• 【儿茶酚胺诱导的交感疼痛中伤害感受器的兴奋。】 复制标题 收藏 收藏
    影响因子 :
    发表时间:2007-02-01
    来源期刊:Pain
    DOI:10.1016/j.pain.2006.08.022 复制DOI
    作者列表:Jørum E,Ørstavik K,Schmidt R,Namer B,Carr RW,Kvarstein G,Hilliges M,Handwerker H,Torebjörk E,Schmelz M
    BACKGROUND & AIMS: :Sympathetically maintained pain could either be mediated by ephaptic interactions between sympathetic efferent and afferent nociceptive fibers or by catecholamine-induced activation of nociceptive nerve endings. We report here single fiber recordings from C nociceptors in a patient with sympathetically maintained pain, in whom sympathetic blockade had repeatedly eliminated the ongoing pain in both legs. We classified eight C-fibers as mechano-responsive and six as mechano-insensitive nociceptors according to their mechanical responsiveness and activity-dependent slowing of conduction velocity (latency increase of 0.5+/-1.1 vs. 7.1+/-2.0 ms for 20 pulses at 0.125 Hz). Two C-fibers were activated with a delay of several seconds following strong endogenous sympathetic bursts; they were also excited for about 3 min following the injection of norepinephrine (10 microl, 0.05%) into their innervation territory. In these two fibers, a prolonged activation by injection of low pH solution (phosphate buffer, pH 6.0, 10 microl) and sensitization of their heat response following prostaglandin E2 injection were recorded, evidencing their afferent nature. Moreover, their activity-dependent slowing was typical for mechano-insensitive nociceptors. We conclude that sensitized mechano-insensitive nociceptors can be activated by endogenously released catecholamines and thereby may contribute to sympathetically maintained pain. No evidence for ephaptic interaction between sympathetic efferent and nociceptive afferent fibers was found.
    背景与目标: : 交感神经的维持性疼痛可以通过交感神经传出和传入伤害性纤维之间的触感相互作用来介导,也可以通过儿茶酚胺诱导的伤害性神经末梢的激活来介导。我们在此报告了一名患有交感持续疼痛的患者的C伤害感受器的单纤维记录,其中交感神经阻滞反复消除了双腿的持续疼痛。我们根据八种C纤维的机械响应性和与活动有关的传导速度减慢 (在0.125Hz下20个脉冲的0.5/-1.1与7.1/-2.0 ms的潜伏期增加),将它们分类为机械敏感的伤害感受器。强烈的内源性交感神经爆发后,两根C纤维被激活,延迟数秒; 在将去甲肾上腺素 (10 microl,0.05%) 注射到其神经支配区域后,它们也被兴奋约3分钟。在这两种纤维中,记录了通过注射低pH溶液 (磷酸盐缓冲液,pH 6.0,10μl) 而延长的活化以及前列腺素E2注射后它们的热响应的敏化,证明了它们的传入性质。此外,对于机械不敏感的伤害感受器,它们的活性依赖性减慢是典型的。我们得出的结论是,内源性释放的儿茶酚胺可以激活敏感的机械不敏感伤害感受器,从而可能导致交感疼痛。没有发现交感传出和伤害性传入纤维之间的触觉相互作用的证据。
  • 【经皮硝酸甘油连续与间歇治疗对清醒兔起搏诱导的预处理的影响。】 复制标题 收藏 收藏
    DOI:10.1038/sj.bjp.0701163 复制DOI
    作者列表:Szilvassy Z,Ferdinandy P,Nagy I,Jakab I,Koltai M
    BACKGROUND & AIMS: :1. Tolerance to the hypotensive effect of nitroglycerin (NG) blocks preconditioning induced by rapid ventricular pacing (RVP) in rabbits. In the present work the effect of continuous versus intermittent treatment with transdermal nitroglycerin on the pacing-induced preconditioning phenomenon was studied in conscious rabbits. 2. RVP (500 beats min-1 over 5 min) increased left ventricular end-diastolic pressure (LVEDP) from baseline 4.1 +/- 0.9 to postpacing 13.8 +/- 2.9 mmHg (P < 0.001) with a right intraventricular ST-segment elevation of 1.25 +/- 0.13 mV, two indicators of myocardial ischaemia. These changes were significantly attenuated when the RVP period was preceded by a preconditioning pacing of the same rate and duration with an interpacing interval of 5 min. 3. Protection by preconditioning was abolished when the animals had been made tolerant to the vasodilator effect of 30 micrograms kg-1 NG by the application of transdermal NG (approx. 0.07 mg kg-1 h-1) over 7 days. Furthermore, transdermal NG per se attenuated both RVP-induced ST-segment elevation and LVEDP-increase over the 7 day period. 4. With intermittent transdermal NG treatment (12 h 'patch on' vs 'patch off'), neither development of vascular tolerance nor attenuation of the NG- or preconditioning-induced anti-ischaemic effects were observed. However, the severity of pacing-induced myocardial ischaemia was significantly increased during the 'patch off' periods. 5. In a second set of experiments, postpacing changes in cardiac cyclic GMP and cyclic AMP levels were determined by means of radioimmunoassay in chronically instrumented anaesthetized open-chest rabbits with the same NG-treatment protocols. Preconditioning reduced postpacing increase in cyclic AMP with an increase in cyclic GMP concentrations in hearts of the untreated animals and in those given patches intermittently during both 'patch on' and 'patch off' periods. However, the preconditioning effect on either cyclic nucleotide was blocked in the tolerant animals. 6. Transdermal NG increased resting levels of both cardiac cyclic nucleotides in the non-tolerant but not in the tolerant state. The postpacing increase in cyclic AMP content was inhibited by transdermal NG, independent of vascular tolerance development, whereas an cyclic GMP content was exclusively seen in the non-tolerant animals. 7. We conclude that the anti-ischaemic effect of NG is independent of the cyclic GMP mechanism in the tolerant state. While intermittent NG therapy prevents development of vascular tolerance and preserves preconditioning, the nitrate-free periods yield an increased susceptibility of the heart to ischaemic challenges.
