孕期/哺乳期砷暴露对子鼠脑发育的影响

目的观察孕期/哺乳期环境水平砷暴露对子鼠中枢神经系统发育的影响。方法对昆明种小鼠全孕期和哺乳期以自由饮水方式连续染毒,饮水砷浓度分别为1、4和16 mg/L,对出生3和21 d的子鼠以ICP-MS法测定脑砷含量,HE染色观察脑形态发育。结果子鼠脑砷含量随母鼠饮水砷浓度升高而升高,呈剂量-反应关系(P!0.05)。光学显微镜下脑形态发育:与对照组比较,染砷子鼠大小脑皮层变薄,大脑单位面积神经元数目减少;染砷子鼠海马出现锥体细胞水肿、核浓缩,锥体细胞层变薄、锥体细胞层数减少,神经毡空隙增大等改变。结论孕期/哺乳期砷暴露可致子鼠脑形态发育异常;后者可能是砷神经发育毒性的解剖学基础。     

三氧化二砷治疗急性早幼粒性白血病患者骨髓和血液中砷分布的临床检测

目的检测使用三氧化二砷(As2O3)治疗急性早幼粒细胞性白血病(APL)后患者骨髓和血液中砷的浓度,分析砷暴露及暴露时间对机体的影响。方法对30名砷暴露患者及28名非砷暴露患者进行调查,对30名暴露者,其中包括砷暴露1年半以上(13人)、一年半以内(17人)以及未暴露组进行调查研究;同时随机抽取7名暴露者,采用氢化物发生原子吸收分光光度法检测骨髓和血液中砷代谢产物,对其骨髓和血液中砷浓度进行对比。结果 7例暴露组患者的骨髓与血液中砷浓度对比,骨髓砷浓度(7.99±0.15)μg/L;血液中的砷浓度(7.98±0.15)μg/L,差异无统计学意义(P>0.05);同时对暴露一年半以上,暴露一年半以内及对照组进行单因素分析t检验的方法,其两两之间进行比较发现暴露一年半以上组与暴露一年半以内组差异有统计学意义(P<0.05),两个暴露组与对照组比较,差异均有统计学意义(P<0.05)。结论 As2O3治疗ALP,砷可以到达骨髓并进行缓慢代谢,且在骨髓中的代谢与在血液中基本相同,随着暴露时间间隔的延长砷浓度有下降趋势。     

胚胎期砷暴露对成年小鼠海马神经炎症反应的影响

目的研究胚胎期砷暴露对成年小鼠海马组织神经炎症反应相关基因表达的影响,探讨砷影响认知发育的毒理学机制。方法 7周龄雌性和雄性ICR小鼠以2∶1的比例合笼交配,受孕小鼠随机分为4组,对照组饮用去离子水,低、中、高砷暴露组分别饮用含0.15 mg/L,1.5 mg/L,15 mg/L三氧化二砷的去离子水,攻毒处理至仔鼠出生,试验组母鼠停止砷暴露。各组分别选12只雌性仔鼠,于65日龄麻醉处死并分离海马组织,Trizol法提取总RNA,采用实时荧光定量-聚合酶链反应(qRT-PCR)技术检测相关基因的表达。结果与对照组相比,低浓度砷暴露组小鼠海马组织同种异体移植炎性因子-1(Aif-1)的表达显著升高(P<0.01);胶质纤维酸性蛋白(GFAP)的表达在低、中、高浓度砷暴露组均升高;CC趋化因子配体3(CCL3)的表达在中浓度砷暴露组中显著升高(P<0.05);N-甲基-D-天冬氨酸受体(NMDAR)亚基NR1的表达在中浓度砷暴露组中显著降低(P<0.05);NR2B的表达在中浓度砷暴露组中显著降低(P<0.01)。结论胚胎期砷暴露会引起小鼠成年期海马组织胶质细胞活化继而释放大量促炎症因子,并降低NMDAR有关亚基的表达,这是砷影响小鼠认知发育的分子机制之一。     

