菟丝子对D-半乳糖致衰老大鼠非酶糖基化及自由基的抑制作用研究

目的:探讨研究菟丝子醇提液对衰老大鼠体内非酶糖基化和自由基的抑制作用及机制.方法:大鼠随机分为青年对照组、衰老模型组和模型给药组,用D-半乳糖制造衰老模型,同时模型给药组灌服菟丝子醇提液并在不同时间杀鼠,测定糖化血红蛋白(GHb)、糖化血清蛋白(GSP),丙二醛(MDA)水平及超氧化物歧化酶(SOD)活性.结果: 菟丝子醇提液使大鼠GHb、GSP、MDA水平明显减低(P<0.05,P<0.01),SOD活性显著升高(P<0.01).结论: 菟丝子抑制非酶糖基化反应,减少自由基生成,具有一定的抗衰老作用.     

菟丝子醇提液对D-半乳糖致衰大鼠脑组织抗氧化作用研究

目的:研究菟丝子醇提液对D-半乳糖致衰大鼠脑组织抗氧化作用。方法:以D-半乳糖侧腹部注射大鼠,6周后连续灌服菟丝子醇提液30d,分别检测大鼠脑组织超氧化物歧化酶(SOD)以及谷胱甘肽过氧化物酶(GSH-Px)的活性;大脑皮质神经细胞丙二醛(MDA)的含量。结果:与D-半乳糖致衰老模型大鼠相比菟丝子醇提液给药组大鼠脑组织SOD,GSH-Px活性显著提高(P<0.05;P<0.01),MDA含量显著下降。结论:菟丝子醇提液可以提高致衰大鼠神经细胞抗氧化物酶的活性,降低自由基代谢产物的含量,具有一定的抗衰老作用。     

葛根素对D-半乳糖诱导大鼠抑制蛋白非酶糖基化及增强胰岛素敏感性的作用

目的观察葛根素对D-半乳糖(D-gal)诱导大鼠体内蛋白非酶糖基化反应、胰岛素抵抗、糖耐量和醛糖还原酶(AR)活性的作用。方法除空白对照组外,其余大鼠均采用腹腔注射(ip)D-gal150mg/kg,1次/d×56d致病,D-gal处理大鼠2周后,将大鼠按体重均衡随机分成:模型对照、葛根素和氨基胍3组,然后继续ipD-gal处理同时灌胃给予葛根素和氨基胍(每10ml300mg/kg)或蒸馏水,1次/d×42d;实验结束时,观察葛根素和氨基胍对D-半乳糖诱导大鼠体内晚期糖基化终末产物(AGEs)、糖化血红蛋白(HbA1c)、果糖胺(FRA)、糖耐量、血糖和胰岛素含量,并计算胰岛素敏感指数(ISI),以及醛糖还原酶(AR)活性的作用。结果与空白对照组比较,D-gal处理大鼠出现血糖升高、糖耐量减退(IGT)、糖基化产物(包括HbA1c,FRA和AGEs)和胰岛素含量增高,ISI降低,以及红细胞内AR活性增强(P<0.01);葛根素和氨基胍均能改善D-gal诱导大鼠IGT和降低空腹血糖、糖基化产物和胰岛素含量(P<0.01～0.05),提高ISI(P<0.01),并明显抑制AR活性(P<0.01～0.05)。结论D-gal能诱导大鼠体内糖基化反应、高胰岛素血症、胰岛素抵抗和醛糖还原酶活性增强;而葛根素和氨基胍能抑制蛋白非酶糖基化反应和醛糖还原酶活性,提高胰岛素敏感性,改善高胰岛素血症,提示葛根素可用于治疗糖尿病某些慢性并发症。     

肉苁蓉水提液对D-半乳糖致衰大鼠肝脏氧化损伤保护作用的研究

目的 :观察肉苁蓉水提液对 D-半乳糖致衰大鼠肝脏氧化损伤的保护作用。方法 :采用 D-半乳糖所致衰老模型大鼠 ,灌服肉苁蓉水提液 6周 ,测定肝脏活性氧单位、Ca2 + - ATP酶活性、肝线粒体 MDA含量、PL A2 活性。结果 :肉苁蓉水提液显著提高衰老模型大鼠肝脏活性氧单位、Ca2 + - ATP酶活性 (P <0 .0 1) ,显著降低肝线粒体 MDA含量、PL A2 活性(P<0 .0 1)。结论 :肉苁蓉水提液能提高衰老模型大鼠肝脏抗氧化能力 ,具有抗衰老作用     

