• 【多发性骨髓瘤中热休克蛋白90(HSP90)的表达和HSP90抑制剂(17-AAG)的作用分析。】 复制标题 收藏 收藏
    DOI:10.1080/10428190500472123 复制DOI
    作者列表:Duus J,Bahar HI,Venkataraman G,Ozpuyan F,Izban KF,Al-Masri H,Maududi T,Toor A,Alkan S
    BACKGROUND & AIMS: :Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.
    背景与目标: :热休克蛋白90(HSP90)是结构折叠和维持各种蛋白质(包括与细胞信号相关的几种蛋白质)构象完整性的必需。利用HSP90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素(17-AAG)的最新研究表明,在实体瘤中具有抗肿瘤作用。为了测试HSP90是否可以靶向于多发性骨髓瘤(MM)患者,我们首先通过免疫荧光和流式细胞术分析了骨髓瘤细胞系(U266)和原发性骨髓瘤细胞中HSP90的表达。在证明HSP90在骨髓瘤细胞中表达后,通过免疫过氧化物酶染色分析了32例MM患者的档案样本。在所有患者中,骨髓瘤细胞在所有样品中均表现出强烈的HSP90细胞质表达,并且55%的患者还表现出并发的核免疫阳性。与未处理的对照细胞相比,用17AAG处理U266细胞和原代MM细胞可导致凋亡明显增加。分析与17-AAG孵育的MM细胞中的抗凋亡BCL2家族蛋白和akt,表明BCL-2,BCL-XL,MCL-1和akt下调。此外,尽管低浓度的硼替佐米不会导致细胞死亡,但是17AAG和硼替佐米治疗的组合显示出对U266细胞系的协同凋亡作用。这些数据表明,针对HSP90的靶向抑制可能被证明是开发MM患者未来治疗选择的有效且创新的策略。
  • 【B细胞慢性淋巴细胞性白血病患者T细胞中的信号分子和细胞因子产生:氟达拉滨和alemtuzumab治疗的长期效果。】 复制标题 收藏 收藏
    DOI:10.1080/10428190600565503 复制DOI
    作者列表:Kiaii S,Choudhury A,Mozaffari F,Rezvany R,Lundin J,Mellstedt H,Osterborg A
    BACKGROUND & AIMS: :Fludarabine and alemtuzumab are routinely used for treatment of B-cell chronic lymphocytic leukemia (B-CLL). The present study aimed to compare the expression of signaling molecules and cytokine production by T cells of B-CLL patients in long-term unmaintained remission/plateau phase following fludarabine or alemtuzumab treatment with that of indolent/untreated B-CLL patients and healthy donors. The frequency and intensity of TCR-CD3zeta chain, p56lck, p59fyn, ZAP-70, PI3-kinase and interferon (IFN)-gamma/interleukin (IL)-4 production in CD4 and CD8 T cells was examined by flow cytometry. T-cell function was assessed by stimulation with purified protein derivative (PPD) and phytohemagglutinin (PHA). Despite a reduction in number, the expression of IFN-gamma/IL-4 in T-cells in patients was significantly higher than in healthy donors. The intensity of most signaling molecules in treated patients was relatively unaffected vs. healthy donors but lower than untreated-indolent patients. However, the total number of T cells which expressed each of the signaling molecules was decreased in patients, with no difference between fludarabine- and alemtuzumab-treated patients. The T-cell response to PHA but not PPD was reduced in treated patients. The results suggest that, despite some alterations in signaling molecules and a reduction in T-cell number, overall T-cell functions may be relatively well preserved long-term after treatment with fludarabine and alemtuzumab.
    背景与目标: :氟达拉滨和阿仑单抗通常用于治疗B细胞慢性淋巴细胞性白血病(B-CLL)。本研究旨在比较氟达拉滨或alemtuzumab治疗后长期未维持的缓解/高原期的B-CLL患者的信号分子表达和T细胞的细胞因子产生与惰性/未经治疗的B-CLL患者和健康供体的长期比较。通过流式细胞术检测TCR-CD3zeta链,p56lck,p59fyn,ZAP-70,PI3-激酶和干扰素(IFN)-γ/白介素(IL)-4在CD4和CD8 T细胞中产生的频率和强度。通过用纯化的蛋白质衍生物(PPD)和植物血凝素(PHA)刺激来评估T细胞功能。尽管数量减少,但患者T细胞中IFN-γ/ IL-4的表达明显高于健康供体。与健康供体相比,已治疗患者中大多数信号分子的强度相对未受影响,但低于未治疗的惰性患者。但是,表达每种信号分子的T细胞总数在患者中减少了,在氟达拉滨和阿仑单抗治疗的患者之间没有差异。在治疗的患者中,对PHA而非TPD的T细胞反应降低了。结果表明,尽管在用氟达拉滨和阿仑单抗治疗后,长期而言,尽管信号分子发生了某些变化并且T细胞数量有所减少,但总体T细胞功能仍可以得到较好的保留。
  • 【透皮三硝酸甘油酯在ERCP中的前瞻性,随机,安慰剂对照试验:对技术成功和ERCP后胰腺炎的影响。】 复制标题 收藏 收藏
    DOI:10.1016/j.gie.2005.11.060 复制DOI
    作者列表:Kaffes AJ,Bourke MJ,Ding S,Alrubaie A,Kwan V,Williams SJ
    BACKGROUND & AIMS: BACKGROUND:Despite the recent improvement in techniques and patient selection, post-ERCP pancreatitis remains the most frequent and dreaded complication of ERCP. Recent studies suggest that pretreatment with glyceryl trinitrate (GTN) may prevent post-ERCP pancreatitis and improve cannulation success. OBJECTIVE:To evaluate the effect of transdermal GTN on ERCP cannulation success and post-ERCP pancreatitis. DESIGN:Prospective, double-blind, placebo-controlled trial. SETTING:Tertiary referral university hospital. PATIENTS:A total of 318 patients (mean age 62 years, 61% women) were randomized to either active (n = 155) or placebo (n = 163) arms. INTERVENTIONS:Active patch (GTN) versus placebo patch. MAIN OUTCOME MEASUREMENTS:Cannulation time and success. Post-ERCP pancreatitis rates. RESULTS:There was no significant difference between the active or placebo arms for the following: successful initial cannulation (96.8% vs 98.8%), deep cannulation (96.1% vs 98.8%), time to successful cannulation, use of guidewire (27% vs 25%) or needle knife (13% vs 13%), and post-ERCP pancreatitis (7.4% of placebo patients and 7.7% active patients). Multivariate analysis identified women, younger patients, pancreatogram, number of attempts on papilla, and poor pancreatic-duct emptying after opacification as risk factors for post-ERCP pancreatitis. Transdermal GTN did not reduce post-ERCP pancreatitis in any of the identified high-risk groups. CONCLUSIONS:Transdermal GTN did not improve the rate of success in ERCP cannulation or prevent post-ERCP pancreatitis in either average or high-risk patient groups.
