重症急性胰腺炎大鼠肺损伤的病理生理变化及机制研究

目的观察重症急性胰腺炎大鼠肺损伤的病理生理变化并探讨其发生机制。方法选取2008年1月至2009年1月健康雄性SD(Sprague-Dawley)大鼠240只,按照随机数字表随机均分为8组,每组30只,即重症急性胰腺炎(SAP)不同时间点组(SAP 1 h、3 h、6 h、9 h、12 h、18 h、24 h组)和对照组。比较各组血清淀粉酶、肺组织湿/干重比、肺髓过氧化物酶(myeloperoxidase,MPO)活性、肺通透性指数的变化。结果观察组大鼠肺损伤组织评分、肺组织湿干重比以及肺髓过氧化物酶(MPO)水平随着时间的延续逐渐升高,各时间点组均明显高于对照组(P<0.05),观察组肺通透性指数随时间延续呈逐渐降低趋势,均低于对照组,差异均有统计学意义(P<0.05)。肺组织MPO水平与肺损伤评分存在正相关(r=0.946,P<0.01),肺湿干重比与肺损伤评分呈正相关(r=0.879,P<0.01),肺通透性指数与肺损伤评分存在负相关(r=-0.859,P<0.01)。结论重症急性胰腺炎大鼠肺损伤的损伤程度随SAP病程延长而逐渐增加,肺组织MPO水平持续升高。     

急性坏死性胰腺炎肺损伤时RegⅠ基因表达

目的 研究RegⅠ在急性坏死性胰腺炎(ANP)大鼠肺组织中的表达及其与ANP肺损伤的关系.方法 健康成年SD大鼠随机分为假手术对照(C)组(30只)和ANP组(60只). C组开腹后只翻动胰腺,ANP组大鼠胰胆管恒速逆行注射3%牛磺胆酸钠,制成ANP大鼠模型.观察胰腺和肺组织的病理改变及肺组织湿/干重比的改变,应用RT- PCR检测胰腺、肺组织中RegⅠ mRNA的表达水平,并研究所观察指标与RegⅠ基因表达的相关性.结果 与C组相比,ANP组肺组织中RegⅠ的mRNA水平过度表达.RegⅠ的表达水平分别与肺组织的病理学评分(r=0.5212,P＜0.01)和肺组织湿/干重比(r=0.4797,P＜0.01)呈正相关.结论 ANP时大鼠肺组织中RegⅠmRNA的表达水平明显上调;RegⅠ mRNA的表达与ANP所致的急性肺损伤的严重程度相关.     

p38 MAPK抑制剂对重症胰腺炎大鼠急性肺损伤的保护作用

目的探究p38MAPK抑制剂对重症胰腺炎大鼠急性肺损伤的保护作用。方法采用随机数字表法将60只大鼠分为三组,A组为假手术组,B组为重症胰腺炎模型组,C组为重症胰腺炎模型加p38MAPK抑制剂组;检测三组大鼠的肺组织病理学切片、肺组织湿干重比、髓过氧化物酶活性以及p38MAPK mRNA的表达水平。结果 B组大鼠与A组大鼠相比,其肺组织损伤病理评分、肺组织湿干重比、肺组织髓过氧化物酶(MPO)活性以及肺组织p38MAPK mRNA的表达水平均显著升高,而C组大鼠与B组大鼠相比上述指标均有所下降,P<0.05。结论 p38MAPK抑制剂能减少TNF-α的释放,降低炎症反应,为临床上治疗重症急性胰腺炎并发急性肺损伤的提供新的方向。     

