乙醇对大鼠血管内皮细胞的促凋亡作用

目的 探讨乙醇对大鼠血管内皮细胞的促凋亡作用.方法 乙醇灌胃制备大鼠实验模型,选用平铺内皮细胞,苏木素-伊红染色染色、末端脱氧核苷酸转移酶介导的-生物素平移末端标记和分光光度法了解乙醇对大鼠血管内皮细胞的促凋亡作用.结果 正常对照组未见凋亡细胞,而实验各组均可见凋亡细胞,其凋亡率有时间依赖性;实验各组血清中丙二醛含量显著增加和总抗氧化能力显著降低,其值具有时间依赖性.结论 过量乙醇使体内氧化-抗氧化系统严重失衡可导致内皮细胞凋亡.     

API0134对氧自由基诱导内皮细胞表达c-sis mRNA和血小板源性生长因子B链的影响

本文应用免疫组织化学和原位杂交方法，观察中药莲成分ＡＰＩ０１３４对氧自由诱导猪主动脉内皮细胞表达癌基因ｃ－＝ｓｉｓｍＲＮＡ和血小板源性生长因子Ｂ链的影响     

API0134对氧自由基诱导内皮细胞表达c-sis mRNA和血小板源性生长因子B链的影响

本文应用免疫组织化学和原位杂交方法，观察中药穿心莲成分ＡＰＩ０１３４对氧自由基诱导猪主动脉内皮细胞表达癌基因ｃ-ｓｉｓｍＲＮＡ和血小板源性生长因子Ｂ链的影响。结果是，氧自由基能诱导内皮细胞ｃｓｉｓｍＲＮＡ的转录和促血小板源性生长因子Ｂ链表达。ＡＰＩ０１３４能显著抑制氧自由基的上述诱导作用，抑制效应与药物浓度呈正相关。因此提示，ＡＰＩ０１３４的这一作用可能是其抗动脉粥样硬化的机制之一。     

Apoptosis: a potential triggering mechanism of neurological manifestation in Plasmodium falciparum malaria

Plasmodium falciparum infection can lead to a life threatening disease and the pathogenetic mechanisms of severe manifestations are not fully understood. Here, we investigated the capacity of P. falciparum-parasitized red blood cells (PRBC) from 45 children with clinical malaria to induce endothelial cell (EC) apoptosis. In all subjects, PRBC that cytoadhered to ECs could be found albeit to a variable degree. By contrast, PRBC that induce EC apoptosis were found only in nine (20%) subjects. Interestingly, children with neurological manifestations were significantly more likely to harbour apoptogenic strains. There was no quantitative relationship between the capacity of these isolates to cytoadhere and apoptosis induction. We hypothesize that P. falciparum-encoded molecules could be responsible for apoptosis induction and therefore suggest new insights in the pathogenesis of P. falciparum malaria. Further investigations are currently in progress to determine whether these results can be confirmed and to identify putative parasite apoptogenic factors.     

休克／再灌注肝损伤中氧自由基的作用

采用电子自旋共振（ｅｌｅｃｔｒｏｎｓｐｉｎｒｅｓｏｎａｎｃｅ，ＥＳＲ）及自旋捕捉技术直接测定兔休克／再灌注不同时限肝组织内氧自由基（ｏｘｙｇｅｎｆｒｅｅｒａｄｉｃａｌｓ，ＯＦＲ）含量的变化，同时观察肝组织内脂质过氧化物（ｌｉｐｉｄｐｅｒｏｘｉｄｅ，ＬＰＯ）含量，超氧化物岐化酶（ｓｕｐｅｒｏｘｉｄｅｄｉｓｍｕｔａｓｅ，ＳＯＤ）及血清ＡＬＴ活性的变化。结果示，ＯＦＲ易被自由基捕捉剂ＰＢＮ（α－ｐｈｅｎｙｌ－ｔｅｒｔ－ｂｕｔｙｌｎｉｔｒｏｅｎｅ）捕捉，并可通过ＥＳＲ而检测。ＯＦＲ在休克１．５小时后即有明显增高，再灌注１５和３０分钟后增高更为显著，ＬＰＯ、ＳＯＤ于再灌注后才分别有显著增高和降低，ＡＬＴ休克１．５小时后即有大幅度增高。ＬＰＯ、ＡＬＴ与ＯＦＲ有良好的线性正相关，ＳＯＤ与ＯＦＲ有良好的线性负相关，提示兔休克／再灌注肝损伤可能由ＯＦＲ介导。     