    背景与目标: 背景:尽管最近在技术和患者选择方面已有改进,但ERCP后胰腺炎仍然是ERCP最常见和最可怕的并发症。最近的研究表明,用三硝酸甘油酯(GTN)进行预处理可以预防ERCP后胰腺炎并提高插管成功率。
    目的:评价经皮GTN对ERCP插管成功和ERCP术后胰腺炎的影响。
    设计:一项前瞻性,双盲,安慰剂对照试验。
    单位:大专转诊大学医院。
    患者:共有318例患者(平均年龄62岁,女性占61%)被随机分配到活动组(n = 155)或安慰剂组(n = 163)。
    干预措施:主动贴片(GTN)与安慰剂贴片。
    主要观察指标:排尿时间和成功率。 ERCP后胰腺炎发生率。
    结果:主动或安慰剂组之间在以下方面没有显着差异:成功的初始插管(96.8%vs 98.8%),深层插管(96.1%vs 98.8%),成功插管的时间,使用导丝(27%vs 25%)或针刀(13%比13%)以及ERCP后胰腺炎(安慰剂患者为7.4%,活动患者为7.7%)。多变量分析确定女性,年轻患者,胰腺造影,乳头尝试次数以及混浊后胰管排空不良是ERCP后胰腺炎的危险因素。在任何已确定的高危人群中,经皮GTN均不能减轻ERCP后胰腺炎的发生。
    结论:无论是普通患者还是高危患者,经皮GTN均不能提高ERCP插管成功率或预防ERCP术后胰腺炎。
  • 【对mu受体有选择性的阿片肽的直接作用:豚鼠心室旁和视上核中的细胞内记录。】 复制标题 收藏 收藏
    DOI:10.1016/0306-4522(90)90426-5 复制DOI
    作者列表:Wuarin JP,Dudek FE
    BACKGROUND & AIMS: :Responses to [D-Ala2, MePhe4, Gly-ol5]enkephalin, a selective agonist for mu-receptors, were recorded intracellularly from 26 neurons in slices of guinea-pig hypothalamus. Of eight cells tested in the supraoptic nucleus, all of which had electrical properties characteristic of magnocellular neuroendocrine cells, four were sensitive to the agonist applied in the perfusion bath or with microdrops. The main effect was a decrease or suppression of spontaneous firing. In the paraventricular nucleus, seven of 18 cells tested also had electrophysiological characteristics similar to magnocellular neurons: two of them were sensitive to the mu-agonist and the effect was similar to that observed in the supraoptic nucleus. The remaining paraventricular neurons displayed low-threshold Ca2+ spikes, and thus had electrophysiological characteristics different from putative magnocellular neurons. Ten of 11 cells with low-threshold Ca2+ spikes were hyperpolarized by more than 10 mV by the mu-agonist, and showed a 33 +/- 1.9% (S.E.M.) decrease in input resistance. In both types of cells, when synaptic transmission was blocked with tetrodotoxin, the mu-agonist could still induce a hyperpolarization, suggesting that the effect was in part direct. Hyperpolarization was also obtained when the Cl- reversal potential was shifted to more positive values by using KCl electrodes, thus excluding a Cl- conductance mechanism. These results provide evidence that opioid peptides can directly inhibit hypothalamic neurons, that the mechanism is an increase in K+ conductance, and that two types of hypothalamic neurons appear to have different sensitivities to a mu-agonist.
