Beyond paraquats: Dialkyl 3,3′- and 3,4′-bipyridinium amphiphiles as antibacterial agents

Dialkyl 4,4′-bipyridinium compounds, known as ‘paraquats’ (PQs), have a long history of use as herbicides, as redox indicators, and more recently as potent antibacterial agents. However, due to their ability to form reactive oxygen species (ROS) in vivo, PQs are also known to be toxic. We proposed that altering the electrochemical properties of PQ, specifically by preparing isomeric bipyridinium structures with 3,3′- and 3,4′-substitution of the nitrogen heteroatoms on the biaryl core, would maintain antibacterial activity, yet decrease toxicity. We have thus prepared a series of 17 amphiphiles, dubbed ‘metaquat’ (MQ) and ‘parametaquat’ (PMQ), respectively, and investigated their antibacterial and electrochemical properties. Optimal inhibition of bacterial growth was observed in symmetric, biscationic structures; minimum inhibitory concentration (MIC) values measured as low as 0.5 μM against both Gram-positive and Gram-negative bacteria for the compound PMQ-11,11. Electrochemical analysis demonstrated the redox properties of the dialkyl 3,3′- and 3,4′-bipyridinium amphiphiles to be distinct from those of the 4,4′-bipyridinium isomer. Thus MQ and PMQ amphiphiles maintain the strong antibacterial activity of the PQ isomers, but show promise for reduced ROS toxicity.     

百草枯对小鼠神经行为发育及学习记忆功能的影响

目的观察百草枯(PQ)对发育期C57BL/6J小鼠神经发育的毒性作用,并探讨百草枯对小鼠学习记忆的影响。方法 80只出生21日龄的仔鼠分为对照组(生理盐水)、1.25、2.5、5、10 mg/(kg·d)五组,灌胃染毒百草枯,每天一次,连续30 d。观察小鼠的一般生理和神经行为发育情况,并在染毒结束后进行Morris水迷宫实验和避暗实验,测试小鼠的学习记忆功能。神经行为学测试结束后取小鼠大脑,称重并进行病理检查,同时利用透射电镜观察各组小鼠中脑黑质部超微结构。结果染毒期间小鼠一般状况没有明显变化,染毒结束后各组体重没有统计学差异;在Morris水迷宫测试中,各组差异没有统计学意义,而避暗实验中与对照组相比,高剂量组的避暗潜伏期延长,差异有显著性(P<0.05);在病理切片和透射电镜观察中,在高剂量组分别观察到黑质细胞减少和神经元细胞凋亡。结论百草枯暴露对发育期小鼠成年后神经行为有影响,同时会使小鼠成年后出现脑组织的病理变化,发生器质性的病变。     

Oxysterols As Indices of Oxidative Stress in Man After Paraquat Ingestion

The aim of this study is to evaluate oxidative stress in man after paraquat ingestion by analyzing 7 &#102 - and 7 &#103 -hydroperoxycholest-5-en-3 &#103 -ol (7 &#102 - and 7 &#103 -OOH) as well as oxysterols, cholesterol oxidation products, as indices of lipid peroxidation. Lung, kidney, and liver were collected at autopsy from seven patients with paraquat poisoning and seven controls matched for age and sex. We identified for the first time 7-ketocholesterol (7-keto) and 7-hydroxycholesterol (7 &#102 -OH and 7 &#103 -OH) in human kidney by LC-MS. Next, we quantified 7 &#102 -OOH and 7 &#103 -OOH by HPLC with postcolumn chemiluminescence as well as oxysterols by HPLC-UV. Both 7 &#102 -OOH and 7 &#103 -OOH detected in lung and kidney from the controls were as low as the paraquat group. In contrast, we found both 7-keto and 7 &#103 -OH in lung and 7-keto in kidney from the paraquat group were significantly higher than from the controls. This is the first report on accumulated oxysterols in lung and kidney from human paraquat poisoning. It seems to reflect greater oxidative stress in the pathology of paraquat intoxication.     

