Alpha-lipoic acid activates eNOS through activation of PI3-kinase/Akt signaling pathway

BackgroundLipoic acid (LA) exerts therapeutic effects on cardiovascular diseases. However, the mechanisms underlying these therapeutic effects remain elusive. Endothelial nitric oxide synthase (eNOS) plays a critical role in cardiovascular homeostasis. LA was shown to potently activate PI3-kinase/Akt pathway, and the latter is critical in the regulation of eNOS activity. In the present study, we test the hypothesis that LA improves endothelial function through PI₃-kinase/Akt-mediated eNOS activation.Methods and ResultsWestern blot analysis showed that LA time- and dose-dependently induced phosphorylation of Akt and eNOS in human umbilical vein endothelial cells (HUVECs). Both PI₃-kinase and Akt inhibitors abolished LA-induced eNOS phosphorylation, indicating that LA induces eNOS phosphorylation through the PI₃-kinase/Akt pathway. This increase in eNOS phosphorylation was paralleled by an increase in NO release by HUVECs, supporting its relevance in eNOS activity regulation. Myograph analysis revealed that LA relaxed phenylephrine-induced contraction. Endothelium removal and NOS inhibition by L-NAME abolished this vasodilator action of LA, and Akt but not AMPK inhibition significantly reduced the vasodilator action of LA, indicating that it is mediated by PI₃-kinase/Akt pathway-dependent activation of eNOS. Consistent with in vitro results, intraperitoneal injection with LA significantly increased plasma nitrite and nitrate levels in C57Bl/6j mice.ConclusionsLA activates eNOS through a PI3-kinase/Akt signaling pathway-dependent mechanism, offering a potential molecular basis for the therapeutic effects of LA on cardiovascular diseases.     

Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects

ObjectivesPolymyxin B is a last-line antibiotic for multidrug-resistant gram-negative bacterial infections. However, limited safety and pharmacokinetic information is available. We investigated the safety and pharmacokinetics of intravenous polymyxin B in healthy subjects.MethodsAn open-label, single-dose clinical trial was conducted in healthy Chinese subjects. Polymyxin B (sulphate) was administered intravenously at 0.75 or 1.5 mg/kg (n = 10 per dose, 5 males and 5 females) to examine the safety and pharmacokinetics.ResultsOne female subject in the 1.5-mg/kg group discontinued due to abdominal pain during administration. The most frequently reported adverse events were perioral paraesthesia, dizziness, and numbness of extremities (7/10 subjects in the 0.75-mg/kg group, all subjects in the 1.5-mg/kg group). All neurotoxicity-related events dissipated without treatment within a maximum of 23 h. Notably, abdominal pain (3/5) and vulvar pruritus (2/5), colpitis (2/5) or abnormal uterine bleeding (1/5) were reported in female subjects receiving the 1.5-mg/kg dose. In the 0.75-mg/kg group, the total clearance, volume of distribution and half-life of polymyxin B were 0.028±0.002 L/h/kg, 0.219±0.023 L/kg and 5.44±0.741 h, respectively; similar values were observed in the 1.5-mg/kg group. Urinary recovery was 3.7 ± 1.1% and 8.1 ± 1.3% in the 0.75- and 1.5-mg/kg groups, respectively. Population pharmacokinetics of polymyxin B was consistent with a three-compartment model. The clearance and distribution of the central compartment were 0.027 L/h/kg and 0.071 L/kg, respectively.ConclusionsThis study is the first to examine the safety and pharmacokinetics of polymyxin B in healthy subjects. Our results highlight that acute toxicity is a dose-limiting factor for intravenous polymyxin B.     