"Evolution Canyon," a potential microscale monitor of global warming across life

Climatic change and stress is a major driving force of evolution. The effects of climate change on living organisms have been shown primarily on regional and global scales. Here I propose the "Evolution Canyon" (EC) microscale model as a potential life monitor of global warming in Israel and the rest of the world. The EC model reveals evolution in action at a microscale involving biodiversity divergence, adaptation, and incipient sympatric speciation across life from viruses and bacteria through fungi, plants, and animals. The EC consists of two abutting slopes separated, on average, by 200 m. The tropical, xeric, savannoid, "African" south-facing slope (AS = SFS) abuts the forested "European" north-facing slope (ES = NFS). The AS receives 200-800% higher solar radiation than the ES. The ES represents the south European forested maquis. The AS and ES exhibit drought and shade stress, respectively. Major adaptations on the AS are because of solar radiation, heat, and drought, whereas those on the ES relate to light stress and photosynthesis. Preliminary evidence suggests the extinction of some European species on the ES and AS. In Drosophila, a 10-fold higher migration was recorded in 2003 from the AS to ES. I advance some predictions that could be followed in diverse species in EC. The EC microclimatic model is optimal to track global warming at a microscale across life from viruses and bacteria to mammals in Israel, and in additional ECs across the planet.     

Protein kinase activation by warm and cold hypoxia- reoxygenation in primary-cultured rat hepatocytes-JNK(1)/SAPK(1) involvement in apoptosis

Ischemia-reperfusion procedures induced severe hepatic damages owing to different processes related to hypoxia and reoxygenation (H/R) phases, including the consecutive oxygen free radical (OFR) release. Stress-activated protein kinases (SAPKs) could be activated by extracellular stimuli. The aim of this study was to show whether H/R stress conditions could stimulate these kinases, and especially c-jun-N-terminal kinase (JNK(1)/SAPK(1)), to reveal a potential role of JNK(1)/SAPK(1) in the control of hepatocyte apoptosis. Primary cultured rat hepatocytes, isolated from other liver cells and blood flow, were subjected to warm and cold hypoxia-reoxygenation phases mimicking surgical and transplant conditions. The activation status of SAPKs was evaluated by immunoprecipitation or Western-blotting experiments, whereas apoptosis was assessed by measuring caspase activation and internucleosomal DNA fragmentation in vitro and by TUNEL reaction, in vivo. Hypoxia, and especially hypoxia-reoxygenation, significantly increased JNK(1)/SAPK(1) activation in cultured hepatocytes. Either in warm or cold conditions, OFR scavengers (N-Acetylcystein, Di-Phenyleneiodonium, Deferoxamine) decreased this stimulation. Warm ischemia-reperfusion also led to JNK activation. Hypoxia and especially hypoxia-reoxygenation induced programmed cell death in vivo and in vitro. This last phenomenon was inhibited when hepatocytes were treated with SB 202190, which was described as a potent inhibitor of p38 and JNK activities. Altogether, these results confirmed that JNK(1)/SAPK(1) was activated during the hypoxia-reoxygenation process, and that this activity participated in the onset of the apoptosis program.     

增龄对小鼠心肌氧自由基浓度、超氧化物歧化酶活性及丙二醛含量的影响

以心肌氧自由基(OFR)浓度、超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量为指标,观察了增龄对心肌自由基反应的影响。结果表明:(1)心肌OFR浓度随增龄上升,至13、17月龄时达到显著水平(P<0.05):(2)心肌SOD活性随增龄下降,至13、17月龄时达到显著水平(P<0.05);(3)心肌MDA含量随增龄而增加,至13、17月龄时增加显著(P<0.05,P<0.01);(4)老年小鼠(17月龄)心肌SOD活性与OFR浓度呈高度显著的负相关关系(P<0.01),而MDA含量与OFR浓度呈显著的正相关关系(P<0.05)。上述结果表明,随增龄心肌自由基损伤性因素(OFR—MDA)增加,而保护性因素(SOD)减弱,这可能是老化心脏在结构、功能、代谢方面发生衰退的原因之一。     

