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1.

Background/Purpose

Ischemic stroke is characterized by high morbidity and mortality worldwide. Matrix metalloproteinase 2 (MMP2), aquaporin (AQP) 4, and AQP9 are linked to permeabilization of the blood-brain barrier (BBB) in cerebral ischemia/reperfusion injury (CIRI). BBB disruption, tissue inflammation, and MMP/AQP upregulation jointly provoke brain edema/swelling after CIRI, while acupuncture and electroacupuncture can alleviate CIRI symptoms. This study evaluated the hypothesis that acupuncture and electroacupuncture can similarly exert neuroprotective actions in a rat model of middle cerebral artery occlusion (MCAO) by modulating MMP2/AQP4/APQ9 expression and inflammatory cell infiltration.

Methods

Eighty 8-week-old Sprague-Dawley rats were randomly divided into sham group S, MCAO model group M, acupuncture group A, electroacupuncture group EA, and edaravone group ED. The MCAO model was established by placement of a suture to block the middle carotid artery, and reperfusion was triggered by suture removal in all groups except group S. Acupuncture and electroacupuncture were administered at acupoints GV20 (governing vessel-20) and ST36 (stomach-36). Rats in groups A, EA, and ED received acupuncture, electroacupuncture, or edaravone, respectively, immediately after MCAO. Neurological function (assessed using the Modified Neurological Severity Score), infarct volume, MMP2/AQP4/AQP9 mRNA and protein expression, and inflammatory cell infiltration were all evaluated at 24 h post-reperfusion.

Results

Acupuncture and electroacupuncture significantly decreased infarct size and improved neurological function. Furthermore, target mRNA and protein levels and inflammatory cell infiltration were significantly reduced in groups A, EA, and ED vs. group M. However, MMP2/AQP levels and inflammatory cell infiltration were generally higher in groups A and EA than in group ED except MMP2 mRNA levels.

Conclusions

Acupuncture and electroacupuncture at GV20 and ST36 both exercised neuroprotective actions in a rat model of MCAO, with no clear differences between groups A and EA. Therefore, acupuncture and electroacupuncture might find utility as adjunctive and complementary treatments to supplement conventional therapy for ischemic stroke.  相似文献   

2.
Siu FK  Lo SC  Leung MC 《Life sciences》2005,77(4):386-399
Reactive oxygen species can directly affect the conformation and activity of sulfhydryl-containing proteins by oxidation of their thiol moiety. During the process of ischemia-reperfusion, the thioredoxin (Trx) system (consisting of thioredoxin reductase (TR), Trx and NADPH) prevents susceptible proteins from this oxidative modification. Oxidative damage is one of the most damaging stress in ischemia. If oxidative stress could be minimized, the damage occurred will be minimized accordingly. We therefore investigated whether electroacupuncture (EA) treatment at Fengchi (GB20) or Zusanli (ST36) acupoints in post-ischemic rats could increase TR-related activities and Trx expression which would translate into maintaining the intact thiol moiety of susceptible proteins in the surrounding. Our results indicated that EA treatment at either acupoint increased the Trx expression in ischemic-reperfused brain tissues. Induced Trx expressed levels gradually increased from post-ischemia day 1 to day 4. Statistical analysis revealed that there was no observable difference in the effect of EA treatment at GB20 and ST36. Sham EA treatment did not induce any Trx expression. EA at either acupoint did not alter TR activities in both non-ischemic and ischemic-reperfused rat brains. Taken overall, our finding suggests that EA treatment at GB20 or ST36 could increase Trx expression which could minimize oxidative modifications of thiol groups of surrounding proteins.  相似文献   

