深海真菌Aspergillus sp. 20220129的次级代谢产物及抑菌活性研究

摘要：目的 研究西太平洋海域深海沉积物来源真菌Aspergillus sp. 20220129的次级代谢产物及抗菌活性。方法 采用 柱层析及高效液相色谱等方法对菌株Aspergillus sp. 20220129的大米发酵产物进行分离纯化。通过质谱和核磁共振等方法确定 化合物的结构。采用微量梯度稀释法对化合物开展抑菌活性评价。结果 共分离到9个化合物,分别为terretonin(1)、terretonin A(2)、methyl dichloroasterrate(3)、methyl asterrate(4)、methyl 6-acetyl-5,7,8-trihydroxy-4-methoxy-2-naphthalenecarboxylate(5)、 territrem B(6)、alantrypinone(7)、butyrolactone I(8)和versicolactone B(9)。化合物5、8和9对金黄色葡萄球菌(Staphylococcus aureus)具有一定的抑菌效果,化合物5和8的最低抑菌浓度为100 μg/mL,化合物9为50 μg/mL。     

稠环磺酰胺衍生物的合成与抗菌活性研究

为了寻找抗菌候选化合物,在前期研究基础上,18个稠环磺酰胺衍生物被设计合成,经1H NMR、13C NMR和MS确认结构。采用两倍稀释法对目标物进行体外抗菌活性测试,结果表明:该类衍生物对所测细菌有不同程度的抑制活性,尤以化合物Ⅱi、Ⅱr的抗菌活性最为突出,其中前者对金葡菌(S.aureus)、大肠埃希菌(E.coli)和耐甲氧西林金葡菌(MRSA)的最小抑菌浓度(MIC)分别为8、32和16μg·mL^-1,后者对S.aureus、E.coli及MRSA的MIC分别为8、64和32μg·mL^-1,两者的抗MRSA活性较显著,值得进一步结构优化和深入研究。     

木犀草素缩磺胺甲恶唑席夫碱及金属配合物的研究

目的:寻找新型席夫碱和新的抑菌药物。方法:以木犀草素和磺胺甲恶唑进行缩合反应制成新的黄酮席夫碱化合物;并以此为配体合成了新的金属配合物。进行了初步的抗菌活性实验。结果:经元素分析、红外光谱、紫外光谱确证其结构组成。结论:结果表明,新化合物对多种菌株有明显的抑菌活性且优于各自的母体。     

氧氟沙星葡萄糖注射液的抗菌作用

通过对氧氟沙星葡萄糖注射液体内外抗菌作用的研究,认为氧氟沙星葡萄糖注射液是一种抗菌谱广,抗菌活性强的抗菌药,它对革兰氏阳性菌的最小抑菌浓度范围为 0.8～0.3βg/ml,与氧氟沙星原料相比没有降低其药效。氧沙星葡萄糖注射液对革兰氏阳性菌的抗菌作用强于诺氟沙星注射液的4倍左右,对小鼠感染金黄色葡萄球菌(S.aureus)和肺炎杆菌(K.Pncumoniae)强3～6倍。     

海鞘来源放线菌Streptomyces pratensis SCSIO LCY05中Anthracimycin类化合物及其抗菌活性研究

目的 研究来源于海鞘的放线菌Streptomyces pratensis SCSIO LCY05产生的抑菌活性物质。 方法 采用硅胶柱色谱、中压制备色谱、半制备HPLC等方法对其发酵产物分离纯化,经HR-ESI-MS、NMR以及X-ray单晶衍射等方法确定化合物的结构;采用微量二倍稀释法对化合物进行抗菌活性评价。 结果 从发酵产物中分离鉴定了3个化合物：anthracimycin C(1)、anthracimycin(2)和anthracimycin B(3),结构得到X-ray单晶衍射的确证,其中化合物1为新化合物。经抗菌活性测定,化合物2和3对6株革兰氏阳性菌具有显著的抑制活性,最小抑菌浓度(MIC)值在0.0675-0.25 μg/mL之间,并首次发现化合物2和3对藤黄微球菌和模仿葡萄球菌生长抑制活性良好。 结论 海洋共附生微生物是天然活性物质的重要来源,从海鞘来源的S. pratensis SCSIO LCY05中分离获得具有抗菌活性的anthracimycin类化合物可作为良好的抗菌药物先导化合物。     

新型红霉素类大环内酯衍生物的合成及抗菌活性研究

目的 对大环内酯类抗生素进行结构改造，拟筛选获得抗菌活性更高的候选药物；方法 分别对氟红霉素和克拉霉素的C-3及C-11，C-12进行结构修饰，设计合成了17个大环内酯类衍生物，采用微量稀释法测定了衍生物的最低抑菌浓度(MIC)。结果 12d、12e和12f对B. subtilis 168和 S. aureus USA 300表现出了较好的抗菌活性；结论 通过结构改造获得了抗菌活性增强的大环内酯类衍生物，进一步探讨了大环内酯类抗生素的构效关系，为后续研究提供了参考。     

