不同剂量右美托咪定治疗对大鼠术后神经功能及Keap1/Nrf2/ARE信号通路的影响

摘要 目的：探讨不同剂量右美托咪定治疗对大鼠术后神经功能及Keap1/Nrf2/ARE信号通路的影响。方法：60只SD大鼠随机分为假手术组（n=12）、脑缺血再灌注组（n=12）、低剂量右美托咪定组（n=12）、中剂量右美托咪定组（n=12）、高剂量右美托咪定组（n=12）,建立脑缺血模型,开展前瞻性研究。假手术组仅接受假手术而不造成脑缺血,术中持续静脉泵注生理盐水;脑缺血再灌注组维持脑缺血片刻,缺血即刻持续静脉泵注生理盐水;低、中、高剂量右美托咪定组脑缺血即刻静脉输注右美托咪定,首次剂量分别为6 μg/kg、60 μg/kg、600 μg/kg,剩余剂量分别以0.05 μg/kg/min、0.5 μg/kg/min、5 μg/kg/min持续静脉泵注。比较各组大鼠神经功能、炎症因子水平、氧化应激指标及Keap1/Nrf2/ARE表达。结果：与假手术组相比,低剂量右美托咪定组、中剂量右美托咪定组、高剂量右美托咪定组、脑缺血再灌注组Longa评分依次升高;与脑缺血再灌注组相比,低剂量右美托咪定组、中剂量右美托咪定组、高剂量右美托咪定组脑梗死体积、脑梗死体积所占百分比依次升高（P<0.05）。与假手术组相比,低剂量右美托咪定组、中剂量右美托咪定组、高剂量右美托咪定组、脑缺血再灌注组白介素6（IL-6）、白介素1β（IL-1β）、肿瘤坏死因子-α（TNF-α）水平依次升高（P<0.05）。与假手术组相比,低剂量右美托咪定组、中剂量右美托咪定组、高剂量右美托咪定组、脑缺血再灌注组神经元特异性烯醇化酶（NSE）、丙二醛（MDA）水平依次升高,超氧化物歧化酶（SOD）水平依次降低（P<0.05）。与假手术组相比,低剂量右美托咪定组、中剂量右美托咪定组、高剂量右美托咪定组、脑缺血再灌注组Keap1/Nrf2/ARE表达依次降低（P<0.05）。结论：低剂量右美托咪定能够保护脑缺血再灌注大鼠术后神经功能,主要通过减轻炎症反应和氧化应激来起作用,其作用机制可能与激活Keap1/Nrf2/ARE信号通路有关。     

诱导前右美托咪定泵注联合髂筋膜阻滞对老年髋部手术患者镇痛效果及术后寒战的影响

摘要 目的：探讨诱导前右美托咪定泵注联合髂筋膜阻滞对老年髋部手术患者镇痛效果及术后寒战的影响。方法：选取我院2019年10月到2023年2月收治的60例髋部手术患者作为研究对象,将其分为观察组与对照组,每组30例。观察组在诱导前15分钟内泵注完20 mL含0.5 μg/kg右美托咪定的溶液,对照组泵注20 mL的生理盐水。在泵注的同时对两组患者采取40 mL 0.33%罗哌卡因进行髂筋膜阻滞,待阻滞效果满意后进行全身麻醉诱导。对比两组患者术后2 h（T1）、术后6 h（T2）、术后12 h（T3）和术后24 h（T4）的VAS评分、Ramsay评分、舒适度评分;术后24 h内寒战发生情况和不良反应发生率。结果：观察组患者术后各个观测时间点的VAS评分低于对照组（P＜0.05）;观察组在T1、T2时间点的Ramsay评分高于对照组（P＜0.05）;观察组患者术后各个观测时间点的舒适度评分较对照组高（P＜0.05）;观察组术后24 h内寒战发生率、寒战持续时间以及单次追加曲马多次数明显低于对照组（P＜0.05）;两组患者心动过缓、低氧血症、低血压的发生率对比无明显差异（P＞0.05）。结论：诱导前右美托咪定泵注联合髂筋膜阻滞可降低髋部手术患者术后疼痛,缓解术后寒战,提高患者舒适度,而未产生明显不良反应。     