3.
INTRODUCTION: Previous studies have shown the presence of oxidative stress in hyperthyroid patients. The aim of this study was to evaluate the influence of hyperthyroidism on lipid peroxidation, plasma lipoprotein oxidation and antioxidant status. We have estimated the clinical utility of the biochemical parameters analysed as markers of oxidative stress in hyperthyroidism. MATERIAL AND METHODS: Twenty five patients with overt hyperthyroidism because of Graves' disease or toxic multinodular goitre and 20 healthy subjects were included in the study. Lipid peroxidation was evaluated by measurement of peroxides and malondialdehyde with 4-hydroxynonenal (MDA + 4-HNE) concentrations. Autoantibodies against oxidised LDL (anti-oxLDL) were assayed as a marker of lipoprotein oxidation. Changes in the antioxidant defence system were estimated by measurement of total antioxidant status in serum (TAS) and erythrocyte superoxide dismutase activity (SOD). RESULTS: A significant increase in serum concentration of peroxides and MDA + 4-HNE was observed in patients with hyperthyroidism. However, no difference was found in anti-oxLDL concentration and antioxidant status parameters (TAS, SOD) between the control group and the patient group. CONCLUSIONS: Our results indicate an intensification of the oxidative processes caused by an excess of thyroid hormones, which is not accompanied by a response from the antioxidant system. Elevated concentrations of lipid peroxidation products in serum, both peroxides and malondialdehyde with 4-hydroxynonenal, may be useful as markers of oxidative stress during the course of hyperthyroidism.  相似文献   

4.
Prolonged hepatic warm ischemia has been incriminated in oxidative stress after reperfusion. However, the magnitude of oxidative stress during ischemia has been controversial. The aims of the present study were to elucidate whether lipid peroxidation progressed during ischemia and to clarify whether oxidative stress during ischemia aggravated the oxidative damage after reperfusion. Rats were subjected to 30 to 120 min of 70% warm ischemia alone or followed by reperfusion for 60 min. Lipid peroxidation (LPO) was evaluated by amounts of phosphatidylcholine hydroperoxide (PC-OOH) and phosphatidylethanolamine hydroperoxide (PE-OOH) as primary LPO products. Total amounts of malondialdehyde and 4-hydroxy-2-nonenal (MDA + 4-HNE), degraded from hydroperoxides, were also determined. PC-OOH and PE-OOH significantly increased at 60 and 120 min ischemia with concomitant increase of oxidized glutathione. These hydroperoxides did not increase at 60 min reperfusion after 60 min ischemia, whereas they did increase at 60 min reperfusion after 120 min ischemia with deactivation of phospholipid hydroperoxide glutathione peroxidase and superoxide dismutase. The amount of MDA + 4-HNE exhibited similar changes, but the velocity of production dropped with ischemic time longer than 60 min. In conclusion, oxidative stress progressed during ischemia and triggered the oxidative injury after reperfusion. Secondary LPO products are less sensitive, especially during ischemia, which may cause possible underestimation and discrepancy.  相似文献   

5.
目的:研究高压氧预处理对大鼠脑缺血再灌注损伤的保护作用。方法:36只SD大鼠随机分为假手术组、模型组及高压氧预处理组,每组12只。高压氧预处理组大鼠在造模前5天给予高压氧预处理。采用线栓法建立大鼠脑缺血再灌注模型,观察高压氧预处理对脑缺血再灌注损伤大鼠神经功能缺损评分、脑梗死面积的影响,检测大鼠缺血脑组织COX-2 mRNA和蛋白的表达以及IL-1β、TNF-α、MDA的含量。结果:高压氧预处理可明显改善脑缺血再灌注大鼠神经功能缺损评分,减少脑梗死面积,降低COX-2m RNA和蛋白表达量,抑制IL-1β、TNF-α的表达,降低MDA水平。结论:高压氧预处理对大鼠脑缺血再灌注损伤具有明显的保护作用,其机制可能与抑制IL-1β、TNF-α、COX-2的表达以及减弱脂质过氧化反应有关。  相似文献   