氨基胍、葛根素、小檗碱、黄芩苷和甘草酸对D-半乳糖诱导大鼠醛糖还原酶活性和蛋白非酶糖化作用的比较

目的观察氨基胍、葛根素、小檗碱、黄芩苷和甘草酸对D-半乳糖(D-gal)诱导大鼠体内醛糖还原酶(AR)活性、糖耐量和蛋白非酶糖基化反应的作用。方法除空白对照组外,其余大鼠均采用腹腔注射(ip)D-gal 150mg? kg-1,qd×56d致病,D-gal处理大鼠2周后,将大鼠按体重均衡随机分成:模型对照、氨基胍、葛根素、小檗碱、黄芩苷和甘草酸5组,然后继续ip D-gal处理同时灌胃给予不同药物(300mg?kg-1?10ml-1)或蒸馏水,qd×42d;实验结束时,观察5药对D-半乳糖诱导大鼠体内醛糖还原酶(AR)活性、糖耐量和蛋白非酶糖基化反应的作用。结果与空白对照组比较,D-gal处理大鼠出现糖耐量减退(IGT)、糖基化产物(包括糖化血红蛋白即HbA1c、果糖胺和晚期糖基化终产物)增高以及红细胞内AR活性增强(P<0．01);氨基胍、葛根素、小檗碱、黄芩苷与甘草酸均能明显抑制AR活性(P<0．01-0．05);氨基胍、葛根素、小檗碱和黄芩苷均能改善D-gal诱导大鼠IGT(P<0．01-<0．05);氨基胍、葛根素和小檗碱能降低糖基化产物的含量(P<0．01-0．05),而黄芩苷仅降低HbA1c含量(P<0．05);甘草酸对糖基化产物含量未见明显影响(P>0．05)。结论氨基胍、葛根素、小檗碱、黄芩苷和甘草酸均能抑制D- gal诱导大鼠体内醛糖还原酶活性,氨基胍、葛根素与小檗碱对D-gal诱致的大鼠糖基化反应具有明显的抑制作用,而黄芩苷对大鼠糖基化反应具有部分抑制作用,甘草酸对大鼠糖基化反应未见抑制作用。     

水飞蓟宾对D-半乳糖诱导衰老大鼠抑制糖氧化应激反应及改善学习记忆作用

目的:观察水飞蓟宾对D-半乳糖(D-gal)诱导衰老大鼠糖化氧化应激反应及学习记忆作用的影响。方法:采用D-gal诱导衰老大鼠模型;采用Morris水迷宫测定法检测大鼠学习记忆能力。实验结束后测定大鼠血浆糖化血红蛋白(HbA1c)、血浆非酶糖基化终产物(AGEs)和果糖胺(FRA)含量、红细胞醛糖还原酶(AR)活性及脑组织超氧化物歧化酶(SOD)活性和丙二醛(MDA)、AGEs含量。结果:水飞蓟宾150mg/kg和75mg/kg均能明显抑制D-gal诱导的AR活性增高(P<0.01),降低FRA、HbA1c和AGEs含量(P<0.01或P<0.05),能不同程度地降低大鼠脑组织AGEs和MDA含量,提高SOD活性(P<0.01)。结论:水飞蓟宾对D-半乳糖所致衰老大鼠学习记忆障碍具有保护作用,能增强学习记忆能力,其机制可能与抑制糖氧化应激反应有关。     

D-半乳糖衰老模型大鼠肝脏形态学及抗氧化能力变化的研究

目的:观察D-半乳糖致衰大鼠肝脏形态学改变及氧化水平和抗氧化能力的变化。方法:采用D-半乳糖所致衰老模型大鼠,做肝组织HE染色光镜观察,测定C a2 -ATP酶活性,肝线粒体M DA含量、PLA2活性。结果:衰老模型大鼠肝组织形态学发生明显变化,肝脏C a2 -ATP酶活性显著降低(P<0.01),肝线粒体M DA含量、PLA2活性显著升高(P<0.01)。结论:D-半乳糖致衰大鼠可作为研究衰老的模型。     