右美托咪定对脓毒症大鼠血线粒体能量代谢相关基因表达的影响

目的基于PCR Assay芯片技术,分析右美托咪定对脓毒症大鼠血线粒体能量代谢相关基因表达变化并推论其可能的作用机制。方法将健康雄性Wistar大鼠30只,按随机数字表法分成3组,即对照组、脓毒症组、右美托咪定预干预组,每组10只。采用盲肠结扎穿孔术(CLP)复制脓毒症大鼠模型,假手术组仅开腹、关腹,不行CLP。其中右美托咪定预干预组则在造模前及造模后2h于腹腔注射右美托咪定40μg/kg,脓毒症组及假手术组肌注平衡液5ml/kg,3组均于术后24h留取血标本,并分离线粒体后提取RNA行PCR Assay基因芯片检测。结果脓毒症组大鼠血液线粒体能量代谢相关基因如Ndufa1、Ndufab1、Ndufb2、Ndufs8、Sdha、Uqcrb、Cox8a、Atp5a1、Atp5i的Fold值下调明显,右美托咪定干预后大鼠血液线粒体能量代谢相关基因如Ndufa1、Ndufab1、Ndufb2、Ndufs8、Sdha、Uqcrb、Cox8a、Atp5a1、Atp5i的Fold值有升高趋势。结论右美托咪定可能通过调节线粒体能量代谢相关基因的表达,从而起到对脓毒症大鼠的保护作用。     

小剂量右美托咪定对老年腹腔镜手术患者围术期心血管反应及应激情况的影响分析

摘要 目的：探讨小剂量右美托咪定对老年腹腔镜手术患者围术期心血管反应及应激情况的影响。方法：选取2020年4月~2022年4月至陕西省人民医院行腹腔镜手术的120例老年患者作为研究对象，根据随机数字表法将其分为观察组和对照组，各60例。麻醉诱导前，观察组予以右美托咪定0.5 μg/kg静脉泵注，对照组予以等容量0.9%氯化钠注射液静脉泵注，持续时间均为10 min。术中麻醉维持，观察组予以右美托咪定0.2 μg/（kg?h）持续静脉泵注，对照组予以0.2 μg/（kg?h）速率持续静脉泵注等量氯化钠注射液，均于手术结束前30 min停止泵注。比较两组患者围术期指标、心血管反应指标、应激反应指标和炎症因子水平。结果：观察组术中舒芬太尼用量、术后24 h 静脉自控镇痛（PCIA）泵按压次数明显少于对照组，差异有统计学意义（P＜0.05）；观察组拔管时间少于对照组，但差异无统计学意义（P＞0.05）。两组患者心率（HR）、平均动脉压（MAP）组间、时间及交互比较，差异均有统计学意义（P＜0.05）；观察组气管插管即刻（T1）、气管插管后30 min（T2）和出手术室时（T3）时点HR、MAP明显低于对照组，差异有统计学意义（P＜0.05）。观察组术后丙二醛（MDA）水平明显低于对照组，过氧化氢酶（CAT）、超氧化物歧化酶（SOD）水平显著高于对照组，差异均有统计学意义（P＜0.05）。观察组术后C反应蛋白（CRP）、白介素（IL）-6及肿瘤坏死因子（TNF）-α水平均明显低于对照组，差异有统计学意义（P＜0.05）。结论：在腹腔镜手术中使用小剂量右美托咪定，可有效维持老年患者围术期血流动力学稳定，降低氧化应激反应和炎症因子水平。     