6.
This paper reports data on the effect of green tea on the lipid peroxidation products formation and parameters of antioxidative system of the liver, blood serum and central nervous tissue of healthy young rats drinking green tea for five weeks. The rats were permitted free access to solubilized extract of green tea. Bioactive ingredients of green tea extract caused in the liver an increase in the activity of glutathione peroxidase and glutathione reductase and in the content of reduced glutathione as well as marked decrease in lipid hydroperoxides (LOOH), 4-hydroksynonenal (4-HNE) and malondialdehyde (MDA). The concentration of vitamin A increased by about 40%. Minor changes in the measured parameters were observed in the blood serum. GSH content increased slightly, whereas the index of the total antioxidant status increased significantly. In contrast, the lipid peroxidation products, particularly MDA was significantly diminished. In the central nervous tissue the activity of superoxide dismutase and glutathione peroxidase decreased while the activity od glutathione reductase and catalase increased after drinking green tea. Moreover the level of LOOH, 4-HNE and MDA significantly decreased. The use of green tea extract appeared to be beneficial to rats in reducing lipid peroxidation products. These results support and substantiate traditional consumption of green tea as protection against lipid peroxidation in the liver, blood serum, and central nervous tissue.  相似文献   

7.
Increasing evidence has been accumulated for the effectiveness of acupuncture therapy in relieving pain. However, there are limited data on regulation of protein expression after electroacupuncture (EA) intervention. Thus, the present study is designed to determine changes in protein expression following EA stimulation in rats with sciatic nerve chronic constrictive injury (CCI) induced neuropathic pain. Sixty Wistar rats were equally randomized into normal control group, CCI group, and CCI with EA stimulation (EA) group. The CCI model was established by ligature of the left sciatic nerve. EA stimulation was applied at Zusanli (ST36) and Yanglingquan (GB34) in the EA group. Differentially expressed hypothalamic proteins in the three groups were identified by 2-D gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry. The functional clustering and pathway of the identified proteins were analyzed by Mascot software. Results showed that, after CCI, the thermal pain threshold of the affected hind footpad was decreased and was reversed gradually by 12 sessions of EA treatment. Following EA intervention, there were 17 hypothalamic proteins identified with significant changes in the expression (>twofold). Three gene-ontologies (oxidoreductase activity, oxidation reduction, and protein binding) were enriched, while there was a significant regulation of glycolysis/gluconeogenesis/hexose metabolism pathway. These data demonstrate that EA intervention can attenuate pain via regulation of expression of multiple proteins in the hypothalamus. Further, hypothalamic glucose metabolism may be important in supporting energy and neurotransmitter homeostasis in the effects of EA intervention.  相似文献   

8.
Antioxidant ebselen reduces oxidative damage in focal cerebral ischemia   总被引:13,自引:0,他引:13  
The antioxidant and neuroprotective potential of the glutathione peroxidase mimic ebselen has been investigated in experimental stroke. Intravenous ebselen (1 mg/kg/h) or vehicle infusion was started 45 min before permanent middle cerebral artery occlusion in the rat, and continued until the end of the experiment. The topography and extent of oxidative damage to the brain was assessed immunohistochemically using an antibody for DNA damage that identified hydroxylated products of 2'-deoxyguanosine (8-OHdG/8-oxodGuo) and an antibody for lipid peroxidation that identified the 4-hydroxynonenal histidine adduct (4-HNE). Ischemic damage was mapped and evaluated with standard histopathology. In the vehicle-treated rats immunopositive staining for both 8-oxodGuo and 4-HNE extended beyond the boundary of ischemic damage. In ebselen-treated rats, the extent of tissue immunopositive for 8-oxodGuo, and 4-HNE was less than that demonstrating ischemic damage confirming the antioxidant mechanism of action in vivo. In addition, ebselen treatment induced a 28% reduction in cortical ischemic damage (p <.02).  相似文献   

