Levels of oxidative stress parameters and the protective effects of melatonin in psychosis model

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虾青素与幽门螺杆菌导致的胃病健康问题

Astaxanthin for Dyspepsia and Helicobacter pyloriDyspepsia is the general term given to a variety of digestive problems localized in the upper abdominal region. Typical symptoms for example include stomach pain, gas,acid-reflux or bloating.Dyspepsia is like the stomach version of the irritable bowel syndrome and its symptoms may appear at any age or to any gender. The medical approach to dyspepsia involves looking for treatable causes and addressing them if identified. Failing that, doctors suggest treatments by trial-and-error. The problem associated with this non-standardized approach involves drugs that may not work, may cause side effects and exacerbate the patient’s condition brought on by stressful attempts to cure symptoms.To understand the benefits of astaxanthin in dyspepsia, it is necessary to categorize specific types; most common forms are either non-ulcer dyspepsia or gastric dyspepsia. Non-ulcerdyspepsia problems usually do not have an identifiable cause, but fortunately, for most cases it is non-disease related and therefore temporary. On the other hand, gastric type dyspepsia is more severe and linked to identifiable causes. For example, thebacterial infection of Helicobacter pylori is a commonly known cause. Pathological symptoms of H.pylori infection include high levels of oxidative stress and inflammation in the stomach lining and symptoms like gastric pain and acid reflux., H.pylori can contribute to mild and severe kinds of symptoms, but on the other hand, people who are H.pylori positive can remain asymptomatic whereas others may develop into clinical problems. It is still unclear what triggers the severe form of infection and how the bacteria is passed on, but scientistssuggested using strong antioxidants like astaxanthin for therapy and better long term protection.in mice lowered inflammation after 10-days of treatment (in vivo), and also inhibit H. pylori growth (in vitro). The mice treated with astaxanthin (10 mg/kg body weight) had the same effect as vitamin C (400 mg/Kg) which significantly lowered gastric inflammation and lipid peroxidation (Figure 4) compared to infected control mice; which continued to develop severe gastritis.Helicobacter pylori in Gastric DyspepsiaThis Gram-negative bacterium is present in approximately half of the world population, and typically resides in the human gastric epithelium (stomach lining). H.pylori infection is generallyacknowledged as the main cause for type B gastritis, peptic ulcer disease and gastric cancer. The pathogenesis of this infection is partly due to the immunological response as shown byBennedsen et al ., (1999). Astaxanthin (200 mg/kg body weight) fed to H.pylori infected mice for 10 days exhibited signs of improved immune system. Normally, the T-helper1 (Th1)response exacerbates inflammation and epithelial cell damage due to infection, but the astaxanthin treated mice responded with a mixed Th1/Th2-response (Figure 1), which lowered gastric inflammation (Figure 2) and bacterial loads (Figure 3).Furthermore, the findings by Wang et al ., (2000) also supportedthe idea that a diet supplemented with astaxanthin or vitamin C120100806040200-20I L - 4 p g /m lAstaxanthin improved the cytokine IL-4 response (Th2 T-cell) to thepresence of H. pylori (in vitro).+infectedInfected treateduninfectedp<0.001G a s t r i c i n f l a m m a t i o n s c o r ep=0.012.42.221.81.61.41.210.80.60.4+infectedInfected treateduninfectedAstaxanthin reduced gastric inflammation inHelicobacter pylori infected mice.p<0.02Astaxanthin reducedHelicobacter pyloricolonization of the stomach of infectedmice.Lipid peroxida-tion levels lowered in H. pylori infected mice aftertreatment with astaxanthin or Vitamin C.C F U120010008006004002000-200+infectedInfected treateduninfectedL i p i d p e r o x i d a n t a t i o n (µm o l /g t i s s u e )6050403020100Normal controlHP controlHP + Meal controlHP + Algal meal (10mg/kg)HP + Vitamin C(400mg/kg)Figure 1. IL-4 release of splenocytes after restimulation with H. pylori sonicateFigure 4. Amount of lipid peroxidation products (MDA and 4-hydroxyalkenals) during H. pylori infectionFigure 2. Gastric inflammation (antrum + corpus)Figure 3. Bacterial load (antrum + corpus)Reflux in Non-Ulcer DyspepsiaOutlookThere are considerable overlaps in a number of gastrointestinal disorders that may be treatable with conventional medicine, but what if it does not work? In that case, astaxanthin may be useful, particularly against H.pylori positive gastritis and non-ulcer dyspepsia acid reflux. The mechanisms of action include the following: decreasing oxidative stress by astaxanthin’s potent antioxidant property; controlling bacterial infection by shifting the immune response; and alleviating dyspeptic symptoms by retarding inflammation. Furthermore, these results infer that acid reflux in connection with either H.pylori positive or negative conditions can still expect improvements with astaxanthin.References1. Kupcinskas et al ., Efficacy of the antioxidant astaxanthin in the treatment of functional dyspepsia in patients with or withoutHelicobacter pylori gastritis: a propective, randomized, double blind, and placebo controlled study. Eur. J. Gastroent and Hepat., (In Press).2. Wang et al ., (2000). Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Antimicrob Agents Chemother. 44(9):2452-7. Symposium.3. Lignell et al ., (1999). 12th International Carotenoid Symposium, Cairns. The safety, tolerability and efficacy of the antioxidant Astaxanthin in the treatment of Helicobacter pylori infection.4. Bennedsen et al ., (1999). Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflammation, bacterial load and modulates cytokine release by splenocytes. Immunol Lett. 70(3):185-9.H.pylori & Dyspepsia PatentsWO98/37874 and WO00/23064.The success of astaxanthin in dyspepsia animal modelsprompted further prospective human studies. In 1999, the first clinical study performed in collaboration with the Centre for Digestive Diseases, Australia, involved ten H.pylori positive subjects (non-ulcer) with typical dyspeptic symptoms such as heartburn and gastric pain, were each treated with 40 mg daily dose of astaxanthin for 21 days. Ten clinical parameters assessed the efficacy before and after the treatment period. The gastric pain, heartburn and total clinical symptoms results showed a significant drop of 66%, 78% and 52% drop respectively (Figure 5). Furthermore, follow-up checks 27 days after the cessation of astaxanthin intake (a total of 49 days from day 0), showed that the dyspeptic symptoms remained low. In summary, astaxanthin effectively controlled the dyspepsia symptoms, and H.pylori eradication trend was observed, but not significant. Approximately one in four people experience dyspepsia at some time that are linked to common causes such as food types, stress, stomach ulcers, or acid reflux (stomach acid backs-up into the esophagus). If the exact causes of non-ulcer dyspepsia are unknown, there are no standardized treatments that exist to effectively treat the patient. The usual procedure involves the problematic remedies of acid blocking medicines, painkillers or antibiotics. However, drug treatment faces problems withincreasing antibiotic resistant bacteria and carries increased risk of damage to the stomach. Therefore, clinically proven non-drug treatments are becoming more attractive to physicians and patients.Astaxanthin efficacy in non-ulcer dyspepsia was demonstrated in a randomized double-blind placebo controlled study involving one-hundred and thirty-one patients complaining of non-ulcer dyspepsia. This collaborative trial conducted by the Kaunas University Hospital, Lithuania; Rigshospitalet, Copenhagen; University of Lund and the Karolinska Institute, Swedendemonstrated that 40 mg astaxanthin treatment up to 4 weekssignificantly reduced refluxcompared to the 16 mg (P<0.05) or placebo (P<0.05) groups (Figure 6). Although there was a strong placebo effect, otherimproved trends included gastric pain and abdominal pain (notsignificant).32,521,51BaselineMean GSRS scoreP<0.054 weeks laterReducedreflux-syndrome score of non-ulcer dyspepsia patients treated with 16 mg and 40 mg astaxanthin.40 mg astaxanthin 16 mg astaxanthin PlaceboDAY 0DAY 22DAY 49384491Figure 6. Reflux-syndromeAX_Pylori_MAR28.07。

杜仲及提取物在家禽养殖中的应用

饲料营养与饲草60 ·2022.110 引言杜仲是我国名贵中药材，广泛分布于四川、陕西等27个省（市、自治区），国家二级保护植物。

杜仲含有丰富的蛋白质、氨基酸、维生素等营养物质，可以作为天然饲料添加剂，具有促进家禽生长发育，增强家禽免疫力等功能。

大力开发杜仲等绿色饲料添加剂，不仅可以带动杜仲产业的发展，也可以促进我国家禽无抗养殖发展[1]。

1 杜仲及提取物主要生物活性物质及药理功能1.1 木质素类迄今为止，已发现杜仲中含有松脂醇二葡萄糖苷、丁香素二糖苷等近30种木质素类化合物。

其中，松脂醇二葡萄糖苷有促进骨细胞生长和降低血压的作用[2-3]，丁香素二糖苷具有抗肿瘤的作用。

1.2 环烯醚萜类据研究，杜仲中主要含有桃叶珊瑚苷、京尼平苷、京尼平苷酸等10余种环烯醚萜类化合物。

其中，桃叶珊瑚苷可以清除自由基、延缓衰老[4]，对大肠杆菌和金黄葡萄球菌有明显抑制作用[5]。

京尼平苷可以促进胰岛素的分泌[6]。

1.3 苯丙素类杜仲中含有多种苯丙素类化合物，主要是绿原酸。

收稿日期：2022-10-28基金项目：2021年四川省大学生创新创业训练计划项目（项目编号：CDNY0026）；成都农业科技职业学院院级孵化项目（自然科学）—抗菌中药材在畜禽常见细菌病防治的研究应用（cny19-23）；成都农业科技职业学院2020年大学生课外学术科技项目“新型乌骨鸡培育及高效养殖技术研究”作者简介：汪熙来（2001-），男，四川成都人，在读学生，主要从事畜牧兽医工作。

*通信作者简介：鲁志平（1982-），男，内蒙古呼和浩特人，硕士，正高级兽医师，主要从事畜禽疾病控制工作。

杜仲及提取物在家禽养殖中的应用汪熙来1，2，成杰1，2，何晴1，郭英博1，鲁志平1*，唐利军3（1.成都农业科技职业学院，四川成都 611130 ；2.西昌学院，四川西昌 615013；3.四川省大英县农业农村局，四川遂宁 629300）摘要：杜仲及提取物不仅含有蛋白质、氨基酸、维生素等营养物质，还含有许多有益的木质素类、环烯醚萜类、苯丙素类、黄酮类、多糖类等生物活性物质。

INFLAMMATION AND OXIDATIVE STRESS LEVEL ASSAY

专利名称：INFLAMMATION AND OXIDATIVE STRESS LEVEL ASSAY发明人：SONNTAG, Denise,KOAL, Therese,RAMSAY, Steven, Lewis,DAMMEIER,Sascha,WEINBERGER, Klaus,Michael,UNTERWURZACHER, Ines申请号：EP2008004323申请日：20080530公开号：WO08/145384P1公开日：20081204专利内容由知识产权出版社提供摘要：The present invention relates to a method for determining the systemic metabolic status of an organism in relation to inflammation and oxidative stress using a biological sample (Inflammation and Oxidative Stress Level Assay). This comprises detection and quantification of one or more derivatives of arachidonic acid (eicosanoids), linoleic acid and/ or docosahexaenoic acid, preferably together with one or more oxidative stress parameters and/or with one or more analytes from other metabolite classes in parallel, as well as a kit adapted for carrying out such a method. Moreover, the invention relates to the biomarkers as employed in the method.申请人：SONNTAG, Denise,KOAL, Therese,RAMSAY, Steven, Lewis,DAMMEIER, Sascha,WEINBERGER, Klaus, Michael,UNTERWURZACHER, Ines地址：AT,AT,AT,AU,AT,AT,AT国籍：AT,AT,AT,AU,AT,AT,AT代理机构：URNER, Peter 更多信息请下载全文后查看。