    背景与目标: : 1。对硝酸甘油 (NG) 的降压作用的耐受性阻断了兔快速心室起搏 (RVP) 引起的预处理。在本工作中,在清醒的兔子中研究了经皮硝酸甘油连续治疗与间歇治疗对起搏诱导的预处理现象的影响。2. RVP (500搏动min-1超过5分钟) 使左室舒张末期压 (LVEDP) 从基线4.1 +/- 0.9增加至起搏后13.8 +/- 2.9 mmHg (P <0.001),右室ST段抬高1.25 +/- 0.13 mV,心肌缺血的两个指标。当在RVP期之前进行相同速率和持续时间的预处理起搏并间隔5分钟时,这些变化会显着减弱。3.当通过在7天内应用透皮NG (约0.07 mg kg-1 h-1) 使动物耐受30微克kg-1 NG的血管舒张作用时,取消了预处理的保护。此外,透皮NG本身在7天内减弱了RVP诱导的ST段抬高和LVEDP升高。4.间歇性经皮NG治疗 (12 h “贴剂” vs “贴剂”),既没有观察到血管耐受性的发展,也没有观察到NG或预处理诱导的抗缺血作用的减弱。然而,起搏引起的心肌缺血的严重程度在 “修补” 期间显着增加。5.在第二组实验中,通过放射免疫分析法确定了具有相同NG治疗方案的慢性仪器麻醉开胸兔的心脏循环GMP和循环AMP水平的起搏后变化。预处理在未处理的动物心脏和给定的补片中,在 “补片” 和 “补片” 期间间歇性地减少了循环AMP的起搏后增加,循环GMP浓度增加。然而,在耐受性动物中,对任一环核苷酸的预处理作用均被阻断。6.透皮NG在非耐受状态下增加了两个心脏环核苷酸的静息水平,但在耐受状态下不增加。经皮NG抑制了循环AMP含量的起搏后增加,与血管耐受性的发展无关,而在非耐受性动物中仅观察到循环GMP含量。7.我们得出结论,在耐受状态下,NG的抗缺血作用与循环GMP机制无关。尽管间歇性NG疗法可防止血管耐受性的发展并保留预处理,但无硝酸盐期会增加心脏对缺血性挑战的敏感性。
  • 【P物质氨基末端代谢物在p物质诱导的小鼠脱敏中的作用。】 复制标题 收藏 收藏
    DOI:10.1016/0306-4522(90)90003-3 复制DOI
    作者列表:Igwe OJ,Sun X,Larson AA
    BACKGROUND & AIMS: :Intrathecal injection of mice with substance P or its C-terminal fragments evokes a well documented behavioral syndrome characterized by caudally-directed biting and scratching. We have previously shown that repeated injections of substance P result in naloxone-sensitive desensitization to this substance P-induced behavior, possibly through interactions of N-terminal fragments of substance P with mu opiate binding sites. The present investigation tests the hypothesis that substance P metabolites play a role in the development of desensitization to substance P by using the biting and scratching behavioral paradigm. While substance P-induced behaviors are produced by as little as 1 pmol of substance P, repeated injections of 7.5 pmol at 60-s intervals was found to be the minimum dose capable of causing desensitization. The C-terminal peptides, substance P3-11 and substance P5-11, elicited substance P-like behaviors, but repeated injection of these compounds did not result in desensitization to this behavior. In contrast to C-terminal fragments, intrathecal injection of N-terminal fragments, (substance P1-4, substance P1-7 and substance P1-9), did not elicit any overt substance P-like behaviors when administered alone, but when co-administered with substance P, decreased the magnitude of substance P-induced behaviors in a dose-related fashion. Various peptidase inhibitors significantly inhibited the catabolism of co-administered substance P. Co-administration of substance P with peptidase inhibitors enhanced and prolonged the substance P-induced behavioral episode, but also prevented the development of substance P-induced desensitization. Together these results support the hypothesis that the accumulation of endogenously generated N-terminal metabolites of substance P mediate desensitization to substance P-induced behaviors in the spinal cord. Substance P metabolism may therefore decrease ongoing substance P activity both by the hydrolysis of the C-terminal portion of substance P as well as by the production of N-terminal metabolites that are capable of inhibiting the effects of substance P.
