from gerbil cortical brain tissue and incubated with purified bilirubin (oxidation were evaluated by immunocytochemistry and phosphatidylserine exposure by annexin V binding. Levels of reduced and oxidized glutathione (GSH and GSSG, respectively), as well as activities of Mg(2+)-ATPase aminophospholipid translocase (flippase) and Na(+),K(+)-ATPase, were also measured. Our results showed that bilirubin induced oxidative stress, due to a rise in lipid (>or=10%, P<0.05) and protein oxidation (>or=20%, P<0.01), ROS content (approximately 17%, P<0.01), and a decrease in GSH/GSSG ratio (>30%, P<0.01). In addition, synaptosomes exposed to bilirubin exhibited increased externalization of phosphatidylserine (approximately 10%, P<0.05), together with decreased flippase and NA(+),K(+)-ATPase (>or=15%, P<0.05) activities, events that were accompanied by enhanced intracellular calcium levels ( approximately 20%, P<0.01). The data obtained point out that interaction of unconjugated bilirubin with synaptosomal membrane vesicles leads to oxidative injury, loss of membrane asymmetry and functionality, and calcium intrusion, thus potentially contributing to the pathogenesis of

  20. Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic–Ischemic Brain Injury

    PubMed Central

    Ten, Vadim S.; Yao, Jun; Ratner, Veniamin; Sosunov, Sergey; Fraser, Deborah A.; Botto, Marina; Baalasubramanian, Sivasankar; Morgan, B. Paul; Silverstein, Samuel; Stark, Raymond; Polin, Richard; Vannucci, Susan J.; Pinsky, David; Starkov, Anatoly A.

    2010-01-01

    Hypoxic–ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia–ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia–ischemia. Only C1q−/− mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q−/− brain mitochondria and preserved activity of the respiratory chain. Compared with C1q+/+ neurons, cortical C1q−/− neurons exhibited resistance to oxygen– glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q−/− neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation. PMID:20147536

  1. Oxidative lipidomics of hyperoxic acute lung injury: mass spectrometric characterization of cardiolipin and phosphatidylserine peroxidation

    PubMed Central

    Tyurin, Vladimir A.; Kaynar, A. Murat; Kapralova, Valentyna I.; Wasserloos, Karla; Li, Jin; Mosher, Mackenzie; Wright, Lindsay; Wipf, Peter; Watkins, Simon; Pitt, Bruce R.; Kagan, Valerian E.

    2010-01-01

    Reactive oxygen species have been shown to play a significant role in hyperoxia-induced acute lung injury, in part, by inducing apoptosis of pulmonary endothelium. However, the signaling roles of phospholipid oxidation products in pulmonary endothelial apoptosis have not been studied. Using an oxidative lipidomics approach, we identified individual molecular species of phospholipids involved in the apoptosis-associated peroxidation process in a hyperoxic lung. C57BL/6 mice were killed 72 h after exposure to hyperoxia (100% oxygen). We found that hyperoxia-induced apoptosis (documented by activation of caspase-3 and -7 and histochemical terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining of pulmonary endothelium) was accompanied by nonrandom oxidation of pulmonary lipids. Two anionic phospholipids, mitochondria-specific cardiolipin (CL) and extramitochondrial phosphatidylserine (PS), were the two major oxidized phospholipids in hyperoxic lung. Using electrospray ionization mass spectrometry, we identified several oxygenation products in CL and PS. Quantitative assessments revealed a significant decrease of CL and PS molecular species containing C18:2, C20:4, C22:5, and C22:6 fatty acids. Similarly, exposure of mouse pulmonary endothelial cells (MLEC) to hyperoxia (95% oxygen; 72 h) resulted in activation of caspase-3 and -7 and significantly decreased the content of CL molecular species containing C18:2 and C20:4 as well as PS molecular species containing C22:5 and C22:6. Oxygenated molecular species were found in the same two anionic phospholipids, CL and PS, in MLEC exposed to hyperoxia. Treatment of MLEC with a mitochondria-targeted radical scavenger, a conjugate of hemi-gramicidin S with nitroxide, XJB-5-131, resulted in significantly lower oxidation of both CL and PS and a decrease in hyperoxia-induced changes in caspase-3 and -7 activation. We speculate that cytochrome c driven oxidation of CL and PS is associated with the signaling

  2. Expression and activity of inducible nitric oxide synthase and endothelial nitric oxide synthase correlate with ethanol-induced liver injury

    PubMed Central

    Yuan, Guang-Jin; Zhou, Xiao-Rong; Gong, Zuo-Jiong; Zhang, Pin; Sun, Xiao-Mei; Zheng, Shi-Hua

    2006-01-01

    AIM: To study the expression and activity of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in rats with ethanol-induced liver injury and their relation with liver damage, activation of nuclear factor-κB (NF-κB) and tumor necrosis factor-α (TNF-α) expression in the liver. METHODS: Female Sprague-Dawley rats were given fish oil (0.5 mL) along with ethanol or isocaloric dextrose daily via gastrogavage for 4 or 6 wk. Liver injury was assessed using serum alanine aminotransferase (ALT) activity and pathological analysis. Liver malondialdehyde (MDA), nitric oxide contents, iNOS and eNOS activity were determined. NF-κB p65,iNOS, eNOS and TNF-α protein or mRNA expression in the liver were detected by immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Chronic ethanol gavage for 4 wk caused steatosis, inflammation and necrosis in the liver, and elevated serum ALT activity. Prolonged ethanol administration (6 wk) enhanced the liver damage. These responses were accompanied with increased lipid peroxidation, NO contents, iNOS activity and reduced eNOS activity. NF-κB p65, iNOS and TNF-α protein or mRNA expression were markedly induced after chronic ethanol gavage, whereas eNOS mRNA expression remained unchanged. The enhanced iNOS activity and expression were positively correlated with the liver damage, especially the necro-inflammation, activation of NF-κB, and TNF-α mRNA expression. CONCLUSION: iNOS expression and activity are induced in the liver after chronic ethanol exposure in rats, which are correlated with the liver damage, especially the necro-inflammation, activation of NF-κB and TNF-α expression. eNOS activity is reduced, but its mRNA expression is not affected. PMID:16688828

  3. Multifaceted role of nitric oxide in an in vitro mouse neuronal injury model: transcriptomic profiling defines the temporal recruitment of death signalling cascades

    PubMed Central

    Peng, Zhao Feng; Chen, Minghui Jessica; Manikandan, Jayapal; Melendez, Alirio J; Shui, Guanghou; Russo-Marie, Françoise; Whiteman, Matthew; Beart, Philip M; Moore, Philip K; Cheung, Nam Sang

    2012-01-01

    Abstract Nitric oxide is implicated in the pathogenesis of various neuropathologies characterized by oxidative stress. Although nitric oxide has been reported to be involved in the exacerbation of oxidative stress observed in several neuropathologies, existent data fail to provide a holistic description of how nitrergic pathobiology elicits neuronal injury. Here we provide a comprehensive description of mechanisms contributing to nitric oxide induced neuronal injury by global transcriptomic profiling. Microarray analyses were undertaken on RNA from murine primary cortical neurons treated with the nitric oxide generator DETA-NONOate (NOC-18, 0.5 mM) for 8–24 hrs. Biological pathway analysis focused upon 3672 gene probes which demonstrated at least a ±1.5-fold expression in a minimum of one out of three time-points and passed statistical analysis (one-way anova, P < 0.05). Numerous enriched processes potentially determining nitric oxide mediated neuronal injury were identified from the transcriptomic profile: cell death, developmental growth and survival, cell cycle, calcium ion homeostasis, endoplasmic reticulum stress, oxidative stress, mitochondrial homeostasis, ubiquitin-mediated proteolysis, and GSH and nitric oxide metabolism. Our detailed time-course study of nitric oxide induced neuronal injury allowed us to provide the first time a holistic description of the temporal sequence of cellular events contributing to nitrergic injury. These data form a foundation for the development of screening platforms and define targets for intervention in nitric oxide neuropathologies where nitric oxide mediated injury is causative. PMID:21352476

  4. Hemodynamic and oxidative mechanisms of tourniquet-induced muscle injury: near-infrared spectroscopy for the orthopedics setting

    NASA Astrophysics Data System (ADS)

    Shadgan, Babak; Reid, W. Darlene; Harris, R. Luke; Jafari, Siavash; Powers, Scott K.; O'Brien, Peter J.

    2012-08-01

    During orthopedic procedures, the tourniquets used to maintain bloodless surgical fields cause ischemia and then reperfusion (I/R), leading to oxidative muscle injury. Established methods exist neither for monitoring orthopedic I/R nor for predicting the extent of tourniquet-associated oxidative injury. To develop a predictive model for tourniquet-associated oxidative muscle injury, this study combined real-time near-infrared spectroscopy (NIRS) monitoring of I/R with Western blotting (WB) for oxidized proteins. We hypothesized strong correlations between NIRS-derived I/R indices and muscle protein oxidation. In 17 patients undergoing ankle fracture repair, a thigh tourniquet was inflated on the injured limb (300 mmHg). Using a continuous-wave (CW) NIRS setup, oxygenated (O2Hb), deoxygenated (HHb), and total (tHb) hemoglobin were monitored bilaterally (tourniquet versus control) in leg muscles. Leg muscle biopsies were collected unilaterally (tourniquet side) immediately after tourniquet inflation (pre) and before deflation (post). Average ischemia duration was 43.2±14.6 min. In post-compared to pre-biopsies, muscle protein oxidation (quantified using WB) increased 172.3%±145.7% (P<0.0005). Changes in O2Hb and tHb were negatively correlated with protein oxidation (respectively: P=0.040, R2=0.25 and P=0.003, R2=0.58). Reoxygenation rate was positively correlated with protein oxidation (P=0.041, R2=0.25). These data indicate that using CW NIRS, it is possible to predict orthopedic tourniquet-associated muscle oxidative injury noninvasively.

  5. Carvacrol and Pomegranate Extract in Treating Methotrexate-Induced Lung Oxidative Injury in Rats

    PubMed Central

    Şen, Hadice Selimoğlu; Şen, Velat; Bozkurt, Mehtap; Türkçü, Gül; Güzel, Abdulmenap; Sezgi, Cengizhan; Abakay, Özlem; Kaplan, Ibrahim

    2014-01-01

    Background This study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats. Material/Methods A total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples. Results Serum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II. Conclusions MTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE. PMID:25326861

  6. Protective effects of erdosteine on rotenone-induced oxidant injury in liver tissue.

    PubMed

    Terzi, Alpaslan; Iraz, Mustafa; Sahin, Semsettin; Ilhan, Atilla; Idiz, Nuri; Fadillioglu, Ersin

    2004-09-01

    Rotenone, an insecticide of botanical origin, causes toxicity through inhibition of complex I of the respiratory chain in mitochondria. This study was undertaken to determine whether rotenone-induced liver oxidant injury is prevented by erdosteine, a mucolytic agent showing antioxidant properties. There were four groups of Male Wistar Albino rats: group one was untreated as control; the other groups were treated with erdosteine (50 mg/kg per day, orally), rotenone (2.5 mg/mL once and 1 mL/kg per day for 60 days, i.p.) or rotenone plus erdosteine, respectively. Rotenone treatment without erdosteine increased xanthine oxidase (XO) enzyme activity and also increased lipid peroxidation in liver tissue (P < 0.05). The rats treated with rotenone plus erdosteine produced a significant decrease in lipid peroxidation and XO activities in comparison with rotenone group (P < 0.05). Erdosteine treatment with rotenone led to an increase in catalase (CAT) and superoxide dismutase (SOD) activities in comparison with the rotenone group (P < 0.05). There was no significant difference in nitric oxide (NO) level between groups. There were negative correlations between CAT activity and malondialdehyde (MDA) level (r = -0.934, P < 0.05) with between CAT and SOD activities (r = -0.714, P < 0.05), and a positive correlation between SOD activity and MDA level (r = 0.828, P < 0.05) in rotenone group. In the rotenone plus erdosteine group, there was a negative correlation between XO activity and NO level in liver tissue (r = -0.833, P < 0.05). In the light of these findings, erdosteine may be a protective agent for rotenone-induced liver oxidative injury in rats.

  7. Corilagin prevents tert-butyl hydroperoxide-induced oxidative stress injury in cultured N9 murine microglia cells.

    PubMed

    Chen, Yiyan; Chen, Chonghong

    2011-08-01

    Oxidative stress plays an important role in neurodegenerative diseases. Reactive oxygen species (ROS)-mediated stress in microglia in vivo could result in cellular injuries and preferentially induces neuronal injury. Corilagin, a novel member of the phenolic tannin family, has been shown to possess antioxidant properties. In this study, we investigated the effects of corilagin on tert-butyl hydroperoxide (TBHP)-induced injury in cultured N9 murine microglial cells and the underlying mechanisms by a methyltetrazolium assay and oxidative damage assay. We found that exposure of N9 cells to TBHP induced cytotoxicity as demonstrated by cell shrinkage, loss of cell viability, increased lactate dehydrogenase (LDH) leakage, and increased intracellular levels of ROS. By contrast, TBHP reduced both superoxide dismutase activity and total cell anti-oxidation capacity, but glutathione was not reduced. Moreover, TBHP treatment was associated with the loss of mitochondrial membrane potential, and it induced cell apoptosis through the mitochondrial-mediated pathway involving the down-regulation of Bcl-2 expression and up-regulation of the Bax/Bcl-2 ratio. Interestingly, pre-treatment with corilagin reversed these reactions. These data collectively indicated that corilagin could attenuate TBHP-induced oxidative stress injury in microglial cells, and its protective effects may be ascribed to its antioxidant and antiapoptotic properties. Our findings suggest that corilagin should be a potential candidate for the treatment of oxidative stress-induced neurodegenerative diseases.

  8. The Beneficial Effect of Ginsenoside Rg1 on Schwann Cells Subjected to Hydrogen Peroxide Induced Oxidative Injury

    PubMed Central

    Ma, Junxiong; Liu, Jun; Wang, Qi; Yu, Hailong; Chen, Yu; Xiang, Liangbi

    2013-01-01

    Ginsenoside Rg1 (GRg1) has been considered to have therapeutic potential in promoting peripheral nerve regeneration and functional recovery after sciatic nerve injuries. However, the mechanism underlying the beneficial effect of GRg1 on peripheral nerve regeneration is currently unclear. The possible effect of GRg1 on Schwann cells (SCs), which were subjected to oxidative injury after nerve injury, might contribute to the beneficial effect of GRg1 on nerve regeneration. The present study was designed to investigate the potential beneficial effect of GRg1 on SCs exposed to oxidative injury. The oxidative injury to SCs was induced by hydrogen peroxide. The effect of GRg1 (50 μM) on SCs exposed to oxidative injury was measured by the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) in SCs. The cell number and cell viability of SCs were evaluated through fluorescence observation and MTT assay. The apoptosis of SCs induced by oxidative injury was evaluated by an apoptosis assay. The expression and secretion of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were evaluated using RT-PCR, Western blotting, and an ELISA method. We found that GRg1 significantly up-regulated the level of SOD, GSH and CAT, and decreased the level of MDA in SCs treated with hydrogen peroxide. In addition, GRg1 has been shown to be able to inhibit the proapoptotic effect of hydrogen peroxide, as well as inhibit the detrimental effect of hydrogen peroxide on cell number and cell viability. Furthermore, GRg1 also increased the mRNA levels, protein levels and secretion of NGF and BDNF in SCs after incubation of hydrogen peroxide. Further study showed that preincubation with H89 (a PKA inhibitor) significantly inhibited the effects induced by hydrogen peroxide, indicating that the PKA pathway might be involved in the antioxidant effect and neurotrophic factors (NTFs) promoting effect of GRg1. In addition, a short-term in vivo

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

    SciTech Connect

    Malaviya, Rama; Venosa, Alessandro; Hall, LeRoy; Gow, Andrew J.; Sinko, Patrick J.; Laskin, Jeffrey D.; Laskin, Debra L.

    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

  10. Protective Effect of Quercetin on the Development of Preimplantation Mouse Embryos against Hydrogen Peroxide-Induced Oxidative Injury

    PubMed Central

    Zhang, Qin-hua; Yan, Zhi-guang; Liang, Hong-xing; Chai, Wei-ran; Yan, Zheng; Kuang, Yan-ping; Qi, Cong

    2014-01-01

    Quercetin, a plant-derived flavonoid in Chinese herbs, fruits and wine, displays antioxidant properties in many pathological processes associated with oxidative stress. However, the effect of quercetin on the development of preimplantation embryos under oxidative stress is unclear. The present study sought to determine the protective effect and underlying mechanism of action of quercetin against hydrogen peroxide (H2O2)-induced oxidative injury in mouse zygotes. H2O2 treatment impaired the development of mouse zygotes in vitro, decreasing the rates of blastocyst formation and hatched, and increasing the fragmentation, apoptosis and retardation in blastocysts. Quercetin strongly protected zygotes from H2O2-induced oxidative injury by decreasing the reactive oxygen species level, maintaining mitochondrial function and modulating total antioxidant capability, the activity of the enzymatic antioxidants, including glutathione peroxidase and catalase activity to keep the cellular redox environment. Additionally, quercetin had no effect on the level of glutathione, the main non-enzymatic antioxidant in embryos. PMID:24586844

  11. p66Shc: A novel biomarker of tubular oxidative injury in patients with diabetic nephropathy

    PubMed Central

    Xu, Xiaoxuan; Zhu, Xuejing; Ma, Mingming; Han, Yachun; Hu, Chun; Yuan, Shuguang; Yang, Yuan; Xiao, Li; Liu, Fuyou; Kanwar, Yashpal S.; Sun, Lin

    2016-01-01

    Increased p66Shc expression has been associated with diabetic nephropathy (DN). However, whether p66Shc can serve as a potential biomarker for tubular oxidative injury in DN is unknown. We measured the expression of p66Shc in peripheral blood monocytes (PBMs) and renal biopsy tissues from DN patients and then analysed the relationship between p66Shc expression and the clinical characteristics of patients with DN. Patients were divided into 4 groups (class IIa, class IIb, class III and the control group). qPCR, Western blotting and immunohistochemistry were performed. The results showed that both p66Shc and p-p66Shc expression significantly increased in PBMs and kidney tissues of DN patients. Moreover, Spearman’s correlation and multiple regression analyses were carried out. A positive relationship between the p66Shc expression and oxidative stress was found. p66Shc and oxidative stress were significant predictors of the degree of tubular damage. In addition, p66Shc expression was positively correlated with the concentrations of β-NAG, UACR and 8-OHdG, low-density lipoprotein and blood glucose levels, and duration of diabetes in patients with DN from class IIa to class III. These data indicated that increased expression of p66Shc may serve as a therapeutic target and a novel biomarker of DN. PMID:27377870

  12. Two-photon dual imaging platform for in vivo monitoring cellular oxidative stress in liver injury.

    PubMed

    Wang, Haolu; Zhang, Run; Bridle, Kim R; Jayachandran, Aparna; Thomas, James A; Zhang, Wenzhu; Yuan, Jingli; Xu, Zhi Ping; Crawford, Darrell H G; Liang, Xiaowen; Liu, Xin; Roberts, Michael S

    2017-03-28

    Oxidative stress reflects an imbalance between reactive oxygen species (ROS) and antioxidants, which has been reported as an early unifying event in the development and progression of various diseases and as a direct and mechanistic indicator of treatment response. However, highly reactive and short-lived nature of ROS and antioxidant limited conventional detection agents, which are influenced by many interfering factors. Here, we present a two-photon sensing platform for in vivo dual imaging of oxidative stress at the single cell-level resolution. This sensing platform consists of three probes, which combine the turn-on fluorescent transition-metal complex with different specific responsive groups for glutathione (GSH), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). By combining fluorescence intensity imaging and fluorescence lifetime imaging, these probes totally remove any possibility of crosstalk from in vivo environmental or instrumental factors, and enable accurate localization and measurement of the changes in ROS and GSH within the liver. This precedes changes in conventional biochemical and histological assessments in two distinct experimental murine models of liver injury. The ability to monitor real-time cellular oxidative stress with dual-modality imaging has significant implications for high-accurate, spatially configured and quantitative assessment of metabolic status and drug response.

  13. Targeting Transporters: Promoting Blood-Brain Barrier Repair in Response to Oxidative Stress Injury

    PubMed Central

    Ronaldson, Patrick T.; Davis, Thomas P.

    2015-01-01

    The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely regulates the ability of endogenous and exogenous substances to accumulate within brain tissue. It possesses structural and biochemical features (i.e., tight junction and adherens junction protein complexes, influx and efflux transporters) that work in concert to control solute permeation. Oxidative stress, a critical component of several diseases including cerebral hypoxia/ischemia and peripheral inflammatory pain, can cause considerable injury to the BBB and lead to significant CNS pathology. This suggests a critical need for novel therapeutic approaches that can protect the BBB in diseases with an oxidative stress component. Recent studies have identified molecular targets (i.e., endogenous transporters, intracellular signaling systems) that can be exploited for optimization of endothelial drug delivery or for control of transport of endogenous substrates such as the antioxidant glutathione (GSH). In particular, targeting transporters offers a unique approach to protect BBB integrity by promoting repair of cell-cell interactions at the level of the brain microvascular endothelium. This review summarizes current knowledge in this area and emphasizes those targets that present considerable opportunity for providing BBB protection and/or promoting BBB repair in the setting of oxidative stress. PMID:25796436

  14. Pilose antler peptide protects osteoblasts from inflammatory and oxidative injury through EGF/EGFR signaling.

    PubMed

    Chunhui, Yang; Wenjun, Cai; Hui, Wen; Liquan, Sha; Changwei, Zhao; Tianzhu, Zhang; Wenhai, Zhao

    2017-02-16

    Epidermal growth factor (EGF)/EFG receptor (EGFR) signaling plays an important role in the osteoblastogenesis. The potential effects of pilose antler peptide (PAP) on osteoblast cell damages was investigated in our present study through EGF/EGFR signaling. In MC3T3-E1 osteoblastic cells, PAP treatment significantly inhibited the production of inflammatory cytokines by decreasing the levels of serum proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). PAP treatment also alleviated the oxidative responses as indicated by increased activities of catalase (SOD) and decreased levels of malondialdehyde (MDA). EGF inhibition, by siRNA knockdown, almost abolished PAP-induced osteoblast cytoprotection against inflammation and oxidant stress. Further, our results showed that PAP stimulated the nuclear erythroid factor 2-related factor 2 (Nrf2)2/heme oxygenase-1(HO-1) signaling, and inhibited the activation of uclear factor kappa B (NF-κB) pathway in MC3T3-E1 cells. On the other hand, EGF siRNA knockdown inhibited PAP-induced cytoprotection, which decreased the expression of Nrf-2, HO-1 and increased the level of p-NF-κBp65, p-IκBα in MC3T3-E1 cells. Thus, our research demonstrated that PAP protects osteoblasts from inflammatory and oxidative injury through EGF/EGFR signaling.

  15. Inhibition of cytoskeletal protein carbonylation may protect against oxidative damage in traumatic brain injury

    PubMed Central

    Zhang, Qiusheng; Zhang, Meng; Huang, Xianjian; Liu, Xiaojia; Li, Weiping

    2016-01-01

    Oxidative stress is the principal factor in traumatic brain injury (TBI) that initiates protracted neuronal dysfunction and remodeling. Cytoskeletal proteins are known to be carbonylated under oxidative stress; however, the complex molecular and cellular mechanisms of cytoskeletal protein carbonylation remain poorly understood. In the present study, the expression levels of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) were investigated in PC12 cells treated with H2O2. Western blot analysis was used to monitor the carbonylation levels of β-actin and β-tubulin. The results indicated that oxidative stress was increased in PC12 cells that were treated with H2O2 for 24 or 48 h. In addition, increased carbonylation levels of β-actin and β-tubulin were detected in H2O2-treated cells. However, these carbonylation levels were reduced by pretreatment with aminoguanidine, a type of reactive carbonyl species chelating agent, and a similar trend was observed following overexpression of proteasome β5 via transgenic technology. In conclusion, the present study results suggested that the development of TBI may cause carbonylation of cytoskeletal proteins, which would then undermine the stability of cytoskeletal proteins. Thus, the development of TBI may be improved via the inhibition of cytoskeletal protein carbonylation. PMID:28101189

  16. Two-photon dual imaging platform for in vivo monitoring cellular oxidative stress in liver injury

    PubMed Central

    Wang, Haolu; Zhang, Run; Bridle, Kim R.; Jayachandran, Aparna; Thomas, James A.; Zhang, Wenzhu; Yuan, Jingli; Xu, Zhi Ping; Crawford, Darrell H. G.; Liang, Xiaowen; Liu, Xin; Roberts, Michael S.

    2017-01-01

    Oxidative stress reflects an imbalance between reactive oxygen species (ROS) and antioxidants, which has been reported as an early unifying event in the development and progression of various diseases and as a direct and mechanistic indicator of treatment response. However, highly reactive and short-lived nature of ROS and antioxidant limited conventional detection agents, which are influenced by many interfering factors. Here, we present a two-photon sensing platform for in vivo dual imaging of oxidative stress at the single cell-level resolution. This sensing platform consists of three probes, which combine the turn-on fluorescent transition-metal complex with different specific responsive groups for glutathione (GSH), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). By combining fluorescence intensity imaging and fluorescence lifetime imaging, these probes totally remove any possibility of crosstalk from in vivo environmental or instrumental factors, and enable accurate localization and measurement of the changes in ROS and GSH within the liver. This precedes changes in conventional biochemical and histological assessments in two distinct experimental murine models of liver injury. The ability to monitor real-time cellular oxidative stress with dual-modality imaging has significant implications for high-accurate, spatially configured and quantitative assessment of metabolic status and drug response. PMID:28349954

  17. Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism.

    PubMed

    Fletcher, Marianne E; Boshier, Piers R; Wakabayashi, Kenji; Keun, Hector C; Smolenski, Ryszard T; Kirkham, Paul A; Adcock, Ian M; Barton, Paul J; Takata, Masao; Marczin, Nandor

    2015-06-15

    Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione-S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD(+)/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.

  18. C-type natriuretic peptide prevents kidney injury and attenuates oxidative and inflammatory responses in hemorrhagic shock.

    PubMed

    Chen, Gan; Song, Xiang; Yin, Yujing; Xia, Sha; Liu, Qingjun; You, Guoxing; Zhao, Lian; Zhou, Hong

    2017-02-01

    Oxidative stress induced by hemorrhagic shock (HS) initiates a systemic inflammatory response, which leads to subsequent kidney injury. This study assessed the efficacy of c-type natriuretic peptide (CNP) in attenuating kidney injury in a rat model of hemorrhagic shock and resuscitation (HS/R). Sodium pentobarbital-anesthetized adult male Wistar rats underwent HS induced by the withdrawal of blood to a mean arterial pressure of 30-35 mmHg for 50 min. Then, the animals received CNP (25 μg/kg) or vehicle (saline) intravenously, followed byresuscitation with 1.5 times the shed blood volume in the form of normal saline. Mean arterial pressure was measured throughout the experiment, and acid-base status, oxidative stress, inflammation, tissue injury and kidney function were evaluated after resuscitation. CNP infusion reduced the malondialdehyde content, lowered the myeloperoxidase activity and decreased the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the kidney. The histologic injury score and the plasma creatinine concentration were also significantly decreased after CNP treatment compared to the vehicle group. CNP treatment ameliorates oxidative stress, the inflammatory response, and consequently acute kidney injury after HS/R. Thus, CNP may represent a promising strategy to improve resuscitation for the treatment of HS and deserves further investigation.

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

    PubMed Central

    Wang, Liangrong; Shan, Yuanlu; Chen, Lei; Lin, Bi; Xiong, Xiangqing; Lin, Lina; Jin, Lida

    2016-01-01

    Objective(s): Neutrophils play an important role in ischemia/reperfusion (IR) induced skeletal muscle injury. Microtubules are required for neutrophil activation in response to various stimuli. This study aimed to investigate the effects of colchicine, a microtubule-disrupting agent, on skeletal muscle IR injury in a rat hindlimb ischemia model. Materials and Methods: Twenty-one Sprague-Dawley rats were randomly allocated into three groups IR group, colchicine treated-IR (CO) group and sham operation (SM) group. Rats of both the IR and CO groups were subjected to 3 hr of ischemia by clamping the right femoral artery followed by 2 hr of reperfusion. Colchicine (1 mg/kg) was administrated intraperitoneally prior to hindlimb ischemia in the CO group. After 2 hr of reperfusion, we measured superoxide dismutase (SOD) and myeloperoxidase (MPO) activities, and malondialdehyde (MDA), tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels in the muscle samples. Plasma creatinine kinase (CK) and lactate dehydrogenase (LDH) levels were measured. We also evaluated the histological damage score and wet/dry weight (W/D) ratio. Results: The histological damage score, W/D ratio, MPO activity, MDA, TNF-α and IL-1β levels in muscle tissues were significantly increased, SOD activity was decreased, and plasma CK and LDH levels were remarkably elevated in both the IR and CO groups compared to the SM group (P<0.05). Colchicine treatment significantly reduced muscle damage and edema, oxidative stress and levels of the inflammatory parameters in the CO group compared to the IR group (P<0.05). Conclusion: Colchicine attenuates IR-induced skeletal muscle injury in rats. PMID:27482349

  20. A protective effect of endomorphins on the oxidative injury of islet.

    PubMed

    Tian, L M; Liu, J; Sun, X L; Gao, C X; Fan, Y; Guo, Q

    2010-08-01

    The antioxidative capacity of endomorphins (EMs), endogenous μ-opioid receptor agonists, has been demonstrated by IN VIVO assays. In this study, we attempt to evaluate the effects of endomorphin 1 (EM1) and endomorphin 2 (EM2) on pancreatic islet injuries induced by streptozotocin (STZ), alloxan (ALX) and H(2)O(2), respectively. Wistar rats' islets were isolated and purified. The function of the islet cells, the insulin response to glucose stimulation was examined by insulin Radio Immuno Assay and the cell viability was measured by MTT assay. DNA fragments were performed to evaluate the apoptosis, while the cell cycle distribution was analyzed by PI staining flow cytometric analysis. Furthermore, the islet were treated with EM1, EM2 or ALX for 24 h, and the expression of p53 and p21 protein were determined by Western blot. The results showed that STZ, ALX, and H(2)O(2) displayed clear concentration-dependent inhibitory effects on the pancreatic islet cells. While EMs improved the viability of islet induced by STZ, ALX or H(2)O(2), and EMs enhanced insulin accumulation of the cell supernatant after ALX and STZ stimulation. Our data also showed both that EMs inhibited cell apoptosis and cell cycle G1 arrest induced by STZ and ALX through down-regulaing p53 and p21 expression. Taken together, these results demonstrate that EMs can protect islet cells from STZ, ALX and H(2)O(2) induced injuries. Our observations imply that the endomorphins may have protective effects on islet cells oxidative injury.

  1. Mitochondria are selective targets for the protective effects of heat shock against oxidative injury.

    PubMed Central

    Polla, B S; Kantengwa, S; François, D; Salvioli, S; Franceschi, C; Marsac, C; Cossarizza, A

    1996-01-01

    Heat shock (HS) proteins (HSPs) induce protection against a number of stresses distinct from HS, including reactive oxygen species. In the human premonocytic line U937, we investigated in whole cells the effects of preexposure to HS and exposure to hydrogen peroxide (H2O2) on mitochondrial membrane potential, mass, and ultrastructure. HS prevented H2O2-induced alterations in mitochondrial membrane potential and cristae formation while increasing expression of HSPs and the protein product of bcl-2. Protection correlated best with the expression of the 70-kDa HSP, hsp70. We propose that mitochondria represent a selective target for HS-mediated protection against oxidative injury. Images Fig. 3 PMID:8692837

  2. Polydatin Protects Bone Marrow Stem Cells against Oxidative Injury: Involvement of Nrf 2/ARE Pathways

    PubMed Central

    Chen, Meihui; Hou, Yu; Lin, Dingkun

    2016-01-01

    Polydatin, a glucoside of resveratrol, has been reported to possess potent antioxidative effects. In the present study, we aimed to investigate the effects of polydatin in bone marrow-derived mesenchymal stem cells (BMSCs) death caused by hydrogen peroxide (H2O2), imitating the microenvironment surrounding transplanted cells in the injured spinal cord in vitro. In our study, MTT results showed that polydatin effectively prevented the decrease of cell viability caused by H2O2. Hochest 33258, Annexin V-PI, and Western blot assay showed H2O2-induced apoptosis in BMSCs, which was attenuated by polydatin. Further studies indicated that polydatin significantly protects BMSCs against apoptosis due to its antioxidative effects and the regulation of Nrf 2/ARE pathway. Taken together, our results indicate that polydatin could be used in combination with BMSCs for the treatment of spinal cord injury by improving the cell survival and oxidative stress microenvironments. PMID:27022401

  3. Sesamin Ameliorates High-Fat Diet-Induced Dyslipidemia and Kidney Injury by Reducing Oxidative Stress.

    PubMed

    Zhang, Ruijuan; Yu, Yan; Deng, Jianjun; Zhang, Chao; Zhang, Jinghua; Cheng, Yue; Luo, Xiaoqin; Han, Bei; Yang, Haixia

    2016-05-09

    The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day). Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV) and α-smooth muscle actin (α-SMA) were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia.

  4. Sesamin Ameliorates High-Fat Diet–Induced Dyslipidemia and Kidney Injury by Reducing Oxidative Stress

    PubMed Central

    Zhang, Ruijuan; Yu, Yan; Deng, Jianjun; Zhang, Chao; Zhang, Jinghua; Cheng, Yue; Luo, Xiaoqin; Han, Bei; Yang, Haixia

    2016-01-01

    The study explored the protective effect of sesamin against lipid-induced renal injury and hyperlipidemia in a rat model. An animal model of hyperlipidemia was established in Sprague-Dawley rats. Fifty-five adult Sprague-Dawley rats were divided into five groups. The control group was fed a standard diet, while the other four groups were fed a high-fat diet for 5 weeks to induce hyperlipidemia. Three groups received oral sesamin in doses of 40, 80, or 160 mg/(kg·day). Seven weeks later, the blood lipids, renal function, antioxidant enzyme activities, and hyperoxide levels in kidney tissues were measured. The renal pathological changes and expression levels of collagen type IV (Col-IV) and α-smooth muscle actin (α-SMA) were analyzed. The administration of sesamin improved the serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, apolipoprotein-B, oxidized-low-density lipoprotein, and serum creatinine levels in hyperlipidemic rats, while it increased the high-density lipoprotein cholesterol and apolipoprotein-A levels. Sesamin reduced the excretion of 24-h urinary protein and urinary albumin and downregulated α-SMA and Col-IV expression. Moreover, sesamin ameliorated the superoxide dismutase activity and reduced malondialdehyde levels in kidney tissue. Sesamin could mediate lipid metabolism and ameliorate renal injury caused by lipid metabolism disorders in a rat model of hyperlipidemia. PMID:27171111

  5. Fermented Chinese Formula Shuan-Tong-Ling Protects Brain Microvascular Endothelial Cells against Oxidative Stress Injury

    PubMed Central

    Tan, Lingjing; Zhang, Xiang; Wang, Jinfeng; Li, Xiaoli; Huang, Weifeng; Yang, Songbai

    2016-01-01

    Fermented Chinese formula Shuan-Tong-Ling (STL), composed of fourteen medicinal herbs, was an experiential formula by Dr. Zhigang Mei for treating vascular encephalopathy, but the underlying mechanisms remained unknown. In this study, we aimed to investigate the protective effects of fermented STL on hydrogen peroxide- (H2O2-) induced injury in rat brain microvascular endothelial cells (BMECs) and the possible mechanisms. Cultured BMECs were treated with H2O2, STL, or nicotinamide (NAM, a SIRT1 inhibitor). Then, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was employed to detect cell proliferation and senescence-associated beta-galactosidase (SA-β-gal) was used to examine cell senescence. Cell nuclei were observed by 4′,6-diamidino-2-phenylindole. Additionally, changes in reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) levels were measured. Expression of SIRT1, p21, and PGC-1α was determined by western blot. Cell proliferation significantly increased with STL treatment in a dose-dependent manner. H2O2 treatment could intensify cell senescence and nuclei splitting or pyknosis. With STL treatment, the reduced ROS level was accompanied by increased SOD and GSH activity. Further assays showed upregulation of SIRT1 and PGC-1α and downregulation of p21 after STL treatment. The results revealed that STL could protect BMECs against oxidative stress injury at least partially through the SIRT1 pathway. PMID:28096886

  6. An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury.

    PubMed

    Takyar, Seyedtaghi; Zhang, Yi; Haslip, Maria; Jin, Lei; Shan, Peiying; Zhang, Xuchen; Lee, Patty J

    2016-03-01

    TLR4 deficiency causes hypersusceptibility to oxidant-induced injury. We investigated the role of TLR4 in lung protection, using used bone marrow chimeras; cell-specific transgenic modeling; and lentiviral delivery in vivo to knock down or express TLR4 in various lung compartments; and lung-specific VEGF transgenic mice to investigate the effect of TLR4 on VEGF-mediated protection. C57/BL6 mice were exposed to 100% oxygen in an enclosed chamber and assessed for survival and lung injury. Primary endothelial cells were stimulated with recombinant VEGF and exposed to hyperoxia or hydrogen peroxide. Endothelium-specific expression of human TLR4 (as opposed to its expression in epithelium or immune cells) increased the survival of TLR4-deficent mice in hyperoxia by 24 h and decreased LDH release and lung cell apoptosis after 72 h of exposure by 30%. TLR4 expression was necessary and sufficient for the protective effect of VEGF in the lungs and in primary endothelial cells in culture. TLR4 knockdown inhibited VEGF signaling through VEGF receptor 2 (VEGFR2), Akt, and ERK pathways in lungs and primary endothelial cells and decreased the availability of VEGFR2 at the cell surface. These findings demonstrate a novel mechanism through which TLR4, an innate pattern receptor, interacts with an endothelial survival pathway.

  7. Curcumin attenuates endothelial cell oxidative stress injury through Notch signaling inhibition.

    PubMed

    Yang, Yang; Duan, Weixun; Liang, Zhenxin; Yi, Wei; Yan, Juanjuan; Wang, Ning; Li, Yue; Chen, Wensheng; Yu, Shiqiang; Jin, Zhenxiao; Yi, Dinghua

    2013-03-01

    Previous studies have demonstrated that Notch signaling pathway plays a regulatory role in cellular oxidative stress injury (OSI). In this study, our aim was to explore the role of the Notch signaling pathway in hydrogen peroxide (H(2)O(2))-induced OSI and the protective effect of curcumin during (H(2)O(2))-induced injury in human umbilical vein endothelial cells (HUVECs). DAPT, a specific inhibitor of the Notch signaling pathway, and Notch1 siRNA were used to study Notch activity. Further, HUVECs were exposed to H(2)O(2) in the absence or presence of curcumin. DAPT and Notch1 siRNA significantly inhibited OSI and the expression of Notch1 and Hes1. Curcumin conferred a protective effect on the HUVECs against H(2)O(2), which was evidenced by improved cell viability, adhesive ability and migratory ability and a decreased apoptotic index, decreased production of reactive oxygen species (ROS) and a reduction in several biochemical parameters. Immunofluorescence and Western blotting analyses demonstrated that H(2)O(2) treatment upregulated the expression of Notch1, Hes1, Caspase3, Bax and cytochrome c downregulated the expression of Bcl2, and treatment with curcumin reversed these effects. We demonstrated for the first time that the inhibition of Notch signaling pathway imparts a protective effect against endothelial OSI. The protective effects of curcumin against OSI are at least in part dependent on Notch1 inhibition.

  8. Avermectin induced liver injury in pigeon: mechanisms of apoptosis and oxidative stress.

    PubMed

    Zhu, Wen-Jun; Li, Ming; Liu, Ci; Qu, Jian-Ping; Min, Ya-Hong; Xu, Shi-Wen; Li, Shu

    2013-12-01

    Extensive use of avermectin (AVM) can result in environment pollution, and it is important to evaluate the potential impact this antibiotic has on ecological systems. Few published literatures have discussed the liver injury mechanisms induced by AVM on birds. In this study, pigeons were exposed to feed containing AVM (0, 20, 40 and 60 mg/kg diet) for 30, 60, 90 days respectively. The results showed that AVM increased the number of apoptosis and the expression level of caspase-3, 8, fas mRNA in the liver of pigeons. Ultrastructural alterations, including mitochondrial damage and chromatin aggregation, become severe with increase exposure dose. Exposure to AVM induced significant changes in antioxidant enzyme {superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)} activities and malondialdehyde (MDA) content, augmented protein carbonyl (PCO) content and DNA-protein crosslink (DPC) coefficient, in a concentration-dependent manner in the liver of pigeons. Our results show that AVM has toxic effect in pigeon liver, and the mechanism of injury caused by AVM is closely related to apoptosis and oxidative stress.

  9. Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes

    PubMed Central

    Yin, Zhaobao; Milatovic, Dejan; Aschner, Judy L.; Syversen, Tore; Rocha, Joao B.T.; Souza, Diogo O.; Sidoryk, Marta; Albrecht, Jan; Aschner, Michael

    2007-01-01

    The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and experimental animals. Astrocytes accumulate MeHg and play a prominent role in mediating MeHg toxicity in the central nervous system (CNS). Although the precise mechanisms of MeHg neurotoxicity are ill-defined, oxidative stress and altered mitochondrial and cell membrane permeability appear to be critical factors in its pathogenesis. The present study examined the effects of MeHg treatment on oxidative injury, mitochondrial inner membrane potential, glutamine uptake and expression of glutamine transporters in primary astrocyte cultures. MeHg caused a significant increase in F2-isoprostanes (F2-IsoPs), lipid peroxidation biomarkers of oxidative damage, in astrocyte cultures treated with 5 or 10 μ M MeHg for 1 or 6 hours. Consistent with this observation, MeHg induced a concentration-dependant reduction in the inner mitochondrial membrane potential (ΔΨm), as assessed by the potentiometric dye, tetramethylrhodamine ethyl ester (TMRE). Our results demonstrate that ΔΨm is a very sensitive endpoint for MeHg toxicity, since significant reductions were observed after only 1 h exposure to concentrations of MeHg as low as 1 μ M. MeHg pretreatment (1, 5 and 10 μ M) for 30 min also inhibited the net uptake of glutamine (3H-glutamine) measured at 1 min and 5 min. Expression of the mRNA coding the glutamine transporters, SNAT3/SN1 and ASCT2, was inhibited only at the highest (10 μ M) MeHg concentration, suggesting that the reduction in glutamine uptake observed after 30 min treatment with lower concentrations of MeHg (1 and 5 μ M) was not due to inhibition of transcription. Taken together, these studies demonstrate that MeHg exposure is associated with increased mitochondrial membrane permeability, alterations in glutamine/glutamate cycling, increased ROS formation and consequent oxidative injury. Ultimately, MeHg initiates multiple additive or synergistic disruptive

  10. Zn(II)-curcumin protects against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism.

    PubMed

    Yu, Chuan; Mei, Xue-Ting; Zheng, Yan-Ping; Xu, Dong-Hui

    2014-03-01

    Curcumin can chelate metal ions, forming metallocomplexes. We compared the effects of Zn(II)-curcumin with curcumin against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism. Oral administration of Zn(II)-curcumin dose-dependently prevented the ethanol-induced elevation of serum malondialdehyde (MDA) content and reductions in glutathione level and superoxide dismutase (SOD) activity. Zn(II)-curcumin also inhibited ethanol-induced liver injury. Additionally, Zn(II)-curcumin dose-dependently inhibited hemorheological abnormalities, including the ethanol-induced elevation of whole blood viscosity, plasma viscosity, blood viscosity at corrected hematocrit (45%), erythrocyte aggregation index, erythrocyte rigidity index and hematocrit. Compared to curcumin at the same dose, Zn(II)-curcumin more effectively elevated SOD activity, ameliorated liver injury and improved hemorheological variables. These results suggest that Zn(II)-curcumin protected the rats from ethanol-induced liver injury and hemorheological abnormalities via the synergistic effect of curcumin and zinc.

  11. Neuroprotective effects of erythropoietin against oxidant injury following brain irradiation: an experimental study

    PubMed Central

    Cebi, Aysegul; Mert, Handan; Mert, Nihat; Serin, Meltem; Erkal, Haldun Sukru

    2016-01-01

    Introduction Radiation therapy (RT) is a major treatment modality, and the central nervous system is a dose-limiting organ in clinical RT. This experimental study aims to present the evaluation of the neuroprotective effects of erythropoietin (EPO) against oxidant injury following brain irradiation in rats. Material and methods Forty Wistar rats were randomly assigned to four groups (n = 10 each). In group 1 the rats received no EPO and underwent sham RT. The rats in groups 2 and 3 received EPO. In group 2 rats underwent sham RT, while in group 3 rats received RT. The rats in group 4 received no EPO and underwent RT. Rats were irradiated using a Cobalt-60 teletherapy machine using a single fraction of 20 Gy covering the whole brain. Cervical dislocation euthanasia was performed. The nitrite and malondialdehyde (MDA) levels and the superoxide dismutase (SOD) and glutathione peroxidase (GSHPX) activities were evaluated in dissected brain tissues. Results The nitrite and MDA levels were higher in the RT group (2.10 ±0.62 ppm, 26.02 ±2.16 nmol/ml; p < 0.05) and lower in the EPO + RT group (1.45 ±0.12 ppm, 25.49 ±1.90 nmol/ml; p < 0.05). The SOD and GSHPX activity was higher in the EPO + RT group (2.62 ±0.49 U/mg, 1.75 ±0.25 U/mg, p < 0.05). Conclusions This study supports the probable neuroprotective effects of EPO against oxidant injury following brain irradiation in a rat model, presumably through decreasing free radical production and increasing expression of antioxidant enzymes. PMID:27904528

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

    PubMed Central

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

    2016-01-01

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

  13. Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury.

    PubMed

    Gao, Wei; Yuan, Cheng; Zhang, Jingying; Li, Lingling; Yu, Like; Wiegman, Coen H; Barnes, Peter J; Adcock, Ian M; Huang, Mao; Yao, Xin

    2015-12-01

    COPD (chronic obstructive pulmonary disease) is associated with sustained inflammation, excessive injury, and accelerated lung aging. Human Klotho (KL) is an anti-aging protein that protects cells against inflammation and damage. In the present study, we quantified KL expression in the lungs of COPD patients and in an ozone-induced mouse model of COPD, and investigated the mechanisms that control KL expression and function in the airways. KL distribution and levels in human and mouse airways were measured by immunohistochemistry and Western blotting. The effect of CSE (cigarette smoke extract) on KL expression was detected in human bronchial epithelial cells. Moreover, the effect of KL on CSE-mediated inflammation and hydrogen peroxide-induced cellular injury/apoptosis was determined using siRNAs. KL expression was decreased in the lungs of smokers and further reduced in patients with COPD. Similarly, 6 weeks of exposure to ozone decreased KL levels in airway epithelial cells. CSE and TNFα (tumour necrosis factor α) decreased KL expression and release from airway epithelial cells, which was associated with enhanced pro-inflammatory cytokine expression. Moreover, KL depletion increased cell sensitivity to cigarette smoke-induced inflammation and oxidative stress-induced cell damage. These effects involved the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and Nrf2 (nuclear factor erythroid 2-related factor 2) pathways. Reduced KL expression in COPD airway epithelial cells was associated with increased oxidative stress, inflammation and apoptosis. These data provide new insights into the mechanisms associated with the accelerated lung aging in COPD development.

  14. Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury

    PubMed Central

    Gao, Wei; Yuan, Cheng; Zhang, Jingying; Li, Lingling; Yu, Like; Wiegman, Coen H.; Barnes, Peter J.; Adcock, Ian M.; Huang, Mao

    2015-01-01

    COPD (chronic obstructive pulmonary disease) is associated with sustained inflammation, excessive injury, and accelerated lung aging. Human Klotho (KL) is an anti-aging protein that protects cells against inflammation and damage. In the present study, we quantified KL expression in the lungs of COPD patients and in an ozone-induced mouse model of COPD, and investigated the mechanisms that control KL expression and function in the airways. KL distribution and levels in human and mouse airways were measured by immunohistochemistry and Western blotting. The effect of CSE (cigarette smoke extract) on KL expression was detected in human bronchial epithelial cells. Moreover, the effect of KL on CSE-mediated inflammation and hydrogen peroxide-induced cellular injury/apoptosis was determined using siRNAs. KL expression was decreased in the lungs of smokers and further reduced in patients with COPD. Similarly, 6 weeks of exposure to ozone decreased KL levels in airway epithelial cells. CSE and TNFα (tumour necrosis factor α) decreased KL expression and release from airway epithelial cells, which was associated with enhanced pro-inflammatory cytokine expression. Moreover, KL depletion increased cell sensitivity to cigarette smoke-induced inflammation and oxidative stress-induced cell damage. These effects involved the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and Nrf2 (nuclear factor erythroid 2-related factor 2) pathways. Reduced KL expression in COPD airway epithelial cells was associated with increased oxidative stress, inflammation and apoptosis. These data provide new insights into the mechanisms associated with the accelerated lung aging in COPD development. PMID:26201096

  15. Snakebite mediated acute kidney injury, prognostic predictors, oxidative and carbonyl stress: A prospective study

    PubMed Central

    Mukhopadhyay, P.; Mishra, R.; Mukherjee, D.; Mishra, R.; Kar, M.

    2016-01-01

    Snake bite is an occupational hazard in India and important preventable cause of acute kidney injury (AKI). This study was done to estimate the magnitude of snakebite-induced AKI (SAKI) who required renal replacement therapy, prognostic predictors, and final outcome, and to measure the oxidative and carbonyl stress (CS) level in SAKI patient who underwent hemodialysis (HD). All SAKI patients dialyzed between April 2010 and July 2011 in NRS Medical College were included. Demographical, clinical, and biochemical data were analyzed, and patients are followed to discharge or death. Oxidative and CS markers (advanced oxidation protein product [AOPP], advanced glycation end product, pentosidine, dityrosine, thioberbituric acid reactive substance, and methylglyoxal [MG]) were measured in 48 SAKI patient requiring HD. About 155 SAKI patients (M: F 2.2:1) received HD. Of them. The age was 36.2 (range 4–74) years. The most common site of the bite was lower limb (88.7%). Oliguria and bleeding manifestation were the common presentation. Hypotension was found in 52 (33.5%) cases, cellulitis and inflammation were found in about 63%. Mean creatinine was 4.56 ± 0.24 mg/dl. About 42 (27.1%) had disseminated intravascular coagulation (DIC). 36 (78.2%) had cellulites, 24 (52.2%) had hypotension or shock at initial presentation (P < 0.05), bleeding manifestation was found in 37 (80.4%), and 22 (47.8%) had DIC (P < 0.05). Forty-six (29.7%) patient died. DIC and hypotension/shock at initial presentation came out as an independent predictor of death. Among all markers measured for oxidative and CS (n = 48) AOPP and MG came out as an independent predictor (P < 0.05) of adverse outcome. Hypotension, DIC, AOPP, and MG were a poor prognostic marker in SAKI patients requiring dialysis. PMID:27942175

  16. Remote effect of kidney ischemia-reperfusion injury on pancreas: role of oxidative stress and mitochondrial apoptosis

    PubMed Central

    Abogresha, Noha M.; Abdelaziz, Eman Z.; Khalil, Waleed F.

    2015-01-01

    Introduction Recent studies have demonstrated remote effects of renal ischemia/reperfusion (IR) injury on some organs such as brain, liver, and lungs. Oxidative stress is reported to be the cornerstone in such ischemic conditions. Associated apoptosis is also reported in remote lung, liver and myocardial injury after acute kidney injury. So, we postulated that renal IR may affect the pancreas by its remote effect. Oxidative stress and mitochondrial mediated apoptosis may play a crucial role in this injury. We investigated the effects of kidney IR on pancreatic exocrine and endocrine functions, antioxidant enzyme activity, and apoptosis. Material and methods The protective effect of vitamin C was also investigated. The animals were submitted to non-traumatic bilateral renal IR, sham operation or treatment with vitamin C after IR. Rats were sacrificed on the 1st, 3rd, and 7th days of the experiment to evaluate the parameters of oxidative stress (catalase, lipid peroxidase, reduced glutathione and superoxide dismutase), pancreatic endocrine and exocrine function (amylase, insulin and fasting blood glucose), renal functions (serum creatinine and blood urea nitrogen), cellular injury and apoptotic markers (Bcl-2, Bax and caspase-3). Results Kidney I/R significantly increased the renal and pancreatic functions at 1, 3 and 7 days, while fasting insulin was significantly increased at day 3 after ischemia. Moreover, I/R significantly increased the studied oxidative stress markers and decreased the antioxidant capacity in pancreatic tissues. In addition, renal I/R induced numerous histopatological lesions in pancreatic tissues and increased the apoptosis-related genes. Treating the rats with vitamin C (100 mg/kg) significantly restored the renal and pancreatic functions, improved the pancreatic antioxidant capacity and protected the pancreatic tissues from apoptotic necrosis. Conclusions The results suggested that bilateral renal ischemia for 45 min caused significant

  17. Ganoderma lucidum polysaccharide peptide prevents renal ischemia reperfusion injury via counteracting oxidative stress

    PubMed Central

    Zhong, Dandan; Wang, Hongkai; Liu, Ming; Li, Xuechen; Huang, Ming; Zhou, Hong; Lin, Shuqian; Lin, Zhibin; Yang, Baoxue

    2015-01-01

    Ganoderma lucidum polysaccharide peptide (GLPP) scavenges oxygen free radicals that are a key factor in the pathogenesis of renal ischemia reperfusion injury (RIRI). The aim of this study was to determine whether GLPP could attenuate RIRI by counteracting the oxidative stress. The mechanism involved was assessed by an in vivo mouse RIRI model and an in vitro hypoxia/reoxygenation model, and tunicamycin-stimulated NRK-52E cells were used to explore the GLPP-mediated alleviation of ER stress. Experimental results showed that renal dysfunction and morphological damage were reduced in GLPP-treated group. The imbalance of redox status was reversed and production of ROS was reduced by GLPP. RIRI-induced mitochondrial- and ER stress-dependent apoptosis were dramatically inhibited in GLPP-treated group. Intriguingly, JNK activation in the kidney with RIRI or hypoxia/reoxygenation was inhibited by GLPP. These results suggest that the protective effect of GLPP against RIRI may be due to reducing oxidative stress, alleviating the mitochondrial and ER stress-dependent apoptosis caused by excessive ROS. PMID:26603550

  18. Perspectives on Molecular Biomarkers of Oxidative Stress and Antioxidant Strategies in Traumatic Brain Injury

    PubMed Central

    Mendes Arent, André; de Souza, Luiz Felipe; Walz, Roger; Dafre, Alcir Luiz

    2014-01-01

    Traumatic brain injury (TBI) is frequently associated with abnormal blood-brain barrier function, resulting in the release of factors that can be used as molecular biomarkers of TBI, among them GFAP, UCH-L1, S100B, and NSE. Although many experimental studies have been conducted, clinical consolidation of these biomarkers is still needed to increase the predictive power and reduce the poor outcome of TBI. Interestingly, several of these TBI biomarkers are oxidatively modified to carbonyl groups, indicating that markers of oxidative stress could be of predictive value for the selection of therapeutic strategies. Some drugs such as corticosteroids and progesterone have already been investigated in TBI neuroprotection but failed to demonstrate clinical applicability in advanced phases of the studies. Dietary antioxidants, such as curcumin, resveratrol, and sulforaphane, have been shown to attenuate TBI-induced damage in preclinical studies. These dietary antioxidants can increase antioxidant defenses via transcriptional activation of NRF2 and are also known as carbonyl scavengers, two potential mechanisms for neuroprotection. This paper reviews the relevance of redox biology in TBI, highlighting perspectives for future studies. PMID:24689052

  19. Changes in Cerebral Oxidative Metabolism during Neonatal Seizures Following Hypoxic–Ischemic Brain Injury

    PubMed Central

    Mitra, Subhabrata; Bale, Gemma; Mathieson, Sean; Uria-Avellanal, Cristina; Meek, Judith; Tachtsidis, Ilias; Robertson, Nicola J.

    2016-01-01

    Seizures are common following hypoxic–ischemic brain injury in newborn infants. Prolonged or recurrent seizures have been shown to exacerbate neuronal damage in the developing brain; however, the precise mechanism is not fully understood. Cytochrome-c-oxidase is responsible for more than 90% of ATP production inside mitochondria. Using a novel broadband near-infrared spectroscopy system, we measured the concentration changes in the oxidation state of cerebral cytochrome-c-oxidase (Δ[oxCCO]) and hemodynamics during recurrent neonatal seizures following hypoxic–ischemic encephalopathy in a newborn infant. A rapid increase in Δ[oxCCO] was noted at the onset of seizures along with a rise in the baseline of amplitude-integrated electroencephalogram. Cerebral oxygenation and cerebral blood volume fell just prior to the seizure onset but recovered rapidly during seizures. Δ[oxCCO] during seizures correlated with changes in mean electroencephalogram voltage indicating an increase in neuronal activation and energy demand. The progressive decline in the Δ[oxCCO] baseline during seizures suggests a progressive decrease of mitochondrial oxidative metabolism. PMID:27559538

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

    PubMed

    Kadkhodaee, Mehri; Najafi, Atefeh; Seifi, Behjat

    2014-11-01

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

  1. Differential Fmo3 Gene Expression in Various Liver Injury Models Involving Hepatic Oxidative Stress in Mice

    PubMed Central

    Rudraiah, Swetha; Moscovitz, Jamie E.; Donepudi, Ajay C.; Campion, Sarah N.; Slitt, Angela L.; Aleksunes, Lauren M.; Manautou, José E.

    2015-01-01

    Flavin-containing monooxygenase-3 (FMO3) catalyzes metabolic reactions similar to cytochrome P450 monooxygenase however, most metabolites of FMO3 are considered non-toxic. Recent findings in our laboratory demonstrated Fmo3gene induction following toxic acetaminophen (APAP) treatment in mice.The goal of this study was to evaluate Fmo3gene expression in diverseother mouse models of hepatic oxidative stress and injury. Fmo3 gene regulation by Nrf2 was also investigated using Nrf2 knockout (Nrf2 KO) mice. In our studies, male C57BL/6J mice were treated with toxic dosesof hepatotoxicants or underwent bile duct ligation (BDL, 10d). Hepatotoxicants included APAP (400 mg/kg, 24 to 72h), alpha-naphthylisothiocyanate (ANIT; 50 mg/kg, 2 to 48h), carbontetrachloride (CCl4;10 or 30 μL/kg, 24 and 48h) and allyl alcohol (AlOH; 30 or 60 mg/kg, 6 and 24h). Because oxidative stress activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2), additional studies investigated Fmo3 gene regulation by Nrf2 using Nrf2 knockout (Nrf2 KO) mice. At appropriate time-points, blood and liver samples were collected for assessment of plasma alanine aminotransferase (ALT) activity, plasma and hepatic bile acid levels, as well as liver Fmo3 mRNA and protein expression. Fmo3 mRNA expression increased significantly by 43-fold at 12h after ANIT treatment,and this increase translates to a 4-fold change in protein levels. BDL also increased Fmo3 mRNA expression by 1899-fold, but with no change in protein levels. Treatment of mice with CCl4decreased liver Fmo3gene expression, whileno change in expression was detected with AlOH treatment. Nrf2 KO mice are more susceptible to APAP (400 mg/kg, 72h) treatment compared to their wild-type (WT) counterparts, which is evidenced by greater plasma ALT activity. Fmo3 mRNA and protein expression increased in Nrf2 KO mice after APAP treatment. Collectively, not all hepatotoxicantsthat produce oxidative stress alter Fmo3gene expression. Along with APAP, toxic ANIT

  2. Isorhamnetin prevent endothelial cell injuries from oxidized LDL via activation of p38MAPK.

    PubMed

    Bao, Meihua; Lou, Yijia

    2006-10-10

    The present investigation was undertaken to determine the protective effects of isorhamnetin on endothelial cell line EA.hy926 injuries induced by oxidized low-density lipoprotein (ox-LDL) and to uncover some of the underlying mechanisms of these effects. Indices such as cell viability, lactate dehydrogenase (LDH), and nitric oxide (NO) release were measured to evaluate the protective effects of isorhamnetin. 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, superoxide dismutase (SOD), superoxide and reactive oxygen species (ROS) generation were also detected to evaluate the antioxidant effects of isorhamnetin. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was used to confirm the expression of endothelial nitric oxide synthase (eNOS) mRNA and lectin-like ox-LDL receptor-1 mRNA. Western blotting was used to evaluate the protein expression of this receptor and eNOS, as well as p38-mitogen-activated protein kinase (p38MAPK) phosphorylation and NF-kappaB p65 translocation. As a result, cell viability decreased significantly (P<0.01) after 24 h treatment with ox-LDL, accompanied with apparent secretion disorders such as NO reduction and LDH increase. Pretreatment with isorhamnetin resulted in remarkable increase of cell viability (P<0.05) and modulation of secretion disorders mediated by ox-LDL in a concentration-dependent manner. Besides, ox-LDL led to upregulation of lectin-like ox-LDL receptor-1, phosphorylation of p38MAPK, translocation of NF-kappaB, and downregulation of the eNOS expression in endothelial cells. Isorhamnetin pretreatment inhibited the ox-LDL-induced downregulation of eNOS, upregulation of lectin-like ox-LDL receptor-1, phosphorylation of the p38MAPK and translocation of NF-kappaB. Moreover, isorhamnetin exhibited strong antioxidant activity, which was shown by its inhibition effects on ox-LDL-induced superoxide, ROS overproduction and significant SOD reduction. The data indicated the protective effects of isorhamnetin on

  3. Lavandula Reduces Heart Injury via Attenuating Tumor Necrosis Factor-Alpha and Oxidative Stress in A Rat Model of Infarct-Like Myocardial Injury

    PubMed Central

    Vakili, Abedin; Sameni, Hamid Reza; Zahedi khorasani, Mahdi; Darabian, Mohsen

    2017-01-01

    Objective Lavender is used in herbal medicine for different therapeutic purposes. Nonetheless, potential therapeutic effects of this plant in ischemic heart disease and its possible mechanisms remain to be investigated. Materials and Methods In this experimental study, lavender oil at doses of 200, 400 or 800 mg/kg was administered through gastric gavage for 14 days before infarct-like myocardial injury (MI). The carotid artery and left ventricle were cannulated to record arterial blood pressure (BP) and cardiac function. At the end of experiment, the heart was removed and histopathological alteration, oxidative stress biomarkers as well as tumor necrosis factor-alpha (TNF-α) level were evaluated. Results Induction of M.I caused cardiac dysfunction, increased levels of lipid peroxidation, TNF-α and troponin I in heart tissue (P<0.001). Pretreatment with lavender oil at doses of 200 and 400 mg/kg significantly reduced myocardial injury, troponin I and TNF-α. In addition, it improved cardiac function and antioxidant enzyme activity (P<0.01). Conclusion Our finding showed that lavender oil has cardioprotective effect through inhibiting oxidative stress and inflammatory pathway in the rat model with infarct-like MI. We suggest that lavender oil may be helpful in prevention or attenuation of heart injury in patients with high risk of myocardial infarction and/or ischemic heart disease. PMID:28367419

  4. Hypoxemic reperfusion of ischemic states: an alternative approach for the attenuation of oxidative stress mediated reperfusion injury.