显脉旋覆花不同部位体内外抗氧化作用比较

目的为合理利用显脉旋覆花资源,研究了显脉旋覆花体内外抗氧化作用。方法通过水煎法、索氏醇提法及超声醇提法对显脉旋覆花地上及地下部分药用成分进行提取,并通过体内外实验比较了不同部位超声醇提物的抗氧化效果。结果超声醇提所得总酚及总黄酮含量最高,提取物中总酚含量明显高于总黄酮含量;显脉旋覆花超声醇提物对DPPH、ABTS及超氧阴离子自由基都有很好的清除效果,地下部分提取物的清除效果明显优于地上部分;提取物灌药可明显提高D-半乳糖致衰小鼠肝脏、肾脏及血清的过氧化氢酶(CAT)、超氧化物歧化酶(SOD)、总抗氧化能力(T-AOC)、谷胱甘肽过氧化物酶(GSH-Px)酶活性,并降低丙二醛(MDA)含量,地上部分高浓度抗氧化效果相当于地下部分低浓度的效果。结论显脉旋覆花醇提物对自由基有良好的清除作用,具有较好的抗氧化能力,地下部分抗氧化的效果明显高于地上部分。     

葛根素对D-半乳糖诱导糖基化模型大鼠血糖和肝肾功能的影响

目的:研究葛根素(puerarin)对D-半乳糖诱导的糖基化模型大鼠血糖、胰岛素敏感指数和肝、肾功能的影响。方法:D-半乳糖(150 mg·kg~(-1)·d~(-1),ip)给药8周,诱导糖基化模型大鼠,并于第3周开始给予葛根素高、中、低剂量(300,150,75 mg·kg~(-1)·d~(-1))处理6周。测定红细胞醛糖还原酶活性、糖化血红蛋白、血清果糖胺和晚期糖基化终末产物(advanced glycation end-products,AGEs)含量,以及血糖、血清胰岛素水平和肝脏、肾脏功能的影响。结果:葛根素高、中剂量能够明显降低D-半乳糖引起的模型大鼠血糖升高,增加胰岛素敏感指数,降低红细胞醛糖还原酶的活性,并显著抑制糖基化产物的形成(P＜0．01);显著降低血清肌酐、尿素氮的含量(P＜0．01或P＜0．05)。结论:葛根素具有抑制D-半乳糖诱导的糖基化反应,恢复胰岛素敏感性,并对糖基化诱致的肝脏和肾脏功能损伤具有保护作用。     

山茱萸活性成分对D-半乳糖致衰星形胶质细胞影响的实验研究

目的研究山茱萸活性成分马钱苷、莫诺苷对D-半乳糖致衰大鼠星形胶质细胞的保护作用。方法常规方法体外培养乳大鼠大脑皮层星形胶质细胞,采用免疫荧光方法进行星形胶质细胞鉴定;MTT法对比不同浓度D-半乳糖对星形胶质细胞的增殖抑制作用,以及马钱苷、莫诺苷对D-半乳糖致衰星形胶质细胞活力的影响;以超氧化物歧化酶(SOD)、丙二醛(MDA)为观察指标,观察马钱苷、莫诺苷对D-半乳糖致衰星形胶质细胞的影响;ELISA法检测胶质细胞源性神经营养因子(GDNF)、碱性成纤维细胞生长因子(bFGF)含量变化;Western blot法检测Bax、caspase-3、磷酸化细胞外信号调节激酶(p-ERK1/2)、磷酸化丝裂原活化蛋白激酶/ERK激酶(p-MEK1/2)的表达水平,以做进一步机制研究。结果马钱苷、莫诺苷组与模型组比较,细胞的增殖能力提高,SOD含量增加,MDA活性降低,且差异有显著性(P<0.05);马钱苷、莫诺苷组生长因子(GDNF、bFGF)的分泌高于模型组;Western blot结果表明,D-半乳糖致衰老的星形胶质细胞中Bax、caspase-3蛋白表达无明显变化,模型组pERK1/2、p-MEK1/2蛋白表达降低,马钱苷、莫诺苷增加pERK1/2、p-MEK1/2蛋白的表达。结论山茱萸活性成分马钱苷、莫诺苷可通过提高D-半乳糖致衰星形胶质细胞的增殖能力,提高衰老细胞的抗氧化能力,发挥抗衰老作用,其机制可能与MEK/ERK介导的信号通路调控有关。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

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.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

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.