腹腔一次注射法构建百草枯致小鼠肺间质纤维化模型

目的建立一种简便易行的百草枯(PQ)致肺间质纤维化动物模型。方法 33只C57BL/6J小鼠随机分为实验组(30只)和对照组(3只)。实验组腹腔一次性注射PQ 10 mg/kg,并于染毒后第2、5、7、14、28天处死小鼠,对照组腹腔注射生理盐水并于第28天处死。观察两组小鼠的一般情况、肺组织大体结构和肺组织病理学改变。结果实验组小鼠在染毒后2 h即出现中毒性改变,肺组织在第28天出现了明显的纤维化改变。结论腹腔一次性注射PQ能简便、可靠的构建出肺纤维化动物模型,可用于进一步研究PQ中毒所致的肺间质纤维化发病机制和治疗方法。     

Male hypofertility induced by Paraquat consumption in the non-target parasitoid Anisopteromalus calandrae (Hymenoptera: Pteromalidae)

The effects of a herbicide – Paraquat – on male development and reproduction were tested on the parasitoid wasp Anisopteromalus calandrae (Hymenoptera, Pteromalidae) by injecting host larvae with different concentrations of this substance. Data measured were: (1) developmental success, (2) sperm stock in seminal vesicles, (3) ability to copulate and transfer sperm, and (4) offspring production. Both developmental success and sperm in seminal vesicles were reduced in the “Paraquat” groups. However, neither sperm stored in the females’ spermatheca, nor offspring production (number of female offspring and sex ratio) differed from controls, whatever the host treatment. The decreased of male sperm reserve in ‘‘Paraquat” group is likely to reduce their reproductive success because they can succefully inseminated less female than control males. These males are thus hyporfertiles. Because Paraquat has non-negligible consequences on non-target parasitoid males, it is likely to affect natural and controlled insect populations.     

α-Tocopheryl succinate pre-treatment attenuates quinone toxicity in prostate cancer PC3 cells

α-Tocopheryl succinate is one of the most effective analogues of vitamin E for inhibiting cell proliferation and inducing cell death in a variety of cancerous cell lines while sparing normal cells or tissues. αTocopheryl succinate inhibits oxidative phosphorylation at the level of mitochondrial complexes I and II, thus enhancing reactive oxygen species generation which, in turn, induces the expression of Nrf2-driven antioxidant/detoxifying genes. The cytoprotective role of Nrf2 downstream genes/proteins prompted us to investigate whether and how α-tocopheryl succinate increases resistance of PC3 prostate cancer cells to pro-oxidant damage. A 4 h α-tocopheryl succinate pre-treatment increases glutathione intracellular content, indicating that the vitamin E derivative is capable of training the cells to react to an oxidative insult. We found that α-tocopheryl succinate pre-treatment does not enhance paraquat-/hydroquinone-induced cytotoxicity whereas it exhibits an additional/synergistic effect on H₂O₂-/docetaxel-induced cytotoxicity.     

大黄治疗急性百草枯中毒的作用研究

目的:通过观察PQ中毒患者SOD、TNF-α、IL-6、PaO2、PaCO2、BUN和Cr水平,及血浆PQ浓度的变化,旨在探讨大黄在治疗PQ中毒中的作用。方法:36例急性百草枯中毒患者随机分为对照组(n=15)和治疗组(n=21),所有患者均给予常规治疗,对照组应用甘露醇导泻,治疗组应用生大黄混悬液导泻,采用酶联免疫吸附法(enzyme linked immunosorbent assay,ELISA)检测所有患者血清SOD、TNF-α、IL-6水平,高效液相色谱法(High Performance Liquid Chromatography,HPLC)测定患者血浆PQ浓度,并测定PaO2、PaCO2、BUN和Cr。结果:治疗组患者第1、3、7天PaO2、SOD水平显著高于对照组,PaCO2、BUN、Cr、TNF-α、IL-6水平和PQ浓度亦较对照组均显著降低(P0.05)。结论:大黄可降低PQ中毒患者血中PQ浓度,抑制TNF-α、IL-6的表达,明显升高SOD的水平,改善PQ中毒患者肺、肾功能。     