    背景与目标: : 鞘内注射p物质或其C末端碎片的小鼠会引起一种有据可查的行为综合症,其特征是尾侧指向的咬伤和抓挠。我们先前已经表明,重复注射p物质会导致纳洛酮对该p物质诱导的行为敏感的脱敏,这可能是通过p物质的N末端片段与mu阿片结合位点的相互作用。本研究通过使用咬和刮擦行为范式来检验p物质代谢物在对p物质脱敏过程中起作用的假设。虽然只有1 pmol的p物质产生p物质诱导的行为,但发现以60s间隔重复注射7.5 pmol是能够引起脱敏的最小剂量。C端肽,物质P3-11和物质P5-11引起了物质P样行为,但是反复注射这些化合物并未导致对该行为的脱敏。与C末端片段相反,鞘内注射N末端片段 (物质P1-4,物质P1-7和物质P1-9) 在单独给药时不会引起任何明显的p物质样行为,但与p物质共同给药时,以剂量相关的方式降低p物质诱导的行为的程度。各种肽酶抑制剂可显着抑制共同施用的p物质的分解代谢。P物质与肽酶抑制剂的共同给药可增强和延长p物质诱导的行为发作,但也阻止了p物质诱导的脱敏反应的发展。这些结果共同支持以下假设: p物质的内源性N末端代谢物的积累介导了对p物质诱导的脊髓行为的脱敏。因此,p物质的代谢可能会通过水解p物质的C末端部分以及产生能够抑制p物质作用的N末端代谢物来降低正在进行的p物质活性。
  • 【抗坏血酸对维生素e缺乏大鼠肾上腺细胞ACTH诱导的环AMP形成和类固醇生成的影响。】 复制标题 收藏 收藏
    DOI:10.1016/0304-4165(75)90255-x 复制DOI
    作者列表:Nathans AH,Kitabchi AE
    BACKGROUND & AIMS: :Isolated adrenal cells from Vitamin E-deficient and control rats were prepared by a trypsin digestion method. Cyclic adenosine 3',5'-monophosphate (cyclic AMP) formation was studied in response to adrenocorticotropin (ACTH) in the presence and absence of ascorbate by measuring the conversion of prelabeled adenosine 5'-triphosphate [14C]ATP to cyclic [14C]AMP. Ascorbate (0.5 mM) inhibited ACTH-induced cyclic [14C]AMP formation in adrenal cells isolated from Vitamin E-deficient rats but had no effect in the control cells. The inhibitory effect of ascorbate on ACTH-induced cyclic AMP formation in Vitamin E-deficient rats decreased as the concentration of ACTH increased. In Vitamin E-deficient rats ascorbate inhibited ACTH-induced cyclic [14C]AMP formation after 30 min of incubation. There was no further significant accumulation of cyclic [14C]AMP at 60 min or 120 min although in the absence of ascorbate cyclic [14C]AMP continued to be formed. The in vitro addition of alpha-tocopherol reduced the inhibition of ACTH-induced cyclic [14C]AMP formation by ascorbate in Vitamin E-deficient rats. These studies suggest that alpha-tocopherol and ascorbate may affect ACTH-induced cyclic AMP formation through interaction with the membrane-bound enzyme adenylate cyclase.
    背景与目标: : 通过胰蛋白酶消化法从缺乏维生素e的大鼠和对照大鼠中分离出的肾上腺细胞。环腺苷3 ',通过测量预标记的5'-三磷酸腺苷 [14C]ATP向环状 [14C] 的转化,研究了在存在和不存在抗坏血酸的情况下对促肾上腺皮质激素 (ACTH) 的响应5 '-单磷酸 (环状AMP) 的形成。抗坏血酸 (0.5 mM) 抑制ACTH诱导的环状 [14C] 从缺乏维生素e的大鼠中分离出的肾上腺细胞中的AMP形成,但在对照细胞中没有作用。抗坏血酸对缺乏维生素e的大鼠中ACTH诱导的环状AMP形成的抑制作用随着ACTH浓度的增加而降低。在缺乏维生素e的大鼠中,抗坏血酸抑制ACTH诱导的环状 [培养30分钟后形成14C]AMP。在60分钟或120分钟时没有进一步显著的循环 [14C]AMP积累,尽管在没有抗坏血酸环 [14C]AMP继续形成。α-生育酚的体外添加降低了促肾上腺皮质激素诱导的循环的抑制 [14C] 抗坏血酸在缺乏维生素e的大鼠中形成AMP。这些研究表明,α-生育酚和抗坏血酸可能通过与膜结合酶腺苷酸环化酶的相互作用影响ACTH诱导的环状AMP形成。
  • 【血红素加氧酶诱导与实验诱导的角膜炎症的衰减。】 复制标题 收藏 收藏
    DOI:10.1016/s0006-2952(97)00080-4 复制DOI
    作者列表:Laniado-Schwartzman M,Abraham NG,Conners M,Dunn MW,Levere RD,Kappas A
    BACKGROUND & AIMS: Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular levels of heme and hemeproteins; certain of the latter, i.e. cytochrome P450s, generate pro-inflammatory products from endogenous substrates. Two HO isozymes, the products of distinct genes, have been described; HO-1 is the inducible one, whereas HO-2 is believed to be constitutively expressed. We studied the inducing effects of several metal compounds [CoCl2, SnCl2, ZnCl2, heme, and cobalt protoporphyrin (CoPP)] on HO-1 mRNA content and enzyme activity in cultures of rabbit corneal epithelial (RCE) cells; these metal compounds are known to induce HO in other tissues. Additionally, we studied HO-1 expression in an experimental model of ocular inflammation produced in rabbit corneas by extended contact lens wear, and the relation of HO expression to the induced inflammatory process. SnCl2 added to RCE cells in vitro produced marked time- and concentration-dependent increases in HO-1 mRNA and HO-1 enzyme activity; CoCl2, ZnCl2, and CoPP were inducers of HO as well, though to a lesser degree than SnCl2. Corneas treated for 6 days with contact lenses impregnated with SnCl2 displayed substantially less corneal inflammation, swelling, and new vessel invasion than did controls; attenuation of ocular inflammation was paralleled by SnCl2-induced increases in HO mRNA and HO activity in corneal epithelial cells from treated eyes. It is suggested that amelioration of the inflammatory response produced by extended contact lens wear is due, in part, to the induction of high levels of HO-1 activity by SnCl2, which results in diminished production of pro-inflammatory mediators generated through heme-dependent metabolic processes. Regulation of HO activity in this manner may have clinical applications.