砷暴露的心血管毒性效应及其机制研究进展

正砷是地壳中普遍分布的有毒元素,其损伤效应主要取决于暴露剂量、暴露时间及暴露频率,可累及神经系统和呼吸系统,直至产生癌症如皮肤癌、肺癌及膀胱癌。IARC将无机砷归类为人类Ⅰ类致癌物。发生频率较低的急性砷中毒主要见于职业性暴露和蓄意投毒,而长期低剂量砷暴露人群分布广泛,所导致的健康效应如皮肤损伤、癌症、发育毒性、神经毒性、心血管疾病、糖代谢异常和糖尿病,及其损伤机制逐渐引起人们     

太白楤木皂苷对砷诱导的肝细胞线粒体途径凋亡的保护作用

目的探讨太白楤木皂苷对砷暴露损伤的保护作用及分子机制。方法人正常肝细胞HL-7702进行砷暴露及太白楤木皂苷保护处理。砷暴露组用10μmol L-1终浓度的NaAsO2处理,太白楤木皂苷保护组用不同浓度太白楤木皂苷预处理12 h后,再进行砷暴露处理。24 h后MTT法检测细胞活力;12 h后收集细胞样品,分别检测细胞的凋亡、活性氧（ROS）、还原型谷胱甘肽（GSH）,氧化损伤产物丙二醛（MDA）水平以及线粒体凋亡途径的重要因子细胞色素C（Cyto C）释放和Caspase-3的激活情况。结果砷暴露可以引起肝细胞活力显著降低,给予不同浓度的太白楤木皂苷具有一定的保护作用,其中5μg mL-1太白楤木皂苷保护效果最佳。砷暴露可以引起细胞凋亡比例显著增加,细胞ROS水平升高,GSH水平降低,氧化损伤产物MDA水平增加,线粒体凋亡途径因子Cyto C和Caspase-3的激活。太白楤木皂苷（5μg mL-1）预处理能够显著拮抗砷暴露引起的细胞上述指标变化。结论砷暴露可以通过诱导细胞氧化应激,激活线粒体途径细胞凋亡,发挥其损伤毒性作用。太白楤木皂苷可以通过抑制细胞氧化应激,抑制线粒体途径的细胞凋亡,从而发挥其抗砷暴露损伤的保护作用。     

NaAsO2通过Hippo通路影响PC12细胞形态和突触蛋白

<正>砷是一种自然环境中广泛存在的非金属元素^[1]。人类在自然环境和工业活动中长期接触受砷污染的水、空气和食物而中毒，造成组织器官损伤、甚至癌变。此外，砷引起神经系统损害也受到人们越来越多的关注^[2]。但目前砷引起神经损伤的具体机制仍不是十分明确。     

砷的健康危害评估

目的在系统文献检索基础上,收集筛选砷(Arsenic)及其化合物的危害识别、危害特征描述的毒理学资料和数据,对砷的健康影响进行危害评估,为风险评估提供毒理学基础数据。方法首先进行系统文献检索,经过初级检索、去重和人工筛选等文献梳理过程,以及文献质量相关性评价,确定纳入的核心参考文献;然后对收集筛选的毒理学信息进行整理、分析,对砷的健康影响进行危害评估。结果砷的毒性与其化学形态和溶解性有关。无机砷的急性经口毒性分级为中毒至剧毒,有机砷为无毒。三价砷毒性强于五价砷。亚慢性和慢性毒性动物试验显示:砷对心血管、呼吸、胃肠、血液、免疫、生殖和神经系统有危害效应。人体通过呼吸吸入、皮肤接触、食物和水等方式摄入过量砷后,会发生急、慢性砷中毒,甚至诱发癌症。2012年,国际癌症研究机构(IARC)将砷和无机砷化合物列为第1类物质(对人类为确定致癌物)。结论砷的长期暴露具有一定的健康危害,其毒性作用主要包括生殖发育毒性、神经毒性、免疫毒性和致癌性等。食品添加剂联合专家委员会(JECFA)基于总膳食暴露评估的无机砷的BMDL_(0.5)为每天2.0～7.0μg/kg·bw。世界卫生组织(WHO)规定生活饮用水的砷限量为10μg/L。我国GB 2762-2017食品安全国家标准"食品中污染物限量"规定,谷物等食品中总砷限量为0.5 mg/kg。     