9.
As a traditional therapeutic method, electroacupuncture (EA) has been adopted as an alternative therapy for stroke recovery. Here, we aimed to evaluate whether EA therapy at points of Quchi (LI11) and Zusanli (ST36) alleviated neuronal apoptosis by PTEN signaling pathway after ischemic stroke. A total of 72 male Sprague–Dawley rats were randomized into three groups, including sham group, MCAO group, and EA group. EA was initiated after 24 h of reperfusion for 3 consecutive days. At 72 h following ischemia/reperfusion, neurological deficits, infarct volumes, and TUNEL staining were evaluated and the PTEN pathway-related proteins together with apoptosis-related proteins were detected. The results indicated that EA treatment significantly decreased cerebral infarct volume, neurological deficits and alleviated proportion of apoptotic cells in cerebral ischemic rats. Furthermore, EA significantly up-regulated the phosphorylation levels of PDK1, Akt(Thr308), GSK-3β, and down-regulated the phosphorylation levels of PTEN, Akt(Ser473) in the peri-infarct cortex. EA treatment significantly reduced the up-regulation of caspase-3, cleaved-caspase-3, Bim, and reversed the reduction of Bcl-2 induced by the ischemic stroke. These findings suggest that EA treatment at points of Quchi (LI11)- and Zusanli (ST36)-induced neuroprotection might involve inhibition of apoptosis via PTEN pathway.  相似文献   

10.
Effects of exogenous dehydroepiendrosterone (DHEA) administration on the levels of lipid proxidation products, malondialdyde (MDA)-a thiobarbuteric acid reactive substance (TBARS) and 4-hydroxynonenal (4-HNE) in different brain regions viz. cerebral cortex, hippocampus cerebellum, and brain stem of 12 and 22 months old rats were studied. DHEA treatment significantly depressed TBARS and 4-HNE in all the brain regions studied, in both the age group rats. Interestingly, the magnitude of decrease was higher in the 22 months old rats than that in 12 months old rats. The results suggest that older the animal, better will be the response of exogenous DHEA administration against age-related peroxidative products.  相似文献   

11.
4-hydroxynonenal (4-HNE) is a major aldehyde produced during the lipid peroxidation of ω-6 polyunsaturated fatty acids. Recently, 4-HNE has been reported to contribute to the pathogenesis of neuronal diseases such as Alzheimer's disease. However, the role of 4-HNE in ischemic stroke is unclear yet. In this study, we found that plasma 4-HNE concentrations were higher in the genetic stroke-prone rats (stroke-prone spontaneously hypertensive rats) and experimental stroke rats with middle cerebral artery occlusion (MCAO). Moreover, administration of 4-HNE via intravenous injection before MCAO surgery not only enlarged cerebral ischemia-induced infarct area, but also increased oxidative stress in brain tissue, which was evidenced by the enhanced ROS/MPA levels, and the reduced GSH/GSSG ratio and MnSOD levels. Overexpression of aldehyde dehydrogenasesbcl-2 (ALDH2), an enzyme catalyses 4-HNE, rescued neuronal survival against 4-HNE treatment in PC12 cells. The plasma 4-HNE concentrations in patients with ischemic stroke were higher than those in control subjects. In a small sample population (N=60), the plasma 4-HNE concentration was positively correlated with the plasma homocysteine concentration, a risk factor for ischemic stroke. Taken together, our study suggests that the plasma 4-HNE level is a potential biomarker for ischemic stroke.  相似文献   

12.
It has been previously reported that Nigella sativa oil (NSO) and thymoquinone (TQ), active constituent of N. sativa seeds oil, may prevent oxidative injury in various models. Therefore, we considered the possible effect of TQ and NSO on lipid peroxidation level following cerebral ischemia-reperfusion injury (IRI) in rat hippocampus. Male NMRI rats were divided into nine groups, namely, sham, control, ischemia and ischemia treated with NSO or TQ. TQ (2.5, 5 and 10 mg/kg), NSO (0.048, 0.192 and 0.384 mg/kg), phenytoin (50 mg/kg, as positive control) and saline (10 ml/kg, as negative control) were injected intraperitoneally immediately after reperfusion and the administration was continued every 24h for 72 h after induction of ischemia. The transient global cerebral ischemia was induced using four-vessel-occlusion method for 20 min. Lipid peroxidation level in hippocampus portion was measured as malondialdehyde (MDA) based on its reaction with thiobarbituric acid (TBA) following ischemic insult. The transient global cerebral ischemia induced a significant increase in TBA reactive substances (TBARS) level (p<0.001), in comparison with sham-operated animal. Pretreatment with TQ and NSO were resulted a significant decrease in MDA level as compared with ischemic group (66.9+/-1.5 vs. 297+/-2.5 nmol/g tissue for TQ, 10 mg/kg; p<0.001 and 153.5+/-1.3 nmol/g tissue for NSO, 0.384 mg/kg; p<0.001). Using a reversed-phase HPLC system, the amount of TQ in NSO was also quantified and was 0.58% w/w. These results suggest that TQ and NSO may have protective effects on lipid peroxidation process during IRI in rat hippocampus.  相似文献   