Saccadic eye movements are associated with a family history of alcoholism at baseline and after exposure to alcohol

OBJECTIVE: To evaluate the influence of family history of alcoholism (FHA) on the response of saccadic eye movements to alcohol. METHOD: Saccadic performance was evaluated in 54 healthy adult subjects with a FHA (family history-positive) and 49 controls (family history-negative). Alcohol and placebo sessions were presented in counterbalanced order. Alcohol was administered intravenously to achieve and maintain a target breath alcohol concentration of 60 mg/100 ml (60%) for 160 min in each subject. During each session, saccadic eye movement testing was performed at baseline (before infusion of alcohol) and twice during the steady-state target breath alcohol concentration. The saccadic testing elicited visually guided saccades (VGS) and antisaccades (AS). Saccadic latency and velocity and the percentage of AS errors were quantified and analyzed using multivariate analysis of variance. RESULTS: The family history-positive and family history-negative groups showed an overall difference at baseline in AS and VGS latencies and velocities in the alcohol and placebo sessions ( p= 0.006). Alcohol delayed saccades such that AS and VGS latencies increased (p = 0.0001) and slowed the execution of saccades such that peak velocities decreased ( p = 0.0002). The percentage of AS errors decreased after alcohol administration, but no significant effect of alcohol (alcohol versus placebo session) was observed (p = 0.1). Latency of AS saccades demonstrated a significant overall FHA effect (p = 0.02) and a significant interaction between FHA and response to alcohol over time (p = 0.02). CONCLUSIONS: Differences in operational characteristics of the saccadic control system are associated with FHA in adult social drinkers, both at baseline and when the brain is exposed to ethanol at 60 mg/100 ml.     

木贼提取物对大鼠动脉粥样硬化早期血管平滑肌细胞增殖与凋亡的影响

目的研究木贼正丁醇提取物对大鼠动脉粥样硬化（AS）早期主动脉平滑肌细胞增殖及凋亡的影响。方法选用雄性SD大鼠，随机分为正常对照、模型、阻性药对照及提取物组。复制食饵性AS早期模型，同时给予提取物预防性给药。以吉非罗齐为阳性药对照。实验9w，观察主动脉壁病理形态学变化，流式细胞术定量检测主动脉壁平滑肌增殖及凋亡率。结果木贼正丁醇提取物组平滑肌凋亡率明显高于模型组（P〈0．01），增殖指数低于模型组（P〈0．01）。结论木贼正丁醇提取物可促进AS早期平滑肌凋亡，抑制其增殖，具有阻断AS早期病变进展的作用。     

Effect of oxygen free radicals on cardiovascular function at organ and cellular levels

Oxygen free radicals (OFR) have been implicated as a causative factor of cell damage in several pathologic conditions. It is possible that OFR could have effects on cardiac function and contractility. The present investigation deals with the effects of OFR in the absence and in the presence of scavangers of OFR (superoxide dismutase and catalase) on cardiac function, index of cardiac contractility, serum creatine kinase (CK), and blood lactate, PO2 and pH in the anesthetized dogs. The hemodynamic measurements and collection of blood samples for measurement of CK, lactate, PO2 and pH were made before and at various intervals after administration of OFR for 1 hour. Xanthine and xanthine oxidase were used to generate OFR. OFR produced a decrease in cardiac function and indices of myocardial contractility and an increase in the serum CK. OFR produced an increase in the systemic and pulmonary vascular resistance. Although there was a tendency for an increase in the blood lactate, the increase was not significant. The blood PO2 and pH were not affected. Superoxide dismutase (SOD), alone or in combination with catalase, tended to protect cardiac function against the deleterious effects of OFR. Scavangers of OFR prevented the OFR-induced rise in serum CK. Although the protective effect of SOD plus catalase was slightly better than SOD alone, the results were not significantly different from each other. These results suggest that OFR are cardiac depressant and increase the peripheral vascular resistance besides causing cellular damage. Scavangers of OFR may be beneficial in counteracting the deleterious effects of OFR on hemodynamic parameters and cellular integrity.     

