人多能干细胞在药物发育毒性评价中的研究进展

发育毒性是毒理学研究中最具挑战性的领域之一,传统的发育毒性评价方法均存在实验成本高、周期长、技术复杂等弊端.人多能干细胞(hPSC)包括人胚胎干细胞(hESC)和诱导多能干细胞(iPSC),具有分化多能性和无限增殖的潜力.近年来hPSC在发育毒性评价方面的研究逐渐增多,主要从hPSCs培养中代谢小分子的变化、hPSCs...     

以细胞融合为基础的重组体细胞分化为诱导性多能干细胞的研究进展

多能细胞是起源于哺乳动物的内部细胞团,它可以通过一定顺序的分化过程最终产生类似于成人某一种组织。尽管经过数十年的研究,决定细胞分化方向的的机制一直没有揭开。包括核转移、提供多个转录因子的"鸡尾酒方案"以及细胞融合等多种实验方法已经验证了重组体细胞可以分化为诱导性多能干细胞。在此笔者综述了以细胞融合为基础的重组体细胞并使之具有多能性的特点。     

诱导性多能干细胞体外诱导的现状和展望

鉴于人的胚胎干细胞在再生医学、组织工程学和药物研发等领域有极高的应用价值,科学家尝试通过各种途径获得胚胎干细胞样的多能干细胞。其中Yamanaka等率先在体外通过病毒载体诱导的方式实现体细胞重新编程,由此得到诱导性多能干细胞。多种无遗传修饰的诱导方式正在尝试和改进中,例如用小分子化合物来代替外源基因进行重编程引起了很大的兴趣。用基于细胞水平的表型筛选法和信号通路筛选法,已筛选出特异小分子或天然产物,也可以特异地将成熟细胞去分化为干细胞,有望运用于组织修复和再生。而利用重组蛋白在体外将体细胞诱导为干细胞,也获得了初步成功。由诱导性多能干细胞在体外诱导分化出的细胞在治疗相应疾病方面展示出一定疗效。不同类型的干细胞向体细胞的定向分化策略都是基于目前对发育生物学的认识,这些研究揭示了一些共同的可能线索。     

新技术可量产心脏“创可贴”

<正>日本研究人员最新发明了一种利用人类诱导多能干细胞大批量培养心肌细胞的技术。这种人工诱导的心肌细胞可以像"创可贴"一样,帮助修复受损心脏,未来有望用于心脏疾病治疗。诱导多能干细胞是通过对成熟体细胞"重新编程"培育出的干细胞,拥有与胚胎干细胞相似的分化潜力。日本庆应大学日前宣布,该校研究人员改进实验方法,把长     

多能干细胞移植的临床应用及中药的调节效应

多能干细胞具有多向分化潜能和自我更新的特征.多能干细胞移植已经成为治疗肿瘤、心力衰竭和帕金森病等多种疾病的重要手段.许多中药具有双向免疫调节作用,它们通过调节骨髓造血机能和增加可移植的干细胞体外扩增效应,从而提高干细胞移植的成功率,增加多能干细胞移植的治疗效应.     

人诱导多能干细胞重编程过程长链非编码RNA的差异表达研究

目的 探讨人诱导多能细胞重编程过程中长链非编码RNA的表达改变及其作用。方法 利用Agilent Human lncRNA (4*180K)芯片检测人体细胞、诱导多能干细胞以及胚胎干细胞中的lncRNA表达情况。通过数据分析比较人体细胞诱导为多能干细胞后lncRNA的差异表达,筛选出在重编程过程中可能发挥作用的lncRNA。结果 人诱导多能干细胞lncRNA表达谱类似于胚胎干细胞而与体细胞不同。通过聚类分析发现干细胞与体细胞之间有3 156个差异表达lncRNA。通过生物学分析发现人体细胞诱导为多能干细胞重编程过程中有222个差异表达的lncRNA。结论 lncRNA在人多能干细胞重编程过程中可能发挥着重要的作用。     

维生素C可提高iPS细胞诱导效率

诱导多能性干细胞（induced pluripotent stem cells，iPS cells）是具有胚胎干细胞特性的一种细胞。由体细胞诱导而来，可作为胚胎干细胞最好的替代品用于科学研究和临床治疗。但iPS细胞的成功诱导比较复杂．诱导效率一直是科学界的难题，通常每万个细胞才能诱导成功一例iPS细胞。     

天门冬对神经干细胞的作用研究

神经干细胞（neural stem cell,NSC）是来源于中枢神经系统的多能干细胞,终身具有自我更新能力,并能分化成神经系统的各类细胞。对神经干细胞的深入研究使人们对神经系统发育、再生和修复有了全新的认识．也给神经系统疾病的治疗带来了希望。分化是神经干细胞研究的重要方面。     

全能干细胞的研究现状与前景

干细胞是具有全能或多能分化潜能（胚胎干细胞ES，EG）和广泛存在于成体器官组织中保留不分化和维持身体自我更新能力（组织干细胞）的特种细胞。由于这种细胞的高度可塑性和在组织修复、疾病的细胞治疗以及生殖遗传工程等方面的潜在应用价值，近年来成为生命科学研究领域中最热点的课题之一。     

组蛋白去乙酰化酶参与调控神经干细胞分化的研究进展

神经干细胞是一种多能干细胞,具有自我更新及多向分化潜能,在一定条件下能分化为神经元、星形胶质细胞、少突胶质细胞。神经干细胞的分化不仅由细胞周围微环境决定,且受基因调控。神经干细胞的分化复杂,其中组蛋白去乙酰化酶[1]结合细胞内转录因子和信号通路可调节神经干细胞的分化,主要影响神经干细胞分化过程中的转录,从而影响细胞的发育。     

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.