丹红注射液改善神经干细胞移植治疗脑缺血损伤效果的机制研究

N+D+M 组
治疗作用
ห้องสมุดไป่ตู้
NSC 组 N+D 组
治疗作用
神经功能评分氧化应激相关指标
大鼠脑缺血模型
丹红注射液 PBS
DH 组 PBS 组
无治疗作用
NSC 存活情况
【摘要】目的探讨丹红注射液能否通过调控核因子 E2 相关因子 2（Nrf2）信号通路增强神经干细胞（NSC）移植修复脑缺血损伤的治疗效果。方法 40 只雄性 SD 大鼠随机分为 NSC 移植治疗组（NSC 组）、丹红注射液组（DH 组）、NSC+ 丹红注射液组（N+D 组）、NSC+ 丹红注射液组 +ML385 组（N+D+M 组）和 PBS 对照组（PBS 组），每组 8 只。所有大鼠均采用大脑中动脉栓塞法建立脑缺血模型，栓塞 1.5 h 后进行再灌注。再灌注后 3 d 对各组大鼠进行相应处理。在 NSC 移植术前和术后 1、2、4 周进行神经功能评分。术后 4 周后处死大鼠，检测氧化应激相关指标，并用免疫荧光染色检测神经元特异核蛋白（NeuN）和血管性血友病因子（vWF）的表达情况。结果在 NSC 移植术前，各组大鼠的神经功能评分比较，差异无统计学意义（P>0.05）。术后 1、2、4 周时，NSC 组、DH 组和 N+D 组大鼠的神经功能评分较 PBS 组和 N+D+M 组均降低（均为 P<0.05）。
丹红注射液是一种广泛用于脑梗死、冠状动脉粥样硬化性心脏病、肺源性心脏病、糖尿病周围神经病变治疗的中药制剂 [12-16]，具有改善血液循环、保护血管内皮、抗炎、抗氧化应激损伤、抗神经元凋亡、保护神经、促进神经元突触重塑、降低血清同型半胱氨酸水平等作用。为了确定丹红注射液是否能通过调控 Nrf2 信号通路改变移植微环境，增强干细胞移植治疗脑缺血损伤的效果，本研究建立大鼠脑缺血模型，探讨丹红注射液协同干细胞移植治疗在脑缺血损伤中的治疗作用。

护理干预对系统性硬化症应用价值论文

护理干预对系统性硬化症应用价值【摘要】目的：探讨护理干预对系统性硬化症治疗效果的影响。

方法：通过心理护理、严格的饮食护理、皮肤护理及呼吸道护理等。

结果：患者的临床症状明显好转或基本消失，并发症相对减少。

【关键词】护理干预；系统性硬化症；并发症；【中图分类号】r473.5 【文献标识码】a 【文章编号】1004-7484（2013）04-0356-01系统性硬化症（ssc）是以局限性和弥漫性皮肤增厚及内脏器官结缔组织纤维化、硬化及萎缩为特点的结缔组织病，可影响心、肺、肾及消化系统等全身脏器。

早期护理干预对治疗效果有着重要的意义。

分析如下：1 临床资料2008～2012年，我科共收住15例系统性硬化症的患者，所有患者均符合美国风湿病协会1980年风湿病诊断标准。

其中男性2例，妇性13例，平均年龄约33.7岁，病程约3个月至1年左右。

本组病人均出现雷诺现象，所有患者均有不同程度的皮肤硬结，肺受累3例，占20%，关节受累9例，占60%。

3例食道受累，占20%。

2 护理2.1 护理内容对系统性硬化症患者心理、饮食、用药观察、防止继发感染、皮肤等方面进行针对性护理。

2.2 护理方法2.2.1 评估详细了解患者病情、身心状况，观察皮肤损害、生命体征、吞咽及呼吸道症状，找出患者存在的主要问题，有针对性地进行护理。

2.2.2 心理护理多种消极因素的存在使 ssc患者情绪发生巨大变化。

本组患者发病时都在30～40岁，是家庭的支柱，可患病后不仅失去劳动能力，且影响容貌，面部硬化呈假面具样，患者难以接受一现实，心情十分痛苦，严重影响了患者的生活质量，给患者的工作和生活带来很大的不便。

因此，要及时做好有效的心理护理，多与患者沟通交流，帮助患者及家属正确认识该病，掌握其相关护理知识，介绍好转病例，保持积极、乐观的生活态度，积极配合治理和护理，树立长期的治疗信心。

2.2.3 雷诺现象的护理雷诺现象往往是硬皮症的首发症状，并贯穿疾病的始终[1] 。

绿原酸减轻脓毒症诱导的小鼠急性肾损伤：基于抑制caspase-1经典细胞焦亡信号通路

综上所述，冠脉狭窄患者血清FDX1、LA水平降低，两者水平变化与冠脉病变支数和Gensini积分有关，且两者共同参与了冠状动脉粥样硬化的发生与进程。

该结果为判断冠脉病变程度及研究CHD致病机制提供了一定参考依据。

血脂异常作为冠状动脉粥样硬化的独立危险因素，通过动物模型进一步证实了FDX1、LA 与高脂血症导致的血管病变有关，为CHD的防治提供参考，尽管本实验证实了FDX1、LA在冠状动脉粥样硬化冠脉病变、高脂血症所致血管损伤之间的相关性，但其具体作用机制及作用途径仍需深入研究。

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32.炮制辅料羊脂油对淫羊藿总黄酮吸收转运及体内药动学的影响----李杰

Agilent1200 系列高效液相色谱仪，四元泵，DAD 检测器（Agilent 公司，美国）；激光粒度分析仪（Zetasizer-Nano-ZS 型，英国 Malvern 公司）；透射电子显微镜（JEM-1010，日本电子公司 JEOL）；恒流泵 PHD2000 Infuse/withdraw pump (Harvard Apparatus Inc. 美国)；二氧化碳培养箱（Hearous, 德国）；Millicell-ERS 跨膜电阻仪（Millipore，美国）；超高压液相色谱仪 Waters AcquityTM （Waters ，美国）；高速冷冻离心机（Beckman，美国）；Milli-Q 纯水机（Millipore，美国）。连续光谱酶标仪（Molecular Devices，SpectraMAX 190） 1.3 大鼠与细胞
essential amino acids， JRH）； DMEM 培养基（Dulbecco’s modified Eagle’s medium， Hyclone）；HEPES（北京拜尔迪生物公司）；氢化可的松注射液（天津金耀药业有限公司，批号：1407271）；丙二醛（MDA）试剂盒（南京凯基生物科技发展有限公司）；甲醇、乙腈为色谱纯，水为超纯水，其他试剂均为分析纯。 1.2 仪器
炮制辅料羊脂油对淫羊藿总黄酮吸收转运及体内药动学的影响
李杰 1,2，孙娥 2，张振海 2，崔莉 2，蒋俊 2，贾晓斌 1,2* [摘要] 本文在模拟人体内环境条件下，研究淫羊藿总黄酮在炮制辅料羊脂油的作用下自组装胶束形成，采用大鼠在体单向肠灌流模型和 Caco-2 细胞单层模型考察炮制辅料羊脂油对淫羊藿总黄酮肠吸收转运的影响。通过建立小鼠肾阳虚模型，采用药理效应法，以丙二醛（MDA）降低量为指标，比较淫羊藿总黄酮及加入羊脂油后的小鼠体内药动学参数。结果显示，在炮制辅料羊脂油的作用下，淫羊藿总黄酮可自组装形成胶束，模拟形成的胶束呈分散状态，类球形且表面光滑。与淫羊藿总黄酮相比，自组装形成胶束后 Caco-2 细胞表观渗透系数显著增加，外排比率下降，在十二指肠和空肠段的渗透系数显著增加，说明吸收转运有明显改善。小鼠体内的 AUC(0-t)，AUC(0-∞)，Cmax 与淫羊藿总黄酮相比显著提高，淫羊藿总黄酮生物利用度提高，体内吸收增加。 [关键词] 淫羊藿总黄酮；羊脂油；自组装胶束；肠吸收；药动学 Effect of suet oil on the transformation and pharmacokinetic in vivo of the flavonoids in Epimedium LI Jie1,2，SUN E2，ZHANG Zhenhai2，Cui Li2，JIANG Jun2，JIA Xiaobin1,2* [Abstract] To research the action of suet oil in the preparation of self-assembled micelles of the Epimedium flavonoids in the simulated human environment. Rat intestinal perfusion model and Caco-2 cell monolayer model were used to study the influence of suet oil on the intestinal absorption of Epimedium flavonoids. The kidney-yang deficiency model were used and oxidative stress level was taken as index to estimate main pharmacokinetics parameters of epimedium flavonoids and its self-assembled micelles. The results showed that the micelles had a dispersed state and spherical smooth surface. The epimedium flavonoids had a bad intestinal

糖化血红蛋白水平和血糖波动与氧化应激关系的研究

中国糖尿病杂志 202 丨年 2 月第 29 卷第 2 期Chin J Diabetes，February 2021，V()l. 29，No. 2•99••血糖管理•糖化血红蛋白水平和血糖波动与氧化应激关系的研究郗光霞安平梁登耀范雪梅任伟杨坤张晓琳【摘要】目的探讨HbAlC水平、血糖波动与氧化应激(O S)的关系。

方法选取2017年8月至2019年8月于山西白求恩医院内分泌科住院的新诊断T2D M患者115例，分为低HbAl C：(5. 5%〜6. 5%)组、中HbAlC(6. 5%〜7. 5%)组、高HbA,c(7. 5%〜8. 5%)组，行持续葡萄糖监测，记录包括平均血糖波动幅度（M A G E)、血糖标准差（SD B G)、最大血糖波动幅度（L A G E)及日间血糖平均绝对差（M ODD);E U S A法测定O S血清指标8-羟基脱氧鸟苷(8-O H dG)，分析H bA,c水平和血糖波动与8-O H dG的关系。

结果与低HbAl(：组比较，中HbAlC组SDBG、M A G E升高（P C0.05);高H b A f组LA G E、SDBG、M A G E及M O D D均高于低HbAlC、中H b A,c组（尸<0.05)。

随着HbAlC水平升高，各组8-O H dG水平依次升高（P<0. 01)。

Pearson相关性分析显示，HbAl(：水平与LA G E、SDBG、M A G E及MODD 呈正相关（尸<0.01),高H b A f 组8-OHdG 与MAGE 呈正相关0=0.202, P=0.036)。

结论SDBG、M A G E是反映血糖波动更敏感的指标，HbAlC<7.5%时显示血糖异常波动。

T2D M患者血糖波动随HbAlC水平升高而增加，O S随血糖波动增加而加重。

【关键词】持续葡萄糖监测；糖化血红蛋白；血糖波动；氧化应激doi ： 10. 3969/j. issn. 1006-6187. 2021. 02. 005Relationship between HbA,c levels and blood glucose fluctuations and oxidative stress XI Guangxia,A N Ping, LIAN G Dengyao, et al. Department o f Endocrinology, Shw u i Bethune Hospital Shanxi Academyo f M edical Sciences, Taiyuan 030032, China【Abstract】Objective To investigate the relationship between glycated hemoglobin (HbA]C) levelsand blood glucose fluctuations and oxidative stress. Methods A total of 120 patients with new-onset of typeZdiabetesmellitusCTZDlVnweregroupedbyHbApS.Sj^—G.Sj^G.SW—l.SMjandy.S%、8. S%. Continuous glucose monitoring was used to obtain blood glucose fluctuation parameters ： mean amplitudeof glycemic excursions (M A G E), standard deviation of blood glucose level (S D B G), largest blood glucosefluctuation (LA G E) , and absolute means of daily difference (M ODD). Serum oxidative stress indicator8_hydroxydeoxyguanosine (8_OHdG) was determined by enzyme-linked immunosorbent assay. The relationshipbetween HbAjC levels and blood glucose fluctuations and 8-〇hdG was analyzed. Results Compared withthe low group, SDBG and MAGE increased in middle group (P<0. 05). Compared with low and middleHbA]C group, LAGE, SDBG, MAGE and MODD increased in high HbAjC group (P<0. 05). The levelof 8-()HdG increased with the increase of HbAiC level (P<0. 01). HbAjC levels were positively correlatedwith LAGE, SDBG, MAGE and MODD (P<0. 01). In high group, 8-〇HdG was positively correlatedwith MAGE (r=0. 202,P=0. 036). Conclusion SDBG and MAGE are sensitive indicators in reflectingblood glucose fluctuations, even in patients with H bA,c<7. 5%. The blood glucose fluctuations of patientswith new-onset of T2DM increased with the increase of HbAiC level* and the level of oxidative stressincreased with the increase of blood glucose fluctuations.【Key words】Continuous glucose monitoring; Glycated hemoglobin A le;Blood glucose fluctuations:Oxidative stress作者单位：030032太原，山西白求恩医院山西医学科学院内分泌科（郗光霞、梁登耀、范雪梅、任伟、杨坤、张晓琳）：中国人民解放军总医院内分泌科(安平）• 100•中国糖域病杂志 2021 年 2 月第 29 卷第 2 期Chin J Diabetes, February 2021 , Vol. 291 No. 2血糖波动可增加体内自由基产生，激活氧化应激(OS),促进炎症反应，破坏血管内皮细胞，增加血管病变风险[12]，促进D M大血管和微血管并发症的发生发展。