    背景与目标: :对豚鼠下丘脑切片中26个神经元的细胞内记录了对[D-Ala2,MePhe4,Gly-ol5]脑啡肽(一种针对mu受体的选择性激动剂)的反应。在视上核中测试的8个细胞中,所有细胞均具有大细胞神经内分泌细胞的电特性,其中4个对灌注浴或微滴中使用的激动剂敏感。主要作用是减少或抑制自发放电。在脑室旁核中,测试的18个细胞中有7个也具有类似于大细胞神经元的电生理特性:其中两个对mu激动剂敏感,作用类似于在视上核中观察到的。其余的脑室旁神经元显示低阈值的Ca2尖峰,因此具有与假定的大细胞神经元不同的电生理特性。 mu激动剂将11个具有低阈值Ca2尖峰的细胞中的10个超极化了10 mV以上,显示输入电阻降低了33 /-1.9%(S.E.M.)。在两种类型的细胞中,当突触传递被河豚毒素阻断时,mu-激动剂仍可诱导超极化,这表明这种作用部分是直接的。当通过使用KCl电极将Cl-反转电位移动到更正值时,也获得了超极化,因此排除了Cl-电导机制。这些结果提供证据证明阿片样物质肽可以直接抑制下丘脑神经元,其机制是钾电导增加,并且两种类型的下丘脑神经元似乎对μ-激动剂具有不同的敏感性。
  • 【限压通气过程中连续气管内气体注入对急性肺损伤家兔肺表面活性物质的影响。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Zhu GF,Zhang W,Zong H,Liang Y
    BACKGROUND & AIMS: BACKGROUND:Pulmonary surfactant dysfunction may contribute to the development of ventilator induced lung injury (VILI). Tracheal gas insufflation (TGI) is a technique in which fresh gas is introduced into the trachea and augment ventilation by reducing the dead space of ventilatory system, reducing ventilatory pressures and tidal volume (V(T)) while maintaining constant partial arterial CO2 pressure (PaCO(2)). We hypothesised that TGI limited peak inspiratory pressure (PIP) and V(T) and would minimize conventional mechanical ventilation (CMV) induced pulmonary surfactant dysfunction and thereby attenuate VILI in rabbits with acute lung injury (ALI). METHODS:ALI was induced by intratracheal administration of lipopolysaccharide in anaesthetized, ventilated healthy adult rabbits randomly assigned to continuous TGI at 0.5 L/min (TGI group) or CMV group (n = 8 for each group), and subsequently ventilated with limited PIP and V(T) to maintain PaCO(2) within 35 to 45 mmHg for 4 hours. Physiological dead space to V(T) ratio (V(D)/V(T)), dynamic respiratory compliance (Cdyn) and partial arterial O(2) pressure (PaO(2)) were monitored. After ventilation, lungs were analysed for total phospholipids (TPL), total proteins (TP), pulmonary surfactant small to large aggregates ratio (SA/LA) in bronchoalveolar lavage fluid (BALF) and for determination of alveolar volume density (V(V)), myeloperoxidase and interleukin (IL)-8. RESULTS:TGI resulted in significant (P < 0.05 or P < 0.01) decrease in PIP [(22.4 +/- 1.8) cmH2O vs (29.5 +/- 1.1) cmH2O], V(T) [(6.9 +/- 1.3) ml/kg vs (9.8 +/- 1.11) ml/kg], V(D)/V(T) [(32 +/- 5)% vs (46 +/- 2)%], TP [(109 +/- 22) mg/kg vs (187 +/- 25) mg/kg], SA/LA (2.5 +/- 0.4 vs 5.4 +/- 0.7), myeloperoxidase [(6.2 +/- 0.5) U/g tissue vs (12.3 +/- 0.8) U/g tissue] and IL-8 [(987 +/- 106) ng/g tissue vs (24 +/- 3) mN/m] of BALF, and significant (P < 0.05) increase in Cdyn [(0.47 +/- 0.02) ml.cmH2O(-1).kg(-1) vs (0.31 +/- 0.02) ml.cmH2O(-1).kg(-1)], PaO(2) [(175 +/- 24) mmHg vs (135 +/- 26) mmHg], TPL/TP (52 +/- 8 vs 33 +/- 11) and Vv (0.65 +/- 0.05 vs 0.44 +/- 0.07) as compared with CMV. CONCLUSIONS:In this animal model of ALI, TGI decreased ventilatory requirements (PIP, V(T) and V(D)/V(T)), resulted in more favourable alveolar pulmonary surfactant composition and function and less severity of lung injury than CMV. TGI in combination with pressure limited ventilation may be a lung protective strategy for ALI.