    背景与目标: 血红素加氧酶 (HO) 通过将血红素分解为胆汁色素,下调血红素和血红素的细胞水平; 某些后者,即细胞色素p450,从内源性底物产生促炎产物。已经描述了两个HO同工酶,即不同基因的产物; HO-1是可诱导的,而HO-2被认为是组成型表达的。我们研究了几种金属化合物 [CoCl2,SnCl2,ZnCl2,血红素和钴原卟啉 (CoPP)] 对兔角膜上皮 (RCE) 细胞培养物中HO-1 mRNA含量和酶活性的诱导作用; 这些金属化合物已知会在其他组织中诱导HO。此外,我们研究了通过长时间戴隐形眼镜在兔角膜中产生的眼部炎症的实验模型中的HO-1表达,以及HO表达与诱导的炎症过程的关系。体外添加到RCE细胞中的SnCl2会导致HO-1 mRNA和HO-1酶活性随时间和浓度的显着增加; CoCl2,ZnCl2和CoPP也是HO的诱导剂,尽管程度低于SnCl2。与对照组相比,用SnCl2浸渍的隐形眼镜治疗6天的角膜表现出明显更少的角膜炎症,肿胀和新血管浸润; 眼部炎症的减弱与治疗眼角膜上皮细胞中HO mRNA和HO活性的SnCl2-induced增加平行。建议延长隐形眼镜佩戴产生的炎症反应的改善部分是由于SnCl2诱导了高水平的HO-1活性,从而导致通过血红素产生的促炎症介质的产生减少依赖代谢过程。以这种方式调节HO活性可能具有临床应用。
  • 【细菌基因lfpA影响Burkholderia pseudomalei诱导的TRAP阳性多核巨细胞中降钙素受体和破骨细胞相关基因的有效诱导。】 复制标题 收藏 收藏
    DOI:10.1111/j.1462-5822.2006.00807.x 复制DOI
    作者列表:Boddey JA,Day CJ,Flegg CP,Ulrich RL,Stephens SR,Beacham IR,Morrison NA,Peak IR
    BACKGROUND & AIMS: :Burkholderia pseudomallei is a facultative intracellular pathogen and the causative agent of melioidosis, a spectrum of potentially fatal diseases endemic in Northern Australia and South-East Asia. We demonstrate that B. pseudomallei rapidly modifies infected macrophage-like cells in a manner analagous to osteoclastogenesis. These alterations include multinucleation and the expression by infected cells of mRNA for factors required for osteoclastogenesis: the chemokines monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 gamma (MIP-1gamma), 'regulated on activation normal T cell expressed and secreted' (RANTES) and the transcription factor 'nuclear factor of activated T-cells cytoplasmic 1' (NFATc1). An increase in expression of these factors was also observed after infection with Burkholderia thailandensis. Expression of genes for the osteoclast markers calcitonin receptor (CTR), cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP) was also increased by B. pseudomallei-infected, but not by B. thailandensis-infected cells. The expression by B. pseudomallei-infected cells of these chemokine and osteoclast marker genes was remarkably similar to cells treated with RANKL, a stimulator of osteoclastogenesis. Analysis of dentine resorption by B. pseudomallei-induced osteoclast-like cells revealed that demineralization may occur but that authentic excavation does not take place under the tested conditions. Furthermore, we identified and characterized lfpA (for lactonase family protein A) in B. pseudomallei, which shares significant sequence similarity with the eukaryotic protein 'regucalcin', also known as 'senescence marker protein-30' (SMP-30). LfpA orthologues are widespread in prokaryotes and are well conserved, but are phylogenetically distinct from eukaryotic regucalcin orthologues. We demonstrate that lfpA mRNA expression is dramatically increased in association with macrophage-like cells. Mutation of lfpA significantly reduced expression of the tested host genes, relative to the response to wild-type B. pseudomallei. We also show that lfpA is required for optimal virulence in vivo.
    背景与目标: : pseudomalei伯克霍尔德菌是一种兼性细胞内病原体,也是类鼻疽病的病原体,类鼻疽是澳大利亚北部和东南亚流行的一系列潜在致命疾病。我们证明假单胞菌以类似于破骨细胞发生的方式快速修饰感染的巨噬细胞样细胞。这些改变包括破骨细胞形成所需的因子的多核和感染细胞的mRNA表达: 趋化因子单核细胞趋化蛋白1 (MCP-1),巨噬细胞炎性蛋白1 γ (MIP-1gamma),“调节活化正常T细胞表达和分泌” (RANTES) 和转录因子 “活化T细胞胞质核因子1” (NFATc1)。感染泰国伯克霍尔德菌后,还观察到这些因子的表达增加。破骨细胞标记物降钙素受体 (CTR),组织蛋白酶K (CTSK) 和耐酒石酸酸性磷酸酶 (TRAP) 的基因表达也被假假性芽孢杆菌感染的细胞增加,但未被泰国芽孢杆菌感染的细胞增加。这些趋化因子和破骨细胞标记基因的假假单胞菌感染细胞的表达与用破骨细胞生成刺激物RANKL处理的细胞非常相似。假单胞菌诱导的破骨细胞样细胞对牙本质的吸收分析表明,可能会发生脱矿质,但在测试条件下不会发生真正的挖掘。此外,我们在假单胞菌中鉴定并鉴定了lfpA (用于内酯酶家族蛋白A),该蛋白与真核蛋白 “regucalin” (也称为 “衰老标记蛋白-30” (SMP-30)) 具有显着的序列相似性。LfpA直系同源物在原核生物中广泛存在,并且保存良好,但在系统发育上与真核生物regucalcin直系同源物不同。我们证明lfpA mRNA表达与巨噬细胞样细胞相关显着增加。相对于对野生型B.Pseudomalei的反应,lfpA的突变显着降低了所测试宿主基因的表达。我们还表明,lfpA是体内最佳毒力所必需的。
  • 【辐射诱导的旁观者和其他非靶向效应: 癌症治疗的新干预要点?】 复制标题 收藏 收藏
    DOI:10.2174/156800906777723976 复制DOI
    作者列表:Mothersill C,Seymour C