精神分裂症患者NLR、氧化应激参数与精神症状的相关性

精神分裂症患者NLR、氧化应激参数与精神症状的相关性费小聪;陈海支;郑燕妮;方瑜;雷礼磊;王振华;宋宝华;崔力军【摘要】目的探讨精神分裂症患者中性粒细胞/淋巴细胞比值(NLR)、氧化应激参数与精神症状的相关性.方法选择64例精神分裂症患者和61例健康志愿者,检测并比较两组对象的NLR、总抗氧化状态(TAS)、总氧化状态(TOS)、氧化应激指数(OSI)、对氧磷酶1(PON1)和硫醇(Thiol)水平;采用阳性与阴性症状量表(PANSS)评价精神症状,分析NLR、PANSS评分和氧化应激参数间的关系.结果与健康对照组比较,精神分裂症组NLR、TAS、TOS明显增高(均P＜0.05),Thiol、Thiol/OSI明显降低(均P＜0.05);两组间PON1、OSI比较,差异均无统计学差异(均P＞0.05).精神分裂症患者PANSS阳性分值与Thiol/OSI呈负相关(r=-0.264);总分值与NLR 呈正相关(r=0.251),与Thiol/OSI呈负相关(r=-0.286).精神分裂症组NLR与Thiol/OSI呈负相关(r=-0.340),健康对照组NLR与ThioI/OSI未见相关(r=-0.040).精神分裂症患者NLR与TOS、OSI均呈正相关(r=0.361、0.307);Thiol/OSI与TOS、OSI均呈负相关(r=-0.685、-0.678),与TAS、Thiol均呈正相关(r=0.256、0.416).结论炎症和氧化应激在精神分裂症的发生、发展中起着重要作用,且与患者临床症状关系密切.NLR是一项可以反映精神分裂症患者氧化应激和精神症状信息的简单、廉价、适合常规应用的指标.%Objective To investigate the association between neutrophil/lymphocyte ratio(NLR) and psychiatric symptoms in patients with schizophrenia.Methods Sixty four patients with schizophrenia and 61 healthy volunteers were included in the study.The NLR,total antioxidant status(TAS),total oxidantstatus(TOS),oxidative stress index (OSI) and paraoxonase 1(PON1) and thiol levels were measured;the psychiatric symptoms were evaluated withpositive and negative symptom table(PANSS).The association of psychiatric symptoms with NLR,PANSS score and oxidative stress parameters was analyzed.Results Compared with healthy controls,the NLR,TAS and TOS in schizophrenia group were increased significantly (P＜0.05),Thiol andThiol/OSI were decreased significantly(P＜0.05).However,there were no significant differences in PON1 and OSI between two groups(P ＞0.05).PANSS positive score was negatively correlated with Thiol/OSl (r=-0.264) in schizophrenic patients,and the PANSS total score was positively correlated with NLR (r=0.251),and negatively correlated with Thiol/OSI (r=-0.286).There was a negative correlation between NLR and Thiol/OSI in schizophrenia group (r=-0.340),but not in control group (r=-0.040).NLR was positively correlated with TOS and OSl in schizophrenic patients(r=0.361,0.307).Thiol/OSI was negatively correlated with TOS and OSI (r=-0.685,-0.678),and positively correlated with TAS and Thiol(r=0.256,0.416).Conclusion Inflammation and oxidative stress may be involved in the occurrence and development of schizophrenia,and are closely related to the clinical symptoms of patients.NLR as a simple and inexpensive indicator may be used for assessment of oxidative stress and psychiatric symptoms in patients with schizophrenia.【期刊名称】《浙江医学》【年(卷),期】2017(039)006【总页数】4页(P449-451,465)【关键词】中性粒细胞/淋巴细胞比值;氧化应激参数;精神分裂症【作者】费小聪;陈海支;郑燕妮;方瑜;雷礼磊;王振华;宋宝华;崔力军【作者单位】313000 湖州市第三人民医院精神科;313000 湖州市第三人民医院精神科;山西省晋城市人民医院医学影像科;313000 湖州市第三人民医院精神科;313000 湖州市第三人民医院精神科;313000 湖州市第三人民医院精神科;313000 湖州市第三人民医院精神科;313000 湖州市第三人民医院检验科【正文语种】中文有学者认为，就人类痛苦和社会支出而言，精神分裂症是最神秘、治疗费用最昂贵的精神疾病之一[1]。