罗格列酮对重症急性胰腺炎合并肺损伤的防治作用

目的 研究抵抗素在过氧化物酶增殖物激活受体(PPAR-γ)激动剂(罗格列酮)对大鼠重症急性胰腺炎(SAP)及其合并肺损伤防治中的作用及其作用机制.方法 用ELISA法检测大鼠血清淀粉酶(AMY)、抵抗素、肿瘤坏死因子(TNF-α)、白细胞介素-1β(IL-1β)和C.反应蛋白(CRP)的水平变化,检测肺组织髓过氧化物酶(MPO)、肺湿/干重比值、胰腺/体质量比值、胰腺和肺组织病理变化;免疫组化检测胰腺组织中抵抗素的表达;实时定量PCR法检测胰腺组织中抵抗素mRNA的水平.结果 罗格列酮预防组和治疗组大鼠血清AMY、抵抗素、TNF-α、IL-1B和CRP水平较SAP组均明显下降(均P＜0.01),预防组和治疗组与对照组相比均有明显升高(均P＜0.01),预防组和治疗组之间相比较有所变化,但两者之间无统计学意义;罗格列酮预防和治疗组胰腺/体质量比、胰腺病理评分、肺组织MPO含量和肺的病理评分较SAP组均明显降低(均P＜0.01);对照组、SAP组、预防组和治疗组大鼠的胰腺组织抵抗素mRNA相对表达量(RQ值)较SAP组明显降低(均P＜0.01),而与对照组相比较均明显升高(P＜0.01),但预防组与治疗组之间差异无统计学意义.结论 罗格列酮对SAP及合并肺损伤有明显的预防和治疗作用.     

急性胰腺炎相关性肺损伤模型的建立

目的采用5%牛磺胆酸钠逆行胰胆管注射建立急性出血坏死性胰腺炎(AHNP)大鼠模型,动态观察肺组织损伤情况,以评价能否建立有效的急性胰腺炎相关性肺损伤(APALI)动物实验模型。方法SD大鼠随机分成假手术对照组和AHNP模型组,动态观察3,6,12和24h四个时相点的血清淀粉酶、胰腺和肺病理组织学改变、肺组织湿干重比和髓过氧化物酶活性,伊文氏蓝法观察1.5,3和6h三个时相点肺血管通透性。结果血清淀粉酶、肺组织湿干重比和髓过氧化物酶活性在5%牛磺胆酸钠诱导后3h明显增高,并持续到24h,肺组织病理检查发现,牛磺胆酸钠诱导后肺组织就出现了明显的充血、出血、炎症细胞浸润、组织结构破坏等肺组织损伤的病理表现,AHNP大鼠1.5h肺血管通透性就显著增高,且随时间呈显著性增加,各指标与假手术组比较差异有显著性(P<0.05)。结论应用5%牛磺胆酸钠能够成功建立APALI大鼠模型,为进一步研究对APALI的防治作用奠定了基础。     

丁酸钠对重症急性胰腺炎大鼠肺损伤的保护作用

目的探讨丁酸钠对大鼠重症急性胰腺炎（SAP）合并肺损伤的治疗作用。方法牛磺胆酸钠逆行胰胆管注射制作SAP动物模型,30只SD大鼠分成对照组、SAP组及丁酸钠（NaB）治疗组,检测胰腺湿/干重比值、胰腺及肺脏病理改变、肺脏细胞凋亡情况。结果 NaB治疗组肺组织湿/干重比值下降;NaB治疗组胰腺及肺组织病理改变明显减轻。NaB治疗组肺组织细胞凋亡指数显著高于SAP组。结论 NaB可以有效诱导SAP大鼠肺组织细胞发生凋亡,减轻肺损伤。     

Protective effect of raffinose-low potassium dextran solution on isolated lung in rats

目的 探讨棉籽糖低钾右旋糖酐(R-LPD)液对大鼠离体供肺保存期间不同时间段的保护作用.方法 健康SD大鼠48只,随机分为低钾右旋糖酐(LPD)液(A组)和R-LPD液(B组).建立大鼠离体肺冷保存模型,观察两组肺冷保存4、8、12、24 h四个时间段的效果,检测肺组织湿干重比(W/D)、丙二醛(MDA)含量、髓过氧化物酶(MPO)活性、超氧化物歧化酶(SOD)活性,HE染色观察肺组织病理形态变化.结果 A组肺冷保存24 h,W/D、MDA含量、MPO活性、SOD活性均明显高于冷保存12 h(P＜0.01);B组肺冷保存24 h,MDA含量、MPO活性、SOD活性均明显高于冷保存12 h(P＜0.01).肺冷保存至12h,B组SOD活性高于A组(P＜0.05).肺冷保存至24h,B组W/D、MDA含量、MPO活性明显低于A组(P＜0.05或P＜0.01);而B组SOD活性明显高于A组(P＜0.01).HE染色可见A组肺冷保存至24h肺泡结构破坏,间质水肿明显,呈现严重不可逆性损伤;而B组肺组织结构清晰,仅轻度炎症反应.结论 大鼠离体肺冷保存至24 h,R-LPD液肺保护效果明显优于LPD液.     

