共查询到20条相似文献,搜索用时 265 毫秒
1.
Jinghan Feng Xingmiao Chen Shengwen Lu Wenting Li Dan Yang Weiwei Su Xijun Wang Jiangang Shen 《Molecular neurobiology》2018,55(12):9029-9042
Excessive autophagy/mitophagy plays important roles during cerebral ischemia-reperfusion (I/R) injury. Peroxynitrite (ONOO?), a representative reactive nitrogen species, mediates excessive mitophagy activation and exacerbates cerebral I/R injury. In the present study, we tested the hypothesis that naringin, a natural antioxidant, could inhibit ONOO?-mediated mitophagy activation and attenuate cerebral I/R injury. Firstly, we demonstrated that naringin possessed strong ONOO? scavenging capability and also inhibited the production of superoxide and nitric oxide in SH-SY5Y cells exposed to 10 h oxygen-glucose-deprivation plus 14 h of reoxygenation or ONOO? donor 3-morpholinosydnonimine conditions. Naringin also inhibited the expression of NADPH oxidase subunits and iNOS in rat brains subjected to 2 h ischemia plus 22 h reperfusion. Next, we found that naringin was able to cross the blood-brain barrier, and naringin decreased neurological deficit score, reduced infarct size, and attenuated apoptotic cell death in the ischemia-reperfused rat brains. Furthermore, naringin reduced 3-nitrotyrosine formation, decreased the ratio of LC3-II to LC3-I in mitochondrial fraction, and inhibited the translocation of Parkin to the mitochondria. Taken together, naringin could be a potential therapeutic agent to prevent the brain from I/R injury via attenuating ONOO?-mediated excessive mitophagy. 相似文献
2.
Jinghan Feng Xingmiao Chen Binghe Guan Caiming Li Jinhua Qiu Jiangang Shen 《Molecular neurobiology》2018,55(8):6369-6386
Activated autophagy/mitophagy has been intensively observed in ischemic brain, but its roles remain controversial. Peroxynitrite (ONOO?), as a representative of reactive nitrogen species, is considered as a critical neurotoxic factor in mediating cerebral ischemia-reperfusion (I/R) injury, but its roles in autophagy/mitophagy activation remain unclear. Herein, we hypothesized that ONOO? could induce PINK1/Parkin-mediated mitophagy activation via triggering dynamin-related protein 1 (Drp1) recruitment to damaged mitochondria, contributing to cerebral I/R injury. Firstly, we found PINK1/Parkin-mediated mitophagy activation was predominant among general autophagy, leading to rat brain injury at the reperfusion phase after cerebral ischemia. Subsequently, increased nitrotyrosine was found in the plasma of ischemic stroke patients and ischemia-reperfused rat brains, indicating the generation of ONOO? in ischemic stroke. Moreover, in vivo animal experiments illustrated that ONOO? was dramatically increased, accompanied with mitochondrial recruitment of Drp1, PINK1/Parkin-mediated mitophagy activation, and progressive infarct size in rat ischemic brains at the reperfusion phase. FeTMPyP, a peroxynitrite decomposition catalyst, remarkably reversed mitochondrial recruitment of Drp1, mitophagy activation, and brain injury. Intriguingly, further study revealed that ONOO? induced tyrosine nitration of Drp1 peptide, which might contribute to mitochondrial recruitment of Drp1 for mitophagy activation. In vitro cell experiments yielded consistent results with in vivo animal experiments. Taken together, all above findings support the hypothesis that ONOO?-induced mitophagy activation aggravates cerebral I/R injury via recruiting Drp1 to damaged mitochondria. 相似文献
3.
Joanna Saluk-Juszczak Beata Olas Paweł Nowak Barbara Wachowicz Edward Bald Rafał Głowacki Izabela Pawlaczyk Roman Gancarz 《Central European Journal of Biology》2010,5(6):800-807
The antioxidative activity of the extract from Conyza canadensis in plasma treated with peroxynitrite (ONOO−) (0.1 mM) was studied. C. canadensis is known to possess a broad set of pharmacological effects because of content of various antioxidants, antiplatelet and anticoagulant
compounds. The aim of our study was to assess if this extract protects plasma proteins against oxidative/nitrative damages
induced by ONOO−. The plasma components are continuously exposed to reactive oxygen/nitrogen species action. Peroxynitrite evokes oxidative
stress and induces undesirable effects in biological systems and causes damage to biomolecules. The extract from Conyza (50–2500 mg/ml) caused a dose-dependent reduction of protein nitration by 90%. The oxidation of plasma proteins was diminished
by about 75%. ONOO− oxidized the plasma thiol groups and this process was inhibited by tested extract. The level of reduced protein thiols was
increased thrice at the lowest concentration of extract (50 mg/ml). The highest concentration of extract decreased twice the
level of protein thiols in reduced forms and increased the homocysteine level about 4.5 times. The obtained results demonstrated
that the extract from Conyza possesses antioxidative properties in vitro, protects plasma proteins against toxicity induced by peroxynitrite and has modulating effects on thiol/disulfide redox status. 相似文献
4.