Oxidative stress, antioxidants and stress tolerance

1360-1385/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1360-1385(02)02312-9Ron MittlerDept of Botany, Plant Sciences Institute,353Bessey Hall, Iowa State University, Ames,IA 50011, USA.e-mail: rmittler@Reactive oxygen intermediates (ROIs) are partially reduced forms of atmospheric oxygen (O 2). Theytypically result from the excitation of O 2to form singlet oxygen (O 21) or from the transfer of one, two or three electrons to O 2to form, respectively , a superoxide radical (O 2−), hydrogen peroxide (H 2O 2) or a hydroxyl radical (HO −). In contrast to atmospheric oxygen, ROIs are capable of unrestricted oxidation of various cellular components and can lead to the oxidative destruction of the cell [1–4].Production of ROIs in cellsThere are many potential sources of ROIs in plants (Table 1). Some are reactions involved in normalmetabolism, such as photosynthesis and respiration.These are in line with the traditional concept,considering ROIs as unavoidable byproducts ofaerobic metabolism [1]. Other sources of ROIs belong to pathways enhanced during abiotic stresses, such as glycolate oxidase in peroxisomes during photorespiration. However, in recent years, new sources of ROIs have been identified in plants,including NADPH oxidases, amine oxidases and cell-wall-bound peroxidases. These are tightlyregulated and participate in the production of ROIs during processes such as programmed cell death (PCD) and pathogen defense [2,4,5].Whereas, under normal growth conditions, the production of ROIs in cells is low (240 µM s −1O 2−and a steady-state level of 0.5 µM H 2O 2in chloroplasts) [6],many stresses that disrupt the cellular homeostasis of cells enhance the production of ROIs (240–720 µM s −1O 2−and a steady-state level of 5–15 µM H 2O 2) [6].These include drought stress and desiccation, salt stress, chilling, heat shock, heavy metals, ultravioletradiation, air pollutants such as ozone and SO 2,mechanical stress, nutrient deprivation, pathogen attack and high light stress [2,7–10]. The production of ROIs during these stresses results from pathways such as photorespiration, from the photosynthetic apparatus and from mitochondrial respiration. In addition, pathogens and wounding or environmental stresses (e.g. drought or osmotic stress) have been shown to trigger the active production of ROIs byNADPH oxidases [4,11–13]. The enhanced production of ROIs during stress can pose a threat to cells but it is also thought that ROIs act as signals for the activation of stress-response and defense pathways [9,14]. Thus, ROIs can be viewed as cellular indicators of stress and as secondary messengers involved in the stress-response signal transduction pathway .Although the steady-state level of ROIs can be used by plants to monitor their intracellular level of stress, this level has to be kept under tight control because over-accumulation of ROIs can result in cell death [1–4]. ROI-induced cell death can result from oxidative processes such as membrane lipidperoxidation, protein oxidation, enzyme inhibition and DNA and RNA damage (the traditional concept).Alternatively , enhanced levels of ROIs can activate a PCD pathway , as was recently demonstrated by the inhibition of oxidative stress (paraquat)-induced cell death in tobacco by anti-apoptotic genes [15].Because ROIs are toxic but also participate in signaling events, plant cells require at least two different mechanisms to regulate their intracellular ROI concentrations by scavenging of ROIs: one that will enable the fine modulation of low levels of ROIs for signaling purposes, and one that will enable the detoxification of excess ROIs, especially during stress.In addition, the types of ROIs produced and the balance between the steady-state levels of different ROIs can also be important. These are determined by theinterplay between different ROI-producing and ROI-scavenging mechanisms, and can change drastically depending upon the physiological condition of the plant and the integration of different environmental,developmental and biochemical stimuli.Scavenging of ROIs in cellsMajor ROI-scavenging mechanisms of plants include superoxide dismutase (SOD), ascorbate peroxidase (APX) and catalase (CAT) [1,7,16] (Table 1). The balance between SOD and APX or CAT activities in cells is crucial for determining the steady-state level ofT raditionally,reactive oxygen intermediates (ROIs) were considered to be toxic by-products of aerobic metabolism,which were disposed of using antioxidants.However,in recent years,it has become apparent that plants actively produce ROIs as signaling molecules to control processes such as programmed cell death,abiotic stress responses,pathogen defense and systemic signaling.Recent advances including microarray studies and the development of mutants with altered ROI-scavenging mechanisms provide new insights into how the steady-state level of ROIs are controlled in cells.In addition,key steps of the signal transduction pathway that senses ROIs in plants have been identified.These raise several intriguing questions about the relationships between ROI signaling,ROI stress and the production and scavenging of ROIs in the different cellular compartments.Published online: 12 August 2002Oxidative stress,antioxidants and stress toleranceRon Mittlersuperoxide radicals and hydrogen peroxide [17]. This balance, together with sequestering of metal ions, is thought to be important to prevent the formation of the highly toxic hydroxyl radical via the metal-dependent Haber–Weiss or the Fenton reactions [1]. The different affinities of APX (µM range) and CAT (m M range) for H 2O 2suggest that they belong to two differentclasses of H 2O 2responsible for the fine modulation of ROIs forsignaling, whereas CAT might be responsible for or the removal of excess ROIs during stress.The major ROI-scavenging pathways of plants (Fig. 1) include SOD, found in almost all cellular compartments, the water–water cycle inchloroplasts (Fig. 1a), the ascorbate–glutathione cycle in chloroplasts, cytosol, mitochondria, apoplast and peroxisomes (Fig. 1b), glutathione peroxidase (GPX; Fig. 1c), and CAT in peroxisomes (Fig. 1d). The finding of the ascorbate–glutathione cycle in almost all cellular compartments tested to date, as well as the high affinity of APX for H 2O 2, suggests that this cycle plays a crucial role in controlling the level ofROIs in these compartments. By contrast, CAT is only present in peroxisomes, but it is indispensable for ROI detoxification during stress, when high levels of ROIs are produced [16]. In addition, oxidative stress causes the proliferation of peroxisomes [18]. Drawingupon the model for bacteria [19], a dense population of peroxisomes might be highly efficient in scavenging of ROIs, especially H 2O 2, which diffuses into peroxisomes from the cytosol.The water–water cycle (Fig. 1a) draws its reducing energy directly from the photosynthetic apparatus [3]. Thus, this cycle appears to be autonomous with respect to its energy supply . However, the source of reducing energy for ROI scavenging by theascorbate–glutathione cycle (Fig. 1b) during normal metabolism and particularly during stress, when the photosynthetic apparatus might be suppressed or damaged, is not entirely clear. In animals and yeast,the pentose-phosphate pathway is the main source of NADPH for ROI removal [20,21]. Because CAT does not require a supply of reducing equivalents for its function, it might be insensitive to the redox status of cells and its function might not be affected during stress, unlike the other mechanisms (Fig. 1).Antioxidants such as ascorbic acid and glutathione,which are found at high concentrations in chloroplasts and other cellular compartments (5–20 m M ascorbic acid and 1–5 m M glutathione) are crucial for plant defense against oxidative stress [8]. Consequently ,both mutants with suppressed ascorbic acid levels [22] and transgenic plants with altered content of glutathione [23] are hypersensitive to stress conditions. It is generally believed that maintaining a high reduced per oxidized ratio of ascorbic acid and glutathione is essential for the proper scavenging of ROIs in cells. This ratio is maintained by glutathione reductase (GR),monodehydroascorbate reductase (MDAR) anddehydroascorbate reductase (DHAR) using NADPH as reducing power (Fig. 1) [3,8]. In addition, the overall balance between different antioxidants has to betightly controlled. Enhanced glutathione biosynthesis in chloroplasts can result in oxidative damage to cells rather than their protection, possibly by altering the overall redox state of chloroplasts [23]. It has also been suggested that the oxidized:reduced ratio of the different antioxidants can serve as a signal for the modulation of ROI-scavenging mechanisms [24].Avoiding ROI productionAvoiding ROI production might be as important as active scavenging of ROIs. Because many abiotic stress conditions are accompanied by an enhanced rate of ROI production, avoiding or alleviating the effects of stresses such as drought or high light on plant metabolism will reduce the risk of ROI production. Mechanisms that might reduce ROI production during stress (Table 1) include:(1)anatomical adaptations such as leaf movement and curling, development of a refracting epidermis and hiding of stomata in specialized structures;(2)physiological adaptations such as C 4and CAM metabolism; and (3) molecular mechanisms that rearrange the photosynthetic apparatus and its antennae in accordance with light quality andintensity or completely suppress photosynthesis. Bybalancing the amount of light energy absorbed by the plant with the availability of CO 2, these mechanisms might represent an attempt to avoid the over-reduction of the photosynthetic apparatus and the transfer of electrons to O 2rather than for CO 2fixation.ROI production can also be decreased by the alternative channeling of electrons in the electron-transport chains of the chloroplasts and mitochondria by a group of enzymes called alternative oxidases (AOXs). AOXs can divert electrons flowing through electron-transport chains and use them to reduce O 2to water (Fig. 2). Thus, they decrease ROI production by two mechanisms: they prevent electrons fromreducing O 2into O 2−and they reduce the overall level of O 2, the substrate for ROI production, in theorganelle. Decreasing the amount of mitochondrial AOX increases the sensitivity of plants to oxidative stress [25]. In addition, chloroplast AOX is induced in transgenic plants that lack APX and/or CAT, and in normal plants in response to high light [50].Production and scavenging of ROIs in different cellular compartmentsRecent manipulations of ROI-scavenging pathways in different cellular compartments suggest someintriguing possibilities. For years, the chloroplast was considered to be the main source of ROI production in cells and consequently one of the main targets for ROI damage during stress. However, it has recently been suggested that the chloroplast is not as sensitive to ROI damage as previously thought [26]. The mitochondrion is another cellular site of ROI production. However,recent studies suggest that the mitochondrion is also a key regulator of PCD in plants and that enhanced ROIs levels at the mitochondria can trigger PCD [27].Both the mitochondrion and the chloroplast contain ROI-scavenging mechanisms. By contrast, little is known about the ROI-scavenging properties of the nucleus, which might contain redox-sensitivetranscription factors [28]. Because H 2O 2can diffuse through aquaporins [29], ROIs produced at a specific cellular site (e.g. the chloroplast during stress or the apoplast during pathogen attack) can affect other cellular compartments, overwhelm theirROI-scavenging capabilities and alter the pattern of gene expression during stress, pathogen infection or PCD. In support of this assumption, stresses that result in the enhanced production of ROIs at thechloroplast induce cytosolic and not chloroplastic ROI-scavenging mechanisms [24,30], and ROI production at the apoplast induces the production of pathogenesis-response proteins [4]. Because the plant mitochondria and nuclei are involved in the activation of PCD [27],the level of ROIs that reaches these compartments during stress or pathogen challenge needs to be tightly controlled to prevent abnormal PCD activation. The cytosol, with its ascorbate–glutathione cycle, and the peroxisomes, with CAT, might therefore act as a buffer zone to control the overall level of ROIs that reaches different cellular compartments during stress and normal metabolism.The importance of peroxisomes in ROI metabolism is beginning to gain recognition [31]. Peroxisomes are not only the site of ROI detoxification by CAT but also the site of ROI production by glycolate oxidase and fatty acid β-oxidation. In addition, peroxisomes might be one of the cellular sites for nitric oxide (NO)biosynthesis [31]. In animal cells, NO activates fatty acid β-oxidation and enhances the production of ROIs in cells. However, although NO has been shown to be involved in ROI-induced cell death in plants [32] and NO is known to be a key regulator of pathogen responses [5], little is known about how NO isinvolved in the response of plants to abiotic stresses.Redundancy in ROI-scavenging mechanismsSome of the complex relationships between the different ROI-scavenging and ROI-producingmechanisms have been revealed in transgenic plants with suppressed production of ROI-detoxifying mechanisms. Thus, plants with suppressed APXFig. 1.Pathways for reactive oxygen intermediate (ROI)scavenging in plants.(a)The water –water cycle.(b) The ascorbate –glutathione cycle. (c) The glutathione peroxidase (GPX) cycle. (d) Catalase (CAT). Superoxidedismutase (SOD) acts as the first line of defense converting O 2−into H 2O 2.Ascorbate peroxidases (APX), GPX and CAT then detoxify H 2O 2. In contrast to CAT (d), APX and GPX require an ascorbate (AsA)and/or a glutathione (GSH)regenerating cycle (a –c).This cycle uses electrons directly from thephotosynthetic apparatus (a) or NAD(P)H (b,c) as reducing power. ROIs are indicated in red,antioxidants in blue and ROI-scavenging enzymes in green. Abbreviations:DHA, dehydroascorbate;DHAR, DHA reductase;Fd,ferredoxin; GR,glutathione reductase;GSSG, oxidized glutathione; MDA,monodehydroascorbate;MDAR, MDA reductase;PSI,photosystem I; tAPX,thylakoid-bound APX.production induce SOD, CAT and GR to compensate for the loss of APX, whereas plants with suppressed CAT production induce APX, GPX and mitochondrial AOX [16,50]. CAT and APX are not completely redundant because they do not compensate for the lack of each other, as shown by the sensitivity of plantswith reduced APX or CAT levels to environmental stresses and pathogen attack [33]. Interestingly ,plants with suppressed APX and CAT appeared, at least under a defined set of environmental conditions,to be less sensitive to oxidative stress than plants with lowered APX or CAT levels. These plants had reduced photosynthetic activity , enhanced chloroplastic AOX production and enhanced expression of genes of the oxidative and reductive pentose-phosphate pathway and MDAR, possibly to avoid ROI production as well as to enhance the non-enzymatic detoxification of H 2O 2by ascorbic acid [50].ROIs at the interface between biotic and abiotic stressesROIs play a central role in the defense of plants against pathogen attack. During this response, ROIs are produced by plant cells via the enhanced enzymatic activity of plasma-membrane-bound NADPH oxidases,cell-wall-bound peroxidases and amine oxidases in the apoplast [4,5]. H 2O 2produced during this response (up to 15 µM ; directly or as a result of superoxide dismutation) is thought to diffuse into cells and,together with salicylic acid (SA) and NO [34], toactivate many of the plant defenses, including PCD [35].The activity of APX and CAT is suppressed during this response by the plant hormones SA and NO [34], the production of APX is post-transcriptionally suppressed [36] and the production of CAT is downregulated at the level of steady-state mRNA [37]. Thus, the plantsimultaneously produces more ROIs and at the same time diminishes its own capacity to scavenge H 2O 2,resulting in the over-accumulation of ROIs and the activation of PCD. The suppression of ROI-scavenging mechanisms together with the synthesis of NO appears to be crucial for the activation of PCD because, in their absence, increased ROI production at the apoplast does not result in the induction of PCD [32,33].The role ROIs play during PCD appears, therefore,to be opposite to the role they play during abiotic stresses, during which ROIs induce ROI-scavenging mechanisms such as APX and CAT that decrease the steady-state level of ROIs in cells (Fig. 3). The differences in the function of ROIs between biotic and abiotic stresses might result from the action of hormones such as SA and NO, from cross-talkbetween different signaling pathways (Fig. 4) or from differences in the steady-state level of ROIs produced during the different stresses. The apparent conflict in ROI metabolism between biotic and abioticstresses (Fig. 3) raises the question of how the plant manipulates its rate of ROI production and ROIscavenging when it comes under biotic attack during an abiotic stress. In support of the possible existence of such a conflict, tobacco plants that were previously subjected to oxidative stress (and consequently had a higher level of antioxidative enzymes) had a reduced rate of PCD compared with unstressed control plants [33]. In addition, plants that overproduce CAT have a decreased resistance to pathogen infection [38].Fig. 2.Involvement of alternative oxidase (AOX) in reactive oxygen intermediate (ROI) avoidance.In both the mitochondrial electron-transport chain (a) and the chloroplast electron-transport chain (b),AOX diverts electrons that can be used to reduce O 2into O 2−and uses these electrons to reduce O 2to H 2O. In addition, AOX reduces the overall level of O 2, the substrate for ROI production, in theorganelle. AOX is indicated in yellow and the different components of the electron-transport chain are indicated in red, green or gray. Abbreviations: Cyt-b 6f , cytochrome b 6f ; Cyt-c, cytochrome c ;Fd,ferredoxin; PC, plastocyanin; PSI, PSII, photosystems I and II.Fig. 3.Differences in the steady-state levels of reactive oxygen intermediates (ROI) during biotic stress and abiotic stress. Biotic stress (a) results in the activation of NADPH oxidase and the suppression of ascorbate peroxidase (APX) and catalase (CAT). This leads to the over-accumulation of ROI and the activation of defense mechanisms. Abiotic stress (b) enhances ROI production by chloroplasts and mitochondria. However, by inducing ROI-scavenging enzymes such as APX and CAT , it reduces ROI levels. The question mark indicates that little is known about the regulation of ROI metabolism during a combination of biotic and abiotic stresses. Chloroplasts are indicated in green, mitochondria in gray and the steady-state levels of ROI in yellow.ROI signal transduction pathwayRecent studies have identified several components involved in the signal transduction pathway of plants that senses ROIs. These include the mitogen-activated protein (MAP) kinase kinase kinases AtANP1 and NtNPK1, and the MAP kinases AtMPK3/6 and Ntp46MAPK [39,40]. In addition, calmodulin has been implicated in ROI signaling [9,41]. A hypothetical model depicting some of the players involved in this pathway is shown in Fig. 4. H 2O 2is sensed by a sensor that might be a two-component histidine kinase, as in yeast [9]. Calmodulin and a MAP-kinasecascade are then activated, resulting in the activation or suppression of several transcription factors. These regulate the response of plants to oxidative stress [9,42]. Cross-talk with the pathogen-response signal transduction pathway also occurs and might involve interactions between different MAP-kinase pathways,feedback loops and the action of NO and SA as key hormonal regulators. This model (Fig. 4) is simplified and is likely to change as research advances our understanding of this pathway .ROIs act as signals that mediate the systemic activation of gene expression in response to pathogenpathway by ROIs? It is possible that the level of H 2O 2that is currently thought to kill cells by direct cellular damage actually induces PCD [15,27], and it might require a higher level of ROIs to kill cells by direct oxidation. Perhaps future studies applying oxidative stress to mutants deficient in different PCD pathways will answer this question.Many questions related to ROI metabolism remain unanswered (Box 1). We are currently at an exciting time, when most of the technologies required to answer these questions are in place. Thus, acomprehensive analysis of gene expression using microarrays and chips, coupled with proteomics andAcknowledgementsI apologize to all colleagues whose work could not be reviewed here because of space limitation. I thank Barbara A.Zilinskas and Eve Syrkin Wurtele for critical reading of the manuscript. Research at my laboratory is supported by funding from the Israeli Academy of Sciences and the Biotechnology Council of Iowa State University.Fig. 4.A suggested model for the activation of signal transduction events during oxidative stress.H 2O 2is detected by a cellular receptor or sensor. Its detection results in the activation of a mitogen-activated-protein kinase (MAPK) cascade and a group of transcription factors that control different cellular pathways. H 2O 2sensing is also linked to changes in the levels of Ca 2+and calmodulin, and to the activation or induction of a Ca 2+–calmodulin kinase that can also activate or suppress the activity of transcription factors. The regulation of gene expression by the different transcription factors results in the induction of various defense pathways, such as reactive oxygen intermediate (ROI) scavenging and heat-shock proteins (HSPs), and in the suppression of some ROI-producing mechanisms and photosynthesis. There is also cross-talk with the plant –pathogen signal transduction pathway, which might depend on pathogen recognition by the gene-for-gene mechanism and can result in an inverse effect on the regulation of ROI-production and ROI-scavenging mechanisms, as well as on theactivation of programmed cell death (PCD). The plant hormones nitric oxide (NO) and salicylic acid (SA) are key regulators of this response.metabolomics to follow different antioxidants and related compounds during oxidative stress, should answer many of these questions. This analysis can be performed on plants responding to abiotic stresses,biotic insults or combinations of both, and can be complemented by using mutants with altered abilityto produce or scavenge ROIs. In addition, thedevelopment of cellular markers that enable the non-destructive quantification of different ROIs in the different cellular compartments, like the markers used for Ca 2+imaging, will considerably advance our understanding of ROI metabolism.References1Asada, K. and Takahashi, M. (1987) Production and scavenging of active oxygen in photosynthesis. In Photoinhibition (Kyle, D.J. et al., eds), pp.227–287,Elsevier2Dat, J. et al.(2000) Dual action of the active oxygen species during plant stress responses. Cell. Mol. Life Sci.57, 779–7953Asada, K. (1999) The water–water cycle in chloroplasts: scavenging of active oxygen and dissipation of excess photons. Annu. Rev. Plant Physiol. Plant Mol. Biol.50, 601–6394Hammond-Kosack, K.E. and Jones, J.D.G. 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达托霉素