右美托咪啶对直肠癌患者术后胃肠功能恢复的影响

目的:观察围术期输注右美托咪啶对直肠癌患者术后镇痛及胃肠功能恢复的影响。方法:60例择期行直肠癌根治术的患者随机分为三组:空白对照组(Ctr组)不输注右美托咪啶;右美托咪啶组的患者入室后给予面罩吸氧并且泵注盐酸右美托咪啶,剂量为1μg/kg,10 min输注完毕后开始麻醉诱导,大剂量组(LD组)患者麻醉维持期间持续泵注右美托咪啶0.7μg/kg/h;小剂量组(MD组)泵注方法同LD组,术中持续泵注剂量为0.1μg/kg/h。手术结束后记录患者离开恢复室时(V1)、术后6 h(V2)、12 h(V3)、和24 h(V4)四个时间点的术后镇痛评分和胃肠功能恢复时间包括肠鸣音出现时间、排气时间、排便时间。结果:与其余两组比较,大剂量组患者各时间点的术后镇痛评分低于小剂量组和空白组,差异有统计学意义(P0.05)。小剂量组患者V1时疼痛评分较空白组减少(P0.05),其余时间点术后疼痛评分两组比较无统计学差异(P0.05)。大剂量组患者术后肠鸣音恢复时间较其余两组增加(P0.05),排气、排便时间与其余两组比较无统计学差异(P0.05)。小剂量组与空白组比较两组术后肠鸣音出现时间、排气时间和排便时间无统计学差异(P0.05)。结论:围术期大剂量输注盐酸右美托咪啶可以改善患者术后疼痛,且不会抑制术后胃肠功能的恢复。     

右美托咪定对脑缺血/再灌注大鼠海马兴奋性氨基酸含量及NMDA受体亚单位NR1表达的影响

目的：观察右美托咪定预处理对全脑缺血/再灌注大鼠海马细胞外谷氨酸（Glu）、天门冬氨酸（Asp）含量及N-甲基-D-天冬氨酸（NMDA）受体1（NR1）表达的影响,探讨右美托咪定脑保护作用及其神经递质机制。方法：雄性Wistar大鼠54只,随机分为3组（n=18）：假手术组、脑缺血/再灌注组和右美托咪定预处理组。用四血管闭塞法建立大鼠全脑缺血模型。收集清醒、缺血15 min及再灌注0~1 h微透析标本。于全脑缺血15 min再灌注1 h后,迅速断头取脑,采用免疫组化法和蛋白免疫印迹法检测海马NMDA受体NR1亚单位的表达情况。结果：与脑缺血/再灌注组相应时点比较,右美托咪定预处理组大鼠海马微透析液中Glu、Asp含量明显降低（P<0.05, 0.01）;免疫组化和Western-blot法检测显示右美托咪定预处理组大鼠海马组织NMDA受体亚单位NR1表达明显受抑制（P<0.05, 0.01）。结论：右美托咪定预处理不仅减少脑缺血/再灌注时兴奋性氨基酸释放,还能抑制NMDA受体亚单位NR1的高表达而产生脑保护作用。     

不同剂量右美托咪定静脉维持对重型颅脑损伤患者术后生命体征、免疫功能和血清神经细胞因子的影响

摘要 目的：观察不同剂量右美托咪定静脉维持在重型颅脑损伤患者中的应用价值。方法：选取2018年9月~2020年9月期间江苏大学附属宜兴市人民医院麻醉与重症医学科接收的重型颅脑损伤患者96例,根据随机数字表法分为三组：A组（右美托咪定剂量为0.3μg/kg?h）、B组（右美托咪定剂量为0.5 μg/kg?h）和C组（右美托咪定剂量为0.7 μg/kg?h）,各32例。观察三组患者不同时间点的生命体征、免疫功能、镇静镇痛情况、血清神经细胞因子,记录三组不良反应发生情况。结果：B组、C组术后24 h、术后72 h的心率（HR）、呼吸频率（RR）、平均动脉压（MAP）低于A组（P<0.05）。B组、C组术后24 h、术后72 h的Ramsay镇静评分、视觉模拟评分法（VAS）评分低于A组（P<0.05）。B组、C组术后24 h、术后72 h的CD3⁺、CD4⁺/CD8⁺高于A组（P<0.05）。B组、C组术后24 h、术后72 h的神经元特异性烯醇化酶（NSE）、中枢神经特异性蛋白（S100β）低于A组（P<0.05）。C组的不良反应总发生率高于A组、B组（P<0.05）。结论：重型颅脑损伤患者术中给予右美托咪定剂量为0.5 μg/kg?h、0.7 μg/kg?h维持,可有效维持患者生命体征平稳,促进患者免疫功能和血清神经细胞因子水平改善,但0.7 μg/kg?h剂量的右美托咪定使用后不良反应发生率相对更高。     