    PubMed

    Tasoulis, Marios-Konstantinos; Douzinas, Emmanuel E

    2016-01-19

    Ischemia and reperfusion (I/R) - induced injury has been described as one of the main factors that contribute to the observed morbidity and mortality in a variety of clinical entities, including myocardial infarction, ischemic stroke, cardiac arrest and trauma. An imbalance between oxygen demand and supply, within the organ beds during ischemia, results in profound tissue hypoxia. The subsequent abrupt oxygen re-entry upon reperfusion, may lead to a burst of oxidative aggression through production of reactive oxygen species by the primed cells. The predominant role of oxidative stress in the pathophysiology of I/R mediated injury, has been well established. A number of strategies that target the attenuation of the oxidative burst have been tested both in the experimental and the clinical setting. Despite these advances, I/R injury continues to be a major problem in everyday medical practice. The aim of this paper is to review the existing literature regarding an alternative approach, termed hypoxemic reperfusion, that has exhibited promising results in the attenuation of I/R injury, both in the experimental and the clinical setting. Further research to clarify its underlying mechanisms and to assess its efficacy in the clinical setting is warranted.

  5. The chalcone compound isosalipurposide (ISPP) exerts a cytoprotective effect against oxidative injury via Nrf2 activation

    SciTech Connect

    Han, Jae Yun; Cho, Seung Sik; Yang, Ji Hye; Kim, Kyu Min; Jang, Chang Ho; Park, Da Eon; Bang, Joon Seok; Jung, Young Suk; Ki, Sung Hwan

    2015-08-15

    The chalcone compound isosalipurposide (ISPP) has been successfully isolated from the native Korean plant species Corylopsis coreana Uyeki (Korean winter hazel). However, the therapeutic efficacy of ISPP remains poorly understood. This study investigated whether ISPP has the capacity to activate NF-E2-related factor (Nrf2)-antioxidant response element (ARE) signaling and induce its target gene expression, and to determined the protective role of ISPP against oxidative injury of hepatocytes. In HepG2 cells, nuclear translocation of Nrf2 is augmented by ISPP treatment. Consistently, ISPP increased ARE reporter gene activity and the protein levels of glutamate cysteine ligase (GCL) and hemeoxygenase (HO-1), resulting in increased intracellular glutathione levels. Cells pretreated with ISPP were rescued from tert-butylhydroperoxide-induced reactive oxygen species (ROS) production and glutathione depletion and consequently, apoptotic cell death. Moreover, ISPP ameliorated the mitochondrial dysfunction and apoptosis induced by rotenone which is an inhibitor of complex 1 of the mitochondrial respiratory chain. The specific role of Nrf2 activation by ISPP was demonstrated using an ARE-deletion mutant plasmid and Nrf2-knockout cells. Finally, we observed that extracellular signal-regulated kinase (ERK) and AMP-activated protein kinase (AMPK), but not protein kinase C (PKC)-δ or other mitogen-activated protein kinases (MAPKs), are involved in the activation of Nrf2 by ISPP. Taken together, our results demonstrate that ISPP has a cytoprotective effect against oxidative damage mediated through Nrf2 activation and induction of its target gene expression in hepatocytes. - Highlights: • We investigated the effect of ISPP on Nrf2 activation. • ISPP increased Nrf2 activity and its target gene expression. • ISPP inhibited the mitochondrial dysfunction and ROS production. • Nrf2 activation by ISPP is dependent on ERK1/2 and AMPK phosphorylation. • ISPP may be a promising

  6. SIRT1 activation by curcumin pretreatment attenuates mitochondrial oxidative damage induced by myocardial ischemia reperfusion injury.

    PubMed

    Yang, Yang; Duan, Weixun; Lin, Yan; Yi, Wei; Liang, Zhenxing; Yan, Juanjuan; Wang, Ning; Deng, Chao; Zhang, Song; Li, Yue; Chen, Wensheng; Yu, Shiqiang; Yi, Dinghua; Jin, Zhenxiao

    2013-12-01

    Ischemia reperfusion (IR) injury (IRI) is harmful to the cardiovascular system and causes mitochondrial oxidative stress. Silent information regulator 1 (SIRT1), a type of histone deacetylase, contributes to IRI. Curcumin (Cur) is a strong natural antioxidant and is the active component in Curcuma longa; Cur has protective effects against IRI and may regulate the activity of SIRT1. This study was designed to investigate the protective effect of Cur pretreatment on myocardial IRI and to elucidate this potential mechanism. Isolated and in vivo rat hearts and cultured neonatal rat cardiomyocytes were subjected to IR. Prior to this procedure, the hearts or cardiomyocytes were exposed to Cur in the absence or presence of the SIRT1 inhibitor sirtinol or SIRT1 siRNA. Cur conferred a cardioprotective effect, as shown by improved postischemic cardiac function, decreased myocardial infarct size, decreased myocardial apoptotic index, and several biochemical parameters, including the up-regulation of the antiapoptotic protein Bcl2 and the down-regulation of the proapoptotic protein Bax. Sirtinol and SIRT1 siRNA each blocked the Cur-mediated cardioprotection by inhibiting SIRT1 signaling. Cur also resulted in a well-preserved mitochondrial redox potential, significantly elevated mitochondrial superoxide dismutase activity, and decreased formation of mitochondrial hydrogen peroxide and malondialdehyde. These observations indicated that the IR-induced mitochondrial oxidative damage was remarkably attenuated. However, this Cur-elevated mitochondrial function was reversed by sirtinol or SIRT1 siRNA treatment. In summary, our results demonstrate that Cur pretreatment attenuates IRI by reducing IR-induced mitochondrial oxidative damage through the activation of SIRT1 signaling.

  7. Protective agent, erdosteine, against cisplatin-induced hepatic oxidant injury in rats.

    PubMed

    Koc, Ahmet; Duru, Mehmet; Ciralik, Harun; Akcan, Ramazan; Sogut, Sadik

    2005-10-01

    Cisplatin, one of the most active cytotoxic agents against cancer, has several toxicities. Hepatotoxicity is one of them occurred during high doses treatment. The aim of this study was to determine the effects of erdosteine against cisplatin-induced liver injury through tissue oxidant/antioxidant parameters and light microscopic evaluation. The rats were randomly divided into three groups: control (n=5), cisplatin (10 mg/kg, n=6) and cisplatin+erdosteine (50 mg/kg/day oral erdosteine, n=8) groups. The rats were sacrificed at the 5th day of cisplatin treatment. The liver tissues were examined with light microscopy and oxidant/antioxidant biochemical parameters. The malondialdehyde (MDA) and nitric oxide (NO) levels were increased in the cisplatin group in comparison with the control and cisplatin+erdosteine groups (p<0.05). There was no significant difference in MDA and NO levels between control and cisplatin+erdosteine groups. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were higher in cisplatin+erdosteine group than cisplatin group (p<0.05). However, the CAT and GSH-Px activities were significantly lower in cisplatin group than in control group (p<0.05). The light microscopic examination revealed that cytoplasmic changes especially around cells of central vein were observed in cisplatin group. Hepatocellular vacuolization was seen in these cells. In the cisplatin plus erdosteine group, a decrease in cytoplasmic changes with the hepatocytes and sinusoidal dilatations around cells of central vein were noticed in as compared to cisplatin group. In the light of microscopic and biochemical results, it was concluded that cisplatin-induced liver damage in high dose and erdosteine prevented this toxic side effect by the way of its antioxidant and radical scavenging effects.

  8. Edaravone protected human brain microvascular endothelial cells from methylglyoxal-induced injury by inhibiting AGEs/RAGE/oxidative stress.

    PubMed

    Li, Wenlu; Xu, Hongjiao; Hu, Yangmin; He, Ping; Ni, Zhenzhen; Xu, Huimin; Zhang, Zhongmiao; Dai, Haibin

    2013-01-01

    Subjects with diabetes experience an increased risk of cerebrovascular disease and stroke compared with nondiabetic age-matched individuals. Increased formation of reactive physiological dicarbonyl compound methylglyoxal (MGO) seems to be implicated in the development of diabetic vascular complication due to its protein glycation and oxidative stress effect. Edaravone, a novel radical scavenger, has been reported to display the advantageous effects on ischemic stroke both in animals and clinical trials; however, little is known about whether edaravone has protective effects on diabetic cerebrovascular injury. Using cultured human brain microvascular endothelial cells (HBMEC), protective effects of edaravone on MGO and MGO enhancing oxygen-glucose deprivation (OGD) induced injury were investigated. Cell injury was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formation, cell account, lactate dehydrogenase (LDH) release and Rhodamine 123 staining. Advanced glycation end-products (AGEs) formation and receptor for advanced glycation end-products (RAGE) expression were measured by western blotting. Cellular oxidative stress was measured by reactive oxygen species (ROS) release. Treatment of MGO for 24 h significantly induced HBMEC injury, which was inhibited by pretreatment of edaravone from 10-100 µmol/l. What's more, treatment of MGO enhanced AGEs accumulation, RAGE expression and ROS release in the cultured HBMEC, which were inhibited by 100 µmol/l edaravone. Finally, treatment of MGO for 24 h and then followed by 3 h OGD insult significantly enhanced cell injury when compared with OGD insult only, which was also protected by 100 µmol/l edaravone. Thus, edaravone protected HBMEC from MGO and MGO enhancing OGD-induced injury by inhibiting AGEs/RAGE/oxidative stress.

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

    PubMed

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

    2016-06-01

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

  10. Pulsed ultrasound associated with gold nanoparticle gel reduces oxidative stress parameters and expression of pro-inflammatory molecules in an animal model of muscle injury

    PubMed Central

    2012-01-01

    Background Nanogold has been investigated in a wide variety of biomedical applications because of the anti-inflammatory properties. The purpose of this study was to evaluate the effects of TPU (Therapeutic Pulsed Ultrasound) with gold nanoparticles (GNP) on oxidative stress parameters and the expression of pro-inflammatory molecules after traumatic muscle injury. Materials and methods Animals were divided in nine groups: sham (uninjured muscle); muscle injury without treatment; muscle injury + DMSO; muscle injury + GNP; muscle injury + DMSO + GNP; muscle injury + TPU; muscle injury + TPU + DMSO; muscle injury + TPU + GNP; muscle injury + TPU + DMSO + GNP. The ROS production was determined by concentration of superoxide anion, modulation of antioxidant defenses was determined by the activity of superoxide dismutase, catalase and glutathione peroxidase enzymes, oxidative damage determined by formation of thiobarbituric acid-reactive substance and protein carbonyls. The levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were measured as inflammatory parameters. Results Compared to muscle injury without treatment group, the muscle injury + TPU + DMSO + GNP gel group promoted a significant decrease in superoxide anion production and lipid peroxidation levels (p < 0.050). It also showed a significant decrease in TNF-α and IL-1β levels (p < 0.050) when compared to muscle injury without treatment group. Conclusions Our results suggest that TPU + DMSO + GNP gel presents beneficial effects on the muscular healing process, inducing a reduction in the production of ROS and also the expression of pro-inflammatory molecules. PMID:22410000

  11. The Effects of Quercetin on Acute Lung Injury and Biomarkers of Inflammation and Oxidative Stress in the Rat Model of Sepsis.

    PubMed

    Gerin, Fethullah; Sener, Umit; Erman, Hayriye; Yilmaz, Ahsen; Aydin, Bayram; Armutcu, Ferah; Gurel, Ahmet

    2016-04-01

    Experimental studies indicate that sepsis causes remote organ injury although the molecular mechanism has not been clearly defined. In this report, the role of oxidative damage, and inflammation on lung injury, following sepsis model by cecal ligation and puncture, and the effects of quercetin, antioxidant, and anti-inflammatory flavonoid, in the lung tissue were investigated. In the present study, we found that administration of single-dose quercetin before cecal ligation and puncture procedure, while markedly diminishing the levels of YKL-40 and oxidant molecules (xanthine oxidase (XO), nitric oxide (NO), and malondialdehyde (MDA)), increases the antioxidant enzymes levels. Quercetin is beneficial to acute lung injury by decreasing the levels of oxidative stress markers and increasing the antioxidant enzyme activities. Quercetin also causes a decrease in the serum levels of YKL-40 and periostin in the oxidative lung injury induced by the experimental sepsis model.

  12. A crucial role of nitric oxide in acute lung injury secondary to the acute necrotizing pancreatitis.

    PubMed

    Cheng, Shi; Yan, Wen-Mao; Yang, Bin; Shi, Jing-dong; Song, Mao-min; Zhao, Yuqian

    2010-04-01

    To investigate the role of nitric oxide (NO) in acute lung inflammation and injury secondary to acute necrotizing pancreatitis (ANP), 5% sodium taurocholate was retrogradely injected into the biliopancreatic duct of rats to ANP model. These ANP rats were given L-Arginine (L-Arg, 100 mg/kg), L-NAME (10 mg/kg), or their combination by intraperitoneal injection 30 min prior to ANP induction. At 1, 3, 6, and 12 hours after ANP induction, lung NO production, and inducible NO synthase (iNOS) expression were measured. Lung histopathological changes, bronchoalveolar lavage (BAL) protein concentration, proinflammatory mediators tumor necrotic factor alpha (TNF-alpha), and lung tissue myeloperoxidase (MPO) activity were examined. Results showed that NO production and iNOS mRNA expression in alveolar macrophages (AMs) were significantly increased along with significant increases in lung histological abnormalities and BAL proteins in the ANP group, all of which were further enhanced by pretreatment with L-Arg and attenuated by pretreatment with L-NAME, respectively. These markers were slightly attenuated by pretreatment with combination of L-Arg + L-NAME, suggesting that NO is required for initiating the acute lung damage in ANP rats, and also that L-Arg-enhanced lung injury is mediated by its NO generation rather than its direct effect. MPO activity and TNF-alpha expression in lung were upregulated in the ANP rats and further enhanced by pretreatment with L-Arg and attenuated by pretreatment with L-NAME, respectively. These results suggest that overproduction of NO mediated by iNOS in the lung is required for the acute lung inflammation and damage secondary to ANP.

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

    NASA Astrophysics Data System (ADS)

    Milivojević, Tamara; Drobne, Damjana; Romih, Tea; Mali, Lilijana Bizjak; Marin, Irena; Lunder, Mojca; Drevenšek, Gorazd

    2016-10-01

    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.

  14. Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats

    PubMed Central

    Fu, Chunlai; Dai, Xingui; Yang, You; Lin, Mengxiang; Cai, Yeping; Cai, Shaoxi

    2016-01-01

    Previous studies have identified that dexmedetomidine (DEX) treatment can ameliorate the acute lung injury (ALI) induced by lipopolysaccharide and ischemia-reperfusion. However, the molecular mechanisms by which DEX ameliorates lung injury remain unclear. The present study investigated whether DEX, which has been reported to exert effects on oxidative stress, mitochondrial permeability transition pores and apoptosis in other disease types, can exert protective effects in lipopolysaccharide (LPS)-induced ALI by inhibiting oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis. It was revealed that LPS-challenged rats exhibited significant lung injury, characterized by the deterioration of histopathology, vascular hyperpermeability, wet-to-dry weight ratio and oxygenation index (PaO2/FIO2), which was attenuated by DEX treatment. DEX treatment inhibited LPS-induced mitochondrial dysfunction, as evidenced by alleviating the cellular ATP and mitochondrial membrane potential in vitro. In addition, DEX treatment markedly prevented the LPS-induced mitochondrial-dependent apoptotic pathway in vitro (increases of cell apoptotic rate, cytosolic cytochrome c, and caspase 3 activity) and in vivo (increases of |terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells, cleaved caspase 3, Bax upregulation and Bcl-2 downregulation). Furthermore, DEX treatment markedly attenuated LPS-induced oxidative stress, as evidenced by downregulation of cellular reactive oxygen species in vitro and lipid peroxides in serum. Collectively, the present results demonstrated that DEX ameliorates LPS-induced ALI by reducing oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis. PMID:27959438

  15. Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats.

    PubMed

    Fu, Chunlai; Dai, Xingui; Yang, You; Lin, Mengxiang; Cai, Yeping; Cai, Shaoxi

    2017-01-01

    Previous studies have identified that dexmedetomidine (DEX) treatment can ameliorate the acute lung injury (ALI) induced by lipopolysaccharide and ischemia-reperfusion. However, the molecular mechanisms by which DEX ameliorates lung injury remain unclear. The present study investigated whether DEX, which has been reported to exert effects on oxidative stress, mitochondrial permeability transition pores and apoptosis in other disease types, can exert protective effects in lipopolysaccharide (LPS)‑induced ALI by inhibiting oxidative stress, mitochondrial dysfunction and mitochondrial‑dependent apoptosis. It was revealed that LPS‑challenged rats exhibited significant lung injury, characterized by the deterioration of histopathology, vascular hyperpermeability, wet‑to‑dry weight ratio and oxygenation index (PaO2/FIO2), which was attenuated by DEX treatment. DEX treatment inhibited LPS‑induced mitochondrial dysfunction, as evidenced by alleviating the cellular ATP and mitochondrial membrane potential in vitro. In addition, DEX treatment markedly prevented the LPS‑induced mitochondrial‑dependent apoptotic pathway in vitro (increases of cell apoptotic rate, cytosolic cytochrome c, and caspase 3 activity) and in vivo (increases of |terminal deoxynucleotidyl transferase dUTP nick‑end labeling positive cells, cleaved caspase 3, Bax upregulation and Bcl‑2 downregulation). Furthermore, DEX treatment markedly attenuated LPS‑induced oxidative stress, as evidenced by downregulation of cellular reactive oxygen species in vitro and lipid peroxides in serum. Collectively, the present results demonstrated that DEX ameliorates LPS‑induced ALI by reducing oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis.

  16. Time courses of post-injury mitochondrial oxidative damage and respiratory dysfunction and neuronal cytoskeletal degradation in a rat model of focal traumatic brain injury.

    PubMed

    Hill, Rachel L; Singh, Indrapal N; Wang, Juan A; Hall, Edward D

    2017-03-23

    Traumatic brain injury (TBI) results in rapid reactive oxygen species (ROS) production and oxidative damage to essential brain cellular components leading to neuronal dysfunction and cell death. It is increasingly appreciated that a major player in TBI-induced oxidative damage is the reactive nitrogen species (RNS) peroxynitrite (PN) which is produced in large part in injured brain mitochondria. Once formed, PN decomposes into highly reactive free radicals that trigger membrane lipid peroxidation (LP) of polyunsaturated fatty acids (e.g. arachidonic acid) and protein nitration (3-nitrotyrosine, 3-NT) in mitochondria and other cellular membranes causing various functional impairments to mitochondrial oxidative phosphorylation and calcium (Ca(2+)) buffering capacity. The LP also results in the formation of neurotoxic reactive aldehyde byproducts including 4-hydroxynonenal (4-HNE) and propenal (acrolein) which exacerbates ROS/RNS production and oxidative protein damage in the injured brain. Ultimately, this results in intracellular Ca(2+) overload that activates proteolytic degradation of α-spectrin, a neuronal cytoskeletal protein. Therefore, the aim of this study was to establish the temporal evolution of mitochondrial dysfunction, oxidative damage and cytoskeletal degradation in the brain following a severe controlled cortical impact (CCI) TBI in young male adult rats. In mitochondria isolated from an 8 mm diameter cortical punch including the 5 mm wide impact site and their respiratory function studied ex vivo, we observed an initial decrease in complex I and II mitochondrial bioenergetics within 3 h (h). For complex I bioenergetics, this partially recovered by 12-16 h, whereas for complex II respiration the recovery was complete by 12 h. During the first 24 h, there was no evidence of an injury-induced increase in LP or protein nitration in mitochondrial or cellular homogenates. However, beginning at 24 h, there was a gradual secondary decline in complex

  17. Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury.

    PubMed

    García, Elisa; Silva-García, Raúl; Mestre, Humberto; Flores, Nayeli; Martiñón, Susana; Calderón-Aranda, Emma S; Ibarra, Antonio

    2012-03-01

    Immunization with neurally derived peptides (INDP) boosts the action of an autoreactive immune response that has been shown to induce neuroprotection in several neurodegenerative diseases, especially after spinal cord (SC) injury. This strategy provides an environment that promotes neuronal survival and tissue preservation. The mechanisms by which this autoreactive response exerts its protective effects is not totally understood at the moment. A recent study showed that INDP reduces lipid peroxidation. Lipid peroxidation is a neurodegenerative phenomenon caused by the increased production of reactive nitrogen species such as nitric oxide (NO). It is possible that INDP could be interfering with NO production. To test this hypothesis, we examined the effect of INDP on the amount of NO produced by glial cells when cocultured with autoreactive T cells. We also evaluated the amount of NO and the expression of the inducible form of nitric oxide synthase (iNOS) at the injury site of SC-injured animals. The neural-derived peptides A91 and Cop-1 were used to immunize mice and rats with SC injury. In vitro studies showed that INDP significantly reduces the production of NO by glial cells. This observation was substantiated by in vivo experiments demonstrating that INDP decreases the amount of NO and iNOS gene expression at the site of injury. The present study provides substantial evidence on the inhibitory effect of INDP on NO production, helpingour understanding of the mechanisms through which protective autoimmunity promotes neuroprotection.

  18. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury.

    PubMed

    Fischer, Marie T; Sharma, Rakhi; Lim, Jamie L; Haider, Lukas; Frischer, Josa M; Drexhage, Joost; Mahad, Don; Bradl, Monika; van Horssen, Jack; Lassmann, Hans

    2012-03-01

    Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, and we recently provided evidence for oxidative damage of oligodendrocytes and dystrophic axons in early stages of active multiple sclerosis lesions. In this study, we identified potential sources of reactive oxygen and nitrogen species through gene expression in carefully staged and dissected lesion areas and by immunohistochemical analysis of protein expression. Genome-wide microarrays confirmed mitochondrial injury in active multiple sclerosis lesions, which may serve as an important source of reactive oxygen species. In addition, we found differences in the gene expression levels of various nicotinamide adenine dinucleotide phosphate oxidase subunits between initial multiple sclerosis lesions and control white matter. These results were confirmed at the protein level by means of immunohistochemistry, showing upregulation of the subunits gp91phox, p22phox, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 in activated microglia in classical active as well as slowly expanding lesions. The subunits gp91phox and p22phox were constitutively expressed in microglia and were upregulated in the initial lesion. In contrast, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 expression were more restricted to the zone of initial damage or to lesions from patients with acute or early relapsing/remitting multiple sclerosis. Double labelling showed co-expression of the nicotinamide adenine dinucleotide phosphate oxidase subunits in activated microglia and

  19. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury

    PubMed Central

    Fischer, Marie T.; Sharma, Rakhi; Lim, Jamie L.; Haider, Lukas; Frischer, Josa M.; Drexhage, Joost; Mahad, Don; Bradl, Monika; van Horssen, Jack

    2012-01-01

    Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, and we recently provided evidence for oxidative damage of oligodendrocytes and dystrophic axons in early stages of active multiple sclerosis lesions. In this study, we identified potential sources of reactive oxygen and nitrogen species through gene expression in carefully staged and dissected lesion areas and by immunohistochemical analysis of protein expression. Genome-wide microarrays confirmed mitochondrial injury in active multiple sclerosis lesions, which may serve as an important source of reactive oxygen species. In addition, we found differences in the gene expression levels of various nicotinamide adenine dinucleotide phosphate oxidase subunits between initial multiple sclerosis lesions and control white matter. These results were confirmed at the protein level by means of immunohistochemistry, showing upregulation of the subunits gp91phox, p22phox, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 in activated microglia in classical active as well as slowly expanding lesions. The subunits gp91phox and p22phox were constitutively expressed in microglia and were upregulated in the initial lesion. In contrast, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 expression were more restricted to the zone of initial damage or to lesions from patients with acute or early relapsing/remitting multiple sclerosis. Double labelling showed co-expression of the nicotinamide adenine dinucleotide phosphate oxidase subunits in activated microglia and

  20. Protective Actions of 17β-Estradiol and Progesterone on Oxidative Neuronal Injury Induced by Organometallic Compounds

    PubMed Central

    Ishihara, Yasuhiro; Takemoto, Takuya; Yamazaki, Takeshi

    2015-01-01

    Steroid hormones synthesized in and secreted from peripheral endocrine glands pass through the blood-brain barrier and play a role in the central nervous system. In addition, the brain possesses an inherent endocrine system and synthesizes steroid hormones known as neurosteroids. Increasing evidence shows that neuroactive steroids protect the central nervous system from various harmful stimuli. Reports show that the neuroprotective actions of steroid hormones attenuate oxidative stress. In this review, we summarize the antioxidative effects of neuroactive steroids, especially 17β-estradiol and progesterone, on neuronal injury in the central nervous system under various pathological conditions, and then describe our recent findings concerning the neuroprotective actions of 17β-estradiol and progesterone on oxidative neuronal injury induced by organometallic compounds, tributyltin, and methylmercury. PMID:25815107

  1. Cysteamine alleviates early brain injury via reducing oxidative stress and apoptosis in a rat experimental subarachnoid hemorrhage model.

    PubMed

    Zhang, Zong-Yong; Yang, Ming-Feng; Wang, Tao; Li, Da-Wei; Liu, Yun-Lin; Zhang, Jin-Hui; Sun, Bao-Liang

    2015-05-01

    Oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). The aim of this study was to assess whether cysteamine prevents post-SAH oxidative stress injury via its antioxidative and anti-apoptotic effects. It was observed that intraperitoneal administration of cysteamine (20 mg/kg/day) could significantly alleviate EBI (including neurobehavioral deficits, brain edema, blood-brain barrier permeability, and cortical neuron apoptosis) after SAH in rats. Meanwhile, cysteamine treatment reduced post-SAH elevated the reactive oxygen species level, the concentration of malondialdehyde, 3-nitrotyrosine, and 8-hydroxydeoxyguanosine and increased the glutathione peroxidase enzymatic activity, the concentration of glutathione and brain-derived neurotrophic factor in brain cortex at 48 h after SAH. These results indicated that administration of cysteamine may ameliorate EBI and provide neuroprotection after SAH in rat models.

  2. Nitric oxide in microgravity-induced orthostatic intolerance: relevance to spinal cord injury

    NASA Technical Reports Server (NTRS)

    Vaziri, N. D.; Purdy, R. E. (Principal Investigator)

    2003-01-01

    Prolonged exposure to microgravity results in cardiovascular deconditioning which is marked by orthostatic intolerance in the returning astronauts and recovering bed-ridden patients. Recent studies conducted in our laboratories at University of California, Irvine have revealed marked elevation of nitric oxide (NO) production in the kidney, heart, brain, and systemic arteries coupled with significant reduction of NO production in the cerebral arteries of microgravity-adapted animals. We have further demonstrated that the observed alteration of NO metabolism is primarily responsible for the associated cardiovascular deconditioning. Recovery from acute spinal cord injury (SCI) is frequently complicated by orthostatic intolerance that is due to the combined effects of the disruption of efferent sympathetic pathway and cardiovascular deconditioning occasioned by prolonged confinement to bed. In this presentation, I will review the nature of altered NO metabolism and its role in the pathogenesis of microgravity-induced cardiovascular deconditioning. The possible relevance of the new findings to orthostatic intolerance in patients with acute SCI and its potential therapeutic implications will be discussed.

  3. Effectiveness of nitric oxide during spontaneous breathing in experimental lung injury.

    PubMed

    Dembinski, Rolf; Hochhausen, Nadine; Terbeck, Sandra; Bickenbach, Johannes; Stadermann, Frederik; Rossaint, Rolf; Kuhlen, Ralf

    2010-04-01

    Inhaled nitric oxide (iNO) improves gas exchange in about 60% of patients with acute respiratory distress syndrome (ARDS). Recruitment of atelectatic lung areas may improve responsiveness and preservation of spontaneous breathing (SB) may cause recruitment. Accordingly, preservation of SB may improve effectiveness of iNO. To test this hypothesis, iNO was evaluated in experimental acute lung injury (ALI) during SB. In 24 pigs with ALI, effects of 10 ppm iNO were evaluated during controlled mechanical ventilation (CMV) and SB in random order. Preservation of SB was provided by 4 different modes: Unassisted SB was enabled by biphasic positive airway pressure (BIPAP), moderate inspiratory assist was provided by pressure support (PS) and volume-assured pressure support (VAPS), maximum assist was ensured by assist control (A/C). Statistical analysis did not reveal gas exchange improvements due to SB alone. Significant gas exchange improvements due to iNO were only achieved during unassisted SB with BIPAP (P <.05) but not during CMV or assisted SB. The authors conclude that effectiveness of iNO may be improved by unassisted SB during BIPAP but not by assisted SB. Thus combined iNO and unassisted SB is possibly most effective to improve gas exchange in severe hypoxemic ARDS.

  4. Protection by N-acetylcysteine against pulmonary endothelial cell damage induced by oxidant injury.

    PubMed

    Sala, R; Moriggi, E; Corvasce, G; Morelli, D

    1993-03-01

    The protective effect of N-acetylcysteine (NAC) against oxidant lung injury was investigated in a model of acute immunological alveolitis in the rat. Intrapulmonary immune complex deposition into rat lungs, induced by intratracheal infusion of immunoglobulin G (IgG) anti-bovine serum albumin (BSA) antibodies and intravenous injection of the antigen, caused lung damage associated with a marked decrease in [14C]5-hydroxytryptamine ([14C]5HT) uptake capacity, taken as a biochemical marker of endothelial cell function. The oral administration of a single dose of NAC (2 mmol.kg-1) 60 min before antigen/antibody (Ag/Ab) treatment was effective in preventing pulmonary endothelial cell [14C]5HT uptake loss induced by immune complex deposition. The mechanisms involved in this lung protective action of NAC were investigated by studying the antioxidant activity of NAC on hypoxanthine/xanthine oxidase-induced lung damage in vitro, and the effectiveness of the drug as lung glutathione (reduced form) (GSH) precursor in diethylmaleate-depleted rats. The results obtained provide further evidence on the ability of NAC to reduce the susceptibility of lung tissue to free radical-induced damage, by potentiating the antioxidant defence systems.

  5. A case of chemical scalp burns after hair highlights: experimental evidence of oxidative injuries.

    PubMed

    Bertani, Roberta; Sgarbossa, Paolo; Pendolino, Flavio; Facchin, Giangiacomo; Snenghi, Rossella

    2016-12-01

    Hair highlights are quite common procedures carried out in hair salons by using a mixture of a lightening powder containing persulfates with a suspension containing hydrogen peroxide: a representative case of chemical scalp burns is described as a consequence of this treatment. The aim of the paper is to demonstrate the strict relationship between the scalp damage and the commercial products used in a case of hair highlighting. The results of some chemical analyses have been reported, showing, in particular, that the chemical reactivity of the mixture changes in the time, thus strongly suggesting that the procedure for the application of the mixture is critical for the occurrence of possible accidents. The presence in the powder of chemical compounds bearing aliphatic chains as surfactants explains the appearance of dramatic symptoms after days due to a slow dissolution of the oxidant compounds in the stratum corneum of skin with no effect in reducing injury of palliative treatments. Safety suggestions and recommendations for producers and workers are also included.

  6. Sensorineural hearing loss and ischemic injury: Development of animal models to assess vascular and oxidative effects.

    PubMed

    Olivetto, E; Simoni, E; Guaran, V; Astolfi, L; Martini, A

    2015-09-01

    Hearing loss may be genetic, associated with aging or exposure to noise or ototoxic substances. Its aetiology can be attributed to vascular injury, trauma, tumours, infections or autoimmune response. All these factors could be related to alterations in cochlear microcirculation resulting in hypoxia, which in turn may damage cochlear hair cells and neurons, leading to deafness. Hypoxia could underlie the aetiology of deafness, but very few data about it are presently available. The aim of this work is to develop animal models of hypoxia and ischemia suitable for study of cochlear vascular damage, characterizing them by electrophysiology and gene/protein expression analyses. The effects of hypoxia in infarction were mimicked in rat by partial permanent occlusion of the left coronary artery, and those of ischemia in thrombosis by complete temporary carotid occlusion. In our models both hypoxia and ischemia caused a small but significant hearing loss, localized at the cochlear apex. A slight induction of the coagulation cascade and of oxidative stress pathways was detected as cell survival mechanism, and cell damages were found on the cuticular plate of outer hair cells only after carotid ischemia. Based on these data, the two developed models appear suitable for in vivo studies of cochlear vascular damage.

  7. rAAV/ABAD-DP-6His attenuates oxidative stress-induced injury of PC12 cells

    PubMed Central

    Jia, Mingyue; Wang, Mingyu; Yang, Yi; Chen, Yixin; Liu, Dujuan; Wang, Xu; Song, Lei; Wu, Jiang; Yang, Yu

    2014-01-01

    Our previous studies have revealed that amyloid β (Aβ)-binding alcohol dehydrogenase (ABAD) decoy peptide antagonizes Aβ42-induced neurotoxicity. However, whether it improves oxidative stress injury remains unclear. In this study, a recombinant adenovirus constitutively secreting and expressing Aβ-ABAD decoy peptide (rAAV/ABAD-DP-6His) was successfully constructed. Our results showed that rAAV/ABAD-DP-6His increased superoxide dismutase activity in hydrogen peroxide-induced oxidative stress-mediated injury of PC12 cells. Moreover, rAAV/ABAD-DP-6His decreased malondialdehyde content, intracellular Ca2+ concentration, and the level of reactive oxygen species. rAAV/ABAD-DP-6His maintained the stability of the mitochondrial membrane potential. In addition, the ATP level remained constant, and apoptosis was reduced. Overall, the results indicate that rAAV/ABAD-DP-6His generates the fusion peptide, Aβ-ABAD decoy peptide, which effectively protects PC12 cells from oxidative stress injury induced by hydrogen peroxide, thus exerting neuroprotective effects. PMID:25206842

  8. Time course changes of oxidative stress and inflammation in hyperoxia-induced acute lung injury in rats

    PubMed Central

    Yu, Shouli; Shi, Min; Liu, Changting; Liu, Qinghui; Guo, Jun; Yu, Senyang; Jiang, Tingshu

    2015-01-01

    Objective(s): Therapies with high levels of oxygen are commonly used in the management of critical care. However, prolonged exposure to hyperoxia can cause acute lung injury. Although oxidative stress and inflammation are purported to play an important role in the pathogenesis of acute lung injury, the exact mechanisms are still less known in the hyperoxic acute lung injury (HALI). Materials and Methods: In this study, we investigated the time course changes of oxidative stress and inflammation in lung tissues of rats exposed to >95% oxygen for 12-60 hr. Results: We found that at 12 hr after hyperoxia challenge, the activities of superoxide dismutase and glutathione peroxidase were significantly reduced with remarkably increased lipid peroxidation. At 12 hr, NF-κB p65 expression was also upregulated, but Iκ-Bα expression showed a remarkable decline. Significant production of inflammatory mediators, e.g, interleukin-1β, occurred 24 hr after hyperoxia exposure. In addition, the expression of intracellular adhesion molecule 1 expression and the activity of myeloperoxidase were significantly increased at 24 hr with a peak at 48 hr. Conclusion: Our data support that hyperoxia-induced oxidative damage and NF-κB pathway activation implicate in the early phase of HALI pathogenesis. PMID:25810882

  9. Effects of carnosine, taurine, and betaine pretreatments on diethylnitrosamine-induced oxidative stress and tissue injury in rat liver.

    PubMed

    Başaran-Küçükgergin, C; Bingül, I; Tekkeşin, M Soluk; Olgaç, V; Doğru-Abbasoğlu, S; Uysal, M

    2016-08-01

    Several chemicals such as N-diethylnitrosamine (DEN) promote hepatocellular cancer in rodents and induce hepatocyte injury. DEN affects the initiation stage of carcinogenesis together with enhanced cell proliferation accompanied by hepatocellular necrosis. DEN-induced hepatocellular necrosis is reported to be related to enhanced generation of reactive oxygen species. Carnosine (CAR), taurine (TAU), and betaine (BET) are known to have powerful antioxidant properties. We aimed to investigate the effects of CAR, TAU, and BET pretreatments on DEN-induced oxidative stress and liver injury in male rats. Rats were given CAR (2 g L(-1) in drinking water), TAU (2.5% in chow), and BET (2.5% in chow) for 6 weeks and DEN (200 mg kg(-1) intraperitoneally) was given 2 days before the end of this period. Serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and γ-glutamyl transferase activities were determined and a histopathologic evaluation was performed on the liver tissue. Oxidative stress was detected in the liver by measuring malondialdehyde, diene conjugate, protein carbonyl and nitrotyrosine levels, glutathione and glutathione peroxidase levels, and superoxide dismutase and glutathione transferase activities. Pretreatments with CAR, TAU, and BET decreased liver prooxidant status without remarkable changes in antioxidant parameters in DEN-treated rats. Pretreatments with TAU and BET, but not CAR, were also found to be effective to reduce liver damage in DEN-treated rats. In conclusion, TAU, BET, and possibly CAR may have an ameliorating effect on DEN-induced hepatic injury by reducing oxidative stress in rats.

  10. Effect of environmental particulates on cultured human and bovine endothelium. Cellular injury via an oxidant-dependent pathway

    SciTech Connect

    Garcia, J.G.; Dodson, R.F.; Callahan, K.S.

    1989-07-01

    The effects of respirable environmental fibers on cultures of human umbilical vein and bovine pulmonary artery endothelial cell monolayers were studied. Interaction among endothelial cell monolayers and amosite and chrysotile asbestos, attapulgite, fiberglass, or latex beads resulted in rapid phagocytosis of the particulates. A gradient of time-dependent and concentration-dependent endothelial cell injury (measured by specific 51Cr release) was observed with amosite and attapulgite being markedly toxic. Chrysotile and fiberglass were much less toxic, and latex beads were not significantly injurious at any time or dose examined. Responses of bovine pulmonary artery and human endothelial vein endothelial cells to fiber phagocytosis and fiber-induced injury were similar. In human umbilical cell monolayers, fiber-mediated stimulation of the arachidonate metabolite prostacyclin paralleled endothelial cell injury; i.e. amosite and attapulgite were stimulatory, whereas fiberglass (0-500 micrograms/ml) and latex beads (10(9) beads/ml) did not significantly increase prostacyclin generation. Although chrysotile was only weakly cytotoxic, significant stimulation of prostacyclin was observed at the highest dose tested (500 micrograms/ml). To investigate whether toxic oxygen species may be involved in fiber-induced cytotoxicity, oxidant scavengers or inhibitors were used in injury studies. Both superoxide dismutase (a scavenger of O2-) and catalase (an inhibitor of H2O2) produced significant protection against fiber-mediated endothelial cell injury. In addition, chelation by deferoxamine of elemental Fe present in the fiber preparations was also protective, suggesting Fe, via the modified Haber-Weiss reaction, may promote hydroxyl radical formation and contribute to endothelial cell injury induced by these particulates.

  11. Lung injury via oxidative stress in mice induced by inhalation exposure to rocket kerosene.

    PubMed

    Xu, Bingxin; Li, Chenglin; Wang, Jianying; Wu, Jihua; Si, Shaoyan; Liu, Zhiguo; Li, Jianzhong; Zhang, Jianzhong; Cui, Yan

    2015-01-01

    injury was through the oxidative stress, inhibition of oxidative stress after RK exposure may be urgently needed.

  12. Lung injury via oxidative stress in mice induced by inhalation exposure to rocket kerosene

    PubMed Central

    Xu, Bingxin; Li, Chenglin; Wang, Jianying; Wu, Jihua; Si, Shaoyan; Liu, Zhiguo; Li, Jianzhong; Zhang, Jianzhong; Cui, Yan

    2015-01-01

    injury was through the oxidative stress, inhibition of oxidative stress after RK exposure may be urgently needed. PMID:26191256

  13. Inhibition of Nitro-Oxidative Stress Attenuates Pulmonary and Systemic Injury Induced by High-Tidal Volume Mechanical Ventilation.

    PubMed

    Martínez-Caro, Leticia; Nin, Nicolás; Sánchez-Rodríguez, Carolina; Ferruelo, Antonio; El Assar, Mariam; de Paula, Marta; Fernández-Segoviano, Pilar; Esteban, Andrés; Lorente, José A

    2015-07-01

    Mechanisms contributing to pulmonary and systemic injury induced by high tidal volume (VT) mechanical ventilation are not well known. We tested the hypothesis that increased peroxynitrite formation is involved in organ injury and dysfunction induced by mechanical ventilation. Male Sprague-Dawley rats were subject to low- (VT, 9 mL/kg; positive end-expiratory pressure, 5 cmH2O) or high- (VT, 25 mL/kg; positive end-expiratory pressure, 0 cmH2O) VT mechanical ventilation for 120 min, and received 1 of 3 treatments: 3-aminobenzamide (3-AB, 10 mg/kg, intravenous, a poly adenosine diphosphate ribose polymerase [PARP] inhibitor), or the metalloporphyrin manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP, 5 mg/kg intravenous, a peroxynitrite scavenger), or no treatment (control group), 30 min before starting the mechanical ventilation protocol (n = 8 per group, 6 treatment groups). We measured mean arterial pressure, peak inspiratory airway pressure, blood chemistry, and gas exchange. Oxidation (fluorescence for oxidized dihydroethidium), protein nitration (immunofluorescence and Western blot for 3-nitrotyrosine), PARP protein (Western blot) and gene expression of the nitric oxide (NO) synthase (NOS) isoforms (quantitative real-time reverse transcription polymerase chain reaction) were measured in lung and vascular tissue. Lung injury was quantified by light microscopy. High-VT mechanical ventilation was associated with hypotension, increased peak inspiratory airway pressure, worsened oxygenation; oxidation and protein nitration in lung and aortic tissue; increased PARP protein in lung; up-regulation of NOS isoforms in lung tissue; signs of diffuse alveolar damage at histological examination. Treatment with 3AB or MnTMPyP attenuated the high-VT mechanical ventilation-induced changes in pulmonary and cardiovascular function; down-regulated the expression of NOS1, NOS2, and NOS3; decreased oxidation and nitration in lung and aortic tissue; and attenuated

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

    SciTech Connect

    Li, Weixin; Wu, Mingchai; Tang, Longguang; Pan, Yong; Liu, Zhiguo; Zeng, Chunlai; Wang, Jingying; Wei, Tiemin; Liang, Guang

    2015-01-15

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

  15. Catalpol Protects Pre-Myelinating Oligodendrocytes against Ischemia-induced Oxidative Injury through ERK1/2 Signaling Pathway

    PubMed Central

    Cai, Qiyan; Ma, Teng; Li, Chengren; Tian, Yanping; Li, Hongli

    2016-01-01

    The vulnerability of pre-myelinating oligodendrocytes (PreOLs) to ischemic injury plays an important role in the pathogenesis and progression of perinatal white matter injury. Although oxidative stress is thought to be a major pathogenic mechanism predisposing the PreOLs to injury, no effective therapies have been identified to date. The present study aimed to investigate the direct protective effects of catalpol, a potent antioxidant and free radical scavenger, on ischemia-induced oxidative damage in PreOLs and to explore whether the ERK1/2 signaling pathway contributed to the protection provided by catalpol. Primary cultures of PreOLs exposed to oxygen-glucose deprivation (OGD) followed by reperfusion were used as an in vitro model of ischemia. Pretreatment with 0.5 mM catalpol for 1 h prior to OGD treatment significantly reversed ischemia-induced apoptosis in PreOLs and myelination deficits by inhibiting intracellular Ca2+ increase, reducing mitochondrial damage, and ameliorating overproduction of reactive oxygen species (ROS). The expression levels of phosphorylated ERK1/2 (p-ERK1/2) and activated poly-ADP-ribose polymerase-1 (PARP-1) were also markedly decreased by catalpol treatment. Blocking the ERK1/2 signaling pathway with the MEK inhibitor U0126 and catalpol significantly protected PreOLs from ROS-mediated apoptosis under OGD. Taken together, these results suggest that catalpol protects PreOLs against ischemia-induced oxidative injury through ERK1/2 signaling pathway. Catalpol may be a candidate for treating ischemic white matter damage. PMID:27994507

  16. Protocatechuic Aldehyde Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Nox-Mediated Oxidative Stress and Renal Inflammation.

    PubMed

    Gao, Li; Wu, Wei-Feng; Dong, Lei; Ren, Gui-Ling; Li, Hai-Di; Yang, Qin; Li, Xiao-Feng; Xu, Tao; Li, Zeng; Wu, Bao-Ming; Ma, Tao-Tao; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Li, Jun; Meng, Xiao-Ming

    2016-01-01

    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 high 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 (Lamiaceae). 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 blocks 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 receiving cisplatin treatment.

  17. Protocatechuic Aldehyde Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Nox-Mediated Oxidative Stress and Renal Inflammation

    PubMed Central

    Gao, Li; Wu, Wei-Feng; Dong, Lei; Ren, Gui-Ling; Li, Hai-Di; Yang, Qin; Li, Xiao-Feng; Xu, Tao; Li, Zeng; Wu, Bao-Ming; Ma, Tao-Tao; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Li, Jun; Meng, Xiao-Ming

    2016-01-01

    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 high 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 (Lamiaceae). 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 blocks 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 receiving cisplatin treatment. PMID:27999546

  18. Effects of triterpenoid from Schisandra chinensis on oxidative stress in alcohol-induced liver injury in rats.

    PubMed

    Li, Bin; Zhu, Lijie; Wu, Ting; Zhang, Jiachen; Jiao, Xinyao; Liu, Xiuying; Wang, Yanqun; Meng, Xianjun

    2015-03-01

    Alcohol-induced oxidative stress plays a crucial role in the pathological development of alcoholic liver disease. The aim of this study was to investigate the effects of triterpenoid from Schisandra chinensis on oxidative stress in alcohol-induced liver injury in rats. We found that the administration of triterpenoid attenuated alcohol-induced oxidative stress in multiple organs including liver. Moreover, the impaired liver function and histological changes resulted from alcohol consumption was improved by triterpenoid treatment. Finally, we found that pretreatment with triterpenoid from Schisandra chinensis to alcohol-fed rats increased the expression level of haem oxygenase-1 (HO-1) while inhibited the induction of cytochrome P-450 2E1 (CYP2E1) in liver microsomes. Further assays revealed that the microsomal activity of HO-1 was accordingly induced whereas CYP2E1 was suppressed in rats received triterpenoid intervention. Our findings suggest that triterpenoid from Schisandra chinensis may protect against alcohol-induced liver injury through ameliorating oxidative stress in rats.

  19. The ameliorative effect of thymol against hydrocortisone-induced hepatic oxidative stress injury in adult male rats.

    PubMed

    Aboelwafa, Hanaa R; Yousef, Hany N

    2015-08-01

    The aim of the present study was to investigate whether hydrocortisone induces oxidative stress in hepatocytes and to evaluate the possible ameliorative effect of thymol against such hepatic injury. Twenty-four adult male rats were divided into control, thymol, hydrocortisone, and hydrocortisone+thymol groups. The 4 groups were treated daily for 15 days. Hydrocortisone significantly induced oxidative stress in the liver tissues, marked by increased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total oxidative capacity (TOC), and tumor necrosis factor-alpha (TNF-α) accompanied by marked decline of serum levels of total protein, albumin, and total antioxidant capacity (TAC). Also, marked elevation in the levels of the thiobarbituric acid reactive substances (TBARS) and TNF-α, beside significant decrease in the level of glutathione (GSH) in hepatic tissues were recorded. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal hepatic architecture, in addition to ultrastructural alterations represented by degenerative features covering almost all the cytoplasmic organelles of the hepatocytes. Supplementation of hydrocortisone-treated rats with thymol reversed most of the biochemical, histological, and ultrastructural alterations. The results of our study confirm that thymol has strong ameliorative effect against hydrocortisone-induced oxidative stress injury in hepatic tissues.

  20. The effect of melatonin on oxidative stress and apoptosis in experimental diabetes mellitus-related ovarian injury.

    PubMed

    Nayki, Umit; Onk, Didem; Balci, Gurhan; Nayki, Cenk; Onk, Alper; Çankaya, Murat; Taskın Kafa, Ayse Humeyra; Kuzucu, Mehmet

    2016-01-01

    We aimed to evaluate the effect of melatonin on oxidative stress and ovarian injury in rats. Twenty-four Sprague-Dawley albino rats were divided into three groups: Group 1 as nondiabetic healthy controls (n = 8), group 2 as nontreated diabetic rats (n = 8) and group 3 as melatonin-treated diabetic rats (n = 8). After overt diabetes was produced by intraperitoneal injection of streptozosin, 20 mg/kg/day of melatonin was given intraperitoneally to group 3 for a week. NF-kB and caspase-3 immunoexpressions, lipid peroxidation, the activities of antioxidative enzymes, total oxidant capacity and total antioxidant capacity were assessed. Immunoexpressions of NF-kB and caspase-3 were significantly lower in group 3 than group 2. There was a significant decrease in superoxide dismutase activity in group 2 than group 1 and a significant increase in group 3 compared with group 2. We observed a nonsignificant decrease in catalase activity between group 1 and group 2 and a nonsignificant increase between group 2 and group 3. There was a nonsignificant increase in the plasma level of total oxidant status in group 2 than group 1, but a significant decrease was observed in group 3 compared to group 2. Total antioxidant status was significantly lower in group 2 compared with group 1 and group 3. In conclusion, melatonin ameliorates the negative effects of oxidative stress on DM-related ovarian injury.

  1. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.

    PubMed

    Jaeschke, Hartmut; McGill, Mitchell R; Ramachandran, Anup

    2012-02-01

    Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through the formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and, eventually, to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in a collapse of mitochondrial membrane potential and cessation of adenosine triphosphate synthesis. In addition, the release of intermembrane proteins, such as apoptosis-inducing factor and endonuclease G, and their translocation to the nucleus, leads to nuclear DNA fragmentation. Together, these events trigger necrotic cell death. Alternatively, the release of cytochrome c and other proapoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with the formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury.

  2. Agaricoglycerides Protect against Hepatic Ischemia/Reperfusion Injury by Attenuating Inflammatory Response, Oxidative Stress, and Expression of NF-κB

    PubMed Central

    Zhao, Xiang-qian; Liang, Bin; Liu, Yang; Huang, Xiao-qiang

    2015-01-01

    We have investigated the effects of agaricoglycerides (AG) in a mouse model of hepatic I/R injury. I/R triggered increases/changes in markers of liver injury, hepatic oxidative stress, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nuclear factor κB (NF-κB). AG significantly reduced the extent of liver inflammation and oxidative stress and also attenuated the NF-κB activation as well as TNF-α and IL-1β production. Our results indicate that AG may represent a novel protective strategy against I/R-induced injury and inflammatory diseases. PMID:25960746

  3. Homer1a attenuates glutamate-induced oxidative injury in HT-22 cells through regulation of store-operated calcium entry

    PubMed Central

    Rao, Wei; Peng, Cheng; Zhang, Lei; Su, Ning; Wang, Kai; Hui, Hao; Dai, Shu-hui; Yang, Yue-fan; Luo, Peng; Fei, Zhou

    2016-01-01

    Calcium disequilibrium is extensively involved in oxidative stress-induced neuronal injury. Although Homer1a is known to regulate several neuronal calcium pathways, its effects on, or its exact relationship with, oxidative stress-induced neuronal injury has not yet been fully elucidated. We found that Homer1a protected HT-22 cells from glutamate-induced oxidative stress injury by inhibiting final-phase intracellular calcium overload and mitochondrial oxidative stress. In these cells, stromal interactive molecule 1 (STIM1) puncta, but not the protein level, was significantly increased after glutamate treatment. Store-operated calcium entry (SOCE) inhibitors and cells in which a key component of SOCE (STIM1) was knocked out were used as glutamate-induced oxidative stress injury models. Both models demonstrated significant improvement of HT-22 cell survival after glutamate treatment. Additionally, increased Homer1a protein levels significantly inhibited SOCE and decreased the association of STIM1-Orai1 triggered by glutamate. These results suggest that up-regulation of Homer1a can protect HT-22 cells from glutamate-induced oxidative injury by disrupting the STIM1-Oria1 association, and then by inhibiting the SOCE-mediated final-phrase calcium overload. Thus, regulation of Homer1a, either alone or in conjunction with SOCE inhibition, may serve as key therapeutic interventional targets for neurological diseases in which oxidative stress is involved in the etiology or progression of the disease. PMID:27681296

  4. Endoplasmic reticulum stress is involved in arsenite-induced oxidative injury in rat brain

    SciTech Connect

    Lin, Anya M.Y.; Chao, P.L.; Fang, S.F.; Chi, C.W.; Yang, C.H.

    2007-10-15

    The mechanism underlying sodium arsenite (arsenite)-induced neurotoxicity was investigated in rat brain. Arsenite was locally infused in the substantia nigra (SN) of anesthetized rat. Seven days after infusion, lipid peroxidation in the infused SN was elevated and dopamine level in the ipsilateral striatum was reduced in a concentration-dependent manner (0.3-5 nmol). Furthermore, local infusion of arsenite (5 nmol) decreased GSH content and increased expression of heat shock protein 70 and heme oxygenase-1 in the infused SN. Aggregation of {alpha}-synuclein, a putative pathological protein involved in several CNS neurodegenerative diseases, was elevated in the arsenite-infused SN. From the breakdown pattern of {alpha}-spectrin, both necrosis and apoptosis were involved in the arsenite-induced neurotoxicity. Pyknotic nuclei, cellular shrinkage and cytoplasmic disintegration, indicating necrosis, and TUNEL-positive cells and DNA ladder, indicating apoptosis was observed in the arsenite-infused SN. Arsenite-induced apoptosis was mediated via two different organelle pathways, mitochondria and endoplasmic reticulum (ER). For mitochondrial activation, cytosolic cytochrome c and caspase-3 levels were elevated in the arsenite-infused SN. In ER pathway, arsenite increased activating transcription factor-4, X-box binding protein 1, C/EBP homologues protein (CHOP) and cytosolic immunoglobulin binding protein levels. Moreover, arsenite reduced procaspase 12 levels, an ER-specific enzyme in the infused SN. Taken together, our study suggests that arsenite is capable of inducing oxidative injury in CNS. In addition to mitochondria, ER stress was involved in the arsenite-induced apoptosis. Arsenite-induced neurotoxicity clinically implies a pathophysiological role of arsenite in CNS neurodegeneration.

  5. Is oxidative stress primarily involved in reperfusion injury of the ischemic heart

    SciTech Connect

    Nohl, H.; Stolze, K.; Napetschnig, S.; Ishikawa, T. )

    1991-01-01

    Reperfusion injury of ischemic organs is suggested to result from metabolic derangements initiating an imbalanced formation of free oxygen radicals. Most investigators in this field have used the spin-trap 5,5'-dimethyl-N-pyrroline-N-oxide (DMPO) to stabilize these short-lived radicals and make them visible by means of the electron spin resonance (ESR) technique. ESR signals obtained from intravascular DMPO were reported to indicate the formation of free OH. radicals and, in some cases, also carbon-centered radicals. We were unable to confirm these findings. Carbon-centered radicals were not obtained irrespectively of conditions studied, while oxygen-centered DMPO-adducts could only be detected in minor amounts. Instead, we observed an ascorbyl-related ESR signal. The addition of ethylenediaminetetraacetic acid (EDTA), which was used by many investigators in this field, was found to greatly influence ESR-spectra of the reperfusion fluid. The ascorbyl radical concentration was clearly reduced and the DMPO-OH. adduct became more prominent. The addition of iron further stimulated this change eliciting a Fenton-type reaction responsible for DMPO-OH.-related ESR spectra in the perfusate after ischemia. Accordingly, we observed the release of iron and ascorbic acid into the perfusate as a consequence of ischemia. We could demonstrate that iron in the presence of ascorbate and EDTA causes both types of radicals detected in the perfusate. DMPO-OH. generation in the presence of EDTA was found to result from free OH. radicals that were not generated in the absence of EDTA.

  6. Neuronal oxidative injury and dendritic damage induced by carbofuran: Protection by memantine

    SciTech Connect

    Gupta, Ramesh C. . E-mail: ramesh.gupta@murraystate.edu; Milatovic, Snjezana; Dettbarn, Wolf-D.; Aschner, Michael; Milatovic, Dejan

    2007-03-15

    Carbamate insecticides mediate their neurotoxicity by acetylcholinesterase (AChE) inactivation. Male Sprague-Dawley rats acutely intoxicated with the carbamate insecticide carbofuran (1.5 mg/kg, sc) developed hypercholinergic signs within 5-7 min of exposure, with maximal severity characterized by seizures within 30-60 min, lasting for about 2 h. At the time of peak severity, compared with controls, AChE was maximally inhibited (by 82-90%), radical oxygen species (ROS) markers (F{sub 2}-isoprostanes, F{sub 2}-IsoPs; and F{sub 4}-neuroprostanes, F{sub 4}-NeuroPs) were elevated 2- to 3-fold, and the radical nitrogen species (RNS) marker citrulline was elevated 4- to 8-fold in discrete brain regions (cortex, amygdala, and hippocampus). In addition, levels of high-energy phosphates (HEPs) were significantly reduced (ATP, by 43-56%; and phosphocreatine, by 37-48%). Values of total adenine nucleotides and total creatine compounds declined markedly (by 41-56% and 35-45%, respectively), while energy charge potential remained unchanged. Quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant decreases in dendritic lengths (by 64%) and spine density (by 60%). Pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (18 mg/kg, sc), in combination with atropine sulfate (16 mg/kg, sc), significantly attenuated carbofuran-induced changes in AChE activity and levels of F{sub 2}-IsoPs and F{sub 4}-NeuroPs, declines in HEPs, as well as the alterations in morphology of hippocampal neurons. MEM and ATS pretreatment also protected rats from carbofuran-induced hypercholinergic behavioral activity, including seizures. These findings support the involvement of ROS and RNS in seizure-induced neuronal injury and suggest that memantine by preventing carbofuran-induced neuronal hyperactivity blocks pathways associated with oxidative damage in neurons.

  7. Effect of inhaled nitric oxide on pulmonary hemodynamics after acute lung injury in dogs

    SciTech Connect

    Romand, J.A.; Pinsky, M.R.; Firestone, L.; Zar, H.A.; Lancaster, J.R. Jr. )

    1994-03-01

    Increased pulmonary vascular resistance (PVR) and mismatch in ventilation-to-perfusion ratio characterize acute lung injury (ALI). Pulmonary arterial pressure (Ppa) decreases when nitric oxide (NO) is inhaled during hypoxic pulmonary vasoconstriction (HPV); thus NO inhalation may reduce PVR and improve gas exchange in ALI. The authors studied the hemodynamic and gas exchange effects of NO inhalation during HPV and then ALI in eight anesthetized open-chest mechanically ventilated dogs. Right atrial pressure, Ppa, and left ventricular and arterial pressures were measured, and cardiac output was estimated by an aortic flow probe. Shunt and dead space were also estimated. The effect of 5-min exposures to 0, 17, 28, 47, and 0 ppm inhaled NO was recorded during hyperoxia, hypoxia, and oleic acid-induced ALI. During ALI, partial [beta]-adrenergic blockage (propanolol, 0.15 mg/kg iv) was induced and 74 ppm NO was inhaled. Nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) levels were measured. During hyperoxia, NO inhalation had no measurable effects. Hypoxia increased Ppa and calculated PVR, both of which decreased with 17 ppm NO. ALI decreased arterial Po[sub 2] and increased airway pressure, shunt, and dead space ventilation. Ppa and PVR were greater during ALI than during hyperoxia. NO inhalation had no measurable effect during ALI before or after [beta]-adrenergic blockage. MetHb remained low, and NO-Hb was unmeasurable. Bolus infusion of nitroglycerin (15 [mu]g) induced an immediate decrease in Ppa and PVR during ALI. Short-term NO inhalation does not affect PVR or gas exchange in dogs with oleic acid-induced ALI, nor does it increase NO-Hb or MetHb. In contrast, NO can diminish hypoxia-induced elevations in pulmonary vascular tone. These data suggest that NO inhalation selectively dilates the pulmonary circulation and specifically reduces HPV but not oleic acid-induced increases in pulmonary vasomotor tone. 28 refs., 3 figs., 2 tabs.