Wang XL Liu HR Tao L Liang F Yan L Zhao RR Lopez BL Christopher TA Ma XL 《Apoptosis : an international journal on programmed cell death》2007,12(7):1209-1217
Polymorphonuclear leukocyte (PMN) accumulation/activation has been implicated as a primary mechanism underlying MI/R injury.
Recent studies have demonstrated that PMNs express inducible nitric oxide synthase (iNOS) and produce toxic reactive nitrogen
species (RNS). However, the role of iNOS-derived reactive nitrogen species and resultant nitrative stress in PMN-induced cardiomyocyte
apoptosis after MI/R remains unclear. Male adult rats were subjected to 30 min of myocardial ischemia followed by 5 h of reperfusion.
Animals were randomized to receive one of the following treatments: MI/R+vehicle; MI/R+L-arginine; PMN depletion followed
by MI/R+vehicle; PMN depletion followed by MI/R+L-arginine; MI/R+1400 W; MI/R+1400 W+L-arginine and MI/R+ FeTMPyP. Ischemia/reperfusion-induced
and L-arginine-enhanced nitrative stress and cardiomyocyte apoptosis were determined. PMN depletion virtually abolished ischemia/reperfusion-
induced PMN accumulation, attenuated ischemic/reperfusion-induced and L-arginine-enhanced nitrative stress, and reduced ischemic/reperfusion-induced
and L-arginine-enhanced cardiomyocyte apoptosis (P values all <0.01). Pre-treatment with 1400 W, a highly selective iNOS inhibitor, had no effect on PMN accumulation in the
ischemic/reperfused tissue. However, this treatment reduced ischemia/reperfusion-induced and L-arginine-enhanced nitrative
stress and cardiomyocyte apoptosis to an extent that is comparable as that seen in PMN depletion group. Treatment with FeTMPyP,
a peroxynitrite decomposition catalyst, had no effect on either PMN accumulation or total NO production. However, treatment
with this ONOO− decomposition catalyst also reduced ischemia/reperfusion-induced and L-arginine-enhanced nitrative stress and cardiomyocyte
apoptosis (P values all <0.01). These results demonstrated that ischemic/reperfusion stimulated PMN accumulation may result in cardiomyocyte
injury by an iNOS-derived nitric oxide initiated and peroxynitrite-mediated mechanism. Therapeutic interventions that block
PMN accumulation, inhibit iNOS activity or scavenge peroxynitrite may reduce nitrative stress and attenuate tissue injury.
Xiao-Liang Wang and Hui-Rong Liu contributed equally to this study. 相似文献
5.
Jun Hu Chun Xia Luo Wei Hua Chu You An Shan Zhong-Ming Qian Gang Zhu Yan Bing Yu Hua Feng 《PloS one》2012,7(12)
Oxidative stress plays an important role in the pathological processes of ischemic brain damage. Many antioxidants have been shown to protect against cerebral ischemia injury by inhibiting oxidative stress both in vitro and in vivo. 20-Hydroxyecdysone (20E), an ecdysteroid hormone, exhibits antioxidative effects. For the work described in this paper, we used an in vitro oxidative damage model and an in vivo ischemic model of middle cerebral artery occlusion (MCAO) to investigate the neuroprotective effects of 20E and the mechanisms related to these effects. Treatment of cells with H2O2 led to neuronal injury, intracellular ROS/RNS generation, mitochondrial membrane potential dissipation, cellular antioxidant potential descent, an increase in malondialdehyde (MDA) and an elevation of intracellular [Ca2+], all of which were markedly attenuated by 20E. Inhibition of the activation of the ASK1-MKK4/7-JNK stress signaling pathway and cleaved caspase-3 induced by oxidative stress were involved in the neuroprotection afforded by 20E. In addition, 20E reduced the expression of iNOS protein by inhibition of NF-κB activation. The neuroprotective effect of 20E was also confirmed in vivo. 20E significantly decreased infarct volume and the neurological deficit score, restored antioxidant potential and inhibited the increase in MDA and TUNEL-positive and cleaved caspase-3-positive cells in the cerebral cortex in MCAO rats. Together, these results support that 20E protects against cerebral ischemia injury by inhibiting ROS/RNS production and modulating oxidative stress-induced signal transduction pathways. 相似文献
6.
