甲基苯丙胺依赖大鼠血清代谢组学研究

目的：建立甲基苯丙胺（MA）依赖动物模型,研究甲基苯丙胺依赖大鼠血清代谢物变化并寻找其可能的潜在标志物。方法：以雄性SD大鼠为实验动物,随机分为依赖组和正常对照组,运用液相色谱联合离子阱一飞行时间质谱（LC／MS—IT—TOF）分析方法研究MA依赖对大鼠血清代谢变化的影响。分别采用主成分分析（PCA）、偏最小二乘法一判别分析（PLS—DA）以及正交偏最小二乘法数据分析（OPLS—DA）分析依赖组和正常对照组之间的代谢差异。结果：依赖组和对照组大鼠在血清代谢水平上存在显著差异,经统计学初步筛选出11个潜在的生物标记物。结论：甲基苯丙胺依赖成瘾代谢组学研究具有一定的可行性,代谢组学在判定甲基苯丙胺依赖与否方面具有一定的潜在价值。     

高血压病肝阳上亢证患者血清样品的核磁共振谱代谢组学研究

目的采用1HNMR结合主成分分析（PCA）方法研究高血压病肝阳上亢证患者和健康志愿者的血液成分谱差异,寻找可能的生物标记物,揭示高血压病肝阳上亢的证候本质。方法根据临床高血压病肝阳上亢证的诊断标准,选择典型病例,以1HNMR分析高血压病肝阳上亢证患者和健康志愿者的血液成分,使用PCA方法进行模式识别,寻找标记物并做出相关代谢途径的可能解释。结果PCA方法处理高血压病肝阳上亢证患者和健康志愿者的血清1HNMR谱数据显示,两组1HNMR谱数据可以在得分图实现分类,与健康志愿者作比较,患者机体相关代谢发生显著变化,体内部分氨基酸代谢和葡萄糖代谢明显异于健康志愿者。结论1HNMR结合PCA模式识别的代谢组学方法具有研究复杂条件下机体病理生理变化的优势,为理解高血压病肝阳上亢证的证侯本质和诊断该类病证提供了科学依据。     

基于气相色谱-质谱联用技术的肥胖儿童血清代谢组学研究

目的：筛选与儿童肥胖相关的血液中差异代谢物,探讨肥胖儿童代谢紊乱的发生机制。方法：采用气相色谱-质谱联用（GC/MS）和模式识别技术分析肥胖儿童血清中代谢物的变化,GC/MS检测25例肥胖儿童（肥胖组）和25例健康儿童（正常组）血清中代谢物,采用偏最小二乘判别分析（partial least squares discrimination analysis,PLS-DA）识别两组样本的血清代谢谱及代谢物。结果：肥胖组和正常组的代谢谱分离良好,肥胖儿童和正常儿童之间的血清代谢成分存在33个差异代谢物,绘制33个差异代谢物ROC曲线,计算曲线下面积,肌酐、马来酸、莽草酸等16个代谢物面积大于0.5,可能是诊断肥胖儿童潜在的生物标志物。结论：肥胖儿童患者血清代谢物的变化机制和甘氨酸,丝氨酸和苏氨酸的代谢、丙氨酸、天冬氨酸和谷氨酸代谢、乙醛酸和二羧酸酯代谢密切相关。     