    BACKGROUND & AIMS: :A major problem in the search for new cancer drug targets is that the drugs are often toxic to normal tissues and require high doses to kill tumor cells. Therefore cellular targets which appear to involve low dose responses to cancer therapy are especially interesting since they could selectively target normal tissues which are not targeted by the treatment and thus may be responsible for unpleasant side effects or may be amenable to exploitation in order to improve the therapeutic ratio. One such target, which is the subject of this review, is radiation-induced bystander effects [RIBE], which result in the observation of radiation like responses in cells which have not been irradiated. RIBE is a novel phenomenon which indicates that at low doses, cell signaling is more important than direct DNA damage. Historically, DNA has always been considered to be the target for radiation therapy. The growing realization that signaling is important opens up several important therapeutic strategies which will be discussed in this review. RIBE appears to be the result of a generalized stress response in tissues or cells which is expressed at the level of the tissue, organ or organism rather than at the level of the individual cell. The signals may be produced by all exposed cells, but the response may require a quorum of cells in order to be expressed. The major response involving low LET (x- or gamma-ray) radiation exposure discussed in the existing literature is a death response. This has many characteristics of apoptosis but may be detected in cell lines without p53 expression, although the death response is suppressed in many tumor cell lines. While a death response in unirradiated normal cells around a tumor might appear to be adverse, it can in fact be protective and remove damaged cells from the population. If harnessed correctly, it could lead to the development of new drugs aimed not at tissue destruction but at enabling homeostatic mechanisms to control tumor expansion. In this scenario, the level of harmful or beneficial response will be related to the background damage, carried by the cell population, and the genetic programme determining response to damage. This focus may be important when attempting to predict the consequences of mixed therapies involving radiation and other cytotoxic agents. In this review, our current knowledge of the mechanisms underlying the induction of bystander effects by ionizing radiation is reviewed, and the question of how bystander effects may be harnessed to produce a new generation of anti-cancer drugs aimed at stabilization of tissue homeostasis rather than tissue destruction is considered.
    背景与目标: : 寻找新的癌症药物靶标的一个主要问题是,这些药物通常对正常组织有毒,需要高剂量才能杀死肿瘤细胞。因此,似乎涉及对癌症治疗的低剂量反应的细胞靶标是特别令人感兴趣的,因为它们可以选择性地靶向不被治疗靶向的正常组织,并且因此可能导致令人不快的副作用或可能易于利用以提高治疗比率。作为本综述主题的一个这样的目标是辐射诱导的旁观者效应 [RIBE],该效应导致在未辐照的细胞中观察到类似辐射的反应。RIBE是一种新现象,表明在低剂量下,细胞信号传导比直接DNA损伤更重要。从历史上看,DNA一直被认为是放射治疗的目标。越来越多的意识到信号很重要,这开辟了一些重要的治疗策略,这些策略将在本文中进行讨论。RIBE似乎是组织或细胞中普遍应激反应的结果,该应激反应在组织,器官或生物体的水平而不是单个细胞的水平上表达。信号可能由所有暴露的细胞产生,但是响应可能需要一定数量的细胞才能表达。现有文献中讨论的涉及低LET (x射线或伽马射线) 辐射暴露的主要反应是死亡反应。这具有许多凋亡特征,但可以在没有p53表达的细胞系中检测到,尽管在许多肿瘤细胞系中死亡反应受到抑制。虽然肿瘤周围未照射的正常细胞的死亡反应似乎是不利的,但实际上它可以起到保护作用并从人群中清除受损的细胞。如果正确使用,它可能会导致新药的开发,其目的不是组织破坏,而是使稳态机制能够控制肿瘤的扩张。在这种情况下,有害或有益反应的水平将与细胞群体携带的背景损害以及确定对损害反应的遗传程序有关。在尝试预测涉及辐射和其他细胞毒性药物的混合疗法的后果时,此重点可能很重要。在这篇综述中,我们对电离辐射诱导旁观者效应的潜在机制的当前知识进行了综述,并讨论了如何利用旁观者效应来生产旨在稳定组织稳态而不是组织破坏的新一代抗癌药物的问题。
  • 【尽管dec1上调,但低氧治疗仍抑制胰岛素诱导的ATDC5细胞软骨形成。】 复制标题 收藏 收藏
    DOI:10.1080/03008200600609558 复制DOI
    作者列表:Chen L,Fink T,Ebbesen P,Zachar V
    BACKGROUND & AIMS: :Chondrogenesis occurs in vivo in a hypoxic environment, in which the hypoxia inducible factor 1, HIF-1, plays a regulatory role, possibly mediated through the transcription factor DEC1. We have analyzed the effect of hypoxia (1% oxygen) alone and in combination with insulin on the chondrogenic differentiation of the mouse embryonic stem cell line ATDC5. Hypoxic treatment alone induced early chondrogenesis as evidenced by enhanced expression of aggrecan and collagen II, whereas hypoxic incubation of insulin-treated cells delayed and suppressed insulin-mediated early chondrogenesis and almost completely blocked hypertrophic differentiation. Paradoxically, the transcriptional activation of DEC1 was invariably enhanced by the hypoxic exposure.