Nanetti L Taffi R Vignini A Moroni C Raffaelli F Bacchetti T Silvestrini M Provinciali L Mazzanti L 《Molecular and cellular biochemistry》2007,303(1-2):19-25
Oxidative stress is probably one of the mechanisms involved in neuronal damage induced by ischemia-reperfusion, and the antioxidant
activity of plasma may be an important factor providing protection from neurological damage caused by stroke-associated oxidative
stress. The aim of this study was to investigate the status of oxidative stress, NO and ONOO− levels in patients with atherothrombotic and lacunar acute ischemic stroke and iNOS, eNOS and nitrotyrosine expression in
the same patients. Plasma ONOO− levels were significantly higher in patients than in controls while NO decreases in patients in respect to controls. Densitometric
analysis of bands indicated that iNOS and N-Tyr protein levels were significantly higher in patients in respect to controls.
This study has highlighted a significant NO decrease in our patients compared with controls and this is most probably due
to the increased expression of inducible NO synthase by the effect of thrombotic attack. In fact, the constitutive NO isoforms,
which produce small amounts of NO, are beneficial, while activation of the inducible isoform of NO, which produces much more
NO, causes injury, being its toxicity greatly enhanced by generation of peroxynitrite. The significant ONOO− increase observed in our patients, compared to controls, is most probably due to reaction of NO with O2·−. These findings suggest that free radical production and oxidative stress in ischemic stroke might have a major role in the
pathogenesis of ischemic brain injury. Peroxynitrite might be the main marker of brain damage and neurological impairment
in acute ischemic stroke. 相似文献
7.
Joanna Kolodziejczyk Joanna Saluk-Juszczak Malgorzata M. Posmyk Krystyna M. Janas Barbara Wachowicz 《Central European Journal of Biology》2011,6(4):565-574
The present in vitro study was designed to examine the antioxidative activity of red cabbage anthocyanins (ATH) in the protection of blood plasma
proteins and lipids against damage induced by oxidative stress. Fresh leaves of red cabbage were extracted with a mixture
of methanol/distilled water/0.01% HCl (MeOH/H2O/HCl, 50/50/1, v/v/w). Total ATH concentration [μM] was determined with cyanidin 3-glucoside as a standard. Phenolic profiles
in the crude red cabbage extract were determined using the HPLC method. Plasma samples were exposed to 100 μM peroxynitrite
(ONOO−) or 2 mM hydrogen peroxide (H2O2) in the presence/absence of ATH extract (5–15 μM); oxidative alterations were then assessed. Pre-incubation of plasma with
ATH extract partly reduced oxidative stress in plasma proteins and lipids. Dose-dependent reduction of both ONOO− and H2O2-mediated plasma protein carbonylation was observed. ATH extract partly inhibited the nitrative action of ONOO−, and significantly decreased plasma lipid peroxidation caused by ONOO− or H2O2. Our results demonstrate that anthocyanins present in red cabbage have inhibitory effects on ONOO− and H2O2-induced oxidative stress in blood plasma components. We suggest that red cabbage ATH, as dietary antioxidants, should be
considered as potentially usable nutraceuticals in the prevention of oxidative stress-related diseases. 相似文献
8.