Generic Name】Daptomycin Injection,Powder,Lyophilized,for Solution[FDA]【Brand Name】Cubicin【Active Ingredients】达托霉素【Description】CUBICIN contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus. The chemical name isN-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthrani loyl-L-alanine ε1-lactone. The chemical structure is:The empirical formula is C72H101N17O26; the molecular weight is 1620.67. CUBICIN issupplied as a sterile, preservative-free, pale yellow to light brown, lyophilized cake containing approximately 900 mg/g of daptomycin for intravenous (IV) use following reconstitution with 0.9% sodium chloride injection. The only inactive ingredient is sodium hydroxide, which is used in minimal quantities for pH adjustment. Freshly reconstituted solutions of CUBICIN range in color from pale yellow to light brown.【Clinical Pharmacology】PharmacokineticsThe mean (SD) pharmacokinetic parameters of daptomycin at steady-state following IV administration of 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 1.Daptomycin pharmacokinetics were generally linear and time-independent at doses of 4 to 12 mg/kg q24h. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following administration of 4, 6, 8, 10, and 12 mg/kg q24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) µg/mL, respectively.Table 1. Mean (SD) CUBICIN Pharmacokinetic Parameters in HealthyVolunteers at Steady-StatePharmacokinetic Parameters*Dose†AUC0-24t1/2V ss CL T C max(mg/kg) (µg*h/mL)(h) (L/kg) (mL/h/kg) (µg/mL)4 (N=6) 494 (75) 8.1(1.0) 0.096(0.009)8.3 (1.3) 57.8 (3.0)6 (N=6) 632 (78) 7.9(1.0) 0.101(0.007)9.1 (1.5) 93.9 (6.0)8 (N=6) 858 (213) 8.3(2.2) 0.101(0.013)9.0 (3.0) 123.3(16.0)10 (N=9) 1039 (178) 7.9(0.6) 0.098(0.017)8.8 (2.2) 141.1(24.0)12 (N=9) 1277 (253) 7.7(1.1) 0.097(0.018)9.0 (2.8) 183.7(25.0)*AUC0-24, area under the concentration-time curve from 0 to 24 hours; t½, terminalelimination half-life; Vss , volume of distribution at steady-state; CLT, plasmaclearance; Cmax, maximum plasma concentration.†Doses of CUBICIN in excess of 6 mg/kg have not been approved.DistributionDaptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranged from 90 to 93%.In clinical studies, mean serum protein binding in subjects with CLCR≥30 mL/min was comparable to that observed in healthy subjects with normal renalfunction. However, there was a trend toward decreasing serum protein binding amongsubjects with CLCR<30 mL/min (87.6%), including those receiving hemodialysis (85.9%) and continuous ambulatory peritoneal dialysis (CAPD) (83.5%). The protein binding of daptomycin in subjects with hepatic impairment (Child-Pugh B) was similar to that in healthy adult subjects.The volume of distribution at steady-state (Vss) of daptomycin in healthy adult subjects was approximately 0.10 L/kg and was independent of dose.MetabolismIn vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. In in vitro studies, daptomycin was not metabolized by human liver microsomes. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system.In 5 healthy young adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. In a separate study, no metabolites were observed in plasma on Day 1 following administration of CUBICIN at 6 mg/kg to subjects. Inactive metaboliteshave been detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.ExcretionDaptomycin is excreted primarily by the kidney. In a mass balance study of 5 healthy subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations) and 5.7% of the dose was recovered from feces (collected for up to 9 days) based on total radioactivity.Because renal excretion is the primary route of elimination, dosage adjustment is necessary in patients with severe renal insufficiency (CLCR<30 mL/min) (see DOSAGE AND ADMINISTRATION).Special PopulationsRenal InsufficiencyPopulation derived pharmacokinetic parameters were determined for infected patients (complicated skin and skin structure infections and S. aureus bacteremia) and noninfected subjects with varying degrees of renal function (Table 2). Plasmaclearance (CLT ), elimination half-life (t1/2), and volume of distribution (Vss) weresimilar in patients with complicated skin and skin structure infections compared with those with S. aureus bacteremia. Following the administration of CUBICIN 4 mg/kg q24h, the mean CLTwas 9%, 22%, and 46% lower among subjects and patients withmild (CLCR 50–80 mL/min), moderate (CLCR30–<50 mL/min), and severe (CLCR<30 mL/min)renal impairment, respectively, than in those with normal renal function (CLCR>80mL/min). The mean steady-state systemic exposure (AUC), t1/2, and Vssincreased withdecreasing renal function, although the mean AUC was not markedly different for patients with CLCR30–80 mL/min compared with those with normal renal function. Themean AUC for patients with CLCR<30 mL/min and for patients on hemodialysis (dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. Following the administration of CUBICIN 4mg/kg q24h, the mean Cmax ranged from 60 to 70 µg/mL in patients with CLCR≥30 mL/min,while the mean Cmax for patients with CLCR<30 mL/min ranged from 41 to 58 µg/mL. Themean Cmaxranged from 80 to 114 µg/mL in patients with mild-to-moderate renal impairment and was similar to that of patients with normal renal function after the administration of CUBICIN 6 mg/kg q24h. In patients with renal insufficiency, both renal function and creatine phosphokinase (CPK) should be monitored more frequently. CUBICIN should be administered following the completion of hemodialysis on hemodialysis days (see DOSAGE AND ADMINISTRATION for recommendeddosage regimens).Table 2. Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of 4 mg/kg or 6 mg/kg to Infected Patients and Noninfected Subjects with Varying Degrees of Renal FunctionRenal Functiont1/2*V ss*CL T*AUC0-∞*AUC ss†C min,ss†(h) (L/kg) (mL/h/kg) (µg*h/mL)(µg*h/mL)(µg*h/mL)4 mg/kg 4 mg/kg 4 mg/kg 4 mg/kg 6 mg/kg 6 mg/kgNote: CL CR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; AUC0-∞, area under theconcentration-time curve extrapolated to infinity; AUC ss, area under the concentration-time curve calculated over the 24-hour dosing interval at steady-state; C min,ss, trough concentration at steady-state; NA, not applicable.Normal 9.39(4.74) 0.13(0.05)10.9 (4.0) 417 (155) 545 (296) 6.9 (3.5)(CL CR >80mL/min)N=165 N=165 N=165 N=165 N=62 N= 61Mild Renal Impairment 10.75(8.36)0.12(0.05)9.9 (4.0) 466 (177) 637 (215) 12.4 (5.6)(CL CR 50−80mL/min)N=64 N=64 N=64 N=64 N=29 N=29Moderate Renal Impairment 14.70(10.50)0.15(0.06)8.5 (3.4) 560 (258) 868 (349) 19.0 (9.0)(CL CR 30−<50mL/min)N=24 N=24 N=24 N=24 N=15 N=14Severe Renal Impairment 27.83(14.85)0.20(0.15)5.9 (3.9) 925 (467) 1050, 892 24.4, 21.4(CL CR <30mL/min)N=8 N=8 N=8 N=8 N=2 N=2Hemodialysis 29.81(6.13) 0.15(0.04)3.7 (1.9) 1244 (374) NA NAN=21 N=21 N=21 N=21*Parameters obtained following a single dose from patients with complicated skin and skin structure infections and healthy subjects.†Parameters obtained at steady-state from patients with S. aureus bacteremia. Hepatic InsufficiencyThe pharmacokinetics of daptomycin were evaluated in 10 subjects with moderatehepatic impairment (Child-Pugh Class B) and compared with healthy volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when administering CUBICIN to patients with mild-to-moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic insufficiency have not been evaluated.GenderNo clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when administering CUBICIN.GeriatricThe pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (≥75 years of age) and 11 healthy young controls (18 to 30 years of age). Following administration of a single 4 mg/kg IV dose, the mean total clearance of daptomycinincreased approximately 58% in was reduced approximately 35% and the mean AUC0-∞elderly subjects compared with young healthy subjects. There were no differences . No dosage adjustment is warranted for elderly patients with normal renal in Cmaxfunction.ObesityThe pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and 6 extremely obese (BMI ≥40 kg/m2) subjects and controls matched for age, sex, and renal function. Following administration of a single 4 mg/kg IV dose based on total body weight, the plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects compared with nonobeseof daptomycin increased approximately 30% in moderately obese controls. The AUC0-∞and 31% in extremely obese subjects compared with nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No dosage adjustment of CUBICIN is warranted in obese subjects.PediatricThe pharmacokinetics of daptomycin in pediatric populations (<18 years of age) have not been established.Drug-Drug InteractionsDrug-drug interaction studies were performed with CUBICIN and other drugs that arelikely to be either coadministered or associated with overlapping toxicity. AztreonamIn a study in which 15 healthy adult subjects received a single dose of CUBICIN 6mg/kg IV, aztreonam 1 g IV, and both in combination, the Cmax and AUC0-∞of daptomycinwere not significantly altered by aztreonam; the Cmax and AUC0-∞of aztreonam alsowere not significantly altered by daptomycin. No dosage adjustment of either antibiotic is warranted when coadministered.TobramycinIn a study in which 6 healthy adult males received a single dose of CUBICIN 2 mg/kgIV, tobramycin 1 mg/kg IV, and both in combination, the mean Cmax and AUC0-∞ofdaptomycin increased 12.7% and 8.7%, respectively, when administered withtobramycin. The mean Cmax and AUC0-∞of tobramycin decreased 10.7% and 6.6%,respectively, when administered with CUBICIN. These differences were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of CUBICIN is unknown. Caution is warranted when CUBICIN is coadministered with tobramycin.WarfarinIn 16 healthy subjects, concomitant administration of CUBICIN 6 mg/kg q24h for 5 days followed by a single oral dose of warfarin (25 mg) had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio) (see PRECAUTIONS, Drug Interactions).SimvastatinIn 20 healthy subjects on a stable daily dose of simvastatin 40 mg, administration of CUBICIN 4 mg/kg IV q24h for 14 days (N=10) was not associated with a higher incidence of adverse events than in subjects receiving placebo once daily (N=10) (see PRECAUTIONS, Drug Interactions).ProbenecidConcomitant administration of probenecid (500 mg 4 times daily) and a single doseof CUBICIN 4 mg/kg IV did not significantly alter the Cmax and AUC0-∞of daptomycin. Nodosage adjustment of CUBICIN is warranted when CUBICIN is coadministered with probenecid.MICROBIOLOGYDaptomycin is an antibacterial agent of a new class of antibiotics, the cyclic lipopeptides. Daptomycin is a natural product that has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevantGram-positive pathogenic bacteria. Daptomycin retains potency againstantibiotic-resistant Gram-positive bacteria, including isolates resistant to methicillin, vancomycin, and linezolid.Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive organisms in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC ratios (minimum bactericidal concentration/minimum inhibitory concentration) using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known.Mechanism of ActionThe mechanism of action of daptomycin is distinct from that of any other antibiotic. Daptomycin binds to bacterial membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death.Mechanism of ResistanceAt this time, no mechanism of resistance to daptomycin has beenidentified. Currently, there are no known transferable elements that confer resistance to daptomycin.Cross-ResistanceCross-resistance has not been observed with any other antibiotic class.Interactions with Other AntibioticsIn vitro studies have investigated daptomycin interactions with other antibiotics. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibiotics, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).Complicated Skin and Skin Structure Infection (cSSSI) StudiesThe emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials. In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 study who received CUBICIN at less than the protocol-specified dose for the initial 5 days of therapy. In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer enrolled in a salvage trial.S. aureus Bacteremia/Endocarditis and Other Post-Approval StudiesIn subsequent clinical trials, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use study and from 7 patients in the S. aureus bacteremia/endocarditis study (see PRECAUTIONS). An E. faecium was isolated from a patient in a VRE study.Daptomycin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.Aerobic and facultative Gram-positive microorganisms:Enterococcus faecalis (vancomycin-susceptible isolates only)Staphylococcus aureus (including methicillin-resistant isolates)Streptococcus agalactiaeStreptococcus dysgalactiae subsp. equisimilisStreptococcus pyogenesThe following in vitro data are available, but their clinical significance is unknown. Greater than 90% of the following microorganisms demonstrate an in vitro MIC less than or equal to the susceptible breakpoint for daptomycin versus the bacterial genus. The efficacy of daptomycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.Aerobic and facultative Gram-positive microorganisms:Corynebacterium jeikeiumEnterococcus faecalis (vancomycin-resistant isolates)Enterococcus faecium (including vancomycin-resistant isolates)Staphylococcus epidermidis (including methicillin-resistant isolates) Staphylococcus haemolyticusSusceptibility Testing MethodsSusceptibility testing by dilution methods requires the use of daptomycin susceptibility powder. The testing of daptomycin also requires the presence of physiological levels of free calcium ions (50 mg/L of calcium, using calcium chloride) in Mueller-Hinton broth medium.Dilution TechniqueQuantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure1, 2 based on a broth dilution method or equivalent using standardized inoculum and concentrations of daptomycin. The use of the agar dilution method is not recommended with daptomycin2. The MICs should be interpreted according to the criteria in Table 3.A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.Table 3. Susceptibility Interpretive Criteria forDaptomycinPathogenBroth Dilution MIC* (µg/mL)S I RNote: S, Susceptible; I, Intermediate; R, Resistant.Staphylococcus aureus≤1(†) (†)(methicillin-susceptible andmethicillin-resistant)Streptococcus pyogenes, Streptococcusagalactiae,≤1(†) (†)and Streptococcus dysgalactiaesubsp. equisimilisEnterococcus faecalis≤4(†) (†)(vancomycin-susceptible only)*The MIC interpretive criteria for S. aureus and E. faecalis are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L; the MIC interpretive criteria for Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L, supplemented with 2 to 5% lysed horse blood, inoculated with a direct colony suspension and incubated in ambient air at 35ºC for 20 to 24 hours.†The current absence of data on daptomycin-resistant isolates precludes defining any categories other than “Susceptible.” Isolates yielding test results suggestive of a “Non-Susceptible” category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for further testing.Diffusion TechniqueQuantitative methods that require measurement of zone diameters have not been shown to provide reproducible estimates of the susceptibility of bacteria to daptomycin. The use of the disk diffusion method is not recommended with daptomycin2, 3.Quality ControlStandardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the procedures. Standard daptomycin powder should provide the range of values noted in Table 4. Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.Table 4. Acceptable Quality ControlRanges for Daptomycin to Be Used inValidation of Susceptibility TestResultsQuality Control StrainBroth DilutionMIC Range*(μg/mL) Enterococcusfaecalis ATCC292121−4Staphylococcusaureus ATCC 292130.25−1Streptococcuspneumoniae ATCC49619†0.06−0.5*The quality control ranges for S. aureus and E. faecalis are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L; the quality control ranges for S. pneumoniae are applicable only to tests performed by broth dilution using Mueller-Hinton broth adjusted to a calcium content of 50 mg/L, supplemented with 2 to 5% lysed horse blood, inoculated witha direct colony suspension and incubated in ambient air at 35ºC for 20 to 24 hours.†This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.【Animal Pharmacology】In animals, daptomycin administration has been associated with effects on skeletal muscle with no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by degenerative/regenerative changes and variable elevations in CPK. No fibrosis or rhabdomyolysis was evident in repeat-dose studies up to the highest doses tested in rats (150 mg/kg/day) and dogs (100 mg/kg/day). The degree of skeletal myopathy showed no increase when treatment was extended from 1 month to up to 6 months. Severity was dose-dependent. All muscle effects, including microscopic changes, were fully reversible within 30 days following cessation of dosing.In adult animals, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by significant losses of patellar reflex, gag reflex, and pain perception) were observed at doses higher than those associated with skeletal myopathy. Deficits in the dogs’ patellar reflexes were seen within 2 weeks of the start of treatment at 40 mg/kg (9 times the human Cat the 6 mg/kgmaxq24h dose), with some clinical improvement noted within 2 weeks of the cessation of dosing. However, at 75 mg/kg/day for 1 month, 7/8 dogs failed to regain full patellar reflex responses within the duration of a 3-month recovery period. In a separate study in dogs receiving doses of 75 and 100 mg/kg/day for 2 weeks, minimal residual histological changes were noted at 6 months after cessation of dosing. However, recovery of peripheral nerve function was evident.Tissue distribution studies in rats have shown that daptomycin is retained in the kidney but appears to only minimally penetrate across the blood-brain barrier following single and multiple doses.【Clinical Studies】Complicated Skin and Skin Structure InfectionsAdult patients with clinically documented cSSSI (Table 10) were enrolled in two randomized, multinational, multicenter, investigator-blinded studies comparing CUBICIN (4 mg/kg IV q24h) with either vancomycin (1 g IV q12h) or ananti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). Patients known to have) bacteremia at baseline were excluded. Patients with creatinine clearance (CLCR between 30 and 70 mL/min were to receive a lower dose of CUBICIN as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of CUBICIN adjusted. Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated.One study was conducted primarily in the United States and South Africa (study 9801), and the second (study 9901) was conducted at non-US sites only. Both studies were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 patients treated with CUBICIN and 558 treated with comparator in the two studies. The majority (89.7%) of patients received IV medication exclusively.The efficacy endpoints in both studies were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with CUBICIN and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76.0% (158/208) in patients treated with CUBICIN and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with CUBICIN and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with CUBICIN and 90.4% (226/250) in patients treated with comparator drugs.The success rates by pathogen for microbiologically evaluable patients are presented in Table 11.Table 10. Invest igator’s Primary Diagnosis in the cSSSI Studies(Population: ITT)Study 9801 Study 9901 Pooled PrimaryDiagnosisCUBICIN/Comparator*CUBICIN/Comparator* CUBICIN/Comparator* N=264/N=266 N=270/N=292 N=534/N=558Wound Infection 99 (37.5%)/116(43.6%)102 (37.8%)/108(37.0%)201 (37.6%)/224(40.1%)Major Abscess 55 (20.8%)/43(16.2%)59 (21.9%)/65(22.3%)114 (21.3%)/108(19.4%)Ulcer Infection 71 (26.9%)/75(28.2%)53 (19.6%)/68(23.3%)124 (23.2%)/143(25.6%)Other Infection†39 (14.8%)/32(12.0%)56 (20.7%)/51(17.5%)95 (17.8%)/83(14.9%)*Vancomycin or anti-staphylococcal semi-synthetic penicillins.†The majority of cases were subsequently categorized as complicated cellulitis, major abscesses, or traumatic wound infections.Table 11. Clinical Success Rates by InfectingPathogen, Primary Comparative cSSSI Studies(Population: Microbiologically Evaluable)Success Rate Pathogen CUBICIN Comparator*n/N (%) n/N (%)Methicillin-susceptible Staphylococcus aureus (MSSA)†170/198(85.9)180/207(87.0)Methicillin-resistant Staphylococcus aureus (MRSA)†21/28(75.0)25/36 (69.4)Streptococcus pyogenes79/84(94.0)80/88 (90.9)Streptococcus agalactiae23/27(85.2)22/29 (75.9)Streptococcus dysgalactiaesubsp. equisimilis8/8 (100) 9/11 (81.8)Enterococcus faecalis (vancomycin-susceptible only)27/37(73.0)40/53 (75.5)*Vancomycin or anti-staphylococcal semi-synthetic penicillins.†As determined by the central laboratory.S. aureus Bacteremia/EndocarditisThe efficacy of CUBICIN in the treatment of patients with S. aureus bacteremia was demonstrated in a randomized, controlled, multinational, multicenter open-label study. In this study, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either CUBICIN (6 mg/kg IV q24h) or standard of care [anti-staphylococcal semi-synthetic penicillin 2 g IV q4h (nafcillin, oxacillin, cloxacillin, or flucloxacillin) or vancomycin 1 g IV q12h, both with initial gentamicin 1 mg/kg IV every 8 hours for first 4 days]. Of the patients in the comparator group, 93% received initial gentamicin for a median of 4 days compared with 1 patient (<1%) in the CUBICIN group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance <30 mL/min, and pneumonia were excluded.Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or NotEndocarditis). Echocardiography, including a transesophageal echocardiogram。