  8. Apigenin Attenuates Oxidative Injury in ARPE-19 Cells thorough Activation of Nrf2 Pathway

    PubMed Central

    Li, Min; Chen, Weiwei; Yu, Haitao; Yang, Yan; Hang, Li

    2016-01-01

    The current study was aimed at evaluating the therapeutic implication of apigenin and to elucidate the underlying mechanism. The tert-butyl hydroperoxide (t-BHP) at 200 μM was used to induce oxidative stress-associated injury in ARPE-19 cells. Apigenin at concentrations less than 800 μM did not cause cytotoxic effects on ARPE-19 cells. Cell viability assay showed that apigenin at 200 μM significantly promoted cell survival in t-BHP-treated ARPE-19 cells. Additionally, apigenin at 100 μM significantly protected ARPE-19 cells from t-BHP-induced apoptosis. Molecular examinations demonstrated that apigenin at 400 μM significantly upregulated the mRNA and protein expression of Nrf2 and stimulated its nuclear translocation in ARPE-19 cells treated with or without t-BHP. Apigenin 400 μM also significantly elevated the expression of HO-1, NQO1, and GCLM at both mRNA and protein levels in the presence or absence of t-BHP. Furthermore, apigenin at 400 μM significantly increased the activities of SOD, CAT, GSH-PX, and T-AOC and reduced the levels of ROS and MDA in t-BHP-treated ARPE-19 cells. However, these effects of apigenin were all abolished by being transfected with Nrf2 siRNA. Collectively, our current data indicated that apigenin exerted potent antioxidant properties in ARPE-19 cells challenged with t-BHP, which were dependent on activation of Nrf2 signaling. PMID:27656262

  9. Apigenin Attenuates Oxidative Injury in ARPE-19 Cells thorough Activation of Nrf2 Pathway.

    PubMed

    Xu, Xinrong; Li, Min; Chen, Weiwei; Yu, Haitao; Yang, Yan; Hang, Li

    The current study was aimed at evaluating the therapeutic implication of apigenin and to elucidate the underlying mechanism. The tert-butyl hydroperoxide (t-BHP) at 200 μM was used to induce oxidative stress-associated injury in ARPE-19 cells. Apigenin at concentrations less than 800 μM did not cause cytotoxic effects on ARPE-19 cells. Cell viability assay showed that apigenin at 200 μM significantly promoted cell survival in t-BHP-treated ARPE-19 cells. Additionally, apigenin at 100 μM significantly protected ARPE-19 cells from t-BHP-induced apoptosis. Molecular examinations demonstrated that apigenin at 400 μM significantly upregulated the mRNA and protein expression of Nrf2 and stimulated its nuclear translocation in ARPE-19 cells treated with or without t-BHP. Apigenin 400 μM also significantly elevated the expression of HO-1, NQO1, and GCLM at both mRNA and protein levels in the presence or absence of t-BHP. Furthermore, apigenin at 400 μM significantly increased the activities of SOD, CAT, GSH-PX, and T-AOC and reduced the levels of ROS and MDA in t-BHP-treated ARPE-19 cells. However, these effects of apigenin were all abolished by being transfected with Nrf2 siRNA. Collectively, our current data indicated that apigenin exerted potent antioxidant properties in ARPE-19 cells challenged with t-BHP, which were dependent on activation of Nrf2 signaling.

  10. Protective effects of hydrogen sulfide inhalation on oxidative stress in rats with cotton smoke inhalation-induced lung injury

    PubMed Central

    HAN, ZHI-HAI; JIANG, YI; DUAN, YUN-YOU; WANG, XIAO-YANG; HUANG, YAN; FANG, TING-ZHENG

    2015-01-01

    The aim of the present study was to investigate the mechanism by which hydrogen sulfide (H2S) inhalation protects against oxidative stress in rats with cotton smoke inhalation-induced lung injury. A total of 24 male Sprague-Dawley rats were separated randomly into four groups, which included the control, H2S, smoke and smoke + H2S groups. A rat model of cotton smoke inhalation-induced lung injury was established following inhalation of 30% oxygen for 6 h. In addition, H2S (80 ppm) was inhaled by the rats in the H2S and smoke + H2S groups for 6 h following smoke or sham-smoke inhalation. Enzyme-linked immunosorbent assays were performed to measure various indices in the rat lung homogenate, while the levels of nuclear factor (NF)-κBp65 in the lung tissue of the rats were determined and semiquantitatively analyzed using immunohistochemistry. In addition, quantitative fluorescence polymerase chain reaction was employed to detect the mRNA expression of inducible nitric oxide synthase (iNOS) in the rat lung tissue. The concentrations of malondialdehyde (MDA), nitric oxide (NO), inducible iNOS and NF-κBp65, as well as the sum-integrated optical density of NF-κBp65 and the relative mRNA expression of iNOS, in the rat lung tissue from the smoke + H2S group were significantly lower when compared with the smoke group. The concentrations of MDA, NO, iNOS and NF-κBp65 in the H2S group were comparable to that of the control group. Therefore, inhalation of 80 ppm H2S may reduce iNOS mRNA transcription and the production of iNOS and NO in rats by inhibiting NF-κBp65 activation, subsequently decreasing oxidative stress and cotton smoke inhalation-induced lung injury. PMID:26170929

  11. Health Risks of Space Exploration: Targeted and Nontargeted Oxidative Injury by High-Charge and High-Energy Particles

    PubMed Central

    Li, Min; Gonon, Géraldine; Buonanno, Manuela; Autsavapromporn, Narongchai; de Toledo, Sonia M.; Pain, Debkumar

    2014-01-01

    Abstract Significance: During deep space travel, astronauts are often exposed to high atomic number (Z) and high-energy (E) (high charge and high energy [HZE]) particles. On interaction with cells, these particles cause severe oxidative injury and result in unique biological responses. When cell populations are exposed to low fluences of HZE particles, a significant fraction of the cells are not traversed by a primary radiation track, and yet, oxidative stress induced in the targeted cells may spread to nearby bystander cells. The long-term effects are more complex because the oxidative effects persist in progeny of the targeted and affected bystander cells, which promote genomic instability and may increase the risk of age-related cancer and degenerative diseases. Recent Advances: Greater understanding of the spatial and temporal features of reactive oxygen species bursts along the tracks of HZE particles, and the availability of facilities that can simulate exposure to space radiations have supported the characterization of oxidative stress from targeted and nontargeted effects. Critical Issues: The significance of secondary radiations generated from the interaction of the primary HZE particles with biological material and the mitigating effects of antioxidants on various cellular injuries are central to understanding nontargeted effects and alleviating tissue injury. Future Directions: Elucidation of the mechanisms underlying the cellular responses to HZE particles, particularly under reduced gravity and situations of exposure to additional radiations, such as protons, should be useful in reducing the uncertainty associated with current models for predicting long-term health risks of space radiation. These studies are also relevant to hadron therapy of cancer. Antioxid. Redox Signal. 20, 1501–1523. PMID:24111926

  12. Detoxification of Mitochondrial Oxidants and Apoptotic Signaling Are Facilitated by Thioredoxin-2 and Peroxiredoxin-3 during Hyperoxic Injury

    PubMed Central

    Forred, Benjamin J.; Daugaard, Darwin R.; Titus, Brianna K.; Wood, Ryan R.; Floen, Miranda J.; Booze, Michelle L.

    2017-01-01

    Mitochondria play a fundamental role in the regulation of cell death during accumulation of oxidants. High concentrations of atmospheric oxygen (hyperoxia), used clinically to treat tissue hypoxia in premature newborns, is known to elicit oxidative stress and mitochondrial injury to pulmonary epithelial cells. A consequence of oxidative stress in mitochondria is the accumulation of peroxides which are detoxified by the dedicated mitochondrial thioredoxin system. This system is comprised of the oxidoreductase activities of peroxiredoxin-3 (Prx3), thioredoxin-2 (Trx2), and thioredoxin reductase-2 (TrxR2). The goal of this study was to understand the role of the mitochondrial thioredoxin system and mitochondrial injuries during hyperoxic exposure. Flow analysis of the redox-sensitive, mitochondrial-specific fluorophore, MitoSOX, indicated increased levels of mitochondrial oxidant formation in human adenocarcinoma cells cultured in 95% oxygen. Increased expression of Trx2 and TrxR2 in response to hyperoxia were not attributable to changes in mitochondrial mass, suggesting that hyperoxic upregulation of mitochondrial thioredoxins prevents accumulation of oxidized Prx3. Mitochondrial oxidoreductase activities were modulated through pharmacological inhibition of TrxR2 with auranofin and genetically through shRNA knockdown of Trx2 and Prx3. Diminished Trx2 and Prx3 expression was associated with accumulation of mitochondrial superoxide; however, only shRNA knockdown of Trx2 increased susceptibility to hyperoxic cell death and increased phosphorylation of apoptosis signal-regulating kinase-1 (ASK1). In conclusion, the mitochondrial thioredoxin system regulates hyperoxic-mediated death of pulmonary epithelial cells through detoxification of oxidants and regulation of redox-dependent apoptotic signaling. PMID:28045936

  13. Soy Isoflavone Protects Myocardial Ischemia/Reperfusion Injury through Increasing Endothelial Nitric Oxide Synthase and Decreasing Oxidative Stress in Ovariectomized Rats

    PubMed Central

    Tang, Yan; Li, Shuangyue; Zhang, Ping; Zhu, Jinbiao; Meng, Guoliang; Xie, Liping; Yu, Ying; Ji, Yong; Han, Yi

    2016-01-01

    There is a special role for estrogens in preventing and curing cardiovascular disease in women. Soy isoflavone (SI), a soy-derived phytoestrogen, has similar chemical structure to endogenous estrogen-estradiol. We investigate to elucidate the protective mechanism of SI on myocardial ischemia/reperfusion (MI/R) injury. Female SD rats underwent bilateral ovariectomy. One week later, rats were randomly divided into several groups, sham ovariectomy (control group), ovariectomy with MI/R, or ovariectomy with sham MI/R. Other ovariectomy rats were given different doses of SI or 17β-estradiol (E2). Four weeks later, they were exposed to 30 minutes of left coronary artery occlusion followed by 6 or 24 hours of reperfusion. SI administration significantly reduced myocardial infarct size and improved left ventricle function and restored endothelium-dependent relaxation function of thoracic aortas after MI/R in ovariectomized rats. SI also decreased serum creatine kinase and lactate dehydrogenase activity, reduced plasma malonaldehyde, and attenuated oxidative stress in the myocardium. Meanwhile, SI increased phosphatidylinositol 3 kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) signal pathway. SI failed to decrease infarct size of hearts with I/R in ovariectomized rats if PI3K was inhibited. Overall, these results indicated that SI protects myocardial ischemia/reperfusion injury in ovariectomized rats through increasing PI3K/Akt/eNOS signal pathway and decreasing oxidative stress. PMID:27057277

  14. MitoTEMPO Prevents Oxalate Induced Injury in NRK-52E Cells via Inhibiting Mitochondrial Dysfunction and Modulating Oxidative Stress

    PubMed Central

    Yu, Xiao; Liu, Jihong

    2017-01-01

    As one of the major risks for urolithiasis, hyperoxaluria can be caused by genetic defect or dietary intake. And high oxalate induced renal epithelial cells injury is related to oxidative stress and mitochondrial dysfunction. Here, we investigated whether MitoTEMPO, a mitochondria-targeted antioxidant, could protect against oxalate mediated injury in NRK-52E cells via inhibiting mitochondrial dysfunction and modulating oxidative stress. MitoSOX Red was used to determine mitochondrial ROS (mtROS) production. Mitochondrial membrane potential (Δψm) and quantification of ATP synthesis were measured to evaluate mitochondrial function. The protein expression of Nox4, Nox2, and p22 was also detected to explore the effect of oxalate and MitoTEMPO on NADPH oxidase. Our results revealed that pretreatment with MitoTEMPO significantly inhibited oxalate induced lactate dehydrogenase (LDH) and malondialdehyde (MDA) release and decreased oxalate induced mtROS generation. Further, MitoTEMPO pretreatment restored disruption of Δψm and decreased ATP synthesis mediated by oxalate. In addition, MitoTEMPO altered the protein expression of Nox4 and p22 and decreased the protein expression of IL-6 and osteopontin (OPN) induced by oxalate. We concluded that MitoTEMPO may be a new candidate to protect against oxalate induced kidney injury as well as urolithiasis. PMID:28116040

  15. Progesterone alleviates acute brain injury via reducing apoptosis and oxidative stress in a rat experimental subarachnoid hemorrhage model.

    PubMed

    Cai, Jing; Cao, Shenglong; Chen, Jingyin; Yan, Feng; Chen, Gao; Dai, Yuying

    2015-07-23

    This study aimed to investigate the therapeutic effect of progesterone on acute brain injury after subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage was induced in male Sprague-Dawley rats (n=72) by endovascular perforation. Progesterone (8 mg/kg or 16 mg/kg) was administered to rats at 1, 6, and 12h after SAH. Mortality, neurologic deficits, cell apoptosis, expression of apoptotic markers, the level of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were assayed at 24h after experimental SAH. Mortality, cell apoptosis and the expression of caspase-3 were decreased, and improved neurological function was observed in the progesterone-treated SAH rats. Further, exploration demonstrated that progesterone significantly reduced the ratio of Bax/Bcl-2 and attenuated the release of cytochrome c from mitochondria. Progesterone also induced anti-oxidative effects by elevating the activity of SOD and decreasing MDA content after SAH. Furthermore, dose-response relationships for progesterone treatment were observed, and high doses of progesterone enhanced the neuroprotective effects. Progesterone treatment could alleviate acute brain injury after SAH by inhibiting cell apoptosis and decreasing damage due to oxidative stress. The mechanism involved in the anti-apoptotic effect was related to the mitochondrial pathway. These results indicate that progesterone possesses the potential to be a novel therapeutic agent for the treatment of acute brain injury after SAH.

  16. Ethanol extract of propolis protects endothelial cells from oxidized low density lipoprotein-induced injury by inhibiting lectin-like oxidized low density lipoprotein receptor-1-mediated oxidative stress.

    PubMed

    Fang, Yongqi; Li, Jinguo; Ding, Mingde; Xu, Xiaoyan; Zhang, Jiajun; Jiao, Peng; Han, Ping; Wang, Jiafu; Yao, Shutong

    2014-12-01

    Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), as the primary oxidized low-density lipoprotein (ox-LDL) receptor on endothelial cells, plays a crucial role in endothelial injury, which is a driving force in the initiation and development of atherosclerosis. Our previous studies have shown that ethanol extract of propolis (EEP) promotes reverse cholesterol transport and inhibits atherosclerotic lesion development. However, the protective effects of EEP against ox-LDL-induced injury in endothelial cells and the underlying mechanisms are still unknown. This study was designed to test the hypothesis that EEP attenuates ox-LDL-induced endothelial oxidative injury via modulation of LOX-1-mediated oxidative stress. Our results showed that exposure of human umbilical vein endothelial cells (HUVECs) to ox-LDL (100 mg/L) led to the decrease in cell viability and increase in lactate dehydrogenase (LDH) release, caspase-3 activation, and apoptosis, whereas pretreatment with EEP (7.5, 15 and 30 mg/L) protected against such damages in a dose-dependent manner. In addition, EEP mitigated ox-LDL uptake by HUVECs and attenuated ox-LDL-upregulated LOX-1 expression both at the mRNA and protein levels. Moreover, EEP suppressed the ox-LDL-induced oxidative stress as assessed by decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, reactive oxygen species (ROS), and malondialdehyde (MDA) generation as well as increased antioxidant enzyme activities. Similar results were observed in the anti-LOX-1 antibody or diphenyleneiodonium (DPI)-pretreated HUVECs. These data indicate that EEP may protect HUVECs from ox-LDL-induced injury and that the mechanism at least partially involves its ability to inhibit endothelial LOX-1 upregulation and subsequent oxidative stress.

  17. Plin5 alleviates myocardial ischaemia/reperfusion injury by reducing oxidative stress through inhibiting the lipolysis of lipid droplets

    PubMed Central

    Zheng, Pengfei; Xie, Zhonglin; Yuan, Yuan; Sui, Wen; Wang, Chao; Gao, Xing; Zhao, Yuanlin; Zhang, Feng; Gu, Yu; Hu, Peizhen; Ye, Jing; Feng, Xuyang; Zhang, Lijun

    2017-01-01

    Myocardial ischaemia-reperfusion (I/R) injury is a complex pathophysiological process. Current research has suggested that energy metabolism disorders, of which the abnormal consumption of fatty acids is closely related, compose the main pathological basis for myocardial I/R injury. Lipid droplets (LD) are critical regulators of lipid metabolism by LD-associated proteins. Among the lipid droplet proteins, the perilipin family members regulate lipolysis and lipogenesis through different mechanisms. Plin5, an important perilipin protein, promotes LD generation and lowers fatty acid oxidation, thus protecting the myocardium from lipotoxicity. This study investigated the protective effects of Plin5 in I/R myocardium. Our results indicated that Plin5 deficiency exacerbated the myocardial infarct area, aggravated left ventricular systolic dysfunction, reduced lipid storage, and elevated free fatty acids. Plin5-deficient myocardium exhibited severely damaged mitochondria, elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity. Furthermore, the decreased phosphorylation of PI3K/Akt in Plin5-null cardiomyocytes might contribute to I/R injury aggravation. In conclusion, Plin5, a new regulator of myocardial lipid metabolism, decreases free fatty acid peroxidation by inhibiting the lipolysis of intracellular lipid droplets, thus providing cardioprotection against I/R injury and shedding new light on therapeutic solutions for I/R diseases. PMID:28218306

  18. Capsaicin protects endothelial cells and macrophage against oxidized low-density lipoprotein-induced injury by direct antioxidant action.

    PubMed

    Chen, Kuo-Shuen; Chen, Pei-Ni; Hsieh, Yih-Shou; Lin, Chin-Yin; Lee, Yi-Hsun; Chu, Shu-Chen

    2015-02-25

    Atherosclerosis is a chronic inflammatory vascular disease. It is characterized by endothelial dysfunction, lipid accumulation, leukocyte activation, and the production of inflammatory mediators and reactive oxygen species (ROS). Capsaicin, a biologically active compound of the red pepper and chili pepper, has several anti-oxidant, anti-inflammatory, anti-cancer, and hypolipidemic biological effects. However, its protective effects on foam cell formation and endothelial injury induced by oxidized low-density lipoprotein (oxLDL) remain unclear. In this study, we evaluated the anti-oxidative activity of capsaicin, and determined the mechanism by which capsaicin rescues human umbilical vein endothelial cells (HUVECs) from oxLDL-mediated dysfunction. The anti-oxidative activity of capsaicin was defined by Apo B fragmentation and conjugated diene production of the copper-mediated oxidation of LDL. Capsaicin repressed ROS generation, as well as subsequent mitochondrial membrane potential collapse, cytochrome c expression, chromosome condensation, and caspase-3 activation induced by oxLDL in HUVECs. Capsaicin also protected foam cell formation in macrophage RAW 264.7 cells. Our results suggest that capsaicin may prevent oxLDL-induced cellular dysfunction and protect RAW 264.7 cells from LDL oxidation.

  19. N-Acetyl-Serotonin Protects HepG2 Cells from Oxidative Stress Injury Induced by Hydrogen Peroxide

    PubMed Central

    Jiang, Jiying; Yu, Shuna; Jiang, Zhengchen; Liang, Cuihong; Yu, Wenbo; Li, Jin; Du, Xiaodong; Wang, Hailiang; Gao, Xianghong; Wang, Xin

    2014-01-01

    Oxidative stress plays an important role in the pathogenesis of liver diseases. N-Acetyl-serotonin (NAS) has been reported to protect against oxidative damage, though the mechanisms by which NAS protects hepatocytes from oxidative stress remain unknown. To determine whether pretreatment with NAS could reduce hydrogen peroxide- (H2O2-) induced oxidative stress in HepG2 cells by inhibiting the mitochondrial apoptosis pathway, we investigated the H2O2-induced oxidative damage to HepG2 cells with or without NAS using MTT, Hoechst 33342, rhodamine 123, Terminal dUTP Nick End Labeling Assay (TUNEL), dihydrodichlorofluorescein (H2DCF), Annexin V and propidium iodide (PI) double staining, immunocytochemistry, and western blot. H2O2 produced dramatic injuries in HepG2 cells, represented by classical morphological changes of apoptosis, increased levels of malondialdehyde (MDA) and intracellular reactive oxygen species (ROS), decreased activity of superoxide dismutase (SOD), and increased activities of caspase-9 and caspase-3, release of cytochrome c (Cyt-C) and apoptosis-inducing factor (AIF) from mitochondria, and loss of membrane potential (ΔΨm). NAS significantly inhibited H2O2-induced changes, indicating that it protected against H2O2-induced oxidative damage by reducing MDA levels and increasing SOD activity and that it protected the HepG2 cells from apoptosis through regulating the mitochondrial apoptosis pathway, involving inhibition of mitochondrial hyperpolarization, release of mitochondrial apoptogenic factors, and caspase activity. PMID:25013541

  20. NQDI 1, an inhibitor of ASK1 attenuates acute ischemic renal injury by modulating oxidative stress and cell death.

    PubMed

    El Eter, Eman

    2013-09-01

    Apoptosis signal-regulating kinase 1 (ASK1) is among the signaling events that lead to postischemic cell death. Inhibition of ASK1 pathway protected hearts from ischemic damage. The present study evaluated the renal protective effects of NQDI 1, an inhibitor of ASK1, in an animal model of acute ischemic renal failure. Male Wistar rats were subjected to right nephrectomy and clamping of left renal pedicle for 45 min, or sham operation. The administration of NQDI 1 attenuated renal dysfunction and histological changes characteristic for renal ischemia/reperfusion injury (IRI). Apoptosis of renal tissues, as detected by TUNEL staining, was also reduced together with p53 protein expression, and renal levels of MDA and SOD with NQDI 1 administration and BCL2 was up regulated. In conclusion, inhibition of ASK1 is of therapeutic potential against acute ischemic renal injury. Its protective effects are mediated via inhibition of apoptosis and oxidative stress.

  1. Chrysin Protects against Focal Cerebral Ischemia/Reperfusion Injury in Mice through Attenuation of Oxidative Stress and Inflammation

    PubMed Central

    Yao, Yang; Chen, Li; Xiao, Jinting; Wang, Chunyang; Jiang, Wei; Zhang, Rongxin; Hao, Junwei

    2014-01-01

    Inflammation and oxidative stress play an important part in the pathogenesis of focal cerebral ischemia/reperfusion (I/R) injury, resulting in neuronal death. The signaling pathways involved and the underlying mechanisms of these events are not fully understood. Chrysin, which is a naturally occurring flavonoid, exhibits various biological activities. In this study, we investigated the neuroprotective properties of chrysin in a mouse model of middle cerebral artery occlusion (MCAO). To this end, male C57/BL6 mice were pretreated with chrysin once a day for seven days and were then subjected to 1 h of middle cerebral artery occlusion followed by reperfusion for 24 h. Our data show that chrysin successfully decreased neurological deficit scores and infarct volumes, compared with the vehicle group. The increases in glial cell numbers and proinflammatory cytokine secretion usually caused by ischemia/reperfusion were significantly ameliorated by chrysin pretreatment. Moreover, chrysin also inhibited the MCAO-induced up-regulation of nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), compared with the vehicle. These results suggest that chrysin could be a potential prophylactic agent for cerebral ischemia/reperfusion (I/R) injury mediated by its anti-inflammatory and anti-oxidative effects. PMID:25402649

  2. Protective Effect of Thalidomide on Liver Injury in Rats with Acute Pancreatitis via Inhibition of Oxidative Stress.

    PubMed

    Lv, Peng; Fan, Li-Juan; Li, Hong-Yun; Meng, Qing-Shun; Liu, Jie

    2015-01-01

    This study was designed to investigate the preventive effect of thalidomide on acute pancreatitis-associated liver injury in the rat and analyze its relationship with oxidative stress. The acute pancreatitis of rats was induced by the retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Thalidomide (100 mg/kg) was given daily via the intragastric route for 8 days before this injection. The levels of oxidative stress parameters including superoxide dismutase (SOD), glutathione peroxidase (GSHpx), and malondialdehyde (MDA) in the liver were detected by biochemical assay. Nuclear factor-κB p65 (NF-κBp65), tumor necrosis factor α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) protein and mRNA levels in the liver were detected using western blots and reverse transcriptase polymerase chain reaction, respectively. Compared with the untreated model group, liver histopathology, SOD, GSHpx, MDA levels, NF-κBp65, TNF-α, ICAM-1 protein, and mRNA levels in the liver of rats given thalidomide were improved significantly. Results demonstrate that thalidomide may exert its effects on oxidative stress to attenuate the progression of acute pancreatitis-associated liver injury in rats.

  3. Glycyrrhizic acid pretreatment prevents sepsis-induced acute kidney injury via suppressing inflammation, apoptosis and oxidative stress.

    PubMed

    Zhao, Hongyu; Liu, Zhenning; Shen, Haitao; Jin, Shuai; Zhang, Shun

    2016-06-15

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. The aim of our study was to investigate the molecular mechanism involved in the protective effects of GA in lipopolysaccharide (LPS) stimulated rat mesangial cells (HBZY-1) and septic rats. Sepsis model was established by injection of 5mg/kg LPS in rats or incubation with 1μg/ml LPS for 24h in HBZY-1 cells. A variety of molecular biological experiments were carried out to assess the effects of GA on inflammation, apoptosis, and oxidative stress. First we found that GA alleviated sepsis-induced kidney injury in vivo. Furthermore, GA suppressed inflammatory response in vivo and in vitro. Additionally, GA inhibited cell apoptosis and the changes in expressions of apoptosis related proteins induced by LPS. Moreover, GA markedly inhibited oxidative stress induced by LPS via activation of ERK signaling pathway. Finally GA could inhibit the activation of NF-κ B induced by LPS. Our present study indicates that GA has a protective effect against sepsis-induced inflammatory response, apoptosis, and oxidative stress damage, which provides a molecular basis for a new medical treatment of septic acute kidney injury.

  4. Andrographis paniculata extract protect against isoproterenol-induced myocardial injury by mitigating cardiac dysfunction and oxidative injury in rats.

    PubMed

    Ojha, Shreesh; Bharti, Saurabh; Golechha, Mahaveer; Sharma, Ashok K; Rani, Neha; Kumari, Santosh; Arya, Dharamvir Singh

    2012-01-01

    Present study evaluated the cardioprotective effect of Andrographis paniculata (100, 200 or 400 mg/kg) against isoproterenol (85 mg/kg, b.w.)-induced cardiotoxicity referred as myocardial infarction in rats. Isoproterenol significantly (p < 0.05) decreased mean arterial pressure, heart rate, contractility and relaxation and increased left ventricular end diastolic pressure. Isoproterenol also significantly (p < 0.05) decreased antioxidants, superoxide dismutase, catalase, glutathione peroxidase, glutathione and increased leakage of cardiac injury markers; creatine phosphokinase-MB isoenzyme, lactate dehydrogenase concomitant to increased lipid peroxidation and histopathological perturbations. However, pretreatment with A. paniculata favorably restored hemodynamic parameters and left ventricular function and significantly (p < 0.05) prevented the depletion of endogenous antioxidants and myocyte marker enzymes as well as inhibited lipid peroxidation. Significant (p < 0.05) reversal of almost all the hemodynamic, biochemical and histopathological parameters by A. paniculata pretreatment in isoproterenol-induced cardiotoxicity depicted the cardioprotective effect of A. paniculata. Results showed that A. paniculata protected heart against cardiotoxic effects of isoproterenol by boosting endogenous antioxidant network, restoring ventricular function and maintaining structural integrity of heart.

  5. Oxidative stress and modification of renal vascular permeability are associated with acute kidney injury during P. berghei ANKA infection.

    PubMed

    Elias, Rosa Maria; Correa-Costa, Matheus; Barreto, Claudiene Rodrigues; Silva, Reinaldo Correia; Hayashida, Caroline Y; Castoldi, Angela; Gonçalves, Giselle Martins; Braga, Tarcio Teodoro; Barboza, Renato; Rios, Francisco José; Keller, Alexandre Castro; Cenedeze, Marcos Antonio; Hyane, Meire Ioshie; D'Império-Lima, Maria Regina; Figueiredo-Neto, Antônio Martins; Reis, Marlene Antônia; Marinho, Cláudio Romero Farias; Pacheco-Silva, Alvaro; Câmara, Niels Olsen Saraiva

    2012-01-01

    Malaria associated-acute kidney injury (AKI) is associated with 45% of mortality in adult patients hospitalized with severe form of the disease. However, the causes that lead to a framework of malaria-associated AKI are still poorly characterized. Some clinical studies speculate that oxidative stress products, a characteristic of Plasmodium infection, as well as proinflammatory response induced by the parasite are involved in its pathophysiology. Therefore, we aimed to investigate the development of malaria-associated AKI during infection by P. berghei ANKA, with special attention to the role played by the inflammatory response and the involvement of oxidative stress. For that, we took advantage of an experimental model of severe malaria that showed significant changes in the renal pathophysiology to investigate the role of malaria infection in the renal microvascular permeability and tissue injury. Therefore, BALB/c mice were infected with P. berghei ANKA. To assess renal function, creatinine, blood urea nitrogen, and ratio of proteinuria and creatininuria were evaluated. The products of oxidative stress, as well as cytokine profile were quantified in plasma and renal tissue. The change of renal microvascular permeability, tissue hypoxia and cellular apoptosis were also evaluated. Parasite infection resulted in renal dysfunction. Furthermore, we observed increased expression of adhesion molecule, proinflammatory cytokines and products of oxidative stress, associated with a decrease mRNA expression of HO-1 in kidney tissue of infected mice. The measurement of lipoprotein oxidizability also showed a significant increase in plasma of infected animals. Together, our findings support the idea that products of oxidative stress, as well as the immune response against the parasite are crucial to changes in kidney architecture and microvascular endothelial permeability of BALB/c mice infected with P. berghei ANKA.

  6. Paeoniflorin attenuates hepatic ischemia/reperfusion injury via anti-oxidative, anti-inflammatory and anti-apoptotic pathways

    PubMed Central

    TAO, YE; WEN, ZHIHONG; SONG, YINGQIAN; WANG, HUI

    2016-01-01

    During liver surgery, hepatic blood flow needs to be blocked in order to reduce bleeding, which inevitably results in hepatic ischemia/reperfusion injury (HI/R). Paeoniflorin (PF) is the main active ingredient of the traditional Chinese herbal medicine peony, which has been shown to exert anti-oxidative and anti-apoptotic properties. In the present study, a mouse model of HI/R was generated by clamping the hepatoportal vein, hepatic artery, and hepatic duct of BALB/c mice with a vascular clamp for 30 min, followed by reperfusion for 6 h under anesthesia. Six mice in the three PF treatment groups (5, 10 and 20 mg/kg) were then injected with PF, via the tail vein. A sham group, consisting of six mice that did not undergo the procedure, and a vehicle group, consisting of 6 mice that underwent the procedure but subsequently received injections of physiological saline only, were used as controls. Liver injury was indicated by serum levels of the enzymes alanine transaminase (ALT) and aspartate transaminase (AST). The activities of oxidative stress biomarkers, including superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-PX) and malondialdehyde (MDA), were also measured. Furthermore, the activity of caspase-3 was analyzed in hepatic tissue using a commercial kit. Treatment with PF significantly attenuated HI/R injury histologically, as compared with the vehicle group. In addition, significant reductions in the serum levels of ALT and AST were observed in the PF-treated ischemic mice. Furthermore, treatment with PF enhanced the activities of hepatic tissue SOD, GSH and GSH-PX, but decreased the MDA content. Treatment of ischemic mice with PF markedly reduced the expression levels of inflammatory mediators, including nuclear factor-κB, tumor necrosis factor-α, interleukin (IL)-6, and IL-1β, and decreased the HI/R injury-induced expression of caspase-3. The results of the present study suggest that PF attenuates the HI/R injury of mice via anti-oxidative

  7. Troglitazone-induced hepatic mitochondrial proteome expression dynamics in heterozygous Sod2{sup +/-} mice: Two-stage oxidative injury

    SciTech Connect

    Lee, Y.H. |; Chung, Maxey C.M. | Lin Qingsong; Boelsterli, Urs A. ||

    2008-08-15

    The determinants of susceptibility to troglitazone-induced idiosyncratic liver injury have not yet been determined; however, troglitazone has been shown to target mitochondria and induce mitochondria-mediated hepatocellular injury in vitro. The aim of this study was to use a systems approach to analyze the dynamics of mitochondrial changes at the proteome level and more clearly define the mechanisms and time course of troglitazone hepatotoxicity by using a previously characterized mouse model that is highly sensitized to troglitazone hepatotoxicity. Mice heterozygous in mitochondrial superoxide dismutase-2 (Sod2{sup +/-}) were injected intraperitoneally with troglitazone (30 mg/kg/day) or vehicle daily for 2 or 4 weeks. Hepatic mitochondria were isolated, purified, and subjected to two-dimensional difference gel electrophoresis (2D-DIGE). We found that among the {approx} 1500 resolved hepatic mitochondrial proteins, 70 exhibited significantly altered abundance after troglitazone treatment. MALDI-TOF/TOF MS/MS analysis revealed that early changes (2 weeks) included increased levels of heat shock protein family members (mortalin, HSP7C), Lon protease, and catalase, indicating induction of a mitochondrial stress response. In contrast, after 4 weeks, a number of critical proteins including ATP synthase {beta}-subunit, aconitase-2, and catalase exhibited decreased abundance, and total protein carbonyls were significantly increased, suggesting uncompensated oxidative damage. Aconitase-2 (ACO2) was decreased at both time points, making this protein a potential sensitive and early biomarker for mitochondrial oxidant stress. These results show that, in this murine model of underlying clinically silent mitochondrial stress, superimposed troglitazone induces a two-stage response: an initial adaptive response, followed by a toxic response involving oxidant injury to mitochondrial proteins.

  8. Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity

    SciTech Connect

    Kashimshetty, Rohini; Desai, Varsha G.; Kale, Vijay M.; Lee, Taewon; Moland, Carrie L.; Branham, William S.; New, Lee S.; Chan, Eric C.Y.; Younis, Husam; Boelsterli, Urs A.

    2009-07-15

    Flutamide, a widely used nonsteroidal anti-androgen, but not its bioisostere bicalutamide, has been associated with idiosyncratic drug-induced liver injury. Although the susceptibility factors are unknown, mitochondrial injury has emerged as a putative hazard of flutamide. To explore the role of mitochondrial sensitization in flutamide hepatotoxicity, we determined the effects of superimposed drug stress in a murine model of underlying mitochondrial abnormalities. Male wild-type or heterozygous Sod2{sup +/-} mice were injected intraperitoneously with flutamide (0, 30 or 100 mg/kg/day) for 28 days. A kinetic pilot study revealed that flutamide (100 mg/kg/day) caused approximately 10-fold greater exposure than the reported therapeutic mean plasma levels. Mutant (5/10), but not wild-type, mice in the high-dose group exhibited small foci of hepatocellular necrosis and an increased number of apoptotic hepatocytes. Hepatic GSSG/GSH, protein carbonyl levels, and serum lactate levels were significantly increased, suggesting oxidant stress and mitochondrial dysfunction. Measurement of mitochondrial superoxide in cultured hepatocytes demonstrated that mitochondria were a significant source of flutamide-enhanced oxidant stress. Indeed, mitochondria isolated from flutamide-treated Sod2{sup +/-} mice exhibited decreased aconitase activity as compared to vehicle controls. A transcriptomics analysis using MitoChips revealed that flutamide-treated Sod2{sup +/-} mice exhibited a selective decrease in the expression of all complexes I and III subunits encoded by mitochondrial DNA. In contrast, Sod2{sup +/-} mice receiving bicalutamide (50 mg/kg/day) did not reveal any hepatic changes. These results are compatible with our concept that flutamide targets hepatic mitochondria and exerts oxidant stress that can lead to overt hepatic injury in the presence of an underlying mitochondrial abnormality.

  9. Dioclea violacea lectin ameliorates oxidative stress and renal dysfunction in an experimental model of acute kidney injury

    PubMed Central

    Freitas, Flavia PS; Porto, Marcella L; Tranhago, Camilla P; Piontkowski, Rogerio; Miguel, Emilio C; Miguel, Thaiz BAR; Martins, Jorge L; Nascimento, Kyria S; Balarini, Camille M; Cavada, Benildo S; Meyrelles, Silvana S; Vasquez, Elisardo C; Gava, Agata L

    2015-01-01

    Acute kidney injury (AKI) is characterized by rapid and potentially reversible decline in renal function; however, the current management for AKI is nonspecific and associated with limited supportive care. Considering the need for more novel therapeutic approaches, we believe that lectins from Dioclea violacea (Dvl), based on their anti-inflammatory properties, could be beneficial for the treatment of AKI induced by renal ischemia/reperfusion (IR). Dvl (1 mg/kg, i.v.) or vehicle (100 µL) was administered to Wistar rats prior to the induction of bilateral renal ischemia (45 min). Following 24 hours of reperfusion, inulin and para-aminohippurate (PAH) clearances were performed to determine glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF) and renal vascular resistance (RVR). Renal inflammation was assessed using myeloperoxidase (MPO) activity. Kidney sections were stained with hematoxylin-eosin to evaluate morphological changes. Intracellular superoxide anions, hydrogen peroxide, peroxynitrite, nitric oxide and apoptosis were analyzed using flow cytometry. IR resulted in diminished GFR, RPF, RBF, and increased RVR; however, these changes were ameliorated in rats receiving Dvl. AKI-induced histomorphological changes, such as tubular dilation, tubular necrosis and proteinaceous casts, were attenuated by Dvl administration. Treatment with Dvl resulted in diminished renal MPO activity, oxidative stress and apoptosis in rats submitted to IR. Our data reveal that Dvl has a protective effect in the kidney, improving renal function after IR injury, probably by reducing neutrophil recruitment and oxidative stress. These results indicate that Dvl can be considered a new therapeutic approach for AKI-induced kidney injury. PMID:26885258

  10. SIRT3 in Neural Stem Cells Attenuates Microglia Activation-Induced Oxidative Stress Injury Through Mitochondrial Pathway

    PubMed Central

    Jiang, De-Qi; Wang, Yan; Li, Ming-Xing; Ma, Yan-Jiao; Wang, Yong

    2017-01-01

    Sirtuin 3 (SIRT3), a mitochondrial protein, is involved in energy metabolism, cell apoptosis and mitochondrial function. However, the role of SIRT3 in neural stem cells (NSCs) remains unknown. In previous studies, we found that microglia activation-induced cytotoxicity negatively regulated survival of NSCs, along with mitochondrial dysfunction. The aim of this study was to investigate the potential neuroprotective effects of SIRT3 on the microglia activation-induced oxidative stress injury in NSCs and its possible mechanisms. In the present study, microglia-NSCs co-culture system was used to demonstrate the crosstalk between both cell types. The cytotoxicity of microglia activation by Amyloid-β (Aβ) resulted in the accumulation of reactive oxygen species (ROS) and down-regulation of SIRT3, manganese superoxide dismutase (MnSOD) gene expression in NSCs, concomitant to cell cycle arrest at G0/G1 phase, increased cell apoptosis rate and opening of the mitochondrial permeability transition pore (mPTP) and enhanced mitochondrial membrane potential (ΔΨm) depolarization. Furthermore, SIRT3 knockdown in NSCs via small interfering RNA (siRNA) accelerated cell injury, whereas SIRT3 overexpression provided resistance to microglia activation-induced oxidative stress cellular damage. The mechanisms of SIRT3 attenuated activated microglia-induced NSC dysfunction included the decreased mPTP opening and cyclophilin D (CypD) protein expression, inhibition of mitochondrial cytochrome C (Cyt C) release to cytoplasm, declined Bax/B-cell lymphoma 2 (Bcl-2) ratio and reduced caspase-3/9 activity. Taken together, these data imply that SIRT3 ameliorates microglia activation-induced oxidative stress injury through mitochondrial apoptosis pathway in NSCs, these results may provide a novel intervention target for NSC survival. PMID:28197079

  11. Tea polyphenols protect against ischemia/reperfusion-induced liver injury in mice through anti-oxidative and anti-apoptotic properties

    PubMed Central

    Tao, Jin; Shen, Xinhong; Ai, Yonghong; Han, Xiaojing

    2016-01-01

    Tea polyphenols (TPs), which are derived from tea extracts, are a class of chemicals containing polyphenol hydroxyls that have been observed to have strong anti-oxidative properties. Previous studies have demonstrated that TP can protect against hepatic ischemia/reperfusion (I/R) injury; however, the underlying mechanism remains unknown. In the present study, the mechanism underlying TPs protective effects against I/R-induced liver damage was investigated, focusing on its anti-oxidative and anti-apoptotic bioactivities. C57BL/6 mice were used to establish a hepatic I/R-induced injury model, and liver injury was analyzed using a biochemical assay. The results from the current study demonstrated that the serum expression levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly increased in mice following hepatic I/R injury, while the ratio of hepatic glutathione (GSH)/oxidized GSH (GSSG) was reduced, indicating that liver damage had occurred. In mice that were orally administered with TP (50 mg/kg) 1 h prior to I/R-induced injury, the extent of liver injury was significantly attenuated. It was also observed that I/R injury significantly decreased the mRNA and protein expression levels of cytokine-inducible nitric oxide synthase in liver tissues, and this was also attenuated by pretreatment with TP. Furthermore, pretreatment with TP significantly attenuated the I/R-induced increase in liver cell apoptosis, and the expression level and activity of pro-apoptotic proteins in the liver, indicating that I/R-induced liver cell apoptosis is inhibited by TP. In conclusion, the results in the present study suggest that TP protects against hepatic I/R-induced injury by inhibiting I/R-induced oxidative damage and liver cell apoptosis. PMID:27882175

  12. Thymoquinone mitigate ischemia-reperfusion-induced liver injury in rats: a pivotal role of nitric oxide signaling pathway.

    PubMed

    Abd-Elbaset, Mohamed; Arafa, El-Shaimaa A; El Sherbiny, Gamal A; Abdel-Bakky, Mohamed S; Elgendy, Abdel Nasser A M

    2017-01-01

    Oxidative and nitrosative stress-induced endothelial cell damage play an essential role in the pathogenesis of hepatic ischemia-reperfusion (IR) injury. IR is associated with reduced eNOS expression and exacerbated by superimposed stress. NOSTRIN induces intracellular endothelial nitric oxide synthase (eNOS) translocation and inducible nitric oxide synthase (iNOS) increases nitric oxide (NO) production. Our aim was to assess hepatic expression of iNOS, eNOS, and NOSTRIN in IR with or without N-acetylcysteine (NAC) or thymoquinone (TQ) pretreatment and to compare their hepatoprotective effects. Surgical induction of IR was performed by occlusion of hepatic pedicle for 30 min with mini-clamp and reperfused for 30 min. The effects of TQ (20 mg/kg/day) or NAC (300 mg/kg/day) administered orally for 10 days were evaluated by serum ALT and AST, oxidative stress parameters, NO production, and histopathological analysis. Also, localization and expression of iNOS, eNOS, and NOSTRIN were assessed by immunofluorescence. TQ or NAC pretreatment significantly decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and myeloperoxidase (MPO) activities, malondialdehyde (MDA) level, and NO production. In addition, they restored the depleted GSH content and alleviated histopathological changes. Furthermore, they up-regulated eNOS and down-regulated iNOS and NOSTRIN expressions. TQ exerts its hepatoprotective effect, at least in part, by nitric oxide signaling pathway through modulation of iNOS, eNOS, and NOSTRIN expressions as well as suppression of oxidative stress.

  13. Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury

    SciTech Connect

    Milatovic, Dejan; Gupta, Ramesh C.; Yu, Yingchun; Zaja-Milatovic, Snjezana; Aschner, Michael

    2011-11-15

    Exposure to excessive manganese (Mn) levels leads to neurotoxicity, referred to as manganism, which resembles Parkinson's disease (PD). Manganism is caused by neuronal injury in both cortical and subcortical regions, particularly in the basal ganglia. The basis for the selective neurotoxicity of Mn is not yet fully understood. However, several studies suggest that oxidative damage and inflammatory processes play prominent roles in the degeneration of dopamine-containing neurons. In the present study, we assessed the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates and associated neuronal dysfunctions both in vitro and in vivo. Results from our in vitro study showed a significant (p < 0.01) increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes (F{sub 2}-IsoPs), as well as the depletion of ATP in primary rat cortical neurons following exposure to Mn (500 {mu}M) for 2 h. These effects were protected when neurons were pretreated for 30 min with 100 of an antioxidant, the hydrophilic vitamin E analog, trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), or an anti-inflammatory agent, indomethacin. Results from our in vivo study confirmed a significant increase in F{sub 2}-IsoPs levels in conjunction with the progressive spine degeneration and dendritic damage of the striatal medium spiny neurons (MSNs) of mice exposed to Mn (100 mg/kg, s.c.) 24 h. Additionally, pretreatment with vitamin E (100 mg/kg, i.p.) or ibuprofen (140 {mu}g/ml in the drinking water for two weeks) attenuated the Mn-induced increase in cerebral F{sub 2}-IsoPs? and protected the MSNs from dendritic atrophy and dendritic spine loss. Our findings suggest that the mediation of oxidative stress/mitochondrial dysfunction and the control of alterations in biomarkers of oxidative injury, neuroinflammation and synaptodendritic degeneration may provide an effective, multi-pronged therapeutic strategy for protecting dysfunctional dopaminergic

  14. Anti-inflammatory and Anti-oxidative Effects of Dexpanthenol on Lipopolysaccharide Induced Acute Lung Injury in Mice.

    PubMed

    Li-Mei, Wan; Jie, Tan; Shan-He, Wan; Dong-Mei, Meng; Peng-Jiu, Yu

    2016-10-01

    The aim of this study is to investigate the effects of dexpanthenol in a model of acute lung injury (ALI) induced by lipopolysaccharides (LPS). Lung injury was induced by exposure to atomized LPS. Mice were randomly divided into four groups: control group; Dxp (500 mg/kg) group; LPS group; LPS + Dxp (500 mg/kg) group. The effects of dexpanthenol on LPS-induced neutrophil recruitment, cytokine levels, total protein concentration, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) contents were examined. Additionally, lung tissue was examined by histology to investigate the changes in pathology in the presence and absence of dexpanthenol. In LPS-challenged mice, dexpanthenol significantly improved lung edema. Dexpanthenol also markedly inhibited the LPS-induced neutrophiles influx, protein leakage, and release of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Furthermore, dexpanthenol attenuated MPO activity and MDA contents and increased SOD and GSH activity in the LPS-challenged lung tissue. These data suggest that dexpanthenol protects mice from LPS-induced acute lung injury by its anti-inflammatory and anti-oxidative activities.

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

    PubMed

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

    2016-10-01

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

  16. The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice

    PubMed Central

    Niatsetskaya, Zoya V.; Sosunov, Sergei A.; Matsiukevich, Dzmitry; Utkina-Sosunova, Irina V.; Ratner, Veniamin I.; Starkov, Anatoly A.; Ten, Vadim S.

    2012-01-01

    Oxidative stress and Ca++ toxicity are mechanisms of hypoxic-ischemic (HI) brain injury. This work investigates if partial inhibition of mitochondrial respiratory chain protects HI-brain by limiting generation of oxidative radicals during reperfusion. HI-insult was produced in p10 mice treated with complex-I (C-I) inhibitor, pyridaben (P), or vehicle. Administration of P significantly decreased extent of HI injury. Mitochondria isolated from the ischemic hemisphere in P-treated animals showed reduced H2O2 emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to Ca++ triggered opening of permeability transition pore. Protective effect of P administration was also observed when the reperfusion-driven oxidative stress was augmented by the exposure to 100% O2 which exacerbated brain injury only in V-treated mice. In vitro, intact brain mitochondria dramatically increased H2O2 emission in response to hyperoxia, resulting in substantial loss of Ca++ buffering capacity. However, in the presence of C-I inhibitor, rotenone, or antioxidant, catalase, these effects of hyperoxia were abolished. Our data suggest that the reperfusion-driven recovery of C-I dependent mitochondrial respiration contributes not only to the cellular survival, but also causes an oxidative damage to the mitochondria, potentiating a loss of Ca++ buffering capacity. This highlights a novel neuroprotective strategy against HI-brain injury where the major therapeutic principle is a pharmacological attenuation, rather than an enhancement of mitochondrial oxidative metabolism during early reperfusion. PMID:22378894

  17. Protein oxidation and lipid peroxidation after renal ischemia-reperfusion injury: protective effects of erdosteine and N-acetylcysteine.

    PubMed

    Erdogan, Hasan; Fadillioglu, Ersin; Yagmurca, Murat; Uçar, Muharrem; Irmak, M Kemal

    2006-02-01

    Oxygen radicals have roles in the renal ischemia-reperfusion (IR) injury usually encountered in several conditions such as renal transplantation. The aim of this study was to investigate the effects of erdosteine and N-acetylcysteine (NAC) on the oxidant/antioxidant status and microscopy of renal tissues after IR injury. Male Sprague-Dawley rats were randomly assigned to four groups: control untreated rats, IR (30 min ischemia and 120 min reperfusion), IR + NAC (i.p.; 180 mg/kg) and IR + erdosteine (oral; 50 mg/kg/day for 2 days before experiments) groups. After unilateral renal IR, the right kidney was rapidly excised and sectioned vertically into two pieces for microscopic examination and biochemical analysis. Erdosteine and NAC treatment did not cause any significant change in the activity of superoxide dismutase (SOD) in comparison with the IR group, even if the SOD activity increased in IR groups than in the control group. Catalase (CAT) activity was decreased in the IR group in comparison with control and IR + erdosteine groups (P<0.05), whereas it was higher in the IR + erdosteine group than in the IR + NAC group (P<0.05). Xanthine oxidase (XO) activity was higher in all the IR-performed groups than in the control group (P<0.05). Thiobarbituric acid-reactive substances (TBARS) level and protein carbonyl (PC) content were increased after IR injury (P<0.05). Erdosteine or NAC treatments ameliorated these increased TBARS and PC contents in comparison with the IR group (P<0.05). Light microscopy of the IR group showed tubular dilatation, tubular necrosis and vacuole formation in epithelial cells. Erdosteine but not NAC apparently reduced the renal tissue damage. The pathological damage score after IR was significantly reduced after erdosteine treatment (P<0.05), but not after NAC treatment. In conclusion, renal IR resulted in oxidative damage as seen in biochemical lipid peroxidation and protein oxidation results with aggravated tubular necrosis. Erdosteine and

  18. Ameliorative effects of 5-hydroxymethyl-2-furfural (5-HMF) from Schisandra chinensis on alcoholic liver oxidative injury in mice.

    PubMed

    Li, Wei; Qu, Xin-Nan; Han, Ye; Zheng, Si-Wen; Wang, Jia; Wang, Ying-Ping

    2015-01-22

    The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF) on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated with different doses of 5-HMF (7.5, 15, and 30 mg/kg) for seven days by gavage feeding. Biochemical markers and enzymatic antioxidants from serum and liver tissue were examined. Our results showed that the activities of ALT (alanine aminotransferase), AST (aspartate transaminase), TC (total cholesterol), TG (triglyceride), L-DLC (low density lipoprotein) in serum and the levels of MDA (malondialdehyde) in liver tissue, decreased significantly (p < 0.05) in the 5-HMF-treated group compared with the alcohol group. On the contrary, enzymatic antioxidants CAT (catalase), GSH-Px (glutathione peroxidase), and GSH SOD (superoxide dismutase) were markedly elevated in liver tissue treated with 5-HMF (p < 0.05). Furthermore, the hepatic levels of pro-inflammatory response marker tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were significantly suppressed (p < 0.05). Histopathological examination revealed that 5-HMF (30 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It is suggested that the hepatoprotective effects exhibited by 5-HMF on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.

  19. Ameliorative Effects of 5-Hydroxymethyl-2-furfural (5-HMF) from Schisandra chinensis on Alcoholic Liver Oxidative Injury in Mice

    PubMed Central

    Li, Wei; Qu, Xin-Nan; Han, Ye; Zheng, Si-Wen; Wang, Jia; Wang, Ying-Ping

    2015-01-01

    The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF) on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated with different doses of 5-HMF (7.5, 15, and 30 mg/kg) for seven days by gavage feeding. Biochemical markers and enzymatic antioxidants from serum and liver tissue were examined. Our results showed that the activities of ALT (alanine aminotransferase), AST (aspartate transaminase), TC (total cholesterol), TG (triglyceride), L-DLC (low density lipoprotein) in serum and the levels of MDA (malondialdehyde) in liver tissue, decreased significantly (p < 0.05) in the 5-HMF-treated group compared with the alcohol group. On the contrary, enzymatic antioxidants CAT (catalase), GSH-Px (glutathione peroxidase), and GSH SOD (superoxide dismutase) were markedly elevated in liver tissue treated with 5-HMF (p < 0.05). Furthermore, the hepatic levels of pro-inflammatory response marker tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were significantly suppressed (p < 0.05). Histopathological examination revealed that 5-HMF (30 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It is suggested that the hepatoprotective effects exhibited by 5-HMF on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties. PMID:25622257

  20. Beneficial effects of quercetin on renal injury and oxidative stress caused by ciprofloxacin in rats: A histological and biochemical study.

    PubMed

    Elbe, H; Dogan, Z; Taslidere, E; Cetin, A; Turkoz, Y

    2016-03-01

    Ciprofloxacin is a broad-spectrum quinolone antibiotic commonly used in clinical practice. Quercetin is an antioxidant belongs to flavonoid group. It inhibits the production of superoxide anion. In this study, we aimed to evaluate the effects of quercetin on renal injury and oxidative stress caused by ciprofloxacin. Twenty-eight female Wistar albino rats were divided into four groups: control, quercetin (20 mg kg(-1) day(-1) gavage for 21 days), ciprofloxacin (20 mg kg(-1) twice a day intraperitoneally for 10 days), and ciprofloxacin + quercetin. Samples were processed for histological and biochemical evaluations. Malondialdehyde (MDA) and glutathione (GSH) levels, superoxide dismutase (SOD), and catalase (CAT) activities were measured in kidney tissue. The ciprofloxacin group showed histopathological changes such as infiltration, dilatation in tubules, tubular atrophy, reduction of Bowman's space, congestion, hemorrhage, and necrosis. In the ciprofloxacin + quercetin group, these histopathological changes markedly reduced. MDA levels increased in the ciprofloxacin group and decreased in the ciptofloxacin + quercetin group. SOD and CAT activities and GSH levels significantly decreased in the ciprofloxacin group. On the other hand, in the ciprofloxacin + quercetin group, SOD and CAT activities and GSH levels significantly increased with regard to the ciprofloxacin group. We concluded that quercetin has antioxidative and therapeutic effects on renal injury and oxidative stress caused by ciprofloxacin in rats.

  1. Indole-TEMPO conjugates alleviate ischemia-reperfusion injury via attenuation of oxidative stress and preservation of mitochondrial function.

    PubMed

    Bi, Wei; Bi, Yue; Gao, Xiang; Li, Pengfei; Hou, Shanshan; Zhang, Yanrong; Bammert, Cathy; Jockusch, Steffen; Legalley, Thomas D; Michael Gibson, K; Bi, Lanrong

    2017-05-01

    Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function.

  2. Limited Link between Oxidative Stress and Ochratoxin A—Induced Renal Injury in an Acute Toxicity Rat Model

    PubMed Central

    Zhu, Liye; Yu, Tao; Qi, Xiaozhe; Gao, Jing; Huang, Kunlun; He, Xiaoyun; Luo, Haoshu; Xu, Wentao

    2016-01-01

    Ochratoxin A (OTA) displays nephrotoxicity and hepatotoxicity. However, in the acute toxicity rat model, there is no evidence on the relationship between OTA and nephrotoxicity and hepatotoxicity. Based on this, the integrated analysis of physiological status, damage biomarkers, oxidative stress, and DNA damage were performed. After OTA treatment, the body weight decreased and AST, ALP, TP, and BUN levels in serum increased. Hydropic degeneration, swelling, vacuolization, and partial drop occurred in proximal tubule epithelial cells. PCNA and Kim-1 were dose-dependently increased in the kidney, but Cox-2 expression and proliferation were not found in the liver. In OTA-treated kidneys, the mRNA expressions of Kim-1, Cox-2, Lcn2, and Clu were dose-dependently increased. The mRNA expressions of Vim and Cox-2 were decreased in OTA-treated livers. Some oxidative stress indicators were altered in the kidneys (ROS and SOD) and livers (SOD and GSH). DNA damage and oxidative DNA damage were not found. In conclusion, there is a limited link between oxidative stress and OTA-induced renal injury in an acute toxicity rat model. PMID:27983637

  3. Sulforaphane Protects Pancreatic Acinar Cell Injury by Modulating Nrf2-Mediated Oxidative Stress and NLRP3 Inflammatory Pathway

    PubMed Central

    Dong, Zhaojun; Shang, Haixiao; Chen, Yong Q.; Pan, Li-Long

    2016-01-01

    Acute pancreatitis (AP) is characterized by early activation of intra-acinar proteases followed by acinar cell death and inflammation. Cellular oxidative stress is a key mechanism underlying these pathological events. Sulforaphane (SFN) is a natural organosulfur antioxidant with undescribed effects on AP. Here we investigated modulatory effects of SFN on cellular oxidation and inflammation in AP. AP was induced by cerulean hyperstimulation in BALB/c mice. Treatment group received a single dose of 5 mg/kg SFN for 3 consecutive days before AP. We found that SFN administration attenuated pancreatic injury as evidenced by serum amylase, pancreatic edema, and myeloperoxidase, as well as by histological examination. SFN administration reverted AP-associated dysregulation of oxidative stress markers including pancreatic malondialdehyde and redox enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). In acinar cells, SFN treatment upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes including quinoneoxidoreductase-1, heme oxidase-1, SOD1, and GPx1. In addition, SFN selectively suppressed cerulein-induced activation of the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome, in parallel with reduced nuclear factor- (NF-) κB activation and modulated NF-κB-responsive cytokine expression. Together, our data suggested that SFN modulates Nrf2-mediated oxidative stress and NLRP3/NF-κB inflammatory pathways in acinar cells, thereby protecting against AP. PMID:27847555

  4. Protocatechualdehyde Protects Against Cerebral Ischemia-Reperfusion-Induced Oxidative Injury Via Protein Kinase Cε/Nrf2/HO-1 Pathway.

    PubMed

    Guo, Chao; Wang, Shiquan; Duan, Jialin; Jia, Na; Zhu, Yanrong; Ding, Yi; Guan, Yue; Wei, Guo; Yin, Ying; Xi, Miaomaio; Wen, Aidong

    2017-03-01

    Oxidative stress is closely related to the pathogenesis of ischemic stroke. Protocatechualdehyde (PCA) is a phenolic acid compound that has the putative antioxidant activities. The present study was aimed to investigate the molecular mechanisms involved in the antioxidative effect of PCA against cerebral ischemia/reperfusion (I/R) injury. The experiment stroke model was produced in Sprague-Dawley rats via middle cerebral artery occlusion (MCAO). To model ischemia-like conditions in vitro, differentiated SH-SY5Y cells were exposed to transient oxygen and glucose deprivation (OGD). Treatment with PCA significantly improved neurologic score, reduced infarct volume and necrotic neurons, and also decreased reactive oxygen species (ROS) production, 4-hydroxynonenal (4-HNE), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) contents at 24 h after reperfusion. Meanwhile, PCA significantly increased the transcription nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expressions in the ischemic cerebral cortex as shown by immunofluorescence staining and Western blot analysis. In vitro experiment showed that PCA protected differentiated SH-SY5Y cells against OGD-induced injury. Likewise, PCA also increased markedly the Nrf2 and HO-1 expressions in a dose-dependent manner. The neuroprotection effect of PCA was abolished by knockdown of Nrf2 and HO-1. Moreover, knockdown of protein kinase Cε (PKCε) also blocked PCA-induced Nfr2 nuclear translocation, HO-1 expression, and neuroprotection. Taken together, these results provide evidences that PCA can protect against cerebral ischemia-reperfusion-induced oxidative injury, and the neuroprotective effect involves the PKCε/Nrf2/HO-1 pathway.

  5. Eriodictyol attenuates cisplatin-induced kidney injury by inhibiting oxidative stress and inflammation.

    PubMed

    Li, Cheng-zhen; Jin, Hai-hong; Sun, Hong-xin; Zhang, Zhong-zhe; Zheng, Jia-xin; Li, Shu-hua; Han, Seong-ho

    2016-02-05

    Eriodictyol, a flavonoid present in citrus fruits, has been reported to have antioxidant and anti-inflammatory effects. In this study, the protective effects of eriodictyol on cisplatin (CP)-induced kidney injury were detected. CP-induced kidney injury model was established by administration of CP (20mg/kg). The results showed that treatment of eriodictyol inhibited the production of blood urea nitrogen (BUN), creatinine, MDA, TBARS, reactive oxygen species (ROS), as well as the production of TNF-α, and IL-1β in kidney tissues induced by CP. Eriodictyol also up-regulated the activities of SOD, CAT, and GSH-PX decreased by CP. Furthermore, eriodictyol was found to up-regulate the expression of Nrf2/HO-1 and inhibited CP-induced NF-κB activation in kidney tissues. In conclusion, eriodictyol protected against CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation.

  6. Amifostine Pretreatment Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Apoptosis and Oxidative Stress

    PubMed Central

    Wu, Shao-ze; Tao, Lu-yuan; Wang, Jiao-ni; Xu, Zhi-qiang; Wang, Jie; Xue, Yang-jing; Huang, Kai-yu; Lin, Jia-feng; Li, Lei

    2017-01-01

    The present study was aimed at investigating the effect of amifostine on myocardial ischemia/reperfusion (I/R) injury of mice and H9c2 cells cultured with TBHP (tert-butyl hydroperoxide). The results showed that pretreatment with amifostine significantly attenuated cell apoptosis and death, accompanied by decreased reactive oxygen species (ROS) production and lower mitochondrial potential (ΔΨm). In vivo, amifostine pretreatment alleviated I/R injury and decreased myocardial apoptosis and infarct area, which was paralleled by increased superoxide dismutase (SOD) and reduced malondialdehyde (MDA) in myocardial tissues, increased Bcl2 expression, decreased Bax expression, lower cleaved caspase-3 level, fewer TUNEL positive cells, and fewer DHE-positive cells in heart. Our results indicate that amifostine pretreatment has a protective effect against myocardial I/R injury via scavenging ROS. PMID:28392886

  7. p62/SQSTM1 Plays a Protective Role in Oxidative Injury of Steatotic Liver in a Mouse Hepatectomy Model

    PubMed Central

    Haga, Sanae; Ozawa, Takeaki; Yamada, Yuma; Morita, Naoki; Nagashima, Izuru; Inoue, Hiroshi; Inaba, Yuka; Noda, Natsumi; Abe, Riichiro; Umezawa, Kazuo

    2014-01-01

    Abstract Aims: Liver injury and regeneration involve complicated processes and are affected by various physio-pathological factors. We investigated the mechanisms of steatosis-associated liver injury and delayed regeneration in a mouse model of partial hepatectomy. Results: Initial regeneration of the steatotic liver was significantly delayed after hepatectomy. Although hepatocyte proliferation was not significantly suppressed, severe liver injury with oxidative stress (OS) occurred immediately after hepatectomy in the steatotic liver. Fas-ligand (FasL)/Fas expression was upregulated in the steatotic liver, whereas the expression of antioxidant and anti-apoptotic molecules (catalase/MnSOD/Ref-1 and Bcl-2/Bcl-xL/FLIP, respectively) and p62/SQSTM1, a steatosis-associated protein, was downregulated. Interestingly, pro-survival Akt was not activated in response to hepatectomy, although it was sufficiently expressed even before hepatectomy. Suppression of p62/SQSTM1 increased FasL/Fas expression and reduced nuclear factor erythroid 2-related factor-2 (Nrf-2)-dependent antioxidant response elements activity and antioxidant responses in steatotic and nonsteatotic hepatocytes. Exogenously added FasL induced severe cellular OS and necrosis/apoptosis in steatotic hepatocytes, with only the necrosis being inhibited by pretreatment with antioxidants, suggesting that FasL/Fas-induced OS mainly leads to necrosis. Furthermore, p62/SQSTM1 re-expression in the steatotic liver markedly reduced liver injury and improved liver regeneration. Innovation: This study is the first which demonstrates that reduced expression of p62/SQSTM1 plays a crucial role in posthepatectomy acute injury and delayed regeneration of steatotic liver, mainly via redox-dependent mechanisms. Conclusion: In the steatotic liver, reduced expression of p62/SQSTM1 induced FasL/Fas overexpression and suppressed antioxidant genes, mainly through Nrf-2 inactivation, which, along with the hypo-responsiveness of Akt

  8. Trichosanatine alleviates oxidized low-density lipoprotein induced endothelial cells injury via inhibiting the LOX-1/p38 MAPK pathway.