Limor Raz Quan-Guang Zhang Cai-feng Zhou Dong Han Priya Gulati Li-cai Yang Fang Yang Rui-min Wang Darrell W. Brann 《PloS one》2010,5(9)
Background
Recent work by our laboratory and others has implicated NADPH oxidase as having an important role in reactive oxygen species (ROS) generation and neuronal damage following cerebral ischemia, although the mechanisms controlling NADPH oxidase in the brain remain poorly understood. The purpose of the current study was to examine the regulatory and functional role of the Rho GTPase, Rac1 in NADPH oxidase activation, ROS generation and neuronal cell death/cognitive dysfunction following global cerebral ischemia in the male rat.Methodology/Principal Findings
Our studies revealed that NADPH oxidase activity and superoxide (O2 −) production in the hippocampal CA1 region increased rapidly after cerebral ischemia to reach a peak at 3 h post-reperfusion, followed by a fall in levels by 24 h post-reperfusion. Administration of a Rac GTPase inhibitor (NSC23766) 15 min before cerebral ischemia significantly attenuated NADPH oxidase activation and O2 − production at 3 h after stroke as compared to vehicle-treated controls. NSC23766 also attenuated “in situ” O2 − production in the hippocampus after ischemia/reperfusion, as determined by fluorescent oxidized hydroethidine staining. Oxidative stress damage in the hippocampal CA1 after ischemia/reperfusion was also significantly attenuated by NSC23766 treatment, as evidenced by a marked attenuation of immunostaining for the oxidative stress damage markers, 4-HNE, 8-OHdG and H2AX at 24 h in the hippocampal CA1 region following cerebral ischemia. In addition, Morris Water maze testing revealed that Rac GTPase inhibition after ischemic injury significantly improved hippocampal-dependent memory and cognitive spatial abilities at 7–9 d post reperfusion as compared to vehicle-treated animals.Conclusions/Significance
The results of the study suggest that Rac1 GTPase has a critical role in mediating ischemia/reperfusion injury-induced NADPH oxidase activation, ROS generation and oxidative stress in the hippocampal CA1 region of the rat, and thus contributes significantly to neuronal degeneration and cognitive dysfunction following cerebral ischemia. 相似文献9.
Kolodziejczyk J Olas B Wachowicz B Szajwaj B Stochmal A Oleszek W 《Journal of physiology and biochemistry》2011,67(3):391-399
Numerous plants (including clovers) have been widely used in folk medicine for the treatment of different disorders. This
in vitro study was designed to examine the antioxidative effects of the clovamide-rich fraction, obtained from aerial parts
of Trifolium pallidum, in the protection of blood platelets and plasma against the nitrative and oxidative damage, caused by peroxynitrite (ONOO−). Carbonyl groups and 3-nitrotyrosine in blood platelet and plasma proteins were determined by ELISA tests. Thiol groups
level was estimated by using 5,5′-dithio-bis(2-nitro-benzoic acid, DTNB). Plasma lipid peroxidation was measured spectrophotometrically
as the production of thiobarbituric acid reactive substances. The results from our work indicate that clovamide-rich T. pallidum extract may reveal the protective properties in the prevention against oxidative stress. The presence of clovamide-rich T. pallidum extract (12.5–100 μg/ml) partly inhibited ONOO−-mediated protein carbonylation and nitration. All the used concentrations of T. pallidum extract reduced lipid peroxidation in plasma. The antioxidative action of the tested extract in the protection of blood platelet
lipids was less effective; the extract at the lowest final concentration (12.5 μg/ml) had no protective effect against lipid
peroxidation. The present results indicate that the extract from T. pallidum is likely to be a source of compounds with the antioxidative properties, useful in the prevention against the oxidative stress-related
diseases. 相似文献
10.
Tanuja Koppal† Jennifer Drake Servet Yatin† Brad Jordan Sridhar Varadarajan† Lori Bettenhausen† & D. Allan Butterfield†‡ 《Journal of neurochemistry》1999,72(1):310-317
Abstract : Peroxynitrite (ONOO-) is a highly reactive, oxidizing anion with a half-life of <1 s that is formed by reaction of superoxide radical anion with nitric oxide. Several reports of ONOO- -induced oxidation of lipids, proteins, DNA, sulfhydryls, and inactivation of key enzymes have appeared. ONOO- has also been implicated as playing a role in the pathology of several neurodegenerative disorders, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis, among others. Continuing our laboratory's interest in free radical oxidative stress in brain cells in AD, the present study was designed to investigate the damage to brain neocortical synaptosomal membrane proteins and the oxidation-sensitive enzyme glutamine synthetase (GS) caused by exposure to ONOO-. These synaptosomal proteins and GS have previously been shown by us and others to have been oxidatively damaged in AD brain and also following treatment of synaptosomes with amyloid β-peptide. The results of the current study showed that exposure to physiological levels of ONOO- induced significant protein conformational changes, demonstrated using electron paramagnetic resonance in conjunction with a protein-specific spin label, and caused oxidation of proteins, measured by the increase in protein carbonyls. ONOO- also caused inactivation of GS and led to neuronal cell death examined in a hippocampal cell culture system. All these detrimental effects of ONOO- were successfully attenuated by the thiol-containing antioxidant tripeptide glutathione. This research shows that ONOO- can oxidatively modify both membranous and cytosolic proteins, affecting both their physical and chemical nature. These findings are discussed with reference to the potential involvement of ONOO- in AD neurodegeneration. 相似文献
11.