神经干细胞在神经发育毒性研究中的应用

<正>人脑的发育需要一个相当长的时间,从胚胎期神经发生到出生后发育成拥有数百亿精确定位、高度特化、高度联系、细胞群集的复杂器官,在此期间每一发育阶段都必须有序、准时按期完成。胎儿期胎盘屏障和婴儿时期血脑屏障不能完全有效地阻挡化学物的暴露,使得神经系统发育早期如胚胎期、胎儿期和新生儿阶段更易受到环境神经毒物的影响。此类在神经系统发育阶段暴露于神经毒性物质后引起的神经系统结构和功能的异常性改变,即所谓的神经发育毒性     

母体铅暴露对仔鼠海马中一氧化氮/环鸟苷酸的影响

目的：通过研究母体铅暴露对发育期仔鼠海马组织NO／cGMP水平变化，分析母体铅暴露对子鼠海马NO／CGMP途径的影响。方法：将母鼠从孕期第1天至仔鼠出生第20天分别饮用双蒸水、200、100、50mg/L醋酸铅溶液，检测20日龄和60日龄仔鼠物血铅、脑铅水平及海马组织nNOS神经原细胞、NO、NOS、cGMP浓度。结果：20日龄染毒组仔鼠的血铅、脑铅浓度与对照组相比有显著性增高，60日龄仔鼠的血铅与对照组相比，差异无显著性，但脑铅仍比对照组高；20日龄和60日龄染毒组仔鼠海马组织nNOS阳性神经元强度值、吸光度（A）、一氧化氮、NOS、cGMP浓度与对照组相比有显著降低，一氧化氮、NOS、cGMP三者相关性较好。结论：母体铅暴露可损伤仔鼠海马组织NO／cGMP途径，这种损伤在停止铅接触一段时间后仍持续存在。     

对《中国药典》一部含朱砂、雄黄成方制剂有关问题的商榷

朱砂、雄黄均为有毒中药，其主要成分分别为硫化汞（HgS）和二硫化二砷（As2S2）。现代药理研究表明，汞和砷均为细胞原浆毒。汞、砷化合物与体内酶蛋白的巯基具有特异的亲和力，可使酶失去活性，影响细胞正常代谢，导致细胞死亡，因而引起神经系统及其他系统的功能与器质性病变。含朱砂、雄黄的中成药中均有可溶性汞和游离汞及三氧化三砷存在。     

Role of glutathione in reduction of arsenate and of gamma-glutamyltranspeptidase in disposition of arsenite in rats

Arsenate (AsV), the environmentally prevalent form of arsenic, is converted sequentially in the body to arsenite (AsIII), monomethylarsonic acid (MMAsV), monomethylarsonous acid (MMAsIII), and dimethylarsinic acid (DMAsV) and some trimethylated metabolites. Although the biliary excretion of arsenic in rats is known to be glutathione (GSH)-dependent, involving transport of arsenic-GSH conjugates, the role of GSH in the reduction of AsV to the more toxic AsIII in vivo has not been defined. Therefore, we studied how the fate of AsV is influenced by buthionine sulfoximine (BSO), which depletes GSH in tissues. Control and BSO-treated rats were given AsV (50 micromol/kg, i.v.) and arsenic metabolites in bile, urine, blood and tissues were analysed by HPLC-HG-AFS. BSO increased retention of AsV in blood and tissues and decreased appearance of AsIII in blood, bile (by 96%) and urine (by 63%). The biliary excretion of MMAsIII was also nearly abolished, the appearance of MMAsIII and MMAsV in the blood was delayed and the renal concentrations of these monomethylated arsenicals were decreased by BSO. Interestingly, appearance of DMAsV in blood and urine remained unchanged and the concentrations of this metabolite in the kidneys and muscle were even increased in response to BSO. To test the role of gamma-glutamyltranspeptidase (GGT) in arsenic disposition, the effect of the of the GGT inhibitor acivicin was investigated in rats injected with AsIII (50 micromol/kg, i.v.). Acivicin lowered the hepatic and renal GGT activities and increased the biliary as well as urinary excretion of GSH, but failed to alter the disposition (i.e. blood and tissue concentrations, biliary and urinary excretion) of AsIII and its metabolites. In conclusion, shortage of GSH decreases not only the hepatobiliary transport of arsenic, but also reduction of AsV and the formation of monomethylated arsenic, while not hindering the production of dimethylated arsenic. While GSH plays an important role in the disposition and toxicity of arsenic, GGT, which hydrolyses GSH and GSH conjugates, apparently does not influence the fate of the GSH-reactive trivalent arsenicals in rats.     