Matrix metalloproteinases and atherogenesis in dependence of age

BACKGROUND: Changes in the proteoglycan metabolism of the intima of arteries belong to the initial lesions of atherosclerosis (AS). The accumulation of proteoglycans, alterations of pericellular glycoproteins and modulations of collagen turnover also play a fundamental role in the progression of AS. They influence lipid retention, cell behavior and calcinosis. The decisive role played by the matrix metalloproteinases (MMPs) and their inhibiting factors (tissue inhibitors of metalloproteinases [TIMPs]) in these processes is not yet fully understood and therefore the subject of this overview. The causes of the abrupt change of a long-term existing stabile AS to a vulnerable plaque as well as the participation of age-related vascular wall remodeling in the progression of AS also remain open questions. DISCUSSION: Apart from the well-known risk factors for AS, less well-known influences like the disturbances of gene expression in vascular smooth muscle cells affect an MMP/TIMP imbalance. The various consequences of this imbalance range from intima cell proliferation as an early change in AS as well as accelerated progression to the destabilization of fibrous plaques by increased collagenolysis as well as the formation of aneurysms. Infectious or toxic influences may trigger these mechanisms; an involvement of age-related vessel wall changes should also be considered. The prognostic significance of circulating MMP concentrations for the existence of instabile plaques are of great interest, as is the plaque stabilizing effect of statins by suppression of MMPs. CONCLUSIONS: MMPs navigate the behavior of vascular wall cells in different AS stages, in adaptive remodeling, in normal aging and in non-atherosclerotic vessel disease. The clinical relevance of a disturbance in the MMP/TIMP balance is demonstrated firstly by the initiation of AS due to migration and proliferation of intima cells and secondly in the collagenolysis, necrotic transformation and apoptosis of existing fibrous lesions resulting in instabile rupture proned plaques. Investigations into the genetic typing of MMPs and the results of experimental gene deficiency models have significantly contributed to the clarification of these facts.     

Effects of drink-stress sequence and gender on alcohol stress response dampening in high and low anxiety sensitive drinkers

BACKGROUND: This study tested the appraisal disruption hypothesis of alcohol stress response dampening (SRD) in male and female high or low anxiety sensitive (AS) undergraduates. The hypothesis predicts that alcohol SRD will be greater when drinking occurs before versus after stress exposure. High AS males' predominant social-evaluative concerns further implied that alcohol SRD to a social stressor (i.e., a speech) would be relatively stronger in high AS males than in high AS females. METHODS: Male and female (n=90/gender) high and low AS participants (>or=70th; 相似文献   

Response of saccadic eye movements to alcohol in African American and non-Hispanic white college students

BACKGROUND: The primary goal of this study was to evaluate how race and sex interact with the effects of a moderate dose of alcohol on different ocular control subsystems in African American (AA) and non-Hispanic white American (WA) college students. METHODS: Horizontal visually guided (VG) saccades and antisaccades (AS) of 80 young adult, healthy, AA and WA college students were recorded with an infrared system. Subjects ingested 10 aliquots of ethanol at 3 min intervals, with the aggregate dose precalculated to yield a peak breath alcohol concentration (BrAC) of 80 mg%. Data from the measures performed at baseline and the ascending and descending limbs of the BrAC at approximately 65 mg% were compared across race and sex by multivariate analysis of variance. A no-alcohol control session, performed in 20 of the subjects, documented test-retest reliability of the VG and AS measurements. RESULTS: Both AA and WA groups demonstrated slowing of AS and VG saccades after alcohol administration, but there was no significant effect of 65 mg% alcohol on VG accuracy or AS errors. AS latency recovered toward baseline values, whereas the slowing of VG latency/velocity progressed, during alcohol exposure. There were significant differences between AA and WA groups in the time course of VG latency after alcohol but not in most other dependent measures. No significant effects for sex were observed in any of the saccade measures. The faster disappearance of alcohol in WA compared with AA was replicated, and some measures demonstrated a significant, albeit small, negative correlation between the alcohol disappearance rate and impairing effects of alcohol on saccades. CONCLUSIONS: Prolonged latencies and unchanged percentage of errors reflect a differential effect of alcohol on neural function in specific areas (parietal eye field, superior colliculus, and frontal eye areas). Race may interact with the effect of ethanol on saccadic eye movements in a college student population.     

