博安霉素抗人肝癌的作用及其作用机制的研究

目的研究新抗肿瘤抗生素博安霉素(BAM)在体外的抗人肝癌的作用及其分子机制.方法采用细胞克隆形成法和NAG酶反应测定BAM抗肝癌作用,利用[3H]标记物参入法测定BAM对肝癌细胞大分子合成的作用,利用斑点杂交检测BAM对肝癌细胞相关癌基因和抗癌基因表达的影响,利用中性凝胶电泳分析DNA损伤后的修复情况.结果BAM作用于BEL-7402细胞克隆形成的最小IC50为8.6×10-9mol·L-1;对BEL-7402细胞的杀伤的IC50为6.2×10-6mol·L-1,表现出很强的抗肿瘤作用和良好的剂量-效应关系.对BEL-7402细胞的DNA,RNA和蛋白质合成均有强抑制作用,以抑制DNA和Pro合成的作用较强.在0.1～10μmol·L-1浓度时,BAM明显抑制人肝癌细胞的c-myc,N-ras和p53基因的表达.BAM造成的人肝癌细胞DNA的损伤难以修复.结论BAM是对人肝癌有效的抗肿瘤抗生素,其作用的分子机制与培洛霉素(PEP)相似.     

浅析平阳霉素的不良反应

平阳霉素(Pingyangmycin,PYM)是从我国浙江省平阳县土壤中的放线菌培养液中分离得到的抗肿瘤抗生素[1],作用机制是能够抑制癌细胞DNA的合成和切断DNA链,影响癌细胞代谢功能,促进癌细胞变性和坏死.     

趋化肽fMLP与博安霉素偶联物制备及其体内抗肿瘤活性的初步评价

目的：建立fMLP与博安霉素（BAM）的偶联物制备方法,初步评价其抗肿瘤活性。方法：以偶联剂EDC和NHS-S03将fMLP与BAM进行偶联,以MALDI—TOF质谱检测其偶联效果,以SephadexG15分离纯化偶联物;以TTC法观察偶联物的抗菌作用,采用小鼠肝癌H22移植瘤模型来观察其抗肿瘤作用。结果：通过SephadexG15分离纯化,收集第1峰前半部分获得了较纯的偶联物;偶联物fMLP—BAM的抗菌活性是BAM的17．0％,偶联物BAM—fMLP5mg·kg^-1组抑瘤率为52．3％,BAM5mg·k^-1组抑瘤率为67．6％（P〉0．05）。结论：根据本文提供的方法可以制备fMLP与BAM的偶联物,但该偶联物体内抗肿瘤活性与博安霉素相比略有下降。     

争光霉素A_6对小鼠腹水肝癌细胞核酸蛋白质合成的影响

争光霉素是一种抗肿瘤抗生素。争光霉素A_6能抑制小鼠腹水肝癌细胞(H_(22))的DNA、RNA和蛋白质的生物合成。对DNA合成的影响比对RNA及蛋白质合成的影响显著得多。实验结果表明,~3H-TdR,~3H-UR及~3H-Leu的掺入抑制率,在一定范围之内随药物浓度的增加而上升。然而此药对正常小鼠骨髓细胞生物大分子的合成则概不抑制。争光霉素A_6对肿瘤细胞的选择性作用,无疑地会提高其在临床使用上的价值。     

盐酸博安霉素注射用原位凝胶的体内分布研究

考察盐酸博安霉素(BAM)注射用原位凝胶在裸鼠体内的扩散情况以评价原位凝胶对盐酸博安霉素的阻滞作用。以荧光染料异硫氰酸荧光素(FITC)标记盐酸博安霉素,制备异硫氰酸荧光素-盐酸博安霉素偶联物(FITC-BAM),采用透析袋透析和Sephadex G25葡聚糖凝胶柱对偶联物进行分离纯化,利用基质辅助激光解析电离/飞行时间(MALDI-TOF)质谱检测偶联效果。建立裸鼠皮下肝癌移植瘤模型,应用动物体内活体光学成像系统定时检测盐酸博安霉素在裸鼠体内的特异性分布情况。MALDI-TOF质谱检测结果显示,FITC成功与BAM发生偶联,且二者偶联的分子比主要为1∶1或2∶1。活体动物成像系统观察显示,盐酸博安霉素注射用原位凝胶组FITC-BAM的扩散较普通注射液组明显延迟。研究表明,将盐酸博安霉素制备成注射用原位凝胶制剂,能够阻滞药物在体内的释放,延长作用时间。     