右美托咪定通过抑制线粒体凋亡水平缓解大鼠脑缺血后记忆障碍的实验研究

摘要 目的：探右美托咪定缓解缺血性脑损伤记忆障碍大鼠记忆功能的作用机制。方法：选择雄性SD大鼠36只,随机分为三组,分别为：假手术组（12只）、缺血性脑损伤模型组（12只）、右美托咪定组（12只）,除假手术组外其余动物均采用双侧颈动脉结扎术建立慢性脑缺血模型。假手术组和模型组给予生理盐水静注,右美托咪定组给予右美托咪定0.5 μg /kg,静注,均在15 min内滴完。比较大鼠给药前和给药后4 w的记忆情况以及线粒体凋亡因子Bcl-2、Cleaved Caspase-3、Caspase-9的表达水平。结果：（1）与假手术组相比,模型组和右美托咪定组大鼠逃逸潜伏期明显增高（P＜0.05）,右美托咪定组逃逸潜伏期与模型组相比有显著降低（P＜0.05）;与假手术组相比,模型组和右美托咪定组大鼠游泳路程明显延长（P＜0.05）,右美托咪定组游泳路程与模型组相比有显著降低（P＜0.05）;（2）与假手术组相比,模型组和右美托咪定组大鼠海马区部分凋亡因子Bcl-2,Cleaved Caspase-9,Cleaved Caspase-3的蛋白表达均有明显提升（P＜0.05）;与模型组相比,右美托咪定组在给药4 w后上述蛋白的表达有明显降低（P＜0.05）。结论：右美托咪定对脑缺血记忆障碍大鼠的记忆功能有显著改善作用,其作用机制可能与抑制线粒体凋亡水平有关,具体信号通路还有待进一步探索。     

右美托咪定对高血压心肌肥厚患者围术期心肌的保护作用

目的：观察右美托咪定（DEX）对高血压心肌肥厚患者心肌的保护作用。方法：将符合诊断标准54例患者随机分为两组（n=27）：DEX组（D组）和对照组（C组）。D组于麻醉诱导前15 min给予负荷剂量右美托咪定1 μg/kg,静脉泵注10 min,随后维持剂量0.5 μg/（kg·h）至手术结束。C组相应时间泵注等量生理盐水。两组患者麻醉前2 h连接Holter记录仪,静息平卧连续记录1 h作为基础值,其后连续记录24 h。并在T0（诱导前）、T1（手术开始1 h）、T2（术后4 h）、T3（术后12 h）、T4（术后24 h）五个时间点采集血样测定缺血修饰白蛋白（IMA）和血清肌钙蛋白I（cTnI）。观察并记录两组患者手术时间、出血量和心血管并发症等临床指标。结果：D组在T1、T2、T3时IMA水平均明显低于C组（P<0.05）,在T1、T2、T3、T4时cTnI水平均明显低于C组（P<0.05）,Holter显示D组ST段缺血样改变和复杂室性心律失常明显低于C组（P<0.05）。结论：DEX可以减轻高血压心肌肥厚患者围术期心肌损伤,减少ST段缺血样改变和复杂室性心律失常的发生率,具有一定的心肌保护作用。     

右美托咪定在小儿气管异物取出术中的应用

目的：观察右美托咪定在气管异物取出术中对患儿呼吸、循环及术后恢复情况的影响。方法：40例行气管异物取出术患,随机分为右美托咪定组（D组）（n=20）和生理盐水组（S组）（n=20）,分别在麻醉诱导前10min静脉输注右美托咪定0.8μg/kg和等容量的生理盐水,输注时间为10min。术中高频射流呼吸机给氧,保持患儿自主呼吸,泵注丙泊酚和瑞芬太尼维持麻醉。结果：D组患儿术中屏气、咳嗽、喉痉挛、术中SP02〈90%显著低于S组（P〈0.05）;D组丙泊酚及瑞芬太尼用量减少（P〈0.05）。结论：在气管异物取出术中应用右美托咪定有很大的优势,对呼吸系统影响小,血流动力学平稳,术后并发症少。     

