巴氯芬对大鼠背根神经节神经元NMDA激活电流的抑制作用(英文)

目的:探索巴氯芬对大鼠初级感觉神经元膜NMDA激活电流的调制作用。方法:全细胞膜片箝技术在新鲜分离的背根神经节(DRG)细胞上进行实验。结果:DRG细胞外加巴氯芬(1-100μmol·L~(-1))未记录到可检测的膜电流改变,但预加巴氯芬对NMDA激活电流则有明显的抑制作用,巴氯芬100μmol·L~(-1)对NMDA(100 μmol·L~(-1))激活电流的抑制可达52％±14％(n=11,P<0.01),此抑制作用被GABA_B受体的拮抗剂沙氯芬(100 μmol·L~(-1))所取消,结论:初级感觉神经元膜上GABA_B受体的激活对NMDA受体介导的膜电流具有抑制作用。     

苄普地尔抑制大鼠海马CA1区锥体细胞钠电流(英文)

目的:研究苄普地尔对大鼠海马CA1区锥体细胞钠电流的影响。方法:膜片箝全细胞记录技术。结果:苄普地尔显著降低大鼠海马CA1区锥体细胞钠电流,作用呈时间及浓度依赖关系。苄普地尔10μmol·L~(-1)的半阻断时间约为10min。IC_(50)为2.6(2.3-2.9)μmol·L~(-1)。苄普地尔10μmol·L~(-1)右移最大电流的激活电位10mV,左移半失活膜电位18mV,表明其电压依赖地影响钠通道的激活和失活过程。结论:苄普地尔阻断大鼠海马CA1区锥体细胞钠电流,可能是其抗脑缺血机制之一。     

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。     

急性分离大鼠脑内神经元上由多巴胺引起的离子电流(英文)

目的:研究多巴胺(DA)诱发神经元的电流反应。 方法:制霉菌素打孔的膜片箝全细胞记录。 结果:在-20mV箝制电压下,DA(0.1—1mmol·L~(-1))对26％黑质神经元(5/19个)引起外向电流;对36％海马CA_1锥体细胞(25/69个)出现3种反应:外向电流伴有膜电导增加、缓慢内向电流伴随膜电导减小、外向—内向电流。DA引起的CA_1锥体细胞电流反应的阈剂量为3mmol·L~(-1),无电压依赖关系。翻转电位(E_(DA))接近K~ 平衡电位,为TEA抑制。结论:DA诱发海马CA_1锥体细胞的外向电流可能是K~ 电流。     

3-Morpholinosydnonimine-N-ethylcarbamide对缺氧诱发离体猪冠脉机械和电反应的影响(英文)

研究3-Morpholinosydnonimine-N-ethylcarbamide(SIN-1)对缺氧诱发离体猪冠脉机械和电反应的影响.方法:同步记录机械张力和膜电位.结果:缺氧可诱发离体猪冠脉平滑肌细胞膜去极化和收缩;SIN-1(100 μmol·L~(-1))和维拉帕米(Ver,10 μLmol·L~(-1))可使其复极化和松弛.SIN-1和Ver还可抑制左旋硝基精氨酸(NLA,0.2 mmol·L~(-1))和KCl(40mmol·L~(-1))诱发的离体猪冠脉去极化和收缩反应.结论:缺氧收缩离体猪冠脉是其抑制一氧化氮释放、增加Ca~(2 )内流的结果.     

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。     

生长抑素与GABA对大鼠海马CA1区长时程增强的影响(英文)

目的:研究生长抑素(SS)和GABA对大鼠海马长时程增强(LTP)的影响.方法:采用穿梭箱主动回避反应(AAR)法和以海马CA1区群体峰电位(PS)为LTP的指标. 结果:AAR习得达标鼠,PS增幅达100％以上;海马内注射(ih)SS(1 g L~(-1))后,PS增幅大于120％;ih SS耗竭剂半胱胺(Cys,20gL~9-1))后,PS不出现(n=8)或PS增幅不及10％(n=3);ih GABA(200g L~(-1))后,PS增幅小于30％,且有拮抗SS增强LTP的效应. 结论:SS有易化LTP的作用,而GABA则有相反的效应,二者共同参与调控海马突触传递的信息,从而影响学习和记忆.     