微透析取样技术在中药体内分析中的应用研究进展

本文综述了微透析取样技术在中药体内分析中的应用,介绍微透析取样技术的原理、组成、探针类型、特点,重点阐述了微透析取样技术在测定脑、血液、皮肤等组织器官中中药有效成分浓度的应用实例。表明微透析取样技术在中药药效研究中具有广阔的前景。     

Role of desacetylation in the detoxification of cephalothin in renal cells in culture

The toxicity of three cephalosporin antibiotics to rabbit kidney cells in culture was compared to their known nephrotoxic potential in vivo (cephaloridine greater than cefazolin greater than cephalothin). While cephalothin is considered to be a relatively nonnephrotoxic cephalosporin when administered to many species including humans and rabbits, in several in vitro systems involving rabbit renal tissue, cephalothin was comparatively more toxic than anticipated based on in vivo data. Cephalothin is extensively desacetylated in rabbits to a less microbiologically active metabolite, desacetylcephalothin. When a microsomal S9 fraction from rabbit kidney was added to the in vitro assay in cultured rabbit renal cells, cephalothin was desacetylated and its toxicity to kidney cells was reduced. The addition of S9 in vitro provided a toxicity ranking of the cephalosporins that correlated with their known in vivo nephrotoxic potentials (cephaloridine greater than cefazolin greater than cephalothin). The in vitro detoxification of cephalothin by S9 was blocked by the coadministration of the esterase inhibitor, aminocarb. Desacetylcephalothin was relatively nontoxic to rabbit renal tissue in vitro. These results suggest that the desacetylation of cephalothin in vivo represents a previously unrecognized mechanism of detoxification of this cephalosporin antibiotic. Furthermore, this mechanism of detoxification may be applicable to other acetylated cephalosporins.     

2009年某院住院患者抗真菌药用药调查

目的:分析讨论某院抗真菌药使用的合理性,为临床安全有效地使用抗真菌药提供参考。方法:回顾性统计分析某院2009年住院患者抗真菌药用药信息。结果:2009年某院住院患者抗真菌药DDDs排名前3名分别为:氟康唑、制霉菌素和伊曲康唑;使用金额排名前3名分别为:氟康唑、米卡芬净及卡泊芬净;更换一种抗真菌药进行治疗的患者数为176人,在全部患者中占13.4%。结论:应进一步强化用药指征的意识,提高标本送检率,同时改善某些抗真菌用药不合理更换的现象,以避免耐药性发生,从而更好更长远地体现抗真菌药的治疗价值。     

应用PASS系统对我院2008年住院医嘱的分析

目的监测分析2008年我院住院患者用药情况。方法将PASS系统嵌入医生工作站、临床药学工作站等子系统,构建合理用药计算机网络系统,对住院医嘱进行及时监测,将监测结果向医生反馈,并对其进行统计、分析。结果2008年共监测医嘱3 620 241条,不合理医嘱908条,占0.02%。不合理医嘱中,配伍禁忌(381条)占41.96%,用法用量(381条)占41.96%,药物相互作用(108条)占11.89%,儿童用药(38条)占4.19%。经与医生沟通后,更改不合理医嘱856条,占94.27%。结论PASS系统可有效监测医嘱中的不合理用药,通过与医生交流,大大减少药物不良事件的发生,值得临床推广应用,也为临床药师开展工作带来了极大的便利。但PASS系统尚存在局限性,有待进一步完善。     