13.
Stroke causes ischemic brain injury and is a leading cause of neurological disability and death. There is, however, no promising therapy to protect the brain from ischemic stress to date. Here we show an exciting finding that optimal electroacupuncture (EA) effectively protects the brain from ischemic injury. The experiments were performed on rats subjected to middle cerebral artery occlusion (MCAO) with continuous monitoring of cerebral blood flow. EA was delivered to acupoints of "Shuigou" (Du 26) and "Baihui" (Du 20) with different intensities and frequencies to optimize the stimulation parameters. The results showed that 1) EA at 1.0-1.2 mA and 5-20 Hz remarkably reduced ischemic infarction, neurological deficit, and death rate; 2) the EA treatment increased the blood flow by >100%, which appeared immediately after the initiation of EA and disappeared after the cessation of EA; 3) the EA treatment promoted the recovery of the blood flow after MCAO; 4) "nonoptimal" parameters of EA (e.g., <0.6 mA or >40 Hz) could not improve the blood flow or reduce ischemic injury; and 5) the same EA treatment with optimal parameters could not increase the blood flow in naive brains. These novel observations suggest that appropriate EA treatment protects the brain from cerebral ischemia by increasing blood flow to the ischemic brain region via a rapid regulation. Our findings have far-reaching impacts on the prevention and treatment of ischemic encephalopathy, and the optimized EA parameters may potentially be a useful clue for the clinical application of EA.  相似文献   

14.
《Reproductive biology》2020,20(1):63-74
In this study, we investigated the mechanism of oxidative damage induced by nicotine and the efficacy of vitamin E, an integral component of cellular membranes, against the damage in follicular/granulosa cells of rat ovaries. The animals were randomly divided into 4 groups; control, nicotine, nicotine + vitaminE, vitamin E (n = 8, per each group). Nicotine and vitamin E were administrated intraperitoneally 1 mg/kg/day and 200 mg/kg/day, respectively, once daily for 2 weeks. Nicotine increased lipid peroxide levels such as lipid peroxide (LPO) and malondialdehyde (MDA) in serum, 4-hydroxynonenal (4-HNE) in granulosa cells and apoptotic granulosa cells in the ovary. Positive correlation occurred between the findings of LPO markers and TUNEL labeling. Level of 17-β estradiol (E2), number of follicles and granulosa cell proliferation decreased with nicotine treatment and negatively correlated with LPO levels and apoptosis in granulosa cells. Ultrastructural study of nicotine treated rat ovaries showed mitochondrial damage and autophagosomes in the granulosa cells. The administration of nicotine and vitamin E together, revealed an increase in E2 level, granulosa cell proliferation and the number of healthy follicles associated with decrease in LPO, MDA, 4-HNE levels and TUNEL reactivity in a manner correlated with each other, compared to the nicotine group. Vitamin E showed to alleviate mitochondrial damage and decrease the number of autophagosomes in granulosa cells. These results suggest that lipid peroxidation may be one of the nicotine’ damage mechanisms on folliculogenesis and vitamin E may prevent nicotine-induced follicular damage through reducing lipid peroxidation level in granulosa cells.  相似文献   