    背景与目标: 背景:肺表面活性物质功能障碍可能导致呼吸机诱发的肺损伤(VILI)的发展。气管内注气(TGI)是一种将新鲜气体引入气管并通过减少通气系统的死腔,降低通气压力和潮气量(V(T))并保持恒定的局部动脉CO2压力来增强通气的技术( PaCO(2))。我们假设TGI限制了峰值吸气压力(PIP)和V(T),并且将传统机械通气(CMV)引起的肺表面活性剂功能异常减至最小,从而减轻了急性肺损伤(ALI)兔的VILI。
    方法:通过气管内脂多糖经气管内施用麻醉的,通气的健康成年兔,以0.5 L / min(TGI组)或CMV组(每组n = 8)随机分配为连续TGI,然后在有限的PIP和通气条件下通气,从而诱发ALI。 V(T)将PaCO(2)维持在35至45 mmHg的范围内4个小时。监测生理死区与V(T)的比率(V(D)/ V(T)),动态呼吸顺应性(Cdyn)和部分动脉O(2)压力(PaO(2))。通气后,对肺中的总磷脂(TPL),总蛋白(TP),支气管肺泡灌洗液(BALF)中的肺表面活性剂小到大聚集比(SA / LA)进行分析,并测定肺泡体积密度(V(V)) ),髓过氧化物酶和白介素(IL)-8。
    结果:TGI导致PIP显着降低(P <0.05或P <0.01)[(22.4 /-1.8)cmH2O与(29.5 /-1.1)cmH2O],V(T)[(6.9 /-1.3)ml / kg vs(9.8 /-1.11)ml / kg],V(D)/ V(T)[(32 /-5)%vs(46 /-2)%],TP [(109 /-22)mg / kg vs(187 /-25)mg / kg],SA / LA(2.5 /-0.4 vs 5.4 /-0.7),髓过氧化物酶[(6.2 /-0.5)U / g组织vs(12.3 /-0.8)U / g组织]和IL-8 [(987 /-106)ng / g组织vs(24 /-3)mN / m] BALF,Cdyn [(0.47 /-0.02)ml.cmH2O显着(P <0.05)增加(-1).kg(-1)vs(0.31 /-0.02)ml.cmH2O(-1).kg(-1)],PaO(2)[(175 /-24)mmHg vs(135 /-26 )mmHg],TPL / TP(52 /-8 vs 33 /-11)和Vv(0.65 /-0.05 vs 0.44 /-0.07)。
    结论:在这种ALI动物模型中,TGI降低了通气需求(PIP,V(T)和V(D)/ V(T)),与CMV相比,肺泡表面活性剂的肺泡表面活性剂组成和功能更佳,肺部损伤的严重程度更低。 TGI结合限压通气可能是ALI的肺保护策略。
  • 【碳水化合物在牛疱疹病毒1型糖蛋白gI和gIV的抗原和免疫原性结构中的作用。】 复制标题 收藏 收藏
    DOI:10.1099/0022-1317-71-9-2053 复制DOI
    作者列表:van Drunen Littel-van den Hurk S,Hughes G,Babiuk LA
    BACKGROUND & AIMS: :The role of carbohydrate in the antigenic and immunogenic structure of bovine herpesvirus type 1 (BHV-1) glycoproteins gI and gIV was investigated. Deglycosylated proteins induced a significantly lower antibody response in rabbits than native glycoproteins suggesting that the immunogenicity of several epitopes on gI and gIV is carbohydrate-dependent. Loss of carbohydrate from gI also resulted in a significantly decreased ability to induce a serum neutralizing antibody response to BHV-1, due to modifications in three distinct carbohydrate-containing continuous epitopes. Similarly, in vitro lysis of BHV-1-infected cells was significantly reduced when antibodies raised against deglycosylated gI were employed; this was attributed to changes in two of the three carbohydrate-dependent neutralizing epitopes on gI. The oligosaccharides may be directly involved as actual components of these continuous epitopes, rather than in stabilization of the conformation of the protein. In contrast, carbohydrate removal from gIV did not have a significant effect on the capacity to stimulate a neutralizing antibody response. Accordingly, none of the neutralizing epitopes on gIV appeared to be carbohydrate-dependent. Similarly, lysis of virus-infected cells was not significantly reduced when antibodies specific for deglycosylated rather than native gIV were used. In contrast to the humoral response, the delayed-type hypersensitivity response was stronger in rabbits immunized with deglycosylated proteins than in those inoculated with native glycoproteins gI or gIV. Consequently, the carbohydrates on gI and gIV may play a dual role in the host's immune recognition and response by contributing to certain epitopes, but masking others. The implications for the development of a subunit vaccine against BHV-1 are discussed.
    背景与目标: :研究了碳水化合物在1型牛疱疹病毒(BHV-1)糖蛋白gI和gIV的抗原和免疫原性结构中的作用。与天然糖蛋白相比,去糖基化蛋白在兔中诱导的抗体反应显着降低,这表明gI和gIV上几个表位的免疫原性是碳水化合物依赖性的。由于三个不同的含碳水化合物的连续表位的修饰,gI中碳水化合物的损失还导致诱导针对BHV-1的血清中和抗体反应的能力大大降低。同样,当使用针对去糖基化gI的抗体时,BHV-1感染细胞的体外裂解显着降低。这归因于gI上三个碳水化合物依赖性中和表位中两个的变化。寡糖可以直接作为这些连续表位的实际成分,而不是稳定蛋白质构象。相反,从gIV中去除碳水化合物对刺激中和抗体反应的能力没有显着影响。因此,gIV上的中和表位似乎都不是碳水化合物依赖性的。类似地,当使用对去糖基化而不是天然gIV具有特异性的抗体时,病毒感染细胞的裂解也没有明显减少。与体液反应相反,用去糖基化蛋白免疫的兔的迟发型超敏反应要强于用天然糖蛋白gI或gIV接种的兔。因此,gI和gIV上的碳水化合物可能通过贡献某些表位而掩盖其他表位,从而在宿主的免疫识别和反应中起双重作用。讨论了开发针对BHV-1的亚单位疫苗的意义。
  • 【E-选择素的代谢变化是由携带唾液酸化的刘易斯A抗原的粘蛋白结合引起的。】 复制标题 收藏 收藏
    DOI:10.1006/bbrc.1997.6683 复制DOI
    作者列表:Nakada H,Inoue M,Yamashina I
    BACKGROUND & AIMS: Mucin-type glycoproteins carrying sialylLeA antigens (SL-GP) were isolated from the ascites fluid of a patient with colorectal cancer. SL-GP bound to E-selectin on endothelial cells in Ca2+- and sialylLeA antigen-dependent manners. To examine the metabolic change in E-selectin caused by ligation, endothelial cells were labeled with 32P-phosphate or 35S-Met and 35S-Cys. Phosphorylation at one or more serine residues of E-selectin was elevated by ligation with SL-GP but not with sialylLeA hexasaccharide. Pulse-labeling of E-selectin with 35S-Met and 35S-Cys in the presence of SL-GP indicated that the degradation of E-selectin was accelerated by SL-GP ligation, but labeling after pre-ligation with SL-GP revealed an increase in the synthesis of E-selectin. The synthesis may reflect compensation for the E-selectin degraded on pre-ligation. These results indicate that the overall metabolism of E-selectin was enhanced by the ligation of SL-GP, with degradation and synthesis being apparently balanced.

