• 【早期物理和化学事件对低能电子诱导的DNA损伤的计算模型。】 复制标题 收藏 收藏
    DOI:10.1080/095530097143798 复制DOI
    作者列表:Nikjoo H,O'Neill P,Goodhead DT,Terrissol M
    BACKGROUND & AIMS: Modelling and calculations are presented as a first step towards mechanistic interpretation and prediction of radiation effects based on the spectrum of initial DNA damage produced by low energy electrons (100 eV-4.5 keV) that can be compared with experimental information. Relative yields of single and clustered strand breaks are presented in terms of complexity and source of damage, either by direct energy deposition or by reaction of OH radicals, and dependence on the activation probability of OH radicals and the amount of energy required to give a single strand break (ssb). Data show that the majority of interactions in DNA do not lead to damage in the form of strand breaks and when they do occur, they are most frequently simple ssb. However, for double-strand breaks (dsb), a high proportion (approximately 30%) are of more complex forms, even without considering additional complexity from base damage. The greater contribution is from direct interactions in the DNA but reactions of OH radicals add substantially to this, both in terms of the total number of breaks and in increasing the complexity within a cluster. It has been shown that the lengths of damaged segments of DNA from individual electron tracks tend to be short, indicating that consequent deletion length (simply by loss of a fragment between nearby dsb) would be short, very seldom exceeding a few tens of base pairs.

    背景与目标: 建模和计算是基于低能电子 (100 eV-4.5 keV) 产生的初始DNA损伤谱的辐射效应的机械解释和预测的第一步,可以与实验信息进行比较。通过直接能量沉积或OH自由基的反应,以及对OH自由基的激活概率和产生所需能量的依赖,以复杂性和损伤来源表示单链断裂 (ssb)。数据表明,DNA中的大多数相互作用不会以链断裂的形式导致损伤,当它们发生时,它们最常见的是简单的ssb。然而,对于双链断裂 (dsb),高比例 (约30%) 是更复杂的形式,甚至不考虑来自基础损伤的额外复杂性。更大的贡献来自DNA中的直接相互作用,但是OH自由基的反应在断裂总数和增加簇内的复杂性方面都大大增加了这一点。已经表明,来自单个电子轨道的DNA受损片段的长度往往很短,这表明随之而来的缺失长度 (仅通过附近dsb之间的片段丢失) 将很短,很少超过几十个碱基对。
  • 【氯氮平治疗帕金森氏病左旋多巴诱发的精神病: 回顾性研究。】 复制标题 收藏 收藏
    DOI:10.1177/089198879701000205 复制DOI
    作者列表:Widman LP,Burke WJ,Pfeiffer RF,McArthur-Campbell D
    BACKGROUND & AIMS: Levodopa-induced psychosis can complicate the treatment of Parkinson's disease (PD). In this retrospective, uncontrolled report, we describe our experience treating PD-related psychosis with clozapine, emphasizing those patients treated for longer than 1 year. Twenty-seven patients were treated, 14 for longer than 1 year. Most patients showed a rapid improvement from baseline within 1 month using the Clinical Global Impression and Global Psychosis Rating Scores. Five patients discontinued the drug due to side effects, but only two patients reported side effects after 6 months of treatment. Clozapine appears to be effective in treating PD related psychotic symptoms while not interfering with motor function.

    背景与目标: 左旋多巴引起的精神病会使帕金森氏病 (PD) 的治疗复杂化。在这份回顾性,不受控制的报告中,我们描述了我们用氯氮平治疗PD相关精神病的经验,强调了那些治疗时间超过1年的患者。27例患者接受了治疗,其中14例超过1年。使用临床总体印象和总体精神病评分,大多数患者在1个月内从基线显示出快速改善。五名患者因副作用而停药,但只有两名患者在治疗6个月后报告副作用。氯氮平似乎可有效治疗PD相关的精神病性症状,同时不干扰运动功能。
  • 【肿瘤诱导的前哨淋巴结免疫调节。】 复制标题 收藏 收藏
    DOI:10.1038/nri1919 复制DOI
    作者列表:Cochran AJ,Huang RR,Lee J,Itakura E,Leong SP,Essner R
    BACKGROUND & AIMS: :Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.