15.
目的 观察电针联合天麻多糖对脑缺血大鼠海马CA3区巢蛋白(Nestin)和脑源性神经营养因子(brain derivedneurotrophic factor,BDNF)表达的影响.方法 将40只SD大鼠随机分为正常对照组、模型组、电针组、天麻多糖组和针药结合组,每组8只.以单侧大脑中动脉栓塞法制备脑缺血模型.造模后2w,天麻多糖组和针药结合组大鼠给予天麻多糖100mg/kg灌胃,每天1次,连续2w;电针组和针药结合组大鼠给予“百会”“足三里”穴电针刺激,持续30 min,每天1次,连续2w.采用免疫组织化学染色法结合图像分析检测海马CA3区Nestin和BDNF的表达.结果 与正常对照组比较,模型组缺血侧海马CA3区Nestin和BDNF阳性表达增加(P<0.05);与模型组比较,电针组、天麻多糖组和针药结合组缺血侧海马CA3区Nestin和BDNF阳性表达显著增加(P<0.05);针药结合组阳性表达显著多于电针组或天麻多糖组(P<0.05).结论 电针与天麻多糖结合可显著增加脑缺血大鼠缺血侧海马CA3区Nestin和BDNF的表达,促进内源性神经干细胞激活,且作用优于单用电针或天麻多糖.  相似文献   

16.
Hepatic oxidative stress and lipid peroxidation are common features of several prevalent disease states, including alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), a common component of the metabolic syndrome. These conditions are characterized in part by excessive accumulation of lipids within hepatocytes, which can lead to autocatalytic degradation of cellular lipids giving rise to electrophilic end products of lipid peroxidation. The pathobiology of reactive lipid aldehydes remains poorly understood. We therefore sought to investigate the effects of 4-hydroxynonenal (4-HNE) and 4-oxononenal (4-ONE) on the transport and secretion of very low-density lipoprotein using HepG2 cells as a model hepatocyte system. Physiologically relevant concentrations of 4-HNE and 4-ONE rapidly disrupted cellular microtubules in a concentration-dependent manner. Interestingly, 4-ONE reduced apolipoprotein B-100 (ApoB) secretion while 4-HNE did not significantly impair secretion. Both 4-HNE and 4-ONE formed adducts with ApoB protein, but 4-HNE adducts were detectable as mono-adducts, while 4-ONE adducts were present as protein–protein cross-links. These results demonstrate that reactive aldehydes generated by lipid peroxidation can differ in their biological effects, and that these differences can be mechanistically explained by the structures of the protein adducts formed.  相似文献   

17.
Production of oxygen radicals by stimulated phagocytes followed by surfactant lipid peroxidation (LPO) and loss of surfactant function have all been implicated in the pathogenesis of acute lung injury. We studied the interactions between natural lung surfactant (Curosurf) and neutrophils in vitro , and compared various antioxidants; (superoxide dismutase (SOD), vitamin E, vitamin C, ebselen and melatonin), or combinations of them in duplicate and triplicate regarding their ability to decrease superoxide production and the peroxidation level of surfactant caused by activated phagocytes. The superoxide production of neutrophils activated by Candida albicans was measured with the nitroblue tetrazolium (NBT) test. The subsequent LPO was estimated as the content of malondialdehyde (MDA) and 4-hydroxyalkenals (4-HNE). We found that lung surfactant decreased the superoxide production by activated neutrophils (29.7%) and that Curosurf was peroxidized with elevated MDA/4-HNE values. With supplements of antioxidants (except vitamin C), superoxide radical production and the surfactant LPO level fell in a dose-dependent manner. The protective effect of the antioxidants differed in each test. SOD had a slight effect in both tests. The findings with vitamin E, melatonin and ebselen were similar. The best combination was that of a natural and a synthetic antioxidant (melatonin-ebselen) with a 60% decrease in comparison to the corresponding control. These findings suggest that antioxidants, particularly in combination, prevent LPO of lung surfactant.  相似文献   

