Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice

Bifunctional drug therapy targeting distinct receptor signalling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA receptors or the potentiation of AMPA receptors is well documented to result in memory enhancement. Here, we compared the efficacy of the low-affinity NMDA receptor blocker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6 J at 1 or 5 mg/kg, ip) with new derivatives of isothiourea (0.5–1 mg/kg, ip) that have bifunctional efficacy. Low-affinity NMDA blockade by these derivatives was achieved by introducing greater flexibility into the molecule, and AMPA receptor stimulation was produced by a sulfamide-containing derivative of isothiourea. Contextual learning was examined in a step-down avoidance task and extinction of contextual memory was studied in a fear-conditioning paradigm. Memantine enhanced contextual learning while QXX facilitated memory extinction; both drugs were effective at 5 mg/kg. The new derivative IPAC-5 elevated memory scores in both tasks at the dose 0.5 mg/kg and exhibited the lowest IC₅₀ values of NMDA receptor blockade and highest potency of AMPA receptor stimulation. Thus, among the new drugs tested, IPAC-5 replicated the properties of memantine and QXX in one administration with increased potency. Our data suggest that a concomitant manipulation of NMDA- and AMPA-receptors results in pro-cognitive effects and supports the concept bifunctional drug therapy as a promising strategy to replace monofunctional therapies with greater efficacy and improved compliance.     

多靶点抗肿瘤药应用与评价

目的：多靶点抗肿瘤药临床合理应用概况。方法：收集国内外相关文献,从多靶点抗肿瘤药的作用机制、应用状况、不良反应等方面进行分析评价。结果及结论：多靶点抗肿瘤药目前已普遍应用于临床。     

Using entropy of drug and protein graphs to predict FDA drug-target network: theoretic-experimental study of MAO inhibitors and hemoglobin peptides from Fasciola hepatica

There are many drugs described with very different affinity to a large number of receptors. In this work, we selected Drug-Target pairs (DTPs/nDTPs) of drugs with high affinity/non-affinity for different targets like proteins. Quantitative Structure-Activity Relationships (QSAR) models become a very useful tool in this context to substantially reduce time and resources consuming experiments. Unfortunately, most QSAR models predict activity against only one protein. To solve this problem, we developed here a multi-target QSAR (mt-QSAR) classifier using the MARCH-INSIDE technique to calculate structural parameters of drug and target plus one Artificial Neuronal Network (ANN) to seek the model. The best ANN model found is a Multi-Layer Perceptron (MLP) with profile MLP 32:32-15-1:1. This MLP classifies correctly 623 out of 678 DTPs (Sensitivity = 91.89%) and 2995 out of 3234 nDTPs (Specificity = 92.61%), corresponding to training Accuracy = 92.48%. The validation of the model was carried out by means of external predicting series. The model classifies correctly 313 out of 338 DTPs (Sensitivity = 92.60%) and 1411 out of 1534 nDTP (Specificity = 91.98%) in validation series, corresponding to total Accuracy = 92.09% for validation series (Predictability). This model favorably compares with other LDA and ANN models developed in this work and Machine Learning classifiers published before to address the same problem in different aspects. These mt-QSARs offer also a good opportunity to construct drug-protein Complex Networks (CNs) that can be used to explore large and complex drug-protein receptors databases. Finally, we illustrated two practical uses of this model with two different experiments. In experiment 1, we report prediction, synthesis, characterization, and MAO-A and MAO-B pharmacological assay of 10 rasagiline derivatives promising for anti-Parkinson drug design. In experiment 2, we report sampling, parasite culture, SEC and 1DE sample preparation, MALDI-TOF MS and MS/MS analysis, MASCOT search, MM/MD 3D structure modeling, and QSAR prediction for different peptides of hemoglobin found in the proteome of the human parasite Fasciola hepatica; which is promising for anti-parasite drug targets discovery.     

Hemidesmus indicus induces apoptosis as well as differentiation in a human promyelocytic leukemic cell line

Ethnopharmacological relevance

The decoction of the roots of Hemidesmus indicus is widely used in the Indian traditional medicine for the treatment of blood diseases, dyspepsia, loss of taste, dyspnea, cough, poison, menorrhagia, fever, and diarrhea. Poly-herbal preparations containing Hemidesmus are often used by traditional medical practitioners for the treatment of cancer. The aim of this study was to investigate the cytodifferentiative, cytostatic and cytotoxic potential of a decoction of Hemidesmus indicus's roots (0.31–3 mg/mL) on a human promyelocytic leukemia cell line (HL-60).

Materials and methods

The decoction of Hemidesmus indicus was characterized by HPLC to quantify its main phytomarkers. Induction of apoptosis, cell-cycle analysis, levels of specific membrane differentiation markers were evaluated by flow cytometry. The analysis of cell differentiation by nitroblue tetrazolium (NBT) reducing activity, adherence to the plastic substrate, α-napthyl acetate esterase activity and morphological analysis was performed through light microscopy (LM) and transmission electron microscopy (TEM).

Results

Starting from the concentration of 0.31 mg/ml, Hemidesmus indicus induced cytotoxicity and altered cell-cycle progression, through a block in the G0/G1 phase. The decoction caused differentiation of HL-60 cells as shown by NBT reducing activity, adherence to the plastic substrate, α-naphtyl acetate esterase activity, and increasing expression of CD14 and CD15. The morphological analysis by LM and TEM clearly showed the presence of granulocytes and macrophages after Hemidesmus indicus treatment.