CYP2E1与非酒精性脂肪肝

CYP2E1与非酒精性脂肪肝王悦之;张玉【摘要】非酒精性脂肪性肝病( nonalcoholie fatty liver disease,NAFLD)是一种最常见的肝脏疾病,它的高发病率越来越受到广泛重视.细胞色素氧化酶P450-2E1亚型(CYP2E1)是参与氧化应激和脂质过氧化过程中的关键酶.“二次打击”学说为医学界普遍接受的非酒精性脂肪肝的发病机制.在非酒精性脂肪肝的“二次打击学说”中,CYP2E1介导的脂质过氧化亦发挥重要的作用.通过对CYP2E1介导的脂质过氧化在脂肪性肝病发病机制中作用的进一步深入研究,有可能探索出有效治疗脂肪性肝病的新途径.%Nonalcoholie fatty liver disease is one of the most common liver diseases. More and more importance has been attached to the high incidence of NAFLD. A key hepatic enzyme producing oxidative stress and lipid peroxidation is cytochrome P-450 2E1 (CYP2E1). The mechanism of nonalcoholic fatty liver remains most investigators accept to the second-hit theory. Lipid peroxidation induced by CYP2E1 also plays a vital role refered to the second-hit theory of nonalcoholic fatty liver. With advanced investigation of the impact of lipid peroxidation induced by CYP2E1 on the mechanism of fatty liver disease, it is likely to explore novel method to treat fatty liver disease effectively.【期刊名称】《胃肠病学和肝病学杂志》【年(卷),期】2012(021)004【总页数】3页(P384-386)【关键词】非酒精性脂肪肝;CYP2E1;氧化应激;“二次打击”学说;发病机制【作者】王悦之;张玉【作者单位】复旦大学附属华山医院老年科,上海200040;复旦大学附属华山医院老年科,上海200040【正文语种】中文【中图分类】R575.5非酒精性脂肪性肝病(nonalcoholie fatty liver disease，NAFLD)是一种最常见的肝脏疾病。