Beth E. Hunter Jolanta Sawicka Danuta Szczesna‐Cordary Peter E. Light Grzegorz Sawicki 《Journal of cellular and molecular medicine》2011,15(5):1136-1147
Damage to cardiac contractile proteins during ischemia followed by reperfusion is mediated by reactive oxygen species such as peroxynitrite (ONOO−), resulting in impairment of cardiac systolic function. However, the pathophysiology of systolic dysfunction during ischemia only, before reperfusion, remains unclear. We suggest that increased ONOO− generation during ischemia leads to nitration/nitrosylation of myosin light chain 1 (MLC1) and its increased degradation by matrix metalloproteinase-2 (MMP-2), which leads to impairment of cardiomyocyte contractility. We also postulate that inhibition of ONOO− action by use of a ONOO− scavenger results in improved recovery from ischemic injury. Isolated rat cardiomyocytes were subjected to 15 and 60 min. of simulated ischemia. Intact MLC1 levels, measured by 2D gel electrophoresis and immunoblot, were shown to decrease with increasing duration of ischemia, which correlated with increasing levels of nitrotyrosine and nitrite/nitrate. In vitro degradation of human recombinant MLC1 by MMP-2 increased after ONOO− exposure of MLC1 in a concentration-dependent manner. Mass spectrometry analysis of ischemic rat cardiomyocyte MLC1 showed nitration of tyrosines 78 and 190, as well as of corresponding tyrosines 73 and 185 within recombinant human cardiac MLC1 treated with ONOO−. Recombinant human cardiac MLC1 was additionally nitrosylated at cysteine 67 and 76 corresponding to cysteine 81 of rat MLC1. Here we show that increased ONOO− production during ischemia induces MLC1 nitration/nitrosylation leading to its increased degradation by MMP-2. Inhibition of MLC1 nitration/nitrosylation during ischemia by the ONOO− scavenger FeTPPS (5,10,15,20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III]), or inhition of MMP-2 activity with phenanthroline, provides an effective protection of cardiomyocyte contractility. 相似文献
12.
Nowak P Saluk-Juszczak J Olas B Kołodziejczyk J Wachowicz B 《Cellular & molecular biology letters》2006,11(1):1-11
Many selenoorganic compounds play an important role in biochemical processes and act as antioxidants, enzyme inhibitors or
drugs. The effects of a new selenocompound — bis(2-aminophenyl)-diselenide on oxidative/nitrative changes in human plasma
proteins induced by peroxynitrite (ONOO−) were studied in vitro and compared with the those of ebselen, a well-known antioxidant. We also studied the role of the tested selenocompounds
in peroxynitrite-induced plasma lipid peroxidation. Exposure of the plasma to peroxynitrite (0.1 mM) resulted in an increase
in the level of carbonyl groups and nitrotyrosine residues in plasma proteins (estimated using the ELISA method and Western
blot analysis). In the presence of different concentrations (0.025–0.1 mM) of the tested selenocompounds, 0.1 mM peroxynitrite
caused a distinct decrease in the level of carbonyl group formation and tyrosine nitration in plasma proteins. Moreover, these
selenocompounds also inhibited plasma lipid peroxidation induced by ONOO−1 (0.1 mM). The obtained results indicate that in vitro bis(2-aminophenyl)-diselenide and ebselen have very similar protective effects against peroxynitrite-induced oxidative/nitrative
damage to human plasma proteins and lipids. 相似文献
13.