    PubMed

    Zhang, Lei; Jia, Yu-Hua; Zhao, Xiao-Shan; Zhou, Feng-Hua; Pan, Yun-Yun; Wan, Qiang; Cui, Xiao-Bing; Sun, Xue-Gang; Chen, Yu-Yao; Zhang, Yu; Cheng, Sai-Bo

    2016-01-01

    The LOX-1/p38 mitogen-activated protein kinase (MAPK) pathway has been proved to participate in the endothelial dysfunction in atherosclerosis. Trichosanatineis is an active compound isolated from the peel of Trichosanthes kirilowii. This study aims to determine whether trichosanatine prevents the oxidized low-density lipoprotein (ox-LDL)-induced insult through inhibition of the LOX-1/p38 MAPK pathway in HUVECs. HUVECs were treated with 150 mg/ml ox-LDL for 24 h to establish an ox-LDL-induced endothelial injury model. Cell viability, mitochondrial membrane potential (MMP), apoptosis, reactive oxygen species (ROS) level, LOX-1 and p38 MAPK expression level were measured. The results indicated that HUVECs were pretreated with either 100 mM trichosanatine or LOX-1 shRNA prior to exposure to ox-LDL for 24 h. Exposure of HUVECs to 150 mg/ml ox-LDL for 24 h significantly up-regulated the expression levels of LOX-1. The increased expression levels of LOX-1 were markedly attenuated by pretreatment with 100 mM trichosanatine. In addition, the ox-LDL-induced increase in phosphorylated (p) p38 MAPK expression was ameliorated by pretreatment with LOX-1 shRNA. Pretreatment of HUVECs with either trichosanatine or LOX-1 shRNA before exposure to ox-LDL significantly inhibited the ox-LDL-induced injuries, as evidenced by an increase in cell viability, a decrease in apoptotic cells, a ROS generation and a loss of MMP. In conclusion, we have demonstrated for the first time that the LOX-1/p38 MAPK pathway contributes to the ox-LDL-induced injury in HUVECs. Meanwhile, the trichosanatine protects the HUVECs against ox-LDL-induced injury at least in part by inhibiting the activated of LOX-1/p38 MAPK pathway.

  9. Trichosanatine alleviates oxidized low-density lipoprotein induced endothelial cells injury via inhibiting the LOX-1/p38 MAPK pathway

    PubMed Central

    Zhang, Lei; Jia, Yu-Hua; Zhao, Xiao-Shan; Zhou, Feng-Hua; Pan, Yun-Yun; Wan, Qiang; Cui, Xiao-Bing; Sun, Xue-Gang; Chen, Yu-Yao; Zhang, Yu; Cheng, Sai-Bo

    2016-01-01

    The LOX-1/p38 mitogen-activated protein kinase (MAPK) pathway has been proved to participate in the endothelial dysfunction in atherosclerosis. Trichosanatineis is an active compound isolated from the peel of Trichosanthes kirilowii. This study aims to determine whether trichosanatine prevents the oxidized low-density lipoprotein (ox-LDL)-induced insult through inhibition of the LOX-1/p38 MAPK pathway in HUVECs. HUVECs were treated with 150 mg/ml ox-LDL for 24 h to establish an ox-LDL-induced endothelial injury model. Cell viability, mitochondrial membrane potential (MMP), apoptosis, reactive oxygen species (ROS) level, LOX-1 and p38 MAPK expression level were measured. The results indicated that HUVECs were pretreated with either 100 mM trichosanatine or LOX-1 shRNA prior to exposure to ox-LDL for 24 h. Exposure of HUVECs to 150 mg/ml ox-LDL for 24 h significantly up-regulated the expression levels of LOX-1. The increased expression levels of LOX-1 were markedly attenuated by pretreatment with 100 mM trichosanatine. In addition, the ox-LDL-induced increase in phosphorylated (p) p38 MAPK expression was ameliorated by pretreatment with LOX-1 shRNA. Pretreatment of HUVECs with either trichosanatine or LOX-1 shRNA before exposure to ox-LDL significantly inhibited the ox-LDL-induced injuries, as evidenced by an increase in cell viability, a decrease in apoptotic cells, a ROS generation and a loss of MMP. In conclusion, we have demonstrated for the first time that the LOX-1/p38 MAPK pathway contributes to the ox-LDL-induced injury in HUVECs. Meanwhile, the trichosanatine protects the HUVECs against ox-LDL-induced injury at least in part by inhibiting the activated of LOX-1/p38 MAPK pathway. PMID:28078016

  10. Preconditioning induced by gentamicin protects against acute kidney injury: The role of prostaglandins but not nitric oxide

    SciTech Connect

    Pessoa, Edson A.; Convento, Marcia B.; Ribas, Otoniel S.; Tristao, Vivian R.; Reis, Luciana Aparecida; Borges, Fernanda T.; Schor, Nestor

    2011-05-15

    Nephrotoxicity is the main side effect of gentamicin (GENTA). Preconditioning (PC) refers to a situation in which an organ subjected to an injury responds less intensely when exposed to another injury. The aim of this study was to evaluate the effect of PC with GENTA on nephrotoxic acute kidney injury (AKI). GENTA group rats were injected daily with GENTA (40 mg/kg/BW) for 10 days. PC animals were injected with GENTA for 3 days (40 mg/kg/BW/daily) and, after one rest week, were injected daily with GENTA for 10 days. Animals of the L-NAME and DICLO groups were preconditioned for 3 days and then received daily injections of GENTA for 10 days; they were concomitantly treated with L-NAME (10 mg/kg/BW) and diclofenac (DICLO, 5 mg/kg/BW) for 13 days. Blood and urine were collected for measurement of serum creatinine, urea, urine sodium, protein, hydroperoxides, lipid peroxidation and nitric oxide (NO). The animals were killed; kidneys were removed for histology and immunohistochemistry for apoptosis and cell proliferation. GENTA group rats showed an increase in plasma creatinine, urea, urine sodium, hydroperoxides, lipid peroxidation, proteinuria, necrosis and apoptosis, characterizing nephrotoxic AKI. PC animals showed a decrease in these parameters and increased proliferation. The blockade of NO synthesis by L-NAME potentiated the protective effect, suggesting that NO contributed to the injury caused by GENTA. The blockade of prostaglandin synthesis with DICLO increased serum and urinary parameters, blunting the protective effect of PC. Our data suggest that PC could be a useful tool to protect against nephrotoxic AKI.

  11. Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide.

    PubMed Central

    Marks, D S; Vita, J A; Folts, J D; Keaney, J F; Welch, G N; Loscalzo, J

    1995-01-01

    Endothelium-derived relaxing factor is important for vascular homeostasis and possesses qualities that may modulate vascular injury, including vasodilation, platelet inhibition, and inhibition of smooth muscle proliferation. S-nitrososerum albumin is a naturally occurring adduct of nitric oxide (NO) with a prolonged biologic half-life and is a potent vasodilator and platelet inhibitor. Given the avidity of serum albumin for subendothelial matrix and the antiproliferative effects of NO, we investigated the effects of locally delivered S-nitroso-bovine serum albumin (S-NO-BSA) and a polythiolated form of bovine serum albumin (pS-BSA) modified to carry several S-nitrosothiol groups (pS-NO-BSA) on neointimal responses in an animal model of vascular injury. Locally delivered S-NO-BSA bound preferentially to denuded rabbit femoral vessels producing a 26-fold increase in local concentration compared with uninjured vessels (P = 0.029). pS-NO-BSA significantly reduced the intimal/medial ratio (P = 0.038) and did so in conjunction with elevations in platelet (P < 0.001) and vascular cGMP content (P < or = 0.001). pS-NO-BSA treatment also inhibited platelet deposition (P = 0.031) after denuding injury. Comparison of BSA, S-NO-BSA, pS-NO-BSA, and control revealed a dose-response relationship between the amount of displaceable NO delivered and the extent of inhibition of neointimal proliferation at 2 wk (P < or = 0.001). Local administration of a stable protein S-nitrosothiol inhibits intimal proliferation and platelet deposition after vascular arterial balloon injury. This strategy for the local delivery of a long-lived NO adduct has potential for preventing restenosis after angioplasty. Images PMID:8675628

  12. Minocycline effects on cerebral edema: relations with inflammatory and oxidative stress markers following traumatic brain injury in mice.

    PubMed

    Homsi, Shadi; Federico, Fabiola; Croci, Nicole; Palmier, Bruno; Plotkine, Michel; Marchand-Leroux, Catherine; Jafarian-Tehrani, Mehrnaz

    2009-09-29

    One of the severe complications following traumatic brain injury (TBI) is cerebral edema and its effective treatment is of great interest to prevent further brain damage. This study investigated the effects of minocycline, known for its anti-inflammatory properties, on cerebral edema and its respective inflammatory markers by comparing different dose regimens, on oxidative stress and on neurological dysfunction following TBI. The weight drop model was used to induce TBI in mice. The brain water content was measured to evaluate cerebral edema. Inflammatory markers were detected by ELISA (IL-1beta), zymography and Western blot (MMP-9). The oxidative stress marker (glutathione levels) and neurological function were measured by Griffith technique and string test, respectively. Minocycline was administered i.p. once (5 min), twice (5 min and 3 h) or triple (5 min, 3 h and 9 h) following TBI. The first dose of minocycline only varied (45 or 90 mg/kg), whereas the following doses were all at 45 mg/kg. The single and double administrations of minocycline reduced the increase of inflammatory markers at 6 h post-TBI. Minocycline also reduced cerebral edema at this time point, only after double administration and at the high dose regimen, although with no effect on the TBI-induced oxidized glutathione increase. The anti-edematous effect of minocycline persisted up to 24 h, upon a triple administration, and accompanied by a neurological recovery. In conclusion, we reported an anti-edematous effect of minocycline after TBI in mice according to a specific treatment regimen. These findings emphasize that the beneficial effects of minocycline depend on the treatment regimen following a brain injury.

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

    PubMed

    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.

  14. In vitro cell injury by oxidized low density lipoprotein involves lipid hydroperoxide-induced formation of alkoxyl, lipid, and peroxyl radicals.

    PubMed Central

    Coffey, M D; Cole, R A; Colles, S M; Chisolm, G M

    1995-01-01

    Mounting evidence supports current theories linking lipoprotein oxidation to atherosclerosis. We sought the cellular biochemical mechanism by which oxidized LDL inflicts cell injury. Inhibitors of candidate pathways of cell death were used to treat human fibroblast target cells exposed to oxidized LDL.. Ebselen, which degrades lipid hydroperoxides, inhibited oxidized LDL toxicity, consistent with our recent report that 7 beta-hydroperoxycholesterol (7 beta-OOH chol) is the major cytotoxin of oxidized LDL. Intracellular chelation of metal ions inhibited, while preloading cells with iron enhanced, toxicity, Inhibition of oxidized LDL and 7 beta-OOH chol toxicity by 2-keto-4-thiolmethyl butyric acid, a putative alkoxyl radical scavenger and by vitamin E, probucol and diphenylphenylenediamine, putative scavengers of peroxyl radicals was consistent with the involvement of these radicals in the lethal sequence. Cell death was thus postulated to occur due to lipid peroxidation via a sequence involving lipid hydroperoxide-induced, iron-mediated formation of alkoxyl, lipid, and peroxyl radicals. Pathways involving other reactive oxygen species, new protein synthesis, or altered cholesterol metabolism were considered less likely, since putative inhibitors failed to lessen toxicity. Understanding the mechanism of cell injury by oxidized LDL and its toxic moiety, 7 beta-OOH chol, may indicate specific interventions in the cell injury believed to accompany vascular lesion development. PMID:7560078

  15. Science review: Redox and oxygen-sensitive transcription factors in the regulation of oxidant-mediated lung injury: role for nuclear factor-κB

    PubMed Central

    Haddad, John J

    2002-01-01

    The primary role of pulmonary airways is to conduct air to the alveolar epithelium, where gas exchange can efficiently occur. Injuries to airways resulting from inhalation of airborne pollutants and parenteral exposure to ingested pollutants that cause oxidative stress have the potential to interfere with this process. A progressive rise of oxidative stress due to altered reduction–oxidation (redox) homeostasis appears to be one of the hallmarks of the processes that regulate gene transcription in lung physiology and pathophysiology. Reactive metabolites serve as signaling messengers for the evolution and perpetuation of the inflammatory process that is often associated with cell death and degeneration. Redox-sensitive transcription factors are often associated with the development and progression of many human disease states and inflammatory-related injury, particularly of the lung. The present review elaborates on the role of the redox-sensitive and oxygen-sensitive transcription factor NF-κB in mediating lung injury. Changes in the pattern of gene expression through regulatory transcription factors are crucial components of the machinery that determines cellular responses to oxidative and redox perturbations. Additionally, the discussion of the possible therapeutic approaches of antioxidants, thiol-related compounds and phosphodiesterase inhibitors as anti-inflammatory agents will thereby help understand the oxidant/redox-mediated lung injury mechanisms. PMID:12493069

  16. Vaccarin attenuates the human EA.hy926 endothelial cell oxidative stress injury through inhibition of Notch signaling.

    PubMed

    Xie, Fengshan; Cai, Weiwei; Liu, Yanling; Li, Yue; Du, Bin; Feng, Lei; Qiu, Liying

    2015-01-01

    Endothelial cell injury is an essential component of atherosclerosis and hypertension. Atherosclerosis and other macrovascular diseases are the most common complications of diabetes. Vaccarin is a major flavonoid glycoside in Vaccariae semen, and is expected to be useful in the treatment of vascular diseases. The aim of the present study was to evaluate the possible effects of vaccarin in human umbilical vein endothelial cells (EA.hy926) induced by hydrogen peroxide (H2O2) and its underlying mechanism in the prevention and treatment of H2O2 injury. In this study, the EA.hy926 cells were exposed to 250, 500 and 1000 µM H2O2 for 2 and 4 h in the absence or presence of vaccarin, and the cell injury induced by H2O2 was examined via SRB. Cell migratory ability, lactate dehydrogenase (LDH) leakage, malondialdehyde (MDA) levels and decreasing superoxide dismutase (SOD) activity were evaluated by the wound healing assay and corresponding assay kits. Cell apoptosis was detected by flow cytometry with Annexin V-fluorescein isothiocyanate/propidium iodide Apoptosis Detection kit and Hoechst staining. Furthermore, western blot detected the protein expressions of Notch1, Hes1 and caspase-3. Following treatment with H2O2, it was found that H2O2 stimulated cell injury in a dose-dependent manner, including reducing cell viability and cell migratory ability, increasing LDH leakage and MDA levels, and decreasing SOD activity. H2O2 further accelerated cell apoptosis via activation of Notch1 and the downstream molecule Hes1. Preincubation with vaccarin was found to protect EA.hy926 cells from H2O2-induced cell oxidative stress injury, which promoted cell viability and cell migratory ability, inhibited the level of LDH and MDA, but enhanced the activity of SOD. In particular, in addition to downregulation Notch signaling, vaccarin treatments also downregulated caspase-3, a cell apoptotic pathway-related protein. These findings indicated that vaccarin may be able to selectively protect

  17. Protective effects of melatonin against oxidative injury in rat testis induced by wireless (2.45 GHz) devices.

    PubMed

    Oksay, T; Naziroğlu, M; Doğan, S; Güzel, A; Gümral, N; Koşar, P A

    2014-02-01

    Wireless devices have become part of everyday life and mostly located near reproductive organs while they are in use. The present study was designed to determine the possible protective effects of melatonin on oxidative stress-dependent testis injury induced by 2.45-GHz electromagnetic radiation (EMR). Thirty-two rats were equally divided into four different groups, namely cage control (A1), sham control (A2), 2.45-GHz EMR (B) and 2.45-GHz EMR+melatonin (C). Group B and C were exposed to 2.45-GHz EMR during 60 min day(-1) for 30 days. Lipid peroxidation levels were higher in Group B than in Group A1 and A2. Melatonin treatment prevented the increase in the lipid peroxidation induced by EMR. Also reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) levels in Group D were higher than that of exposure group. Vitamin A and E concentrations decreased in exposure group, and melatonin prevented the decrease in vitamin E levels. In conclusion, wireless (2.45 GHz) EMR caused oxidative damage in testis by increasing the levels of lipid peroxidation and decreasing in vitamin A and E levels. Melatonin supplementation prevented oxidative damage induced by EMR and also supported the antioxidant redox system in the testis.

  18. Preliminary study of injury from heating systemically delivered, nontargeted dextran–superparamagnetic iron oxide nanoparticles in mice

    PubMed Central

    Kut, Carmen; Zhang, Yonggang; Hedayati, Mohammad; Zhou, Haoming; Cornejo, Christine; Bordelon, David; Mihalic, Jana; Wabler, Michele; Burghardt, Elizabeth; Gruettner, Cordula; Geyh, Alison; Brayton, Cory; Deweese, Theodore L; Ivkov, Robert

    2013-01-01

    Aim To assess the potential for injury to normal tissues in mice due to heating systemically delivered magnetic nanoparticles in an alternating magnetic field (AMF). Materials & methods Twenty three male nude mice received intravenous injections of dextran–superparamagnetic iron oxide nanoparticles on days 1–3. On day 6, they were exposed to AMF. On day 7, blood, liver and spleen were harvested and analyzed. Results Iron deposits were detected in the liver and spleen. Mice that had received a high-particle dose and a high AMF experienced increased mortality, elevated liver enzymes and significant liver and spleen necrosis. Mice treated with low-dose superparamagnetic iron oxide nanoparticles and a low AMF survived, but had elevated enzyme levels and local necrosis in the spleen. Conclusion Magnetic nanoparticles producing only modest heat output can cause damage, and even death, when sequestered in sufficient concentrations. Dextran–superparamagnetic iron oxide nanoparticles are deposited in the liver and spleen, making these the sites of potential toxicity. PMID:22830502

  19. Ischemic-Anoxia of the Central Nervous System: Iron Dependent Oxidative Injury during Reperfusion.

    DTIC Science & Technology

    1986-10-15

    damage. .% EXPERIMENT II-B: Effects of Treatment with Deferoxamine, Flunarizine, and SOD on LMWS Iron, Lipid Peroxidation, and Tissue Ions at 8 Hours of...8217 - During this period, flunarizine (Caj antagonist) a-n a-c h6lropromazine ( effects in myocardium include inhibition of both phospholipase and of lipid...peroxidation) for protective effects across the injury parameters were examined. Neither flunarizine nor chloropromazine have so far exhibited marked

  20. Aqueous extract of Saussurea lappa root ameliorate oxidative myocardial injury induced by isoproterenol in rats

    PubMed Central

    Saleem, T. S. Mohamed; Lokanath, N.; Prasanthi, A.; Madhavi, M.; Mallika, G.; Vishnu, M. N.

    2013-01-01

    Saussurea lappa Clarke (Compositae), is commonly known as Kushta. In Ayurvedha, it is mentioned that the aqueous extract of the root S. lappa was used for treatment of angina pectoris. The present study was designed to investigate the cardioprotective effect of aqueous extract of root of S. lappa against isoproterenol induced myocardial injury. Myocardial injury in rat was induced by the administration of isoproterenol at a dose of 85 mg/kg, i.p., The rats were pretreated with the aqueous extract of S. lappa (AESL) in three different doses (100, 200 and 300 mg/kg, p.o.) through the oral route. Isoproterenol alone-treated rats showed increased serum concentration of lactate dehydrogenase (LDH), creatinine kinase (CK), and aspartate transaminase (AST), increased myocardial thiobarbituric acid reactive substances (TBARS) level, and decreased myocardial glutathione (GSH) level due to myocardial damage produced by isoproterenol. This is further conformed by histopathological changes. Chronic oral administration of AESL in three different doses significantly restored the level of myocardial LDH, CK, AST, TBARS, and GSH. The extract effect was compared with the reference standard α-tocopherol which also offered similar protection in biochemical and histopathological changes. The overall beneficial effect which was observed with the dose of 200 mg/kg indicated that AESL produced significant dose-dependent activity against isoproterenol induced myocardial injury. PMID:23833749

  1. Aqueous extract of Saussurea lappa root ameliorate oxidative myocardial injury induced by isoproterenol in rats.

    PubMed

    Saleem, T S Mohamed; Lokanath, N; Prasanthi, A; Madhavi, M; Mallika, G; Vishnu, M N

    2013-04-01

    Saussurea lappa Clarke (Compositae), is commonly known as Kushta. In Ayurvedha, it is mentioned that the aqueous extract of the root S. lappa was used for treatment of angina pectoris. The present study was designed to investigate the cardioprotective effect of aqueous extract of root of S. lappa against isoproterenol induced myocardial injury. Myocardial injury in rat was induced by the administration of isoproterenol at a dose of 85 mg/kg, i.p., The rats were pretreated with the aqueous extract of S. lappa (AESL) in three different doses (100, 200 and 300 mg/kg, p.o.) through the oral route. Isoproterenol alone-treated rats showed increased serum concentration of lactate dehydrogenase (LDH), creatinine kinase (CK), and aspartate transaminase (AST), increased myocardial thiobarbituric acid reactive substances (TBARS) level, and decreased myocardial glutathione (GSH) level due to myocardial damage produced by isoproterenol. This is further conformed by histopathological changes. Chronic oral administration of AESL in three different doses significantly restored the level of myocardial LDH, CK, AST, TBARS, and GSH. The extract effect was compared with the reference standard α-tocopherol which also offered similar protection in biochemical and histopathological changes. The overall beneficial effect which was observed with the dose of 200 mg/kg indicated that AESL produced significant dose-dependent activity against isoproterenol induced myocardial injury.

  2. The attenuation of hemorrhage-induced liver injury by exogenous nitric oxide, L-arginine, and inhibition of inducible nitric oxide synthase.

    PubMed

    Anaya-Prado, Roberto; Toledo-Pereyra, Luis H; Guo, R F; Reuben, J; Ward, Peter A; Walsh, J

    2003-01-01

    We investigated the role of nitric oxide (NO) in its ability to reduce liver injury in an animal model of hemorrhagic shock (HS). Ninety-six Sprague-Dawley rats weighing 250 to 300 g were divided in 6 groups (n = 16 per group) that included treatment at the beginning of resuscitation with normal saline (groups 1, 3) sodium nitroprusside (NP) (0.5 mg/kg) (groups 2, 4) L-arginine (300 mg/kg) (group 5), and L-N6-(1-iminoethyl) lysine (L-NIL, 40 mg/kg) (group 6). The experimental model of HS consisted of the withdrawal of 3 mL blood per 100 g in a 15-min period, tail amputation (75%), and drug administration at 30 min. This was followed by fluid resuscitation (FR) with lactated Ringer's (LR) solution to reach a mean arterial pressure (MAP) of 40 mm Hg, then a hospital phase of 60 min with hemostasis and FR with LR solution to reach a MAP of 70 mm Hg with a 3-day observation phase. NP, L-Arginine, and L-NIL significantly reduced fluid requirements for resuscitation (p =.0001) as well as significantly increased MAP after resuscitation from hemorrhage. We also observed an improved statistically significant difference (p =.001) in tests demonstrating less hepatic injury and histology damage. The mRNA expression of cytokines in the liver (interleukin [IL]-1alpha, IL-beta1, tumor necrosis factor [TNF]beta, IL-3, IL-4, IL-5, IL-6, IL-10, TNFalpha, IL-2, interferon [IFN]gamma) was reduced by NP treatment, L-arginine, and L-NIL. These data suggest that excess NO mediates hemorrhage-induced liver injury and that the suppression of inducible nitric oxide synthase (iNOS)-generated NO bioavailability with the NO donor sodium nitroprusside may reduce the pathophysiologic consequences of severe hemorrhage. This effect could be possibly related to the scavenging of to superoxide radicals (O2-) or the blockade of the deleterious effects of TNF and other inflammatory cytokines. The protective action noted with L-arginine cannot be fully explained within the context of this article

  3. Neuroprotective effects of sevoflurane against electromagnetic pulse-induced brain injury through inhibition of neuronal oxidative stress and apoptosis.

    PubMed

    Deng, Bin; Xu, Hao; Zhang, Jin; Wang, Jin; Han, Li-Chun; Li, Li-Ya; Wu, Guang-Li; Hou, Yan-Ning; Guo, Guo-Zhen; Wang, Qiang; Sang, Han-Fei; Xu, Li-Xian

    2014-01-01

    Electromagnetic pulse (EMP) causes central nervous system damage and neurobehavioral disorders, and sevoflurane protects the brain from ischemic injury. We investigated the effects of sevoflurane on EMP-induced brain injury. Rats were exposed to EMP and immediately treated with sevoflurane. The protective effects of sevoflurane were assessed by Nissl staining, Fluoro-Jade C staining and electron microscopy. The neurobehavioral effects were assessed using the open-field test and the Morris water maze. Finally, primary cerebral cortical neurons were exposed to EMP and incubated with different concentration of sevoflurane. The cellular viability, lactate dehydrogenase (LDH) release, superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were assayed. TUNEL staining was performed, and the expression of apoptotic markers was determined. The cerebral cortexes of EMP-exposed rats presented neuronal abnormalities. Sevoflurane alleviated these effects, as well as the learning and memory deficits caused by EMP exposure. In vitro, cell viability was reduced and LDH release was increased after EMP exposure; treatment with sevoflurane ameliorated these effects. Additionally, sevoflurane increased SOD activity, decreased MDA levels and alleviated neuronal apoptosis by regulating the expression of cleaved caspase-3, Bax and Bcl-2. These findings demonstrate that Sevoflurane conferred neuroprotective effects against EMP radiation-induced brain damage by inhibiting neuronal oxidative stress and apoptosis.

  4. Citicoline protects brain against closed head injury in rats through suppressing oxidative stress and calpain over-activation.

    PubMed

    Qian, Ke; Gu, Yi; Zhao, Yumei; Li, Zhenzong; Sun, Ming

    2014-07-01

    Citicoline, a natural compound that functions as an intermediate in the biosynthesis of cell membrane phospholipids, is essential for membrane integrity and repair. It has been reported to protect brain against trauma. This study was designed to investigate the protective effects of citicoline on closed head injury (CHI) in rats. Citicoline (250 mg/kg i.v. 30 min and 4 h after CHI) lessened body weight loss, and improved neurological functions significantly at 7 days after CHI. It markedly lowered brain edema and blood-brain barrier permeability, enhanced the activities of superoxide dismutase and the levels of glutathione, reduced the levels of malondialdehyde and lactic acid. Moreover, citicoline suppressed the activities of calpain, and enhanced the levels of calpastatin, myelin basic protein and αII-spectrin in traumatic tissue 24 h after CHI. Also, it attenuated the axonal and myelin sheath damage in corpus callosum and the neuronal cell death in hippocampal CA1 and CA3 subfields 7 days after CHI. These data demonstrate the protection of citicoline against white matter and grey matter damage due to CHI through suppressing oxidative stress and calpain over-activation, providing additional support to the application of citicoline for the treatment of traumatic brain injury.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26209813

  6. OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM)

    EPA Science Inventory

    OXIDATIVE STRESS PARTICIPATES IN ACUTE LUNG INJURY AND ACTIVATION OF MITOGEN ACTIVATED PROTEIN KINASES (MAPK) FOLLOWING AIR POLLUTION PARTICLE EXPOSURE (PM). E S Roberts1, R Jaskot2, J Richards2, and K L Dreher2. 1College of Veterinary Medicine, NC State University, Raleigh, NC a...

  7. DIETARY FLAXSEED PREVENTS RADIATION-INDUCED OXIDATIVE LUNG DAMAGE, INFLAMMATION AND FIBROSIS IN A MOUSE MODEL OF THORACIC RADIATION INJURY

    PubMed Central

    Lee, James C.; Krochak, Ryan; Blouin, Aaron; Kanterakis, Stathis; Chatterjee, Shampa; Arguiri, Evguenia; Vachani, Anil; Solomides, Charalambos C.; Cengel, Keith A.; Christofidou-Solomidou, Melpo

    2009-01-01

    Flaxseed (FS) has high contents of omega-3 fatty acids and lignans with antioxidant properties. Its use in preventing thoracic X-ray radiation therapy (XRT)-induced pneumonopathy has never been evaluated. We evaluated FS supplementation given to mice given before and post-XRT. FS-derived lignans, known for their direct antioxidant properties, were evaluated in abrogating ROS generation in cultured endothelial cells following gamma radiation exposure. Mice were fed 10% FS or isocaloric control diet for three weeks and given 13.5 Gy thoracic XRT. Lungs were evaluated at 24 hours for markers of radiation-induced injury, three weeks for acute lung damage (lipid peroxidation, lung edema and inflammation), and at four months for late lung damage (inflammation and fibrosis). FS-Lignans blunted ROS generation in vitro, resulting from radiation in a dose-dependent manner. FS-fed mice had reduced expression of lung injury biomarkers (Bax, p21, and TGF-beta1) at 24 hours following XRT and reduced oxidative lung damage as measured by malondialdehyde (MDA) levels at 3 weeks following XRT. In addition, FS-fed mice had decreased lung fibrosis as determined by hydroxyproline content and decreased inflammatory cell influx into lungs at 4 months post XRT. Importantly, when Lewis Lung carcinoma cells were injected systemically in mice, FS dietary supplementation did not appear to protect lung tumors from responding to thoracic XRT. Dietary FS is protective against pulmonary fibrosis, inflammation and oxidative lung damage in a murine model. Moreover, in this model, tumor radioprotection was not observed. FS lignans exhibited potent radiation-induced ROS scavenging action. Taken together, these data suggest that dietary flaxseed may be clinically useful as an agent to increase the therapeutic index of thoracic XRT by increasing the radiation tolerance of lung tissues. PMID:18981722

  8. Tumour necrosis factor-α inhibition with lenalidomide alleviates tissue oxidative injury and apoptosis in ob/ob obese mice.

    PubMed

    Zhu, Xiaoling; Jiang, Shasha; Hu, Nan; Luo, Fuling; Dong, Hailong; Kang, Yu-Ming; Jones, Kyla R; Zou, Yunzeng; Xiong, Lize; Ren, Jun

    2014-07-01

    Lenalidomide (Revlimid; Selleck Chemicals, Houston, TX, USA), an analogue of thalidomide, possesses potent cytokine modulatory capacity through inhibition of cytokines such as tumour necrosis factor (TNF)-α, a cytokine pivotal for the onset and development of complications in obesity and diabetes mellitus. The present study was designed to evaluate the effect of lenalidomide on oxidative stress, protein and DNA damage in multiple organs in an ob/ob murine model of obesity. To this end, C57BL/6 lean and ob/ob obese mice were administered lenalidomide (50 mg/kg per day, p.o.) for 5 days. Oxidative stress, protein and DNA damage were assessed using the conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG), carbonyl formation and Comet assay, respectively. Apoptosis was evaluated using caspase 3 activity, and levels of Bax, Bcl-2, Bip, caspase 8, caspase 9 and TNF-α were assessed using western blot analysis. Lenalidomide treatment did not affect glucose clearance in lean or ob/ob mice. Obese mice exhibited a reduced GSH/GSSG ratio in the liver, gastrocnemius skeletal muscle and small intestine, as well as enhanced protein carbonyl formation, DNA damage and caspase 3 activity in the liver, kidney, skeletal muscle and intestine; these effects were alleviated by lenalidomide, with the exception of obesity-associated DNA damage in the liver and kidney. Western blot analysis revealed elevated TNF-α, Bax, Bcl-2, Bip, caspase 8 and caspase 9 in ob/ob mice with various degrees of reversal by lenalidomide treatment. Together, these data indicate that lenalidomide protects against obesity-induced tissue injury and protein damage, possibly in association with antagonism of cytokine production and cytokine-induced apoptosis and oxidative stress.

  9. Quercetin phospholipid complex significantly protects against oxidative injury in ARPE-19 cells associated with activation of Nrf2 pathway.

    PubMed

    Xu, Xin-Rong; Yu, Hai-Tao; Yang, Yan; Hang, Li; Yang, Xue-Wen; Ding, Shu-Hua

    2016-01-05

    Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Oxidative stress plays a crucial role in the pathogenesis of dry AMD. Quercetin has potent anti-oxidative activities, but poor bioavailability limits its therapeutic application. Herein, we prepared the phospholipid complex of quercetin (quercetin-PC), characterized its structure by differential scanning calorimetry, infrared spectrum and x-ray diffraction. Quercetin-PC had equilibrium solubility of 38.36 and 1351.27μg/ml in water and chloroform, respectively, which was remarkably higher than those of quercetin alone. Then we established hydrogen peroxide (H2O2)-induced oxidative injury model in human ARPE-19 cells to examine the effects of quercetin-PC. Quercetin-PC, stronger than quercetin, promoted cell proliferation, and the proliferation rate was increased to be 78.89% when treated with Quercetin-PC at 400μM. Moreover, quercetin-PC effectively prevented ARPE-19 cells from apoptosis, and the apoptotic rate was reduced to be 3.1% when treated with Quercetin-PC at 200μM. In addition, quercetin-PC at 200μM significantly increased the activities of SOD, CAT and GSH-PX, and reduced the levels of reactive oxygen species and MDA in H2O2-treated ARPE-19 cells, but quercetin at 200μM failed to do so. Molecular examinations revealed that quercetin-PC at 200μM significantly activated Nrf2 nuclear translocation and significantly enhanced the expression of target genes HO-1, NQO-1 and GCL by different folds at both mRNA and protein levels. Our current data collectively indicated that quercetin-PC had stronger protective effects against oxidative-induced damages in ARPE-19 cells, which was associated with activation of Nrf2 pathway and its target genes implicated in antioxidant defense.

  10. Cyclosporin-A inhibits constitutive nitric oxide synthase activity and neuronal and endothelial nitric oxide synthase expressions after spinal cord injury in rats.

    PubMed

    Diaz-Ruiz, Araceli; Vergara, Paula; Perez-Severiano, Francisca; Segovia, Jose; Guizar-Sahagún, Gabriel; Ibarra, Antonio; Ríos, Camilo

    2005-02-01

    Nitric oxide (NO) plays a role in the pathophysiology of spinal cord injury (SCI). NO is produced by three types of nitric oxide synthase (NOS) enzymes: The constitutive Ca2+/calmodulin-dependent neuronal NOS (nNOS) and endothelial NOS (eNOS) isoforms, and the inducible calcium-independent isoform (iNOS). During the early stages of SCI, nNOS and eNOS produce significant amounts of NO, therefore, the regulation of their activity and expression may participate in the damage after SCI. In the present study, we used Cyclosporin-A (CsA) to further substantiate the role of Ca-dependent NOS in neural responses associated to SCI. Female Wistar rats were subjected to SCI by contusion, and killed 4 h after lesion. Results showed an increase in the activity of constitutive NOS (cNOS) after lesion, inhibited by CsA (2.5 mg/kg i.p.). Western blot assays showed an increased expression of both nNOS and eNOS after trauma, also antagonized by CsA administration.

  11. Association of oxidative DNA damage, protein oxidation and antioxidant function with oxidative stress induced cellular injury in pre-eclamptic/eclamptic mothers during fetal circulation.

    PubMed

    Negi, Reena; Pande, Deepti; Karki, Kanchan; Kumar, Ashok; Khanna, Ranjana S; Khanna, Hari D

    2014-02-05

    Pre-eclampsia is a devastating multi system syndrome and a major cause of maternal, fetal, neonatal morbidity and mortality. Pre-eclampsia is associated with oxidative stress in the maternal circulation. To have an insight on the effect of pre-eclampsia/eclampsia on the neonates, the study was made to explore the oxidative status by quantification of byproducts generated during protein oxidation and oxidative DNA damage and deficient antioxidant activity in umbilical cord blood of pre-eclamptic/eclamptic mothers during fetal circulation. Umbilical cord blood during delivery from neonates born to 19 pre-eclamptic mothers, 14 eclamptic mothers and 18 normotensive mothers (uncomplicated pregnancy) as control cases was collected. 8-OHdG (8-hydroxy-2-deoxyguanosine), protein carbonyl, nitrite, catalase, non-enzymatic antioxidants (vitamin A, E, C), total antioxidant status and iron status were determined. Significant elevation in the levels of 8-OHdG, protein carbonyl, nitrite and iron along with decreased levels of catalase, vitamin A, E, C, total antioxidant status were observed in the umbilical cord blood of pre-eclamptic and eclamptic pregnancies. These parameters might be influential variables for the risk of free radical damage in infants born to pre-eclamptic/eclamptic pregnancies. Increased oxidative stress causes oxidation of DNA and protein which alters antioxidant function. Excess iron level and decreased unsaturated iron binding capacity may be the important factor associated with oxidative stress and contribute in the pathogenesis of pre-eclampsia/eclampsia which is reflected in fetal circulation.

  12. N-acetylcysteine attenuates copper overload-induced oxidative injury in brain of rat.

    PubMed

    Ozcelik, Dervis; Uzun, Hafize; Nazıroglu, Mustafa

    2012-06-01

    Copper is an integral part of many important enzymes involved in a number of vital biological processes. Even though it is essential to life, at elevated tissue concentrations, copper can become toxic to cells. Recent studies have reported oxidative damage due to copper in various tissues. Considering the vulnerability of the brain to oxidative stress, this study was undertaken to explore possible beneficial antioxidant effects of N-acetylcysteine on oxidative stress induced by copper overload in brain tissue of rats. Thirty-two Wistar rats were equally divided into four groups. The first group was used as control. The second, third, and fourth groups were given 1 g/L copper in their drinking water for 1 month. At the end of this period, the group 2 rats were sacrificed. During the next 2 weeks, the rats in group 3 were injected intraperitoneally with physiological saline and those in group 4 with 20 mg/kg intraperitoneal injections of N-acetylcysteine. In group 2 the lipid peroxidation and nitric oxide levels were increased in the brain cortex while the activities of superoxide dismutase and catalase and the concentration of glutathione were decreased. In rats treated with N-acetylcysteine, lipid peroxidation decreased and the activities of antioxidant enzyme improved in the brain cortex. In conclusion, treatment with N-acetylcysteine modulated the antioxidant redox system and reduced brain oxidative stress induced by copper.

  13. Endothelin-1, interleukin-4 and nitric oxide synthase modulators of gastric mucosal injury by indomethacin: effect of antiulcer agents.

    PubMed

    Slomiany, B L; Piotrowski, J; Slomiany, A

    1999-06-01

    Endothelin-1 (ET-1), nitric oxide, and cytokines are recognized mediators of the inflammatory processes associated with gastric mucosal injury. In this study, we investigated mucosal expression of ET-1, interleukin-4 (IL-4), and the activity of constitutive nitric oxide synthase (cNOS) during indomethacin-induced gastric mucosal injury, and evaluated the effect of antiulcer agents on this process. The experiments were conducted with groups of rats pretreated intragastrically with ranitidine (100 mg/kg), ebrotidine (100 mg/kg), sulglycotide (200 mg/kg) or vehicle, followed 30 min later by an intragastric dose of indomethacin (60 mg/kg). The animals were killed 2 h later and their mucosal tissue subjected to macroscopic damage assessment and the measurements of epithelial cell apoptosis, ET-1, IL-4, and cNOS. In the absence of antiulcer agents, indomethacin caused multiple hemorrhagic lesions and extensive epithelial cell apoptosis, accompanied by a 20.7% reduction in IL-4, a 3.1-fold increase in mucosal expression of ET-1 and a 4.2-fold decline in cNOS. Pretreatment with H2-receptor antagonist, ranitidine produced a 15.7% reduction in the mucosal damage caused by indomethacin, 29.5% decrease in epithelial cell apoptosis and a 19.6% reduction in ET-1, while the expression of IL-4 increased by 10.8% and that of cNOS showed a 2-fold increase. The H2-blocker, ebrotidine, also known for its gastroprotective effects, reduced the indomethacin-induced lesions by 90.2%, epithelial cell apoptosis decreased by 61% and ET-1 showed a 58.2% decline, while IL-4 increased by 30.6% and that of cNOS showed a 3.1-fold increase. Pretreatment with gastroprotective agent, sulglycotide, led to a 51.2% reduction in the extent of mucosal damage caused by indomethacin, a 43.9% decrease in apoptosis, and a 63.5% decrease in ET-1, while the expression of cNOS increased by 3.4-fold and the level of IL-4 showed a 32.2% increase. The results suggest that an increase in vasoconstrictive ET-1 level

  14. Grape seed and skin extract protects kidney from doxorubicin-induced oxidative injury.

    PubMed

    Mokni, Meherzia; Hamlaoui, Sonia; Kadri, Safwen; Limam, Ferid; Amri, Mohamed; Marzouki, Lamjed; Aouani, Ezzedine

    2016-05-01

    The study investigated the protective effect of grape seed and skin extract (GSSE) against doxorubicin-induced renal toxicity in healthy rats. Animals were treated with GSSE or not (control), for 8 days, administered with doxorubicin (20mg/kg) in the 4th day, and renal function as well as oxidative stress parameters were evaluated. Data showed that doxorubicin induced renal toxicity by affecting renal architecture and plasma creatinine. Doxorubicin also induced an oxidative stress characterized by an increase in malondialdehyde (MDA), calcium and H(2)O(2) and a decrease in catalase (CAT) and superoxide dismutase (SOD). Unexpectedly doxorubicin increased peroxidase (POD) and decreased carbonyl protein and plasma urea. Treatment with GSSE counteracted almost all adverse effects induced by doxorubicin. Data suggest that doxorubicin induced an oxidative stress into rat kidney and GSSE exerted antioxidant properties, which seem to be mediated by the modulation of intracellular calcium.

  15. Evidence of oxidative injury of the spinal cord in 2 horses with equine degenerative myeloencephalopathy.

    PubMed

    Wong, D M; Ghosh, A; Fales-Williams, A J; Haynes, J S; Kanthasamy, A G

    2012-11-01

    The cervical spinal cords of 2 horses with equine degenerative myeloencephalopathy (EDM) were evaluated for evidence of oxidative damage to the central nervous system (CNS) using immunohistochemical staining for 3-nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE). Neurons of the CNS from horses with EDM had positive immunohistochemical staining, whereas control samples did not, thus supporting the theory that oxidative damage is a potential underlying factor in horses with EDM. In addition, serum vitamin E concentration was low in both EDM-affected horses, and vitamin E concentration was also deficient in the cerebrospinal fluid in 1 EDM horse, further supporting the association between low vitamin E concentrations and oxidative damage to the CNS. Continued research is necessary to further define the pathophysiologic mechanisms of EDM.

  16. Prevention of in vitro oxidant-mediated alveolar macrophage injury by cellular glutathione and precursors.

    PubMed

    Voisin, C; Aerts, C; Wallaert, B

    1987-01-01

    To evaluate the toxic effects of various oxidants on alveolar macrophages (O2, NO2, tobacco smoke and silica), we used an original method of cell culture in aerobiosis, which permitted direct contact between the atmosphere and the target cells. Our results demonstrated that the variations of cell sensitivity to the cytotoxic effects of oxidants were associated with various levels in cellular antioxidant equipment. A significant correlation was found between cytotoxicity and antioxidant enzymes (superoxide dismutase and catalase) and/or cellular glutathione. Addition of N-acetylcysteine, a polypeptide known to have an antioxidant activity and to be a precursor of glutathione, was responsible for a decrease of oxidant-mediated cytotoxicity. Whether this protective effect was due to an increase in glutathione cell content or to a scavenger effect of N-acetylcysteine still needs to be elucidated.

  17. PPAR{alpha} agonist fenofibrate protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress and MAPK activity

    SciTech Connect

    Hou, Xiaoyang; Shen, Ying H.; Li, Chuanbao; Wang, Fei; Zhang, Cheng; Bu, Peili; Zhang, Yun

    2010-04-09

    Oxidative stress has been shown to play an important role in the development of hypertensive renal injury. Peroxisome proliferator-activated receptors {alpha} (PPAR{alpha}) has antioxidant effect. In this study, we demonstrated that fenofibrate significantly reduced proteinuria, inflammatory cell recruitment and extracellular matrix (ECM) proteins deposition in the kidney of SHRs without apparent effect on blood pressure. To investigate the mechanisms involved, we found that fenofibrate treatment markedly reduced oxidative stress accompanied by reduced activity of renal NAD(P)H oxidase, increased activity of Cu/Zn SOD, and decreased phosphorylation of p38MAPK and JNK in the kidney of SHRs. Taken together, fenofibrate treatment can protect against hypertensive renal injury without affecting blood pressure by inhibiting inflammation and fibrosis via suppression of oxidative stress and MAPK activity.

  18. Troxerutin protects the mouse liver against oxidative stress-mediated injury induced by D-galactose.

    PubMed

    Zhang, Zi-feng; Fan, Shao-hua; Zheng, Yuan-lin; Lu, Jun; Wu, Dong-mei; Shan, Qun; Hu, Bin

    2009-09-09

    Troxerutin, a trihydroxyethylated derivative of rutin, has been well-demonstrated to exert hepatoprotective properties. In the present study, we attempted to explore whether the antioxidant and anti-inflammatory mechanisms were involved in troxerutin-mediated protection from D-gal-induced liver injury. The effects of troxerutin on liver lipid peroxidation, antioxidant enzymatic activities, and the expression of inflammatory mediator were investigated in D-gal-treated mice. The results showed that troxerutin largely attenuated the D-gal-induced TBARS content increase and also markedly renewed the activities of Cu, Zn-SOD, CAT, and GPx in the livers of D-gal-treated mice. Furthermore, troxerutin inhibited the upregulation of the expression of NF-kappaB p65, iNOS, and COX-2 induced by D-gal. D-Gal-induced tissue architecture changes and serum ALT and AST increases were effectively suppressed by troxerutin. In conclusion, these results suggested that troxerutin could protect the mouse liver from D-gal-induced injury by attenuating lipid peroxidation, renewing the activities of antioxidant enzymes and suppressing inflammatory response. This study provided novel insights into the mechanisms of troxerutin in the protection of the liver.

  19. Erdosteine improves oxidative damage in a rat model of renal ischemia-reperfusion injury.

    PubMed

    Gurel, A; Armutcu, F; Cihan, A; Numanoglu, K V; Unalacak, M

    2004-01-01

    The aim of the present study was to determine the effects of erdosteine, a new antioxidant and anti-inflammatory agent, on lipid peroxidation, neutrophil infiltration, and antioxidant enzyme activities in a rat model of renal ischemia-reperfusion (I/R) injury. Twenty-eight rats were divided into three groups: sham operation, I/R, and I/R plus erdosteine groups. After the experimental procedure, rats were sacrificed and kidneys were removed and prepared for malondialdehyde (MDA) levels, myeloperoxidase (MPO), xanthine oxidase (XO), catalase (CAT) and superoxide dismutase (SOD) activities. MDA level, MPO and XO activities were significantly increased in the I/R group. On the other hand, SOD and CAT activities were found to be decreased in the I/R group compared to the sham group. Pretreatment with erdosteine significantly diminished tissue MDA level, MPO and XO activities. Our data support a role for erdosteine in attenuation in renal damage after I/R injury of the kidney, in part at least by inhibition of neutrophil sequestration and XO activity.

  20. Resveratrol mitigates hepatic injury in rats by regulating oxidative stress, nuclear factor-kappa B, and apoptosis

    PubMed Central

    Seif el-Din, Sayed Hassan; El-Lakkany, Naglaa Mohamed; Salem, Maha Badr; Hammam, Olfat Ali; Saleh, Samira; Botros, Sanaa Sabet

    2016-01-01

    Resveratrol is a naturally occurring polyphenol, possesses several pharmacological activities including anticancer, antioxidant, antidiabetic, antinociceptive, and antiasthmatic activity. Little is known about its hepatoprotective action mechanisms. This study was conceived to explore the possible protective mechanisms of resveratrol compared with the hepatoprotective silymarin in thioacetamide (TAA)-induced hepatic injury in rats. Thirty-two rats were equally divided into four groups; normal control (i), TAA (100 mg/kg) (ii), TAA + silymarin (50 mg/kg) (iii), and TAA + resveratrol (10 mg/kg) (iv). Liver function and histopathology, pro-inflammatory cytokines, oxidative stress, and apoptotic markers were examined. Data were analyzed using ANOVA test followed by Tukey post hoc test. Compared to TAA-intoxicated group, resveratrol mitigated liver damage, and inflammation as noted by less inflammatory infiltration, hydropic degeneration with decreased levels of tumor necrosis factor-alpha, interleukin-6, and interferon-gamma by 78.83, 18.12, and 64.49%, respectively. Furthermore, it reduced (P < 0.05) alanine and aspartate aminotransferases by 36.64 and 48.09%, respectively, restored hepatic glutathione content and normalized superoxide dismutase and malondialdehyde levels. While it inhibited nuclear factor-kappa B, cytochrome 2E1, and enhanced apoptosis of necrotic hepatocytes via increasing caspase-3 activity. Our findings indicated that the potential hepatoprotective mechanisms of resveratrol are associated with inhibition of inflammation, enhancing the apoptosis of necrotic hepatocytes, and suppression of oxidative stress. PMID:27429929

  1. Bazhen Decoction Protects against Acetaminophen Induced Acute Liver Injury by Inhibiting Oxidative Stress, Inflammation and Apoptosis in Mice

    PubMed Central

    Song, Erqun; Fu, Juanli; Xia, Xiaomin; Su, Chuanyang; Song, Yang

    2014-01-01

    Bazhen decoction is a widely used traditional Chinese medicinal decoction, but the scientific validation of its therapeutic potential is lacking. The objective of this study was to investigate corresponding anti-oxidative, anti-inflammatory and anti-apoptosis activities of Bazhen decoction, using acetaminophen-treated mice as a model system. A total of 48 mice were divided into four groups. Group I, negative control, treated with vehicle only. Group II, fed with 500 mg/kg/day Bazhen decoction for 10 continuous days. Group III, received a single dose of 900 mg/kg acetaminophen. Group IV, fed with 500 mg/kg/day Bazhen decoction for 10 continuous days and a single dose of 900 mg/kg acetaminophen 30 min before last Bazhen decoction administration. Bazhen decoction administration significantly decrease acetaminophen-induced serum ALT, AST, ALP, LDH, TNF-α, IL-1β, ROS, TBARS and protein carbonyl group levels, as well as GSH depletion and loss of MMP. Bazhen decoction restore SOD, CAT, GR and GPx activities and depress the expression of pro-inflammatory factors, such as iNOS, COX-2, TNF-α, NF-κB, IL-1β and IL-6, respectively. Moreover, Bazhen decoction down-regulate acetaminophen-induced Bax/Bcl-2 ratio, caspase 3, caspase 8 and caspase 9. These results suggest the anti-oxidative, anti-inflammatory and anti-apoptosis properties of Bazhen decoction towards acetaminophen-induced liver injury in mice. PMID:25222049

  2. Bifunctional viscous nanovesicles co-loaded with resveratrol and gallic acid for skin protection against microbial and oxidative injuries.

    PubMed

    Vitonyte, Justina; Manca, Maria Letizia; Caddeo, Carla; Valenti, Donatella; Peris, Josè Esteban; Usach, Iris; Nacher, Amparo; Matos, Maria; Gutiérrez, Gemma; Orrù, Germano; Fernàndez-Busquets, Xavier; Fadda, Anna Maria; Manconi, Maria

    2017-05-01

    Resveratrol and gallic acid were co-loaded in phospholipid vesicles aiming at protecting the skin from external injuries, such as oxidative stress and microbial infections. Liposomes were prepared using biocompatible phospholipids dispersed in water. To improve vesicle stability and applicability, the phospholipids and the phenols were dispersed in water/propylene glycol or water/glycerol, thus obtaining PEVs and glycerosomes, respectively. The vesicles were characterized by size, morphology, physical stability, and their therapeutic efficacy was investigated in vitro. The vesicles were spherical, unilamellar and small in size: liposomes and glycerosomes were around 70nm in diameter, while PEVs were larger (∼170nm). The presence of propylene glycol or glycerol increased the viscosity of the vesicle systems, positively affecting their stability. The ability of the vesicles to promote the accumulation of the phenols (especially gallic acid) in the skin was demonstrated, as well as their low toxicity and great ability to protect keratinocytes and fibroblasts from oxidative damage. Additionally, an improvement of the antimicrobial activity of the phenols was shown against different skin pathogens. The co-loading of resveratrol and gallic acid in modified phospholipid vesicles represents an innovative, bifunctional tool for preventing and treating skin affections.

  3. Assessment of C-phycocyanin effect on astrocytes-mediated neuroprotection against oxidative brain injury using 2D and 3D astrocyte tissue model

    PubMed Central

    Min, Seul Ki; Park, Jun Sang; Luo, Lidan; Kwon, Yeo Seon; Lee, Hoo Cheol; Jung Shim, Hyun; Kim, Il-Doo; Lee, Ja-Kyeong; Shin, Hwa Sung

    2015-01-01

    Drugs are currently being developed to attenuate oxidative stress as a treatment for brain injuries. C-phycocyanin (C-Pc) is an antioxidant protein of green microalgae known to exert neuroprotective effects against oxidative brain injury. Astrocytes, which compose many portions of the brain, exert various functions to overcome oxidative stress; however, little is known about how C-Pc mediates the antioxidative effects of astrocytes. In this study, we revealed that C-Pc intranasal administration to the middle cerebral artery occlusion (MCAO) rats ensures neuroprotection of ischemic brain by reducing infarct size and improving behavioral deficits. C-Pc also enhanced viability and proliferation but attenuated apoptosis and reactive oxygen species (ROS) of oxidized astrocytes, without cytotoxicity to normal astrocytes and neurons. To elucidate how C-Pc leads astrocytes to enhance neuroprotection and repair of ischemia brain, we firstly developed 3D oxidized astrocyte model. C-Pc had astrocytes upregulate antioxidant enzymes such as SOD and catalase and neurotrophic factors BDNF and NGF, while alleviating inflammatory factors IL-6 and IL-1β and glial scar. Additionally, C-Pc improved viability of 3D oxidized neurons. In summary, C-Pc was concluded to activate oxidized astrocytes to protect and repair the ischemic brain with the combinatorial effects of improved antioxidative, neurotrophic, and anti-inflammatory mechanisms. PMID:26399322

  4. Assessment of C-phycocyanin effect on astrocytes-mediated neuroprotection against oxidative brain injury using 2D and 3D astrocyte tissue model.

    PubMed

    Min, Seul Ki; Park, Jun Sang; Luo, Lidan; Kwon, Yeo Seon; Lee, Hoo Cheol; Shim, Hyun Jung; Kim, Il-Doo; Lee, Ja-Kyeong; Shin, Hwa Sung

    2015-09-24

    Drugs are currently being developed to attenuate oxidative stress as a treatment for brain injuries. C-phycocyanin (C-Pc) is an antioxidant protein of green microalgae known to exert neuroprotective effects against oxidative brain injury. Astrocytes, which compose many portions of the brain, exert various functions to overcome oxidative stress; however, little is known about how C-Pc mediates the antioxidative effects of astrocytes. In this study, we revealed that C-Pc intranasal administration to the middle cerebral artery occlusion (MCAO) rats ensures neuroprotection of ischemic brain by reducing infarct size and improving behavioral deficits. C-Pc also enhanced viability and proliferation but attenuated apoptosis and reactive oxygen species (ROS) of oxidized astrocytes, without cytotoxicity to normal astrocytes and neurons. To elucidate how C-Pc leads astrocytes to enhance neuroprotection and repair of ischemia brain, we firstly developed 3D oxidized astrocyte model. C-Pc had astrocytes upregulate antioxidant enzymes such as SOD and catalase and neurotrophic factors BDNF and NGF, while alleviating inflammatory factors IL-6 and IL-1β and glial scar. Additionally, C-Pc improved viability of 3D oxidized neurons. In summary, C-Pc was concluded to activate oxidized astrocytes to protect and repair the ischemic brain with the combinatorial effects of improved antioxidative, neurotrophic, and anti-inflammatory mechanisms.

  5. CARDIOVASCULAR DISEASES, SUSCEPTIBILITY TO OXIDATIVE INJURY AND COMPENSATORY MECHANISMS: INSIGHTS FROM RODENT MODELS

    EPA Science Inventory

    Cardiovascular diseases (CVD) are the number one cause for human mortality and nearly 25% of the population develops chronic CVD at an age of 65 years or older. Environmental and genetic interactions govern pathogenesis. Increased oxidative stress and compromised antioxidant stat...

  6. Iron and Oxidative Stress in Parkinson's Disease: An Observational Study of Injury Biomarkers.

    PubMed

    Medeiros, Marcio S; Schumacher-Schuh, Arthur; Cardoso, Andreia Machado; Bochi, Guilherme Vargas; Baldissarelli, Jucimara; Kegler, Aline; Santana, Daniel; Chaves, Carolina Maria Martins Behle Soares; Schetinger, Maria Rosa Chitolina; Moresco, Rafael Noal; Rieder, Carlos R M; Fighera, Michele Rechia

    2016-01-01

    Parkinson's disease (PD) is characterized by progressive motor impairment attributed to progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. In addition to an accumulation of iron, there is also an increased production of reactive oxygen/nitrogen species (ROS/RNS) and inflammatory markers. These observations suggest that iron dyshomeostasis may be playing a key role in neurodegeneration. However, the mechanisms underlying this metal-associated oxidative stress and neuronal damage have not been fully elucidated. To determine peripheral levels of iron, ferritin, and transferrin in PD patients and its possible relation with oxidative/nitrosative parameters, whilst attempting to identify a profile of peripheral biomarkers in this neurological condition. Forty PD patients and 46 controls were recruited to compare serum levels of iron, ferritin, transferrin, oxidative stress markers (superoxide dismutase (SOD), catalase (CAT), nitrosative stress marker (NOx), thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), advanced oxidation protein products (AOPP), ferric reducing ability of plasma (FRAP) and vitamin C) as well as inflammatory markers (NTPDases, ecto-5'-nucleotidase, adenosine deaminase (ADA), ischemic-modified albumin (IMA) and myeloperoxidase). Iron levels were lower in PD patients, whereas there was no difference in ferritin and transferrin. Oxidative stress (TBARS and AOPP) and inflammatory markers (NTPDases, IMA, and myeloperoxidase) were significantly higher in PD, while antioxidants FRAP, vitamin C, and non-protein thiols were significantly lower in PD. The enzymes SOD, CAT, and ecto-5'-nucleotidase were not different among the groups, although NOx and ADA levels were significantly higher in the controls. Our data corroborate the idea that ROS/RNS production and neuroinflammation may dysregulate iron homeostasis and collaborate to reduce the periphery levels of this ion, contributing to alterations

  7. Overexpression of DJ-1 reduces oxidative stress and attenuates hypoxia/reoxygenation injury in NRK-52E cells exposed to high glucose

    PubMed Central

    Shen, Zi-Ying; Sun, Qian; Xia, Zhong-Yuan; Meng, Qing-Tao; Lei, Shao-Qing; Zhao, Bo; Tang, Ling-Hua; Xue, Rui; Chen, Rong

    2016-01-01

    Patients with diabetes are more vulnerable to renal ischemia/reperfusion (I/R) injury, which is implicated in hyperglycemia-induced oxidative stress. We previously reported that the hyperglycemia-induced inhibition of DJ-1, a novel oncogene that exhibits potent antioxidant activity, is implicated in the severity of myocardial I/R injury. In the present study, we aimed to explore the role of DJ-1 in hypoxia/reoxygenation (H/R) injury in renal cells exposed to high glucose (HG). For this purpose, NRK-52E cells were exposed to HG (30 mM) for 48 h and then exposed to hypoxia for 4 h and reoxygenation for 2 h, which significantly decreased cell viability and superoxide dismutase (SOD) activity, and increased the malondialdehyde (MDA) content, accompanied by a decrease in DJ-1 protein expression. The overexpression of DJ-1 by transfection with a DJ-1 overexpression plasmid exerted protective effects against HG-induced H/R injury, as evidenced by increased CCK-8 levels and SOD activity, the decreased release of lactate dehydrogenase (LDH) and the decreased MDA content, and increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. Similar effects were observed following treatment with the antioxidant, N-acetylcysteine. These results suggest that the overexpression of DJ-1 reduces oxidative stress and attenuates H/R injury in NRK-52E cells exposed to HG. PMID:27430285

  8. Protective Effects of Dioscin against Lipopolysaccharide-Induced Acute Lung Injury through Inhibition of Oxidative Stress and Inflammation

    PubMed Central

    Yao, Hong; Sun, Yiping; Song, Shasha; Qi, Yan; Tao, Xufeng; Xu, Lina; Yin, Lianhong; Han, Xu; Xu, Youwei; Li, Hua; Sun, Huijun; Peng, Jinyong

    2017-01-01

    The protective effects of dioscin, a natural steroidal saponin from some medicinal plants including Dioscorea nipponica Makino, against lipopolysaccharide (LPS)- induced acute liver and renal damages have been reported in our previous works. However, the actions of dioscin against LPS-induced acute lung injury (ALI) is still unknown. In the present study, we investigated the effects and mechanisms of dioscin against LPS-induced ALI in vitro and in vivo. The results showed that dioscin obviously inhibited cell proliferation and markedly decreased reactive oxidative species level in 16HBE cells treated by LPS. In addition, dioscin significantly protected LPS-induced histological changes, inhibited the infiltration of inflammatory cells, as well as decreased the levels of MDA, SOD, NO and iNOS in mice and rats (p < 0.05). Mechanistically, dioscin significantly decreased the protein levels of TLR4, MyD88, TRAF6, TKB1, TRAF3, phosphorylation levels of PI3K, Akt, IκBα, NF-κB, and the mRNA levels of IL-1β, IL-6, and TNF-α against oxidative stress and inflammation (p < 0.05). Dioscin significantly reduced the overexpression of TLR4, and obviously down-regulated the levels of MyD88, TRAF6, TKB1, TRAF3, p-PI3K, p-Akt, p-IκBα, and p-NF-κB. These findings provide new perspectives for the study of ALI. Dioscin has protective effects on LPS-induced ALI via adjusting TLR4/MyD88- mediated oxidative stress and inflammation, which should be a potent drug in the treatment of ALI. PMID:28377715

  9. Melatonin, quercetin and resveratrol attenuates oxidative hepatocellular injury in streptozotocin-induced diabetic rats.