    背景与目标: 从患有结肠直肠癌的患者的腹水中分离出带有唾液酸LeA抗原的粘蛋白型糖蛋白(SL-GP)。 SL-GP以Ca2-和sialylLeA抗原依赖性方式与内皮细胞上的E-选择素结合。为了检查由连接引起的E-选择蛋白的代谢变化,用32P-磷酸或35S-Met和35S-Cys标记内皮细胞。通过与SL-GP而非唾液酸LeA六糖连接,可增强E-选择蛋白一个或多个丝氨酸残基的磷酸化作用。在SL-GP存在下用35S-Met和35S-Cys脉冲标记E-选择素表明SL-GP连接可加速E-选择素的降解,但与SL-GP预连接后的标记显示E-选择素的降解E-选择素的合成增加。该合成可以反映对在预连接时降解的E-选择蛋白的补偿。这些结果表明SL-GP的连接增强了E-选择素的整体代谢,降解和合成明显平衡。

  • 【辐射诱发的旁观者和其他非靶向效应:癌症治疗中的新干预点?】 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主要问题是该药物通常对正常组织有毒性,需要高剂量才能杀死肿瘤细胞。因此,细胞靶标似乎涉及对癌症治疗的低剂量反应,因此特别令人感兴趣,因为它们可以选择性地靶向未被治疗靶标的正常组织,因此可能引起令人不快的副作用,或者可能适合于剥削以改善治疗效果。治疗比率。辐射诱导的旁观者效应[RIBE]是本综述的主题之一,该效应导致在未辐射的细胞中观察到辐射样反应。 RIBE是一种新现象,表明在低剂量时,细胞信号传导比直接DNA损伤更为重要。从历史上看,DNA一直被认为是放射治疗的目标。人们日益认识到信号转导很重要,这开启了几种重要的治疗策略,本文将对此进行讨论。 RIBE似乎是组织或细胞中普遍的应激反应的结果,这种应激反应是在组织,器官或生物体的水平而不是单个细胞的水平表达的。信号可能由所有暴露的细胞产生,但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γ射线)辐射暴露的主要反应是死亡反应。这具有许多细胞凋亡特征,但尽管在许多肿瘤细胞系中死亡反应受到抑制,但在没有p53表达的细胞系中可能检测到。虽然在肿瘤周围未辐射的正常细胞中的死亡反应似乎是不利的,但实际上可以起到保护作用,并从群体中清除受损的细胞。如果利用得当,它可能会导致开发新药物,其目的不是破坏组织,而是使稳态机制能够控制肿瘤的扩展。在这种情况下,有害或有益反应的水平将与细胞群体所携带的背景损伤以及决定对损伤的反应的遗传程序有关。当试图预测涉及放射线和其他细胞毒剂的混合疗法的后果时,这一重点可能很重要。在这篇综述中,我们对电离辐射诱发旁观者效应的潜在机制的现有知识进行了综述,并探讨了如何利用旁观者效应来生产旨在稳定组织稳态而不是稳定组织的新一代抗癌药物的问题。考虑组织破坏。
  • 【新的胆囊收缩素类似物(JMV 236)对大鼠食物摄入和脑单胺的影响。】 复制标题 收藏 收藏
    DOI:10.1016/0143-4179(90)90158-u 复制DOI
    作者列表:Gourch A,Orosco M,Rodriguez M,Martinez J,Cohen Y,Jacquot C
    BACKGROUND & AIMS: :JMV 236, a new cholecystokinin-octapeptide-sulfate (CCK 8 S) derivative (Boc-Tyr (SO3)-Nle-Gly-Trp-Nle-Asp-Phe-NH2) has been synthesized in the Centre de Pharmacologie-Endocrinologie (Montpellier). This peptide has been shown to present the same activity as CCK 8 S on pancreatic amylase secretion and has the advantage of a better chemical stability. With a view to further characterization, the effect of JMV 236 on food intake and brain monoamine and metabolite variations was assayed in the rat after intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations. JMV 236 decreased food intake 2 and 3 hours after i.p. administration of 12.5 and 50 micrograms/kg but was inactive after i.c.v. injection. Its global action was similar to that of CCK 8 S, but was less marked with delayed onset of response. As in our previous work with CCK 8 S, JMV 236 was more potent in inducing monoaminergic variations after i.p. than after i.c.v. administration. The main effects were decreases in striatal dopamine metabolite levels and increases in hypothalamic and striatal serotonin metabolite (5-HIAA) levels. These effects are classically observed with CCK 8 S and are described in our previous reports. The interesting peptide will require further characterization and may serve as a possible reference compound for studies on CCK derivatives.