机体铁储存与动脉粥样硬化危险因素的关系的研究

in the hypercholesterolemic rabbit 1997
37.Kirk EA.Heinecke JW.LeBoeuf RC Iron overload diminishes atherosclerosis in apoE-deficient mice 2001
38.Berge LN.Bonaa KH.Nordoy A Serum ferritin,sex hormones,and cardiovascular risk factors in healthy women 1994(04)
35.Weiner MA.Paige SB.Bailey SR Antioxidant therapy decreases atherosclerotic piaque burden in an iron loaded animal model 1994
36.Dabbagh AJ.Shwaery GT.Keaney JF Jr Effect of iron overload and iron deficiency on atherosclerosis
rats,but does not affect NF-kappa B activation induced by the peroxisome proliferator,Wy-14,643 2002 17.Day SM.Duquaine D.Mundada LV Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis 2003
33.Lee HT.Chiu LL.Lee TS Dietary iron restriction increases plaque stability in apolipoprotein-E-deficient mice 2003

牛磺酸对脂多糖诱导的小鼠肝脏损伤的缓解作用

牛磺酸对脂多糖诱导的小鼠肝脏损伤的缓解作用付凌;宋剑波;胡春燕;曾黎明【摘要】This study aimed to investigate the mitigative effect of taurine on lipopolysaccharides ( LPS )-in-duced liver injury in mice. Thirty ICR male mice with the similar body weight of (22±3) g were randomly di-vided into three groups ( ten mice in each group, n=10): a control group and a LPS group in which mice re-ceived a basal diet, and a taurine group in which mice received the basal diet+2.5% taurine. After fed 1 week, mice in the LPS group and taurine group were intraperitoneally injected 10 mg/kg LPS ( LPS was dissolved in physiological saline, and injection dose was 0.2 mL per mouse) and mice in the control group were intraperito-neally injected the same dose of physiological saline. Blood samples were harvested from eyes and all mice were killed at 24 h after injection to collect liver. Serum alanine aminotransferase ( ALT) and aspartate amin-otransferase ( AST) activities were measured and liver weight, oxidative stress parameters, and the relative ex-pression of antioxidant genes, nuclear factor E2-related factor 2 ( Nrf2) and Kelch like ECH associated protein 1 ( Keap1) were determined. The results showed as follows:1) LPS treatment significantly increased liver in-dex, while taurine supplementation significantly reduced the liver index to normal level (P<0.05). 2) LPS treatment significantly enhanced serum ALT and AST activities ( P<0.05) , and taurine supplementation exhib-ited some beneficial effects on serum ALT and AST activities, and no significant difference in serum AST ac-tivity betweentaurine group and control group (P>0.05). 3) LPS caused marked liver injury in mice, and mice in taurine group suffered little liver injury. 4 ) Compared with control group, liver malondialdehyde ( MDA) content was significantly increased and live glutathione peroxidase ( GPx) activity was significantly decreased in LPS group (P<0.05), while those parameters in taurine group had no significant changes (P>0.05) . 5) Taurine significantly mitigated the LPS-induced inhibition of GPx1 and Nrf2 expression( P<0.05) . In conclusion, diet supplemented with 2.5% taurine plays a certain mitigative effect on LPS-induced liver injury in mice.%本试验旨在研究牛磺酸对脂多糖( LPS)诱导的小鼠肝脏损伤的缓解作用。

水飞蓟宾对内毒素血症心肌损伤的保护作用及机制

实验研究水飞蓟宾对内毒素血症心肌损伤的保护作用及机制陈旭1，王晓武2，江丽青2，马继鹏2，冯建宇2△摘要：目的探究水飞蓟宾（SIL）对小鼠内毒素血症心肌损伤的保护作用和分子机制。

方法24只C57BL/6小鼠分为对照（Control）组、SIL组、LPS组、LPS+SIL组，每组6只。

通过腹腔注射脂多糖（LPS，10mg/kg）制备内毒素血症心肌损伤小鼠模型。

LPS注射前3d，SIL组和LPS+SIL组每日通过灌胃方式给予SIL（100mg/kg），共给药3次；Control 组和LPS组每日通过灌胃方式给予等量（0.2mL）生理盐水，共灌胃3次。

LPS注射6h后超声检测各组小鼠心脏收缩功能；ELISA检测血清IL-1β和TNF-α表达水平；DHE染色观察各组小鼠心肌组织内活性氧（ROS）产量；TUNEL染色检测心肌凋亡率；Western blot检测凋亡相关蛋白Bax、Bcl-2、Caspase3和NOX2表达。

结果与Control组相比，LPS组小鼠左心室射血分数、左心室短轴缩短率和Bcl-2表达量明显降低，而ROS产量、NOX2、Bax、Caspase3、IL-1β与TNF-α表达量以及心肌凋亡率明显增加（P＜0.05）。

与LPS组相比，LPS+SIL组经水飞蓟宾预处理后可明显改善LPS引起的上述改变（P＜0.05）。

与Control组相比，单纯给予SIL干预对上述指标的变化无明显影响（P＞0.05）。

结论水飞蓟宾可有效缓解内毒素血症心肌损伤，其作用可能与抑制氧化应激、炎症反应和抗凋亡有关。

关键词：内毒素血症；脂多糖类；心肌收缩；细胞凋亡；活性氧；炎症；水飞蓟宾中图分类号：R285.5文献标志码：A DOI：10.11958/20190284The protective effect and mechanism of silibinin on cardiac injury induced by endotoxemiaCHEN Xu1,WANG Xiao-wu2,JIANG Li-qing2,MA Ji-peng2,FENG Jian-yu2△1Department of Cardiovascular Surgery,Shenzhen People’s Hospital,Shenzhen518000,China;2Department of Cardiovascular Surgery,Xijing Hospital,Air Force Military Medical University△Corresponding Author E-mail:xjyyfjy@Abstract:Objective To explore the protective effect and molecular mechanism of silibinin(SIL)on myocardial injury in endotoxemic mice.Methods Twenty-four C57BL/6mice were grouped as follows:Control group,SIL group,LPS group and LPS+SIL group(n=6in each group).The mouse model of endotoxemic cardiomyopathy was established by intraperitoneal injection of lipopolysaccharide(LPS,10mg/kg).Three days before LPS injection,SIL was administered daily by gavage at a dose of100mg/kg for3times in the SIL group and the LPS+SIL group.The mice in the Control group and the SIL group were treated with normal saline(0.2mL,by gavage)for3times.Six hours after LPS injection,the cardiac contractile function was detected by ultrasound in mice,the expression levels of serum IL-1βand TNF-αwere detected by ELISA,the production of reactive oxygen species(ROS)in heart tissue was observed by DHE staining,the apoptotic ratio was detected by TUNEL staining and the expression of apoptosis-related proteins(Bax,Bcl-2,Caspase3)and NOX2were detected by Western blot assay.Results Compared with the Control group,the left ventricular ejection fraction,left ventricular fractional shortening and Bcl-2expression were significantly decreased,while ROS production,the expressions of NOX2,Bax,Caspase3,IL-1β,TNF-αand the apoptotic ratio were significantly increased in the LPS group(P＜0.05). Compared with the LPS group,silibinin pretreatment significantly improved the above changes caused by LPS(P＜0.05). Compared with the Control group,SIL alone showed little influence on the parameters metioned above(P＞0.05).Conclusion Silibinin can effectively alleviate myocardial injury in endotoxemic mice,and its cardioprotective role is possibly mediated by inhibiting oxidative stress,inflammatory response and apoptosis.Key words:endotoxemia;lipopolysaccharides;myocardial contraction;apoptosis;reactive oxygen species; inflammation;silibinin基金项目：国家自然科学基金资助项目（81600295）作者单位：1深圳市人民医院心脏大血管外科（邮编518000）；2空军军医大学西京医院心血管外科作者简介：陈旭（1985），男，硕士，主治医师，主要从事心肌保护策略机制方面研究△通讯作者E-mail：xjyyfjy@脓毒症是重症患者死亡的主要原因［1］。

格列喹酮对胰岛β细胞氧化应激的影响

［文章编号］1002-0179（2006）03-0548-02格列喹酮对胰岛!细胞氧化应激的影响Oxidative Stress Properties of Gliguidone on Pancreatic !Cells刘述益1，汤志梅1，李秀钧1!，张建梅1，邱平，李小平2，张祥迅1，龙洋1LIU Shu -yi ，TANG Zhi -mei ，LI Xiu -jun ，et al .（1.四川大学华西医院内分泌科实验室，四川成都610041；2.四川大学华西口腔医学院组织与细胞工程实验室，四川成都610041）（1.Endocrinology Intemal Meddicine ，West China Hospital ，Sichuan Uniuersity ，Chengdu 610041，China ）摘要：目的：研究格列喹酮对胰岛p 细胞超氧化物歧化酶（SOD ）和脂质过氧化物含量的影响。

方法：格列哇酮、格列苯脲、N -乙酰半胱氨酸（NAC ）加入培养基和仓鼠胰岛瘤p 细胞株HIT -15细胞共同孵育5天后，应用硫代巴比妥法和黄嘌呤氧化酶法测定p 细胞内SOD 和丙二醛（MDA ）。

结果：格列苯脲组MDA 水平明显升高，SOD 降低（P <0.05），格列喹酮组无影响。

结论：格列喹酮不增加胰岛p 细胞的氧化应激。

关键词：超氧化物歧化酶；丙二醛；胰岛p 细胞；格列喹酮；格列苯脲［中图分类号］R335+.6［文献标识码］A Abstract ：Objective ：To anaiyze if the orai hypogiycemic drug giiguidone affects oxidative stress of HIT -T15ceiis.Method ：HIT -T15ceiis were incubated with giiguidone 、giibenciamide 、N -acetyicysteine （NAC ）5days ，totai protein extraction ofHIT -T15ceiis is appiied to anaiyze the superoxide dismutaase （SOD ），maionaidehyde （MDA ）.Resuits ：MDA was increased and SOD decreased in giibenciamide incubated groups but not in giiguidone incubated groups.Conciusion ：giiguidone didn ’t af-fect the oxidative stress parameters of pancreatic p -ceiis.Key words ：SOD ；MDA ；Panereatic p -ceii ；giiguidone ；giibenciamide（Received date ：2006-04-12）表1.各组细胞MDA 、SOD 测量结果（"X i S ）组别复瓶数n蛋白浓度（mg /mi ）MDA （nmoi /mgprot ）SOD （u /mgprot ）Controi 40.89510.212 2.1210.9321.9512.49Gib 10-8M 50.74510.082 4.0310.23!#13.1211.38!#Gig 10-8M 50.75710.109 2.7011.0920.7912.40Gib 10-6M 40.85810.133 5.4010.86!#10.1111.62!#Gig 10-6M 50.89110.088 2.7510.7720.4212.47NAC40.83410.1021.8210.6530.8312.42#注：!表示与对照组比较P <0.01，#表示与Controi 、Gig 、NAC 组比较P <0.01，#表示与其它各组比较P <0.01。