Activation and function of hepatocyte NF-kappaB in postischemic liver injury

The inhibitor of NF-kappaB (I-kappaB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-kappaB essential modulator (NEMO), and is involved in the activation of NF-kappaB by various stimuli. IKK2 or NEMO constitutive knockout mice die during embryogenesis as a result of massive hepatic apoptosis. Therefore, we examined the role of IKK2 in TNF-induced apoptosis and ischemia/reperfusion (I/R) injury in the liver by using conditional knockout mice. Hepatocyte-specific ablation of IKK2 did not lead to impaired activation of NF-kappaB or increased apoptosis after TNF-alpha stimulation whereas conditional NEMO knockout resulted in complete block of NF-kappaB activation and massive hepatocyte apoptosis. In a model of partial hepatic I/R injury, mice lacking IKK2 in hepatocytes displayed significantly reduced liver necrosis and inflammation than wild-type mice. AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.     

人巨细胞病毒对培养人脐静脉内皮细胞增殖和凋亡的影响

目的 :探讨人巨细胞病毒 (CMV)在动脉粥样硬化发生和发展中的作用。　　方法 :采用流式细胞计数仪观察了人 CMV对离体培养的人脐静脉内皮细胞 (HUVEC)增殖和凋亡的影响。本实验分为 5组 ,分别为正常对照组 ,肿瘤坏死因子细胞凋亡组 ,无血清培养细胞凋亡组 ,CMV感染 肿瘤坏死因子细胞凋亡组 ,CMV感染 无血清培养细胞凋亡组。　　结果 :实验发现无血清培养和肿瘤坏死因子诱导的细胞凋亡率较正常对照组升高 ,而 CMV感染的细胞凋亡率明显降低 ;细胞计数的结果表明 CMV感染后 3天的 HUVEC细胞数是未感染的 5倍。流式细胞仪的检测结果表明 :CMV感染细胞的增殖指数明显高于正常对照组 ,CMV可使细胞耐受无血清培养条件 ,保持细胞增殖。　　结论 :人 CMV感染 HUVEC后能够改变 HUVEC的细胞增殖过程 ,抑制细胞凋亡 ,HUVEC的过度增生及 HUVEC感染引起的炎性反应可能影响内皮细胞的功能 ,甚至破坏内皮细胞 ,导致血栓形成、脂质代谢紊乱 ,最终形成动脉粥样硬化。     

Effects of alcohol on the response to hyperventilation of participants high and low in anxiety sensitivity

BACKGROUND: Previous research suggests that high levels of anxiety sensitivity (AS; fear of anxiety symptoms) may constitute a risk factor for alcohol abuse. The present study evaluated the hypothesis that high AS levels may increase risk for alcohol abuse by promoting a heightened sober reactivity to theoretically relevant stressors and heightened sensitivity to alcohol's emotional reactivity dampening effects, which would negatively reinforce drinking in this population. METHODS: One hundred and two undergraduate participants (51 high AS, 51 low AS) with no history of panic disorder were assigned to either a placebo, low-dose alcohol, or high-dose alcohol beverage condition (17 high AS, 17 low AS per beverage condition). After beverage consumption and absorption, participants underwent a 3 min voluntary hyperventilation challenge. RESULTS AND CONCLUSIONS: High-AS/placebo participants displayed greater affective and cognitive reactivity to the challenge than low-AS/placebo participants, which indicated increased fear and negative thoughts (e.g., "losing control") during hyperventilation among sober high AS individuals. Dose-dependent alcohol dampening of affective and cognitive reactivity to hyperventilation was observed only among high-AS participants, which suggested that high-AS individuals may be particularly sensitive to alcohol-induced reductions in their degree of fear and negative thinking in response to the experience of physical arousal sensations. In contrast, dose-dependent alcohol dampening of self-reported somatic reactivity was observed among both high- and low-AS participants. We discuss implications of these results for understanding risk for alcohol abuse in high-AS individuals, as well as directions for future research.     