内质网应激信号通路在高脂诱导的心肌细胞损伤中的作用

目的探讨内质网应激信号通路在高脂诱导的心肌细胞损伤中的作用。方法棕榈酸(0.1~0.4 mmol·L~(-1))刺激心肌细胞(0~48 h),CCK-8法评估细胞生长状态,免疫印迹法评估细胞内内质网应激信号通路相关蛋白表达水平及细胞凋亡蛋白表达水平。结果棕榈酸(0.1~0.4 mmol·L~(-1))刺激H9C2心肌细胞24 h,0.2、0.4 mmol·L~(-1)组细胞增殖率均出现明显下降。棕榈酸(0.2 mmol·L~(-1))刺激H9C2心肌细胞时,24、48 h组细胞增殖率均出现明显下降。棕榈酸(0.2 mmol·L~(-1))刺激24 h,GRP78、CHOP、PERKphos、IRE1phos、ATF6等内质网应激相关蛋白及Bax蛋白表达均明显增高(P<0.05),而Bcl-2表达出现明显降低(P<0.05)。预处理内质网应激抑制剂普伐他汀(pravastatin,10mol·L~(-1))的棕榈酸(0.2 mmol·L~(-1))组与不加pravastatin的棕榈酸(0.2 mmol·L~(-1))组相比,Bcl-2及Bax的表达均恢复至正常水平。结论内质网应激信号通路对高脂引起的心肌损伤的发病及治疗均起到重要作用。     

多柔比星对大鼠离体胸主动脉和颈总动脉血管环的舒张作用及其机制

目的研究多柔比星(DOX)对大鼠离体胸主动脉和颈总动脉血管环的作用及其机制。方法采用离体血管环恒温灌流系统,通过累积加药法每10 min加入DOX依次使其终浓度递增为1,3,10,30和100μmol·L~(-1),观察其对基础状态、去氧肾上腺素(PE,1μmol·L~(-1))和氯化钾(KCl,60 mmol·L~(-1))预收缩的胸主动脉及颈总动脉血管环的作用,并采用左旋硝基精氨酸甲酯(L-NAME)、4-氨基吡啶(4-AP)、溴化四乙铵(TEA)、氯化钡(BaCl_2)、格列苯脲(Gli)、吲哚美辛(Indo)和普萘洛尔预处理探讨其对血管作用的可能机制。结果 DOX对基础状态下及KCl预收缩的胸主动脉和颈总动脉血管环张力无明显影响;DOX可浓度依赖性地舒张PE预收缩的内皮完整胸主动脉和颈总动脉环(P<0.05),且其对去内皮胸主动脉血管环也有舒张作用,但舒张程度弱于内皮完整组(P<0.05);一氧化氮合酶抑制剂L-NAME 0.1 mmol·L~(-1)、电压依赖性钾通道(K_V)抑制剂4-AP 1 mmol·L~(-1)、钙敏感性钾通道(K_(Ca))抑制剂TEA 1 mmol·L~(-1)和内向整流型钾通道(K_(IR))抑制剂BaCl_21 mmol·L~(-1)均可明显抑制DOX的舒血管作用(P<0.05),环氧化酶抑制剂Indo 0.01 mmol·L~(-1)、ATP敏感性钾通道抑制剂Gli 0.01 mmol·L~(-1)和β肾上腺素能受体阻滞剂普萘洛尔0.01 mmol·L~(-1)对DOX舒血管作用无明显影响;DOX 1,10和100μmol·L~(-1)可浓度依赖性减弱无钙液中PE诱发的血管收缩,并可使氯化钙量效曲线右移。结论 DOX对大鼠离体胸主动脉和颈总动脉血管环有浓度依赖性舒张作用,其舒血管机制可能与血管内皮细胞一氧化氮/cGMP途径、K_V、K_(Ca)、K_(IR)、血管平滑肌细胞内钙释放和外钙内流有关。     

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.

     

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.     

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.     

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.     

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.     

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.