卡马西平增强γ-氨基丁酸对大鼠脑片的作用(英文)

目的:研究卡马西平(Car)对γ-氨基丁酸(GABA)在海马区域作用的影响.方法:在海马脑片(350μm)上刺激(0.5 Hz,50μs)Schaffer氏纤维,记录CA1区锥体细胞的诱发场电位.结果:Car 0.2mmol·L~(-1)对CA1区锥体细胞的诱发场电位没有明显影响,但Car 0.2 mmol·L~(-1)和GABA(0.1-1 mmol·L~(-1))同用抑制场电位作用比单用GABA时显著增强.Bicuculline不能翻转被Car加强的GABA的抑制作用.继而,左旋巴氯芬抑制场电位作用强于GABA.Car 0.2 mmol·L~(-1)和左旋巴氯芬(1-5μmol·L~(-1))同用抑制场电位作用比单用左旋巴氯芬时显著增强.结论:Car增强GABA对海马CA1区锥体细胞的抑制作用,其作用机制可能与GABA_B受体有关.     

戈那瑞林对大鼠脊神经节细胞GABA引起的去极化及GABA激活电流的调制作用(英文)

目的:探索戈那瑞林对大鼠初级感觉神经元膜GABA引起的去极化和GABA激活电流的调制作用。方法:应用细胞内记录和全细胞膜片钳技术分别在大鼠脊神经节(SG)标本和新鲜分离神经元进行实验。结果:GABA(10 μmol·L~(-1)—1mmol·L~(-1))在大多数神经元引起可为荷包牡丹碱(100μmol·L~(-1))所阻断的膜去极化。预加戈那瑞林(50μmol·L~(-1))可减少GABA引起的去极化,抑制率为79±22％(n=29),而戈那瑞林本身不产生膜反应或只引起轻微去极化。在11个细胞中有6个细胞GABA激活电流也为戈那瑞林的预处理所抑制,另5个细胞无改变或反应稍有增加。结论:戈那瑞林对初级感觉神经元GABA介导的去极化和GABA激活电流具有抑制作用。     

NMDA受体在皮质酮介导海马突触可塑性损伤中的作用

目的考察皮质酮(CORT)致突触可塑性损伤与N-甲基-D-天冬氨酸(NMDA)受体的关系。方法雄性C57BL/6J小鼠(7～9周龄)剥离海马切片用于长时程增强(LTP)和长时程抑制(LTD)实验;采用灌流给药的方式,观察1μmol·L~(-1)CORT和非选择性NMDA受体拮抗剂D-AP5(50μmol·L~(-1))、选择性NR2A拮抗剂PEAQX(0.2μmol·L~(-1))和TCN-201(3μmol·L~(-1))、选择性NR2B拮抗剂Ifenprodil(3μmol·L~(-1))和Ro25-6981(1μmol·L~(-1))及NMDA受体共激活剂D-丝氨酸对LTP和LTD的影响。结果与正常组小鼠相比,CORT组小鼠海马的LTP和LTD均显著损伤(P<0.01),D-AP5可显著损伤小鼠海马的LTP和LTD(P<0.01),PEAQX和TCN-201及Ifenprodil和Ro25-6981均可显著损伤小鼠海马的LTP(P<0.01),对LTD则无显著影响;而D-Serine可显著改善CORT引起的LTP和LTD损伤(P<0.01)。结论 CORT和D-AP5对海马LTP和LTD具有相似的损伤作用,且D-丝氨酸对CORT致海马LTP和LTD损伤具有显著改善作用,提示CORT可能通过抑制NMDA受体功能影响海马突触可塑性。     

方波溶出伏安法测定山药中微量元素铜和锌

目的:建立山药中 Zn、Cu 微量元素的电化学测定方法。方法:在三电极系统中,以 NH_4Cl为底液,银基汞膜电极为工作电极,铂电极为辅助电极,饱和甘汞电极为参比电极,采用方波溶出伏安法进行测定。结果:在 pH 值5.4～5.6的 NH_4Cl 底液中,在0.3935～5.509 μmol·L~(-1)范围内峰电流与铜(Ⅱ)离子浓度呈现良好的线性关系,线性回归方程:i_p(μA)=102.4C(μmol·L~(-1))-1.038,r 为0.9993,检出限为0.06776 μmol·L~(-1);在 pH 值6.0～6.5的 NH_4Cl 底液中,在0.3823～6.881 μmol·L~(-1)范围内峰电流与锌(Ⅱ)离子浓度呈良好的线性关系,回归方程:i_p(μA)=7.731C(μmol·L~(-1))-2.061,r 为0.9996;检出限为0.2753 μmol·L~(-1)。铜和锌测定的相对标准偏差分别是1.3%和2.9%,加标回收率分别为97%～103%和97%～105%。结论:该方法简便、灵敏度高、准确度好、精密度好,能够满足山药中的微量铜和锌的测定要求。     