四氯化碳诱导大鼠非酒精性脂肪肝的生物标记物研究

摘 要 目的：应用代谢组学的方法研究四氯化碳（CCl4）诱导的非酒精性脂肪肝（NAFLD）大鼠模型的血浆代谢产物变化,探讨NAFLD的发病机制,提示该代谢途径中的特异性生物标记物。方法: 将雄性大鼠分成空白对照组、CCl4诱导的模型组、给予具有改善脂类代谢功能的中药配方通络祛浊方的干预组和治疗组,于第9周静脉取血,使用高效液相 四极杆飞行时间质谱（HPLC QTOF/MS）检测到超过2 300个内源性代谢产物,并解剖做病理观察。使用PCA、双聚类及OPLS DA模型筛选潜在的NAFLD的生物标记物,并通过Metaboanalyst对关键的代谢产物进行代谢通路分析。结果:游离脂肪酸（FFA）及磷脂类化合物在模型组相比空白对照组明显减少,干预组或治疗组中部分代谢产物的含量相对于模型组有所回升,甚至恢复至空白对照组水平。亚油酸及磷脂酰胆碱PC（0∶〖KG-*2〗0/18∶〖KG-*2〗0）在空白对照组与模型组间、干预组与模型组间、治疗组与模型组间差异均有统计学意义（P<0.05）。结论:代谢产物亚油酸及磷脂酰胆碱PC（0∶〖KG-*2〗0/18∶〖KG-*2〗0）可能是CCl4诱导的NAFLD的生物标记物。中药通络祛浊方对本模型的干预和治疗均有疗效,能够改善NAFLD大鼠的肝脏脂肪积蓄状况。     

精神障碍的代谢组学研究进展

代谢组学是基础生物学的一个组成部分,能从总体水平上反映机体的代谢途径。代谢组学通过识别生物标记物来体现机体在疾病状况下的病理变化,并监测机体对治疗的应答,为医疗实践提供重要依据。精神障碍与多种神经递质、脂肪酸以及线粒体功能的代谢途径受干扰有关。代谢组学能详细地描记受到扰动的生化途径和链接在这些途径中能够反映疾病特征的关键性生物标记物。本文阐述了代谢组学的概念、相关技术及精神障碍的代谢组学研究进展。     

性早熟患儿骨矿含量分析

目的探讨性早熟儿童骨矿含量的变化．．方法1995年5月～2004年12月对符合诊断标准的372例性早熟儿童进行桡骨骨矿含量的测定,对照组选自郑州市区同龄健康儿。结果两组骨矿含量和骨面密度比较均有显著差异（P〈0．05）,性早熟惠儿骨矿含量和骨面密度较健康正常儿童明显减低。结论性早熟儿童骨矿物质含量低于健康同龄儿,因此性早熟患儿应积极补充钙荆,加强营养。     

基于血浆代谢组学评价不同神经保护剂联用方案对缺血性脑卒中生物标志物的影响

目的：通过代谢组学挖掘神经保护剂联用治疗缺血性脑卒中患者血浆的回调性生物标志物,从代谢路径角度评价神经保护剂联用的合理性。方法：通过高效液相色谱与飞行时间质谱（Q-TOF）联用的非靶向代谢组学平台,获取缺血性脑卒中患者的血浆代谢组学数据,用多元变量统计分析进行数据处理,筛选出药物干预后回调的生物标记物及其代谢路径。结果：代谢组学研究表明缺血性脑卒中患者体内主要呈氨基酸、脂类及能量代谢紊乱,给予不同神经保护剂联用方案后整体代谢轮廓回调,经数据库鉴定和匹配后得到两药联用-丁苯酞+依达拉奉组、两药联用-丁苯酞+单唾液酸组和三药联用-丁苯酞+依达拉奉+单唾液酸组显著变化的共性回调生物标记物及特征性回调生物标记物（溶血磷脂酰胆碱18∶0、色氨酸和苹果酸等）。结论：神经保护剂联合应用可使缺血性脑卒中患者的代谢紊乱恢复。调节能量代谢（三羧酸循环）、脂类代谢（甘油磷脂代谢、脂肪酸代谢）和氨基酸代谢（芳香族氨基酸代谢、鸟氨酸代谢）通路等可能是其治疗缺血性脑卒中的神经保护机制。     