    背景与目标: :JMV 236是一种新的胆囊收缩素-八肽硫酸盐(CCK 8 S)衍生物(Boc-Tyr(SO3)-Nle-Gly-Trp-Nle-Asp-Phe-NH2),已在药理学-内分泌中心(蒙彼利埃)。已显示该肽在胰腺淀粉酶分泌方面具有与CCK 8 S相同的活性,并且具有更好的化学稳定性的优点。为了进一步表征,在大鼠腹膜内(i.p.)和脑室内(i.c.v.)给药后,在大鼠中测定了JMV 236对食物摄入以及脑单胺和代谢产物变化的影响。腹腔注射后2和3小时,JMV 236的食物摄入量减少。静脉注射12.5和50微克/公斤,但在静脉内注射后无效。注射。它的整体作用与CCK 8 S相似,但反应迟缓的症状较少。就像我们以前使用CCK 8 S所做的一样,JMV 236腹腔内注射后在诱导单胺能变化方面更有效。比在i.c.v.之后行政。主要影响是纹状体多巴胺代谢物水平降低,下丘脑和纹状体5-羟色胺代谢物(5-HIAA)水平升高。这些效应在CCK 8 S上得到了经典观察,并在我们以前的报告中进行了描述。令人感兴趣的肽将需要进一步表征,并可能用作研究CCK衍生物的可能参考化合物。
  • 【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: :在最大程度的全身运动过程中,VO2峰值受O2释放量的限制。反过来,虽然必须在交感神经系统的约束下进行接近最大运动量的血流以维持平均动脉压。为了确定在近乎最大和最大运动量的情况下,增强腿部血管舒张程度是否会导致较高的O2输送量和腿部VO2,七名男性在自行车测功计上进行了两次最大的增量运动测试。以随机顺序进行一项试验,一项试验不进行(对照运动)以80 microg.kg体重-1.min-的速率向右股动脉中输注ATP(1毫升等渗盐溶液中8毫克)。 1。在接近最大运动量(VO2峰值的92%)期间,输注ATP可增加腿部血管电导率(43%,P <0.05),腿部血流量(20%,1.7 l / min,P <0.05)和腿部O2递送(20%,0.3l / min,P <0.05)。没有观察到对腿部或全身VO2的影响。输注腿中的腿部O2分数提取率从85 / -3(对照)降至78 / -4%(ATP)(P <0.05),而在左腿中则保持不变(84 / -2和83 /- 2%;对照和ATP; n = 3)。进行最大运动量的ATP输注可使腿部血管电导增加17%(P <0.05),而腿部血流则倾向于增加0.8 l / min(P = 0.08)。但是,在对照和ATP条件下,由于O2提取量分别从84 / -4降低到76 / -4%,全身和腿部VO2峰值均未升高(P <0.05)。总之,在人类进行近乎最大或最大运动时,下肢骨骼肌的VO2不会因肢体血管扩张而得到增强。 ATP输注导致运动腿上的O2提取减少的事实表明ATP对不太活跃的肌纤维和其他非收缩性组织的血管舒张作用,并且在正常情况下,这些区域处于高血管收缩作用下,以确保最有效的血流有效心输出量到运动肢体最活跃的肌肉纤维的分布。
  • 【冷暴露对大鼠肾上腺酪氨酸羟化酶的影响:RNA,蛋白质,酶活性和辅因子水平的分析。】 复制标题 收藏 收藏
    DOI:10.1111/j.1471-4159.1990.tb01232.x 复制DOI
    作者列表:Baruchin A,Weisberg EP,Miner LL,Ennis D,Nisenbaum LK,Naylor E,Stricker EM,Zigmond MJ,Kaplan BB
    BACKGROUND & AIMS: :Long-term cold exposure (5-7 days) is known to induce concomitant increases in the levels of adrenomedullary tyrosine hydroxylase (TH) RNA, protein, and enzyme activity. In this report, we compare the time courses of these changes and investigate the effects of cold exposure on the levels of biopterin, the cofactor required for tyrosine hydroxylation. After only 1 h of cold exposure, TH mRNA abundance increased 71% compared with nonstressed controls. Increases in total cellular TH RNA levels were maximal (threefold over control values) within 3-6 h of cold exposure and remained elevated throughout the duration of the experiment (72 h). TH protein levels increased rapidly after 24 h of cold exposure and reached a maximal value threefold above that of controls at 48-72 h. Despite the relatively rapid and large elevations in TH RNA and protein content, only modest increases in TH activity were detected during the initial 48 h of cold exposure. Adrenomedullary biopterin increased rapidly after the onset of cold exposure, rising to a level approximately twofold that of the nonstressed controls at 24 h, and remained at this level throughout the duration of the stress period. Taken together, the results of this time course study indicate that cold-induced alterations in adrenal TH activity are mediated by multiple cellular control mechanisms, which may include pre- and posttranslational regulation. Our findings also suggest that cold stress-induced increases in the levels of the TH cofactor may represent another key event in the sympathoadrenal system's response to cold stress.