N-乙酰半胱氨酸联合维生素E对大鼠急性出血坏死性胰腺炎NF-κB的作用研究

目的 研究抗氧化剂N-乙酰半胱氨酸(NAC)联合维生素E(VitE)对大鼠急性胰腺炎动物模型胰腺组织NF-κB的作用,探讨两药的联合使用对急性胰腺炎的影响.方法 40只SD大鼠随机分为假手术(SO)组、出血坏死性胰腺炎(AHNP)组、NAC治疗组、NAC+ VitE治疗组,4组各10只.造模后12h取材,同时观察大鼠胰腺病理评分、血清淀粉酶(AMY)、丙二醛(MDA)、胰腺组织髓过氧化物酶(MPO)及胰腺组织中核因子-κB(NF-κB)的表达.结果 AHNP组胰腺病理评分、AMY、丙二醛、MPO及胰腺组织NF-κB的表达明显高于其他组(P＜0.01),NAC治疗组上述指标均低于AHNP组(P＜0.01),但仍高于SO组(P＜0.01),NAC+ VitE治疗组上述指标均低于AHNP组(P＜0.01)及NAC治疗组(P＜0.01),高于SO组(P＜0.01).结论 在AHNP时应用NAC+ VitE能明显减轻胰腺组织病理损伤,降低胰腺炎时血清AMY、丙二醛的浓度和胰腺组织MPO的活性,抑制胰腺组织中核因子-κB(NF-κB)的表达.     

趋化因子fractalkine在急性坏死性胰腺炎模型大鼠的表达

目的了解趋化因子fractalkine(FKN)在急性坏死性胰腺炎(ANP)发病机制中的作用。方法用4%牛磺胆酸钠逆行胆胰管注射,建立24只SD大鼠ANP模型(A组),用ELISA法测定大鼠不同时间点血清FKN蛋白;实时荧光定量PCR检测胰腺和肺组织FKN mRNA的表达;观察胰腺和肺组织的病理变化。结果与24只健康大鼠对照(C组)。结果与C组比较,A组3、6和12 h后血清FKN水平、肺和胰腺组织FKN mRNA表达均明显高于C组(P<0.05或P<0.01)。A组胰腺病理检查显示典型ANP改变。结论 FKN可能在ANP发病过程及与ANP相关的急性肺损伤中起了重要的作用。     

DATS对LPS诱导ALI小鼠抗氧化功能及ICAM-1表达的影响

目的探讨二烯丙基三硫(DATS)对脂多糖(LPS)诱导急性肺损伤(ALI)小鼠抗氧化功能及细胞间黏附分子-1(ICAM-1)的影响。方法腹腔注射LPS复制小鼠ALI模型,实验动物随机分为生理盐水对照组、ALI组、DATS预防组、DATS治疗组。测定肺系数、肺组织湿/干重量比值(W/D),以及肺组织丙二醛(MDA)含量、髓过氧化物酶(MPO)活性、超氧化物歧化酶(SOD)活性、总抗氧化能力(T-AOC)活性及ICAM-1的表达。结果 ALI组肺系数、肺组织W/D明显升高,肺组织MDA含量增加,MPO活性升高、SOD活性及T-AOC活性降低,ICAM-1表达增加;预防性应用DATS可减轻肺水肿,减少MDA生成,降低MPO活性、增加SOD活性及T-AOC活性,并使ICAM-1表达减少。DATS治疗组与ALI组相比,各指标均无明显变化。结论预防性应用DATS对LPS诱导的ALI小鼠可发挥抗氧化作用,减轻肺损伤程度。     

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.     

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.