The Perplexing Paradox of Paraquat: The Case for Host‐Based Susceptibility and Postulated Neurodegenerative Effects

Paraquat is an herbicide used extensively in agriculture and has also been proposed to be a risk factor for Parkinson's disease. To date, experimental, clinical, and epidemiological data on paraquat neurotoxicity have been equivocal. In this short review, we discuss some technical and biological mechanisms that contribute to inconsistencies regarding paraquat neurotoxicity. We hypothesize that individual genetic variations in susceptibility generate major differences in neurotoxic risk and functional outcome. Identifying these heritable sources of variation in host susceptibility, and their role in complex gene–environment interactions, is crucial to identify risk biomarkers and to devise better prevention and treatment for those exposed to paraquat and other potential neurotoxicants.     

血液透析对急性百草枯中毒的临床疗效分析

目的：探讨血液透析（hemodilalysis,HD）治疗急性百草枯中毒的临床疗效,为临床应用HD治疗急性百草枯中毒提供依据。方法：选择我院2003 年3 月~2012 年7 月收治的百草枯中毒患者40 例,根据患者使用是否行透析治疗分为透析组（A组17 例）和非透析组（B 组23 例）,比较分析两组患者治疗后的肝功能、肾功能、肺功能及心肌酶学指标的变化,治疗效果及存活情况。结果：两组患者入院后前3 天ALT、AST、BUN、CR、CK、CK-MB 水平均呈上升趋势,且非透析组患者以上指标的水平高于透析组患者,但差异无统计学意义（P〉0.05）,入院后第7 天,两组以上指标的比较亦无统计学差异（P〉0.05）;两组患者之间入院时和入院后72小时内最低的SPO2%、血气分析中PaO2和PaCO2水平比较无统计学意义（P〉0.05）;透析组和非透析组患者的病死率分别为70.6%和69.6%,差异无统计学意义（P〉0.05）。结论：百草枯溶液中毒的患者预后差、病死率高,血液透析治疗并不能显著提高急性百草枯中毒患者的生存率。     

百草枯通过SOCE途径促进肺纤维化的发生

摘要 目的：探讨SOCE对百草枯（PQ）致肺纤维化过程的具体调控作用。方法：体外培养肺泡上皮A549细胞,设置分组为对照组、PQ组和PQ+SKF96365组。对照组不作任何处理;PQ组给予800 μM的PQ溶液处理细胞24 h;PQ+SKF96365组先加入10 μM的SKF96365预处理细胞2 h,然后再加800 μM PQ处理24 h。免疫荧光检测PQ染毒后SOCE相关蛋白的活化和胞内分布、NFATc1的表达和入核情况。清洁级小鼠40只,随机分为空白对照组、PQ组、SKF96365组和PQ+SKF96365组。PQ组及PQ+SKF96365组给予百草枯（20 mg/kg）一次性腹腔注射,对照组给予等量生理盐水;SKFS96365组及PQ+SKF96365组每天腹腔注射一次10 mg/kg的SKF96365溶液,持续3天,行HE染色、Masson染色观察肺组织病理状态改变以及胶原纤维的变化情况。结果：与正常组相比,PQ染毒组STIM1蛋白活化出现寡聚化现象并且ORAI1、TRPC1膜定位显著;PQ引起细胞质内NFATc1信号向细胞核内转移,密度差异具有统计学意义（P<0.01）,使用SOCE抑制剂后NFATc1信号减弱向细胞质内转移（P<0.01）。与对照组相比,PQ中毒的小鼠肺泡结构被破坏,肺间质大量胶原纤维沉积;与PQ组相比,PQ+SKF96365组肺泡结构相对完整并且间质胶原纤维沉积减少。结论：PQ中毒可活化SOCE并通过增加NFAT入核激活下游转录信号,促进肺纤维化的发生。