乳源性复合益生菌对糖尿病大鼠肾组织 TLR2、TLR4/NFκB信号通路的影响

目的 研究乳源性复合益生菌对糖尿病大鼠肾组织Toll样受体2(TLR2)、Toll样受体4(TLR4)、核转录因子κB(NFκB)表达的影响。 方法 将高脂饮食和链脲佐菌素(STZ)诱导的糖尿病SD大鼠模型随机分为模型组、二甲双胍组、利拉鲁肽组、复合益生菌低剂量组和复合益生菌高剂量组,正常SD大鼠为对照组,每组8只。血糖仪检测不同时段血糖值,ELISA法检测糖化血红蛋白(HbA1c)含量,生化仪检测大鼠尿素氮(BUN)、肌酐(Scr)、24 h尿蛋白定量(24h Alb)的变化,HE染色观察肾脏组织形态,qPCR法检测肾组织TLR2、TLR4的mRNA的表达以及Western blot检测TLR2、NFκBpp65蛋白表达量。 结果 与模型组相比,复合益生菌组大鼠HbA1c、BUN、Scr及24h Alb水平明显下降,并且复合益生菌能够明显改善肾脏的组织形态,显著降低TLR2、TLR4的mRNA的表达和TLR2、NFκBpp65蛋白表达量。 结论 复合益生菌可显著改善糖尿病大鼠早期肾脏损害,其机制与部分抑制糖尿病大鼠肾组织中TLR2、TLR4/NFκB信号通路有关。     

tBHQ和SFN在创伤性脑损伤小鼠中的疗效比较性分析

目的:探讨叔丁基对苯二酚(t BHQ)和莱菔硫烷(SFN)在患有创伤性脑损伤大鼠的疗效差异性。方法:80只健康成年的雄性SD大鼠分为假手术组、常规损伤组、t BHQ治疗组和SFN治疗组,使用电子颅脑损伤仪(e CCI)制备TBI模型。其中t BHQ治疗组在伤前24 h大鼠腹腔注射三次t BHQ(50 mg/kg),每8 h一次;SFN治疗组在伤后15 min给予腹腔注射SFN(5 mg/kg)。给药24 h后,采用m NSS方法评价各组大鼠神经功能缺损状况,利用干湿称量法计算脑含水量,Western blot和ELISA方法分别测定大鼠脑组织的NOX2和Nrf2的表达水平。结果:损伤发生后第24 h,t BHQ治疗组和SFN治疗组在m NSS评分((4.5±0.71)vs(9.2±0.79),(6.0±0.82)vs(9.2±0.79))、脑水肿(79.4%vs 85.6%,80.3%vs 85.6%)、NOX2和Nrf2(0.93 ng/m L vs 0.81 ng/m L,0.87 ng/m L vs 0.81 ng/m L)表达上与常规损伤组差异明显,而t BHQ治疗组和SFN治疗组间在m NSS评分((4.5±0.71)vs(6.0±0.82))、NOX2和Nrf2(0.93 ng/m L vs 0.87 ng/m L)表达上差异显著。结论:在大鼠TBI模型中,t BHQ和SFN均可以有效的降低机体自身的氧化应激作用,并改善神经功能,但t BHQ的疗效要好于SFN。     