    背景与目标: :已知长期冷暴露(5-7天)会引起肾上腺髓质酪氨酸羟化酶(TH)RNA,蛋白质和酶活性的同时升高。在本报告中,我们比较了这些变化的时程,并研究了冷暴露对生物蝶呤水平的影响,生物蝶呤是酪氨酸羟化所需的辅助因子。低温暴露仅1小时后,与未受压力的对照组相比,TH mRNA的丰度增加了71%。在冷暴露的3-6小时内,总细胞TH RNA水平的增加最大(比对照值高三倍),并且在整个实验过程中(72小时)保持升高。在冷暴露24小时后,TH蛋白水平迅速升高,在48-72 h时达到最大值,是对照的三倍。尽管TH RNA和蛋白质含量的升高相对较快且幅度较大,但在冷暴露的最初48小时内仅检测到TH活性的适度增加。冷暴露开始后,肾上腺髓质生物蝶呤迅速增加,在24 h时升高至非应激对照组的两倍,并在整个应激期一直保持在该水平。两者合计,此时间过程研究的结果表明,冷诱导的肾上腺TH活性的改变是由多种细胞控制机制介导的,其中可能包括翻译前和翻译后调控。我们的发现还表明,冷应激诱导的TH辅助因子水平升高可能代表交感肾上腺系统对冷应激反应的另一个关键事件。
  • 【早期大剂量左甲状腺素治疗对先天性甲状腺功能减退症儿童入学时听性脑事件相关电位的影响。】 复制标题 收藏 收藏
    DOI:10.1159/000095069 复制DOI
    作者列表:Marti S,Alvarez M,Simoneau-Roy J,Leroux S,Van Vliet G,Robaey P
    BACKGROUND & AIMS: AIMS:We tested whether brain event-related potentials (ERPs) are normal in children with congenital hypothyroidism (CH) after early high-dose levothyroxine treatment. METHODS:Auditory ERPs were recorded in 33 normal controls and in 15 children with CH at 5 years 9/12. Based on bone maturation at diagnosis, the CH group was divided into severe (n = 8) and moderate (n = 7) subgroups. CH patients were treated at a median age of 14 days with a mean initial dose of levothyroxine of 11.6 microg/kgxday. Two ERP components (N100 and N200) were measured and clinical follow-up variables collected. RESULTS:The functional anatomical and cognitive organisation of the auditory system, as revealed by the analyses of ERP measures, did not differ between CH and controls, or between severe and moderate CH subjects. However, N200 latency was globally longer in the CH than in the control group (p = 0.01) and was positively correlated with the over-treatment index (r = 0.61; p < 0.05) and verbal IQ. N200 amplitude was negatively correlated with initial dose (r = -0.74; p < 0.005). CONCLUSION:These data suggest that sensitive tools such as ERPs can reveal differences between CH and controls and relate these differences to the adequacy of treatment of CH.
    背景与目标: 目的:我们测试了大剂量左甲状腺素早期治疗后先天性甲状腺功能减退症(CH)儿童的脑事件相关电位(ERP)是否正常。
    方法:在33名正常对照者和15名5岁9/12的CH儿童中记录了听诊ERP。根据诊断时的骨成熟度,将CH组分为严重(n = 8)和中度(n = 7)亚组。 CH患者的中位年龄为14天,左甲状腺素的平均初始剂量为11.6 microg / kgxday。测量了两个ERP组件(N100和N200),并收集了临床随访变量。
    结果:ERP措施的分析显示,听觉系统的功能解剖和认知组织在CH和对照之间,或在重度和中度CH患者之间没有差异。但是,CH中的N200潜伏期总体上比对照组长(p = 0.01),并且与过度治疗指数(r = 0.61; p <0.05)和言语智商呈正相关。 N200振幅与初始剂量呈负相关(r = -0.74; p <0.005)。
    结论:这些数据表明,诸如ERPs之类的敏感工具可以揭示CH与对照之间的差异,并将这些差异与CH的治疗充分性联系起来。
  • 【冰按摩对艾滋病患者神经性疼痛的影响。】 复制标题 收藏 收藏
    DOI:10.1016/j.jana.2006.07.002 复制DOI
    作者列表:Ownby KK
    BACKGROUND & AIMS: :Peripheral neuropathic pain is a unique form of chronic pain that afflicts up to 50% of persons with AIDS. The purpose of this pilot study was to examine the effects of ice massage to reduce neuropathic pain and improve sleep quality and to determine the feasibility of a larger study. A repeated measures design was used. The three treatments consisted of ice massage, dry-towel massage, and presence. Consecutive sampling was used to select 33 persons with AIDS who had neuropathic pain. Although the results of the study were negative, there was a decrease in pain intensity over time with both the ice massage and towel massage, suggesting that the intervention has some clinical benefit.
    背景与目标: :周围神经性疼痛是慢性疼痛的一种独特形式,可折磨多达50%的艾滋病患者。这项初步研究的目的是检验冰按摩对减轻神经性疼痛和改善睡眠质量的作用,并确定一项更大研究的可行性。使用了重复测量设计。这三种治疗包括冰按摩,干毛巾按摩和临场感。连续抽样选择了33名患有神经性疼痛的艾滋病患者。尽管研究结果为阴性,但冰按摩和毛巾按摩的疼痛强度均随时间降低,表明该干预措施具有一定的临床益处。
  • 【比目鱼肌的代谢特征与高血压父母的后代中胰岛素作用有关。】 复制标题 收藏 收藏
    DOI:10.1016/j.metabol.2006.06.010 复制DOI
    作者列表:Kratochvílová S,Vyhnanovská P,Vlasáková Z,Hájek M,Skibová J,Pelikánová T