川芎嗪对大鼠背根神经节细胞P2X嘌呤受体介导反应的作用

目的探讨川芎嗪(tetram ethy1pyrazine,TMP)对嘌呤2X(P2X)受体介导反应的作用。方法在大鼠新鲜分离的背根神经节(dorsal root ganglion,DRG)神经元标本上应用全细胞膜片钳技术记录川芎嗪对P2X受体激动剂激活电流的影响。结果外加ATP(1~1 000μmol.L-1)可引起DRG神经元产生激活电流(n=102),ATP-激活电流(IATP)显示快失敏和慢失敏两种形式的内向电流。预加川芎嗪(0.1~10mmol.L-1)后,大部分(89.2%,91/102)受检细胞可观察到ATP(100μmol.L-1)-激活电流出现明显的抑制作用。川芎嗪(1 mmol.L-1)使α,-βm eATP(10μmol.L-1)-激活电流减小。预加川芎嗪(1 mmol.L-1)后ATP(1~1 000μmol.L-1)激活电流的剂量-效应曲线明显下移。预加川芎嗪(1 mmol.L-1)前后ATP(100μmol.L-1)的I-V曲线反转电位值不变,均接近0 mV。川芎嗪(1 mmol.L-1)可明显抑制被前列腺素E2(100μmol.L-1)或P物质(0.1μmol.L-1)增大的ATP激活电流。通过微电极胞内透析注入PKA抑制剂H89(10μmol.L-1)至胞内,使川芎嗪(1 mmol.L-1)抑制ATP(100μmol.L-1)激活电流的作用减小。结论川芎嗪可能是通过PKA系统以及P2X受体离子通道复合体细胞外环的变构调制点影响P2X受体激动剂在大鼠DRG神经元的激活电流。     

甲苯喹哌对培养爪蟾胚胎肌细胞和神经细胞离子通道的作用(英文)

目的:研究新型抗心律失常药甲苯喹哌对离子通道的作用.方法:通过膜片钳技术记录培养爪蟾胚胎肌细胞和神经细胞全细胞离子通道电流.结果:甲苯喹哌(0.1,1,10,100μmolL~(-1))可浓度依赖性地抑制肌细胞的钠通道,其IC_(50)为7.2μmol L~(-1)(5.3—9.8μmol L~(-1)).甲苯喹哌(10μmol L~(-1))可抑制神经细胞的高电压激活的钙通道.然而,肌细胞上的稳态外向钾电流却受到甲苯喹哌(10μmol L~(-1))的激活.结论:甲苯喹哌抑制钠、钙通道,但激活稳态外向钾通道.     

鸡胚心肌细胞的膨胀激活氯电流

目的:研究白羽鸡胚心肌细胞的膨胀激活氯电流及氯丙嗪对其的模拟作用.方法:膜片箝技术的全细胞记录模式.结果:低渗膨胀在白羽鸡胚心肌上诱发出一个可逆变化的氯电流,渗透压从300 mmol·L~(-1)减小至270 mmol·L~(-1)时,该电流从(452±200)pA增加到(849±373)pA.DIDS 100 μmol·L~(-1)使氯电流从(1196±505)pA减至(830±328)pA.I(Cl,swell)不能被CPZ 30μmol·L~(-1)模拟出来,该结果不同于大肠杆菌原生质体的结果.结论:白羽鸡胚心肌细胞的膨胀激活氯通道能被低渗激活,其激活的机制与大肠杆菌的机制敏感性离子通道激活的机制不同.     

粉防己碱抑制豚鼠离体气道C神经纤维兴奋引起的收缩(英文)

目的:研究粉防己碱(Tet)对豚鼠离体气管/支气管的感觉神经C纤维兴奋的抑制作用.方法:记录电场刺激所致的C纤维兴奋所产生的标本收缩(phase Ⅱ)张力,了解Tet的作用.结果:Tet 0.3—30 μmol·L~(-1)抑制phase Ⅱ收缩,在气管/支气管上,Tet 1 μmol·L~(-1)的抑制率分别是:40±38％和75±22％;用氯苯那敏或阿托品作用后,Tet 1 μmol·L~(-1)的抑制率分别是70±16％和64±16％;Tet不抑制外源性P物质引起的标本收缩.结论:Tet 1μmol·L~(-1)抑制豚鼠离体气道收缩的机理与其抑制感觉神经C纤维兴奋释放神经肽的作用有关.     

替芬泰对HepG2细胞的线粒体毒性

目的采用HepG2细胞来评价首次合成的马蹄金素衍生物替芬泰在抗乙肝病毒的同时对肝细胞的线粒体毒性,为临床试验剂量设计和合理用药提供参考。方法测定替芬泰对HepG2细胞增殖的抑制率,对培养上清液乳酸含量、细胞活性氧含量、线粒体膜电位变化及线粒体呼吸链复合物酶Ⅰ~Ⅳ活性的影响,综合评价替芬泰的线粒体毒性。结果替芬泰对HepG2细胞增殖的半数抑制浓度为359μmol·L~(-1)。与对照组比较,替芬泰400μmol·L~(-1)(196 mg·L~(-1))时明显降低HepG2细胞的线粒体膜电位,明显增加细胞活性氧含量,升高乳酸生成水平,降低线粒体呼吸链复合物酶Ⅰ、Ⅱ、Ⅲ的活性,具有明显的线粒体毒性。与拉米夫定、阿德福韦酯比较,同为100μmol·L~(-1)的替芬泰对上述指标均无影响。结论替芬泰的线粒体毒性安全范围较大,实验结果对临床试验剂量设计和临床用药具有一定的指导意义。     

内皮舒张因子抑制剂对低氧收缩离体猪冠脉的影响(英文)

左旋硝基精氨酸,NLA (0.2 mmol·L~(-1))可阻断离体猪冠脉依内皮性缺氧收缩反应,用左旋精氨酸,L-Arg(2mmol·L~(-1))预处理可显著降低NLA的抑制作用,四乙胺,TEA(10mmol·L~(-1))和格列本脲,Gli(1 μmol·L~(-1))对缺氧收缩反应无明显影响,而Cro-makalim,Cro(1 μmol·L~(-1))则可抑制缺氧冠脉收缩。     

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.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

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.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

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.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.