Genipin attenuates sepsis by inhibiting Toll-like receptor signaling

The pathogenesis of sepsis is characterized by overwhelming inflammatory responses that lead to tissue damage and organ failure. Toll-like receptor (TLR) signaling is crucial for induction of hyperinflammatory responses and tissue injury during sepsis. Genipin, an aglycon of geniposide, has antiinflammatory and antimicrobial activities. The purpose of this study was to test the hypothesis that genipin reduces multiple organ dysfunction and mortality during sepsis through inhibition of TLR signaling. Male ICR were subjected to sepsis by cecal ligation and puncture (CLP) or endotoxemia by lipopolysaccharide (LPS). Various doses of genipin (1, 2.5 and 5 mg/kg) or a vehicle were administered intravenously immediately after CLP or intraperitoneally after LPS treatment. In another set of survival tests, mice were treated with 2.5 mg/kg of genipin 0 and 24 h after CLP. Genipin was found to improve survival and to attenuate multiple organ dysfunction. Genipin attenuated production of proinflammatory cytokines and release of high-mobility group box 1 (HMGB1). Genipin prevented TLR2 and TLR4, myeloid differentiation factor 88 and the Toll/interleukin-1 receptor domain-containing adaptor protein, inducing interferon-β overexpression. Phosphorylation of mitogen-activated protein kinases and interferon regulatory factor 3 and translocation of nuclear factor (NF)-κB were prevented by genipin. Moreover, genipin attenuated increases in serum tumor necrosis factor-α and HMGB1 in LPS-induced endotoxemia. Pam3CSK4- and LPS-mediated production of nitrites and proinflammatory cytokines was suppressed by genipin in RAW264.7 cells. Genipin attenuated mortality and organ injuries during sepsis through interference with TLR signaling. Therefore, genipin might be useful as a potential therapeutic agent for treatment of sepsis.     

血红素加氧酶-1对急性重症胰腺炎相关肺损伤TLR4/NF-κB通路的影响

目的:探讨血红素加氧酶-1(HO-1)对急性重症胰腺炎相关肺损伤(PALI)Toll样受体-4(TLR4)/核因子-κB(NF-κB)信号传导通路的影响。方法:32只SD大鼠随机分为Sham组、PALI组、HO-1促进剂组、HO-1抑制剂组,每组8只。PALI组经胆胰管注入牛磺胆酸钠制备急性重症胰腺炎(ANP)动物模型。Sham组胆胰管内不注入牛磺胆酸钠,其余操作同PALI组。HO-1促进剂组于造模后30 min经腹腔注射牛血晶素75μg/kg;HO-1抑制剂组于造模后30 min经腹腔注射锌-原卟啉20μmol/kg。PALI组和Sham组均于造模后30 min经腹腔注射等量生理盐水。各组大鼠术后24 h,进行肺损伤学评分,统计肺湿/干重比值。检测大鼠术后24 h血清淀粉酶、TNF-α、IL-6、NGAL水平。检测大鼠术后24 h肺组织中TLR4、NF-κB p65蛋白表达。结果:PALI组肺损伤学评分、肺湿/干重比值、淀粉酶、TNF-α、IL-6、NGAL、TLR4、NF-κB p65明显高于Sham组;HO-1促进剂组肺损伤学评分、肺湿/干重比值、淀粉酶、TNF-α、IL-6、NGAL、TLR4、NF-κB p65明显低于PALI组;HO-1抑制剂组肺损伤学评分、肺湿/干重比值、淀粉酶、TNF-α、IL-6、NGAL、TLR4、NF-κBp65明显高于PALI组;差异均有统计学意义(P<0.05)。结论:HO-1能够通过抑制TLR4/NF-κB信号通路的激活,下调TNF-α、IL-6、NGAL等炎症因子的释放,从而发挥减轻急性重症胰腺炎相关肺损伤的作用。     

一株白僵菌对红火蚁的毒力及对免疫酶活性与基因表达的影响

白僵菌是最具防治害虫潜力的一类昆虫病原真菌。本研究测定了球孢白僵菌Beauveria bassiana 237菌株对红火蚁Solenopsis invicta的感染毒力,并探究了白僵菌侵染对红火蚁免疫相关酶活性及相关基因表达的影响。结果显示,该白僵菌菌株对红火蚁的毒力较强,在孢子悬浮液108孢子/mL浓度下,对红火蚁的致死中时间LT50为5.288±0.2014 d;在10^4~10^8孢子/mL的不同浓度处理下,红火蚁死亡率随孢子浓度的增加而显著增加。经计算,第4~10天致死中浓度LC50值由8.82×10^6孢子/mL降低到8.95×10^5孢子/mL。红火蚁被球孢白僵菌感染后,体内保护酶和解毒酶发生了不同程度的改变。其中保护酶类酚氧化酶（PO）的活性在白僵菌处理后的第12 h已出现抑制,而在第24 h、48 h、72 h时均显著高于对照;超氧化物歧化酶（SOD）活性在12 h时与对照无显著差异,但在24~48 h阶段酶活显著上升,之后下降;过氧化物酶（POD）在较早时段保持与对照无显著差异水平,至中后期48~72 h出现持续升高。解毒酶类混合功能氧化酶系（MFO）的活性在整个检测时间段内表现为抑制-上升-抑制-上升的波动状态;谷胱甘肽S-转移酶（GSTs）活性的变化与SOD相似,只在24~48 h阶段出现上升。白僵菌还导致红火蚁免疫信号通路Toll途径相关基因表达量变化。在处理后12 h,识别因子GNBP1、Spaetzle即被激活,维持上调-回调波动趋势;而信号传递因子Myd88、pelle在检测的12~72 h内基本处于被抑制状态,只有Myd88在48 h时表达量上升;转录因子Dorsal以及抗菌肽Defensin在12~24 h都已被显著激活,而在后续48~72 h被抑制。综上所述,球孢白僵菌237菌株通过调节红火蚁酶活以及免疫相关基因的表达量实现成功侵染和致病作用,具有很高的生防应用价值。     