    PubMed

    Elbe, H; Esrefoglu, M; Vardi, N; Taslidere, E; Ozerol, E; Tanbek, K

    2015-09-01

    In this study, effects of melatonin, quercetin and resveratrol on hepatocellular injury in streptozotocin (STZ)-induced experimental diabetes were aimed to be investigated by histological and biochemical methods. Thirty-five male Wistar albino rats were divided into five groups, namely, control, diabetes (STZ 45 mg/kg/single dose/intraperitoneally (ip)), diabetes + melatonin (10 mg/kg/30 days/ip), diabetes + quercetin (25 mg/kg/30 days/ip) and diabetes + resveratrol (10 mg/kg/30 days/ip). Initial and final blood glucose levels and body weights (BWs) were measured. At the end of the experimentation, following routine tissue processing procedure, sections were stained with haematoxylin-eosin (H-E), periodic acid Schiff and Masson's trichrome. Tissue malondialdehyde (MDA) and glutathione (GSH) levels and superoxide dismutase (SOD) and catalase (CAT) activities were examined. The diabetic rats had significantly higher blood glucose levels than those of control rats (p = 0.0001). Mean BWs of diabetic rats were significantly decreased when compared with the control rats (p = 0.0013). Histopathological alterations including cellular glycogen depletion, congestion, sinusoidal dilatation, inflammation and fibrosis were detected in diabetes group. On the other hand, histopathological changes markedly reduced in all of the treatment groups (p = 0.001). Mean tissue MDA level was increased but mean tissue CAT and SOD activities and GSH levels were decreased in the diabetes group. Melatonin, quercetin and resveratrol administered diabetic rats showed an increase in CAT activities and GSH levels and a decrease in MDA levels (p < 0.05, for all). Melatonin, quercetin and resveratrol administrations markedly reduced hepatocellular injury in STZ-induced experimental diabetes.

  10. Interferon Gamma potentiates the injury caused by MPP(+) on SH-SY5Y cells, which is attenuated by the nitric oxide synthases inhibition.

    PubMed

    Titze-de-Almeida, Simoneide S; Lustosa, Cátia Faria; Horst, Camila Hillesheim; Bel, Elaine Del; Titze-de-Almeida, Ricardo

    2014-12-01

    This study examined whether the cytokine interferon (IFN) gamma plays a role in the injury of SH-SY5Y cells caused by MPP(+) (1-methyl-4-phenylpyridinium). First of all, IFN-gamma sensitized cells to the neurotoxin MPP(+), as determined by MTT (3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide) assay. MPP(+)-injured cells showed higher reactive oxygen species (ROS) levels, which was reinforced by IFN-gamma. The injury triggered a marked expression of the neuronal NOS (nNOS) enzyme. L-NAME [N(ω)-nitro-L-arginine methyl ester, a non-specific NOS inhibitor] reestablished the cell viability after IFN-gamma challenging, and recovered cells from MPP(+) injury (95.0 vs. 84.7 %; P < 0.05). Seven-NI (7-nitroindazole, a nNOS inhibitor) protected cells against the injury by MPP(+) co-administered with IFN-gamma. Both inhibitors restrained the apoptosis of SH-SY5Y cells caused by MPP(+)/IFN-gamma. Regarding oxidative stress, L-NAME and 7-NI attenuated the increase in ROS levels caused by MPP(+) (45.3 or 48.4 vs. 87.9 %, P < 0.05). Indeed, L-NAME was more effective than 7-NI for reducing oxidative stress caused by MPP(+) under IFN-gamma exposition. The nNOS gene silencing by small-interfering RNAs recovered cells challenged by IFN-gamma (24 h), or MPP(+) (8 h). In conclusion, IFN-gamma sensitizes cells to MPP(+)-induced injury, also causing an increase in ROS levels. Pretreating cells with L-NAME or 7-NI reverts both the oxidative stress and apoptosis triggered by the neurotoxin MPP(+). Taking together, our data reinforce that IFN-gamma and NOS enzymes play a role in oxidative stress and dopaminergic cell death triggered by MPP(+).

  11. Kinetics of Nitrogen Oxide Production Following Experimental Thermal Injury in Rats,

    DTIC Science & Technology

    1993-01-01

    sulfanilamide and N - naphthyl ethylenediamine ) fol- of the experiment. In contrast to other amino acids, arginine is lowing reduction of NO3 to NO2 by...8217 5N2-guanido-arginine to burned and sham-burned rats and observing an immediate enrichment of 15N in nitrate. The amount of administered 1" N ...baseline recovery in burned rats. The arginine analog N -monomethyl-arginine, an Inhibitor of the enzyme nitric oxide synthase, blocked the postbum rise in

  12. Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury.

    PubMed

    Jung, Michaela; Hotter, Georgina; Viñas, Jose Luis; Sola, Anna

    2009-01-15

    The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxide formation has been implicated in the toxicity of cisplatin, this formation has not so far been related to a possible activation of mitochondrial nitric oxide synthase (mNOS). We show here that the upregulation of oxide mNOS and peroxynitrite formation in cisplatin treatment are key events that influence the development of the harmful parameters described in cisplatin-associated kidney failure. We confirm this by isolating the mitochondrial fraction of the kidney and across different access routes such as the use of a specific inhibitor of neuronal NOS, L-NPA, a peroxynitrite scavenger, FeTMPyP, and a peroxynitrite donor, SIN-1. The in vitro studies corroborated the information obtained in the in vivo experiments. The administration of cisplatin reveals a clear upregulation in the transcription of neuronal NOS and an increase in the levels of nitrites in the mitochondrial fractions of the kidneys. The upregulated transcription directly affects the cytoskeleton structure and the apoptosis. The inhibition of neuronal NOS reduces the levels of nitrites, cell death, and cytoskeleton derangement. Peroxynitrite is involved in the mechanism promoting the NOS transcription. In addition, in controls SIN-1 imitates the effects of cisplatin. In summary, we demonstrate that upregulation of mNOS in cisplatin treatment is a key component in both the initiation and the spread of cisplatin-associated damage in the kidney. Furthermore, peroxynitrite formation is directly involved in this process.

  13. Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury

    SciTech Connect

    Jung, Michaela; Sola, Anna

    2009-01-15

    The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxide formation has been implicated in the toxicity of cisplatin, this formation has not so far been related to a possible activation of mitochondrial nitric oxide synthase (mNOS). We show here that the upregulation of oxide mNOS and peroxynitrite formation in cisplatin treatment are key events that influence the development of the harmful parameters described in cisplatin-associated kidney failure. We confirm this by isolating the mitochondrial fraction of the kidney and across different access routes such as the use of a specific inhibitor of neuronal NOS, L-NPA, a peroxynitrite scavenger, FeTMPyP, and a peroxynitrite donor, SIN-1. The in vitro studies corroborated the information obtained in the in vivo experiments. The administration of cisplatin reveals a clear upregulation in the transcription of neuronal NOS and an increase in the levels of nitrites in the mitochondrial fractions of the kidneys. The upregulated transcription directly affects the cytoskeleton structure and the apoptosis. The inhibition of neuronal NOS reduces the levels of nitrites, cell death, and cytoskeleton derangement. Peroxynitrite is involved in the mechanism promoting the NOS transcription. In addition, in controls SIN-1 imitates the effects of cisplatin. In summary, we demonstrate that upregulation of mNOS in cisplatin treatment is a key component in both the initiation and the spread of cisplatin-associated damage in the kidney. Furthermore, peroxynitrite formation is directly involved in this process.

  14. Neuroprotective Properties of Panax notoginseng Saponins via Preventing Oxidative Stress Injury in SAMP8 Mice

    PubMed Central

    Jing, Xin; Tian, Xin; Qin, Mei-Chun; Xu, Zhe-Hao

    2017-01-01

    Inhibiting oxidative damage in early stage of Alzheimer's disease (AD) is considered as a strategy for AD treatment. Our previous study has shown that Panax notoginseng saponins (PNS) have an antiaging action by increasing the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) in the serum of aged rats. In this study, we aimed to investigate the effects of PNS on antioxidant enzymes and uncoupling proteins (UCPs) involved in oxidative stress in AD mice. The results showed that PNS prevented neuronal loss in hippocampal CA1 region and alleviated pathomorphological change of neurons in CA1 region. Moreover, PNS inhibited the production of 8-hydroxydeoxyguanosine (8-OHdG), enhanced the expressions and activities of SOD, CAT, and GSH-PX, and improved the mRNA and protein levels of UCP4 and UCP5 in the brains of SAMP8 mice. Together, our study shows that PNS has the ability to protect neurons in AD brain from oxidative stress damage through attenuating the production of 8-OHdG, enhancing the activities of antioxidant enzymes and the expressions levels of UCP4 and UCP5. Accordingly, PNS may be a promising agent for AD treatment. PMID:28250796

  15. Increased sensitivity of apolipoprotein E knockout mice to copper-induced oxidative injury to the liver.

    PubMed

    Chen, Yuan; Li, Bin; Zhao, Ran-ran; Zhang, Hui-feng; Zhen, Chao; Guo, Li

    2015-04-10

    Apolipoprotein E (ApoE) genotypes are related to clinical presentations in patients with Wilson's disease, indicating that ApoE may play an important role in the disease. However, our understanding of the role of ApoE in Wilson's disease is limited. High copper concentration in Wilson's disease induces excessive generation of free oxygen radicals. Meanwhile, ApoE proteins possess antioxidant effects. We therefore determined whether copper-induced oxidative damage differ in the liver of wild-type and ApoE knockout (ApoE(-/-)) mice. Both wild-type and ApoE(-/-) mice were intragastrically administered with 0.2 mL of copper sulfate pentahydrate (200 mg/kg; a total dose of 4 mg/d) or the same volume of saline daily for 12 weeks, respectively. Copper and oxidative stress markers in the liver tissue and in the serum were assessed. Our results showed that, compared with the wild-type mice administered with copper, TBARS as a marker of lipid peroxidation, the expression of oxygenase-1 (HO-1), NAD(P)H dehydrogenase, and quinone 1 (NQO1) significantly increased in the ApoE(-/-) mice administered with copper, meanwhile superoxide dismutase (SOD) activity significantly decreased. Thus, it is concluded that ApoE may protect the liver from copper-induced oxidative damage in Wilson's disease.

  16. CLIC1 Inhibition Attenuates Vascular Inflammation, Oxidative Stress, and Endothelial Injury

    PubMed Central

    Hu, Xiao; Wang, Cui; Lu, Dezhao; Gong, Chenxue; Yang, Jinhuan; Zong, Lei

    2016-01-01

    Endothelial dysfunction, which includes endothelial oxidative damage and vascular inflammation, is a key initiating step in the pathogenesis of atherosclerosis (AS) and an independent risk factor for this disorder. Intracellular chloride channel 1 (CLIC1), a novel metamorphic protein, acts as a sensor of cell oxidation and is involved in inflammation. In this study, we hypothesize that CLIC1 plays an important role in AS. Apolipoprotein E-deficient mice were supplied with a normal diet or a high-fat and high-cholesterol diet for 8 weeks. Overexpressed CLIC1 was associated with the accelerated atherosclerotic plaque development, amplified oxidative stress, and in vivo release of inflammatory cytokines. We subsequently examined the underlying molecular mechanisms through in vitro experiments. Treatment of cultured human umbilical vein endothelial cells (HUVECs) with H2O2 induced endothelial oxidative damage and enhanced CLIC1 expression. Suppressing CLIC1 expression through gene knocked-out (CLIC1−/−) or using the specific inhibitor indanyloxyacetic acid-94 (IAA94) reduced ROS production, increased SOD enzyme activity, and significantly decreased MDA level. CLIC1−/− HUVECs exhibited significantly reduced expression of TNF-α and IL-1β as well as ICAM-1 and VCAM-1 at the protein levels. In addition, H2O2 promoted CLIC1 translocation to the cell membrane and insertion into lipid membranes, whereas IAA94 inhibited CLIC1 membrane translocation induced by H2O2. By contrast, the majority of CLIC1 did not aggregate on the cell membrane in normal HUVECs, and this finding is consistent with the changes in cytoplasmic chloride ion concentration. This study demonstrates for the first time that CLIC1 is overexpressed during AS development both in vitro and in vivo and can regulate the accumulation of inflammatory cytokines and production of oxidative stress. Our results also highlight that deregulation of endothelial functions may be associated with the membrane

  17. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

    PubMed Central

    Azzam, Edouard I.; Jay-Gerin, Jean-Paul; Pain, Debkumar

    2013-01-01

    Cellular exposure to ionizing radiation leads to oxidizing events that alter atomic structure through direct interactions of radiation with target macromolecules or via products of water radiolysis. Further, the oxidative damage may spread from the targeted to neighboring, non-targeted bystander cells through redox-modulated intercellular communication mechanisms. To cope with the induced stress and the changes in the redox environment, organisms elicit transient responses at the molecular, cellular and tissue levels to counteract toxic effects of radiation. Metabolic pathways are induced during and shortly after the exposure. Depending on radiation dose, dose-rate and quality, these protective mechanisms may or may not be sufficient to cope with the stress. When the harmful effects exceed those of homeostatic biochemical processes, induced biological changes persist and may be propagated to progeny cells. Physiological levels of reactive oxygen and nitrogen species play critical roles in many cellular functions. In irradiated cells, levels of these reactive species may be increased due to perturbations in oxidative metabolism and chronic inflammatory responses, thereby contributing to the long-term effects of exposure to ionizing radiation on genomic stability. Here, in addition to immediate biological effects of water radiolysis on DNA damage, we also discuss the role of mitochondria in the delayed outcomes of ionization radiation. Defects in mitochondrial functions lead to accelerated aging and numerous pathological conditions. Different types of radiation vary in their linear energy transfer (LET) properties, and we discuss their effects on various aspects of mitochondrial physiology. These include short and long-term in vitro and in vivo effects on mitochondrial DNA, mitochondrial protein import and metabolic and antioxidant enzymes. PMID:22182453

  18. The Effect of Inhaled Nitric Oxide on Smoke Inhalation Injury in an Ovine Model.

    DTIC Science & Technology

    1994-08-01

    maceuticals, West Orange, NJ), and bronchoalveolar lavage (1.5 mL/kg/ h ). (BAL) was performed under mechanical ventilation. Twenty milliliters of 0.9...carboxyhemoglobin levels, and platelet counts. Methe- moglobin in group 2 was significantly higher than in 10 group 1 at 3 hours and for the duration of the study...decreases free cytosolic calcium lev- moglobin with production of nitrite and nitrate, which es.4 - 6’ 27 Nitric oxide also appears to inhibit the are then

  19. Quercitrin offers protection against brain injury in mice by inhibiting oxidative stress and inflammation.

    PubMed

    Ma, Jie-Qiong; Luo, Rong-Zhen; Jiang, Hai-Xia; Liu, Chan-Min

    2016-01-01

    Quercitrin is one of the primary flavonoid compounds present in vegetables and fruits. The aim of the present study was to evaluate the effects of quercitrin against carbon tetrachloride (CCl4) induced brain injury and further to elucidate its probable mechanisms. ICR mice received CCl4 intraperitoneally with or without quercitrin co-administration for 4 weeks. Our data showed that quercitrin significantly suppressed the elevation of reactive oxygen species (ROS) production and malondialdehyde (MDA) content, reduced tissue plasminogen activator (t-PA) activity, enhanced the antioxidant enzyme activities and abrogated cytochrome P450 2E1 (CYP2E1) induction in mouse brains. Quercitrin also prevented CCl4 induced cerebral function disorders associated with its ability to inhibit the activities of monoamine oxidase (MAO), acetylcholine esterase (AChE) and the N-methyl-d-aspartate receptor 2B subunit (NR2B). In addition, western blot analysis showed that quercitrin suppressed the release of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Taken together, our findings suggested that quercitrin may be a potential candidate to be developed as a neuroprotective agent.

  20. N-Palmitoylethanolamide protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress.

    PubMed

    Mattace Raso, Giuseppina; Simeoli, Raffaele; Russo, Roberto; Santoro, Anna; Pirozzi, Claudio; d'Emmanuele di Villa Bianca, Roberta; Mitidieri, Emma; Paciello, Orlando; Pagano, Teresa Bruna; Orefice, Nicola Salvatore; Meli, Rosaria; Calignano, Antonio

    2013-10-01

    Hypertension is an important risk factor for kidney failure and renal events in the general population. Palmitoylethanolamide (PEA) is a member of the fatty acid ethanolamine family with profound analgesic and anti-inflammatory effects, resulting from its ability to activate peroxisome proliferator activated receptor (PPAR)α. A role for this nuclear receptor has been addressed in cardiovascular system and PPARα ligands have been shown to protect against inflammatory damage especially resulting from angiotensin II hypertension. In this study, we demonstrated that PEA significantly reduced blood pressure in spontaneously hypertensive rats (SHR) and limited kidney damage secondary to high perfusion pressure. To investigate the mechanisms involved in PEA effect, we found that PEA reduced cytochrome P450 (CYP) hydroxylase CYP4A, epoxygenase CYP2C23 and soluble epoxide hydrolase enzyme expression in the kidney, accompanied by a reduction of 20-hydroxyeicosatetraenoic acid excretion in the urine. Moreover, it markedly reduced kidney oxidative and nitrosative stress accompanied by decreased expression of renal NAD(P)H oxidase and inducible nitric oxide synthase and increased expression of Cu/Zn superoxide dismutase, in the kidney of SHR. Moreover, angiotensin II receptor (AT) evaluation revealed a decrease in AT1 receptor expression and a restoration of AT2 receptor level in the kidney from PEA-treated SHR. Consistently, angiotensin converting enzyme expression was reduced, implying a decrease in angiotensin II synthesis. These results indicate that PEA treatment lowers blood pressure and can protect against hypertensive renal injury by increasing the antioxidant defense and anti-inflammatory response and modulating renin-angiotensin system.

  1. Subthreshold nitric oxide synthase inhibition improves synergistic effects of subthreshold MMP-2/MLCK-mediated cardiomyocyte protection from hypoxic injury.

    PubMed

    Bil-Lula, Iwona; Lin, Han-Bin; Biały, Dariusz; Wawrzyńska, Magdalena; Diebel, Lucas; Sawicka, Jolanta; Woźniak, Mieczyslaw; Sawicki, Grzegorz

    2016-06-01

    Injury of myocardium during ischaemia/reperfusion (I/R) is a complex and multifactorial process involving uncontrolled protein phosphorylation, nitration/nitrosylation by increased production of nitric oxide and accelerated contractile protein degradation by matrix metalloproteinase-2 (MMP-2). It has been shown that simultaneous inhibition of MMP-2 with doxycycline (Doxy) and myosin light chain kinase (MLCK) with ML-7 at subthreshold concentrations protects the heart from contractile dysfunction triggered by I/R in a synergistic manner. In this study, we showed that additional co-administration of nitric oxide synthase (NOS) inhibitor (1400W or L-NAME) in subthreshold concentrations improves this synergistic protection in the model of hypoxia-reoxygenation (H-R)-induced contractile dysfunction of cardiomyocytes. Isolated cardiomyocytes were subjected to 3 min. of hypoxia and 20 min. of reoxygenation in the presence or absence of the inhibitor cocktails. Contractility of cardiomyocytes was expressed as myocyte peak shortening. Inhibition of MMP-2 by Doxy (25-100 μM), MLCK by ML-7 (0.5-5 μM) and NOS by L-NAME (25-100 μM) or 1400W (25-100 μM) protected myocyte contractility after H-R in a concentration-dependent manner. Inhibition of these activities resulted in full recovery of cardiomyocyte contractility after H-R at the level of highest single-drug concentration. The combination of subthreshold concentrations of NOS, MMP-2 and MLCK inhibitors fully protected cardiomyocyte contractility and MLC1 from degradation by MMP-2. The observed protection with addition of L-NAME or 1400W was better than previously reported combination of ML-7 and Doxy. The results of this study suggest that addition of NOS inhibitor to the mixture of inhibitors is better strategy for protecting cardiomyocyte contractility.

  2. Tongxinluo Protects against Hypertensive Kidney Injury in Spontaneously-Hypertensive Rats by Inhibiting Oxidative Stress and Activating Forkhead Box O1 Signaling

    PubMed Central

    Luo, Wei-min; Kong, Jing; Gong, Yan; Liu, Xiao-qiong; Yang, Rui-xue; Zhao, Yu-xia

    2015-01-01

    Hypertension is an independent risk factor for the progression of chronic renal failure, and oxidative stress plays a critical role in hypertensive renal damage. Forkbox O1(FoxO1) signaling protects cells against oxidative stress and may be a useful target for treating oxidative stress-induced hypertension. Tongxinluo is a traditional Chinese medicine with cardioprotective and renoprotective functions. Therefore, this study aimed to determine the effects of Tongxinluo in hypertensive renal damage in spontaneously hypertensive rats(SHRs)and elucidate the possible involvement of oxidative stress and FoxO1 signaling in its molecular mechanisms. SHRs treated with Tongxinluo for 12 weeks showed a reduction in systolic blood pressure. In addition to increasing creatinine clearance, Tongxinluo decreased urinary albumin excretion, oxidative stress injury markers including malondialdehyde and protein carbonyls, and expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and its activity in SHR kidneys. While decreasing phosphorylation of FoxO1, Tongxinluo also inhibited the phosphorylation of extracellular signal-regulated kinase1/2 and p38 and enhanced manganese superoxide dismutase and catalase activities in SHR kidneys. Furthermore, histology revealed attenuation of glomerulosclerosis and renal podocyte injury, while Tongxinluo decreased the expression of α-smooth muscle actin, extracellular matrixprotein, transforming growth factor β1 and small mothers against decapentaplegic homolog 3,and improved tubulointerstitial fibrosis in SHR kidneys. Finally, Tongxinluo inhibited inflammatory cell infiltration as well as expression of tumor necrosis factor-α and interleukin-6. In conclusion, Tongxinluo protected SHRs against hypertension-induced renal injury by exerting antioxidant, antifibrotic, and anti-inflammatory activities. Moreover, the underlying mechanisms of these effects may involve inhibition of oxidative stress and functional activation of Fox

  3. Exogenous Nitric Oxide Protects Human Embryonic Stem Cell-Derived Cardiomyocytes against Ischemia/Reperfusion Injury

    PubMed Central

    Pálóczi, János; Varga, Zoltán V.; Szebényi, Kornélia; Sarkadi, Balázs; Madonna, Rosalinda; De Caterina, Raffaele; Csont, Tamás; Eschenhagen, Thomas; Ferdinandy, Péter; Görbe, Anikó

    2016-01-01

    Background and Aims. Human embryonic stem cell- (hESC-) derived cardiomyocytes are one of the useful screening platforms of potential cardiocytoprotective molecules. However, little is known about the behavior of these cardiomyocytes in simulated ischemia/reperfusion conditions. In this study, we have tested the cytoprotective effect of an NO donor and the brain type natriuretic peptide (BNP) in a screening platform based first on differentiated embryonic bodies (EBs, 6 + 4 days) and then on more differentiated cardiomyocytes (6 + 24 days), both derived from hESCs. Methods. Both types of hESC-derived cells were exposed to 150 min simulated ischemia, followed by 120 min reperfusion. Cell viability was assessed by propidium iodide staining. The following treatments were applied during simulated ischemia in differentiated EBs: the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) (10−7, 10−6, and 10−5 M), BNP (10−9, 10−8, and 10−7 M), and the nonspecific NO synthase inhibitor Nω-nitro-L-arginine (L-NNA, 10−5 M). Results. SNAP (10−6, 10−5 M) significantly attenuated cell death in differentiated EBs. However, simulated ischemia/reperfusion-induced cell death was not affected by BNP or by L-NNA. In separate experiments, SNAP (10−6 M) also protected hESC-derived cardiomyocytes. Conclusions. We conclude that SNAP, but not BNP, protects differentiated EBs or cardiomyocytes derived from hESCs against simulated ischemia/reperfusion injury. The present screening platform is a useful tool for discovery of cardiocytoprotective molecules and their cellular mechanisms. PMID:27403231

  4. Saikokeishito Extract Exerts a Therapeutic Effect on alpha-Naphthylisothiocyanate-Induced Liver Injury in Rats through Attenuation of Enhanced Neutrophil Infiltration and Oxidative Stress in the Liver Tissue.

    PubMed

    Ohta, Yoshiji; Kongo-Nishimura, Mutsumi; Hayashi, Takahiro; Kitagawa, Akira; Matsura, Tatsuya; Yamada, Kazuo

    2007-01-01

    We examined whether Saikokeishito extract (TJ-10), a traditional Japanese herbal medicine, exerts a therapeutic effect on alpha-naphthylisothiocyanate (ANIT)-induced liver injury in rats through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue. In rats treated once with ANIT (75 mg/kg, i.p.), liver injury with cholestasis occurred 24 h after treatment and progressed at 48 h. When ANIT-treated rats orally received TJ-10 (0.26, 1.3 or 2.6 g/kg) at 24 h after the treatment, progressive liver injury with cholestasis was significantly attenuated at 48 h after the treatment at the dose of 1.3 or 2.6 g/kg. At 24 h after ANIT treatment, increases in hepatic lipid peroxide and reduced glutathione contents and myeloperoxidase activity occurred with decreases in hepatic superoxide dismutase and glutathione reductase activities. At 48 h after ANIT treatment, these changes except for reduced glutathione were enhanced with decreases in catalase, Se-glutathione peroxidase, and glucose-6-phosphate dehydrogenase activities. TJ-10 (1.3 or 2.6 g/kg) post-administered to ANIT-treated rats attenuated these changes found at 48 h after the treatment significantly. These results indicate that TJ-10 exerts a therapeutic effect on ANIT-induced liver injury in rats possibly through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue.

  5. Hydrogen-Rich Saline Protects against Ischemia/Reperfusion Injury in Grafts after Pancreas Transplantations by Reducing Oxidative Stress in Rats

    PubMed Central

    Luo, Zhu-Lin; Cheng, Long; Fang, Chen; Xiang, Ke; Xu, Hao-Tong; Tang, Li-Jun; Wang, Tao; Tian, Fu-Zhou

    2015-01-01

    Purpose. This study aimed to investigate the therapeutic potential of hydrogen-rich saline on pancreatic ischemia/reperfusion (I/R) injury in rats. Methods. Eighty heterotopic pancreas transplantations (HPT) were performed in syngenic rats. The receptors were randomized blindly into the following three groups: the HPT group and two groups that underwent transplantation and administration of hydrogen-rich saline (HS, >0.6 mM, 6 mL/kg) or normal saline (NS, 6 mL/kg) via the tail vein at the beginning of reperfusion (HPT + HS group, HPT + NS group). Samples from the pancreas and blood were taken at 12 hours after reperfusion. The protective effects of hydrogen-rich saline against I/R injury were evaluated by determining the changes in histopathology and measuring serological parameters, oxidative stress-associated molecules, and proinflammatory cytokines. Results. Administration of hydrogen-rich saline produced notable protection against pancreatic I/R injury in rats. Histopathological improvements and recovery of impaired pancreatic function were observed. In addition, TNF-α, IL-1β, and IL-6 were reduced markedly in the HPT + HS group. Additionally, there were noticeable inhibitory effects on the pancreatic malondialdehyde level and considerable recruitment of SOD and GPx, which are antioxidants. Conclusion. Hydrogen-rich saline treatment significantly attenuated the severity of pancreatic I/R injury in rats, possibly by reducing oxidative stress and inflammation. PMID:25873757

  6. Role of nitric oxide in inflammation and tissue injury during endotoxemia and hemorrhagic shock.

    PubMed Central

    Shah, N S; Billiar, T R

    1998-01-01

    Since the discovery that nitric oxide (.NO) accounts for the biologic activity of endothelial-derived relaxing factor, a torrent of research over the last decade has focused on its role, protective or detrimental, in myriad pathophysiologic conditions. Recently, increasing attention has focused on .NO as a possible mediator of the severe hypotension and impaired vasoreactivity characteristic of circulatory failure. Given the ubiquitous and complex role of .NO in biologic systems, inhibition of .NO synthesis in experimental and clinical studies of shock has yielded mixed, sometimes contradictory, results. Although overproduction of .NO in the vasculature may result in systemic vasodilation, .NO synthesis has also clearly been shown to have a beneficial role in regulating organ perfusion and mediating cytotoxicity. In this review, the pathophysiologic importance of .NO in septic shock and hemorrhagic shock is discussed, and novel therapeutic strategies for manipulation of .NO formation are examined. PMID:9788888

  7. Thymoquinone and curcumin prevent gentamicin-induced liver injury by attenuating oxidative stress, inflammation and apoptosis.

    PubMed

    Galaly, S R; Ahmed, O M; Mahmoud, A M

    2014-12-01

    This study was conducted to assess the preventive effect of two plant constituents, thymoquinone and curcumin, on gentamicin-induced deleterious effect on liver function, integrity and histological architecture. The gentamicin was intraperitoneally injected to rats at dose level of 100 mg/kg b.w. (every other day) for 21 days. The thymoquinone and curcumin were concurrently and orally administered at dose level of 20 mg/kg b.w. (every other day) to gentamicin-injected rats. The present data indicated that thymoquinone and curcumin significantly prevented the gentamicin-induced elevations of serum AST, ALT and LDH activities as well as tumor necrosis factor alpha (TNF-α) and total bilirubin levels. On the other hand, both agents markedly ameliorated the gentamicin-induced decrease in serum total protein, albumin and albumin/globulin ratio. In addition, the gentamicin-induced liver histological alterations including hydropic degeneration of hepatocytes, fatty changes, inflammatory cell infiltration and congestion of portal vein were successfully amended by thymoquinone and curcumin. The elevated proapoptotic proteins caspase 3 and Bax expression in cytoplasm and nucleus of hepatocytes of gentamicin-injected rats were reduced to normal value as a result of thymoquinone and curcumin administration while the lowered expression of antiapoptotic protein Bcl-2 was increased. Based on the previous findings, it can be concluded that thymoquinone and curcumin successfully prevents the deleterious effects on liver function and histological integrity to more or less the same degree by enhancing anti-oxidant defense system, suppression of oxidative stress and attenuation of inflammation and apoptosis.

  8. Royal jelly modulates oxidative stress and tissue injury in gamma irradiated male Wister Albino rats

    PubMed Central

    Azab, Khaled Shaaban; Bashandy, Mohamed; Salem, Mahmoud; Ahmed, Osama; Tawfik, Zaki; Helal, Hamed

    2011-01-01

    Background: Royal jelly is a nutritive secretion produced by the worker bees, rich in proteins, carbohydrates, vitamins and minerals. Aim: The present study was designed to determine the possible protective effects of royal jelly against radiation induced oxidative stress, hematological, biochemical and histological alterations in male Wister albino rats. Materials and Methods: Male Wister albino rats were exposed to a fractionated dose of gamma radiation (2 Gy every 3 days up to 8 Gy total doses). Royal jelly was administrated (g/Kg/day) by gavages 14 days before exposure to the 1st radiation fraction and the treatment was continued for 15 days after the 1st irradiation fraction till the end of the experiment. The rats were sacrificed 3rd, equivalent to 3rd post 2nd irradiation fraction, and equivalent to 3rd day post last irradiation fraction. Results: In the present study, gamma- irradiation induced hematological, biochemical and histological effects in male Wister albino rats. In royal jelly treated irradiated group, there was a noticeable decrease recorded in thiobarbituric reactive substances concentration when compared to γ-irradiated group. Also, the serum nitric oxide concentration was significantly improved. The administration of royal jelly to irradiated rats according to the current experimental design significantly ameliorates the changes induced in serum lipid profile. Moreover, in royal jelly treated irradiated group, there was a noticeable amelioration recorded in all hematological parameters along the three experimental intervals. The microscopic examination of cardiac muscle of royal jelly treated irradiated rats demonstrated structural amelioration, improved nuclei and normal features of capillaries and veins in endomysium when compared to gamma-irradiated rats. Conclusion: It was suggested that the biochemical, hematological and histological amelioration observed in royal jelly (g/Kg/day) treated irradiated rats might be due to the antioxidant

  9. Exercise Intensity and Recovery: Biomarkers of Injury, Inflammation, and Oxidative Stress.

    PubMed

    Bessa, Artur L; Oliveira, Vanessa N; Agostini, Guilherme G; Oliveira, Renato J S; Oliveira, Ana C S; White, Gillian E; Wells, Greg D; Teixeira, David N S; Espindola, Foued S

    2016-02-01

    Biomarkers of inflammation, muscle damage, and oxidative stress after high-intensity exercise have been described previously; however, further understanding of their role in the postexercise recovery period is necessary. Because these markers have been implicated in cell signaling, they may be specifically related to the training adaptations induced by high-intensity exercise. Thus, a clear model showing their responses to exercise may be useful in characterizing the relative recovery status of an athlete. The purpose of this study was twofold: (a) to investigate the time course of markers of muscle damage and inflammation in the blood from 3 to 72 hours after combined training exercises and (b) to investigate indicators of oxidative stress and damage associated with increased reactive oxygen species production during high-intensity exercise in elite athletes. Nineteen male athletes performed a combination of high-intensity aerobic and anaerobic training exercises. Samples were acquired immediately before and at 3, 6, 12, 24, 48, and 72 hours after exercise. The appearance and clearance of creatine kinase and lactate dehydrogenase in the blood occurred faster than previous studies have reported. The neutrophil/lymphocyte ratio summarizes the mobilization of 2 leukocyte subpopulations in a single marker and may be used to predict the end of the postexercise recovery period. Further analysis of the immune response using serum cytokines indicated that high-intensity exercise performed by highly trained athletes only generated inflammation that was localized to the skeletal muscle. Biomarkers are not a replacement for performance tests, but when used in conjunction, they may offer a better indication of metabolic recovery status. Therefore, the use of biomarkers can improve a coach's ability to assess the recovery period after an exercise session and to establish the intensity of subsequent training sessions.

  10. Oxidative damage: the biochemical mechanism of cellular injury and necrosis in choline deficiency.

    PubMed

    Repetto, Marisa G; Ossani, Georgina; Monserrat, Alberto J; Boveris, Alberto

    2010-02-01

    Oxidative stress and damage are characterized by decreased tissue antioxidant levels, consumption of tissue alpha-tocopherol, and increased lipid peroxidation. These processes occur earlier than necrosis in the liver, heart, kidney, and brain of weanling rats fed a choline deficient (CD) diet. In tissues, water-soluble antioxidants were analyzed as total reactive antioxidant potential (TRAP), alpha-tocopherol content was estimated from homogenate chemiluminescence (homogenate-CL), and lipid peroxidation was evaluated by thiobarbituric acid reactive substances (TBARS). Histopathology showed hepatic steatosis at days 1-7, tubular and glomerular necrosis in kidney at days 6 and 7, and inflammation and necrosis in heart at days 6 and 7. TRAP levels decreased by 18%, 48%, 56%, and 66% at day 7, with t(1/2) (times for half maximal change) of 2.0, 1.8, 2.5, and 3.0 days in liver, kidney, heart, and brain, respectively. Homogenate-CL increased by 97%, 113%, 18%, and 297% at day 7, with t(1/2) of 2.5, 2.6, 2.8, and 3.2 days in the four organs, respectively. TBARS contents increased by 98%, 157%, 104%, and 347% at day 7, with t(1/2) of 2.6, 2.8, 3.0, and 5.0 days in the four organs, respectively. Plasma showed a 33% decrease in TRAP and a 5-fold increase in TBARS at day 5. Oxidative stress and damage are processes occurring earlier than necrosis in the kidney and heart. In case of steatosis prior to antioxidant consumption and increased lipid peroxidation, no necrosis is observed in the liver.

  11. Stress preconditioning attenuates oxidative injury to the alveolar epithelium of the lung following haemorrhage in rats

    PubMed Central

    Pittet, J F; Lu, L N; Geiser, T; Lee, H; Matthay, M A; Welch, W J

    2002-01-01

    Inhibition of cAMP-dependent stimulation of vectorial fluid transport across the alveolar epithelium following haemorrhagic shock is mediated by reactive nitrogen species released within the airspaces of the lung. We tested here the hypothesis that the prior activation of the cellular heat shock or stress response, via exposure to either heat or geldanamycin, would attenuate the release of airspace nitric oxide (NO) responsible for the shock-mediated failure of the alveolar epithelium to respond to catecholamines in rats. Rats were haemorrhaged to a mean arterial pressure of 30–35 mmHg for 60 min, and then resuscitated with a 4 % albumin solution. Alveolar fluid clearance was measured by change in concentration of a protein solution instilled into the airspaces 5 h after the onset of haemorrhage. Stress preconditioning restored the cAMP-mediated upregulation of alveolar liquid clearance after haemorrhage. The protective effect of stress preconditioning was mediated in part by a decrease in the expression of iNOS in the lung. Specifically, stress preconditioning decreased the production of nitrite by endotoxin-stimulated alveolar macrophages removed from haemorrhaged rats or by A549 and rat alveolar epithelial type II cell monolayers stimulated with cytomix (a mixture of TNF-α, IL-1β and IFN-γ) for 24 h. In summary, these results provide the first in vivo evidence that stress preconditioning restores a normal fluid transport capacity of the alveolar epithelium in the early phase following haemorrhagic shock by attenuating NO-mediated oxidative stress to the lung epithelium. PMID:11790821

  12. Epigallocatechin 3-Gallate Ameliorates Bile Duct Ligation Induced Liver Injury in Mice by Modulation of Mitochondrial Oxidative Stress and Inflammation

    PubMed Central

    Su, Rong; Xie, Haiyang; Zhou, Lin; Zheng, Shusen

    2015-01-01

    Cholestatic liver fibrosis was achieved by bile duct ligation (BDL) in mice. Liver injury associated with BDL for 15 days included significant reactive oxygen/nitrogen species generation, liver inflammation, cell death and fibrosis. Administration of Epigallocatechin 3-Gallate (EGCG) in animals reduced liver fibrosis involving parenchymal cells in BDL model. EGCG attenuated BDL-induced gene expression of pro-fibrotic markers (Collagen, Fibronectin, alpha 2 smooth muscle actin or SMA and connective tissue growth factor or CTGF), mitochondrial oxidative stress, cell death marker (DNA fragmentation and PARP activity), NFκB activity and pro-inflammatory cytokines (TNFα, MIP1α, IL1β, and MIP2). EGCG also improved BDL induced damages of mitochondrial electron transport chain complexes and antioxidant defense enzymes such as glutathione peroxidase and manganese superoxide dismutase. EGCG also attenuated hydrogen peroxide induced cell death in hepatocytes in vitro and alleviate stellate cells mediated fibrosis through TIMP1, SMA, Collagen 1 and Fibronectin in vitro. In conclusion, the reactive oxygen/nitrogen species generated from mitochondria plays critical pathogenetic role in the progression of liver inflammation and fibrosis and this study indicate that EGCG might be beneficial for reducing liver inflammation and fibrosis. PMID:25955525

  13. Inhibition of inducible nitric oxide synthase prevents graft injury after transplantation of livers from rats after cardiac death.

    PubMed

    Shi, Yanjun; Rehman, Hasibur; Wright, Gary L; Zhong, Zhi

    2010-11-01

    This study investigated the roles of inducible nitric oxide synthase (iNOS) in the failure of rat liver grafts from cardiac death donors (GCDD). Livers were explanted after 30-minute aorta clamping and implanted after 4-hour storage in University of Wisconsin solution. The iNOS expression increased slightly in grafts from non-cardiac death donors (GNCDD) but markedly in GCDD. Serum nitrite and nitrate and hepatic 3-nitrotyrosine adducts, indicators of NO and peroxynitrite production, respectively, were substantially higher after transplantation of GCDD than GNCDD. Production of reactive nitrogen species (RNS) was largely blocked by 1400W (N-[1-naphthyl]ethylenediamine dihydrochloride; 5 μM), a specific iNOS inhibitor. Alanine aminotransferase release, bilirubin, necrosis, and apoptosis were 6.4-fold, 6.5-fold, 2.3-fold, and 2.7-fold higher, respectively, after transplantation of GCDD than GNCDD. The inhibitor 1400W effectively blocked these alterations and also increased survival of GCDD to 80% from 33%. Increased RNS production and failure of GCDD were associated with activation of c-Jun-N-terminal kinase (JNK), an effect that was blocked by inhibition of iNOS. Inhibition of JNK also improved the outcome after transplantation of GCDD. Together, the data indicate that iNOS increases substantially in GCDD, leading to RNS overproduction, JNK activation, and more severe graft injury. Inhibitors of iNOS are suggested as effective therapies to improve the outcome after transplantation of GCDD.

  14. Hyperglycemia enhances excessive superoxide anion radical generation, oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion rats.

    PubMed

    Tsuruta, Ryosuke; Fujita, Motoki; Ono, Takeru; Koda, Yoichi; Koga, Yasutaka; Yamamoto, Takahiro; Nanba, Masahiro; Shitara, Masaki; Kasaoka, Shunji; Maruyama, Ikuro; Yuasa, Makoto; Maekawa, Tsuyoshi

    2010-01-14

    The aim of this study was to confirm the effect of acute hyperglycemia on the superoxide anion radical (O(2)(-)) generation, using a novel electrochemical O(2)(-) sensor in forebrain ischemia/reperfusion rats. Fourteen male Wistar rats were allocated to a normoglycemia group (n= 7) and a hyperglycemia group (n=7). Hyperglycemia was induced by intravenous infusion of glucose solution. Forebrain ischemia was induced by bilateral common carotid arteries occlusion with hemorrhagic hypotension for 10 min and then was reperfused. The generated O(2)(-) was measured as the current produced, which was integrated as a quantified partial value of electricity (Q), in the jugular vein using the O(2)(-) sensor. The reacted O(2)(-) current and the Q began to increase gradually during the forebrain ischemia in both groups. These values increased remarkably just after reperfusion in the normoglycemia group and were further increased significantly in the hyperglycemia group after the reperfusion. Concentrations of malondialdehyde (MDA) and high-mobility group box 1 (HMGB1) in the brain and plasma, and soluble intercellular adhesion molecule-1 (ICAM-1) in the plasma in the hyperglycemia group were significantly higher than those in the normoglycemia group. Brain and plasma MDA, HMGB1, and ICAM-1 were correlated with a sum of Q during ischemia and after reperfusion. In conclusion, acute transient hyperglycemia enhanced the O(2)(-) generation in blood and exacerbated oxidative stress, early inflammation, and endothelial injury after the forebrain ischemia/reperfusion in the rats.

  15. Protective Effects of Panax notoginseng Saponins against High Glucose-Induced Oxidative Injury in Rat Retinal Capillary Endothelial Cells

    PubMed Central

    Fan, Yue; Qiao, Yuan; Huang, Jianmei

    2016-01-01

    Diabetic retinopathy, a leading cause of visual loss and blindness, is characterized by microvascular dysfunction. Hyperglycemia is considered the major pathogenic factor for diabetic retinopathy and is associated with increased oxidative stress in the retina. In this study, we investigated the potential protective effects of Panax notoginseng Saponins (PNS) in retinal capillary endothelial cells (RCECs) exposed to high glucose conditions. We found a pronounced increase in cell viability in rat RCECs incubated with both PNS and high glucose (30 mM) for 48 h or 72 h. The increased viability was accompanied by reduced intracellular hydrogen peroxide (H2O2) and superoxide (O2−), decreased mitochondrial reactive oxygen species (ROS), and lowered malondialdehyde (MDA) levels. PNS also increased the activities of total superoxide dismutase (SOD), MnSOD, catalase (CAT), and glutathione peroxidase (GSH-PX). The glutathione (GSH) content also increased after PNS treatment. Furthermore, PNS reduced NADPH oxidase 4 (Nox4) expression. These results indicate that PNS exerts a protective effect against high glucose-induced injury in RCECs, which may be partially attributed to its antioxidative function. PMID:27019662

  16. Apocynin protects against global cerebral ischemia-reperfusion-induced oxidative stress and injury in the gerbil hippocampus.

    PubMed

    Wang, Qun; Tompkins, Kenneth D; Simonyi, Agnes; Korthuis, Ronald J; Sun, Albert Y; Sun, Grace Y

    2006-05-23

    Increased production of reactive oxygen species (ROS) following cerebral ischemia-reperfusion (I/R) is an important underlying cause for neuronal injury leading to delayed neuronal death (DND). In this study, apocynin, a specific inhibitor for NADPH oxidase, was used to test whether suppression of ROS by the NADPH oxidase inhibitor can protect against ischemia-induced ROS generation and decrease DND. Global cerebral ischemia was induced in gerbils by a 5-min occlusion of bilateral common carotid arteries (CCA). Using measurement of 4-hydroxy-2-nonenal (HNE) as a marker for lipid peroxidation, apocynin (5 mg/kg body weight) injected i.p. 30 min prior to ischemia significantly attenuated the early increase in HNE in hippocampus measured at 3 h after I/R. Apocynin also protected against I/R-induced neuronal degeneration and DND, oxidative DNA damage, and glial cell activation. Taken together, the neuroprotective effects of apocynin against ROS production during early phase of I/R and subsequent I/R-induced neuronal damage provide strong evidence that inhibition of NADPH oxidase could be a promising therapeutic mechanism to protect against stroke damage in the brain.

  17. Flavonoids from the heartwood of Dalbergia odorifera and their protective effect on glutamate-induced oxidative injury in HT22 cells.

    PubMed

    An, Ren-Bo; Jeong, Gil-Saeng; Kim, Youn-Chul

    2008-12-01

    Two flavonoids, 4,2',5'-trihydroxy-4'-methoxychalcone (1) and (2S)-6,7,4'-trihydroxyflavan (2), along with fourteen known flavonoids and two other known arylbenzofurans were isolated from the heartwood of Dalbergia odorifera. The structure of compounds 1 and 2 were established by spectroscopic (NMR and MS) analyses. Of the isolates, eight compounds (1, 4, 7, 10, 12, 14, 15, 17) were found to have potent protective effect on glutamate-induced oxidative injury in HT22 cells.

  18. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death

    PubMed Central

    Mukhopadhyay, Partha; Rajesh, Mohanraj; Horváth, Béla; Bátkai, Sándor; Park, Ogyi; Tanashian, Galin; Gao, Rachel Y; Patel, Vivek; Wink, David A.; Liaudet, Lucas; Haskó, György; Mechoulam, Raphael; Pacher, Pál

    2011-01-01

    Ischemia-reperfusion (I/R) is a pivotal mechanism of liver damage following liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol(CBD), the non-psychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor alpha (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, inter-cellular adhesion molecule 1 mRNA levels, tissue neutrophil infiltration, nuclear factor kappa B (NF-KB) activation), stress signaling (p38MAPK and JNK) and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress and cell death, and also attenuated the bacterial endotoxin-triggered NF-KB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecules expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α, and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent from classical CB1/2 receptors. PMID:21362471

  19. Nobiletin ameliorates cisplatin-induced acute kidney injury due to its anti-oxidant, anti-inflammatory and anti-apoptotic effects.

    PubMed

    Malik, Salma; Bhatia, Jagriti; Suchal, Kapil; Gamad, Nanda; Dinda, Amit Kumar; Gupta, Yogender Kumar; Arya, Dharamvir Singh

    2015-01-01

    Cisplatin is an effective anti-cancer drug which causes remarkable toxicity to kidney by generating reactive oxygen species and by stimulating inflammatory and apoptotic pathway. Citrus flavonoid, like nobiletin has been reported to possess anti-oxidant, anti-inflammatory and anti-apoptotic properties. Hence, the present study was aimed to evaluate these properties of nobiletin, a polymethoxy flavone in cisplatin-induced acute renal injury. Adult male albino Wistar rats were divided into 6 groups. Nobiletin was administered at the dose of 1.25, 2.5 and 5mg/kg for a period of 10 days. On 7th day, a single injection of cisplatin (8 mg/kg) was injected to rats. Cisplatin administration resulted in renal dysfunction as evident by increase in serum creatinine and BUN levels. Oxidative stress in cisplatin group was reflected by increase in MDA level, and depletion of anti-oxidants such as glutathione, superoxide dismutase and catalase in renal tissue. Furthermore, cisplatin increased the expressions of Bax, caspase-3 and DNA damage along with decreased expression of Bcl-2 in the renal tissue. Histological analysis also revealed acute tubular necrosis. However, pretreatment with nobiletin preserved renal function and restored anti-oxidant status. Nobiletin supplementation inhibited activation of apoptotic pathways and DNA damage. It also attenuated tubular injury histologically. Collectively, the result of this study suggests the nephroprotective potential of nobiletin which may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

  20. Protection against age-dependent renal injury in the F344xBrown Norway male rat is associated with maintained nitric oxide synthase.

    PubMed

    Moningka, Natasha C; Sasser, Jennifer M; Croker, Byron; Carter, Christy; Baylis, Chris

    2011-01-01

    Age-dependent renal damage is influenced by genetic background and the Fisher344xBrown Norway (F344xBN) rat is resistant to glomerular injury. In vulnerable strains, a fall in renal nitric oxide synthase (NOS) contributes to age-dependent renal damage. Here, we investigated renal NOS in young (3 months) and old (30 months) male F344xBN to test the hypothesis that renal NOS is maintained in "protected" strains. We also examined if 6 months of renin-angiotensin system (RAS) blockade using angiotensin converting enzyme inhibition (ACEI) and angiotensin receptor blockade (ARB) provides further benefit in these "protected" old rats. Aging increased tubulointerstitial injury but glomerular sclerosis was minimal and NOS and superoxide dismutase abundance increased. There was no change in the NOS inhibitor, ADMA (asymmetric dimethylarginine) or its regulatory enzymes. RAS blockade with ARB protected against tubulointerstitial injury and increased nNOSα, but ACEI, which also increased nNOSα, had no protective effect on the tubulointerstitium. We conclude that the glomerular sclerosis-resistant aged male F344xBN rat maintains renal NOS, thus reinforcing our hypothesis that progressive glomerular injury is related to renal NOS deficiency. The tubulointerstitial injury seen with aging is reversed with 6 months of ARB but not ACEI and is not associated with renal NOS.

  1. Nrf2 protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative injury and steatohepatitis

    SciTech Connect

    Lu Hong; Cui Wei; Klaassen, Curtis D.

    2011-10-15

    Previous studies demonstrate that Nrf2, a master regulator of antioxidative responses, is essential in mediating induction of many antioxidative enzymes by acute activation of the AhR. However, the role of Nrf2 in protecting against oxidative stress and DNA damage induced by sustained activation of the AhR remains unknown and was investigated herein. Tissue and blood samples were collected from wild-type (WT) and Nrf2-null mice 21 days after administration of a low-toxic dose (10 {mu}g/kg ip) of TCDD. Only Nrf2-null mice lost body weight after TCDD treatment; however, blood levels of ALT were not markedly changed in either genotype, indicating a lack of extensive necrosis. Compared to livers of TCDD-treated WT mice, livers of TCDD-treated Nrf2-null mice had: 1) degenerated hepatocytes, lobular inflammation, marked fat accumulation, and higher mRNA expression of inflammatory and fibrotic genes; 2) depletion of glutathione, elevation in lipid peroxidation and marker of DNA damage; 3) attenuated induction of phase-II enzymes Nqo1, Gsta1/2, and Ugt2b35 mRNAs, but higher induction of cytoprotective Ho-1, Prdx1, Trxr1, Gclc, and Epxh1 mRNAs; 4) higher mRNA expression of Fgf21 and triglyceride-synthesis genes, but down-regulation of bile-acid-synthesis genes and cholesterol-efflux transporters; and 5) trend of induction/activation of c-jun and NF-kB. Additionally, TCDD-treated Nrf2-null mice had impaired adipogenesis in white adipose tissue. In conclusion, Nrf2 protects livers of mice against oxidative stress, DNA damage, and steatohepatitis induced by TCDD-mediated sustained activation of the AhR. The aggravated hepatosteatosis in TCDD-treated Nrf2-null mice is due to increased lipogenesis in liver and impaired lipogenesis in white adipose tissue. - Highlights: > TCDD causes hepatosteatosis and induction of Nrf2-target genes in wild-type mice. > TCDD causes weight loss, oxidative injury, and steatohepatitis in Nrf2-null mice. > Livers of TCDD-treated Nrf2-null mice have

  2. Spirulina exhibits hepatoprotective effects against lead induced oxidative injury in newborn rats.

    PubMed

    Gargouri, M; Ben Saad, H; Ben Amara, I; Magné, C; El Feki, A

    2016-08-31

    Lead is a toxic metal that induces a wide range of biochemical and physiological effects. The present investigation was designed at evaluating the toxic effects of a prenatal exposure to lead of mothers on hepatic tissue of newborn rats, and potent protective effects of spirulina. Female rats were randomly divided into 4 groups which were given a normal diet (control),a diet enriched with spirulina (S), lead acetate administered through drinking water (Pb), or a diet enriched with spirulina and lead contaminated water (S Pb), respectively. The duration of treatments was from the 5th day of gestation to 14 days postpartum. Lead toxicity was assessed by measuring body and liver weights, blood and stomach lead levels, hepatic DNA, RNA and protein amounts, blood enzyme activities (AST and ALT), as well as lipid peroxidation level and activities of antioxidant enzymes in hepatic tissues of neonates. Lead intoxication of mothers caused reduction of liver weight as well as of hepatic DNA, mRNA and protein levels in newborns. Moreover, oxidative stress and changes in antioxidant enzyme activities were recorded. Conversely, supplementation of mothers with spirulina mitigated these effects induced by lead. These results substantiated the potential hepatoprotective and antioxidant activity of spirulina.

  3. Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis

    SciTech Connect

    Shaker, Mohamed E.; Zalata, Khaled R.; Mehal, Wajahat Z.; Shiha, Gamal E.; Ibrahim, Tarek M.

    2011-04-15

    Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl{sub 4}) rat model. Male Wistar rats received intraperitoneal injections of CCl{sub 4} twice weekly for 8 weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20 mg/kg), nilotinib (10 and 20 mg/kg) and silymarin (100 mg/kg) during the last 4 weeks of CCl{sub 4}-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20 mg/kg) was the most effective treatment to counteract CCl{sub 4}-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10 mg/kg), nilotinib (20 mg/kg) and silymarin (100 mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl{sub 4}-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl{sub 4}-induced fibrosis was ameliorated significantly by nilotinib (20 mg/kg) and imatinib (20 mg/kg). Unlike nilotinib, imatinib (20 mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans. - Graphical abstract: Display Omitted Research Highlights: > The anti-fibrotic effects of imatinib, nilotinib and silymarin were compared

  4. Green tea catechins, alleviate hepatic lipidemic-oxidative injury in Wistar rats fed an atherogenic diet.

    PubMed

    Ramesh, E; Jayakumar, T; Elanchezhian, R; Sakthivel, M; Geraldine, P; Thomas, P A

    2009-06-15

    In the present study, the efficacy of green tea catechins (GTC from the plant Camellia sinensis), with epigallocatechin gallate (EGCG), as the major component, was studied in relation to hepatic oxidative abnormalities in atherosclerotic rats. When male albino Wistar rats were fed an atherogenic diet for 30 days and then treated with saline for 7 or 15 days, there was a significant decline in hepatic mean activities of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase and glutathione-S-transferase), and non-enzymatic antioxidants (reduced glutathione, vitamins C and E) while there was a significant elevation in the mean level of hepatic malondialdehyde (MDA), in comparison to the values noted in control rats fed a normal diet. In addition, a concomitant increase in the activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) was noted, when compared to the values in control rats. Following intraperitoneal administration of GTC (100mg/kg) for 7 or 15 days to rats fed the atherogenic diet, significantly higher mean activities of enzymatic and non-enzymatic antioxidants and lower mean levels of MDA in hepatic tissue and lower mean activities of AST, ALT, ALP and LDH in serum were observed, compared to the values in the rats fed the atherogenic diet and treated with saline. Histopathological studies were performed to provide direct evidence of the atherogenic diet-induced hepatic changes and of the hepatoprotective effect of GTC. These results suggest that EGCG as a major component of green tea catechins may protect against the hepatic abnormalities occurring in Wistar rats fed an atherogenic diet.

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

    PubMed

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

    2016-07-08

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

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

    PubMed Central

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

    2016-01-01

    The effects of total flavonoids (TFs) from Rosa laevigata Michx fruit against liver damage and cerebral ischemia/reperfusion (I/R) injury have been reported, but its action on hepatic I/R injury remains unknown. In this work, the effects and possible mechanisms of TFs against hepatic I/R injury were examined using a 70% partial hepatic warm ischemia rat model. The results demonstrated TFs decreased serum aspartate transaminase (AST), alanine aminotransferase (ALT), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) activities, improved liver histopathology and ultrastructure through hematoxylin-eosin (HE) staining and electron microscope observation. In addition, TFs significantly decreased malondialdehyde (MDA) and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), which indicated that TFs alleviated oxidative stress caused by I/R injury. RT-PCR results proved that TFs downregulated the gene levels of inflammatory factors including interleukin-1 beta (IL-1β), interleukin-1 (IL-6), and tumor necrosis factor alpha (TNF-α). Further research indicated that TF-induced hepatoprotection was completed through inhibiting TLR4/MyD88 and activating Sirt1/Nrf2 signaling pathways. Blockade of the TLR4 pathway by TFs inhibited NF-κB and AP-1 transcriptional activities and inflammatory reaction. Activation of Sirt1/Nrf2 pathway by TFs increased the protein levels of HO-1 and GST to improve oxidative stress. Collectively, these findingsconfirmed the potent effects of TFs against hepatic I/R injury, which should be developed as a candidate for the prevention of this disease. PMID:27399769

  7. Forsythia suspensa extract attenuates corticosterone-induced growth inhibition, oxidative injury, and immune depression in broilers.

    PubMed

    Zeng, Z K; Li, Q Y; Piao, X S; Liu, J D; Zhao, P F; Xu, X; Zhang, S; Niu, S

    2014-07-01

    Forsythia suspensa extract (FSE) has been demonstrated to attenuate physiological stress induced by high temperature or high stocking density. This experiment was conducted with 144 male Arbor Acre broilers (1-d-old, weighing 42.7 ± 1.7 g) to determine the effects of FSE on performance, nutrient digestibility, antioxidant activities, serum metabolites, and immune parameters for birds treated with corticosterone (CS). The birds were randomly allotted to 1 of 4 treatments in a 2 × 2 factorial arrangement that included FSE supplementation (0 or 100 mg/kg) and CS administration (0 or 20 mg/kg of diet for 7 consecutive days starting on d 14). The feeding program consisted of a starter diet from d 1 to 21 and a finisher diet from d 22 to 42. Corticosterone administration decreased (P < 0.01) ADG and impaired (P < 0.01) feed conversion ratio in both phases and overall, which were alleviated (P < 0.01) by dietary FSE supplementation in the finisher phase and overall. At d 21, CS administration caused decreases (P < 0.05) in the apparent digestibility of energy, relative weight of bursa and thymus, total antioxidant capacity, superoxide dismutase (SOD) activity, and antibody titers to Newcastle disease virus (NDV); however, serum malondialdehyde and uric acid were increased. All of these changes were attenuated (P < 0.05) by dietary FSE supplementation. At d 42, FSE supplementation improved (P < 0.05) the apparent digestibility of DM and CP, relative weights of bursa, SOD activity, and antibody titers to NDV, which were impaired by CS administration. Interactions (P < 0.05) were noted between CS and FSE for ADG and feed conversion ratio in the finisher phase and overall, as well as total antioxidant capacity, SOD activity, uric acid, and antibody titers to NDV at d 21, as well as relative weights of thymus at d 42. In conclusion, dietary FSE supplementation enhanced nutrient digestibility and performance of broiler possibly by reducing oxidative stress and immune

  8. Caffeoylquinic Acid Derivatives Protect SH-SY5Y Neuroblastoma Cells from Hydrogen Peroxide-Induced Injury Through Modulating Oxidative Status.

    PubMed

    Jiang, Xiao-Wen; Bai, Jun-Peng; Zhang, Qiao; Hu, Xiao-Long; Tian, Xing; Zhu, Jun; Liu, Jia; Meng, Wei-Hong; Zhao, Qing-Chun

    2017-04-01

    Oxidative stress has been confirmed as a contribution to the pathogenesis and pathophysiology of many neurological disorders such as Alzheimer's disease and Parkinson's disease. Caffeoylquinic acids (CQAs) are considered to have anti-oxidative stress ability in a previous study, but the structure-activity relationships (SARs) of CQAs in neuroprotective effects are still unclear. In the present study, we primarily expound the SARs of CQAs in counteracting H2O2-induced injury in SH-SY5Y cells. We found that CQAs (1-10) represented the protection of SH-SY5Y cells against H2O2-induced injury in varying degrees and malonyl groups could obviously increase the anti-oxidative stress ability of CQAs. Intensive studies of 4,5-O-dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid (MDCQA) indicated that the mechanisms could potentially involve activation of endogenous antioxidant enzymes and the regulation of the phosphorylation of MAPKs and AKT. In conclusion, MDCQA could serve as a neuroprotective agent with a potential to attenuate oxidative stress.