Kolodziejczyk J Saluk-Juszczak J Wachowicz B 《Journal of physiology and biochemistry》2011,67(2):175-183
Oxidative stress has been implicated in the pathogenesis of variety of diseases. Since the endogenous antioxidant defense
may be not adequate to counteract the enhanced generation of oxidants, a growing interest in research for exogenous nutrients
has been observed. The present study was designed to assess in vitro the antioxidative properties of the glucose derivatives:
calcium d-glucarate, d-gluconic acid lactone, and sodium d-gluconate (0.5–3 mM) in the protection of plasma proteins and lipids, against the damage caused by 0.1 mM peroxynitrite (ONOO−). Exposure of plasma to ONOO− resulted in carbonyl groups increase, 3-nitrotyrosine (3-NT) formation, reduction in thiol groups, and enhanced lipid peroxidation.
d-Gluconic acid lactone and sodium d-gluconate effectively decreased 3-NT formation; the antinitrative action of calcium d-glucarate was less effective. In plasma samples incubated with ONOO− and tested compounds, the level of carbonyl groups was decreased in comparison to plasma samples treated only with ONOO−. The level of protein −SH groups and glutathione was significantly higher in the presence of glucose derivatives than in
plasma samples treated with ONOO− only. All the tested compounds had the inhibitory effect on the peroxynitrite-induced plasma lipids peroxidation. The results
obtained from our work indicate that calcium d-glucarate, d-gluconic acid lactone, and sodium d-gluconate may partly protect plasma proteins and lipids against peroxynitrite-induced damages. 相似文献
14.
We have previously shown that homocysteine (Hcy) can induce monocyte chemoattractant protein-1 (MCP-1) secretion via reactive oxygen species (ROS) in human monocytes. Here, we show that Hcy upregulates expression of an important antioxidative protein, thioredoxin (Trx), via NADPH oxidase in human monocytes in vitro. The increase of Trx expression and activity inhibited Hcy-induced ROS production and MCP-1 secretion. Of note, 2-week hyperhomocysteinemia (HHcy) ApoE−/− mice showed accelerated lesion formation and parallel lower Trx expression in macrophages than ApoE−/− mice, suggesting that HHcy-induced sustained oxidative stress in vivo might account for impaired Trx and hence increased ROS production and MCP-1 secretion from macrophages, and subsequently accelerated atherogenesis. 相似文献
15.
Peroxynitrite (ONOO−) is a potent oxidant and nitrating species, generated by the reaction of nitric oxide and superoxide in one of the most rapid reactions known in biology. It is widely accepted that an enhanced ONOO− formation contributes to oxidative and nitrosative stress in various biological systems. However, an increasing number of studies have reported that ONOO− cannot only be considered as a mediator of cellular dysfunction, but also behaves as a potent modulator of the redox regulation in various cell signal transduction pathways.Although the formation of ONOO− has been demonstrated in vivo in plant cells, the relevance of this molecule during plant physiological responses is still far from being clarified. Admittedly, the detection of protein tyrosine nitration phenomena provides some justification to the speculations that ONOO is generated during various plant stress responses associated with pathophysiological mechanisms. On the other hand, it was found that ONOO− itself is not as toxic for plant cells as it is for animal ones. Based on the concepts of the role played by ONOO− in biological systems, this review is focused mainly on the search for potential functions of ONOO− in plants. Moreover, it is also an attempt to stimulate a discussion on the significance of protein nitration as a paradigm in signal modulation, since the newest reports identified proteins associated with signal transduction cascades within the plant nitroproteome. 相似文献
16.
Cerebral ischemic damage and infarction are well documented in stroke, which is presenting a foremost health concern globally with very high mortality and morbidity rates. Mechanisms that are associated with excitotoxicity, inflammation and oxidative stress are found to be critically involved in ischemic damage. Adverse effects of current therapies are imposing the need in development of neuroprotective agents that are very effective. To explore this we experimentally induced ischemic brain injury and investigated the effects of plumbagin. Induction of cerebral infarction and ischemia-reperfusion (I/R) was done by middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. Plumbagin (50, 100 or 200 mg/kg b.wt) was intragastrically administered for 9 days before ischemia induction and an hour prior on the day of ischemic insult. Plumbagin treatment attenuated pulmonary edema, neuronal apoptosis and reduced cerebral infarct volume. Cleaved caspase-3 and apoptotic cascade protein expressions were regulated. Overproduction of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and nitric oxide (NO) following I/R were reduced. Prior plumbagin administration had down-regulated NF-κB signalling and MMP-2 and MMP-9 expression. Overall, the results reveal the potent neuroprotective efficacy of plumbagin against I/R-induced brain injury via effectively modulating apoptotic pathways, MMPs and neuro-inflammatory cascades. 相似文献
17.