    背景与目标: : 软骨发生在体内低氧环境中,其中低氧诱导因子1 HIF-1发挥调节作用,可能通过转录因子dec1介导。我们已经分析了单独缺氧 (1% 氧) 以及与胰岛素联合使用对小鼠胚胎干细胞系atdc5软骨分化的影响。单独的低氧治疗可诱导早期软骨形成,这可以通过增强聚集蛋白聚糖和胶原蛋白II的表达来证明,而胰岛素处理的细胞的低氧孵育会延迟并抑制胰岛素介导的早期软骨形成,并且几乎完全阻断了肥厚分化。矛盾的是,低氧暴露总是会增强DEC1的转录激活。
  • 【脓毒症诱导的肺先天免疫抑制是由IRAK-M介导的。】 复制标题 收藏 收藏
    DOI:10.1172/JCI28054 复制DOI
    作者列表:Deng JC,Cheng G,Newstead MW,Zeng X,Kobayashi K,Flavell RA,Standiford TJ
    BACKGROUND & AIMS: :Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonasaeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M(-/-) animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M(-/-) animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.
    背景与目标: 败血症导致相对免疫抑制状态,使重症患者易继发感染并增加死亡率。从败血症患者和实验动物中分离出的单核细胞显示出 “失活” 表型,其特征是炎症和抗菌反应受损,包括对LPS的低反应性。我们研究了LPS/TLR4轴及其抑制剂IL-1受体相关激酶M (IRAK-M) 在调节脓毒症免疫抑制中的作用,该模型使用腹膜炎诱导的脓毒症,然后通过气管内假单胞菌继发攻击的鼠模型。与非败血症对照组相比,败血症小鼠的肺泡巨噬细胞功能受损,死亡率增加。脓毒症后肺中TLR2和TLR4表达不变,而IRAK-M水平上调。与WT对应物相比,来自IRAK-M缺陷脓毒症小鼠的巨噬细胞在体外产生更高水平的促炎细胞因子,并在体内产生更大的共刺激分子表达。与WT小鼠相比,在败血症和继发性肺内细菌攻击后,IRAK-M(-/-) 动物具有更高的存活率,并且从肺和血液中清除细菌。此外,在IRAK-M(-/-) 动物中观察到肺趋化因子和炎性细胞因子的产生增加,导致中性粒细胞向空气空间的募集增强。总的来说,这些发现表明IRAK-M介导了先天免疫的关键方面,从而导致败血症期间的免疫功能低下状态。
  • 【ATP诱导的腿部血管舒张对人体最大运动过程中VO2峰值和腿部O2提取的影响。】 复制标题 收藏 收藏
    DOI:10.1152/ajpregu.00746.2005 复制DOI
    作者列表:Calbet JA,Lundby C,Sander M,Robach P,Saltin B,Boushel R
    BACKGROUND & AIMS: :During maximal whole body exercise VO2 peak is limited by O2 delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2 delivery and leg VO2 during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 microg.kg body mass-1.min-1. During near-maximal exercise (92% of VO2 peak), the infusion of ATP increased leg vascular conductance (+43%, P<0.05), leg blood flow (+20%, 1.7 l/min, P<0.05), and leg O2 delivery (+20%, 0.3 l/min, P<0.05). No effects were observed on leg or systemic VO2. Leg O2 fractional extraction was decreased from 85+/-3 (control) to 78+/-4% (ATP) in the infused leg (P<0.05), while it remained unchanged in the left leg (84+/-2 and 83+/-2%; control and ATP; n=3). ATP infusion at maximal exercise increased leg vascular conductance by 17% (P<0.05), while leg blood flow tended to be elevated by 0.8 l/min (P=0.08). However, neither systemic nor leg peak VO2 values where enhanced due to a reduction of O2 extraction from 84+/-4 to 76+/-4%, in the control and ATP conditions, respectively (P<0.05). In summary, the VO2 of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2 extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active muscle fibers of the exercising limb.
    背景与目标: : 在最大的全身运动期间,VO2峰值受到O2输送的限制。反过来,尽管在接近最大运动时的血流必须受到交感神经系统的限制,以维持平均动脉压。为了确定在人类接近最大和最大运动期间,增强腿部的血管舒张是否会导致较高的O2递送和腿部VO2,七名男子在自行车测功机上进行了两次最大增量运动测试。以随机顺序,进行一次测试,其中一次 (对照运动) 以80微克kg身体mass-1.min-1的速率将ATP (8 mg在1毫升的等渗盐溶液中) 输注到右股动脉中。在接近最大运动 (VO2峰的92%) 期间,ATP的输注增加了腿部血管电导 (43%,P<0.05),腿部血流量 (20%,1.7 l/min,P<0.05) 和腿部O2的输送 (20%,0.3 l/min,P<0.05)。未观察到对腿部或全身vo2的影响。腿部O2分数提取在输注的腿部从85 +/-3 (对照) 降低到78 +/-4% (ATP) (P & lt; 0.05),而在左腿保持不变 (84 +/-2和83 +/-2%; 对照和ATP; n = 3)。最大运动时ATP输注可增加17% (P<0.05),而腿部血流量可增加0.8 l/min (P = 0.08)。然而,在对照和ATP条件下,由于O2提取从84 +/-4降低到76 +/-4% 而增强的体循环或腿部峰值VO2值都没有增强 (P<0.05)。总而言之,在人类几乎最大或最大的运动中,肢体血管舒张不会增强下肢骨骼肌的VO2。ATP输注导致运动腿部O2提取减少的事实表明,ATP对活动较少的肌纤维和其他非收缩组织具有血管舒张作用,并且在正常条件下,这些区域处于较高的血管收缩作用下,以确保最有效的血流分布。锻炼肢体的肌肉纤维。
  • 【血管紧张素II体外诱导大鼠和人小肠壁肌肉组织收缩。】 复制标题 收藏 收藏
    DOI:10.1111/j.1748-1716.2006.01600.x 复制DOI
    作者列表:Ewert S,Spak E,Olbers T,Johnsson E,Edebo A,Fändriks L
    BACKGROUND & AIMS: BACKGROUND:Angiotensin II (Ang II) is a well-known activator of smooth muscle in the vasculature but has been little explored with regard to intestinal wall muscular activity. This study investigates pharmacological properties of Ang II and expression of its receptors in small-intestinal smooth muscle from rats and humans. METHODS:Isometric recordings were performed in vitro on small intestinal longitudinal muscle strips. Protein expressions of Ang II typ 1 (AT1R) and typ 2 (AT2R) receptors were assessed by Western blot. RESULTS:Ang II elicited concentration-dependent contractions of rat jejunal and ileal muscle preparations. The concentration-response curve (rat ileum, EC(50): 1.5 +/- 0.9 x 10(-8) M) was shifted to the right by the AT1R receptor antagonist losartan (10(-7) M) but was unaffected by the AT2R antagonist PD123319 (10(-7) M) as well as by the adrenolytic guanethidine (3 x 10(-6) M) and the anticholinergic atropine (10(-6) M). Human duodenal, jejunal and ileal longitudinal muscle preparations all contracted concentration-dependently in response to Ang II. The concentration-response curve (human jejunum, EC(50): 1.5 +/- 0.8 x 10(-8) M) was shifted to the right by losartan (10(-7) M) but was unaffected by PD123319 (10(-7) M). Both AT1R and AT2R were detected in all segments of the rat small intestinal wall musculature, whereas only AT1R was readily detectable in the human samples. CONCLUSION:Ang II elicits contractions of small-intestinal longitudinal muscle preparations from the small intestine of rats and man. The pharmacological pattern and protein expression analyses indicate mediation via the AT1R.