Gastrin-Releasing Peptide Receptor Antagonism Induces Protection from Lethal Sepsis: Involvement of Toll-like Receptor 4 Signaling

In sepsis, toll-like receptor (TLR)-4 modulates the migration of neutrophils to infectious foci, favoring bacteremia and mortality. In experimental sepsis, organ dysfunction and cytokines released by activated macrophages can be reduced by gastrin-releasing peptide (GRP) receptor (GRPR) antagonist RC-3095. Here we report a link between GRPR and TLR-4 in experimental models and in sepsis patients. RAW 264.7 culture cells were exposed to lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α and RC-3095 (10 ng/mL). Male Wistar rats were subjected to cecal ligation and puncture (CLP), and RC-3095 was administered (3 mg/kg, subcutaneously); after 6 h, we removed the blood, bronchoalveolar lavage, peritoneal lavage and lung. Human patients with a clinical diagnosis of sepsis received a continuous infusion with RC-3095 (3 mg/kg, intravenous) over a period of 12 h, and plasma was collected before and after RC-3095 administration and, in a different set of patients with systemic inflammatory response syndrome (SIRS) or sepsis, GRP plasma levels were determined. RC-3095 inhibited TLR-4, extracellular-signal–related kinase (ERK)-1/2, Jun NH₂-terminal kinase (JNK) and Akt and decreased activation of activator protein 1 (AP-1), nuclear factor (NF)-κB and interleukin (IL)-6 in macrophages stimulated by LPS. It also decreased IL-6 release from macrophages stimulated by TNF-α. RC-3095 treatment in CLP rats decreased lung TLR-4, reduced the migration of cells to the lung and reduced systemic cytokines and bacterial dissemination. Patients with sepsis and systemic inflammatory response syndrome have elevated plasma levels of GRP, which associates with clinical outcome in the sepsis patients. These findings highlight the role of GRPR signaling in sepsis outcome and the beneficial action of GRPR antagonists in controlling the inflammatory response in sepsis through a mechanism involving at least inhibition of TLR-4 signaling.     

Intravenous epoprostenol sodium does not increase hepatic microsomal enzyme activity in rats

Previous studies have indicated that epoprostenol may increase hepatic microsomal enzyme activity both in animals and humans. However, interpretation of the results of these studies may be confounded by the route of epoprostenol administration or small sample sizes. The primary objective of the present investigation was to evaluate the effects of epoprostenol (given as a continuous intravenous infusion) on hepatic microsomal enzyme activity in rats. Male Sprague Dawley rats (220–290 g) received infusions of either vehicle (glycine buffer, 1 mL/hr) or 0.2 μg/kg/min epoprostenol through a jugular vein cannula for 24 hr or 7 days. At the end of the infusion, a 25 mg/kg ix. bolus of antipyrine was administered and blood samples were collected over 6 hr. Serum antipyrine concentrations were determined by HPLC. Twenty-four hr post-infusion, hepatic microsomes were prepared, and cytochrome P-450 content was determined by difference spectroscopy. Cytochrome P-450 content and antipyrine clearance values determined from serum antipyrine concentration-time profiles were not significantly different between treatment groups. Antipyrine clearance [mean (SD)] in the 24-hr vehicle-treated group was 3.68 (0.49) mL/min/kg versus 4.35 (1.1)mL/min/kg in the epoprostenol-treated group. In the 7-day vehicle-treated rats, antipyrine clearance was 5.43 (1.0) mL/min/kg compared to 4.68 (0.61)mL/min/kg in epoprostenol-treated rats. A statistically significant effect of infusion duration was observed in the control group, i.e., antipyrine clearance in rats treated with vehicle for 7 days was significantly greater than that observed in rats treated with vehicle for 24 hr. However, the increase was less than 50%. These data suggest that when epoprostenol is administered as an intravenous infusion to rats, no significant alterations in hepatic microsomal enzyme activity occur. Based on these data, long term changes in heparic metabolism in response to chronic epoprostenol administration are nor expected.     