Conclusions

The cytodifferentiating, cytotoxic and cytostatic activities of Hemidesmus indicus offers a scientific basis for its use in traditional medicine. Its potent antileukemic activity provides a pre-clinical evidence for its traditional use in anticancer pharmacology. Further experiments are worthwhile to determine the in vivo anticancer potential of this plant decoction and its components.     

First multi-target QSAR model for predicting the cytotoxicity of acrylic acid-based dental monomers

ObjectiveAcrylic acid derivatives are frequently used as dental monomers and their cytotoxicity towards various cell lines is well documented. This study aims to probe the structural and physicochemical attributes responsible for higher toxicity of dental monomers, using quantitative structure-activity relationships (QSAR) modeling approaches.MethodsA regression-based linear single-target QSAR (st-QSAR) model was developed with a comparatively small dataset containing 39 compounds, the cytotoxicity of which has been assessed over the Hela S3 cell line. By contrast, a classification-based multi-target QSAR model was developed with 138 compounds, the cytotoxicity of which has been reported against 18 different cell lines. Both models were set up following rigorous validation protocols confirming their statistical significance and robustness.ResultsThe performance of the linear mt-QSAR model, developed with various feature selection and post-selection similarity searching-based schemes, superseded that of all non-linear models produced with six machine learning methods by hyperparameter optimization. The final derived st-QSAR and mt-QSAR linear models are shown to be highly predictive, as well as revealing the crucial structural and physicochemical factors responsible for higher cytotoxicity of the dental monomers.SignificanceThis study is the first attempt on unveiling the cytotoxicity of dental monomers over several cell lines by means of a single multi-target QSAR model. Further, such a model is ready to get widespread applicability in the screening of new monomers, judging from its almost accurate predictions over diverse experimental assay conditions.     

多指标成分含量测定与指纹图谱分析在中药制备工艺与质量控制中的应用

现有的以单一化学指标的变化情况来控制中药制备工艺的方法,难以体现制备过程中化学成分的整体变化情况,也很难保证中药药效物质基础的有效传递。采用多指标成分含量测定+色谱指纹图谱的控制模式,可以实现对制备工艺的全程把关,以及对产品质量的精确控制,有效保证中药的有效性和稳定性,并将成为中药质控的重要手段,具有较好的应用前景。     

立体定向下多靶点毁损治疗先天性精神发育迟滞症12例报告

目的 探讨立体定向下多靶点毁损治疗先天性精神发育迟滞症的临床效果。方法 在CT定位下，应用脑立体定向技术对12例先天性精神发育迟滞症病人进行颅内多靶点毁损治疗。按全国精神外科协作组织于1988年制定的评定方法、韦氏儿童智力量表（WISC）及简明精神病评定量表（BPRS）、社会功能量表（SFRS）、阳性症状量表（SAPS）进行疗效评定。结果 12例患者术后随访，精神测评结果：恢复1例，显著进步8例，进步2例，无效1例；手术对智力无影响；BPRS、SAPS和SFRS总分较术前显著减低（P=0.000）。结论 立体定向下多靶点毁损术是治疗先天性精神发育迟滞症的有效方法．有利于患儿提高生活自理和适应社会的能力．     

多靶联合治疗在进展性脑卒中治疗中的临床应用价值

目的探讨和分析进展性脑卒中多靶联合治疗的临床效果与安全性。方法选取该院自2012年11月—2013年10月收治的进展性脑卒中患者共172例,按照随机原则分成观察组和对照组,对照组给予参麦、单唾液酸四己糖神经节苷脂与低分子肝素进行治疗,观察组则在对照组的基础上另外加用药物巴曲酶注射液,然后对比该两组患者的治疗效果和不良临床事件的发生状况。结果经治疗后,观察组患者的总有效率为89.8%,明显高于对照组患者的72.9%,在治疗以后的第11天,观察组血纤维蛋白原（FIB）指标明显低于对照组患者,但是两组间的活化部分凝血酶原时间（APTT）以及凝血酶原时间（PT）指标对比,没有明显的差异,该两组患者均没有明显的并发症发生。结论对于进展性脑卒中患者,通过抗凝、降纤及抗血小板聚集等多靶联合治疗,效果明显,且不良临床事件的发生率低,值得临床推广。     

多靶点亚核团毁损治疗难治性精神分裂症1232例

目的探讨双侧多靶点亚核团毁损手术治疗难治性精神分裂症的疗效和安全性。方法采用螺旋CT定位，对1232例难治性精神分裂症患者，实施立体定向同期双侧多靶点亚核团射频热凝毁损手术。结果1232例患者术后2周随访：显著进步428例，进步722例，无效81例，无加重病例，死亡1例（术后3d死于急性肺动脉栓塞），有效率93.34％；1134例术后远期（6-54个月）随访：恢复204例，显著进步424例，进步410例，无效96例，无加重病例，有效率91.53％；术后除早期一过性并发症外，远期并发症发生率小于1％。结论多靶点亚核团毁损手术治疗难治性精神分裂症疗效显著，安全性高；对阳性、阴性症状均有效果，亚核团毁损既保留了正常的脑功能,又控制了精神症状。