过敏性鼻炎患者血液代谢组学研究

目的：采用代谢组学方法分析过敏性鼻炎患者血清中小分子代谢物的变化。方法：采用气相色谱-质谱联用技术（GC-MS）检测20例过敏性鼻炎患者（病例）和同期20例健康者（对照组）血清中代谢物,采用正交偏最小二乘法（OPLS）的方法,观察病例组和对照组的代谢谱变化,并寻找有差异的小分子代谢物。结果：对照组和病例组的代谢谱能明显区分,鉴定了23个差异代谢物,并对差异代谢物进行了ROC曲线绘制,计算ROC曲线下的面积,得出曲线下面积大于0.5的物质有甘油酸、丝氨酸、苏氨酸、甲硫氨酸、半胱氨酸、天冬酰胺、谷氨酰胺、色氨酸和十九烷酸。结合代谢途径分析,发现过敏性鼻炎患者体内存在丙氨酸、天冬氨酸和谷氨酸代谢,甘氨酸、丝氨酸和苏氨酸代谢,半胱氨酸和甲硫氨酸代谢和色氨酸代谢异常。结论：基于GC/MS的代谢组学技术能全面客观地反映过敏性鼻炎患者体内血液中的代谢物变化,小分子代谢物分析及代谢途径探讨将为过敏性鼻炎的诊断和发病机制研究提供一个可借鉴的思路和手段。     

中枢性性早熟女童身体质量指数与骨龄、胰岛素样生长因子1、血清25-羟维生素D的相关性分析

目的 探讨身体质量指数（BMI）对中枢性性早熟（CPP）女童的骨龄、胰岛素样生长因子1(IGF-1)、25-羟维生素D[25(OH)D]的影响。方法 选取2016年1月至2018年12月因过早出现第二性征而至苏州大学附属张家港医院儿童内分泌专科就诊的158例女童为研究对象，中枢性性早熟组90例，其中肥胖组（n=20）、超重组（n=30）、正常体质量组（n=40）；单纯性乳房早发育组68例，检测各组骨龄、IGF-1、25(OH)D，并将各指标水平与BMI进行Pearson相关分析。结果 中枢性性早熟组骨龄（10.01±1.44）岁、IGF-1(328.73±143.57)μg/L均显著高于单纯性乳房早发育组（8.81±1.13）岁、（259.86±118.62）μg/L(P<0.05)，中枢性性早熟组25(OH)D(23.16±4.86)μg/L显著低于单纯性乳房早发育组（25.86±5.84）μg/L(P<0.05)。中枢性性早熟女童25(OH)D超重组（23.197±3.558）μg/L和肥胖组（16.395±3.254）μg/L均显著低于正常体质量组（26.505±5....     

发病6个月以上性早熟女童与在校女童社交焦虑及抑郁情绪差异研究

目的：初步了解发病6个月以上的性早熟女童抑郁情绪和社交焦虑的分布,讨论性早熟女童与在校女童抑郁和社交焦虑的常见表现以及差异。方法：2013年1月—2014年12月采用抑郁量自评表（CES-D）及儿童社交焦虑量表（SASC）调查上海两家医院发病6个月以上的性早熟女童（性早熟组）194人及上海地区四所学校的在校女童（在校组）333人的抑郁和社交焦虑的常见表现以及差异。结果：在校组抑郁评分为（15.48±7.22）分,高于性早熟组的（11.46±7.23）分,组间差异有统计学意义（P＜0.001）。在校组抑郁情绪阳性率为24.6%（82/333）,性早熟组为11.3%（22/194）,组间差异有统计学意义（P＜0.001）。在校组8~,9~,≥10岁三个年龄段的社交焦虑的总分高于性早熟组,组间差异有统计学意义（P＜0.05）。结论：在校组抑郁和社交焦虑情绪的比例高于性早熟组,学校应重视在校女童的心理疏导及干预。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Nachweis einiger Heilmittel in der Kniegelenksynovialflüssigkeit

Zusammenfassung Mittels Gaschromatographie und Dünschichtchromatographie wiesen die Autoren 11 Substanzen nach, welche durch Injektion oder nach Verabreichung per os in die Kniegelenksynovialflüssigkeit eindrangen. In ihrer Aufstellung konnten sie eine direkte Beziehung zwischen Struktur sowie chemischphysikalischen Eigenschaften der Substanz und ihrer Fähigkeit, aus dem Blut in die Kniegelenksynovialflüssigkeit einzudringen, nicht nachweisen, außer der Tatsache, daß Substanzen mit starker Affinität zu Eiweißstoffen erst in höheren Dosen nachweisbar waren.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.