    背景与目标: 前哨淋巴结 (sln) 是第一个从原发肿瘤接受淋巴结的淋巴结,也是最初肿瘤转移的优先部位,被大量暴露于肿瘤细胞和其他相关细胞的生物活性产物。这使得它们非常适合研究确定选择性组织对转移的敏感性的因素。我们假设,肿瘤诱导的sln的免疫调节通过抑制对原发性和转移性黑色素瘤的肿瘤细胞具有活性的肿瘤特异性细胞毒性T细胞的产生来促进淋巴结转移。可以通过粒细胞/巨噬细胞集落刺激因子 (gm-csf) 逆转淋巴结的免疫调节,这一发现对淋巴结转移的未来治疗有影响。
  • 【碳酸磷灰石诱发的关节病: 多关节炎病例的考虑。】 复制标题 收藏 收藏
    DOI:10.1038/ncprheum0174 复制DOI
    作者列表:Blair-Levy JM
    BACKGROUND & AIMS: BACKGROUND:A 79-year-old woman was referred for evaluation of her painful and swollen joints. She had a medical history of congestive heart failure, renal insufficiency and peptic ulcer disease. For the past 3 years she had experienced recurrent bouts of debilitating arthritis, lasting approximately 3-4 weeks at a time. The symptoms were most severe in the hands and knees, where the joints were warm, swollen and tender. During each flare-up, the patient was housebound and required therapeutic dosing of nonsteroidal anti-inflammatory drugs and codeine to control joint pain. INVESTIGATIONS:Physical examination, fine-detailed radiographs of the hands, standing radiographs of the knees, arthrocentesis including cell count and gram stain, compensated polarized light microscopy, alizarin-red staining, X-ray diffraction, scanning and transmission electron microscopy with energy dispersive spectrometry, electron microprobe analysis with energy dispersive spectrometry, Fourier transform infrared spectroscopy, and atomic force microscopy. DIAGNOSIS:Carbonated-substituted apatite arthropathy. MANAGEMENT:Both knees were aspirated and large volumes of a straw-colored synovial fluid was removed. The knees were injected with corticosteroid, resulting in excellent symptomatic response.
    背景与目标:
  • 【蛋白激酶D2通过NF-κ b介导溶血磷脂酸诱导的白细胞介素8在未转化的人结肠上皮细胞中产生。】 复制标题 收藏 收藏
    DOI:10.1152/ajpcell.00308.2006 复制DOI
    作者列表:Chiu TT,Leung WY,Moyer MP,Strieter RM,Rozengurt E
    BACKGROUND & AIMS: :The signaling pathways mediating lysophosphatidic acid (LPA)-stimulated PKD(2) activation and the potential contribution of PKD(2) in regulating LPA-induced interleukin 8 (IL-8) secretion in nontransformed, human colonic epithelial NCM460 cells were examined. Treatment of serum-deprived NCM460 cells with LPA led to a rapid and striking activation of PKD(2), as measured by in vitro kinase assay and phosphorylation at the activation loop (Ser706/710) and autophosphorylation site (Ser876). PKD(2) activation induced by LPA was abrogated by preincubation with selective PKC inhibitors GF-I and Ro-31-8220 in a dose-dependent manner. These inhibitors did not have any direct inhibitory effect on PKD(2) activity. LPA induced a striking increase in IL-8 production and stimulated NF-kappaB activation, as measured by NF-kappaB-DNA binding, NF-kappaB-driven luciferase reporter activity, and IkappaBalpha phosphorylation. PKD(2) gene silencing utilizing small interfering RNAs targeting distinct PKD(2) sequences dramatically reduced LPA-stimulated NF-kappaB promoter activity and IL-8 production. PKD(2) activation is a novel early event in the biological action of LPA and mediates LPA-stimulated IL-8 secretion in NCM460 cells through a NF-kappaB-dependent pathway. Our results demonstrate, for the first time, the involvement of a member of the PKD family in the production of IL-8, a potent proinflammatory chemokine, by epithelial cells.