Kinetics of in vitro metabolism of methoxyphenamine in rats

1. Methoxyphenamine (MP) was metabolized in vitro by rat liver preparations to O-desmethylmethoxyphenamine (O-desmethyl-MP), N-desmethylmethoxyphenamine (N-desmethyl-MP) and 5-hydroxymethoxyphenamine (5-hydroxy-MP). These metabolic pathways were inhibited by SKF 525-A and carbon monoxide, which indicates that these reactions were mediated at least partly by an NADPH-dependent cytochrome P-450 system. 2. Strain differences in the metabolism of this drug in vitro were observed in female Lewis and Dark Agouti (DA) rats, which are proposed models for human debrisoquine phenotypes. Methoxyphenamine O-demethylase and 5-hydroxylase activity in DA rats were lower than those in Lewis rats. 3. The metabolic transformation of methoxyphenamine in vitro to O-desmethyl-MP was inhibited competitively by debrisoquine and sparteine. This indicates that the cytochrome P-450 isoenzyme mediating the metabolism of MP to O-desmethyl-MP is similar to that mediating metabolism of debrisoquine and sparteine. However, no inhibition was observed with methenytoin.     

应用PASS系统分析我院2010年住院医嘱

目的:了解我院2010年住院患者的合理用药情况,探讨如何利用合理用药监测系统( PASS)提高合理用药水平.方法:利用PASS对我院2010年15 966例住院患者的1 184 997条用药医嘱进行监测,以黑色警示医嘱为依据,收集不合理用药信息,并对监测结果进行统计、分析.结果:不合理用药医嘱50 261条,发生率为4.24％.绝对禁止黑色医嘱5441条,主要为药物相互作用(66.54％)、注射液体外配伍(17.86％)、用法用量(15.46％)、儿童警告(1.14％).结论:应用PASS系统能有效监测医嘱中的不合理用药情况,有利于提高临床合理用药水平,但PASS系统尚存在局限性,有待进一步完善.     

Changes in levels of dependency and predictors of mortality in elderly people in institutional care in Dunedin

The 1983 study of dependency of subjects in institutional care in Dunedin was repeated two years later. A significant increase in levels of dependency in residential homes, particularly in the Religious and Welfare sector was found. In 1983 there were 29 high dependency residents and 73 medium dependency residents in residential homes. In 1985 these numbers had increased to 55 and 86 respectively. There was no change in the number of low dependency residents. In 1983, 6 high dependency residents had been admitted to residential home care in the year prior to the study. In 1985 the number of high dependency residents recently admitted had increased to 23. There had also been a significant increase in the dependency of patients in Religious and Welfare continuing care hospitals. Of the 933 subjects in institutional care in 1983 who were able to be followed, 354 (37.9%) died in the following 2 years. Mortality rate was higher for those in hospital care (48.1%) than for those in residential home care (29.6%). Mortality rates were higher in more dependent subjects and this was evident for each measure of dependency.     

Chondroprotective Effects of Wogonin in Experimental Models of Osteoarthritis in vitro and in vivo

We evaluated the chondroprotective effects of wogonin by investigating its effects on the gene expression and production of matrix metalloproteinase-3 (MMP-3) in primary cultured rabbit articular chondrocytes, as well as on production of MMP-3 in the rat knee. Rabbit articular chondrocytes were cultured in a monolayer, and RT-PCR was used to measure interleukin-1β (IL-1β)-induced expression of MMP-3, MMP-1, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), and type II collagen. In rabbit articular chondrocytes, the effects of wogonin on IL-1β-induced production and proteolytic activity of MMP-3 were investigated using western blot analysis and casein zymography, respectively. The effect of wogonin on MMP-3 protein production was also examined in vivo. In rabbit articular chondrocytes, wogonin inhibited the expression of MMP-3, MMP-1, MMP-13, and ADAMTS-4, but increased expression of type II collagen. Furthermore, wogonin inhibited the production and proteolytic activity of MMP-3 in vitro, and inhibited production of MMP-3 protein in vivo. These results suggest that wogonin can regulate the gene expression and production of MMP-3, by directly acting on articular chondrocytes.