老年冠心病合并高同型半胱氨酸血症患者阿司匹林抵抗发生率及危险因素调查

老年冠心病合并高同型半胱氨酸血症患者阿司匹林抵抗发生率及危险因素调查黄志坚;叶伟祥;李秀研【摘要】目的分析老年冠心病合并高同型半胱氨酸血症患者的阿司匹林抵抗发生率,并探讨其危险因素.方法选取2015年1月至2017年5月我科门诊及收治住院的185例老年冠心病患者,其中合并高同型半胱氨酸血症的患者108例未合并高同型半胱氨酸血症的患者77例;AR24例,AS161例.通过对比Hhcy患者和非Hhcy患者及AR和AS患者的各项临床指标,分析患者的阿司匹林抵抗发生率,并对其危险因素进行探讨.结果Hhcy患者的糖尿病发病率显著低于非Hhcy患者,Hcy水平、CD62P水平、肌酐水平均显著高于非Hhcy患者,AR发生率、服用钙拮抗剂比例均明显高于非Hhcy患者,以上各项组间比较差异均具有统计学意义(P＜0.05).AR患者的Hhcy比例为75.00％(18/24)明显高于AS患者55.90％(90/161),组间比较差异均具有统计学意义(P＜0.05).经多元Logistic回归分析显示,Hhcy是引起AR发生的独立危险因素(OR=2.405,95％CI:1.201～4.820,P=0.012);以hcy水平为因变量经多元线性回归分析显示,hcy水平与肌酐水平、患者年龄及BMI呈正相关关系(P＜0.05,见表2所示).经相关性分析显示,hcy水平与AA诱导的血小板聚集率呈正相关趋势(r=0.030,P=0.565).结论老年冠心病合并高同型半胱氨酸血症患者的AR发生率显著增加,高同型半胱氨酸血症是老年冠心病患者AR发生的高危因素.【期刊名称】《心血管病防治知识（下半月）》【年(卷),期】2017(000)011【总页数】3页(P6-8)【关键词】老年冠心病;高同型半胱氨酸血症;阿司匹林抵抗;危险因素【作者】黄志坚;叶伟祥;李秀研【作者单位】福建医科大学附属泉州第一医院,福建泉州362000;福建医科大学附属泉州第一医院,福建泉州362000;福建医科大学附属泉州第一医院,福建泉州362000【正文语种】中文临床研究明确指出，高同型半胱氨酸血症（Hhcy）是引起动脉硬化的一个独立高危因素[1]。

甲状腺功能减退与亚临床甲减症患者氧化应激指标变化分析

甲状腺功能减退与亚临床甲减症患者氧化应激指标变化分析宋长虹【期刊名称】《中国医学创新》【年(卷),期】2012(000)027【摘要】目的：探讨甲减和亚临床甲减患者氧化应激指标的变化.方法：测定46例甲减患者和44例亚临床甲减患者的丙二醛(MDA)水平、超氧化物歧化酶(SOD)活力、氧化型低密度脂蛋白(ox-LDL)含量等氧化应激指标的变化,并与44例正常健康体检者进行比较.结果：与对照组相比较,甲减和亚临床甲减患者SOD活性显著降低(P<0.01,P<0.05),MDA和ox-LDL水平显著升高(P<0.05,P<0.01).结论：MDA、SOD和ox-LDL等氧化应激指标,在甲减和亚临床甲减患者血清中有显著变化,这对临床上研究和诊断甲减和亚临床甲减具有重要的指导意义.% Objective:To investigate the changes of oxidative stress in patients with hypothyroidism and subclinical hypothyroidism. Method:Determination of 46 cases of patients with hypothyroidism and 44 patients with subclinical hypothyroidism in patients with MDA,SOD,ox-LDL,and 44 cases of normal healthy individuals for comparison.Result:Compared with the control group,SOD activity in patients with hypothyroidism and subclinical hypothyroidism was significantly decreased (P<0.01,P<0.05),MDA and ox-LDL were significantly increased (P<0.05,P<0.01).Conclusion:MDA,SOD,and ox-LDL oxidative stress parameters have significant changes in the serum of patients with hypothyroidism and subclinical hypothyroidism,which has important guiding significance forclinical research and diagnosis of hypothyroidism and subclinical hypothyroidism.【总页数】2页(P61-61,62)【作者】宋长虹【作者单位】青岛大学医学院山东费县人民医院山东青岛 266003【正文语种】中文【相关文献】1.亚临床甲状腺功能减退症患者血脂及超敏C反应蛋白变化分析 [J], 范进绵;郑东波;张州平2.48例亚临床甲减患者血脂变化分析 [J], 刘艳梅;于建成;仇颖3.亚临床甲状腺功能减退症患者血脂、血糖和血尿酸变化分析 [J], 王春容;4.亚临床甲状腺功能减退症患者血脂、血糖和血尿酸变化分析 [J], 王春容5.分析亚临床甲状腺功能减退症(甲减)伴冠心病的临床特点及其中西医治疗效果[J], 李莉因版权原因，仅展示原文概要，查看原文内容请购买。

高同型半胱氨酸血症与精神疾病的关系

高同型半胱氨酸血症与精神疾病的关系梁瑞华;景艳玲;孙祥虹【期刊名称】《四川精神卫生》【年(卷),期】2012(025)004【总页数】3页(P252-254)【作者】梁瑞华;景艳玲;孙祥虹【作者单位】266034 山东省青岛市精神卫生中心;266034 山东省青岛市精神卫生中心;266034 山东省青岛市精神卫生中心【正文语种】中文【中图分类】R749同型半胱氨酸(homocy steine，Hcy)是蛋氨酸循环的中间代谢产物，是一种含巯基的非必需氨基酸，它在结构上与同型半胱氨酸相似。

血浆中总同型半胱氨酸(tHcy)在体内有再甲基化、转硫化以及释放到细胞外基质三条代谢途径，它的代谢途径以维生素B6和维生素B12为辅酶。

近年大量文献报道，高同型半胱氨酸血症(HHcy)与妊娠期高血压症、心脑血管疾病、糖尿病等疾病的发病有关，同样Hcy与精神疾病的发病也密切联系。

Eberhard等［1］研究发现由于叶酸或维生素B12缺乏引起的HHcy可导致痴呆、抑郁症及认知功能的损害。

为此，本文就HHcy与精神疾病的研究进展作一综述。

Bjelland［2］等通过荷兰 Hcy 队列研究筛查5948例焦虑和抑郁病人，发现HHcy与抑郁具有明显的相关性，血清Hcy水平越高，患抑郁症的风险越大。

国内李曦等［3］发现血清叶酸、维生素B12缺乏和血浆Hcy升高与抑郁的严重程度呈正相关。

焦志安［4］等报道抑郁症患者血清Hcy水平较正常对照升高，抑郁症患者 HHcy发生率为45.45%，明显高于正常对照组。

乔娟等［5］对94例抑郁症的研究发现，抑郁症组HHcy的发生率高于正常组，同型半胱氨酸值与汉密尔顿抑郁量表呈正相关。

提示HHcy在抑郁症的发生发展中起着重要的作用，HHcy可能是抑郁症发病的重要危险因素之一。

综合Hcy在抑郁症中的作用，Folstein等［6］提出了抑郁症的Hcy假说，Hcy 与抑郁症可能有关的作用机制［7］:①血浆中Hcy异常升高提示Hcy再甲基化生成蛋氨酸的能力下降，甲基化代谢无法正常进行，引起需要甲基的单胺、神经递质等生成减少;②Hcy明显影响DNA的甲基化，从而影响各种与抑郁有关的各种神经递质代谢相关基因的表达，如5－羟色胺转运体基因等;③Hcy是N－甲基－D－天门冬氨酸(NMDA)受体的激动剂，通过影响神经细胞存活，从而导致抑郁。

4-苯基丁酸对糖尿病大鼠的心脏保护作用

4-苯基丁酸对糖尿病大鼠的心脏保护作用何玉莲;熊燕;张梅【摘要】目的：观察4-苯基丁酸(4-PBA)对糖尿病大鼠心脏功能的影响并初步探讨其机制。

方法♂Sprague-Dawley ( SD)大鼠随机分成3组：对照组、糖尿病组和糖尿病+4-PBA组。

单次腹腔注射链脲佐菌素(60 mg·kg-1)诱发大鼠糖尿病，在1型糖尿病模型制备成功后第5周开始每天给予大鼠4-PBA(1g·kg-1)灌胃，连续治疗20周。

实验结束后，经右颈总动脉插管检测大鼠大动脉和左心室血流动力学变化，同时收集血清和心脏，比色法检测血糖，血清和心肌组织中超氧化物歧化酶( SOD)和一氧化氮合酶( NOS)活性，丙二醛(MDA)和一氧化氮(NO)含量。

结果4-PBA治疗对糖尿病大鼠血糖、体重和心脏重量无明显影响，但可改善糖尿病大鼠血流动力学，表现为大动脉收缩压和舒张压、心率、左心室收缩压和左心室内压最大上升和下降速率(± dp/dt)的轻度升高，左心室舒张压的轻度降低和舒张时程的缩短(P>0.05)，左心室弛缓时间明显缩短(P<0.05)。

4-PBA治疗尚可明显升高糖尿病大鼠血清和心肌组织SOD和NOS活力以及NO含量，并降低MDA含量(P<0.05)。

结论4-PBA治疗对糖尿病大鼠心脏有潜在保护作用，这一作用是通过改善糖尿病大鼠血流动力学和明显缓解其心脏舒张功能障碍而实现，并与其抑制动物体内氧化应激和促进心肌NO生成有关。

%Aim Tostudytheeffectof4-phenlybuty-rate acid(4-PBA) on the heart function of diabetic rats and to explore its underlying mechanism. Methods MaleSprague-Dawley(SD)ratsweredividedintothree groups randomly: ( 1 ) control rats;( 2 ) diabetic rats;(3) 4-PBA treated diabetic rats. Type 1 diabetic mod-el was induced by single intraperitoneal injection of strepotozotocin (60 mg·kg-1 ) . After five weeks dia-betic model was established, diabetic rats weretreated with 4-PBA by P. O at the dose of 1 g·kg-1 per day for 20 weeks. At the end of the experiment, hemody-namics of the left ventricle and main artery were detec-ted through right carotid artery cannulation in rats. The level of blood glucose, the activity of superoxide dis-mutase( SOD) and nitric oxide synthetase ( NOS) and the content of malondialdehyde ( MDA ) and nitric ox-ide( NO) of serum and myocardial tissue in rats were measuredbycolorimetry.Results Thetreatmentof4-PBA had no effect on blood glucose, the weight of body and heart, but slightly increased systolic and diastolic pressure of artery, heart rate, systolic pressure of left ventricular, maximum increase rate and minimum de-crease rate of left ventricular pressure( ± dp/dt) in di-abetic rats. It also slightly decreased diastolic pressure of left ventricular, shortened diastolic duration of left ventricular ( P > 0. 05 ) . Moreover, it significantly shortened relaxation time of left ventricular in diabetic rats (P<0. 05). In addition, the treatment of 4-PBA obviously enhanced the activity of SOD and NOS, NO content, and reduced the content of MDA in serum andheartofdiabeticrats(P<0.05).Conclusion 4-PBA has a potential protective effect on heart function in diabetic rats, which is achieved by ameliorating he-modynamics and significantly improving diastolic dys-function in diabetic rats. The underlying mechanism may be related to the inhibition of oxidative stress and promoting the genesis of NO in myocardial tissue.【期刊名称】《中国药理学通报》【年(卷),期】2014(000)008【总页数】5页(P1137-1141)【关键词】糖尿病;心功能;4-苯基丁酸;血流动力学;氧化应激;一氧化氮【作者】何玉莲;熊燕;张梅【作者单位】广州医科大学药学院蛇毒研究所，广东广州 510082;广州医科大学药学院蛇毒研究所，广东广州 510082;广州医科大学药学院药理学教研室，广东广州 510082【正文语种】中文【中图分类】R-332;R322.11;R331.31;R587.102.2糖尿病患者易并发心血管疾病，其中糖尿病心肌病(diabetic cardiomyopathy，DCM)是患者的主要致死原因之一。

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