Neurohormonal Imbalance: A Neglected Problem—And Potential Therapeutic Target—In Acute Heart Failure

Decompensated or acute heart failure (AHF) is characterized by increased ventricular and atrial pressures which may lead to and be caused by circulatory congestion. Unless due to a primary decrease in cardiac function, congestion arises from volume expansion or vasoconstriction. In turn, volume expansion and vasoconstriction are due to neurohormonal imbalance since both result from activation of the sympathetic nervous system, the renin-angiotensin-aldosterone axis and excess secretion of arginine vasopressin. Outcomes in AHF remain dismal. Loop diuretics are the mainstay of therapy for AHF and may themselves aggravate neurohormonal imbalance. No adjunctive pharmacotherapy has yielded improvement in outcomes in AHF despite many attempts with various vasodilators and inotropes. We, therefore, propose that insufficient attention has been paid to neurohormonal imbalance in AHF. As in chronic HF, rectifying the effects of neurohormonal imbalance may lead to better outcomes. The use of alternative decongestive strategies or adjunctive pharmacotherapy directed at neurohormonal activation could yield benefit.     

Can fructose 1–6 diphosphate (FDP) be an additive to ECC during cardiac surgery?

Extracorporeal circulation (ECC) is the basic support system for patients undergoing cardiac surgery, during which oxygen free radicals (OFR) are generated and involved in ischemic reperfusion injury. This study was done to investigate the protective function of fructose 1–6 diphosphate (FDP) with fresh human red blood cells (RBCs) as a model in vitro and presumably during ECC and cardiac surgery. RBCs were exposed to OFR and mechanical trauma, and then FDP was incubated to RBCs alone and then to RBCs plus OFR. Malondialdehyde (MDA) and red cell filtration rate (RFR) were measured. There was a significant decrease of MDA in RBCs exposed to FDP plus OFR (p<0.01,p<0.001) and an increase of RFR (p<0.05,p<0.001) when compared with RBCs alone or with OFR. A negative correlation was found between MDA and RFR. These results suggest that the protective action of FDP is promising as an additive during ECC in man so as to improve the blood cell rheology and the microcirculation in cardiac surgery with ECC.     

Differential effects of acute alcohol on prepulse inhibition and event-related potentials in adolescent and adult Wistar rats

Background: Previous studies have demonstrated that adolescent and adult rats show differential sensitivity to many of the acute effects of alcohol. We recently reported evidence of developmental differences in the effects of acute alcohol on the cortical electroencephalogram. However, it is unclear whether developmental differences are also observed in other neurophysiological and neurobehavioral measurements known to be sensitive to alcohol exposure. The present study determined the age‐related effects of acute alcohol on behavioral and event‐related potential (ERP) responses to acoustic startle (AS) and prepulse inhibition (PPI). Methods: Male adolescent and adult Wistar rats were implanted with cortical recording electrodes. The effects of acute alcohol (0.0, 0.75, and 1.5 g/kg) on behavioral and ERP responses to AS and PPI were assessed. Results: Acute alcohol (0.75 and 1.5 g/kg) significantly reduced the behavioral and electrophysiological response to AS in adolescent and adult rats. Both 0.75 and 1.5 g/kg alcohol significantly enhanced the behavioral response to PPI in adolescent, but not in adult rats. During prepulse + pulse trials, 1.5 g/kg alcohol significantly increased the N10 pulse response in the adolescent frontal cortex. Acute alcohol (0.75 and 1.5 g/kg) also increased the N1 ERP pulse response to prepulse stimuli in frontal and parietal cortices in adult rats, but not in adolescent rats. Conclusions: These data suggest that alcohol’s effect on behavioral and electrophysiological indices of AS do not differ between adults and adolescents whereas developmental stage does appear to significantly modify alcohol‐influenced response to PPI.