    背景与目标:
  • 【过氧化物酶体增殖物激活受体配体的直接抗氧化和抗炎作用与链脲佐菌素诱导的糖尿病大鼠主动脉中血管紧张素转化酶表达的抑制有关。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2006.08.036 复制DOI
    作者列表:Toba H,Miki S,Shimizu T,Yoshimura A,Inoue R,Sawai N,Tsukamoto R,Murakami M,Morita Y,Nakayama Y,Kobara M,Nakata T
    BACKGROUND & AIMS: :Peroxisome proliferator-activated receptors (PPARs) are expressed on vascular tissue. To investigate the direct vasoprotective effects of PPARgamma and PPARalpha ligands, pioglitazone (3 mg/kg/day) and bezafibrate (10 mg/kg/day) were given by gavage to streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, i.p.) significantly increased NADPH oxidase, vascular call adhesion molecule-1 (VCAM-1), and osteopontin mRNA levels in the aorta, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Immunohistochemical analysis revealed that the expression of osteopontin protein was also enhanced in the streptozotocin-injected rat aorta. Pioglitazone or bezafibrate attenuated the streptozotocin-induced increase in the expression of NADPH oxidase and VCAM-1 mRNA. The enhanced expression of osteopontin gene and protein induced by streptozotocin was suppressed by pioglitazone, whereas treatment with bezafibrate had no effect on the expression of osteopontin. We also demonstrated that pioglitazone or bezafibrate prevented the streptozotocin-induced increase in angiotensin converting enzyme (ACE) gene and protein content, by the means of RT-PCR and Western blotting. On the other hand, the treatment of pioglitazone or bezafibrate in the present study did not affect glucose tolerance, serum insulin or lipid level in streptozotocin-induced diabetic rats. These results suggest that the direct anti-oxidant and anti-inflammatory effects of PPARs ligands in the aorta of streptozotocin-induced diabetic rats were not likely to have been mediated by the normalization of glucose or lipid metabolism, but instead these salutary effects appear to have been associated with the inhibition of the expression of ACE. In addition, pioglitazone appeared to be more effective on the suppression of osteopontin expression compared with bezafibrate.
    背景与目标: : 过氧化物酶体增殖物激活受体 (ppar) 在血管组织上表达。为研究PPARgamma和PPARalpha配体的直接血管保护作用,将吡格列酮 (3 mg/kg/天) 和苯扎贝特 (10 mg/kg/天) 灌胃给链脲佐菌素诱导的糖尿病大鼠4周。通过逆转录 (RT)-聚合酶链反应 (PCR) 测定,链脲佐菌素 (65 mg/kg,i.p.) 显着增加主动脉中的NADPH氧化酶,血管呼叫粘附分子-1 (VCAM-1) 和骨桥蛋白mRNA水平。免疫组织化学分析显示,在注射链脲佐菌素的大鼠主动脉中,骨桥蛋白的表达也得到了增强。吡格列酮或苯扎贝特减弱了链脲佐菌素诱导的NADPH氧化酶和VCAM-1 mRNA表达的增加。吡格列酮抑制了链脲佐菌素诱导的骨桥蛋白基因和蛋白的增强表达,而苯扎贝特治疗对骨桥蛋白的表达没有影响。我们还证明,吡格列酮或苯扎贝特通过rt-pcr和Western印迹阻止了链脲佐菌素诱导的血管紧张素转化酶 (ACE) 基因和蛋白质含量的增加。另一方面,本研究中吡格列酮或苯扎贝特的治疗不会影响链脲佐菌素诱导的糖尿病大鼠的葡萄糖耐量,血清胰岛素或脂质水平。这些结果表明,链脲佐菌素诱导的糖尿病大鼠主动脉中ppar配体的直接抗氧化和抗炎作用不太可能由葡萄糖或脂质代谢的正常化介导。但是,这些有益的作用似乎与抑制ACE的表达有关。此外,与苯扎贝特相比,吡格列酮似乎对抑制骨桥蛋白表达更有效。
  • 【蛋白酶抑制剂、激肽和海绵植入诱导的大鼠炎症反应。】 复制标题 收藏 收藏
    DOI:10.1016/0014-2999(90)90573-o 复制DOI
    作者列表:Damas J,Bourdon V,Remacle-Volon G,Adam A
    BACKGROUND & AIMS: :We studied the influence of aprotinin and soya bean trypsin inhibitor (SBTI) on the inflammatory reaction induced by the implantation of dry sponges in normal Wistar rats and in kininogen-deficient Brown Norway rats, during the first day after the implantation. In normal rats, aprotinin reduced the volume and total protein content of the exudates at 3 h but not thereafter. Aprotinin also markedly reduced the immunoreactive kinins and kallikrein in the exudates. Aprotinin did not modify the volume of the exudates of the Brown Norway rats. SBTI reduced the inflammatory reaction in both rat strains but did not significantly modify the formation of immunoreactive kinins. The inflammatory reaction developed more slowly in Brown Norway rats. The kinin system is thus involved during the first hours of the development of this acute inflammatory reaction. The anti-inflammatory effect of SBTI does not depend on the inhibition of kinin formation.