  9. Association between inflammatory mediators and response to inhaled nitric oxide in a model of endotoxin-induced lung injury

    PubMed Central

    Trachsel, Sebastien; Deby-Dupont, Ginette; Maurenbrecher, Edwige; Nys, Monique; Lamy, Maurice; Hedenstierna, Göran

    2008-01-01

    Introduction Inhaled nitric oxide (INO) allows selective pulmonary vasodilation in acute respiratory distress syndrome and improves PaO2 by redistribution of pulmonary blood flow towards better ventilated parenchyma. One-third of patients are nonresponders to INO, however, and it is difficult to predict who will respond. The aim of the present study was to identify, within a panel of inflammatory mediators released during endotoxin-induced lung injury, specific mediators that are associated with a PaO2 response to INO. Methods After animal ethics committee approval, pigs were anesthetized and exposed to 2 hours of endotoxin infusion. Levels of cytokines, prostanoid, leucotriene and endothelin-1 (ET-1) were sampled prior to endotoxin exposure and hourly thereafter. All animals were exposed to 40 ppm INO: 28 animals were exposed at either 4 hours or 6 hours and a subgroup of nine animals was exposed both at 4 hours and 6 hours after onset of endotoxin infusion. Results Based on the response to INO, the animals were retrospectively placed into a responder group (increase in PaO2 ≥ 20%) or a nonresponder group. All mediators increased with endotoxin infusion although no significant differences were seen between responders and nonresponders. There was a mean difference in ET-1, however, with lower levels in the nonresponder group than in the responder group, 0.1 pg/ml versus 3.0 pg/ml. Moreover, five animals in the group exposed twice to INO switched from responder to nonresponder and had decreased ET-1 levels (3.0 (2.5 to 7.5) pg/ml versus 0.1 (0.1 to 2.1) pg/ml, P < 0.05). The pulmonary artery pressure and ET-1 level were higher in future responders to INO. Conclusions ET-1 may therefore be involved in mediating the response to INO. PMID:18954441

  10. Busulphan-Cyclophosphamide Cause Endothelial Injury, Remodeling of Resistance Arteries and Enhanced Expression of Endothelial Nitric Oxide Synthase

    PubMed Central

    Al-Hashmi, Sulaiman; Boels, Piet J. M.; Zadjali, Fahad; Sadeghi, Behnam; Sällström, Johan; Hultenby, Kjell; Hassan, Zuzana; Arner, Anders; Hassan, Moustapha

    2012-01-01

    Stem cell transplantation (SCT) is a curative treatment for malignant and non malignant diseases. However, transplantation-related complications including cardiovascular disease deteriorate the clinical outcome and quality of life. We have investigated the acute effects of conditioning regimen on the pharmacology, physiology and structure of large elastic arteries and small resistance-sized arteries in a SCT mouse model. Mesenteric resistance arteries and aorta were dissected from Balb/c mice conditioned with busulphan (Bu) and cyclophosphamide (Cy). In vitro isometric force development and pharmacology, in combination with RT-PCR, Western blotting and electron microscopy were used to study vascular properties. Compared with controls, mesenteric resistance arteries from the Bu-Cy group had larger internal circumference, showed enhanced endothelium mediated relaxation and increased expression of endothelial nitric oxide synthase (eNOS). Bu-Cy treated animals had lower mean blood pressure and signs of endothelial injury. Aortas of treated animals had a higher reactivity to noradrenaline. We conclude that short-term consequences of Bu-Cy treatment divergently affect large and small arteries of the cardiovascular system. The increased noradrenaline reactivity of large elastic arteries was not associated with increased blood pressure at rest. Instead, Bu-Cy treatment lowered blood pressure via augmented microvascular endothelial dependent relaxation, increased expression of vascular eNOS and remodeling toward a larger lumen. The changes in the properties of resistance arteries can be associated with direct effects of the compounds on vascular wall or possibly indirectly induced via altered translational activity associated with the reduced hematocrit and shear stress. This study contributes to understanding the mechanisms that underlie the early effects of conditioning regimen on resistance arteries and may help in designing further investigations to understand the late

  11. Inhaled nitric oxide alleviates hyperoxia suppressed phosphatidylcholine synthesis in endotoxin-induced injury in mature rat lungs

    PubMed Central

    Gong, Xiaohui; Guo, Chunbao; Huang, Shibing; Sun, Bo

    2006-01-01

    Background We investigated efficacy of inhaled nitric oxide (NO) in modulation of metabolism of phosphatidylcholine (PC) of pulmonary surfactant and in anti-inflammatory mechanism of mature lungs with inflammatory injury. Methods Healthy adult rats were divided into a group of lung inflammation induced by i.v. lipopolysaccharides (LPS) or a normal control (C) for 24 h, and then exposed to: room air (Air), 95% oxygen (O), NO (20 parts per million, NO), both O and NO (ONO) as subgroups, whereas [3H]-choline was injected i.v. for incorporation into PC of the lungs which were processed subsequently at 10 min, 4, 8, 12 and 24 h, respectively, for measurement of PC synthesis and proinflammatory cytokine production. Results LPS-NO subgroup had the lowest level of labeled PC in total phospholipids and disaturated PC in bronchoalveolar lavage fluid and lung tissue (decreased by 46–59%), along with the lowest activity of cytidine triphosphate: phosphocholine cytidylyltransferase (-14–18%) in the lungs, compared to all other subgroups at 4 h (p < 0.01), but not at 8 and 12 h. After 24-h, all LPS-subgroups had lower labeled PC than the corresponding C-subgroups (p < 0.05). LPS-ONO had higher labeled PC in total phospholipids and disaturated PC, activity of cytidylyltransferase, and lower activity of nuclear transcription factor-κB and expression of proinflammatory cytokine mRNA, than that in the LPS-O subgroup (p < 0.05). Conclusion In LPS-induced lung inflammation in association with hyperoxia, depressed PC synthesis and enhanced proinflammatory cytokine production may be alleviated by iNO. NO alone only transiently suppressed the PC synthesis as a result of lower activity of cytidylyltransferase. PMID:16403237

  12. Ultratrace Level Determination and Quantitative Analysis of Kidney Injury Biomarkers in Patient Samples Attained by Zinc Oxide Nanorods

    PubMed Central

    Singh, Manpreet; Alabanza, Anginelle; Gonzalez, Lorelis E.; Wang, Weiwei; Reeves, W. Brian; Hahm, Jong-in

    2016-01-01

    Determining ultratrace amounts of protein biomarkers in patient samples in a straightforward and quantitative manner is extremely important for early disease diagnosis and treatment. Here, we successfully demonstrate the novel use of zinc oxide nanorods (ZnO NRs) in the ultrasensitive and quantitative detection of two acute kidney injury (AKI)-related protein biomarkers, tumor necrosis factor (TNF)-α and interleukin (IL)-8, directly from patient samples. We first validate the ZnO NRs-based IL-8 results via comparison with those obtained from using a conventional enzyme-linked immunosorbent method in samples from 38 individuals. We further assess the full detection capability of the ZnO NRs-based technique by quantifying TNF-α, whose levels in human urine are often below the detection limits of conventional methods. Using the ZnO NR platforms, we determine the TNF-α concentrations of all 46 patient samples tested, down to the fg/mL level. Subsequently, we screen for TNF-α levels in approximately 50 additional samples collected from different patient groups in order to demonstrate a potential use of the ZnO NRs-based assay in assessing cytokine levels useful for further clinical monitoring. Our research efforts demonstrate that ZnO NRs can be straightforwardly employed in the rapid, ultrasensitive, quantitative, and simultaneous detection of multiple AKI-related biomarkers directly in patient urine samples, providing an unparalleled detection capability beyond those of conventional analysis methods. Additional key advantages of the ZnO NRs-based approach include a fast detection speed, low-volume assay condition, multiplexing ability, and easy automation/integration capability to existing fluorescence instrumentation. Therefore, we anticipate that our ZnO NRs-based detection method will be highly beneficial for overcoming the frequent challenges in early biomarker development and treatment assessment, pertaining to the facile and ultrasensitive quantification of

  13. Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model.

    PubMed

    Jung, Kyung Hee; Hong, Sang-Won; Zheng, Hong-Mei; Lee, Don-Haeng; Hong, Soon-Sun

    2009-09-01

    Melatonin has potent hepatoprotective effects as an antioxidant. However, the signaling pathway of melatonin in the induction of antioxidant enzymes against acute liver injury is not fully understood. The study aimed to determine whether melatonin could prevent dimethylnitrosamine (DMN)-induced liver injury through nuclear erythroid 2-related factor 2 (Nrf2) and inflammation. Liver injury was induced in rats by a single injection of DMN (30 mg/kg, i.p.). Melatonin treatment (50 mg/kg/daily, i.p.) was initiated 24 hr after DMN injection for 14 days, after which the rats were killed and samples were collected. Serum and antioxidant enzyme activities improved in melatonin-treated rats, compared with DMN-induced liver injury group (P < 0.01). Melatonin reduced the infiltration of inflammatory cells and necrosis in the liver, and increased the expression of NADPH: quinone oxidoreductase-1, heme oxygenase-1, and superoxide dismutase-2, which were decreased by DMN. Melatonin increased expression of novel transcription factor, Nrf2, and decreased expression of inflammatory mediators including tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and inducible nitric oxide synthase. The increased nuclear binding of nuclear factor-kappa B (NF-kappaB) in the DMN-induced liver injury group was inhibited by melatonin. Our results show that melatonin increases antioxidant enzymes and Nrf2 expression in parallel with the decrease of inflammatory mediators in DMN-induced liver injury, suggesting that melatonin may play a role of antioxidant defense via the Nrf2 pathway, by reducing inflammation by NF-kappaB inhibition.

  14. Chrysin, a PPAR-γ agonist improves myocardial injury in diabetic rats through inhibiting AGE-RAGE mediated oxidative stress and inflammation.

    PubMed

    Rani, Neha; Bharti, Saurabh; Bhatia, Jagriti; Nag, T C; Ray, Ruma; Arya, Dharamvir Singh

    2016-04-25

    AGE-RAGE interaction mediated oxidative stress and inflammation is the key mechanism involved in the pathogenesis of cardiovascular disease in diabetes. Inhibition of AGE-RAGE axis by several PPAR-γ agonists has shown positive results in ameliorating cardio-metabolic disease conditions. Chrysin, a natural flavonoid has shown to possess PPAR-γ agonist activity along with antioxidant and anti-inflammatory effect. Therefore, the present study was designed to evaluate the effect of chrysin in isoproterenol-induced myocardial injury in diabetic rats. In male albino Wistar rats, diabetes was induced by single injection of streptozotocin (70 mg/kg, i.p.). After confirmation of the diabetes, rats were treated with vehicle (1.5 mL/kg, p.o.), chrysin (60 mg/kg, p.o.) or PPAR-γ antagonist GW9662 (1 mg/kg, i.p.) for 28 days. Simultaneously, on 27th and 28th day myocardial injury was induced by isoproterenol (85 mg/kg, s.c.). Chrysin significantly ameliorated cardiac dysfunction as reflected by improved MAP, ±LVdP/dtmax and LVEDP in diabetic rats. This improvement was associated with increased PPAR-γ expression and reduced RAGE expression in diabetic rats. Chrysin significantly decreased inflammation through inhibiting NF-κBp65/IKK-β expression and TNF-α level. Additionally, chrysin significantly reduced apoptosis as indicated by augmented Bcl-2 expression and decreased Bax and caspase-3 expressions. Furthermore, chrysin inhibited nitro-oxidative stress by normalizing the alteration in 8-OHdG, GSH, TBARS, NO and CAT levels and Nox4, MnSOD, eNOS and NT expressions. Co-administration of GW9662 significantly blunted the chrysin mediated cardioprotective effect as there was increase in oxidative stress, inflammation and apoptosis markers. Chrysin significantly ameliorated isoproterenol-induced myocardial injury in diabetic rats via PPAR-γ activation and inhibition of AGE-RAGE mediated oxidative stress and inflammation.

  15. Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV seropositive individuals with cognitive impairment

    PubMed Central

    Sacktor, Ned; Miyahara, Sachiko; Evans, Scott; Schifitto, Giovanni; Cohen, Bruce; Haughey, Norman; Drewes, Julia L.; Graham, David; Zink, M. Christine; Anderson, Caroline; Nath, Avindra; Pardo, Carlos A.; McCarthy, Sean; Hosey, Lara; Clifford, David

    2014-01-01

    Elevated cerebrospinal fluid (CSF) levels of markers of oxidative stress, neuronal injury, and inflammation, and decreased neurotransmitter levels have been reported in HIV-associated neurocognitive disorders (HAND). Minocycline may have a neuroprotective effect by inhibiting inducible nitric oxide synthase, which produces nitric oxide, a compound that induces oxygen free radical production. In A5235, “Phase II, Randomized, Placebo-Controlled, Double-Blind Study of Minocycline in the Treatment of HIV-associated Cognitive Impairment”, minocycline was not associated with cognitive improvement, but the effect on the above CSF measures was not examined previously. The objective of this study was to examine the effect of minocycline on markers of oxidative stress, neuronal injury, neurotransmitter levels, and inflammation from CSF in participants in A5235. 107 HIV+ individuals received either minocycline 100 mg or placebo orally every 12 hours for 24 weeks. 21 HIV+ individuals received the optional lumbar punctures. Lipid and protein markers of oxidative stress (e.g., ceramides and protein carbonyls), glutamate, neurotransmitter precursors, kynurenine metabolites, neurofilament heavy chain and inflammatory cytokines were measured in the CSF before and after treatment. The 24-week change in ceramides was larger in a beneficial direction in the minocycline group compared to the placebo group. The two groups did not differ in the 24-week changes for other markers. These results suggest that minocycline may decrease lipid markers of oxidative stress (ceramides) in individuals with HAND; however, an effect of minocycline on other CSF markers was not observed. A larger sample size is needed to further validate these results. PMID:25377444

  16. Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV-seropositive individuals with cognitive impairment.

    PubMed

    Sacktor, Ned; Miyahara, Sachiko; Evans, Scott; Schifitto, Giovanni; Cohen, Bruce; Haughey, Norman; Drewes, Julia L; Graham, David; Zink, M Christine; Anderson, Caroline; Nath, Avindra; Pardo, Carlos A; McCarthy, Sean; Hosey, Lara; Clifford, David

    2014-12-01

    Elevated cerebrospinal fluid (CSF) levels of markers of oxidative stress, neuronal injury, and inflammation and decreased neurotransmitter levels have been reported in HIV-associated neurocognitive disorders (HAND). Minocycline may have a neuroprotective effect by inhibiting inducible nitric oxide synthase, which produces nitric oxide, a compound that induces oxygen free radical production. In A5235, "Phase II, Randomized, Placebo-Controlled, Double-Blind Study of Minocycline in the Treatment of HIV-Associated Cognitive Impairment," minocycline was not associated with cognitive improvement, but the effect on the above CSF measures was not examined previously. The objective of this study was to examine the effect of minocycline on markers of oxidative stress, neuronal injury, neurotransmitter levels, and inflammation from CSF in participants in A5235. One hundred seven HIV+ individuals received either minocycline 100 mg or placebo orally every 12 h for 24 weeks. Twenty-one HIV+ individuals received the optional lumbar punctures. Lipid and protein markers of oxidative stress (e.g., ceramides and protein carbonyls), glutamate, neurotransmitter precursors, kynurenine metabolites, neurofilament heavy chain, and inflammatory cytokines were measured in the CSF before and after treatment. The 24-week change in ceramides was larger in a beneficial direction in the minocycline group compared to the placebo group. The two groups did not differ in the 24-week changes for other markers.These results suggest that minocycline may decrease lipid markers of oxidative stress (ceramides) in individuals with HAND; however, an effect of minocycline on other CSF markers was not observed. A larger sample size is needed to further validate these results.

  17. Choline and Cystine Deficient Diets in Animal Models with Hepatocellular Injury: Evaluation of Oxidative Stress and Expression of RAGE, TNF-α, and IL-1β

    PubMed Central

    Santos, Juliana Célia F.; de Araújo, Orlando R. P.; Valentim, Iara B.; de Andrade, Kívia Queiroz; Moura, Fabiana Andréa; Smaniotto, Salete; dos Santos, John Marques; Gelain, Daniel P.; Goulart, Marília O. F.

    2015-01-01

    This study aims to evaluate the effects of diets deficient in choline and/or cystine on hepatocellular injury in animal models (young male Wistar rats, aged 21 days), by monitoring some of the oxidative stress biomarkers and the expression of RAGE, TNF-α, and IL-1β. The animals were divided into 6 groups (n = 10) and submitted to different diets over 30 days: AIN-93 diet (standard, St), AIN-93 choline deficient (CD) diet and AIN-93 choline and cystine deficient (CCD) diet, in the pellet (pl) and powder (pw) diet forms. Independently of the diet form, AIN-93 diet already led to hepatic steatosis and CD/CCD diets provoked hepatic damage. The increase of lipid peroxidation, represented by the evaluation of thiobarbituric acid reactive species, associated with the decrease of levels of antioxidant enzymes, were the parameters with higher significance toward redox profile in this model of hepatic injury. Regarding inflammation, in relation to TNF-α, higher levels were evidenced in CD(pl), while, for IL-1β, no significant alteration was detected. RAGE expression was practically the same in all groups, with exception of CCD(pw) versus CCD(pl). These results together confirm that AIN-93 causes hepatic steatosis and choline and/or cysteine deficiencies produce important hepatic injury associated with oxidative stress and inflammatory profiles. PMID:26137185

  18. Hepatoprotective Activity of Water Extracts from Chaga Medicinal Mushroom, Inonotus obliquus (Higher Basidiomycetes) Against Tert-Butyl Hydroperoxide-Induced Oxidative Liver Injury in Primary Cultured Rat Hepatocytes.

    PubMed

    Hong, Ki Bae; Noh, Dong Ouk; Park, Yooheon; Suh, Hyung Joo

    2015-01-01

    We examined the hepatoprotective activity of Inonotus obliquus water extract (IO-W) against tert-butyl hydroperoxide (t-BHP)-induced oxidative liver injury in the primary cultured rat hepatocyte. The 50% radical scavenging concentrations (SC50s) of IO-W for radical-scavenging activity against 2,2'-azino-bis-(3-ethylbenzothi- azoline-6-sulfonic acid) (ABTS) and 1,1-diphenyl-2-picryl-hydrazyl (DPPH) were 5.19 mg/mL and 0.39 mg/mL, respectively. IO-W pretreatment to the primary cultured hepatocytes significantly (p<0.05) protected the cells from t-BHP-induced cytotoxic injury even at a low concentration of IO-W (10 µg/mL). The cellular leakage of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), as well as malondialdehyde (MDA) formation caused by t-BHP were significantly (p<0.05) suppressed by IO-W pretreatment (>100 µg/ mL). In conclusion, this study demonstrates that IO-W exhibited hepatoprotective activity against t-BHP-induced oxidative liver injury in the primary cultured hepatocyte probably via its abilities of quenching free radicals, inhibiting the leakage of ALT, AST, and LDH, and decreasing MDA formation.

  19. Angiotensin-(1-7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis

    PubMed Central

    Lu, W.; Kang, J.; Hu, K.; Tang, S.; Zhou, X.; Yu, S.; Xu, L.

    2017-01-01

    We aimed to study the renal injury and hypertension induced by chronic intermittent hypoxia (CIH) and the protective effects mediated by angiotensin 1-7 [Ang(1-7)]. We randomly assigned 32 male Sprague-Dawley rats (body weight 180-200 g) to normoxia control, CIH, Ang(1-7)-treated normoxia, and Ang(1-7)-treated CIH groups. Systolic blood pressure (SBP) was monitored at the start and end of each week. Renal sympathetic nerve activity (RSNA) was recorded. CTGF and TGF-β were detected by immunohistochemistry and western blotting. Tissue parameters of oxidative stress were also determined. In addition, renal levels of interleukin-6, tumor necrosis factor-α, nitrotyrosine, and hypoxia-inducible factor-1α were determined by immunohistochemistry, immunoblotting, and ELISA. TUNEL assay results and cleaved caspase 3 and 12 were also determined. Ang(1-7) induced a reduction in SBP together with a restoration of RSNA in the rat model of CIH. Ang(1-7) treatment also suppressed the production of reactive oxygen species, reduced renal tissue inflammation, ameliorated mesangial expansion, and decreased renal fibrosis. Thus, Ang(1-7) treatment exerted renoprotective effects on CIH-induced renal injury and was associated with a reduction of oxidative stress, inflammation and fibrosis. Ang(1-7) might therefore represent a promising therapy for obstructive sleep apnea-related hypertension and renal injury. PMID:28076452

  20. Melatonin exerts a more potent effect than S-adenosyl-l-methionine against iron metabolism disturbances, oxidative stress and tissue injury induced by obstructive jaundice in rats.

    PubMed

    Muñoz-Castañeda, Juan R; Túnez, Isaac; Herencia, Carmen; Ranchal, Isidora; González, Raúl; Ramírez, Luz M; Arjona, Alvaro; Barcos, Montserrat; Espejo, Isabel; Cruz, Adolfo; Montilla, Pedro; Padillo, Francisco J; Muntané, Jordi

    2008-07-30

    Melatonin and S-adenosyl-l-methionine (SAMe) prevent oxidative stress and tissue dysfunction in obstructive jaundice (OJ). Lipid peroxidation is exacerbated in the presence of trace amounts of iron (Fe). The study investigated the regulation by melatonin and SAMe the induction of oxidative stress, iron metabolism disturbances and tissue injury in an experimental model of OJ. Different parameters of lipid peroxidation, antioxidant status, tissue injury and Fe metabolism were determined in liver and blood. OJ induced Fe accumulation in liver, and increased transferrin (Tf) saturation and loosely bound Fe content in blood. Melatonin, and SAMe at lesser extent, enhanced protein Tf content in liver and blood, that reduced loosely bound Fe content in blood. Melatonin and SAMe did not affect ferritin (FT) and Tf mRNA expression, but reduced Tf receptor (TfR) mRNA expression in liver. In conclusion, the effect of melatonin and SAMe on Fe metabolism may be included in the beneficial properties of these agents on lipid peroxidation and tissue injury induced by OJ.

  1. Oxidized lipids and lipid-mediators are involved in cardiovascular injury induced by diesel exhaust particles and ozone

    EPA Science Inventory

    The mechanisms by which air pollutants induce cardiac and vascular injuries are unknown. We hypothesized that these injuries involve alterations in'aortic membrane lipids and lipid-mediators. We exposed male Wistar Kyoto rats (12-15 wk old), nose-only to air, ozone (03; 0.5 ppm),...

  2. Prodigiosin inhibits gp91{sup phox} and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia

    SciTech Connect

    Chang, Chia-Che; Wang, Yea-Hwey; Chern, Chang-Ming; Liou, Kuo-Tong; Hou, Yu-Chang; Peng, Yu-Ta; Shen, Yuh-Chiang

    2011-11-15

    This study aimed to explore the mechanisms by which prodigiosin protects against hypoxia-induced oxidative/nitrosative brain injury induced by middle cerebral artery occlusion/reperfusion (MCAo/r) injury in mice. Hypoxia in vitro was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone MCAo/r injury with prodigiosin (10 and 100 {mu}g/kg, i.v.) at 1 h after hypoxia ameliorated MCAo/r-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. MCAo/r induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (gp91{sup phox}), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b leukocytes due to breakdown of blood-brain barrier (BBB) by activation of nuclear factor-kappa B (NF-{kappa}B). All these changes were significantly diminished by prodigiosin. In BV-2 cells, OGD induced ROS and nitric oxide production by up-regulating gp91{sup phox} and iNOS via activation of the NF-{kappa}B pathway, and these changes were suppressed by prodigiosin. In conclusion, our results indicate that prodigiosin reduces gp91{sup phox} and iNOS expression possibly by impairing NF-{kappa}B activation. This compromises the activation of microglial and/or inflammatory cells, which then, in turn, mediates prodigiosin's protective effect in the MCAo/r mice. -- Highlights: Black-Right-Pointing-Pointer Prodigiosin ameliorated brain infarction and deficits. Black-Right-Pointing-Pointer Prodigiosin protected against hypoxia/reperfusion-induced brain injury. Black-Right-Pointing-Pointer Prodigiosin diminished oxidative/nitrosativestress and leukocytes infiltration. Black-Right-Pointing-Pointer Prodigiosin reduced BBB breakdown. Black

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

    PubMed Central

    Reyes-Gordillo, Karina; Shah, Ruchi; Varatharajalu, Ravi; Garige, Mamatha; Leckey, Leslie C.

    2016-01-01

    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. PMID:28074114

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

    PubMed

    Reyes-Gordillo, Karina; Shah, Ruchi; Varatharajalu, Ravi; Garige, Mamatha; Leckey, Leslie C; Lakshman, M Raj

    2016-01-01

    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.

  5. Sesame oil improves functional recovery by attenuating nerve oxidative stress in a mouse model of acute peripheral nerve injury: role of Nrf-2.

    PubMed

    Hsu, Che-Chia; Huang, Hui-Cheng; Wu, Po-Ting; Tai, Ta-Wei; Jou, I-Ming

    2016-12-01

    Peripheral nervous injury (PNI) is a common form of trauma in modern society, especially in sport players. Despite the advance of therapy for PNI, the recovery of function can never reach the preinjury level after treatments. Recently, inhibiting neural oxidative stress shows a beneficial effect in improving functional recovery after PNI. In addition, sesame oil has been reported to possess the excellent antioxidative properties. However, whether sesame oil can improve the functional recovery after PNI by its antioxidative effect has never been investigated. Thirty mice were randomly divided into five groups of six: group I mice received sham operation; group II mice received sciatic nerve crush; and groups III-V mice daily ingested 0.5, 1 and 2 ml/kg of sesame oil for 6 days, respectively, after sciatic nerve crush. Oxidative stress, GAP43 and nuclear Nrf2 levels as well as spinal somatosensory evoked potentials were assessed on day 6, while paw withdrawal latency and sciatic function index were assessed on days 0, 3, and 6. Sesame oil significantly decreased lipid peroxidation and increased nuclear factor erythroid 2-related factor 2 and GAP43 expression in sciatic nerve. Furthermore, sesame oil improved electrophysiological and functional assessments in mice with sciatic nerve crush. In conclusion, sesame oil may improve nerve functional recovery by attenuating nerve oxidative stress in mouse acute peripheral nerve injury. Further, application of natural product sesame oil may be an alternative approach for improving nerve functional recovery in the clinical setting.

  6. Identification of hepatoprotective xanthones from the pericarps of Garcinia mangostana, guided with tert-butyl hydroperoxide induced oxidative injury in HL-7702 cells.

    PubMed

    Wang, Anqi; Liu, Qianyu; Ye, Yang; Wang, Yitao; Lin, Ligen

    2015-09-01

    Bioactivity-guided fractionation of an ethanol-soluble extract from the pericarps of Garcinia mangostana, using tert-butyl hydroperoxide (t-BHP) induced oxidative damage in human normal hepatocytes (HL-7702), led to the identification of 10 known xanthones. Among them, γ-mangostin (γ-Man) exhibited the most potent activity to attenuate t-BHP induced hepatocyte injury. γ-Man significantly ameliorated t-BHP induced reactive oxygen species accumulation, mitochondrial membrane depolarization and cell nuclei morphology change in HL-7702 cells. t-BHP decreased the intracellular levels of key enzymes including glutamate oxaloacetate transaminase and glutamate pyruvate transaminase, which was totally reversed by γ-Man. Moreover, γ-Man significantly decreased the level of lipid peroxidation and increased the levels of superoxide dismutase and reduced glutathione, resulting in the alleviation of oxidative stress. The above results suggest γ-Man is a potential hepatoprotective agent against t-BHP induced oxidative injury, which may benefit the further application of G. mangostana as a health food.

  7. Saikokeishito Extract Exerts a Therapeutic Effect on α-Naphthylisothiocyanate-Induced Liver Injury in Rats through Attenuation of Enhanced Neutrophil Infiltration and Oxidative Stress in the Liver Tissue

    PubMed Central

    Ohta, Yoshiji; Kongo-Nishimura, Mutsumi; Hayashi, Takahiro; Kitagawa, Akira; Matsura, Tatsuya; Yamada, Kazuo

    2007-01-01

    We examined whether Saikokeishito extract (TJ-10), a traditional Japanese herbal medicine, exerts a therapeutic effect on α-naphthylisothiocyanate (ANIT)-induced liver injury in rats through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue. In rats treated once with ANIT (75 mg/kg, i.p.), liver injury with cholestasis occurred 24 h after treatment and progressed at 48 h. When ANIT-treated rats orally received TJ-10 (0.26, 1.3 or 2.6 g/kg) at 24 h after the treatment, progressive liver injury with cholestasis was significantly attenuated at 48 h after the treatment at the dose of 1.3 or 2.6 g/kg. At 24 h after ANIT treatment, increases in hepatic lipid peroxide and reduced glutathione contents and myeloperoxidase activity occurred with decreases in hepatic superoxide dismutase and glutathione reductase activities. At 48 h after ANIT treatment, these changes except for reduced glutathione were enhanced with decreases in catalase, Se-glutathione peroxidase, and glucose-6-phosphate dehydrogenase activities. TJ-10 (1.3 or 2.6 g/kg) post-administered to ANIT-treated rats attenuated these changes found at 48 h after the treatment significantly. These results indicate that TJ-10 exerts a therapeutic effect on ANIT-induced liver injury in rats possibly through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue. PMID:18437211

  8. Tetrahydrocurcumin reduces oxidative stress-induced apoptosis via the mitochondrial apoptotic pathway by modulating autophagy in rats after traumatic brain injury

    PubMed Central

    Gao, Yongyue; Zhuang, Zong; Gao, Shanting; Li, Xiang; Zhang, Zihuan; Ye, Zhennan; Li, Liwen; Tang, Chao; Zhou, Mengliang; Han, Xiao; Li, Jie

    2017-01-01

    Tetrahydrocurcumin (THC) has been identified as a multi-functional neuroprotective agent in numerous neurological disorders. Oxidative stress as a result of injury may induce neuronal apoptosis after traumatic brain injury (TBI). Treatment with THC may improve neurological function following TBI by attenuating oxidative stress and apoptosis and by enhancing autophagy. The purpose of this study was to investigate the mechanism of neuroprotection by THC against oxidative stress-induced neuronal apoptosis after TBI. We hypothesized that neuroprotection by THC may involve modulation of autophagy and the mitochondria apoptotic pathway. We used western blot analysis to evaluate the effect of THC on proteins involved in mitochondrial autophagy and apoptosis after TBI. The terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay and immunofluorescence staining were used to confirm the role of THC in apoptosis and autophagy, respectively. THC-induced neuroprotection was assessed by neurological severity scoring (NSS) and by measuring the brain water content. We demonstrated that treatment with THC increased expression of autophagy-associated proteins LC3-II and Beclin-1 at 24 h post-TBI. Treatment with THC also reduced expression of malondialdehyde (MDA) and increased glutathione peroxidase (GPx) activity. Further, treatment with THC attenuated apoptosis by modulating mitochondrial apoptosis and reducing oxidative stress. Treatment with 3-methyladenine (3-MA) mitigated autophagy activation and reversed the inhibitory effect of THC on the translocation of Bax to the mitochondrial membrane. Moreover, treatment with THC improved neurological function and reduced the brain water content in rats after TBI. We concluded that the neuroprotective effects of THC are mediated by enhancing autophagy activation and by attenuation of oxidative stress and apoptosis after TBI, probably by modulating the mitochondrial apoptotic pathway. We suggest that THC may be an

  9. Pyrazole induced oxidative liver injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency.

    PubMed

    Lu, Yongke; Gong, Pengfei; Cederbaum, Arthur I

    2008-10-30

    Pyrazole can induce CYP2E1 and 2A5, which produce reactive oxygen species (ROS). Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates important antioxidant enzymes to remove ROS. In this study, we applied Nrf2 knockout mice to test the hypothesis that pyrazole will cause hepatotoxicity and elevate oxidative stress to a greater extent in Nrf2 knockout mice compared to wild type mice. Pyrazole induced severe oxidative liver damage in Nrf2 knockout mice but not in wild type mice. Activities and levels of CYP2E1 and 2A5 were elevated by pyrazole in the wild type mice but not in the Nrf2 knockout mice. However, expression or activity of Nrf2-regulated antioxidant enzymes, such as gamma-glutamylcysteine synthetase (GCS), heme oxygenase-1 (HO-1) and glutathione-S-transferase (GST), were upregulated in the pyrazole-treated wild type mice, but to a lesser extent or not at all in the pyrazole-treated Nrf2 knockout mice. Treatment with antioxidants such as vitamin C or S-adenosyl-l-methionine (SAM) or an inhibitor of iNOS prevented the pyrazole-induced oxidative liver damage, thus validating the role of oxidative/nitrosative stress in the pyrazole induced liver injury to the Nrf2 knockout mice. In summary, even though ROS-producing CYP2E1/2A5 were not elevated by pyrazole, impaired antioxidant capacity resulting from Nrf2 deficiency appear to be sufficient to promote pyrazole-induced oxidative liver injury.

  10. The role of functionalized magnetic iron oxide nanoparticles in the central nervous system injury and repair: new potentials for neuroprotection with Cerebrolysin therapy.

    PubMed

    Sharma, Hari Shanker; Menon, Preeti K; Lafuente, José Vicente; Aguilar, Zoraida P; Wang, Y Andrew; Muresanu, Dafin Fior; Mössler, Herbert; Patnaik, Ranjana; Sharma, Aruna

    2014-01-01

    Functionalized Magnetic Iron Oxide Nanoparticles (FMIONPs) are being explored for the development of various biomedical applications, e.g., cancer chemotherapy and/or several other radiological or diagnostic purposes. However, the effects of these NPs per se on the central nervous system (CNS) injury or repair are not well known. This review deals with different aspects of FMIONPs in relation to brain function based on the current literature as well as our own investigation in animal models of CNS injuries. It appears that FMIONPs are innocuous when administered intravenously within the CNS under normal conditions. However, abnormal reactions to FMIONPs in the brain or spinal cord could be seen if they are combined with CNS injuries e.g., hyperthermia or traumatic insults to the brain or spinal cord. Thus, administration of FMIONPs in vivo following whole body hyperthermia (WBH) or a focal spinal cord injury (SCI) exacerbates cellular damage. Since FMIONPs could help in diagnostic purposes or enhance the biological effects of radiotherapy/chemotherapy it is likely that these NPs may have some adverse reaction as well under disease condition. Thus, under such situation, adjuvant therapy e.g., Cerebrolysin (Ever NeuroPharma, Austria), a suitable combination of several neurotrophic factors and active peptide fragments are the need of the hour to contain such cellular damages caused by the FMIONPs in vivo. Our observations show that co-administration of Cerebrolysin prevents the FMIONPs induced pathologies associated with CNS injuries. These observations support the idea that FMIONPs are safe for the CNS in disease conditions when co-administered with cerebrolysin. This indicates that cerebrolysin could be used as an adjunct therapy to prevent cellular damages in disease conditions where the use of FMIONPs is required for better efficacy e.g., cancer treatment.

  11. Puerarin protects endothelial cells from oxidized low density lipoprotein induced injuries via the suppression of LOX-1 and induction of eNOS.

    PubMed

    Bao, Mei-hua; Zhang, Yi-wen; Lou, Xiao-ya; Xiao, Yan; Cheng, Yu; Zhou, Hong-hao

    2014-04-01

    Oxidized low density lipoprotein (oxLDL) induced injury of endothelial cells is considered to be the first step in the pathogenesis of atherosclerosis. This study aimed to investigate some of the effects and mechanisms of puerarin on oxLDL-induced endothelial injuries. We measured cell viability, and the release of lactate dehydrogenase (LDH), nitric oxide (NO), and interleukin-8 (IL-8) to evaluate the protective effects of puerarin. Intracellular reactive oxygen species (ROS) were detected using 2',7'-dichlorofluorescein diacetate (DCFH-DA). The expression of lectin-like low-density lipoprotein receptor-1 (LOX-1), endothelial nitric oxide synthase (eNOS), cyclooxygenase 2 (COX-2), p38MAPK, and protein kinase B (PKB) phosphorylation, nuclear factor-κB (NF-κB) nuclear translocation, and inhibitor of κB (IκB) degradation were detected using quantitative real-time PCR or Western blot. The results showed that oxLDL significantly decreased cell viability, increased LDH and IL-8 release, inhibited NO production, and induced COX-2 expression. Pretreatment with puerarin led to a strong inhibition of these effects. OxLDL stimulated the expression of LOX-1, the overproduction of ROS, the phosphorylation of p38MAPK, the dephosphorylation of PKB, activation of NF-κB, and the degradation of IκB. These oxLDL-induced effects were suppressed after puerarin pretreatment. These results suggest that puerarin inhibits oxLDL-induced endothelial cell injuries, at least in part, via inhibition of the LOX-1-mediated p38MAPK-NF-κB inflammatory and the PKB-eNOS signaling pathways.

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

    PubMed

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

    2016-02-01

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

  13. Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

    SciTech Connect

    McGill, Mitchell R.; Williams, C. David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut

    2012-11-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The

  14. Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Protects Against Acute Kidney Injury-Mediated Chronic Kidney Disease: Role of Oxidative Stress.

    PubMed

    Lattenist, Lionel; Lechner, Sebastian M; Messaoudi, Smail; Le Mercier, Alan; El Moghrabi, Soumaya; Prince, Sonia; Bobadilla, Norma A; Kolkhof, Peter; Jaisser, Frédéric; Barrera-Chimal, Jonatan

    2017-05-01

    Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR consequences; however, the potential benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone has to be further explored. In this study, we evaluated the efficacy of finerenone to prevent the acute and chronic consequences of ischemic acute kidney injury. For the acute study (24 hours), 18 rats were divided into sham, bilateral renal ischemia of 25 minutes, and rats that received 3 doses of finerenone at 48, 24, and 1 hour before the ischemia. For the chronic study (4 months), 23 rats were divided into sham, rats that underwent 45 minutes of bilateral ischemia, and rats treated with finerenone at days 2 and 1 and 1 hour before IR. We found that after 24 hours of reperfusion, the untreated IR rats presented kidney dysfunction and tubular injury. Kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin mRNA levels were increased. In contrast, the rats treated with finerenone displayed normal kidney function and significantly lesser tubular injury and kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin levels. After 4 months, the IR rats developed chronic kidney disease, evidenced by kidney dysfunction, increased proteinuria and renal vascular resistance, tubular dilation, extensive tubule-interstitial fibrosis, and an increase in kidney transforming growth factor-β and collagen-I mRNA. The transition from acute kidney injury to chronic kidney disease was fully prevented by finerenone. Altogether, our data show that in the rat, finerenone is able to prevent acute kidney injury induced by IR and the chronic and progressive deterioration of kidney function and structure.

  15. Ultratrace level determination and quantitative analysis of kidney injury biomarkers in patient samples attained by zinc oxide nanorods

    NASA Astrophysics Data System (ADS)

    Singh, Manpreet; Alabanza, Anginelle; Gonzalez, Lorelis E.; Wang, Weiwei; Reeves, W. Brian; Hahm, Jong-In

    2016-02-01

    Determining ultratrace amounts of protein biomarkers in patient samples in a straightforward and quantitative manner is extremely important for early disease diagnosis and treatment. Here, we successfully demonstrate the novel use of zinc oxide nanorods (ZnO NRs) in the ultrasensitive and quantitative detection of two acute kidney injury (AKI)-related protein biomarkers, tumor necrosis factor (TNF)-α and interleukin (IL)-8, directly from patient samples. We first validate the ZnO NRs-based IL-8 results via comparison with those obtained from using a conventional enzyme-linked immunosorbent method in samples from 38 individuals. We further assess the full detection capability of the ZnO NRs-based technique by quantifying TNF-α, whose levels in human urine are often below the detection limits of conventional methods. Using the ZnO NR platforms, we determine the TNF-α concentrations of all 46 patient samples tested, down to the fg per mL level. Subsequently, we screen for TNF-α levels in approximately 50 additional samples collected from different patient groups in order to demonstrate a potential use of the ZnO NRs-based assay in assessing cytokine levels useful for further clinical monitoring. Our research efforts demonstrate that ZnO NRs can be straightforwardly employed in the rapid, ultrasensitive, quantitative, and simultaneous detection of multiple AKI-related biomarkers directly in patient urine samples, providing an unparalleled detection capability beyond those of conventional analysis methods. Additional key advantages of the ZnO NRs-based approach include a fast detection speed, low-volume assay condition, multiplexing ability, and easy automation/integration capability to existing fluorescence instrumentation. Therefore, we anticipate that our ZnO NRs-based detection method will be highly beneficial for overcoming the frequent challenges in early biomarker development and treatment assessment, pertaining to the facile and ultrasensitive quantification

  16. Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

    SciTech Connect

    Sunil, Vasanthi R.; Shen, Jianliang; Patel-Vayas, Kinal; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-05-15

    Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS −/− mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS −/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS −/− mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS −/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS −/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning. -- Highlights: ► Lung injury, inflammation and oxidative stress are induced by the model vesicant CEES ► RNS generated via iNOS are important in the CEES-induced pulmonary toxicity ► iNOS −/− mice are protected from CEES-induced lung toxicity and

  17. Protective effects of β-glucan against oxidative injury induced by 2.45-GHz electromagnetic radiation in the skin tissue of rats.

    PubMed

    Ceyhan, Ali Murat; Akkaya, Vahide Baysal; Güleçol, Şeyma Celik; Ceyhan, Betül Mermi; Özgüner, Fehmi; Chen, WenChieh

    2012-09-01

    In recent times, there is widespread use of 2.45-GHz irradiation-emitting devices in industrial, medical, military and domestic application. The aim of the present study was to investigate the effect of 2.45-GHz electromagnetic radiation (EMR) on the oxidant and antioxidant status of skin and to examine the possible protective effects of β-glucans against the oxidative injury. Thirty-two male Wistar albino rats were randomly divided into four equal groups: control; sham exposed; EMR; and EMR + β-glucan. A 2.45-GHz EMR emitted device from the experimental exposure was applied to the EMR group and EMR + β-glucan group for 60 min daily, respectively, for 4 weeks. β-glucan was administered via gavage at a dose of 50 mg/kg/day before each exposure to radiation in the treatment group. The activities of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), as well as the concentration of malondialdehyde (MDA) were measured in tissue homogenates of the skin. Exposure to 2.45-GHz EMR caused a significant increase in MDA levels and CAT activity, while the activities of SOD and GSH-Px decreased in skin tissues. Systemic β-glucan significantly reversed the elevation of MDA levels and the reduction of SOD activities. β-glucan treatment also slightly enhanced the activity of CAT and prevented the depletion of GSH-Px activity caused by EMR, but not statistically significantly. The present study demonstrated the role of oxidative mechanisms in EMR-induced skin tissue damages and that β-glucan could ameliorate oxidative skin injury via its antioxidant properties.

  18. Wedelolactone protects human bronchial epithelial cell injury against cigarette smoke extract-induced oxidant stress and inflammation responses through Nrf2 pathway.

    PubMed

    Ding, Shumin; Hou, Xuefeng; Yuan, Jiarui; Tan, Xiaobin; Chen, Juan; Yang, Nan; Luo, Yi; Jiang, Ziyu; Jin, Ping; Dong, Zibo; Feng, Liang; Jia, Xiaobin

    2015-12-01

    Cigarette smoke is the leading cause of the development of various lung diseases including lung cancer through triggering oxidant stress and inflammatory responses which contributed to the lesions of normal human bronchial epithelial (NHBE) cell. Wedelolactone (WEL), a natural compound from Eclipta prostrata L., has been found to possess the inhibitive effects on the proliferation and growth of cancers. In the present study, we investigated the effects of WEL on NHBE cell injury induced by cigarette smoke extract (CSE) in vitro. It showed that the pretreatment WEL (2.5-20μM) resulted in a significant protective effect on 10% CSE-induced cell death in NHBE cells. The pretreatment with WEL dose-dependently and significantly reversed the activities of SOD, CAT, GSH and the level of MDA to normal level. We also found that the protein expression levels of COX-2 and ICAM-1 which are related to inflammatory response were remarkably reduced by WEL compared with 10% CSE treatment. Additionally, WEL also reduced the expressions of antioxidases including NAD(P)H dehydrogenase:Quinone 1 (NQO1) and heme oxygenase-1 (HO-1). Moreover, Nrf2 inhibitor all-trans-retinoic acid (ATRA) decreased remarkably their expressions. These results suggest that WEL protects NHBE cell against CSE-induced injury through modulating Nrf2 pathway. Our study indicates that WEL may be a new potential protective agent against CSE-induced lung injury.

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

    PubMed

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

    2016-10-01

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

  20. Asbestos-induced endothelial cell activation and injury. Demonstration of fiber phagocytosis and oxidant-dependent toxicity.

    PubMed

    Garcia, J G; Gray, L D; Dodson, R F; Callahan, K S

    1988-10-01

    Vascular endothelial cell injury is important in the development of a variety of chronic interstitial lung disorders. However, the involvement of such injury in the inflammatory response associated with the inhalation of asbestos fibers is unclear and the mechanism of asbestos fiber cytotoxicity remains unknown. In the present study, human umbilical vein endothelial cells were challenged with amosite asbestos and several parameters of cellular function were examined. Electron microscopic examination revealed that endothelial cell exposure to asbestos resulted in active phagocytosis of these particulates. Biochemical evidence of dose-dependent asbestos-mediated endothelial cell activation was indicated by increased metabolism of arachidonic acid. For example, amosite asbestos (500 micrograms/ml) produced a ninefold increase in prostacyclin (PGI2) levels over those levels in non-exposed cells. Incubation of human endothelial cells with asbestos fibers induced specific 51Cr release in both a dose- and time-dependent fashion indicative of cellular injury. Injury induced by amosite asbestos was not significantly attenuated by treatment of the endothelial cell monolayer with either the iron chelator deferoxamine, which prevents hydroxyl radical (.OH) formation, or by the superoxide anion (O2-) scavenger, superoxide dismutase. However, significant dose-dependent protection was observed with the hydrogen peroxide (H2O2) scavenger, catalase. Chelation of elemental iron present within amosite asbestos fibers by deferoxamine produced a 33% reduction in asbestos cytotoxicity, suggesting a potential role for hydroxyl radical-mediated injury via the iron-catalyzed Haber-Weiss reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Hepatoprotective Effects of Antrodia cinnamomea: The Modulation of Oxidative Stress Signaling in a Mouse Model of Alcohol-Induced Acute Liver Injury

    PubMed Central

    Liu, Yange; Wang, Juan; Li, Lanzhou; Hu, Wenji; Qu, Yidi; Ding, Yipei; Meng, Lina

    2017-01-01

    In the present study, the components of A. cinnamomea (AC) mycelia were systematically analyzed. Subsequently, its hepatoprotective effects and the underlying mechanisms were explored using a mouse model of acute alcohol-induced liver injury. AC contained 25 types of fatty acid, 16 types of amino acid, 3 types of nucleotide, and 8 types of mineral. The hepatoprotective effects were observed after 2 weeks of AC treatment at doses of 75 mg/kg, 225 mg/kg, and 675 mg/kg in the mouse model. These effects were indicated by the changes in the levels of aspartate aminotransferase, alanine aminotransferase, several oxidation-related factors, and inflammatory cytokines in serum and/or liver samples. AC reduced the incidence rate of necrosis, inflammatory infiltration, fatty droplets formation, and cell apoptosis in liver detecting via histological and TUNEL assay. In addition, AC reduced the expression of cleaved caspase-3, -8, and -9 and the levels of phosphor-protein kinase B (Akt) and phosphor-nuclear factor-κB (NF-κB) in the liver samples. Collectively, AC-mediated hepatoprotective effects in a mouse model of acute alcohol-induced liver injury are the result of reduction in oxidative stress. This may be associated with Akt/NF-κB signaling. These results provide valuable evidence to support the use of A. cinnamomea as a functional food and/or medicine. PMID:28337253

  2. Gamma-Glutamylcysteine Ethyl Ester Protects against Cyclophosphamide-Induced Liver Injury and Hematologic Alterations via Upregulation of PPARγ and Attenuation of Oxidative Stress, Inflammation, and Apoptosis

    PubMed Central

    Alqahtani, Sultan

    2016-01-01

    Gamma-glutamylcysteine ethyl ester (GCEE) is a precursor of glutathione (GSH) with promising hepatoprotective effects. This investigation aimed to evaluate the hepatoprotective effects of GCEE against cyclophosphamide- (CP-) induced toxicity, pointing to the possible role of peroxisome proliferator activated receptor gamma (PPARγ). Wistar rats were given GCEE two weeks prior to CP. Five days after CP administration, animals were sacrificed and samples were collected. Pretreatment with GCEE significantly alleviated CP-induced liver injury by reducing serum aminotransferases, increasing albumin, and preventing histopathological and hematological alterations. GCEE suppressed lipid peroxidation and nitric oxide production and restored GSH and enzymatic antioxidants in the liver, which were associated with downregulation of COX-2, iNOS, and NF-κB. In addition, CP administration significantly increased serum proinflammatory cytokines and the expression of liver caspase-3 and BAX, an effect that was reversed by GCEE. CP-induced rats showed significant downregulation of PPARγ which was markedly upregulated by GCEE treatment. These data demonstrated that pretreatment with GCEE protected against CP-induced hepatotoxicity, possibly by activating PPARγ, preventing GSH depletion, and attenuating oxidative stress, inflammation, and apoptosis. Our findings point to the role of PPARγ and suggest that GCEE might be a promising agent for the prevention of CP-induced liver injury. PMID:28074115

  3. Activation of Na(+)-K(+)-ATPase with DRm217 attenuates oxidative stress-induced myocardial cell injury via closing Na(+)-K(+)-ATPase/Src/Ros amplifier.

    PubMed

    Yan, Xiaofei; Xun, Meng; Dou, Xiaojuan; Wu, Litao; Zhang, Fujun; Zheng, Jin

    2017-04-01

    Reduced Na(+)-K(+)-ATPase activity has close relationship with cardiomyocyte death. Reactive oxygen species (ROS) also plays an important role in cardiac cell damage. It has been proved that Na(+)-K(+)-ATPase and ROS form a feed-forward amplifier. The aim of this study was to explore whether DRm217, a proved Na(+)/K(+)-ATPase's DR-region specific monoclonal antibody and direct activator, could disrupt Na(+)-K(+)-ATPase/ROS amplifier and protect cardiac cells from ROS-induced injury. We found that DRm217 protected myocardial cells against hydrogen peroxide (H2O2)-induced cardiac cell injury and mitochondrial dysfunction. DRm217 also alleviated the effect of H2O2 on inhibition of Na(+)-K(+)-ATPase activity, Na(+)-K(+)-ATPase cell surface expression, and Src phosphorylation. H2O2-treatment increased intracellular ROS, mitochondrial ROS and induced intracellular Ca(2+), mitochondrial Ca(2+) overload. DRm217 closed Na(+)-K(+)-ATPase/ROS amplifier, alleviated Ca(2+) accumulation and finally inhibited ROS and mitochondrial ROS generation. These novel results may help us to understand the important role of the Na(+)-K(+)-ATPase in oxidative stress and oxidative stress-related disease.

  4. Identifying the Long-Term Role of Inducible Nitric Oxide Synthase after Contusive Spinal Cord Injury Using a Transgenic Mouse Model

    PubMed Central

    Maggio, Dominic M.; Singh, Amanpreet; Iorgulescu, J. Bryan; Bleicher, Drew H.; Ghosh, Mousumi; Lopez, Michael M.; Tuesta, Luis M.; Flora, Govinder; Dietrich, W. Dalton; Pearse, Damien D.

    2017-01-01

    Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study investigated the effects of chronic iNOS ablation after SCI using inos-null mice. iNOS−/− knockout and wild-type (WT) control mice underwent a moderate thoracic (T8) contusive SCI. Locomotor function was assessed weekly, using the Basso Mouse Scale (BMS), and at the endpoint (six weeks), by footprint analysis. At the endpoint, the volume of preserved white and gray matter, as well as the number of dorsal column axons and perilesional blood vessels rostral to the injury, were quantified. At weeks two and three after SCI, iNOS−/− mice exhibited a significant locomotor improvement compared to WT controls, although a sustained improvement was not observed during later weeks. At the endpoint, iNOS−/− mice showed significantly less preserved white and gray matter, as well as fewer dorsal column axons and perilesional blood vessels, compared to WT controls. While short-term antagonism of iNOS provides histological and functional benefits, its long-term ablation after SCI may be deleterious, blocking protective or reparative processes important for angiogenesis and tissue preservation. PMID:28125047

  5. Cardioprotective effects of Notoginsenoside R1 against ischemia/reperfusion injuries by regulating oxidative stress- and endoplasmic reticulum stress- related signaling pathways

    PubMed Central

    Yu, Yingli; Sun, Guibo; Luo, Yun; Wang, Min; Chen, Rongchang; Zhang, Jingyi; Ai, Qidi; Xing, Na; Sun, Xiaobo

    2016-01-01

    Background: Recent reports suggested the involvement of oxidative stress- and endoplasmic reticulum stress (ERS)-associated pathways in the progression of ischemia/reperfusion (I/R) injury. Notoginsenoside R1 (NGR1) is a novel saponin isolated from P. notoginseng, which has a history of prevention and treatment of cardiovascular diseases. Objective: We aimed to examine the cardioprotective effects of NGR1 on I/R-induced heart dysfunction ex vivo and in vitro. Methods: H9c2 cadiomyocytes were incubated with NGR1 for 24 h and exposed to hypoxia/reoxygenation. Isolated rat hearts were perfused by NGR1 for 15 min and then subjected to global ischemia/reperfusion. Hemodynamic parameters were monitored as left ventricular systolic pressure (LVSP), heart rate, and maximal rate of increase and decrease of left ventricular pressure (±dP/dt max/min). Results: NGR1 pretreatment prevents cell apoptosis and delays the onset of ERS by decreasing the protein expression levels of ERS-responsive proteins GRP78, P-PERK, ATF6, IRE, and inhibiting the expression of pro-apoptosis proteins CHOP, Caspase-12, and P-JNK. Besides, NGR1 scavenges free radical, and increases the activity of antioxidase. NGR1 inhibits Tunicamycin-induced cell death and cardic dysfunction. Conclusion: We elucidated the significant cardioprotective effects of NGR1 against I/R injuries, and demonstrated the involvement of oxidative stress and ERS in the protective effects of NGR1. PMID:26888485

  6. BNC Protects H9c2 Cardiomyoblasts from H2O2-Induced Oxidative Injury through ERK1/2 Signaling Pathway

    PubMed Central

    Huang, Bin; Zhao, Ye; Tang, Shihuan; Wang, Lan; Liang, Rixin

    2013-01-01

    Buchang naoxintong capsule (BNC) is a traditional Chinese medicine approved for the treatment of cerebrovascular and cardiovascular diseases. However, little is known about the specific protective function or mechanism by which BNC protects against myocardial injury. This research was designed to investigate the cardioprotective effects of BNC in vitro model of hydrogen peroxide (H2O2)-induced H9c2 rat cardiomyoblasts. BNC intestinal absorption liquid was used in this study instead of drug-containing serum or extracting solution. Our study revealed that BNC preconditioning enhanced antioxidant function by increasing the activities of total-antioxygen capacity, total-superoxide dismutase, and catalase and by decreasing the production of reactive oxygen species and malondialdehyde. BNC preconditioning also activated extracellular signal-regulated kinases (ERK1/2) and inhibited apoptosis-related proteins such as poly ADP-ribose polymerase (PARP) and caspase-3. Additionally, preincubation with BNC reduced intracellular Ca2+ concentration, improved mitochondrial membrane potential, and decreased the apoptosis rate of H9c2 cells in a dose-dependent manner. These data demonstrated that BNC protects H9c2 cardiomyoblasts from H2O2-induced oxidative injury by increasing antioxidant abilities, activating ERK1/2, and blocking Ca2+-dependent and mitochondria-mediated apoptosis. Based on our results, the potency of BNC for protecting H9c2 cells from oxidative damage is comparable to that of trimetazidine. PMID:24223618

  7. NAP prevents acute cerebral oxidative stress and protects against long-term brain injury and cognitive impairment in a model of neonatal hypoxia-ischemia.

    PubMed

    Greggio, Samuel; de Paula, Simone; de Oliveira, Iuri M; Trindade, Cristiano; Rosa, Renato M; Henriques, João A P; DaCosta, Jaderson C

    2011-10-01

    Hypoxia-ischemia (HI) is a common cause of neonatal brain damage with lifelong morbidities in which current therapies are limited. In this study, we investigated the effect of neuropeptide NAP (NAPVSIPQ) on early cerebral oxidative stress, long-term neurological function and brain injury after neonatal HI. Seven-day-old rat pups were subjected to an HI model by applying a unilateral carotid artery occlusion and systemic hypoxia. The animals were randomly assigned to groups receiving an intraperitoneal injection of NAP (3 μg/g) or vehicle immediately (0 h) and 24 h after HI. Brain DNA damage, lipid peroxidation and reduced glutathione (GSH) content were determined 24 h after the last NAP injection. Cognitive impairment was assessed on postnatal day 60 using the spatial version of the Morris water maze learning task. Next, the animals were euthanized to assess the cerebral hemispheric volume using the Cavalieri principle associated with the counting point method. We observed that NAP prevented the acute HI-induced DNA and lipid membrane damage and also recovered the GSH levels in the injured hemisphere of the HI rat pups. Further, NAP was able to prevent impairments in learning and long-term spatial memory and to significantly reduce brain damage up to 7 weeks following the neonatal HI injury. Our findings demonstrate that NAP confers potent neuroprotection from acute brain oxidative stress, long-term cognitive impairment and brain lesions induced by neonatal HI through, at least in part, the modulation of the glutathione-mediated antioxidant system.

  8. Protective action of the immunomodulator ginsan against carbon tetrachloride-induced liver injury via control of oxidative stress and the inflammatory response

    SciTech Connect

    Shim, Ji-Young; Kim, Mi-Hyoung; Kim, Hyung-Doo; Ahn, Ji-Yeon; Yun, Yeon-Sook; Song, Jie-Young

    2010-02-01

    The aim of the present study was to evaluate immunomodulator ginsan, a polysaccharide extracted from Panax ginseng, on carbon tetrachloride (CCl{sub 4})-induced liver injury. BALB/c mice were injected i.p. with ginsan 24 h prior to CCl{sub 4} administration. Serum liver enzyme levels, histology, expression of antioxidant enzymes, and several cytokines/chemokines were subsequently evaluated. Ginsan treatment markedly suppressed the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and hepatic histological necrosis increased by CCl{sub 4} treatment. Ginsan inhibited CCl{sub 4} induced lipid peroxidation through the cytochrome P450 2E1 (CYP2E1) downregulation. The hepatoprotective effect of ginsan was attributed to induction of anti-oxidant protein contents, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) as well as restoration of the hepatic glutathione (GSH) concentration. The marked increase of proinflammatory cytokines (IL-1beta, IFN-gamma) and chemokines (MCP-1, MIP-2beta, KC) in CCl{sub 4} treated mice was additionally attenuated by ginsan, thereby preventing leukocyte infiltration and local inflammation. Our results suggest that ginsan effectively prevent liver injury, mainly through downregulation of oxidative stress and inflammatory response.

  9. Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity.

    PubMed

    McGill, Mitchell R; Williams, C David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut

    2012-11-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity.

  10. Suppression of the inducible form of nitric oxide synthase prior to traumatic brain injury improves cytochrome c oxidase activity and normalizes cellular energy levels.

    PubMed

    Hüttemann, M; Lee, I; Kreipke, C W; Petrov, T

    2008-01-02

    We have previously shown that the observed immediate increase in nitric oxide (NO) plays a significant role in the control of the cerebral microcirculation following traumatic brain injury (TBI). However, a second consequence of increased NO production after TBI may be impaired mitochondrial function, due to the fact that NO is a well-known inhibitor of cytochrome c oxidase (CcO). CcO is a key enzyme of the mitochondrial oxidative phosphorylation (OxPhos) machinery, which creates cellular energy in the form of ATP. NO competes with oxygen at the heme a(3)-Cu(B) reaction center of CcO. We thus hypothesized that TBI triggers inhibition of CcO, which would in turn lead to a decreased energy production by OxPhos at a time of an elevated energy demand for tissue remodeling. Here we show that TBI as induced by an acceleration weight drop model of diffuse brain injury in rats leads to CcO inhibition and dramatically decreased ATP levels in brain cortex. CcO inhibition can be partially restored by application of iNOS antisense oligonucleotides prior to TBI, which leads to a normalization of ATP levels similar to the controls. We propose that a lack of energy after TBI caused by inhibition of CcO is an important aspect of trauma pathology.

  11. 3,4-Dihydroxyphenylethanol alleviates early brain injury by modulating oxidative stress and Akt and nuclear factor-κB pathways in a rat model of subarachnoid hemorrhage

    PubMed Central

    FU, PENG; HU, QUAN

    2016-01-01

    3,4-Dihydroxyphenylethanol (DOPET) is a naturally occurring polyphenolic compound, present in olive oil and in the wastewater generated during olive oil processing. DOPET has various biological and pharmacological activities, including anticancer, antibacterial and anti-inflammatory effects. This study was designed to determine whether DOPET alleviates early brain injury (EBI) associated with subarachnoid hemorrhage (SAH) through suppression of oxidative stress and Akt and nuclear factor (NF)-κB pathways. Rats were randomly divided into the following groups: Sham group, SAH group, SAH + vehicle group and SAH + DOPET group. Mortality, blood-brain barrier (BBB) permeability and brain water content were assessed. Oxidative stress, Akt, NF-κB p65 and caspase-3 assays were also performed. DOPET induced a reduction in brain water content, and decreased the BBB permeability of SAH model rats. Furthermore, DOPET effectively controlled oxidative stress, NF-κB p65 and caspase-3 levels, in addition to significantly increasing Akt levels in the cortex following SAH. These results provide evidence that DOPET attenuates apoptosis in a rat SAH model through modulating oxidative stress and Akt and NF-κB signaling pathways. PMID:27168841

  12. NecroX-5 protects mitochondrial oxidative phosphorylation capacity and preserves PGC1α expression levels during hypoxia/reoxygenation injury

    PubMed Central

    Thu, Vu Thi; Kim, Hyoung Kyu; Long, Le Thanh; Nyamaa, Bayalagmaa; Song, In-Sung; Thuy, To Thanh; Huy, Nguyen Quang; Marquez, Jubert; Kim, Soon Ha; Kim, Nari; Ko, Kyung Soo; Rhee, Byoung Doo

    2016-01-01

    Although the antioxidant and cardioprotective effects of NecroX-5 on various in vitro and in vivo models have been demonstrated, the action of this compound on the mitochondrial oxidative phosphorylation system remains unclear. Here we verify the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity during hypoxia-reoxygenation (HR). Necrox-5 treatment (10 µM) and non-treatment were employed on isolated rat hearts during hypoxia/reoxygenation treatment using an ex vivo Langendorff system. Proteomic analysis was performed using liquid chromatography-mass spectrometry (LC-MS) and non-labeling peptide count protein quantification. Real-time PCR, western blot, citrate synthases and mitochondrial complex activity assays were then performed to assess heart function. Treatment with NecroX-5 during hypoxia significantly preserved electron transport chain proteins involved in oxidative phosphorylation and metabolic functions. NecroX-5 also improved mitochondrial complex I, II, and V function. Additionally, markedly higher peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC1α) expression levels were observed in NecroX-5-treated rat hearts. These novel results provide convincing evidence for the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity and in preserving PGC1α during cardiac HR injuries. PMID:26937217

  13. Comprehensive Profiling of Modulation of Nitric Oxide Levels and Mitochondrial Activity in the Injured Brain: An Experimental Study Based on the Fluid Percussion Injury Model in Rats.

