Analysis of traditional Chinese medicine prescriptions based on support vector machine and analytic hierarchy process / 中国中药杂志

Combined use of drugs is a hot spot in the research of new drugs nowadays, and traditional Chinese medicine (TCM) is a classic practice in the combined use of drugs. In this paper, the compatibility of TCM prescriptions and the related properties of composed herbs were calculated and studied to verify and discuss the feasibility of the results in guiding compatibility. Research Group on New Drug Design, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences had established a structured database of TCM prescriptions by using traditional Chinese medicine inheritance support system (TCMISS V2.0), including 4 012 prescription compatibilities, 2 072 drug components, 381 kinds of TCM diseases, 316 kinds of TCM syndromes and 26 kinds of drug properties. On the basis of the created database above, Support Vector Machine (SVM) was used to analyze the prescription compatibility data and establish a model for predicting feasibility of drug compatibilities. Analytic Hierarchy Process (AHP) and cluster analysis were used to study the influence of drug properties in the rationality of prescription compatibility. The computational results showed that the accuracy in efficacy prediction of two data sets, i.e. prescription-disease and prescription-syndrome, was up to 90% in the linear SVM model. The macro₋averaging and micro₋averaging of the two models were around 0.92, 0.46, respectively. After AHP mapping, most of the incompatible combinations showed significant difference with other drug combinations during the clustering process in the vertical icicle, indicating that the proper machine learning algorithm can be used to lay the foundation for further exploring the combination rules in TCM and establishing more detailed drug-disease and syndrome predicting models, and provide theoretical guidance for the study of the combined use of drugs to a certain degree.

Advances on anti-neoplastic STAT3 inhibitors / 药学学报

Signal transducer and activator of transcription 3 (STAT3) is a kind of signal transduction protein involved in cell proliferation, differentiation, apoptosis and other important physiological processes in response to a large number of cytokines and growth factors in cells. It has been shown that constitutive activation of STAT3 is closely associated with oncogenesis and tumorigenesis. Inhibition of aberrant STAT3 signaling has been one of promising strategies for the development of anti-neoplastic therapeutics. The review summarizes the latest progress of STAT3 inhibitors in recent years from the perspective of targeting N-terminal domain, DNA binding domain, SH2 domain and C-terminal transactivation domain of STAT3.

Identification of novel selective TRPV3 antagonists based on virtual screening, molecular docking and bioassay / 药学学报

Transient receptor potential vanilloid member 3 (TRPV3) is a temperature-sensitive cation channel protein, which contributes to nociception, itch, hair growth, emotional control and the pathophysiology of migraine. However, research progress on TRPV3 fundamental molecular biology is rather slow, compared to other TRP channels due to the lack of its selective antagonists. It's necessary to identify TRPV3 selective antagonists for the study on TRPV3 physiological functions. In this study, several selective TRPV3 antagonists were identified by ligand-based virtual screening of shape-based similarity and electrostatic matching. The most potent one (V-39) blocked 2-APB-activated currents in a stable human TRPV3 expressed HEK293T cell line with IC50=18.0 ±1.1 μmol·L-1 (n=4). Besides, the interaction pattern between TRPV3 and its antagonists were studied through docking the antagonists into a homology model (TRPV3_HM4) generated from the crystal structure of TPRV1. The docking results show that the binding site of TRPV3 locates between linker domain (of N-terminus and TM1) and TRP Box. There are a π-π stacking interaction and hydrogen bonding interactions between compound V-39 and residues His-310, His-314 and Arg-577 of the pocket. Identification of these antagonists provides new probes for understanding the pharmacological function of TRPV3 channel.

Synthesis, biological activity and molecular docking research of N-{(4-oxo-thiochroman-3-yl)phenyl-methyl}acetamide derivatives as α-glucosidase inhibitors / 药学学报

In order to develop potent antidiabetic agents that have inhibitory effect to α-glucosidase, twelve β-acetamido ketone derivatives such as N-{[(substituted-4-oxo-thiochroman-3-yl)phenyl]-methyl}acetamide are designed and synthesized through one-pot Dakin-West reaction. Their chemical structures are confirmed by 1H NMR, 13C NMR, IR and HR-MS. In vitro α-glucosidase inhibition assays of compounds 4a-4l were carried out using glucose oxidase method. The result indicated that most of them possess inhibitory activity in vitro. Compound 4k showed the most potent inhibitory activity with 87.3% inhibition of α-glucosidase at the concentration of 5.39 mmol·L-1. The structure-activity relationship of these β-acetamido ketone derivatives was discussed preliminarily. Moreover, the molecular docking method was used to study the interaction mode of compound 4k and α-glucosidase. Our results will be helpful for designing of α-glucosidase inhibitors in the future.

Synthesis, biological activity and molecular docking research of N-{(4-oxo-thiochroman-3-yl)phenyl-methyl}acetamide derivatives as α-glucosidase inhibitors / 药学学报

In order to develop potent antidiabetic agents that have inhibitory effect to a-glucosidase, twelve β-acetamido ketone derivatives such as N-{[(substituted-4-oxo-thiochroman-3-yl)phenyl]-methyl}acetamide are designed and synthesized through one-pot Dakin-West reaction. Their chemical structures are confirmed by 1H NMR, 13C NMR, IR and HR-MS. In vitro α-glucosidase inhibition assays of compounds 4a-41 were carried out using glucose oxidase method. The result indicated that most of them possess inhibitory activity in vitro. Compound 4k showed the most potent inhibitory activity with 87.3% inhibition of α-glucosidase at the concentration of 5.39 mmol x L(-1). The structure-activity relationship of these β-acetamido ketone derivatives was discussed preliminarily. Moreover, the molecular docking method was used to study the interaction mode of compound 4k and α-glucosidase. Our results will be helpful for designing of α-glucosidase inhibitors in the future.