    背景与目标: : 我们在植入后的第一天研究了抑肽酶和大豆胰蛋白酶抑制剂 (SBTI) 对正常Wistar大鼠和缺乏激肽原的棕色挪威大鼠中干海绵植入诱导的炎症反应的影响。在正常大鼠中,抑肽酶在3小时内减少了渗出物的体积和总蛋白含量,但此后并未减少。抑肽酶还显着降低了分泌物中的免疫反应性激肽和激肽释放酶。抑肽酶不会改变棕色挪威大鼠的渗出物的体积。SBTI降低了两种大鼠品系的炎症反应,但并未显着改变免疫反应性激肽的形成。棕色挪威大鼠的炎症反应发展较慢。因此,在这种急性炎症反应发生的最初几个小时内,激肽系统就参与其中。SBTI的抗炎作用不取决于激肽形成的抑制作用。
  • 【双膦酸盐诱导的颌骨骨坏死: 对比增强MR成像,[18F] 氟化物PET/CT和圆锥束CT成像的疾病程度比较。】 复制标题 收藏 收藏
    DOI:10.3174/ajnr.A3355 复制DOI
    作者列表:Guggenberger R,Fischer DR,Metzler P,Andreisek G,Nanz D,Jacobsen C,Schmid DT
    BACKGROUND & AIMS: BACKGROUND AND PURPOSE:Imaging of bisphosphonate-induced osteonecrosis of the jaw is essential for surgical planning. We compared the extent of BONJ on contrast-enhanced MR imaging, [(18)F] fluoride PET/CT, and panoramic views derived from standard conebeam CT with clinical pre- and intraoperative examinations. MATERIALS AND METHODS:Between February 2011 and January 2012, ten subjects with written informed consent (9 women; mean, 69.6 years; range, 53-88 years) were included in this prospective ethics-board-approved study. Patients underwent CEMR imaging, [(18)F] fluoride PET/CT, and CBCT and were clinically examined pre- and intraoperatively. Surgery was performed, and BONJ was histologically confirmed in 9 patients. Location and extent of BONJ on different modalities/examinations were graphically compared (0 = no pathologic finding, 1 = smallest, 5 = largest extent of BONJ). Rank tests were used to assess overall and paired differences of ratings in 9 patients. A P value <.05 was considered statistically significant. RESULTS:Significant differences in BONJ extent among different modalities and examinations were found (P < .001). The highest median rank was seen in PET/CT (4 ± 1.12) and CEMR imaging (4 ± 1.01), followed by intraoperative examinations (3 ± 0.71), CBCT (2 ± 0.33), and preoperative examinations (1 ± 0). No significant differences were found between PET/CT and CEMR imaging (P = .23), except when comparing PET/CT to either CBCT, pre- and intraoperative examinations (all P < .05). Preoperative examinations showed significantly less extensive disease than all other modalities/examinations (all P < .05). CONCLUSIONS:[(18)F] fluoride PET/CT and CEMR imaging revealed more extensive involvement of BONJ compared with panoramic views from CBCT and clinical examinations.
    背景与目标:
  • 【7,12-二甲基苯并 [a] 蒽 (DMBA) 的化学预防5-脂氧合酶抑制剂,藤黄酚引起的仓鼠颊袋致癌作用。】 复制标题 收藏 收藏
    DOI:10.1080/01635581.2012.718032 复制DOI
    作者列表:Chen X,Zhang X,Lu Y,Shim JY,Sang S,Sun Z,Chen X
    BACKGROUND & AIMS: :Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis.
    背景与目标: : 我们以前的研究表明,异常的花生四烯酸代谢,尤其是5-脂氧合酶 (5-Lox) 途径,与口腔癌的发生有关,可以作为预防癌症的靶标。为了开发用于口腔癌化学预防的有效局部药物,在计算机上评估了饮食和合成来源的5种已知的5-Lox抑制剂 (Zileuton,ABT-761,licofelone,姜黄素和藤黄酚) 的潜在功效。根据理论活性指数的计算,发现藤黄酚是一种来自藤黄属果皮的聚异戊二烯化二苯甲酮,是一种有前途的试剂。计算机建模表明,藤酚非常适合5-Lox的活性位点,并通过酚羟基和非血红素催化铁之间的相互作用潜在地抑制了酶活性。在对7,12-二甲基苯并 [a] 蒽 (DMBA) 处理的仓鼠颊袋进行的短期研究中,外用藤黄酚抑制了白三烯B4 (LTB4) 的生物合成并抑制了口腔上皮的炎症和细胞增殖。在一项长期的致癌研究中,外用藤黄酚可显着减少可见肿瘤的大小,癌症病变的数量,细胞增殖和LTB4生物合成。这些结果表明,局部应用5-Lox抑制剂藤黄酚对DMBA诱导的仓鼠颊袋致癌具有化学预防作用。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录