    PubMed

    Üçal, Muammer; Kraitsy, Klaus; Weidinger, Adelheid; Paier-Pourani, Jamile; Patz, Silke; Fink, Bruno; Molcanyi, Marek; Schäfer, Ute

    2017-01-15

    Nitric oxide (NO) has frequently been associated with secondary damage after brain injury. However, average NO levels in different brain regions before and after traumatic brain injury (TBI) and its role in post-TBI mitochondrial dysfunction remain unclear. In this comprehensive profiling study, we demonstrate for the first time that basal NO levels vary significantly in the healthy cortex (0.44 ± 0.04 μM), hippocampus (0.26 ± 0.03 μM), and cerebellum (1.24 ± 0.08 μM). Within 4 h of severe lateral fluid percussion injury, NO levels almost doubled in these regions, thereby preserving regional differences in NO levels. TBI-induced NO generation was associated with inducible NO synthase (iNOS) increase in ipsilateral but not in contralateral regions. The transient NO increase resulted in a persistent tyrosine nitration adjacent to the injury site. Nitrosative stress-associated cell loss via apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necrosis were also observed in the ipsilateral cortex, despite high levels of NO in the contralateral cortex. NO-mediated impairment of mitochondrial state 3 respiration dependent on complex I substrates was transient and confined to the ipsilateral cortex. Our results demonstrate that NO dynamics and associated effects differ in various regions of the injured brain. A potential association between the observed mitochondrial electron flow through complex I, but not complex II, and the modulation of TBI induced NO levels in different brain regions has to be prospectively analyzed in more detail.

  14. Prostaglandin E2 reduces swine myocardial ischemia reperfusion injury via increased endothelial nitric oxide synthase and vascular endothelial growth factor expression levels

    PubMed Central

    Zhou, Ying; Yang, Peng; Li, Aili; Ye, Xiaojun; Ren, Shiyan; Li, Xianlun

    2017-01-01

    Prostaglandin E2 (PGE2) has been demonstrated to attenuate cardiac ischemia-reperfusion (I/R) injury. However, the underlying mechanism of PGE2 in cardiac I/R injury remains unknown. Upregulated expression levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were reported in acute myocardial infarction (AMI), and were demonstrated to diminish I/R injury. In the current study the involvement of VEGF and eNOS in the myocardial protective effect of PGE2 were investigated in a catheter-based porcine model of AMI. Twenty-two Chinese miniature pigs were randomized into sham-surgery (n=6), control (n=8) and PGE2 (n=8) groups. PGE2 (1 µg/kg) was injected from 10 min prior to left anterior descending occlusion up to 1 h after reperfusion in the PGE2 group. Subsequently, the hemodynamic parameters were evaluated. Thioflavin-S and Evans Blue double staining were performed to evaluate the extent of the myocardial reperfusion area (RA) and no-reflow area (NRA). Immunohistochemical and western blot analysis were used to evaluate protein expression levels of VEGF and eNOS. Left ventricular (LV) systolic pressure significantly improved and LV end-diastolic pressure significantly decreased in the PGE2 group when compared with the control group 2 h after occlusion and 3 h after reperfusion (P<0.05, respectively). The RA and NRA were smaller in the PGE2 group than in the control group (P<0.05, respectively). Furthermore, PGE2 treatment increased the myocardial content of VEGF and eNOS when compared with the control group (P<0.05, respectively). Thus, the results of the present study demonstrate the cardio-protective mechanisms of PGE2, which may protect the heart from I/R injury via enhancement of VEGF and eNOS expression levels. PMID:28357071

  15. Nitric oxide inhibits neointimal hyperplasia following vascular injury via differential, cell-specific modulation of SOD-1 in the arterial wall.

    PubMed

    Bahnson, Edward S M; Koo, Nathaniel; Cantu-Medellin, Nadiezhda; Tsui, Aaron Y; Havelka, George E; Vercammen, Janet M; Jiang, Qun; Kelley, Eric E; Kibbe, Melina R

    2015-01-30

    Superoxide (O2(•-)) promotes neointimal hyperplasia following arterial injury. Conversely, nitric oxide ((•)NO) inhibits neointimal hyperplasia through various cell-specific mechanisms, including redox regulation. What remains unclear is whether (•)NO exerts cell-specific regulation of the vascular redox environment following arterial injury to inhibit neointimal hyperplasia. Therefore, the aim of the present study was to assess whether (•)NO exerts cell-specific, differential modulation of O2(•-) levels throughout the arterial wall, establish the mechanism of such modulation, and determine if it regulates (•)NO-dependent inhibition of neointimal hyperplasia. In vivo, (•)NO increased superoxide dismutase-1 (SOD-1) levels following carotid artery balloon injury in a rat model. In vitro, (•)NO increased SOD-1 levels in vascular smooth muscle cells (VSMC), but had no effect on SOD-1 in endothelial cells or adventitial fibroblasts. This SOD-1 increase was associated with an increase in sod1 gene expression, increase in SOD-1 activity, and decrease in O2(•-) levels. Lastly, to determine the role of SOD-1 in (•)NO-mediated inhibition of neointimal hyperplasia, we performed the femoral artery wire injury model in wild type and SOD-1 knockout (KO) mice, with and without (•)NO. Interestingly, (•)NO inhibited neointimal hyperplasia only in wild type mice, with no effect in SOD-1 KO mice. In conclusion, these data show the cell-specific modulation of O2(•-) by (•)NO through regulation of SOD-1 in the vasculature, highlighting its importance on the inhibition of neointimal hyperplasia. These results also shed light into the mechanism of (•)NO-dependent redox balance, and suggest a novel VSMC redox target to prevent neointimal hyperplasia.

  16. The effect of a spinal cord hemisection on changes in nitric oxide synthase pools in the site of injury and in regions located far away from the injured site.

    PubMed

    Lukácová, Nadezda; Kolesárová, Mária; Kuchárová, Karolína; Pavel, Jaroslav; Kolesár, Dalibor; Radonák, Jozef; Marsala, Martin; Chalimoniuk, Malgorzata; Langfort, Jozef; Marsala, Jozef

    2006-01-01

    1. The present study was designed to examine the nitric oxide synthase activities (constitutive and inducible) in the site of injury in response to Th10-Th11 spinal cord hemisection and, to determine whether unilateral disconnection of the spinal cord influences the NOS pools on the contra- and ipsilateral sides in segments located far away from the epicentre of injury. 2. A radioassay detection was used to determine Ca(2+)-dependent and inducible nitric oxide synthase activities. Somal, axonal and neuropil neuronal nitric oxide synthase was assessed by immunocytochemical study. A quantitative assessment of neuronal nitric oxide synthase immunoreactivity was made by an image analyser. The level of neuronal nitric oxide synthase protein was measured by the Western blot analysis. 3. Our data show the increase of inducible nitric oxide synthase activity and a decrease of Ca(2+)-dependent nitric oxide synthase activity in the injured site analysed 1 and 7 days after surgery. In segments remote from the epicentre of injury the inducible nitric oxide synthase activity was increased at both time points. Ca(2+)-dependent nitric oxide synthase activity had decreased in L5-S1 segments in a group of animals surviving for 7 days. A hemisection performed at thoracic level did not cause significant difference in the nitric oxide synthase activities and in the level of neuronal nitric oxide synthase protein between the contra- and ipsilateral sides in C6-Th1 and L5-S1 segments taken as a whole. Significant differences were observed, but only when the spinal cord was analysed segment by segment, and/or was divided into dorsal and ventral parts. The cell counts in the cervicothoracic (C7-Th1) and lumbosacral (L5-S1) enlargements revealed changes in neuronal nitric oxide synthase immunoreactivity on the ipsilateral side of the injury. The densitometric area measurements confirmed the reduction of somal, neuropil and axonal neuronal nitric oxide synthase immunoreactive staining in

  17. The let-7 microRNA enhances heme oxygenase-1 by suppressing Bach1 and attenuates oxidant injury in human hepatocytes.

    PubMed

    Hou, Weihong; Tian, Qing; Steuerwald, Nury M; Schrum, Laura W; Bonkovsky, Herbert L

    2012-01-01

    The let-7 microRNA (miRNA) plays important roles in human liver development and diseases such as hepatocellular carcinoma, liver fibrosis and hepatitis wherein oxidative stress accelerates the progression of these diseases. To date, the role of the let-7 miRNA family in modulation of heme oxygenase 1 (HMOX1), a key cytoprotective enzyme, remains unknown. Our aims were to determine whether let-7 miRNA directly regulates Bach1, a transcriptional repressor of the HMOX1 gene, and whether indirect up-regulation of HMOX1 by let-7 miRNA attenuates oxidant injury in human hepatocytes. The effects of let-7 miRNA on Bach1 and HMOX1 gene expression in Huh-7 and HepG2 cells were determined by real-time qRT-PCR, Western blot, and luciferase reporter assays. Dual luciferase reporter assays revealed that let-7b, let-7c, or miR-98 significantly decreased Bach1 3'-untranslated region (3'-UTR)-dependent luciferase activity but not mutant Bach1 3'-UTR-dependent luciferase activity, whereas mutant let-7 miRNA containing base complementarity with mutant Bach1 3'-UTR restored its effect on mutant reporter activity. let-7b, let-7c, or miR-98 down-regulated Bach1 protein levels by 50-70%, and subsequently up-regulated HMOX1 gene expression by 3-4 fold, compared with non-specific controls. Furthermore, Huh-7 cells transfected with let-7b, let-7c or miR-98 mimic showed increased resistance against oxidant injury induced by tert-butyl-hydroperoxide (tBuOOH), whereas the protection was abrogated by over-expression of Bach1. In conclusion, let-7 miRNA directly acts on the 3'-UTR of Bach1 and negatively regulates expression of this protein, and thereby up-regulates HMOX1 gene expression. Over-expression of the let-7 miRNA family members may represent a novel approach to protecting human hepatocytes from oxidant injury.

  18. Hypericum perforatum Attenuates Spinal Cord Injury-Induced Oxidative Stress and Apoptosis in the Dorsal Root Ganglion of Rats: Involvement of TRPM2 and TRPV1 Channels.

    PubMed

    Özdemir, Ümit Sinan; Nazıroğlu, Mustafa; Şenol, Nilgün; Ghazizadeh, Vahid

    2016-08-01

    Oxidative stress and cytosolic Ca(2+) overload have important roles on apoptosis in dorsal root ganglion (DRG) neurons after spinal cord injury (SCI). Hypericum perforatum (HP) has an antioxidant property in the DRGs due to its ability to modulate NADPH oxidase and protein kinase C pathways. We aimed to investigate the protective property of HP on oxidative stress, apoptosis, and Ca(2+) entry through transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) channels in SCI-induced DRG neurons of rats. Rats were divided into four groups as control, HP, SCI, and SCI + HP. The HP groups received 30 mg/kg HP for three concessive days after SCI induction. The SCI-induced TRPM2 and TRPV1 currents and cytosolic free Ca(2+) concentration were reduced by HP. The SCI-induced decrease in glutathione peroxidase and cell viability values were ameliorated by HP treatment, and the SCI-induced increase in apoptosis, caspase 3, caspase 9, cytosolic reactive oxygen species (ROS) production, and mitochondrial membrane depolarization values in DRG of SCI group were overcome by HP treatment. In conclusion, we observed a protective role of HP on SCI-induced oxidative stress, apoptosis, and Ca(2+) entry through TRPM2 and TRPV1 in the DRG neurons. Our findings may be relevant to the etiology and treatment of SCI by HP. Graphical Abstract Possible molecular pathways of involvement of Hypericum perforatum (HP) on apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in DRG neurons of SCI-induced rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress through activation of ADP-ribose pyrophosphate although it was inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethyl diphenylborinate (2APB). The TRPV1 channel is activated by oxidative stress and capsaicin and it is blocked by capsazepine. Injury in the DRG can result in augmented ROS release, leading to Ca(2+) uptake through

  19. In vivo radioprotective effects of Nigella sativa L oil and reduced glutathione against irradiation-induced oxidative injury and number of peripheral blood lymphocytes in rats.

    PubMed

    Cemek, Mustafa; Enginar, Hüseyin; Karaca, Turan; Unak, Perihan

    2006-01-01

    Radiotherapy is one of the most common therapies for treating human cancers. Several studies have indicated that irradiation induces reactive oxygen species (ROS), which play an important role in radiation damage of the cell. It has been shown that Nigella sativa L. (NS) and reduced glutathione (GSH) have both an antiperoxidative effect on different tissues and a scavenger effect on ROS. The purpose of this study was to determine the antioxidant and radio-protective roles of NS and GSH against irradiation-induced oxidative injury in an experimental model. The NS group was administrated NS (1 mL/kg body weight), the GSH group was injected GSH (150 mg/kg body weight) and the control group was given physiologic saline solution (1 mL/kg body weight) for 30 consecutive days before exposure to a single dose of 6 Gy of radiation. Animals were sacrificed after irradiation. Malondialdehyde, nitrate, nitrite (oxidative stress markers) and ascorbic acid, retinol, beta-carotene, GSH and ceruloplasmin (nonenzymatic antioxidant markers) levels and peripheral blood lymphocytes were measured in all groups. There were statistically significant differences between the groups for all parameters (P < 0.05). Whole-body irradiation caused a significant increase in blood malondialdehyde, nitrate and nitrite levels. The blood oxidative stress marker levels in irradiated rats that were pretreated with NS and GSH were significantly decreased; however, non-enzymatic antioxidant levels were significantly increased. Also, our results suggest that NS and GSH administration prior to irradiation prevent the number of alpha-naphthyl acetate esterase peripheral blood T lymphocytes from declining. These results clearly show that NS and GSH treatment significantly antagonize the effects of radiation. Therefore, NS and GSH may be a beneficial agent in protection against ionizing radiation-related tissue injury.

  20. The hepatocurative effects of Cynara scolymus L. leaf extract on carbon tetrachloride-induced oxidative stress and hepatic injury in rats.

    PubMed

    Colak, Emine; Ustuner, Mehmet Cengiz; Tekin, Neslihan; Colak, Ertugrul; Burukoglu, Dilek; Degirmenci, Irfan; Gunes, Hasan Veysi

    2016-01-01

    Cynara scolymus is a pharmacologically important medicinal plant containing phenolic acids and flavonoids. Experimental studies indicate antioxidant and hepatoprotective effects of C. scolymus but there have been no studies about therapeutic effects of liver diseases yet. In the present study, hepatocurative effects of C. scolymus leaf extract on carbon tetrachloride (CCl4)-induced oxidative stress and hepatic injury in rats were investigated by serum hepatic enzyme levels, oxidative stress indicator (malondialdehyde-MDA), endogenous antioxidants, DNA fragmentation, p53, caspase 3 and histopathology. Animals were divided into six groups: control, olive oil, CCl4, C. scolymus leaf extract, recovery and curative. CCl4 was administered at a dose of 0.2 mL/kg twice daily on CCl4, recovery and curative groups. Cynara scolymus extract was given orally for 2 weeks at a dose of 1.5 g/kg after CCl4 application on the curative group. Significant decrease of serum alanine-aminotransferase (ALT) and aspartate-aminotransferase (AST) levels were determined in the curative group. MDA levels were significantly lower in the curative group. Significant increase of superoxide dismutase (SOD) and catalase (CAT) activity in the curative group was determined. In the curative group, C. scolymus leaf extract application caused the DNA % fragmentation, p53 and caspase 3 levels of liver tissues towards the normal range. Our results indicated that C. scolymus leaf extract has hepatocurative effects of on CCl4-induced oxidative stress and hepatic injury by reducing lipid peroxidation, providing affected antioxidant systems towards the normal range. It also had positive effects on the pathway of the regulatory mechanism allowing repair of DNA damage on CCl4-induced hepatotoxicity.

  1. Mechanism of phytoestrogen puerarin-mediated cytoprotection following oxidative injury: Estrogen receptor-dependent up-regulation of PI3K/Akt and HO-1

    SciTech Connect

    Hwang, Yong Pil; Jeong, Hye Gwang

    2008-12-15

    Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. The phytoestrogen puerarin, the main isoflavone glycoside found in the root of Pueraria lobata, has been used for various medicinal purposes in traditional Chinese medicines for thousands of years. Recent studies have indicated that the estrogen receptor (ER), through interaction with p85, regulates phosphoinositide 3-kinase (PI3K) activity, revealing a physiologic, non-nuclear function of ER that may be relevant in cytoprotection. In this study, we demonstrate that the phytoestrogen puerarin inhibits tert-butyl hydroperoxide (t-BHP)-induced oxidative injury via an ER-dependent G{beta}1/PI3K/Akt and heme oxygenase-1 (HO-1) pathway. Pretreatment of Hepa1c1c7 and HepG2 cells with puerarin significantly reduced t-BHP-induced caspase-3 activation and subsequent cell death. Also, puerarin up-regulated HO-1 expression and this expression conferred cytoprotection against oxidative injury induced by t-BHP. Moreover, puerarin induced Nrf2 nuclear translocation, which is upstream of puerarin-induced HO-1 expression, and PI3K activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. Puerarin-induced up-regulation of HO-1 and cytoprotection against t-BHP were abolished by silencing Nrf2 expression with specific siRNA. Also, puerarin-mediated increases in PI3K activation and HO-1 induction were reversed by co-treatment with ICI 182,780 and pertussis toxin. Taken together, these results suggest that puerarin augments cellular antioxidant defense capacity through ER-dependent HO-1 induction via the G{beta}1/PI3K/Akt-Nrf2 signaling pathway, thereby protecting cells from oxidative stress.

  2. Absence of malonyl coenzyme A decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Acute pharmacological inhibition of cardiac malonyl coenzyme A decarboxylase (MCD) protects the heart from ischemic damage by inhibiting fatty acid oxidation and stimulating glucose oxidation. However, it is unknown whether chronic inhibition of MCD results in altered cardiac function, energy metabo...

  3. Long-term high-fat diet induces pancreatic injuries via pancreatic microcirculatory disturbances and oxidative stress in rats with hyperlipidemia

    SciTech Connect

    Yan Mingxian; Li Yanqing . E-mail: mx8902@163.com; Meng Min; Ren Hongbo; Kou Yi

    2006-08-18

    Relations between hyperlipidemia and chronic pancreatitis remain unclear. Microcirculatory disturbances and oxidative stress are involved in pathogeneses of a high numbers of diseases. The objective of this study was to induce hyperlipidemia in rats by long-term high-fat diet intake, then investigate the biochemical, microcirculatory, and histological alterations in blood and pancreatic tissues of these animals, and discuss their potential significances. Pancreatic blood flow was detected by intravital microscope; malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured in pancreatic tissues for assessment of oxidative stress and {alpha}-smooth muscle actin ({alpha}-SMA) expression was determined by immunohistochemical staining and RT-PCR. The results showed that the velocity of pancreatic microvascular blood flow of rats with hyperlipidemia decreased significantly as compared to control value (p = 0.008). Pancreatic MDA content increased whereas SOD activity decreased in these rats (p = 0.022; p = 0.039, respectively). Histologically, microvesicles in acinar and islet cells, dilated rough endoplasmic reticulum, swollen mitochondrion and modified vascular endothelial cells were observed under light microscope and transmission electron microscope. In addition, {alpha}-SMA expression was up-regulated significantly (p < 0.05). These results suggest that long-term high-fat diet can induce chronic pancreatic injuries which could be considered as 'nonalcoholic fatty pancreatic disease', and pancreatic microcirculatory disturbances and oxidative stress may play an important part in the underlying pathogenesis.

  4. An oral absorbent, surface-deacetylated chitin nano-fiber ameliorates renal injury and oxidative stress in 5/6 nephrectomized rats.

    PubMed

    Anraku, Makoto; Tabuchi, Ryo; Ifuku, Shinsuke; Nagae, Tomone; Iohara, Daisuke; Tomida, Hisao; Uekama, Kaneto; Maruyama, Toru; Miyamura, Shigeyuki; Hirayama, Fumitoshi; Otagiri, Masaki

    2017-04-01

    In this study, we report that surface-deacetylated chitin nano-fibers (SDACNFs) are more effective in decreasing renal injury and oxidative stress than deacetylated chitin powder (DAC) in 5/6 nephrectomized rats. An oral administration of low doses of SDACNFs (40mg/kg/day) over a 4 week period resulted in a significant decrease in serum indoxyl sulfate, creatinine and urea nitrogen levels, compared with a similar treatment with DAC or AST-120. The SDACNFs treatment also resulted in an increase in antioxidant potential, compared with that for DAC or AST-120. Immunohistochemical analyses also demonstrated that SDACNFs treated CRF rats showed a decrease in the amount of accumulated 8-OHdG compared with the CRF group. These results suggest that the ingestion of SDCH-NF results in a significant reduction in the levels of pro-oxidants, such as uremic toxins, in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation.

  5. EGFR mediates hyperlipidemia-induced renal injury via regulating inflammation and oxidative stress: the detrimental role and mechanism of EGFR activation

    PubMed Central

    Fang, Qilu; Zou, Chunpeng; Zhong, Peng; Lin, Feng; Li, Weixin; Wang, Lintao; Zhang, Yali; Zheng, Chao; Wang, Yi; Li, Xiaokun; Liang, Guang

    2016-01-01

    Previous studies have implicated inflammation, oxidative stress, and fibrosis as key factors in the development of obesity-induced kidney diseases. Epidermal growth factor receptor (EGFR) plays an important role in cancer development. Recently, the EGFR pathway has been increasingly implicated in chronic cardiovascular diseases via regulating inflammation and oxidative stress. However, it is unclear if EGFR is involved in obesity-related kidney injury. Using ApoE−/− and C57BL/6 mice models and two specific EGFR inhibitors, we investigated the potential effects of EGFR inhibition in the treatment of obesity-related nephropathy and found that EGFR inhibition alleviates renal inflammation, oxidative stress and fibrosis. In NRK-52E cells, we also elucidated the mechanism behind hyperlipidemia-induced EGFR activation. We observed that c-Src and EGFR forms a complex, and following PA stimulation, it is the successive phosphorylation, not formation, of the c-Src/EGFR complex that results in the subsequent cascade activation. Second, we found that TLR4 regulates the activation EGFR pathway mainly through the phosphorylation of the c-Src/EGFR complex. These results demonstrate the detrimental role of EGFR in the pathogenesis of obesity-related nephropathy, provide a new understanding of the mechanism behind hyperlipidemia/FFA-induced EGFR activation, and support the use of EGFR inhibitors in the treatment of obesity-induced kidney diseases. PMID:27014908

  6. Association of inflammatory response and oxidative injury in the pathogenesis of liver steatosis and insulin resistance following subchronic exposure to malathion in rats.

    PubMed

    Lasram, Mohamed Montassar; Dhouib, Ines Bini; Bouzid, Kahna; Lamine, Aicha Jrad; Annabi, Alya; Belhadjhmida, Nadia; Ahmed, Malika Ben; Fazaa, Saloua El; Abdelmoula, Jaouida; Gharbi, Najoua

    2014-09-01

    Insulin resistance and risk of type 2 diabetes are the most important complications following exposure to organophosphorous (OPs) pesticides. Regarding the importance of liver on metabolic pathways regulation, in particular blood glucose homeostasis, we focused on liver inflammation and oxidative damages in a subchronic model of toxicity by malathion. Adult male Wistar rats of body weight 200-250g were used for the study. Malathion (200mg/kg b.w./day) was administered to rats by oral intubation for 28 days. Glycemic and insulin resistance indices, markers of liver injury, markers of inflammation and oxidative stress were assessed. Malathion-treated rats showed increased glycemia, insulinemia and glycated hemoglobin level, HOMA-IR and HOMA-β indices, plasma activities of hepatocellular enzymes, lipid peroxidation index, CD3(+)/CD4(+) and CD3(+)/CD4(+) and pro-inflammatory cytokines when decreased antioxidant status in liver was noted. Most of our study indicates that malathion promotes insulin resistance, inflammation and Hepatosteatosis in subchronic model of exposure. On the basis of biochemical and molecular findings, it is concluded that insulin resistance induced by malathion occurs through oxidative stress and related pro-inflammatory markers in a way to result in a reduced function of insulin in liver cells.

  7. Protective effects of Tat-NQO1 against oxidative stress-induced HT-22 cell damage, and ischemic injury in animals

    PubMed Central

    Jo, Hyo Sang; Kim, Duk-Soo; Ahn, Eun Hee; Kim, Dae Won; Shin, Min Jea; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Yeo, Eun Ji; Choi, Yeon Joo; Yeo, Hyeon Ji; Chung, Christine Seok Young; Cho, Sung-Woo; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2016-01-01

    Oxidative stress is closely associated with various diseases and is considered to be a major factor in ischemia. NAD(P)H: quinone oxidoreductase 1 (NQO1) protein is a known antioxidant protein that plays a protective role in various cells against oxidative stress. We therefore investigated the effects of cell permeable Tat-NQO1 protein on hippocampal HT-22 cells, and in an animal ischemia model. The Tat-NQO1 protein transduced into HT-22 cells, and significantly inhibited against hydrogen peroxide (H2O2)-induced cell death and cellular toxicities. Tat-NQO1 protein inhibited the Akt and mitogen activated protein kinases (MAPK) activation as well as caspase-3 expression levels, in H2O2 exposed HT-22 cells. Moreover, Tat-NQO1 protein transduced into the CA1 region of the hippocampus of the animal brain and drastically protected against ischemic injury. Our results indicate that Tat-NQO1 protein exerts protection against neuronal cell death induced by oxidative stress, suggesting that Tat-NQO1 protein may potentially provide a therapeutic agent for neuronal diseases. PMID:27616357

  8. PPAR-γ activator induces neuroprotection in hypercholesterolemic rats subjected to global cerebral ischemia/reperfusion injury: in vivo and in vitro inhibition of oxidative stress.

    PubMed

    Al Rouq, Fawzia; El Eter, Eman

    2014-03-01

    Hypercholesterolemia (HC) and aging combine to increase the incidence of cerebrovascular disease through oxidative stress. Our investigation examined the effects of diet-induced hypercholesterolemia (2% for 8weeks) on the extent of brain injury in response to global cerebral ischemia/reperfusion (GCI/R) and the neuroprotective potentials of rosiglitazone in relation to oxidative stress. HC exacerbated the decline in the brain levels of GSH and the increase in MPO, proinflammatory markers and hippocampal lesions in response to GCI/R. HC rats receiving rosiglitazone, PPAR-γ agonist, demonstrated preservation of cell viability of CA1 hippocampal region and attenuation of brain edema. They also showed elevated levels of GSH and low levels of the other parameters similar to non-HC rats subjected to GCI/R. In vitro, rosiglitazone dose-dependently inhibited ROS generation by neutrophils. The results suggest exacerbation of brain lesions by HC in response to GCI/R. The neuroprotective therapeutic potentials of rosiglitazone are comparable to non-HC animals. Mechanisms of protection are possibly due to anti-oxidant, anti-inflammatory effects and scavenging properties of rosiglitazone. These results add to the beneficial therapeutic effects of rosiglitazone and its significance for age-associated diseases including hypercholesterolemia.

  9. Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: Molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor.

    PubMed

    Goldkorn, Tzipora; Filosto, Simone; Chung, Samuel

    2014-11-20

    Chronic obstructive pulmonary disease (COPD) and lung cancer are frequently caused by tobacco smoking. However, these diseases present opposite phenotypes involving redox signaling at the cellular level. While COPD is characterized by excessive airway epithelial cell death and lung injury, lung cancer is caused by uncontrolled epithelial cell proliferation. Notably, epidemiological studies have demonstrated that lung cancer incidence is significantly higher in patients who have preexisting emphysema/lung injury. However, the molecular link and common cell signaling events underlying lung injury diseases and lung cancer are poorly understood. This review focuses on studies of molecular mechanism(s) underlying smoking-related lung injury (COPD) and lung cancer. Specifically, the role of the ceramide-generating machinery during cigarette smoke-induced oxidative stress leading to both apoptosis and proliferation of lung epithelial cells is emphasized. Over recent years, it has been established that ceramide is a sphingolipid playing a major role in lung epithelia structure/function leading to lung injury in chronic pulmonary diseases. However, new and unexpected findings draw attention to its potential role in lung development, cell proliferation, and tumorigenesis. To address this dichotomy in detail, evidence is presented regarding several protein targets, including Src, p38 mitogen-activated protein kinase, and neutral sphingomyelinase 2, the major sphingomyelinase that controls ceramide generation during oxidative stress. Furthermore, their roles are presented not only in apoptosis and lung injury but also in enhancing cell proliferation, lung cancer development, and resistance to epidermal growth factor receptor-targeted therapy for treating lung cancer.

  10. The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo

    PubMed Central

    Khazim, Khaled; Gorin, Yves; Cavaglieri, Rita Cassia; Abboud, Hanna E.

    2013-01-01

    Podocyte injury, a major contributor to the pathogenesis of diabetic nephropathy, is caused at least in part by the excessive generation of reactive oxygen species (ROS). Overproduction of superoxide by the NADPH oxidase isoform Nox4 plays an important role in podocyte injury. The plant extract silymarin is attributed antioxidant and antiproteinuric effects in humans and in animal models of diabetic nephropathy. We investigated the effect of silybin, the active constituent of silymarin, in cultures of mouse podocytes and in the OVE26 mouse, a model of type 1 diabetes mellitus and diabetic nephropathy. Exposure of podocytes to high glucose (HG) increased 60% the intracellular superoxide production, 90% the NADPH oxidase activity, 100% the Nox4 expression, and 150% the number of apoptotic cells, effects that were completely blocked by 10 μM silybin. These in vitro observations were confirmed by similar in vivo findings. The kidney cortex of vehicle-treated control OVE26 mice displayed greater Nox4 expression and twice as much superoxide production than cortex of silybin-treated mice. The glomeruli of control OVE26 mice displayed 35% podocyte drop out that was not present in the silybin-treated mice. Finally, the OVE26 mice experienced 54% more pronounced albuminuria than the silybin-treated animals. In conclusion, this study demonstrates a protective effect of silybin against HG-induced podocyte injury and extends this finding to an animal model of diabetic nephropathy. PMID:23804455

  11. Effects of Maternal Exposure to Cadmium Oxide Nanoparticles During Pregnancy on Maternal and Offspring Kidney Injury Markers Using a Murine Model.

    PubMed

    Blum, Jason L; Edwards, Joshua R; Prozialeck, Walter C; Xiong, Judy Q; Zelikoff, Judith T

    2015-01-01

    Nanoparticles (NP) are pervasive in many areas of modern life, with little known about their potential toxicities. One commercially important NP is cadmium oxide (CdO), which is used to synthesize other Cd-containing NP, such as quantum dots. Cadmium (Cd) is a well-known nephrotoxicant, but the nephrotoxic potential of CdO NP remains unknown, particularly when exposure occurs during pregnancy. Therefore, pregnant CD-1 mice were used to examine the effects of inhaled CdO NP (230 μg CdO NP/m(3)) on maternal and neonatal renal function by examining urinary creatinine and urinary biomarkers of kidney injury, including kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL). Inhalation of CdO NP by dams produced a fivefold increase in urinary Kim-1 with no marked effect on urinary creatinine levels. Kim-1 mRNA expression peaked by gestational day (GD) 10.5, and NGAL expression increased from GD 10.5 to 17.5. In addition, histological analyses revealed proximal tubular pathology at GD 10.5. Neonatal Kim-1 mRNA expression rose between postnatal days (PND) 7 and 14, with mammary glands/milk being the apparent source of Cd for offspring. These studies demonstrate that, similar to what is seen with other Cd forms, Cd associated with inhaled CdO NP results in renal injury to both directly exposed dam and offspring. As commercial uses for nanotechnology continue to expand throughout the world, risks for unintentional exposure in the workplace increase. Given the large number of women in the industrial workforce, care needs to be taken to protect these already vulnerable populations.

  12. Chongcao-Shencha Attenuates Liver and Kidney Injury through Attenuating Oxidative Stress and Inflammatory Response in D-Galactose-Treated Mice

    PubMed Central

    Li, Cailan; Mo, Zhizhun; Xie, Jianhui; Xu, Lieqiang; Tan, Lihua; Luo, Dandan; Chen, Hanbin; Yang, Hongmei; Li, Yucui; Su, Ziren; Su, Zuqing

    2016-01-01

    The Chongcao-Shencha (CCSC), a Chinese herbal compound formula, has been widely used as food material and medicine for enhancing physical strength. The present study investigated the possible effect of CCSC in alleviating the liver and kidney injury in D-galactose- (D-gal-) treated mice and the underlying mechanism. Mice were given a subcutaneous injection of D-gal (200 mg/kg) and orally administered CCSC (200, 400, and 800 mg/kg) daily for 8 weeks. Results indicated that CCSC increased the depressed body weight and organ index induced by D-gal, ameliorated the histological deterioration, and decreased the levels of ALT, AST, BUN, and CRE as compared with D-gal group. Furthermore, CCSC not only elevated the activities of antioxidant enzymes SOD, CAT, and GPx but also upregulated the mRNA expression of SOD1, CAT, and GPx1, while decreasing the MDA level in D-gal-treated mice. Results of western blotting analysis showed that CCSC significantly inhibited the upregulation of expression of nuclear factor kappa B (NF-κB) p65, p-p65, p-IκBα, COX2, and iNOS and inhibited the downregulation of IκBα protein expression caused by D-gal. This study demonstrated that CCSC could attenuate the liver and kidney injury in D-gal-treated mice, and the mechanism might be associated with attenuating oxidative stress and inflammatory response. PMID:27340415

  13. Polyphenols from hawthorn peels and fleshes differently mitigate dyslipidemia, inflammation and oxidative stress in association with modulation of liver injury in high fructose diet-fed mice.

    PubMed

    Han, Xiao; Li, Wenfeng; Huang, Di; Yang, Xingbin

    2016-09-25

    Hawthorn ingestion is linked to health benefits due to the various polyphenols. The present study investigated the differential effects of polyphenols-enriched extracts from hawthorn fruit peels (HPP) and fleshes (HFP) against liver injury induced by high-fructose diet in mice. It was found that the main species of polyphenols in hawthorn was chlorogenic acid, epicatechin, rutin and hyperoside, and their contents in HPP were all higher than those in HFP. Administration of HPP was better than HFP to alleviate liver injury and hepatocyte apoptosis, reflected by the reduction of ALT, AST and ALP activities, as well as the ratio of Bax/Bcl-2 in mice. Meanwhile, HPP was also more effective than HFP to mitigate liver inflammation and oxidative stress by inhibiting inflammatory cytokine (TNF-α, IL-1 and IL-6) release, and elevating antioxidant enzyme activities and PPARα expression, while reducing Nrf-2 and ARE expression in mice. Interestingly, HPP-treated mice also showed the lower levels of TC, TG, LDL-C, VLDL-C and Apo-B, and the higher levels of HDL-C and Apo-A1 than HFP-treated mice via reducing FAS express. These results together with the histopathology of the liver with H&E and oil red O staining suggest that hawthorn fruit, especially its peel, is an excellent source of natural polyphenolic chemopreventive agents in the treatment of liver disorders.

  14. Mdivi-1 Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats, Possibly via Inhibition of Drp1-Activated Mitochondrial Fission and Oxidative Stress.

    PubMed

    Wu, Pei; Li, Yuchen; Zhu, Shiyi; Wang, Chunlei; Dai, Jiaxing; Zhang, Guang; Zheng, Bingjie; Xu, Shancai; Wang, Ligang; Zhang, Tongyu; Zhou, PeiQuan; Zhang, John H; Shi, Huaizhang

    2017-02-16

    Mdivi-1 is a selective inhibitor of mitochondrial fission protein, Drp1, and can penetrate the blood-brain barrier. Previous studies have shown that Mdivi-1 improves neurological outcomes after ischemia, seizures and trauma but it remains unclear whether Mdivi-1 can attenuate early brain injury after subarachnoid hemorrhage (SAH). We thus investigated the therapeutic effect of Mdivi-1 on early brain injury following SAH. Rats were randomly divided into four groups: sham; SAH; SAH + vehicle; and SAH + Mdivi-1. The SAH model was induced by standard intravascular perforation and all of the rats were subsequently sacrificed 24 h after SAH. Mdivi-1 (1.2 mg/kg) was administered to rats 30 min after SAH. We found that Mdivi-1 markedly improved neurologic deficits, alleviated brain edema and BBB permeability, and attenuated apoptotic cell death. Mdivi-1 also significantly reduced the expression of cleaved caspase-3, Drp1 and p-Drp1((Ser616)), attenuated the release of Cytochrome C from mitochondria, inhibited excessive mitochondrial fission, and restored the ultra-structure of mitochondria. Furthermore, Mdivi-1 reduced levels of MDA, 3-NT, and 8-OHdG, and improved SOD activity. Taken together, our data suggest that Mdivi-1 exerts neuroprotective effects against cell death induced by SAH and the underlying mechanism may be inhibition of Drp1-activated mitochondrial fission and oxidative stress.

  15. Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway.

    PubMed

    Gong, Juanjuan; Sun, Fumou; Li, Yihang; Zhou, Xiaoling; Duan, Zhenzhen; Duan, Fugang; Zhao, Lei; Chen, Hansen; Qi, Suhua; Shen, Jiangang

    2015-04-01

    Momordica charantia (MC) is a medicinal plant for stroke treatment in Traditional Chinese Medicine, but its active compounds and molecular targets are unknown yet. M. charantia polysaccharide (MCP) is one of the important bioactive components in MC. In the present study, we tested the hypothesis that MCP has neuroprotective effects against cerebral ischemia/reperfusion injury through scavenging superoxide (O2(-)), nitric oxide (NO) and peroxynitrite (ONOO(-)) and inhibiting c-Jun N-terminal protein kinase (JNK3) signaling cascades. We conducted experiments with in vivo global and focal cerebral ischemia/reperfusion rat models and in vitro oxygen glucose deprivation (OGD) neural cells. The effects of MCP on apoptotic cell death and infarction volume, the bioactivities of scavenging O2(-), NO and ONOO(-), inhibiting lipid peroxidation and modulating JNK3 signaling pathway were investigated. Major results are summarized as below: (1) MCP dose-dependently attenuated apoptotic cell death in neural cells under OGD condition in vitro and reduced infarction volume in ischemic brains in vivo; (2) MCP had directing scavenging effects on NO, O2(-) and ONOO(-) and inhibited lipid peroxidation; (3) MCP inhibited the activations of JNK3/c-Jun/Fas-L and JNK3/cytochrome C/caspases-3 signaling cascades in ischemic brains in vivo. Taken together, we conclude that MCP could be a promising neuroprotective ingredient of M. charantia and its mechanisms could be at least in part attributed to its antioxidant activities and inhibiting JNK3 signaling cascades during cerebral ischemia/reperfusion injury.

  16. Variation of plasma levels of endothelin, calcitonin gene-related peptide, nitric oxide, and malondialdehyde in acute myocardial ischemia reperfusion injury in a rabbit model.

    PubMed

    Zhao, Y B; Wang, Y Z; Yue, Y H; Zhao, W C; Feng, G X

    2015-05-25

    We examined the variation in plasma levels of endothelin (ET), calcitonin gene-related peptide (CGRP), nitric oxide (NO), and malondialdehyde (MDA), as well as superoxide dismutase (SOD) activity, in acute myocardial ischemia reperfusion injury in a rabbit model. Seventy rabbits were randomly assigned into 3 groups. Open-chest surgery (OCS) was performed for all rabbits. Group A (N = 20) received sham-surgery, group B (N = 25) was the reperfusion group, and group C (N = 25) was the infarction group. At 12 h after chest clo-sure, plasma ET levels in groups B and C were clearly increased, while CGRP levels were clearly decreased, particularly in group B. At 24 h after chest closure, ET levels were higher than before OCS, while there was no significant difference between groups B and C. ET in group B was decreased, while that in group C was increased at 12 h. No significant difference in CGRP was observed between 12 and 24 h after chest closure. NO levels in groups B and C at 12 h after chest closure were significantly decreased compared to those before OCS. NO levels in group B at 24, 48, and 72 h were significantly lower than those at 12 h, while those of group C were not significantly changed after 12 h. Dynamic monitoring and comparison of plasma levels of ET, CGRP, NO, and MDA as well as SOD activity revealed that appropriate intervention of these factors may reduce reperfusion injury.

  17. Schisandra Lignan Extract Protects against Carbon Tetrachloride-Induced Liver Injury in Mice by Inhibiting Oxidative Stress and Regulating the NF-κB and JNK Signaling Pathways

    PubMed Central

    Chen, Qingshan; Zhan, Qi; Li, Ying; Sun, Sen; Zhao, Liang

    2017-01-01

    Schisandra chinensis (S. chinensis) is a traditional Chinese herbal medicine widely used for the treatment of liver disease, whose main active components are lignans. However, the action mechanisms of the lignans in S. chinensis remain unclear. This study aimed to investigate the protective effect and related molecular mechanism of Schisandra lignan extract (SLE) against carbon tetrachloride- (CCl4-) induced acute liver injury in mice. Different doses of SLE at 50, 100, and 200 mg/kg were administered daily by gavage for 5 days before CCl4 treatment. The results showed that SLE significantly decreased the activities of serum ALT/AST and reduced liver pathologic changes induced by CCl4. Pretreatment with SLE not only decreased the content of MDA but increased SOD, GSH, and GSH-Px activities in the liver, suggesting that SLE attenuated CCl4-induced oxidative stress. The expression levels of inflammatory cytokines TNF-a, IL-1β, and IL-6 were decreased after oral administration of SLE, probably because lignans inhibited the NF-κB activity. Additionally, SLE also inhibited hepatocyte apoptosis by suppressing JNK activation and regulating Bcl-2/Bax signaling pathways. In conclusion, these results suggested that SLE prevented CCl4-induced liver injury through a combination of antioxidative stress, anti-inflammation, and antihepatocyte apoptosis and alleviated inflammation and apoptosis by regulating the NF-κB, JNK, and Bcl-2/Bax signaling pathways. PMID:28246539

  18. Peripheral Nerve and Brain Differ in Their Capacity to Resolve N,N-Diethyldithiocarbamate-mediated Elevations in Copper and Oxidative Injury

    PubMed Central

    Valentine, Holly L.; Viquez, Olga M.; Valentine, William M.

    2010-01-01

    Previous studies have demonstrated that N,N-diethyldithiocarbamate (DEDC) elevates copper and promotes oxidative stress within the nervous system. However, whether these effects resolve following cessation of exposure or have the potential to persist and result in cumulative injury has not been determined. In this study, an established model for DEDC myelin injury in the rat was used to determine whether copper levels, oxidative stress, and neuromuscular deficits resolve following the cessation of DEDC exposure. Rats were exposed to DEDC for 8 weeks and then either euthanized or maintained for 2, 6 or 12 weeks after cessation of exposure. At each time point copper levels were measured by inductively coupled mass spectrometry to assess the ability of sciatic nerve, brain, spinal cord and liver to eliminate excess copper post exposure. The protein expression levels of glutathione transferase alpha, heme oxygenase 1 and superoxide dismutase 1 in peripheral nerve and brain were also determined by western blot to assess levels of oxidative stress as a function of post exposure duration. As an initial assessment of the bioavailability of the excess copper in brain the protein expression levels of copper chaperone for superoxide dismutase 1, and prion protein were determined by western blot as a function of exposure and post exposure duration. Neuromuscular function in peripheral nerve was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. The data demonstrated that in peripheral nerve, copper levels and oxidative stress return to control levels within several weeks after cessation of exposure. Neuromuscular function also showed a trend towards pre-exposure values, although the resolution of myelin lesions was more delayed. In contrast, total copper and antioxidant enzyme levels remained significantly elevated in brain for longer post exposure periods. The persistence of effects observed in brain suggests

  19. Teduglutide, a glucagon-like peptide 2 analogue: a novel protective agent with anti-apoptotic and anti-oxidant properties in mice with lung injury.

    PubMed

    Arda-Pirincci, Pelin; Oztay, Fusun; Bayrak, Bertan Boran; Yanardag, Refiye; Bolkent, Sehnaz

    2012-12-01

    Teduglutide is a long-acting synthetic analogue of human glucagon-like peptide-2 (GLP-2). GLP-2 regulates cell proliferation and apoptosis as well as normal physiology in the gastrointestinal tract. In the present study, possible cytoprotective and reparative effects of teduglutide were analyzed on a mouse model with lung injury induced by tumor necrosis factor-alpha (TNF-α) and actinomycin D (Act D). BALB/c mice were divided into six groups: control mice (I), mice injected intraperitoneally with 15 μg/kg TNF-α (II), 800 μg/kg Act D (III), Act D 2 min prior to TNF-α administration with the same doses (IV), mice injected subcutaneously with 200 μg/kg teduglutide every 12h for 10 consecutive days (V), and mice given Act D 2 min prior to TNF-α administration on day 11 after receiving teduglutide for 10 days (VI). The TNF-α/Act D administration made the lung a sensitive organ to damage. Mice lung subjected to TNF-α/Act D were characterized by the disruption of alveolar wall, induced pulmonary endothelial/epithelial cell apoptosis and expression of active caspase-3. These mice exhibited an increase in lipid peroxidation, glutathione levels, and activities of myeloperoxidase, superoxide dismutase, catalase, glutathione peroxidase and xanthine oxidase, as well as reduced tissue factor and sodium-potassium/ATPase activities. Teduglutide pretreatment regressed the structural damage, cell apoptosis and oxidative stress by reducing lipid peroxidation in mice received TNF-α/Act D. GLP-2 receptors were present on the cell membrane of type II pneumocytes and interstitial cells. Thus, teduglutide can be suggested as a novel protective agent, which possesses anti-apoptotic and anti-oxidant properties, against lung injury.

  20. Matrix metalloproteinase-9, -10, and -12, MDM2 and p53 expression in mouse liver during dimethylnitrosamine-induced oxidative stress and genomic injury.

    PubMed

    Syed, Ismail; Rathod, Jasmine; Parmar, Mayur; Corcoran, George B; Ray, Sidhartha D

    2012-06-01

    Treatment during early tumor development has greater success because tissue growth remains largely confined to its original locus. At later stages, malignant cells migrate from their original location, invade surrounding normal areas, and can disseminate widely throughout the body. Remodeling of the extracellular matrix (ECM) serves as a key facilitator of this dissemination. Proteolytic enzymes including plasmin and matrix metalloproteinases (MMPs) play an integral role in degrading the surrounding ECM proteins and clearing a path for tumor cell migration. Specific MMPs are highly expressed late during malignant tumor invasion. It is not understood whether early changes in MMPs influence apoptotic and necrotic cell death, processes known to govern the early stages of carcinogenesis. Similarly, the interaction between MDM2 and p53 is tightly controlled by a complex array of post-translational modifications, which in turn dictates the stability and activity of both p53 and MDM2. The present studies examine the hypothesis that model hepatotoxin dimethylnitrosamine (DMN), which is also a model carcinogen, will induce the MMP family of proteins after administration in hepatotoxic doses. Doses of 25, 50, and 100 mg/kg DMN were administered i.p. to male C3H mice. Changes in parameters associated with apoptotic and necrotic cell death, DNA damage, cell proliferation, and extracellular proteinases were examined in liver at 24 h. Serum ALT activity, oxidative stress [malondialdehyde], and caspase-activated DNAse mediated DNA laddering increased in a dose-dependent manner, as did the level of MDM2 protein. MMP-9, -10 and -12 (gelatinase-B, stromelysin-2, macrophage elastase), and p53 protein levels increased following 25 mg/kg DMN, but were successively decreased after higher DMN doses. The results of this study demonstrate changes in MDM2 and MMPs during DMN-induced acute liver injury and provide a plausible linkage between DMN-induced oxidative stress-mediated genomic

  1. Moderate hypothermia suppresses jugular venous superoxide anion radical, oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion rats.

    PubMed

    Koda, Yoichi; Tsuruta, Ryosuke; Fujita, Motoki; Miyauchi, Takashi; Kaneda, Kotaro; Todani, Masaki; Aoki, Tetsuya; Shitara, Masaki; Izumi, Tomonori; Kasaoka, Shunji; Yuasa, Makoto; Maekawa, Tsuyoshi

    2010-01-22

    The aim of this study was to assess the effect of moderate hypothermia (MH) on generation of jugular venous superoxide radical (O2-.), oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion (FBI/R) rats. Twenty-one Wistar rats were allocated to a control group (n=7, 37 degrees C), a pre-MH group (n=7, 32 degrees C before ischemia), and a post-MH group (n=7, 32 degrees C after reperfusion). MH was induced before induction of ischemia in the pre-MH group and just after reperfusion in the post-MH group. Forebrain ischemia was induced by occlusion of bilateral common carotid arteries with hemorrhagic hypotension for 10 min, followed by reperfusion. O(2)(-)(.) in the jugular vein was measured from the produced current using a novel O2-. sensor. The O2-. current showed a gradual increase during forebrain ischemia in the control and post-MH groups but was attenuated in the pre-MH group. Following reperfusion, the current showed a marked increase in the control group but was strongly attenuated in the pre- and post-MH groups. Concentrations of malondialdehyde, high-mobility group box 1 (HMGB1) protein, and intercellular adhesion molecule-1 (ICAM-1) in the brain and plasma 120 min after reperfusion in the pre- and post-MH groups were significantly lower than those in the control group, except for plasma HMGB1 in the post-MH group. In conclusion, MH suppressed O2-. measured in the jugular vein, oxidative stress, early inflammation, and endothelial injury in FBI/R rats.

  2. Targeting oxidative injury and cytokines' activity in the treatment with anti-tumor necrosis factor-α antibody for complex regional pain syndrome 1.

    PubMed

    Miclescu, Adriana A; Nordquist, Lena; Hysing, Eva-Britt; Butler, Stephen; Basu, Samar; Lind, Anne-Li; Gordh, Torsten

    2013-11-01

    Cytokines and oxygen free radicals have been implicated in the potential pathogenic development of complex regional pain syndrome (CRPS). We aimed to analyze the relationship between clinical status, circulating levels of cytokines, and markers of oxidative damage during the treatment with anti-TNFα antibodies. The patient chosen for treatment had not had improvement through a number of conventional therapies and fulfilled the current diagnostic criteria for CRPS-1. We investigated the clinical variables before and after systemic administration of 1.4 mg/kg anti-TNFα antibody (infliximab), repeated after 1 month in a dose of 3 mg/kg. Blood samples were collected before and after anti-TNFα antibodies administration, and plasma was analyzed for 8-isoprostane-prostaglandin F2α (8-iso-PGF2α, a marker of oxidative injury) and cytokines (TNF-α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-17A). Plasma concentrations of 8-iso-PGF2α were measured with radioimmunoassay (RIA), and the kinetics of cytokines were detected in plasma by antibody-based proximity ligation (PLA). Pathologically high levels of 8-iso-PGF2α were found in the patient. Immediately after each administration of infliximab, the levels of 8-iso-PGF2α decreased. Although the patient showed an improvement of the cutaneous dystrophic symptoms and diminished pain associated with these lesions, the levels of circulating TNFα increased after the administration of anti-TNFα antibodies. In a patient with CRPS-1 treated with anti-TNFα antibodies, we report increased levels of circulating TNFα and a temporary mitigation of oxidative stress as measured by plasma F2 -isoprostane. This case report provides evidence 2 supporting the indication of monitoring the oxidative stress biomarkers during treatment with anti-TNFα antibodies in CRPS 1.

  3. The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity

    SciTech Connect

    Ramachandran, Anup; Lebofsky, Margitta; Weinman, Steven A.; Jaeschke, Hartmut

    2011-03-15

    Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in many countries. The mechanism of cell death is initiated by formation of a reactive metabolite that binds to mitochondrial proteins and promotes mitochondrial dysfunction and oxidant stress. Manganese superoxide dismutase (SOD2) is a critical defense enzyme located in the mitochondrial matrix. The objective of this investigation was to evaluate the functional consequences of partial SOD2-deficiency (SOD2+/-) on intracellular signaling mechanisms of necrotic cell death after APAP overdose. Treatment of C57Bl/6J wild type animals with 200 mg/kg APAP resulted in liver injury as indicated by elevated plasma alanine aminotransferase activities (2870 {+-} 180 U/L) and centrilobular necrosis at 6 h. In addition, increased tissue glutathione disulfide (GSSG) levels and GSSG-to-GSH ratios, delayed mitochondrial GSH recovery, and increased mitochondrial protein carbonyls and nitrotyrosine protein adducts indicated mitochondrial oxidant stress. In addition, nuclear DNA fragmentation (TUNEL assay) correlated with translocation of Bax to the mitochondria and release of apoptosis-inducing factor (AIF). Furthermore, activation of c-jun-N-terminal kinase (JNK) was documented by the mitochondrial translocation of phospho-JNK. SOD2+/- mice showed 4-fold higher ALT activities and necrosis, an enhancement of all parameters of the mitochondrial oxidant stress, more AIF release and more extensive DNA fragmentation and more prolonged JNK activation. Conclusions: the impaired defense against mitochondrial superoxide formation in SOD2+/- mice prolongs JNK activation after APAP overdose and consequently further enhances the mitochondrial oxidant stress leading to exaggerated mitochondrial dysfunction, release of intermembrane proteins with nuclear DNA fragmentation and more necrosis.

  4. Reduction in traumatic brain injury-induced oxidative stress, apoptosis, and calcium entry in rat hippocampus by melatonin: Possible involvement of TRPM2 channels.

    PubMed

    Yürüker, Vehbi; Nazıroğlu, Mustafa; Şenol, Nilgün

    2015-02-01

    Melatonin, which is a very effective reactive oxygen species (ROS) scavenger, acts through a direct reaction with free radicals. Ca(2+) entry induced by traumatic brain injury (TBI) has deleterious effects on human hippocampal function. TRPM2 is a Ca(2+) permeable non-selective channel in hippocampal neurons, and its activation of during oxidative stress has been linked to cell death. Despite the importance of oxidative stress in TBI, its role in apoptosis and Ca(2+) entry in TBI is poorly understood. Therefore, we tested the effects of melatonin on apoptosis, oxidative stress, and Ca(2+) entry through the TRPM2 channel in the hippocampal neurons of TBI-induced rats. Thirty-two rats were divided into the following four groups: control, melatonin, TBI, and TBI + melatonin groups. Melatonin (5 mg/kg body weight) was intraperitoneally given to animals in the melatonin group and the TBI + melatonin group after 1 h of brain trauma. Hippocampal neurons were freshly isolated from the four groups, incubated with a nonspecific TRPM2 blocker (2-aminoethyl diphenylborinate, 2-APB), and then stimulated with cumene hydroperoxide. Apoptosis, caspase-3, caspase-9, intracellular ROS production, mitochondrial membrane depolarization and intracellular free Ca(2+) ([Ca(2+)]i) values were high in the TBI group, and low in the TBI + melatonin group. The [Ca(2+)]i concentration was decreased in the four groups by 2-APB. In our TBI experimental model, TRPM2 channels were involved in Ca(2+) entry-induced neuronal death, and the negative modulation of the activity of this channel by melatonin pretreatment may account for the neuroprotective activity of TRPM2 channels against oxidative stress, apoptosis, and Ca(2+) entry.

  5. ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury.

    PubMed

    Fiocchetti, Marco; Camilli, Giulia; Acconcia, Filippo; Leone, Stefano; Ascenzi, Paolo; Marino, Maria

    2015-05-01

    Besides other mechanism(s) 17β-estradiol (E2) facilitates neuronal survival by increasing, via estrogen receptor β (ERβ), the levels of neuroglobin (NGB) an anti-apoptotic protein. In contrast, E2 could exert protective effects in cancer cells by activating apoptosis when the ERβ level prevails on that of ERα as in colon cancer cell lines. These apparently contrasting results raise the possibility that E2-induced NGB up-regulation could regulate the ERβ activities shunning this receptor subtype to trigger an apoptotic cascade in neurons but not in non-neuronal cells. Here, human colorectal adenocarcinoma cell line (DLD-1) that only expresses ERβ and HeLa cells transiently transfected with ERβ encoding vector has been used to verify this hypothesis. In addition, neuroblastoma SK-N-BE cells were used as positive control. Surprisingly, E2 also induced NGB up-regulation, in a dose- and time-dependent manner, in DLD-1 cells. The ERβ-mediated activation of p38/MAPK was necessary for this E2 effect. E2 induced NGB re-allocation in mitochondria where, subsequently to an oxidative stress injury (i.e., 100μM H2O2), NGB interacted with cytochrome c preventing its release into the cytosol and the activation of an apoptotic cascade. As a whole, these results demonstrate that E2-induced NGB up-regulation could act as an oxidative stress sensor, which does not oppose to the pro-apoptotic E2 effect in ERβ-containing colon cancer cells unless a rise of oxidative stress occurs. These results support the concept that oxidative stress plays a critical role in E2-induced carcinogenesis and further open an important scenario to develop novel therapeutic strategies that target NGB against E2-related cancers.

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

    PubMed

    Han, Zhenying; Shen, Fanxia; He, Yue; Degos, Vincent; Camus, Marine; Maze, Mervyn; Young, William L; Su, Hua

    2014-01-01

    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.

  7. Back Injuries

    MedlinePlus

    ... extending from your neck to your pelvis. Back injuries can result from sports injuries, work around the house or in the garden, ... back is the most common site of back injuries and back pain. Common back injuries include Sprains ...

  8. Head Injuries

    MedlinePlus

    ... before. Often, the injury is minor because your skull is hard and it protects your brain. But ... injuries can be more severe, such as a skull fracture, concussion, or traumatic brain injury. Head injuries ...

  9. Formation of copper oxychloride and reactive oxygen species as causes of uterine injury during copper oxidation of Cu-IUD.

    PubMed

    Beltran-Garcia, M J; Espinosa, A; Herrera, N; Perez-Zapata, A J; Beltran-Garcia, C; Ogura, T

    2000-02-01

    The lining of the uterus and cervix might be injured by a variety of oxidation products of Cu in a Cu-IUD, including cuprous ions, dissolved and precipitated cupric ions, and reactive oxygen species such as superoxide radicals, hydrogen peroxide, and hydroxyl radicals. In this study, the human amnious WISH cell line was employed as a model of uterine cells in the presence of copper. The cell viability was decreased by elemental copper, which was alleviated up to 70% by the addition of catalase. The addition of copper oxychloride caused cell death in a dose-dependent manner. Hydroxyl radicals in the presence of copper were determined by the formation of malondialdehyde. Soluble cuprous chloride complexes are formed in the uterus by slowly entering oxygen. The complexes are partly oxidized to insoluble copper oxychloride. which damages the endometrium. Unoxidized cuprous ions migrate to the oxygen-rich cervix and are oxidized to copper oxychloride, causing cervix damage.

  10. Attenuation of oxidative stress, inflammation and apoptosis by ethanolic and aqueous extracts of Crocus sativus L. stigma after chronic constriction injury of rats.

    PubMed

    Amin, Bahareh; Abnous, Khalil; Motamedshariaty, Vahideh; Hosseinzadeh, Hossein

    2014-12-01

    In our previous study, the ethanolic and aqueous extracts of Crocus sativus elicited antinociceptive effects in the chronic constriction injury (CCI) model of neuropathic pain. In this study, we explored anti-inflammatory, anti-oxidant and anti-apoptotic effects of such extracts in CCI animals. A total of 72 animals were divided as vehicle-treated CCI rats, sham group, CCI animals treated with the effective dose of aqueous and ethanolic extracts (200 mg/kg, i.p.). The lumbar spinal cord levels of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin 6 (IL-6), were evaluated at days 3 and 7 after CCI (n=3, for each group). The apoptotic protein changes were evaluated at days 3 and 7 by western blotting. Oxidative stress markers including malondialdehyde (MDA) and glutathione reduced (GSH), were measured on day 7 after CCI. Inflammatory cytokines levels increased in CCI animals on days 3 and 7, which were suppressed by both extracts. The ratio of Bax/ Bcl2 was elevated on day 3 but not on day 7, in CCI animals as compared to sham operated animals and decreased following treatment with both extracts at this time. Both extracts attenuated MDA and increased GSH levels in CCI animals. It may be concluded that saffron alleviates neuropathic pain, at least in part, through attenuation of proinflammatory cytokines, antioxidant activity and apoptotic pathways.

  11. Inositol hexa phosphoric acid (phytic acid), a nutraceuticals, attenuates iron-induced oxidative stress and alleviates liver injury in iron overloaded mice.

    PubMed

    Bhowmik, Anwesha; Ojha, Durbadal; Goswami, Debayan; Das, Rashmi; Chandra, Nidhi S; Chatterjee, Tapan K; Chakravarty, Amit; Chakravarty, Sudipa; Chattopadhyay, Debprasad

    2017-03-01

    Inositol hexa phosphoric acid (IP6) or Phytic acid, a natural antioxidant of some leguminous plants, known to act as a protective agent for seed storage in plants by suppressing iron catalyzed oxidative process. Following the same mechanism, we have tested the effect of IP6 on iron overloaded in vitro oxidative stress, and studied it's in vivo hepatoprotective ability in iron-dextran (injection)-induced iron overloaded liver injury in mice (intraperitoneal). Our results showed that IP6 had in vitro iron chelation (IC50 38.4μg/ml) activity, with the inhibition of iron-induced lipid peroxidation (IC50 552μg/ml), and deoxyribose sugar degrading hydroxyl radicals (IC50 448.6μg/ml). Oral administration of IP6 (0-200mg/kg) revealed significant decrease in biochemical markers such as serum iron, total iron binding, serum ferritin and serum enzymes. Histopathology of liver stained with hematoxylin-eosin and Prussian blue showed reduced hepatocellular necrosis, ballooning and inflammation, indicating the restoration of normal cellular integrity. Interestingly, the IP6 was found to down-regulate the mRNA expression of tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, and IL-6 in iron overloaded liver tissues. Thus, we provide an insight that IP6, a natural food component, can serve as an iron chelator against iron overload diseases like Thalassemia, and also as a dietary hepatoprotective supplement.