    背景与目标: : 检测了介导溶血磷脂酸 (LPA) 刺激的PKD(2) 激活的信号通路,以及PKD(2) 在调节LPA诱导的白介素8 (IL-8) 分泌中的潜在作用。未转化的人结肠上皮NCM460细胞。用LPA处理血清剥夺的NCM460细胞导致PKD(2) 的快速和惊人的激活,如通过体外激酶测定和激活环 (Ser706/710) 和自磷酸化位点 (Ser876) 测量的。通过与选择性PKC抑制剂gf-i预孵育消除LPA诱导的PKD(2) 激活,并以剂量依赖性方式Ro-31-8220。这些抑制剂对PKD(2) 活性没有任何直接抑制作用。通过NF-κ b-DNA结合,NF-κ b驱动的荧光素酶报告活性和ikappaba磷酸化来测量,LPA诱导了IL-8产生的显着增加并刺激了NF-κ b活化。利用靶向不同PKD(2) 序列的小干扰rna沉默PKD(2) 基因显著降低LPA刺激的NF-κ b启动子活性和IL-8产生。PKD(2) 激活是LPA生物学作用中的一个新的早期事件,并通过NF-κ b依赖性途径介导NCM460细胞中LPA刺激的IL-8分泌。我们的结果首次证明了PKD家族成员参与了上皮细胞产生IL-8 (一种有效的促炎趋化因子)。
  • 【自分泌在汉氏巴尔通体诱导的血管生成中interleukin-8的作用。】 复制标题 收藏 收藏
    DOI:10.1128/IAI.00622-06 复制DOI
    作者列表:McCord AM,Resto-Ruiz SI,Anderson BE
    BACKGROUND & AIMS: :The gram-negative bacterium Bartonella henselae is capable of causing angiogenic lesions as a result of infection. Previously, it has been shown that B. henselae infection can result in production of the chemokine interleukin-8 (IL-8). In this study, we demonstrated that monocytes, endothelial cells, and hepatocytes produce IL-8 in response to B. henselae infection. We also investigated the role of IL-8 in B. henselae-induced endothelial cell proliferation and capillary tube formation. Both in vitro angiogenesis assays were IL-8 dependent. B. henselae-mediated inhibition of apoptosis, as indicated by gene expression of Bax and Bcl-2, was also shown to be IL-8 dependent in endothelial cells. Furthermore, infection of endothelial cells with B. henselae stimulated upregulation of the IL-8 chemokine receptor CXCR2. Infection of human endothelial cells by B. henselae resulting in IL-8 production likely plays a central role in the ability of this organism to cause angiogenesis during infection.
    背景与目标: : 革兰氏阴性细菌Bartonella henselae能够由于感染而引起血管生成病变。以前,已经显示出B. henselae感染可导致趋化因子interleukin-8 (IL-8) 的产生。在这项研究中,我们证明了单核细胞,内皮细胞和肝细胞对B. henselae感染产生IL-8。我们还研究了IL-8在B. henselae诱导的内皮细胞增殖和毛细管形成中的作用。两种体外血管生成测定都是IL-8依赖性的。B. henselae介导的凋亡抑制,如Bax和Bcl-2的基因表达所表明的,也显示在内皮细胞中IL-8依赖性。此外,B. henselae感染内皮细胞会刺激IL-8趋化因子受体cxcr2的上调。B. henselae感染人内皮细胞导致IL-8产生可能在该生物体在感染期间引起血管生成的能力中起核心作用。
  • 【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,在 “修补” 期间,起搏引起的心肌缺血的严重程度显着增加。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增强并延长了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: :通过胰蛋白酶消化方法,从维生素E缺乏和对照大鼠中分离出肾上腺细胞。通过测量预先标记的5'-三磷酸腺苷[14C] ATP向环状[14C]的转化,研究了存在和不存在抗坏血酸时对肾上腺皮质激素(ACTH)的响应,研究了环状腺苷3',5'-单磷酸(环状AMP)的形成AMP。抗坏血酸(0.5 mM)抑制ACTH诱导的从维生素E缺乏症大鼠分离的肾上腺细胞中环[14C] AMP的形成,但对对照细胞没有作用。随着ACTH浓度的增加,抗坏血酸对ACTH诱导的维生素E缺乏症大鼠环AMP形成的抑制作用降低。在维生素E缺乏的大鼠中,孵育30分钟后,抗坏血酸会抑制ACTH诱导的环状[14C] AMP的形成。尽管在不存在抗坏血酸盐的情况下仍继续形成环状[14C] AMP,但在60分钟或120分钟时没有进一步显着的环状[14C] AMP蓄积。在维生素E缺乏的大鼠中,体外添加α-生育酚可降低抗坏血酸对ACTH诱导的环[14C] AMP形成的抑制作用。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相互作用而影响ACTH诱导的环AMP的形成。
  • 【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。

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