Longitudinal associations between cancer history and cognitive functioning among older adults

ObjectivesThis study aimed to examine (1) whether cancer history accelerates older adults’ rates of cognitive decline over time and (2) whether chemotherapy increases older cancer patients’/ survivors’ rates of cognitive decline over time.MethodsThis longitudinal study drew a subsample of 8811 adults aged 65 or older from Wave 6 of the Health and Retirement Study in 2002 and followed biennually until Wave 13 in 2016. Linear mixed-effects models were performed to test whether cancer history and chemotherapy were associated with accelerated rates of cognitive decline over time among older adults in different age groups.ResultsMiddle-old adults (aged 75–84) with a cancer history had significantly reduced rates of cognitive decline over time, including the global measure of cognitive functioning (B = 0.16, p< .01), mental status (B = 0.08, p< .01), and episodic memory (B = 0.09, p< .05) compared to their counterparts without a cancer history. This effect was not significant for the youngest-old (aged 65–74) or oldest-old adults (aged 85 or older). Also, chemotherapy was not significantly associated with older cancer patients’/survivors’ cognitive functioning at baseline or over time in different age groups.ConclusionsThis study finds that cancer history and chemotherapy do not further exacerbate older adults’ cognitive functioning over time. On the contrary, cancer history shows a “protective” effect on middle-old adults’ cognitive functioning. This encouraging finding indicates that older adults can be more actively engaged in the decision-making of treatments and following care plans. Future mediation studies are needed to further investigate underlying mechanisms.     

Efficacy and safety of low intensity vitamin K antagonists in Western and East-Asian patients with left-sided mechanical heart valves

Journal of Thrombosis and Thrombolysis - The optimal INR target in patients with mechanical heart valves is unclear. Higher INR targets are often used in Western compared with East Asian countries....     

磁耦合驱动搏动式血泵的可行性研究

目的提出一种磁耦合驱动搏动式血泵结构并验证其可行性。方法基于磁场传递往复作用力模型以及推拉互挽式结构设计磁耦合驱动搏动血泵,通过建立磁力驱动模型,计算耦合力大小,制作样机并对样机进行体外循环模拟试验,获得压力和流量实验数据。结果采用生理盐水作为循环介质,固定后负荷,增加前负荷,血泵输出量减少,没有明显线性趋势;固定前负荷,增加后负荷,血泵输出量减少,且具有一定线性趋势。设置驱动频率为75次/min时,调节前、后负荷改变范围分别为0.665~3.990 k Pa(5~30 mm Hg)和5.320~11.970 k Pa(5~30 mm Hg),可使输出量在保证线性关系条件下达到2.0~3.1 L/min。结论该搏动式血泵流体力学特性基本满足体外膜肺循环的需要,仍需进一步研究和改进;研究结果具有重要的应用前景,尤其对替代目前临床体外膜肺氧合设备的血泵装置具有重要意义。     

胆囊结石与胆囊黏膜细胞IL-1β成熟分泌的相关性研究

探讨胆囊结石与胆囊组织IL1-SymbolbA@表达及其成熟分泌的相关性。 〖HT5”H〗方法〖HT5”K〗〓收集胆结石胆囊及其胆汁样本21例,其中胆固醇结石4例、色素结石7例、混合结石10例,采用PCR检测细菌感染情况,ELISA检测胆汁中IL1-SymbolbA@, 蛋白印迹杂交方法检测IL1-SymbolbA@蛋白表达,免疫组化检测胆囊黏膜IL1-SymbolbA@表达,并分析临床相关性。结果在排除伴有细菌感染的情况下, 结石患者胆汁IL1-SymbolbA@含量在1.93～11.80ng/ml,混合结石组胆汁IL1-SymbolbA@（4.753±2.651）显著高于胆固醇结石组（2.640±0.167）和色素结石组（2.762±1.081） （P＜0.05）;免疫组化、蛋白印迹杂交检测表明胆囊黏膜proIL1-SymbolbA@、IL1-SymbolbA@高表达,推测是胆汁IL1-SymbolbA@重要来源之一、 并示胆结石患者胆囊黏膜有炎症小体激活。结论胆结石患者在非细菌感染情况下,胆汁IL1-SymbolbA@增加可能与胆囊黏膜细胞炎症小体的激活密切相关。     