  12. Ameliorating effect of chicory (Chichorium intybus L.) fruit extract against 4-tert-octylphenol induced liver injury and oxidative stress in male rats.

    PubMed

    Saggu, Shalini; Sakeran, Mohamed I; Zidan, Nahla; Tousson, Ehab; Mohan, Anand; Rehman, Hasibur

    2014-10-01

    The current study was carried out to elucidate the modulating effect of chicory (Cichorium intybus L.) fruit extract (CFR) against 4-tert-OP induced oxidative stress and hepatotoxicity in male rats. Rats were divided into four groups and treated for 8 weeks as follow: group 1: normal control-treated (saline); group 2: chicory fruit extract-treated (100 mg/kg); group 3: 4-tert-OP treated; group 4: 4-tert-OP plus chicory fruit extract. The obtained results revealed that rats which received 4-tert-OP showed a significant increase in liver TBARS and bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGTP) activities. While a significant decrease in the levels of GSH, SOD, catalase recorded. On the other hand, CFR extract succeeded to modulate these observed abnormalities resulting from 4-tert-OP as indicated by the reduction of TBARS and the pronounced improvement of the investigated biochemical and antioxidant parameters. Histopathological evidence, together with observed PCNA and DNA fragmentation, supported the detrimental effect of 4-tert-OP and the ameliorating effect of CFR extract on liver toxicity. So, it could be concluded that chicory has a promising role and it worth to be considered as a natural substance for ameliorating the oxidative stress and hepatic injury induced by 4-tert-OP compound.

  13. Ameliorating effect of chicory (Cichorium intybus L.)-supplemented diet against nitrosamine precursors-induced liver injury and oxidative stress in male rats.

    PubMed

    Hassan, Hanaa A; Yousef, Mokhtar I

    2010-01-01

    The current study was carried out to elucidate the modulating effect of chicory (Cichorium intybus L.)-supplemented diet against nitrosamnine-induced oxidative stress and hepatotoxicity in male rats. Rats were divided into four groups and treated for 8 weeks as follow: group 1 served as control; group 2 fed on chicory-supplemented diet (10% w/w); group 3 received simultaneously nitrosamine precursors [sodium nitrite (0.05% in drinking water) plus chlorpromazine (1.7 mg/kg body weight)] and group 4 received nitrosamine precursors and fed on chicory-supplemented diet. The obtained results revealed that rats received nitrosamine precursors showed a significant increase in liver TBARS and total lipids, total cholesterol, bilirubin, and enzymes activity (AST, ALT, ALP and gamma-GT) in both serum and liver. While a significant decrease in the levels of GSH, GSH-Rx, SOD, catalase, total protein and albumin was recorded. On the other hand, chicory-supplemented diet succeeded to modulate these observed abnormalities resulting from nitrosamine compounds as indicated by the reduction of TBARS and the pronounced improvement of the investigated biochemical and antioxidant parameters. So, it could be concluded that chicory has a promising role and it worth to be considered as a natural substance for ameliorating the oxidative stress and hepatic injury induced by nitrosamine compounds.

  14. Ameliorative effect of septilin, an ayurvedic preparation against gamma-irradiation-induced oxidative stress and tissue injury in rats.

    PubMed

    Mansour, Heba Hosny; Ismael, Naglaa El-Sayed Rifaat; Hafez, Hafez Farouk

    2014-04-01

    Ionizing radiation is known to induce multiple organ dysfunctions directly related to an increase of cellular oxidative stress, due to overproduction of reactive oxygen species (ROS). This study was aimed to investigate the effect of septilin (an ayurvedic poly-herbal formulation containing the principal herbs, namely Commiphora wightii, Trinospora cordifolia, Rubia cardifolia, Emblica officinalis, Saussurea lappa and Glycyrrhiza glabra) against whole body gamma-irradiation-induced oxidative damage in hepatic and brain tissues in rats. Administration of septilin for 5 days (100 mg/kg) prior to radiation resulted in a significant increase in both superoxide dismutase (SOD) activity and total glutathione (GSH) level in hepatic and brain tissues, while serum high-density lipoprotein-cholesterol (HDL) was reduced by gamma-irradiation. Also, septilin resulted in a significant decrease in NO(x), nitric oxide and malondialdehyde (MDA) levels in hepatic and brain tissues and a significant decrease in serum triglycerides, low-density lipoprotein-cholesterol (LDL) and total cholesterol levels and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels and alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) activities, as well as serum tumor necrosis factor-alpha (TNF-alpha), compared to irradiated group. In conclusion, data obtained from this study indicated that septilin exhibited potential antioxidant activity and showed radioprotective effect against gamma-radiation by preventing oxidative stress and scavenging free radicals.

  15. Curcumin attenuates chronic ethanol-induced liver injury by inhibition of oxidative stress via mitogen-activated protein kinase/nuclear factor E2-related factor 2 pathway in mice

    PubMed Central

    Xiong, Zhang E; Dong, Wei Guo; Wang, Bao Ying; Tong, Qiao Yun; Li, Zhong Yan

    2015-01-01

    Objective: This study aimed to investigate the protective effect of curcumin on chronic ethanol-induced liver injury in mice and to explore its underlying mechanisms. Materials and Methods: Ethanol-exposed Balb/c mice were simultaneously treated with curcumin for 6 weeks. Liver injury was evaluated by biochemical and histopathological examination. Lipid peroxidation and anti-oxidant activities were measured by spectrophotometric method. Anti-oxidative genes expression such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and superoxide dismutase (SOD) were determined by real-time polymerase chain reaction. The nuclear factor E2-related factor 2 (Nrf2) and the phosphorylation states of specific proteins central to intracellular signaling cascades were measured by western blotting. Results: Curcumin treatment protected liver from chronic ethanol-induced injury through reducing serum alanine aminotransferase and aspartate aminotransferase activities, improving liver histological architecture, and reversing lipid disorders indicated by decrease of triglyceride, total cholesterol and low-density lipoprotein-cholesterol levels and increase of High-density lipoprotein-cholesterol levels. Meanwhile, curcumin administration attenuated oxidative stress via up-regulating SOD and glutathione peroxidase activities, leading to a reduction of lipid hydroperoxide production. In addition, curcumin increased Nrf2 activation and anti-oxidative genes expressions such as NQO1, HO-1, and SOD through inducing extracellular signal-regulated kinase (ERK) and p38 phosphorylation. Conclusion: Our data suggested that curcumin protected the liver from chronic-ethanol induced injury through attenuating oxidative stress, at least partially, through ERK/p38/Nrf2-mediated anti-oxidant signaling pathways. PMID:26600714

  16. Phenolic Content of Hypodaphnis Zenkeri and Its Antioxidant Effects against Fenton Reactions’ Mediated Oxidative Injuries on Liver Homogenate

    PubMed Central

    Moukette Moukette, Bruno; Pieme, Constant Anatole; Nya Biapa, Prosper Cabral; Njimou, Jacques Romain; Ama Moor, Vicky Jocelyne; Stoller, Marco; Bravi, Marco; Ngogang, Jeanne Yonkeu

    2014-01-01

    Under oxidative stress conditions, endogenous antioxidant defenses are unable to completely inactivate the free radicals generated by an excessive production of reactive oxygen species (ROS). This state causes serious cell damage leading to a variety of human diseases. Natural antioxidants can protect cells against oxidative stress. Hypaodaphnis zenkeri (H. zenkiri) is a plant consumed as a spice in the Cameroonian diet, and its bark has been used in traditional medicine for the treatment of several diseases. The present study aims at investigating the antioxidant activity, which includes free radical scavenging and protective properties of an extract from H. Zenkiri against oxidative damage on a liver homogenate. The free radical assays determined the scavenging activities of 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl (OH), nitrite oxide (NO) and 2,2-azinobis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS) radicals and the enzymes, whose protection was to be considered in the liver homogenate, including superoxide dismutase, catalase, and peroxidase. The antioxidative activities were studied using the ferric reducing antioxidant power (FRAP), reductive activity, and phosphomolybdenum antioxidant power (PAP) methods. In addition, the phenolic contents of the extracts were examined. The results showed that these extracts demonstrated significant scavenging properties and antioxidant activities, with the hydro-ethanolic extract of the bark of H. zenkeri (EEH) being the most potent. This extract had the highest total polyphenol (21.77 ± 0.05 mg caffeic acid (CAE)/g dried extract (DE)) and flavonoids (3.34 ± 0.13 mg quercetin (QE)/g dried extract) content. The same extract had significantly greater protective effects on enzyme activities compared to other extracts. The high performance liquied chromatography (HPLC) profile showed higher levels of caffeic acid, OH-tyrosol acid, and rutin in the leaves compared to the bark of H. zenkeri. In conclusion, the ethanolic

  17. Phenolic Content of Hypodaphnis Zenkeri and Its Antioxidant Effects against Fenton Reactions' Mediated Oxidative Injuries on Liver Homogenate.

    PubMed

    Moukette, Bruno Moukette; Pieme, Constant Anatole; Biapa, Prosper Cabral Nya; Njimou, Jacques Romain; Moor, Vicky Jocelyne Ama; Stoller, Marco; Bravi, Marco; Ngogang, Jeanne Yonkeu

    2014-12-16

    Under oxidative stress conditions, endogenous antioxidant defenses are unable to completely inactivate the free radicals generated by an excessive production of reactive oxygen species (ROS). This state causes serious cell damage leading to a variety of human diseases. Natural antioxidants can protect cells against oxidative stress. Hypaodaphnis zenkeri (H. zenkiri) is a plant consumed as a spice in the Cameroonian diet, and its bark has been used in traditional medicine for the treatment of several diseases. The present study aims at investigating the antioxidant activity, which includes free radical scavenging and protective properties of an extract from H. Zenkiri against oxidative damage on a liver homogenate. The free radical assays determined the scavenging activities of 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl (OH), nitrite oxide (NO) and 2,2-azinobis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS) radicals and the enzymes, whose protection was to be considered in the liver homogenate, including superoxide dismutase, catalase, and peroxidase. The antioxidative activities were studied using the ferric reducing antioxidant power (FRAP), reductive activity, and phosphomolybdenum antioxidant power (PAP) methods. In addition, the phenolic contents of the extracts were examined. The results showed that these extracts demonstrated significant scavenging properties and antioxidant activities, with the hydro-ethanolic extract of the bark of H. zenkeri (EEH) being the most potent. This extract had the highest total polyphenol (21.77 ± 0.05 mg caffeic acid (CAE)/g dried extract (DE)) and flavonoids (3.34 ± 0.13 mg quercetin (QE)/g dried extract) content. The same extract had significantly greater protective effects on enzyme activities compared to other extracts. The high performance liquied chromatography (HPLC) profile showed higher levels of caffeic acid, OH-tyrosol acid, and rutin in the leaves compared to the bark of H. zenkeri. In conclusion, the ethanolic

  18. Nano-Se attenuates cyclophosphamide-induced pulmonary injury through modulation of oxidative stress and DNA damage in Swiss albino mice.

    PubMed

    Bhattacharjee, Arin; Basu, Abhishek; Biswas, Jaydip; Bhattacharya, Sudin

    2015-07-01

    Chemotherapy is an integral part of modern day treatment regimen but anticancer drugs fail to demarcate between cancerous and normal cells thereby causing severe form of systemic toxicity. Among which pulmonary toxicity is a dreadful complication developed in cancer patients upon cyclophosphamide (CP) therapy. Oxidative stress, fibrosis, and apoptosis are the major patho-mechanisms involved in CP-induced pulmonary toxicity. In the present study, we have synthesized Nano-Se, nanotechnology-based new form of elemental selenium which has significantly lower toxicity and acceptable bioavailability. In order to meet the need of effective drugs against CP-induced adverse effects, nano selenium (Nano-Se) was tested for its possible protective efficacy on CP-induced pulmonary toxicity and bone marrow toxicity. CP intoxication resulted in structural and functional lung impairment which was revealed by massive histopathological changes. Lung injury was associated with oxidative stress/lipid peroxidation as evident by increased in reactive oxygen species, nitric oxide level, and malondialdehyde (MDA) formation with decreased in level of antioxidants such as reduced glutathione, glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, and catalase. Furthermore, CP at a dose of 25 mg/kg b.w. increased pulmonary DNA damage ('comet tail') and triggered DNA fragmentation and apoptosis in mouse bone marrow cells. On the other hand, Nano-Se at a dose of 2 mg Se/kg b.w., significantly inhibited CP-induced DNA damage in bronchoalveolar lavage cells, and decreased the apoptosis and percentage of DNA fragmentation in bone marrow cells and also antagonized the reduction of the activities of antioxidant enzymes and the increase level of MDA. Thus, our results suggest that Nano-Se in pre- and co-administration may serve as a promising preventive strategy against CP-induced pulmonary toxicity.

  19. Effects of surfactant/budesonide therapy on oxidative modifications in the lung in experimental meconium-induced lung injury.

    PubMed

    Mikolka, P; Kopincova, J; Tomcikova Mikusiakova, L; Kosutova, P; Antosova, M; Calkovska, A; Mokra, D

    2016-02-01

    Meconium aspiration syndrome (MAS) is a serious condition, which can be treated with exogenous surfactant and mechanical ventilation. However, meconium-induced inflammation, lung edema and oxidative damage may inactivate delivered surfactant and thereby reduce effectiveness of the therapy. As we presumed that addition of anti-inflammatory agent into the surfactant may alleviate inflammation and enhance efficiency of the therapy, this study was performed to evaluate effects of surfactant therapy enriched with budesonide versus surfactant-only therapy on markers of oxidative stress in experimental model of MAS. Meconium suspension (25 mg/ml, 4 ml/kg) was instilled into the trachea of young rabbits, whereas one group of animals received saline instead of meconium (C group, n = 6). In meconium-instilled animals, respiratory failure developed within 30 min. Then, meconium-instilled animals were divided into 3 groups according to therapy (n = 6 each): with surfactant therapy (M + S group), with surfactant + budesonide therapy (M + S + B), and without therapy (M group). Surfactant therapy consisted of two bronchoalveolar lavages (BAL) with diluted surfactant (Curosurf, 5 mg phospholipids/ml, 10 ml/kg) followed by undiluted surfactant (100 mg phospholipids/kg), which was in M + S + B group enriched with budesonide (Pulmicort, 0.5 mg/ml). Animals were oxygen-ventilated for additional 5 hours. At the end of experiment, blood sample was taken for differential white blood cell (WBC) count. After euthanizing animals, left lung was saline-lavaged and cell differential in BAL was determined. Oxidative damage, i.e. oxidation of lipids (thiobarbituric acid reactive substance (TBARS) and conjugated dienes) and proteins (dityrosine and lysine-lipoperoxidation products) was estimated in lung homogenate and isolated mitochondria. Total antioxidant capacity was evaluated in lung homogenate and plasma. Meconium instillation increased transmigration of neutrophils and production of free

  20. Mice Deficient in the Gene for Cytochrome P450 (CYP)1A1 Are More Susceptible Than Wild-Type to Hyperoxic Lung Injury: Evidence for Protective Role of CYP1A1 Against Oxidative Stress

    PubMed Central

    Wang, Lihua; Wang, Gangduo; Couroucli, Xanthi I.; Shivanna, Binoy; Welty, Stephen E.; Barrios, Roberto; Khan,  M. Firoze; Nebert, Daniel W.; Roberts, L. Jackson; Moorthy, Bhagavatula

    2014-01-01

    Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome in adults and bronchopulmonary dysplasia in premature infants. Cytochrome P450 (CYP)1A1 has been shown to modulate hyperoxic lung injury. The mechanistic role(s) of CYP1A1 in hyperoxic lung injury in vivo is not known. In this investigation, we hypothesized that Cyp1a1(–/–) mice would be more susceptible to hyperoxic lung injury than wild-type (WT) mice, and that the protective role of CYP1A1 is in part due to CYP1A1-mediated decrease in the levels of reactive oxygen species-mediated lipid hydroperoxides, e.g., F2-isoprostanes/isofurans, leading to attenuation of oxidative damage. Eight- to ten-week-old male WT (C57BL/6J) or Cyp1a1(–/–) mice were exposed to hyperoxia (>95% O2) or room air for 24–72 h. The Cyp1a1(–/–) mice were more susceptible to oxygen-mediated lung damage and inflammation than WT mice, as evidenced by increased lung weight/body weight ratio, lung injury, neutrophil infiltration, and augmented expression of IL-6. Hyperoxia for 24–48 h induced CYP1A expression at the mRNA, protein, and enzyme levels in liver and lung of WT mice. Pulmonary F2-isoprostane and isofuran levels were elevated in WT mice after hyperoxia for 24 h. On the other hand, Cyp1a1(–/–) mice showed higher levels after 48–72 h of hyperoxia exposure compared to WT mice. Our results support the hypothesis that CYP1A1 protects against hyperoxic lung injury by decreasing oxidative stress. Future research could lead to the development of novel strategies for prevention and/or treatment of acute lung injury. PMID:24893714

  1. Nox‐4 deletion reduces oxidative stress and injury by PKC‐α‐associated mechanisms in diabetic nephropathy

    PubMed Central

    Thallas‐Bonke, Vicki; Jha, Jay C.; Gray, Stephen P.; Barit, David; Haller, Hermann; Schmidt, Harald H.H.W.; Coughlan, Melinda T.; Cooper, Mark E.; Forbes, Josephine M.; Jandeleit‐Dahm, Karin A.M.

    2014-01-01

    Abstract Current treatments for diabetic nephropathy (DN) only result in slowing its progression, thus highlighting a need to identify novel targets. Increased production of reactive oxygen species (ROS) is considered a key downstream pathway of end‐organ injury with increasing data implicating both mitochondrial and cytosolic sources of ROS. The enzyme, NADPH oxidase, generates ROS in the kidney and has been implicated in the activation of protein kinase C (PKC), in the pathogenesis of DN, but the link between PKC and Nox‐derived ROS has not been evaluated in detail in vivo. In this study, global deletion of a NADPH‐oxidase isoform, Nox4, was examined in mice with streptozotocin‐induced diabetes (C57Bl6/J) in order to evaluate the effects of Nox4 deletion, not only on renal structure and function but also on the PKC pathway and downstream events. Nox4 deletion attenuated diabetes‐associated increases in albuminuria, glomerulosclerosis, and extracellular matrix accumulation. Lack of Nox4 resulted in a decrease in diabetes‐induced renal cortical ROS derived from the mitochondria and the cytosol, urinary isoprostanes, and PKC activity. Immunostaining of renal cortex revealed that major isoforms of PKC, PKC‐α and PKC‐β1, were increased with diabetes and normalized by Nox4 deletion. Downregulation of the PKC pathway was observed in tandem with reduced expression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)‐β1 and restoration of the podocyte slit pore protein nephrin. This study suggests that deletion of Nox4 may alleviate renal injury via PKC‐dependent mechanisms, further strengthening the view that Nox4 is a suitable target for renoprotection in diabetes. PMID:25367693

  2. Coenzyme Q10 Protects Human Endothelial Cells from β-Amyloid Uptake and Oxidative Stress-Induced Injury

    PubMed Central

    Durán-Prado, Mario; Frontiñán, Javier; Santiago-Mora, Raquel; Peinado, Juan Ramón; Parrado-Fernández, Cristina; Gómez-Almagro, María Victoria; Moreno, María; López-Domínguez, José Alberto; Villalba, José Manuel; Alcaín, Francisco J.

    2014-01-01

    Neuropathological symptoms of Alzheimer's disease appear in advances stages, once neuronal damage arises. Nevertheless, recent studies demonstrate that in early asymptomatic stages, ß-amyloid peptide damages the cerebral microvasculature through mechanisms that involve an increase in reactive oxygen species and calcium, which induces necrosis and apoptosis of endothelial cells, leading to cerebrovascular dysfunction. The goal of our work is to study the potential preventive effect of the lipophilic antioxidant coenzyme Q (CoQ) against ß-amyloid-induced damage on human endothelial cells. We analyzed the protective effect of CoQ against Aβ-induced injury in human umbilical vein endothelial cells (HUVECs) using fluorescence and confocal microscopy, biochemical techniques and RMN-based metabolomics. Our results show that CoQ pretreatment of HUVECs delayed Aβ incorporation into the plasma membrane and mitochondria. Moreover, CoQ reduced the influx of extracellular Ca2+, and Ca2+ release from mitochondria due to opening the mitochondrial transition pore after β-amyloid administration, in addition to decreasing O2.− and H2O2 levels. Pretreatment with CoQ also prevented ß-amyloid-induced HUVECs necrosis and apoptosis, restored their ability to proliferate, migrate and form tube-like structures in vitro, which is mirrored by a restoration of the cell metabolic profile to control levels. CoQ protected endothelial cells from Aβ-induced injury at physiological concentrations in human plasma after oral CoQ supplementation and thus could be a promising molecule to protect endothelial cells against amyloid angiopathy. PMID:25272163

  3. Suppression of alkali-induced oxidative injury in the cornea by mesenchymal stem cells growing on nanofiber scaffolds and transferred onto the damaged corneal surface.

    PubMed

    Cejkova, Jitka; Trosan, Peter; Cejka, Cestmir; Lencova, Anna; Zajicova, Alena; Javorkova, Eliska; Kubinova, Sarka; Sykova, Eva; Holan, Vladimir

    2013-11-01

    The purpose of this study was to investigate whether rabbit bone marrow-derived mesenchymal stem cells (MSCs) effectively decrease alkali-induced oxidative stress in the rabbit cornea. The alkali (0.15 N NaOH) was applied on the corneas of the right eyes and then rinsed with tap water. In the first group of rabbits the injured corneas remained untreated. In the second group MSCs were applied on the injured corneal surface immediately after the injury and eyelids sutured for two days. Then the sutures were removed. In the third group nanofiber scaffolds seeded with MSCs (and in the fourth group nanofibers alone) were transferred onto the corneas immediately after the injury and the eyelids sutured. Two days later the eyelid sutures were removed together with the nanofiber scaffolds. The rabbits were sacrificed on days four, ten or fifteen after the injury, and the corneas were examined immunohistochemically, morphologically, for the central corneal thickness (taken as an index of corneal hydration) using an ultrasonic pachymeter and by real-time PCR. Results show that in untreated injured corneas the expression of malondialdehyde (MDA) and nitrotyrosine (NT) (important markers of lipid peroxidation and oxidative stress) appeared in the epithelium. The antioxidant aldehyde dehydrogenase 3A1 (ALDH3A1) decreased in the corneal epithelium, particularly in superficial parts, where apoptotic cell death (detected by active caspase-3) was high. (In control corneal epithelium MDA and NT are absent and ALDH3A1 highly present in all layers of the epithelium. Cell apoptosis are sporadic). In injured untreated cornea further corneal disturbances developed: The expressions of matrix metalloproteinase 9 (MMP9) and proinflammatory cytokines, were high. At the end of experiment (on day 15) the injured untreated corneas were vascularized and numerous inflammatory cells were present in the corneal stroma. Vascular endothelial growth factor (VEGF) expression and number of macrophages

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

    PubMed Central

    Li, Li; Du, GaiPing; Wang, DaJiang; Zhou, Jin; Jiang, Guomin

    2017-01-01

    Retinal ischemia/reperfusion (I/R) injury, involving several ocular diseases, seriously threatens human ocular health, mainly treated by attenuating I/R-induced oxidative stress. Currently, mesenchymal stem cells (MSCs) could restore I/R-injured retina through paracrine secretion. Additionally, heme oxygenase-1 (HO-1) could ameliorate oxidative stress and thus retinal apoptosis, but the expression of HO-1 in MSC is limited. Here, we hypothesized that overexpression of HO-1 in MSC (MSC-HO-1) may significantly improve their retina-protective potentials. The overexpression of HO-1 in MSC was achieved by lentivirus transduction. Then, MSC or MSC-HO-1 was cocultured with retinal ganglion cells (RGC-5) in H2O2-simulated oxidative condition and their protection on RGC-5 was systemically valuated in vitro. Compared with MSC, MSC-HO-1 significantly attenuated H2O2-induced injury of RGC-5, including decrease in cellular ROS level and apoptosis, activation of antiapoptotic proteins p-Akt and Bcl-2, and blockage of proapoptotic proteins cleaved caspase 3 and Bax. In retinal I/R rats model, compared with control MSC, MSC-HO-1-treated retina significantly retrieved its structural thickness, reduced cell apoptosis, markedly attenuated retinal oxidative stress level, and largely regained the activities of typical antioxidant enzymes, SOD and CAT. Therefore, it could be concluded that overexpression of HO-1 provides a promising strategy to enhance the MSC-based therapy for I/R-related retinal injury. PMID:28255307

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

    PubMed Central

    Yu, Shuchun; Luo, Zhenzhong; Hua, Fuzhou; Yuan, Linhui; Zhou, Zhidong; Liu, Qin; Du, Xiaohong; Chen, Sisi; Zhang, Lieliang; Xu, Guohai

    2015-01-01

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

  6. Oxidant-induced cardiomyocyte injury: identification of the cytoprotective effect of a dopamine 1 receptor agonist using a cell-based high-throughput assay.

    PubMed

    Gerö, Domokos; Módis, Katalin; Nagy, Nóra; Szoleczky, Petra; Tóth, Zoltán Dóri; Dormán, György; Szabó, Csaba

    2007-11-01

    Myocyte injury due to myocardial reperfusion injury plays a crucial role in the pathogenesis of acute myocardial infarction even after successful coronary revascularization. Identification of compounds that reduce reperfusion-associated myocyte death is important. Therefore, we developed an in vitro model of myocardial reperfusion injury in H9c2 rat cardiomyocytes and applied a cell-based high-throughput approach to screen a standard library of pharmacologically active compounds (LOPAC) in order to identify drugs with cardioprotective effects. Oxidative stress was induced with hydrogen peroxide (H2O2) treatment, which resulted in approximately 50% reduction in cell viability. Test compounds were added at a 3-microM final concentration as a pretreatment or in a delayed fashion (30 min after the peroxide challenge in order to imitate pharmacological treatment following angioplasty). Cells were cultured for 3 or 24 h. Viability was quantitated with the methylthiazolyldiphenyl-tetrazolium bromide method. Cytotoxicity and cytoprotection were also evaluated by measuring the lactate dehydrogenase activity in the cell culture supernatant. The screening identified a number of compounds with cytoprotective action, including molecules that are known to interfere with components of DNA repair and cell cycle progression, e.g. poly(ADP-ribose) polymerase (PARP) inhibitors, topoisomerase inhibitors, and cyclin dependent kinase inhibitors, or reduce energy consumption by interfering with cardiac myofilament function. A number of dopamine D1 receptor agonists also provided significant cytoprotection at 3 h, but only three of them showed a similar effect at 24 h: chloro- and bromo-APB and chloro-PB hydrobromide. Chloro-APB hydrobromide significantly reduced peroxide-induced PARP activation in the myocytes independently of its action on dopamine D1 receptors, but lacked PARP inhibitor capacity in a cell-free PARP assay system. In conclusion, the pattern of cytoprotective drugs

  7. A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury

    PubMed Central

    Horváth, Bėla; Magid, Lital; Mukhopadhyay, Partha; Bátkai, Sándor; Rajesh, Mohanraj; Park, Ogyi; Tanchian, Galin; Gao, Rachel Y; Goodfellow, Catherine E; Glass, Michelle; Mechoulam, Raphael; Pacher, Pál

    2012-01-01

    BACKGROUND AND PURPOSE Cannabinoid CB2 receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia-reperfusion (I/R) injury. EXPERIMENTAL APPROACH We have investigated the effects of a novel CB2 receptor agonist ((1S,4R)-2-(2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl)-7,7-dimethylbicyclo[2.2.1]hept-2-en-1-yl)methanol (HU-910) on liver injury induced by 1 h of ischaemia followed by 2, 6 or 24 h of reperfusion, using a well-established mouse model of segmental hepatic I/R. KEY RESULTS Displacement of [3H]CP55940 by HU-910 from specific binding sites in CHO cell membranes transfected with human CB2 or CB1 receptors (hCB1/2) yielded Ki values of 6 nM and 1.4 µM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB2 CHO cells (EC50= 162 nM) and yielded EC50 of 26.4 nM in [35S]GTPγS binding assays using hCB2 expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic pro-inflammatory chemokines (CCL3 and CXCL2), TNF-α, inter-cellular adhesion molecule-1, neutrophil infiltration, oxidative stress and cell death. Some of the beneficial effect of HU-910 also persisted when given at the beginning of the reperfusion or 1 h after the ischaemic episode. Furthermore, HU-910 attenuated the bacterial endotoxin-triggered TNF-α production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-α. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of HU-910, while pretreatment with a CB1 antagonist tended to enhance them. CONCLUSION AND IMPLICATIONS HU-910 is a potent CB2 receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph

  8. Augmented O-GlcNAc signaling via glucosamine attenuates oxidative stress and apoptosis following contrast-induced acute kidney injury in rats.

    PubMed

    Hu, Jiachang; Chen, Rongyi; Jia, Ping; Fang, Yi; Liu, Tongqiang; Song, Nana; Xu, Xialian; Ji, Jun; Ding, Xiaoqiang

    2017-02-01

    Contrast-induced acute kidney injury (CI-AKI) is an iatrogenic renal injury and associated with substantial morbidity and mortality in susceptible individuals. Despite extensive study of a variety of agents for renal protection, limited strategies have been shown to be effective in the reduction of CI-AKI. O-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational regulatory modification of intracellular proteins and governs the function of numerous proteins, both cytosolic and nuclear. Increasing evidence suggests that O-GlcNAc levels are increased in response to stress and that acute augmentation of this reaction is cytoprotective. However, the underlying mechanisms by which augmented OGlcNAc signaling provides renoprotection against contrast media insults is still unknown. Here, we investigated the effect of augmented O-GlcNAc signaling via glucosamine on CI-AKI and explored the underlying molecular mechanisms, particularly its relationship with PI3-kinase (PI3K)/Akt signaling. We used a novel and reliable CI-AKI model consisting of 5/6 nephrectomized (NE) rats, and a low-osmolar contrast media (iohexol, 10mL/kg, 3.5gI) injected via the tail vein after dehydration for 48h. The results showed that augmented O-GlcNAc signaling by glucosamine prevented the kidneys against iohexol-induced injury characterized by the attenuation of renal dysfunction, tubular damage, apoptosis and oxidative stress. Furthermore, this renoprotection was blocked by treatment with alloxan, an O-GlcNAc transferase inhibitor. Augmented O-GlcNAc signaling also increased the protein expression levels of phospho-Akt (Ser473, but not Thr308 and Thr450), phospho-GSK-3β, Nrf2, and Bcl-2, and decreased the levels of Bax and cleaved caspase-3. Both alloxan and specific inhibitors of PI3K (Wortmannin and LY294002) blocked the protection of glucosamine via inhibiting Akt signaling pathway. We further identified O-GlcNAcylated Akt through immunoprecipitation and western blot. We confirmed

  9. Brain derived neurotrophic factor and insulin like growth factor-1 attenuate upregulation of nitric oxide synthase and cell injury following trauma to the spinal cord. An immunohistochemical study in the rat.

    PubMed

    Sharma, H S; Nyberg, F; Westman, J; Alm, P; Gordh, T; Lindholm, D

    1998-01-01

    The possibility that brain derived neurotrophic factor (BDNF) and insulin like growth factor-1 (IGF) induced neuroprotection is influenced by mechanisms involving nitric oxide was examined in a rat model of focal spinal cord injury. BDNF or IGF-I (0.1 microgram/10 microliters in phosphate buffer saline) was applied topically 30 min before injury on the exposed spinal cord followed by repeated doses of growth factors immediately before and 30 min after injury. Thereafter application of BDNF or IGF was carried out at every 1 h interval until sacrifice. Five hours after injury, the tissue pieces from the T9 segment were processed for nNOS immunostaining, edema and cell injury. Untreated injured rats showed a profound upregulation of nNOS which was most pronounced in the nerve cells of the ipsilateral side. A marked increase in the blood-spinal cord barrier (BSCB) permeability to 125I-albumin, water content and cell injury in these perifocal segments was also found. Pretreatment with BDNF and IGF significantly reduced the upregulation of nNOS in the spinal cord. This effect of the growth factors was most pronounced in the contralateral side. Rats treated with these neurotrophic factors showed much less signs of BSCB damage, edema and cell injury. These results suggest that BDNF and IGF pretreatment is neuroprotective in spinal cord injury and that these neurotrophic factors have the capacity to down regulate nNOS expression following trauma to the spinal cord. Our data provide new experimental evidences which suggest that BDNF and IGF may exert their potential neuroprotective effects probably via regulation of NOS activity.

  10. Mn (III) tetrakis (4-benzoic acid) porphyrin scavenges reactive species, reduces oxidative stress, and improves functional recovery after experimental spinal cord injury in rats: comparison with methylprednisolone

    PubMed Central

    2013-01-01

    Background Substantial experimental evidence supports that reactive species mediate secondary damage after traumatic spinal cord injury (SCI) by inducing oxidative stress. Removal of reactive species may reduce secondary damage following SCI. This study explored the effectiveness of a catalytic antioxidant - Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) - in removing reactive oxygen species (ROS), reducing oxidative stress, and improving functional recovery in vivo in a rat impact SCI model. The efficiency of MnTBAP was also compared with that of methylprednisolone – the only drug used clinically in treating acute SCI. Results In vivo measurements of time courses of ROS production by microdialysis and microcannula sampling in MnTBAP, methylprednisolone, and saline (as vehicle control)-treated SCI rats showed that both agents significantly reduced the production of hydrogen peroxide, but only MnTBAP significantly reduced superoxide elevation after SCI. In vitro experiments further demonstrated that MnTBAP scavenged both of the preceding ROS, whereas methylprednisolone had no effect on either. By counting the immuno-positive neurons in the spinal cord sections immunohistochemically stained with anti-nitrotyrosine and anti-4-hydroxy-nonenal antibodies as the markers of protein nitration and membrane lipid peroxidation, we demonstrated that MnTBAP significantly reduced the numbers of 4-hydroxy-nonenal-positive and nitrotyrosine-positive neurons in the sections at 1.55 to 2.55 mm and 1.1 to 3.1 mm, respectively, rostral to the injury epicenter compared to the vehicle-treated animals. By behavioral tests (open field and inclined plane tests), we demonstrated that at 4 hours post-SCI treatment with MnTBAP and the standard methylprednisolone regimen both significantly increased test scores compared to those produced by vehicle treatment. However, the outcomes for MnTBAP-treated rats were significantly better than those for methylprednisolone-treated animals

  11. Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities

    PubMed Central

    Spasojevic, Ivan; Tse, Hubert M.; Tovmasyan, Artak; Rajic, Zrinka; St. Clair, Daret K.; Vujaskovic, Zeljko; Dewhirst, Mark W.; Piganelli, Jon D.

    2010-01-01

    The most efficacious Mn(III) porphyrinic (MnPs) scavengers of reactive species have positive charges close to the Mn site, whereby they afford thermodynamic and electrostatic facilitation for the reaction with negatively charged species such as O2•− and ONOO−. Those are Mn(III) meso tetrakis(N-alkylpyridinium-2-yl)porphyrins, more specifically MnTE-2-PyP5+ (AEOL10113) and MnTnHex-2-PyP5+ (where alkyls are ethyl and n-hexyl, respectively), and their imidazolium analog, MnTDE-2-ImP5+ (AEOL10150, Mn(III) meso tetrakis(N,N′-diethylimidazolium-2-yl) porphyrin). The efficacy of MnPs in vivo is determined not only by the compound antioxidant potency, but also by its bio-availability. The former is greatly affected by the lipophilicity, size, structure, and overall shape of the compound. These porphyrins have the ability to both eliminate reactive oxygen species and impact the progression of oxidative stress-dependent signaling events. This will effectively lead to the regulation of redox-dependent transcription factors and the suppression of secondary inflammatory- and oxidative stress-mediated immune responses. We have reported on the inhibition of major transcription factors HIF-1α, AP-1, SP-1, and NF-κB by Mn porphyrins. While the prevailing mechanistic view of the suppression of transcription factors activation is via antioxidative action (presumably in cytosol), the pro-oxidative action of MnPs in suppressing NF-κB activation in nucleus has been substantiated. The magnitude of the effect is dependent upon the electrostatic (porphyrin charges) and thermodynamic factors (porphyrin redox ability). The pro-oxidative action of MnPs has been suggested to contribute at least in part to the in vitro anticancer action of MnTE-2-PyP5+ in the presence of ascorbate, and in vivo when combined with chemotherapy of lymphoma. Given the remarkable therapeutic potential of metalloporphyrins, future studies are warranted to further our understanding of in vivo action/s of Mn

  12. Differentially expressed miRNAs in sepsis-induced acute kidney injury target oxidative stress and mitochondrial dysfunction pathways

    PubMed Central

    Ge, Qin-Min; Huang, Chun-Mei; Zhu, Xiang-Yang; Bian, Fan; Pan, Shu-Ming

    2017-01-01

    Objective To identify specific miRNAs involved in sepsis-induced AKI and to explore their targeting pathways. Methods The expression profiles of miRNAs in serum from patients with sepsis-induced AKI (n = 6), sepsis-non AKI (n = 6), and healthy volunteers (n = 3) were investigated by microarray assay and validated by quantitative PCR (qPCR). The targets of the differentially expressed miRNAs were predicted by Target Scan, mirbase and Miranda. Then the significant functions and involvement in signaling pathways of gene ontology (GO) and KEGG pathways were analyzed. Furthermore, eight miRNAs were randomly selected out of the differentially expressed miRNAs for further testing by qPCR. Results qPCR analysis confirmed that the expressions levels of hsa-miR-23a-3p, hsa-miR-4456, hsa-miR-142-5p, hsa-miR-22-3p and hsa-miR-191-5p were significantly lower in patients with sepsis compared with the healthy volunteers, while hsa-miR-4270, hsa-miR-4321, hsa-miR-3165 were higher in the sepsis patients. Statistically, miR-4321; miR-4270 were significantly upregulated in the sepsis-induced AKI compared with sepsis-non AKI, while only miR-4321 significantly overexpressed in the sepsis groups compared with control groups. GO analysis showed that biological processes regulated by the predicted target genes included diverse terms. They were related to kidney development, regulation of nitrogen compound metabolic process, regulation of cellular metabolic process, cellular response to oxidative stress, mitochondrial outer membrane permeabilization, etc. Pathway analysis showed that several significant pathways of the predicted target genes related to oxidative stress. miR-4321 was involved in regulating AKT1, mTOR and NOX5 expression while miR-4270 was involved in regulating PPARGC1A, AKT3, NOX5, PIK3C3, WNT1 expression. Function and pathway analysis highlighted the possible involvement of miRNA-deregulated mRNAs in oxidative stress and mitochondrial dysfunction. Conclusion This study

  13. Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress.

    PubMed

    Bazan, Nicolas G

    2005-04-01

    The biosynthesis of oxygenated arachidonic acid messengers triggered by cerebral ischemia-reperfusion is preceded by an early and rapid phospholipase A2 activation reflected in free arachidonic and docosahexaenoic acid (DHA) accumulation. These fatty acids are released from membrane phospholipids. Both fatty acids are derived from dietary essential fatty acids; however, only DHA, the omega-3 polyunsaturated fatty acyl chain, is concentrated in phospholipids of various cells of brain and retina. Synaptic membranes and photoreceptors share the highest content of DHA of all cell membranes. DHA is involved in memory formation, excitable membrane function, photoreceptor cell biogenesis and function, and neuronal signaling, and has been implicated in neuroprotection. In addition, this fatty acid is required for retinal pigment epithelium cell (RPE) functional integrity. Here we provide an overview of the recent elucidation of a specific mediator generated from DHA that contributes at least in part to its biological significance. In oxidative stress-challenged human RPE cells and rat brain undergoing ischemia-reperfusion, 10,17S-docosatriene (neuroprotectin D1, NPD1) synthesis evolves. In addition, calcium ionophore A23187, IL-1beta, or the supply of DHA enhances NPD1 synthesis. A time-dependent release of endogenous free DHA followed by NPD1 formation occurs, suggesting that a phospholipase A2 releases the mediator's precursor. When NPD1 is infused during ischemia-reperfusion or added to RPE cells during oxidative stress, apoptotic DNA damage is down-regulated. NPD1 also up-regulates the anti-apoptotic Bcl-2 proteins Bcl-2 and BclxL and decreases pro-apoptotic Bax and Bad expression. Moreover, NPD1 inhibits oxidative stress-induced caspase-3 activation. NPD1 also inhibits IL-1beta-stimulated expression of COX-2. Overall, NPD1 protects cells from oxidative stress-induced apoptosis. Because photoreceptors are progressively impaired after RPE cell damage in retinal

  14. Superparamagnetic iron oxide nanoparticles as a means to track mesenchymal stem cells in a large animal model of tendon injury.

    PubMed

    Scharf, Alexandra; Holmes, Shannon; Thoresen, Merrilee; Mumaw, Jennifer; Stumpf, Alaina; Peroni, John

    2015-01-01

    The goal of this study was to establish an SPIO-based cell-tracking method in an ovine model of tendonitis and to determine if this method may be useful for further study of cellular therapies in tendonitis in vivo. Functional assays were performed on labeled and unlabeled cells to ensure that no significant changes were induced by intracellular SPIOs. Following biosafety validation, tendon lesions were mechanically (n = 4) or chemically (n = 4) induced in four sheep and scanned ex vivo at 7 and 14 days to determine the presence and distribution of intralesional cells. Ovine MSCs labeled with 50 µg SPIOs/mL remained viable, proliferate, and undergo tri-lineage differentiation (p < 0.05). Labeled ovine MSCs remained detectable in vitro in concentrated cell numbers as low as 10 000 and in volumetric distributions as low as 100 000 cells/mL. Cells remained detectable by MRI at 7 days, as confirmed by correlative histology for dually labeled SPIO+/GFP+ cells. Histological evidence at 14 days suggested that SPIO particles remained embedded in tissue, providing MRI signal, although cells were no longer present. SPIO labeling has proven to be an effective method for cell tracking for a large animal model of tendon injury for up to 7 days post-injection. The data obtained in this study justify further investigation into the effects of MSC survival and migration on overall tendon healing and tissue regeneration.

  15. Connexin32 deficiency is associated with liver injury, inflammation and oxidative stress in experimental non-alcoholic steatohepatitis.

    PubMed

    Tiburcio, Taynã Cristina; Willebrords, Joost; da Silva, Tereza Cristina; Pereira, Isabel Veloso Alves; Nogueira, Marina Sayuri; Crespo Yanguas, Sara; Maes, Michaël; Silva, Elisangela Dos Anjos; Dagli, Maria Lucia Zaidan; de Castro, Inar Alves; Oliveira, Cláudia Pinto; Vinken, Mathieu; Cogliati, Bruno

    2017-02-01

    Non-alcoholic steatohepatitis is a highly prevalent liver pathology featured by hepatocellular fat deposition and inflammation. Connexin32, which is the major building block of hepatocellular gap junctions, has a protective role in hepatocarcinogenesis and is downregulated in chronic liver diseases. However, the role of connexin32 in non-alcoholic steatohepatitis remains unclear. Connexin32(-/-) mice and their wild-type littermates were fed a choline-deficient high-fat diet. The manifestation of non-alcoholic steatohepatitis was evaluated based on a battery of clinically relevant read-outs, including histopathological examination, diverse indicators of inflammation and liver damage, in-depth lipid analysis, assessment of oxidative stress, insulin and glucose tolerance, liver regeneration and lipid-related biomarkers. Overall, more pronounced liver damage, inflammation and oxidative stress were observed in connexin32(-/-) mice compared to wild-type animals. No differences were found in insulin and glucose tolerance measurements and liver regeneration. However, two lipid-related genes, srebf1 and fabp3, were upregulated in Cx32(-/-) mice in comparison with wild-type animals. These findings suggest that connexin32-based signalling is not directly involved in steatosis as such, but rather in the sequelae of this process, which underlie progression of non-alcoholic steatohepatitis.

  16. Protective effect of atmospheric pressure plasma on oxidative stress-induced neuronal injuries: an in vitro study

    NASA Astrophysics Data System (ADS)

    Yan, Xu; Qiao, Yajun; Ouyang, Jiting; Jia, Mei; Li, Jiaxin; Yuan, Fang

    2017-03-01

    Atmospheric pressure plasma jet (APPJ) can produce biological active species for biomedical applications. This work proves direct evidence of the protective effects of APPJ against oxidative stress. SH-SY5Y cells, a commonly used cell model for the study of neurotoxicity and neuroprotection, were treated with APPJ for different durations. Then, cells were exposed to 200 µM H2O2 for 24 h and cell viability was measured using a CCK-8 kit. Changes in cell apoptosis were further confirmed by calcein-AM fluorescence imaging and flow cytometry. Extracellular NO production was detected using the Griess method. The results showed that APPJ protected SH-SY5Y from H2O2-induced apoptosis in a time-dependent manner. Moreover, extracellular NO production was significantly increased with the APPJ treatment. The results show in vitro that APPJ treatment could protect SH-SY5Y cells from oxidative stress by reducing cell apoptosis, which might be related to the reactive nitrogen species induced by the APPJ treatment. Our results indicate that the APPJ may have therapeutic potential as a novel ‘NO donor drug’ in neuroprotection and in the treatment of neurodegenerative diseases.

  17. Benidipine, a dihydropyridine-calcium channel blocker, inhibits lysophosphatidylcholine-induced endothelial injury via stimulation of nitric oxide release.

    PubMed

    Matsubara, Masahiro; Yao, Kozo; Hasegawa, Kazuhide

    2006-01-01

    Benidipine hydrochloride (benidipine), which is a long-lasting dihydropyridine calcium channel blocker, exerts antihypertensive action via inhibition of Ca(2+) influx through L-type voltage-dependent calcium channels. In addition, benidipine is shown to restore endothelial function. However, the mechanisms whereby benidipine has protective effects on endothelium are poorly defined. Nitric oxide (NO), which is produced by endothelial NO synthase (eNOS), plays important roles in endothelial function. In this study, we examined effects of benidipine on NO production from human umbilical vein endothelial cells. Benidipine (0.3-10 microM) augmented eNOS expression and total eNOS enzymatic activities. Benidipine also promoted the production of NO and the accumulation of cGMP, a second messenger of NO. Lysophosphatidylcholine (lysoPC), a component of oxidized low-density lipoproteins, induced caspase-3 activation followed by apoptosis of endothelial cells. Benidipine (0.3-10 microM) prevented lysoPC-induced caspase-3 activation, which was canceled by Nomega-nitro-L-arginine-methyl ester (L-NAME) (250-2500 microM), an inhibitor of NOS. Moreover, diethylenetetraamine NONOate (30-100 microM), a NO donor, inhibited the caspase-3 activation. These results suggested that the increase in NO production by benidipine might be involved in the inhibition of caspase induction. The direct enhancement of endothelial NO release by benidipine may be in part responsible for amelioration of endothelial dysfunction.

  18. Knee Injuries

    MedlinePlus

    ... injuries. Try weightlifting to strengthen your muscles and stretching, Pilates, and yoga to improve your flexibility because ... lead to injuries and inflammation from overuse. Regular stretching can help. After an injury or surgery has ...

  19. Eye Injuries

    MedlinePlus

    The structure of your face helps protect your eyes from injury. Still, injuries can damage your eye, sometimes severely enough that you could lose your vision. Most eye injuries are preventable. If you play sports or ...

  20. Sports Injuries

    MedlinePlus

    ... sometimes you can injure yourself when you play sports or exercise. Accidents, poor training practices, or improper ... can also lead to injuries. The most common sports injuries are Sprains and strains Knee injuries Swollen ...

  1. Protective effects of melatonin against 12C6+ beam irradiation-induced oxidative stress and DNA injury in the mouse brain

    NASA Astrophysics Data System (ADS)

    Wu, Z. H.; Zhang, H.; Wang, X. Y.; Yang, R.; Liu, B.; Liu, Y.; Zhao, W. P.; Feng, H. Y.; Xue, L. G.; Hao, J. F.; Niu, B. T.; Wang, Z. H.

    2012-01-01

    The purpose of this experiment was to estimate the protective effects of melatonin against radiation-induced brain damages in mice induced by heavy ion beams. Kun-Ming mice were randomly divided into five groups: normal control group, irradiation control group, and three different doses of melatonin (5, 10, and 20 mg/kg, i.p.) treated groups. Apart from the normal control group, the other four groups were exposed to whole-body 4.0 Gy carbon ion beam irradiation (approximately 0.5 Gy/min) after i.p. administration of normal saline or melatonin 1 h before irradiation. The oxidative redox status of brain tissue was assessed by measurement of malondiadehyde (MDA) levels, total superoxide dismutase (T-SOD), cytosolic superoxide dismutase (Cu/ZnSOD, SOD1) and mitochondrial superoxide dismutase (MnSOD, SOD2) activities at 8 h after irradiation. DNA damages were determined using the Comet assay and apoptosis and cell cycle distribution were detected by flow cytometric analyses. A dramatic dose-dependent decrease in MDA levels, tail moment, rates of tailing cells, and apoptosis, and a dose-dependent increase in T-SOD and SOD2 activities, in brain tissues in the melatonin-treated groups were detected compared with the irradiation only group. Furthermore, flow cytometric analysis demonstrated that the percentage of brain cells in the G0/G1 phase decreased significantly, while those in the S and G2/M stage increased dramatically, with mice pretreated with melatonin compared to the irradiation control group. These data indicate that melatonin has protective effects against irradiation-induced brain injury, and that its underlying protective mechanisms may relate to modulation of oxidative stress induced by heavy ionirradiation.

  2. Metal Ion Imbalance-Related Oxidative Stress Is Involved in the Mechanisms of Liver Injury in a Rat Model of Chronic Aluminum Exposure.

    PubMed

    Yang, Yang; Wang, Hong; Guo, Yuanxin; Lei, Wenjuan; Wang, Jianfeng; Hu, Xinyue; Yang, Junqing; He, Qin

    2016-09-01

    The objective of the study is to investigate the effects of chronic aluminum overload on rat liver function and its induction of pathological changes in metal ion levels and oxidative stress in hepatic tissues. Wistar rats were intragastrically administered aluminum gluconate (200 mg Al(3+)/Kg) once a day, 5 days a week, for 20 weeks. HE staining was used to visualize pathological changes in rat liver tissue. A biochemical method was adopted to detect ALT, AST, ALP, and GGT levels, as well as liver SOD activity and blood plasma MDA content. A plasma atomic emission spectrophotometer was used to detect Al, Mn, Fe, Zn, and Cu ion contents in liver tissue. Our results showed obvious vacuolar degeneration, granular degeneration, and spotty necrosis in chronic Al-overload rat hepatocytes. The levels of ALT, AST, ALP, and GGT were significantly increased. Liver SOD activity was significantly decreased, and MDA content was significantly increased. In Al-overload rat liver, Al, Mn, Fe, and Cu contents were significantly increased, and in Al-overload rat serum, Mn, Fe, Zn, and Cu contents were significantly decreased. However, the Al level in Al-overload rat serum was not significantly different from that in control rat serum. These results suggest that chronic aluminum overload causes obvious damage to rat liver and causes imbalances in Al, Mn, Fe, Zn, and Cu levels in rat liver and serum. Metal ion imbalance-related oxidative stress may be involved in the mechanism of chronic liver injury caused by aluminum overload.

  3. Gestational hypermethioninaemia alters oxidative/nitrative status in skeletal muscle and biomarkers of muscular injury and inflammation in serum of rat offspring.

    PubMed

    Schweinberger, Bruna M; Turcatel, Elias; Rodrigues, André F; Wyse, Angela T S

    2015-10-01

    In this study we evaluated oxidative/nitrative stress parameters (reactive oxygen species production, lipid peroxidation, sulfhydryl content, superoxide dismutase, catalase and nitrite levels), as well as total protein content in the gastrocnemius skeletal muscle of the offspring of rats that had been subjected to gestational hypermethioninaemia. The occurrence of muscular injury and inflammation was also measured by creatine kinase activity, levels of creatinine, urea and C-reactive protein and the presence of cardiac troponin I in serum. Wistar female rats (70-90 days of age) received methionine (2.68 μmol/g body weight) or saline (control) twice a day by subcutaneous injections during the gestational period (21 days). After the rats gave birth, pups were killed at the twenty-first day of life for removal of muscle and serum. Methionine treatment increased reactive oxygen species production and lipid peroxidation and decreased sulfhydryl content, antioxidant enzymes activities and nitrite levels, as well as total protein content in skeletal muscle of the offspring. Creatine kinase activity was reduced and urea and C-reactive protein levels were increased in serum of pups. These results were accompanied by reduced muscle mass. Our findings showed that maternal gestational hypermethioninaemia induced changes in oxidative/nitrative status in gastrocnemius skeletal muscle of the offspring. This may represent a mechanism which can contribute to the myopathies and loss of muscular mass that is found in some hypermethioninaemic patients. In addition, we believe that these results may be relevant as gestational hypermethioninaemia could cause damage to the skeletal muscle during intrauterine life.

  4. Pterostilbene attenuates high glucose-induced oxidative injury in hippocampal neuronal cells by activating nuclear factor erythroid 2-related factor 2.

    PubMed

    Yang, Yang; Fan, Chongxi; Wang, Bodong; Ma, Zhiqiang; Wang, Dongjin; Gong, Bing; Di, Shouyin; Jiang, Shuai; Li, Yue; Li, Tian; Yang, Zhi; Luo, Erping

    2017-04-01

    In the present study, neuroblastoma (SH-SY5Y) cells were used to investigate the mechanisms mediating the potential protective effects of pterostilbene (PTE) against mitochondrial metabolic impairment and oxidative stress induced by hyperglycemia for mimicking the diabetic encephalopathy. High glucose medium (100mM) decreased cellular viability after 24h incubation which was evidenced by: (i) reduced mitochondrial complex I and III activities; (ii) reduced mitochondrial cytochrome C; (iii) increased reactive oxygen species (ROS) generation; (iv) decreased mitochondrial membrane potential (ΔΨm); and (v) increased lactate dehydrogenase (LDH) levels. PTE (2.5, 5, and 10μM for 24h) was nontoxic and induced the nuclear transition of Nrf2. Pretreatment of PTE (2.5, 5, and 10μM for 2h) displayed a dose-dependently neuroprotective effect, as indicated by significantly prevented high glucose-induced loss of cellular viability, generation of ROS, reduced mitochondrial complex I and III activities, reduced mitochondrial cytochrome C, decreased ΔΨm, and increased LDH levels. Moreover, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and glutathione S-transferase (GST) were elevated after PTE treatment. In addition, the elevation of nuclear Nrf2 by PTE treatment (10μM for 2h) was abolished by Nrf2 siRNA. Importantly, Nrf2 siRNA induced the opposite changes in mitochondrial complex I and III activities, mitochondrial cytochrome C, reactive species generation, ΔΨm, and LDH. Overall, the present findings were the first to show that pterostilbene attenuated high glucose-induced central nervous system injury in vitro through the activation of Nrf2 signaling, displaying protective effects against mitochondrial dysfunction-derived oxidative stress.

  5. Lung injury-dependent oxidative status and chymotrypsin-like activity of skeletal muscles in hamsters with experimental emphysema

    PubMed Central

    2013-01-01

    Background Peripheral skeletal muscle is altered in patients suffering from emphysema and chronic obstructive pulmonary disease (COPD). Oxidative stress have been demonstrated to participate on skeletal muscle loss of several states, including disuse atrophy, mechanical ventilation, and chronic diseases. No evidences have demonstrated the occurance in a severity manner. Methods We evaluated body weight, muscle loss, oxidative stress, and chymotrypsin-like proteolytic activity in the gastrocnemius muscle of emphysemic hamsters. The experimental animals had 2 different severities of lung damage from experimental emphysema induced by 20 mg/mL (E20) and 40 mg/mL (E40) papain. Results The severity of emphysema increased significantly in E20 (60.52 ± 2.8, p < 0.05) and E40 (52.27 ± 4.7; crossed the alveolar intercepts) groups. As compared to the control group, there was a reduction on body (171.6 ± 15.9 g) and muscle weight (251.87 ± 24.87 mg) in the E20 group (157.5 ± 10.3 mg and 230.12 ± 23.52 mg, for body and muscle weight, respectively), which was accentuated in the E40 group (137.4 ± 7.2 g and 197.87 ± 10.49 mg, for body and muscle weight, respectively). Additionally, the thiobarbituric acid reactive substances (TBARS), tert-butyl hydroperoxide-initiated chemiluminescence (CL), carbonylated proteins, and chymotrypsin-like proteolytic activity were elevated in the E40 group as compared to the E20 group (p < 0.05 for all comparisons). The severity of emphysema significantly correlated with the progressive increase in CL (r = −0.95), TBARS (r = −0.98), carbonyl proteins (r = −0.99), and chymotrypsin-like proteolytic activity (r = −0.90). Furthermore, augmentation of proteolytic activity correlated significantly with CL (r = 0.97), TBARS (r = 0.96), and carbonyl proteins (r = 0.91). Conclusions Taken together, the results of the present study suggest that muscle atrophy observed in this model of emphysema is mediated by increased muscle chymotrypsin

  6. Critical role of gap junction communication, calcium and nitric oxide signaling in bystander responses to focal photodynamic injury.

    PubMed

    Calì, Bianca; Ceolin, Stefano; Ceriani, Federico; Bortolozzi, Mario; Agnellini, Andrielly H R; Zorzi, Veronica; Predonzani, Andrea; Bronte, Vincenzo; Molon, Barbara; Mammano, Fabio

    2015-04-30

    Ionizing and nonionizing radiation affect not only directly targeted cells but also surrounding "bystander" cells. The underlying mechanisms and therapeutic role of bystander responses remain incompletely defined. Here we show that photosentizer activation in a single cell triggers apoptosis in bystander cancer cells, which are electrically coupled by gap junction channels and support the propagation of a Ca2+ wave initiated in the irradiated cell. The latter also acts as source of nitric oxide (NO) that diffuses to bystander cells, in which NO levels are further increased by a mechanism compatible with Ca(2+)-dependent enzymatic production. We detected similar signals in tumors grown in dorsal skinfold chambers applied to live mice. Pharmacological blockade of connexin channels significantly reduced the extent of apoptosis in bystander cells, consistent with a critical role played by intercellular communication, Ca2+ and NO in the bystander effects triggered by photodynamic therapy.

  7. Critical role of gap junction communication, calcium and nitric oxide signaling in bystander responses to focal photodynamic injury

    PubMed Central

    Calì, Bianca; Ceolin, Stefano; Ceriani, Federico; Bortolozzi, Mario; Agnellini, Andrielly H.R.; Zorzi, Veronica; Predonzani, Andrea; Bronte, Vincenzo

    2015-01-01

    Ionizing and nonionizing radiation affect not only directly targeted cells but also surrounding “bystander” cells. The underlying mechanisms and therapeutic role of bystander responses remain incompletely defined. Here we show that photosentizer activation in a single cell triggers apoptosis in bystander cancer cells, which are electrically coupled by gap junction channels and support the propagation of a Ca2+ wave initiated in the irradiated cell. The latter also acts as source of nitric oxide (NO) that diffuses to bystander cells, in which NO levels are further increased by a mechanism compatible with Ca2+-dependent enzymatic production. We detected similar signals in tumors grown in dorsal skinfold chambers applied to live mice. Pharmacological blockade of connexin channels significantly reduced the extent of apoptosis in bystander cells, consistent with a critical role played by intercellular communication, Ca2+ and NO in the bystander effects triggered by photodynamic therapy. PMID:25868859

  8. Betaine supplementation protects against renal injury induced by cadmium intoxication in rats: role of oxidative stress and caspase-3.

    PubMed

    Hagar, Hanan; Al Malki, Waleed

    2014-03-01

    Cadmium (Cd) is an environmental and industrial pollutant that can induce a broad spectrum of toxicological effects that affect various organs in humans and experimental animals. This study aims to investigate the effect of betaine supplementation on cadmium-induced oxidative impairment in rat kidney. The animals were divided into four groups (n=10 per group): control, cadmium, betaine and betaine+cadmium (1) saline control group; (2) cadmium group in which cadmium chloride (CdCl2) was given orally at a daily dose of 5 mg/kg body weight for four weeks; (3) betaine group, in which betaine was given to rats at a dose of 250 mg/kg/day, orally via gavage for six weeks; (4) cadmium+betaine group in which betaine was given at a dose of 250 mg/kg/day, orally via gavage for two weeks prior to cadmium administration and concurrently during cadmium administration for four weeks. Cadmium nephrotoxicity was indicated by elevated blood urea nitrogen (BUN) and serum creatinine levels. Kidneys from cadmium-treated rats showed an increase in lipid peroxidation measured as thiobarbituric acid-reactive substances (TBARS) concentration and reductions in total antioxidant status (TAS), reduced glutathione (GSH) content, glutathione peroxidase (GSH-Px) activity, superoxide dismutase concentration (SOD) and catalase activity. Caspase-3 activity, a marker of DNA damage was also elevated in renal tissues of cadmium-treated rats. Pre-treatment of rats with betaine substantially attenuated the increase in BUN and serum creatinine levels. Betaine also inhibited the increase in TBARS concentration and reversed the cadmium-induced depletion in total antioxidant status, GSH, GSH-Px, SOD and catalase concentrations in renal tissues. Renal caspase-3 activity was also reduced with betaine supplementation. These data emphasize the importance of oxidative stress and caspase signaling cascade in cadmium nephrotoxicity and suggest that betaine pretreatment reduces severity of cadmium nephrotoxicity

  9. Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide-High Angiotensin II-Induced Cardiovascular Injury.

    PubMed

    Pojoga, Luminita H; Yao, Tham M; Opsasnick, Lauren A; Siddiqui, Waleed T; Reslan, Ossama M; Adler, Gail K; Williams, Gordon H; Khalil, Raouf A

    2015-10-01

    Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1-replete or -deficient states would alter vascular function in a mouse model of low nitric oxide (NO)-high angiotensin II (AngII)-induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1-0.2 mg/ml in drinking water at days 1-11) plus AngII (0.7-2.8 mg/kg per day via an osmotic minipump at days 8-11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1(-/-) mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1(-/-) mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1(-/-) mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1(-/-) versus WT mice, further increased with L-NAME + AngII, and not affected by EPL