一株海兔来源真菌 Aspergillus terreus丁内酯类化合物及其生物活性研究

摘要：目的 在生物活性和化学方法指导下,从1株海兔来源真菌 Aspergillus terreus (RA29-5)中分离鉴定海洋天然产物,并对其进行生物活性评价。方法 运用硅胶柱层析、Sephadex LH-20凝胶柱层析和HPLC等方法分离纯化化合物,利用NMR等现代波谱分析方法,对化合物进行结构鉴定,并对化合物进行抗菌、卤虫致死和斑马鱼胚胎毒性活性评价。结果 鉴定了 9 个丁内酯类化合物 (1～9) 的结构;抗菌活性表明,除化合物 6 和 9 外,所有化合物对四株致病细菌白色葡萄球菌 Staphylococcus epidermidis、金黄色葡萄球菌 Staphylococcus aureus、蜡状芽孢杆菌 Bacillus subtilis 和四联球菌 Tetragenococcus halophilus 都显示一定的抗菌活性;化合物 1～4 和7均对真菌芒果叶枯菌 Pestalotia mangiferae 显示抗菌活性;特别的,化合物 7 对测试的13株致病菌都具有广谱地抗菌活性,其MIC值在1.11~8.88 μmol/L之间;此外,还对化合物的抗菌活性构效关系进行了初步探讨。结论 海兔来源真菌 A. terreus (RA29-5) 可产生结构多样的丁内酯类化合物,该类化合物具有开发成抗菌剂的潜力。     

鲍曼不动杆菌对米诺环素等抗菌药物的耐药性研究

目的 初步探讨米诺环素等16种临床常用抗菌药物对鲍曼不动杆菌的体外抗菌活性,为临床合理用药提供实验依据.方法 四川大学华西医院抗感染药物研究室分离自临床感染患者的115株非重复多重耐药鲍曼不动杆菌菌株,采用琼脂二倍稀释法进行16种临床常用抗菌药物体外抗菌活性测定.结果 米诺环素和多黏菌素B对鲍曼不动杆菌有很好的抗菌活性,MIC50分别为4μg/mL与0.25μg/mL,MIC90分别为16μg/mL与4μg/mL,亚胺培南等碳青霉烯类抗生素对多重耐药的鲍曼不动杆菌也有较强的抗菌活性,MIC50为2μg/mL,MIC90为32μg/mL.结论 米诺环素、多黏菌素B、亚胺培南对临床分离鲍曼不动杆菌具有良好的抗菌活性,可作为治疗选择药物.     

国产替考拉宁体内外抗菌作用研究

目的：为了评价国产替考拉宁对510株临分离菌的体外抗菌活性，并与进口产品替考拉宁及万古霉素进行比较，方法：采用琼脂二倍稀释法和试管二倍稀释法测定药物的最低抑菌浓度（MIC）及最低杀菌浓度（MBC）。结果：国产替考拉宁的抗菌活性与万古霉素相似或略强，其对MRSDA和MSSA的MIC50分别为4、1mg/L，对MRSE和MSSE的MIC50分别为1、0.5mg/L。对所试大多数菌株MIC50为0．06－4mg/L，与进口的替考拉宁的抗菌活性无显著差异，替考拉宁在2－4MIC浓度时呈杀菌作用，替考拉宁的MIC值随接种菌量增加升高2－8倍，受PH和血清浓度影响不大，体内保护试验表明，替考拉宁静脉和皮下给药对金葡球菌981925、肺炎链球菌98135和肠球菌9804所致小鼠全身感染的ED50分别为0．59、0．38、0．17mg/kg（静脉注射）和1．08、0．87、0．36mg/kg（皮下注射）。其体内抗菌作用比万古霉素中6－12倍以上。     

新的碳青霉烯类抗生素BO—2727的抗菌特性

BO-2727是一种新的可注射的碳青霉烯类抗生素,其抗菌谱广、抗菌活性强.就BO-2727的体内外抗菌活性与美罗培南、亚胺培甫和比阿培南进行比较,BO-2727对甲氧西林耐药性金葡球菌的活性为后3种药物的4～8倍;当浓度为12.5mg/L时,可抑制90%以上的临床分离菌,对铜绿假单胞菌的活性亦强,对亚胺培南耐药菌的活性是亚胺培南的2～4倍.与美罗培南和亚胺培南相似,BO-2727对金葡球菌、大肠杆菌和铜绿假单胞菌的活性表现出剂量依赖性.BO-2727可诱导大肠杆菌呈球形,使铜绿假单胞菌出现膨胀.BO-2727对大肠杆菌PBP2的亲和力约为亚胺培南的2倍,对铜绿假单胞菌PBP2和PBP3也有强亲和力.BO-2727与亚胺培南和比阿培南相似,对革兰阳性和阴性菌全身性感染有预防作用.     

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.

---

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.     

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.