Effect of 17beta-estradiol on Kv2.1 current and delayed rectifier potassium current in cultured rat hippocampal neurons / 药学学报

<p><b>AIM</b>To study the effects of 17beta-estradiol on Kv2.1 potassium channel current and delayed rectifier potassium current (IK) in cultured rat hippocampal neurons.</p><p><b>METHODS</b>The effects of 17beta-estradiol on Kv2.1 channel current and IK in cultured rat hippocampal neurons were observed using the whole cell patch clamp techniques.</p><p><b>RESULTS</b>17beta-Estradiol was shown to reduce the amplitude of Kv2.1 current and IK in concentration-dependent manners. The IC50s of 17beta-estradiol blocking Kv2.1 and IK were 2.4 and 4.0 micromol x L(-1), respectively. 17beta-Estradiol (3 micromol x l(-1)) significantly shifted the steady-state activation and inactivation curves of Kv2.1 current to negative potentials. However, it only produced the shift of the steady-state activation curve of IK to the negative potential without effect on the steady-state inactivation of IK.</p><p><b>CONCLUSION</b>17beta-Estradiol inhibits Kv2.1 and IK of hippocampus at similar level. The inhibition of 17beta-estradiol on IK current may be partially via blocking Kv2.1 current.</p>

Inhibition of tacrine on delayed rectifier and transient outward potassium currents in cultured rat hippocampal neurons / 药学学报

<p><b>AIM</b>To study the effects of tacrine on IK and IA potassium current in primary cultured rat hippocampal neurons.</p><p><b>METHODS</b>Whole cell patch clamp and primary rat hippocampal neuron cultures were used.</p><p><b>RESULTS</b>Tacrine was shown to reduce the amplitude of IK and IA, in concentration-dependent manners. The IC50s at +40 mV for reduction of IK and IA were 23 and 52.6 mumol.L-1, respectively. Tacrine (30 mumol.L-1) shifted the steady state activation of IK and IA to negative potentials by 12 and 15 mV, respectively. The V1/2 of activation curves for IK current before and after the application of tacrine were (6.7 +/- 1.4) mV and (-5.4 +/- 1.3) mV, respectively. The k of activation curves for IK current was 13.4 + 1.3 and 12.5 + 1.4 without and with tacrine, respectively. The V1/2 of activation curve for IA current were (-9.9 +/- 2.6) mV and (-24 +/- 5) mV in the absence and presence of tacrine, respectively, and the k value was not changed.</p><p><b>CONCLUSION</b>Tacrine inhibited IK and IA currents in rat hippocampal neurons and it is more potent for blocking IK.</p>

Electrophysiological correspondence between Kv4.2 current and transient outward potassium current in the cultured rat hippocampal neuron / 生理学报

The present study was carried out to determine the functional properties of Kv4.2 expressed in mammalian cells in comparison with native transient potassium outward current (I(A)) in the hippocampal neurons. Transient transfection, cell culture and whole cell voltage clamp techniques were used. The results showed that I(A) in cultured rat hippocampal neurons and Kv4.2 expressed in HEK293 cells both displayed "A"-type current properties. The activation curves of I(A) and Kv4.2 were better fitted by simple Boltzmann function with V(1/2) 10.0+/-3.3 mV, k 13.9+/-2.6 mV for I(A) and V1/2 -9.7+/-4.1 mV, k 15.8+/-5.7 mV for Kv4.2, respectively. The steady-state inactivation curves of I(A) had a midpoint of -93.0+/-11.4 mV and a slope of 9.0+/-1.5 mV. The voltage-dependence of inactivation for Kv4.2 exhibited midpoint and slope values of -59.4+/-12.2 mV and 8.0+/-3.1 mV, respectively. The time constants (tau) of recovery from inactivation of I(A) and Kv4.2 were 27.9+/-14.1 ms and 172.8+/-10.0 ms, respectively. These results suggest that Kv4.2 is probably a major isoform contributing to I(A) in hippocampus neurons.

Effects of chronic exposure to beta-amyloid-peptide25-35 on the mRNA expressions of voltage-gated outward potassium channel subunits in cultured rat hippocampal neurons / 药学学报

<p><b>AIM</b>To investigate mRNA expression changes of voltage-gated outward potassium channel subtypes in cultured rat hippocampal neurons after chronic exposure to beta-amyloid-petitde25-35 (beta-AP25-35).</p><p><b>METHODS</b>mRNA expression was detected by RT-PCR, comparative expression levels were determined by imaging densitometer.</p><p><b>RESULTS</b>Delayed rectifying (Kv2.1, Kv1.5), transient outward (Kv1.4, Kv4.2) and large conductance calcium-activated (rSlo) potassium channel mRNA were expressed in cultured rat hippocampal. In the presence of beta-AP25-35 3 mumol.L-1 for 24 h, the relative expression level of Kv2.1 was significantly increased (n = 3, P < 0.05); the other subtypes were not changed obviously (n = 3, P > 0.05). The increase of Kv2.1 mRNA mainly happened between 24 and 36 h after exposure to beta-AP25-35. After exposure to beta-AP25-35 for 60 h, Kv2.1 mRNA decreased significantly (n = 3, P < 0.01).</p><p><b>CONCLUSION</b>The upregulation of Kv2.1 on transcription levels may be involved in the enhancement of delayed rectifying outward potassium (Ik) current induced by beta-AP25-35.</p>