18.
Production of oxygen radicals by stimulated phagocytes followed by surfactant lipid peroxidation (LPO) and loss of surfactant function have all been implicated in the pathogenesis of acute lung injury. We studied the interactions between natural lung surfactant (Curosurf) and neutrophils in vitro, and compared various antioxidants; (superoxide dismutase (SOD), vitamin E, vitamin C, ebselen and melatonin), or combinations of them in duplicate and triplicate regarding their ability to decrease superoxide production and the peroxidation level of surfactant caused by activated phagocytes. The superoxide production of neutrophils activated by Candida albicans was measured with the nitroblue tetrazolium (NBT) test. The subsequent LPO was estimated as the content of malondialdehyde (MDA) and 4-hydroxyalkenals (4-HNE). We found that lung surfactant decreased the superoxide production by activated neutrophils (29.7%) and that Curosurf was peroxidized with elevated MDA/4-HNE values. With supplements of antioxidants (except vitamin C), superoxide radical production and the surfactant LPO level fell in a dose-dependent manner. The protective effect of the antioxidants differed in each test. SOD had a slight effect in both tests. The findings with vitamin E, melatonin and ebselen were similar. The best combination was that of a natural and a synthetic antioxidant (melatonin-ebselen) with a 60% decrease in comparison to the corresponding control. These findings suggest that antioxidants, particularly in combination, prevent LPO of lung surfactant.  相似文献   

19.
Kupffer cells are known to participate in the early events of liver injury involving lipid peroxidation. 4-Hydroxy-2,3-(E)-nonenal (4-HNE), a major aldehydic product of lipid peroxidation, has been shown to modulate numerous cellular systems and is implicated in the pathogenesis of chemically induced liver damage. The purpose of this study was to characterize the metabolic ability of Kupffer cells to detoxify 4-HNE through oxidative (aldehyde dehydrogenase; ALDH), reductive (alcohol dehydrogenase; ADH), and conjugative (glutathione S-transferase; GST) pathways. Aldehyde dehydrogenase and GST activity was observed, while ADH activity was not detectable in isolated Kupffer cells. Additionally, immunoblots demonstrated that Kupffer cells contain ALDH 1 and ALDH 2 isoforms as well as GST A4-4, P1-1, Ya, and Yb. The cytotoxicity of 4-HNE on Kupffer cells was assessed and the TD50 value of 32.5+/-2.2 microM for 4-HNE was determined. HPLC measurement of 4-HNE metabolism using suspensions of Kupffer cells incubated with 25 microLM 4-HNE indicated a loss of 4-HNE over the 30-min time period. Subsequent production of 4-hydroxy-2-nonenoic acid (HNA) suggested the involvement of the ALDH enzyme system and formation of the 4-HNE-glutathione conjugate implicated GST-mediated catalysis. The basal level of glutathione in Kupffer cells (1.33+/-0.3 nmol of glutathione per 10(6) cells) decreased significantly during incubation with 4-HNE concurrent with formation of the 4-HNE-glutathione conjugate. These data demonstrate that oxidative and conjugative pathways are primarily responsible for the metabolism of 4-HNE in Kupffer cells. However, this cell type is characterized by a relatively low capacity to metabolize 4-HNE in comparison to other liver cell types. Collectively, these data suggest that Kupffer cells are potentially vulnerable to the increased concentrations of 4-HNE occurring during oxidative stress.  相似文献   

20.
Incubation of rat striatal synaptosomes in ascorbic acid induced the production of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and 4-hydroxynonenal (4-HNE), a lipid peroxidation aldehydic product. Incubations with 4-HNE, used at a range of concentrations comparable to those obtained during peroxidation, induced a simultaneous, dose-dependent decrease of dopamine (DA) uptake and Na+/K+ ATPase activity and a loss of sulfhydryl (SH) groups. Similar results were observed in a previous study when lipid peroxidation was induced after incubation of synaptosomes in ascorbic acid. Taken together, these data suggest that 4-HNE is an important mediator of oxidative stress and may alter DA uptake after binding to SH groups of the DA transporter and to Na+/K+ ATPase. These toxic events may contribute to the onset and progression of Parkinsons disease.  相似文献   

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