急性阑尾炎患者术中寒战的临床研究

目的 探讨长托宁对急性阑尾炎患者术中寒战的预防作用。方法 蛛网膜下腔阻滞麻醉下行急性阑尾炎手术患者120例,随机分为3组: Ⅰ组(对照组),Ⅱ组(长托宁组),Ⅲ组(哌替啶组)。观察三组患者术中寒战的发生率及严重分级;记录静脉注药前1min(T₀)、静脉注药后3min(T₁)、5min(T₂)、10min(T₃)、15min(T₄)、20min(T₅)、30min(T₆)的血氧饱和度(SPO₂)、平均动脉压(MAP)、心率(HR)的变化情况;用药后不良反应的发生情况;注药前1min(T₀)、注药后30min(T₆)、麻醉后30min(T₇)和手术结束时(T₈)体温变化情况。结果 Ⅱ组、Ⅲ组的寒战发生率分别为10％、7.5％,显著低于Ⅰ组的65％(P<0.01),Ⅱ组和Ⅲ组之间比较差异无显著性(P>0.05);Ⅱ组、Ⅲ组寒战严重程度分级显著低于Ⅰ组(P<0.05),Ⅱ组和Ⅲ组之间比较差异无显著性(P>0.05)。血氧饱和度(SPO₂)的变化,Ⅲ组用药后下降明显,与Ⅰ组和Ⅱ组比较有显著性差异(P<0.01)。平均动脉压(MAP)、心率(HR)、体温,三组变化比较差异均无统计学意义(P>0.05)。Ⅲ组静脉注药后,发生恶心呕吐6例(15％),嗜睡5例(12.5％),明显高于Ⅱ组和Ⅰ组(P<0.05)。结论 麻醉前预防性静脉注射长托宁(0.01mg/kg)具有预防术中寒战发生的作用,效用与预防性静脉注射哌替啶(0.5mg/kg)相似,但长托宁无类似哌替啶的呼吸抑制作用,且无哌替啶高发生率的恶心呕吐、嗜睡不良反应,对血压、心率、体温无影响,在临床预防术中寒战的应用中优于哌替啶。     

糖尿病合并不同程度冠状动脉粥样硬化患者外周血EMP及EPC水平的研究

目的探讨糖尿病患者EMPs、EPCs与不同程度冠状动脉粥样硬化病变及糖代谢异常的关系。方法117例糖尿病患者,根据临床症状、心肌标记物水平以及冠状动脉造影及冠脉内血管超生(IVUS)结果,将患者分为急性冠脉综合症组(A组,n=45)、稳定型心绞痛组(B组,n=27)、冠状动脉病变组(狭窄＜50%,C组,n=45)。采用流式细胞术检测3组患者外周血中CD144⁺/Annexin V+的内皮微颗粒以及CD34⁺/CD39⁺内皮祖细胞的水平,并检测血脂、血糖、糖化血红蛋白、炎性指标、心肌标记物、肝肾功能等各项指标。结果 3组相比,年龄、性别、血压、吸烟、体质量指数、血脂等组间差异均无统计学意义。超敏C反应蛋白、CK-MB、HsTnT均在A组中较高,与其余两组相比差异有统计学意义(P＜0.001)。3组之间空腹血糖、餐后血糖及糖化血红蛋白差异无统计学意义。外周血的CD144⁺/Annexin V+EMPs水平3组间差异有统计学意义,其中A组显著高于B组(P＜0.05),且A、B组CD144⁺/Annexin V+EMPs水平显著高于C组(P＜0.05),EMPs水平与糖化血红蛋白不相关。A、B组外周血CD34⁺/CD39⁺EPCs水平显著低于C组(P＜0.05),而A、B组间无差异,且EPCs水平与糖化血红蛋白呈负相关。结论 糖尿病患者冠脉病变加重是导致外周血CD144⁺/Annexin V+EMPs水平升高的主导损伤因素。糖代谢异常对内皮功能的损伤主要是通过损伤内皮修复功能因素实现的。