在肿瘤临床前研究中的新的微生物次级代谢产物

近十五年来,抗肿瘤化合物细胞毒作用机制的研究已有很大进展。这些研究表明抗肿瘤化合物与 DNA 结合或作用,抑制 DNA 或 RNA 合成,抑制蛋白质合成,干扰膜功能或与微管相互作用。另外对人体肿瘤有疗效的一些抗肿瘤抗生素的细胞毒和治疗作用机制也已作了研究。即使对良性和恶性细胞都有抑制作用的这些抗肿瘤化合物很可能对人体某种肿瘤有疗效。     

粉防已甲素、乙素对L7712和S180细胞DNA、RNA和蛋白质合成的抑制作用

粉防已甲素和乙素对L7712和S180癌细胞DNA合成的ID_(50)分别为2.6,3.5和27.5,24.5mg/L;它们对L7712细胞DNA合成的抑制是由DNA复制模板受到损伤而引起的。它们对两种癌细胞DNA和RNA的合成有很强的抑制作用,对蛋白质合成的抑制作用较弱。两种药物对癌细胞抑制程度和作用方式相似。     

博安霉素临床前毒理研究

博安霉素(Boanmycin,BAM)是博来霉素复合物中的A_6组份,与平阳霉素的区别在于侧链为精胺。BAM对各种实验性肿瘤有良好的抗肿瘤作用,对小鼠食管癌、艾氏腹水癌、肉瘤180和人体肝癌均有较强抗瘤效果。本文报道了BAM的急性亚急性毒性和特殊毒性。 一、急性毒性试验: 选用外观健康18～20克小白鼠若干,随机分组,每组10只,雌雄各半。将配制好的BAM(天津河北制药厂产品,本所新抗三室     

沙利度胺调控PD-L1抑制HT-29结肠癌细胞的作用及机制研究

目的：探讨沙利度胺对HT-29结肠癌细胞的抑制作用及其机制。方法：CCK-8检测沙利度胺对HT-29结肠癌细胞增殖的作用;流式细胞术检测沙利度胺对HT-29结肠癌细胞凋亡的作用和对HT-29结肠癌细胞PD-L1表达的作用;Western Blot检测沙利度胺对HT-29结肠癌细胞c-Myc、STAT3、HIF-1蛋白表达的影响。结果：沙利度胺各浓度（40、80、160、320 μmol·L-1）明显抑制HT-29结肠癌细胞的增殖;沙利度胺各浓度（20、40、80 μmol·L-1）明显促进HT-29结肠癌细胞的凋亡,明显减少HT-29结肠癌细胞表面PD-L1的表达,明显减少HT-29结肠癌细胞c-Myc、STAT3、HIF-1蛋白的表达。结论：沙利度胺对HT-29结肠癌细胞具有抑制作用,其机制可能与减少PD-L1表达及抑制癌细胞上游c-Myc、STAT3、HIF-1信号分子表达有关。     

沙利度胺调控PD-L1抑制HT-29结肠癌细胞的作用及机制研究

目的：探讨沙利度胺对HT-29结肠癌细胞的抑制作用及其机制。方法：CCK-8检测沙利度胺对HT-29结肠癌细胞增殖的作用;流式细胞术检测沙利度胺对HT-29结肠癌细胞凋亡的作用和对HT-29结肠癌细胞PD-L1表达的作用;Western Blot检测沙利度胺对HT-29结肠癌细胞c-Myc、STAT3、HIF-1蛋白表达的影响。结果：沙利度胺各浓度（40、80、160、320 μmol·L-1）明显抑制HT-29结肠癌细胞的增殖;沙利度胺各浓度（20、40、80 μmol·L-1）明显促进HT-29结肠癌细胞的凋亡,明显减少HT-29结肠癌细胞表面PD-L1的表达,明显减少HT-29结肠癌细胞c-Myc、STAT3、HIF-1蛋白的表达。结论：沙利度胺对HT-29结肠癌细胞具有抑制作用,其机制可能与减少PD-L1表达及抑制癌细胞上游c-Myc、STAT3、HIF-1信号分子表达有关。     

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.     

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.