Simão F Matté A Matté C Soares FM Wyse AT Netto CA Salbego CG 《The Journal of nutritional biochemistry》2011,22(10):921-928
Increased oxidative stress and energy metabolism deficit have been regarded as an important underlying cause for neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. In this study, we investigated the oxidative mechanisms underlying the neuroprotective effects of resveratrol, a potent polyphenol antioxidant found in grapes, on structural and biochemical abnormalities in rats subjected to global cerebral ischemia. Experimental model of transient global cerebral ischemia was induced in Wistar rats by the four vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl and fluoro jade C stained indicated extensive neuronal death at 7 days after I/R. These findings were preceded by a rapid increase in the generation of reactive oxygen species (ROS), nitric oxide (NO), lipid peroxidation, as well as by a decrease in Na+K+-ATPase activity and disrupted antioxidant defenses (enzymatic and non-enzymatic) in hippocampus and cortex. Administrating resveratrol 7 days prior to ischemia by intraperitoneal injections (30 mg/kg) significantly attenuated neuronal death in both studied structures, as well as decreased the generation of ROS, lipid peroxidation and NO content. Furthermore, resveratrol brought antioxidant and Na+K+-ATPase activity in cortex and hippocampus back to normal levels. These results support that resveratrol could be used as a preventive, or therapeutic, agent in global cerebral ischemia and suggest that scavenging of ROS contributes, at least in part, to resveratrol-induced neuroprotection. 相似文献
18.
Kylie Venardos Wei-Zheng Zhang Charles Lang David M. Kaye 《The international journal of biochemistry & cell biology》2009,41(12):2522-2527
Under conditions of oxidative stress it is well known that the bioavailability of nitric oxide (NO) is known to be significantly reduced. This process is in part due to the combination of NO with superoxide radicals to form peroxynitrite (ONOO?). While this process inactivates NO per se, it is not certain to which extent this process may also further impair ongoing NO production. Given the pivotal role of arginine availability for NO synthesis we determined the impact of ONOO? on endothelial arginine transport and intracellular arginine metabolism. Peroxynitrite reduced endothelial [3H]-l-arginine transport and increased the rate of arginine efflux in a concentration-dependent manner (both p < 0.05). In conjunction, exposure to ONOO? significantly reduced the intracellular concentration of l-arginine, NG-hydroxy-l-arginine (an intermediate of NO biosynthesis) and citrulline by 46%, 45% and 60% respectively (all p < 0.05), while asymmetric dimethyl arginine (ADMA) levels rose by 180% (p < 0.05). ONOO? exposure did not alter the cellular distribution of the principal l-arginine transporter, CAT1, rather the effect on CAT1 activity appeared to be mediated by protein nitrosation. Conclusion Peroxynitrite negatively influences NO production by combined effects on arginine uptake and efflux, most likely due to a nitrosative action of ONOO? on CAT-1. 相似文献
19.
Cerebral ischemia is a major cause of adult disability and death worldwide. Evidence suggests that Bax-dependent initiation and activation of intrinsic apoptotic pathways contribute to ischemic brain injury. We investigated the Bax-inhibiting peptide VPALR, designed from the rat Ku70-Bax inhibiting domain, on the apoptotic neuronal cell death and behavioral deficits following global cerebral ischemia. The pentapeptide was infused into the left lateral ventricle of the rat brain by intracerebroventricular (i.c.v.) injection 1 h after cerebral ischemia, and results showed that it highly permeated hippocampal neurons and bound to Bax protein in vivo. Post-treatment with VPALR reduced the delayed neuronal damage by approximately 78% compared to the non-treated ischemic control and scrambled peptide-treated rats. TUNEL analysis revealed that VPALR markedly reduced the ischemia-induced increase in apoptotic neuronal death in rat hippocampal CA1 region. VPALR post-treatment also significantly attenuated Bax activation and its mitochondrial translocation as compared with scrambled peptide-treated animals. Concomitantly, Bax-inhibiting peptide-treated rats showed reduced cytochrome c release from mitochondria to cytosol and reduced caspase-3 activation in response to cerebral ischemia, indicating that activation of the intrinsic apoptotic pathway was reduced. Furthermore, Bax-inhibiting peptide improved spatial learning and memory performance in the Morris water maze, which was seriously affected by global cerebral ischemia. In conclusion, Bax inhibition by cell-permeable pentapeptides reduced apoptotic neuronal injury in the hippocampal CA1 region and behavioral deficits following global ischemia. These results suggest that Bax is a potential target for pharmacological neuroprotection and that Bax-inhibiting peptide may be a promising neuroprotective strategy for cerebral ischemia. 相似文献