不同浓度右美托咪啶对小儿麻醉后血清肌钙蛋白I、C反应蛋白以及补体水平的影响

目的:探讨不同浓度右美托咪啶对小儿麻醉后血清肌钙蛋白I、C反应蛋白(CRP)及补体水平的影响。方法:选取我院收治的拟行手术的患儿60例,根据应用右美托咪定的浓度随机分为A、B、C三组,每组各20例。A、B组患儿予右美托咪啶0.5、0.25μg/kg的负荷剂量静脉推注给药10分钟,然后以0.2-0.7μg/kg/h的速度持续静脉微量泵入维持患者镇静状态,C组直接以右美托咪啶0.2-0.7μg/kg/h的速度持续泵入维持镇静状态。比较三组患儿麻醉术后的苏醒情况,麻醉前后不同时点血清肌钙蛋白I、C反应蛋白及补体水平的变化。结果:治疗前,三组患儿的各项指标比较均无统计学差异(P0.05);治疗后,与A、C两组比较,B组患者自主呼吸恢复时间、气管导管拔管时间、解除监护时间显著缩短(P0.05),术后24、72 h血清CRP水平更低,术后1、6、24 h血清肌钙蛋白I水平较低(P0.05),术后1、24、72 h血清补体水平较高(P0.05)。结论:0.25μg/kg浓度的右美托咪啶对于对小儿麻醉后血清肌钙蛋白I、C反应蛋白及补体水平的影响明显,且有助于患儿术后的苏醒。     

The role of nuclear factor‐κB in rats of radiocontrast‐media‐induced nephropathy

This study was undertaken to examine the possible role of the DNA‐binding activity of nuclear factor‐kappa B (NF‐κB) in rat of radiocontrast‐media‐induced nephropathy (RCIN) and to explore the characteristic of RCIN in rats and the role of NF‐κB in its occurrence. Forty‐eight adult male Sprague–Dawley (SD) rats were randomly divided into Groups A–D. Rats of Groups A and B were intravenously injected with NG‐nitro‐L ‐arginine methyl ester (L‐NAME) (10 mg/kg) and indomethacin (10 mg/kg), respectively. Rats of Groups C and D were intravenously injected with 1‐M phosphate buffer (PH = 8.4 3 mL/kg) and normal saline (NS 2 mL/kg), respectively. After 30 min, Groups A and D were injected with NS (8 mL/kg) and Groups B and C were injected with diatrizoate (DTZ 8 mL/kg). After injected contrast media (CM) for 6 h, the serum creatinine and blood urea nitrogen of rat in Group B increased sharply as compared with Groups A, C, and D. After 48 h, the data recovered to 49.28 ± 8.81 μmol/L and 6.72 ± 2.75 mmol/L, respectively. Vacuolization of the tubule epithelial cells of the kidney was observed in Group A. Especially, these pathological changes were most obvious in outer medulla. Contrast to group A, the DNA‐binding activity of NF‐κB in rat kidney of Group B reached a peak at the 6th h and recovered to the normal level after the 48th h. CM mainly damages renal tubular–interstitial, which appears the earliest and most serious in the outer medulla. Activation of NF‐κB of renal may be one of the mechanisms of RCIN occurrence. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:416–421, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20256