    BACKGROUND & AIMS: :Insulin resistance affecting skeletal muscle metabolism is present in the prehypertensive state. The aim of our study was to test the hypothesis that blood pressure value is related to skeletal muscle composition, measured by (31)P magnetic resonance (MR) spectroscopy, and to insulin sensitivity in the offspring of hypertensive parents (OH) and healthy controls. Study groups consisted of 10 healthy young lean OH with normal glucose tolerance, confirmed with oral glucose tolerance test, and 13 controls matched for age, sex, and body mass index. Insulin action was estimated as glucose disposal (M), glucose metabolic clearance rate (MCR), and insulin sensitivity index (M/I) during a 10-hour hyperinsulinemic euglycemic clamp. The sum of immunoreactive insulin values from the oral glucose tolerance test was calculated. (31)P MR spectroscopy was performed on a whole-body MR scanner (Siemens Vision, Erlangen, Germany) operating at 1.5 T and equipped with actively shielded gradient coils. There were no differences in common metabolic and anthropometric parameters between OH and controls except for the blood pressure, which was in the range of normal to high-normal level in OH. Mean blood pressure was significantly higher in OH (95.73 +/- 4.39 vs 83.76 +/- 3.95 mm Hg; P < .001). Trend toward insulin resistance was registered in OH with significantly lower M/I (0.74 +/- 0.47 vs 1.42 +/- 0.65 mg x kg(-1) x min(-1) x mIU(-1) x L(-1); P < .05). There were no significant differences in total serum magnesium (sMg) levels between OH and controls, although a positive correlation exists between sMg and insulin sensitivity expressed as M (r = 0.63, P < .01), MCR (r = 0.54, P < .01), and M/I (r = 0.51, P < .05). No differences in signal intensities of phosphocreatine (PCr), phosphomonoesters, phosphodiesters, inorganic phosphates (Pi), adenosine triphosphates (Patp and betaATP), and calculated concentrations of intracellular ionized magnesium (Mgi) and H(+) ions between the groups were detected. Systolic blood pressure correlates positively with PCr/Patp (r = 0.43, P < .05), Pi/Patp (r = 0.413, P < .05), and Pi/betaATP (r = 0.48, P < .05). Diastolic blood pressure correlates positively only with the ratio Pi/betaATP (r = 0.42, P < .05). The sum of immunoreactive insulin values correlates with PCr/betaATP (r = 0.53, P < .01) and with Pi/betaATP (r = 0.6, P < .01). In conclusion, increase in blood pressure and insulin resistance were confirmed in offspring of OH. Insulin sensitivity is related to sMg and the elevation of blood pressure is associated with the activation of energy metabolism in skeletal muscle. The relationship between muscle energetic characteristics and markers of insulin resistance suggests that the alteration of energy metabolism may be present in early stages of metabolic syndrome.
    背景与目标: :在高血压前状态下,会影响骨骼肌新陈代谢的胰岛素抵抗。我们研究的目的是检验以下假设:血压值与通过(31)P磁共振(MR)光谱法测量的骨骼肌成分以及高血压父母(OH)和健康对照的后代的胰岛素敏感性有关。研究组包括10名健康正常的年轻瘦肉OH,其葡萄糖耐量正常,经口服葡萄糖耐量试验确认,另有13个对照的年龄,性别和体重指数匹配。在10小时高胰岛素正常血糖钳制期间,胰岛素作用估计为葡萄糖处置(M),葡萄糖代谢清除率(MCR)和胰岛素敏感性指数(M / I)。计算来自口服葡萄糖耐量试验的免疫反应性胰岛素值的总和。 (31)P MR光谱是在全身MR扫描仪(Siemens Vision,Erlangen,德国)上以1.5 T操作并配备有源屏蔽梯度线圈进行的。 OH和对照组之间的共同代谢和人体测量学参数没有差异,除了血压处于OH正常水平到高正常水平的范围之内。 OH的平均血压显着升高(95.73 /-4.39与83.76 /-3.95 mm Hg; P <.001)。在OH中出现胰岛素抵抗的趋势,M / I显着降低(0.74 /-0.47对1.42 /-0.65 mg x kg(-1)x min(-1)x mIU(-1)x L(-1); P <.05)。尽管sMg与胰岛素敏感性之间呈正相关,分别以M(r = 0.63,P <.01),MCR(r = 0.54,P < .01)和M / I(r = 0.51,P <.05)。两组之间没有发现磷酸肌酸(PCr),磷酸单酯,磷酸二酯,无机磷酸盐(Pi),三磷酸腺苷(Patp和betaATP)的信号强度差异以及计算出的细胞内离子化镁(Mgi)和H()离子浓度。收缩压与PCr / Patp(r = 0.43,P <.05),Pi / Patp(r = 0.413,P <.05)和Pi / betaATP(r = 0.48,P <.05)正相关。舒张压仅与Pi / betaATP比率呈正相关(r = 0.42,P <.05)。免疫反应性胰岛素值的总和与PCr / betaATP(r = 0.53,P <.01)和Pi / betaATP(r = 0.6,P <.01)相关。总之,在OH的后代中证实了血压升高和胰岛素抵抗。胰岛素敏感性与sMg有关,血压升高与骨骼肌能量代谢的激活有关。肌肉能量特性与胰岛素抵抗标志物之间的关系表明,能量代谢的改变可能在代谢综合征的早期出现。
  • 【过氧化物酶体增殖物激活的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。为了研究PPARγ和PPARα配体的直接血管保护作用,通过链饲法对链脲佐菌素诱导的糖尿病大鼠给予吡格列酮(3 mg / kg /天)和苯扎贝特(10 mg / kg /天)。通过逆转录(RT)-聚合酶链反应(PCR)确定,链脲佐菌素(65 mg / kg,腹膜内)显着增加主动脉中的NADPH氧化酶,血管调用粘附分子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质表达的增强,而苯扎贝特治疗对骨桥蛋白的表达没有影响。我们还证明了吡格列酮或苯扎贝特通过RT-PCR和Western印迹可以阻止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并未影响链脲佐菌素诱发的糖尿病大鼠的葡萄糖耐量,血清胰岛素或血脂水平。这些结果表明,链脲佐菌素诱导的糖尿病大鼠主动脉中PPARs配体的直接抗氧化和抗炎作用不可能由葡萄糖或脂质代谢的正常化介导,但这些有益的作用似乎具有与抑制ACE表达有关。此外,吡格列酮似乎比苯扎贝特对抑制骨桥蛋白的表达更有效。

+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