Emodin Inhibits Resistance to Imatinib by Downregulation of Bcr-Abl and STAT5 and Allosteric Inhibition in Chronic Myeloid Leukemia Cells.

Imatinib-resistance is a significant concern for Bcr-Abl-positive chronic myelogenous leukemia (CML) treatment. Emodin, the predominant compound of traditional medicine rhubarb, was reported to inhibit the multidrug resistance by downregulating P-glycoprotein of K562/ADM cells with overexpression of P-glycoprotein in our previous studies. In the present study, we found that emodin can be a potential inhibitor for the imatinib-resistance in K562/G01 cells which are the imatinib-resistant subcellular line of human chronic myelogenous leukemia cells with overexpression of breakpoint cluster region-abelson (Bcr-Abl) oncoprotein. Emodin greatly enhanced cell sensitivity to imatinib, suppressed resistant cell proliferation and increased potentiated apoptosis induced by imatinib in K562/G01 cells. After treatment of emodin and imatinib together, the levels of p-Bcr-Abl and Bcr-Abl were significantly downregulated. Moreover, Bcr-Abl important downstream target, STAT5 and its phosphorylation were affected. Furthermore, the expression of Bcr-Abl and signal transducers and activators of transcription 5 (STAT5) related molecules, including c-MYC, MCL-1, poly(ADP-ribose)polymerase (PARP), Bcl-2 and caspase-3, were changed. Emodin also decreased Src expression and its phosphorylation. More importantly, emodin simultaneously targeted both the ATP-binding and allosteric sites on Bcr-Abl by molecular docking, with higher affinity with the myristoyl-binding site for enhanced Bcr-Abl kinase inhibition. Overall, these data indicated emodin might be an effective therapeutic agent for inhibiting resistance to imatinib in CML treatment.

A Novel Cooperative Path Planning for Multi-robot Persistent Coverage with Obstacles and Coverage Period Constraints.

In this paper, a multi-robot persistent coverage of the region of interest is considered, where persistent coverage and cooperative coverage are addressed simultaneously. Previous works have mainly concentrated on the paths that allow for repeated coverage, but ignored the coverage period requirements of each sub-region. In contrast, this paper presents a combinatorial approach for path planning, which aims to cover mission domains with different task periods while guaranteeing both obstacle avoidance and minimizing the number of robots used. The algorithm first deploys the sensors in the region to satisfy coverage requirements with minimum cost. Then it solves the travelling salesman problem to obtain the frame of the closed path. Finally, the approach partitions the closed path into the fewest segments under the coverage period constraints, and it generates the closed route for each robot on the basis of portioned segments of the closed path. Therefore, each robot can circumnavigate one closed route to cover the different task areas completely and persistently. The numerical simulations show that the proposed approach is feasible to implement the cooperative coverage in consideration of obstacles and coverage period constraints, and the number of robots used is also minimized.

A node influence based label propagation algorithm for community detection in networks.

Label propagation algorithm (LPA) is an extremely fast community detection method and is widely used in large scale networks. In spite of the advantages of LPA, the issue of its poor stability has not yet been well addressed. We propose a novel node influence based label propagation algorithm for community detection (NIBLPA), which improves the performance of LPA by improving the node orders of label updating and the mechanism of label choosing when more than one label is contained by the maximum number of nodes. NIBLPA can get more stable results than LPA since it avoids the complete randomness of LPA. The experimental results on both synthetic and real networks demonstrate that NIBLPA maintains the efficiency of the traditional LPA algorithm, and, at the same time, it has a superior performance to some representative methods.

Mean-shift exploration in shape assembly of robot swarms.

The fascinating collective behaviors of biological systems have inspired extensive studies on shape assembly of robot swarms. Here, we propose a strategy for shape assembly of robot swarms based on the idea of mean-shift exploration: when a robot is surrounded by neighboring robots and unoccupied locations, it would actively give up its current location by exploring the highest density of nearby unoccupied locations in the desired shape. This idea is realized by adapting the mean-shift algorithm, which is an optimization technique widely used in machine learning for locating the maxima of a density function. The proposed strategy empowers robot swarms to assemble highly complex shapes with strong adaptability, as verified by experiments with swarms of 50 ground robots. The comparison between the proposed strategy and the state-of-the-art demonstrates its high efficiency especially for large-scale swarms. The proposed strategy can also be adapted to generate interesting behaviors including shape regeneration, cooperative cargo transportation, and complex environment exploration.

Effects of some antihypertensive drugs on the metabolism and pharmacokinetics of indapamide in rats.

PURPOSE: Indapamide, a non-thiazide antihypertensive diuretic agent, has been widely coadministered with other classes of antihypertensive agents to reach target systolic blood pressure. Indapamide is extensively metabolized by cytochromes P450. Interaction of indapamide and other antihypertensive drugs are unknown. We investigated the effects of other antihypertensive drugs on the metabolism and pharmacokinetics of indapamide in vitro and in vivo. METHODS: Indapamide metabolism was studies in vitro using human liver microsomes pretreated with or without different concentrations of CYP-selective inhibitors and seven major antihypertensive drugs, felodipine, nifedipine, nitrendipine, telmisartan, irbesartan, valsartan and puerarin. Furthermore, the pharmacokinetics of indapamide was determined by HPLC-MS/MS to evaluate the effects of felodipine coadministered on the bioavailability of indapamide in rats in vivo. RESULTS: The Km and Vmax of indapamide metabolism were 114.35 ± 3.47 µM and 23.13 ± 6.61 µmol/g/min. The metabolites of indapamide, hydroxyl-indapamide and dehydrogen-indapamide, were followed. CYP3A4 and CYP2C19 were involved in indapamide metabolism in human live microsomes. In addition, felodipine, nifedipine and nitrendipine significantly inhibited indapamide metabolism with the maximum inhibitory rates of 82.6%, 72% and 95%, respectively. Felodipine significantly elevated indapamide plasma concentration and prolonged its half-life. CONCLUSIONS: Combination therapy of indapamide and felodipine might lead to the alteration of indapamide metabolism and pharmacokinetics. The consequence of such an interaction that may include increased effectiveness and side effect needs to be tudeis in human.

Construction of doxorubicin-loading magnetic nanocarriers for assaying apoptosis of glioblastoma cells.

Magnetic nanoparticles (MNPs), in comparison with traditional drug solutions or suspensions, represent a promising vehicle to achieve the controlled drug delivery to targeted cell/tissue regions in cancer treatment. In this study, the biodegradable chitosan-modified magnetite (Fe3O4) NPs (CS-MNPs) are firstly synthesized using as nanocarriers, and then encapsulated with anti-tumor drug doxorubicin (DOX) to construct DOX-loaded CS-MNPs (DOX-CS-MNPs), which are further applied to assay apoptosis of glioblastoma multiforme U251 cells. The properties of the DOX-CS-MNPs including particle size, shape and magnetization, are characterized. The stability, drug release, magnetic response and redispersion of the DOX-CS-MNPs within an external magnetic field are evaluated. Furthermore, the biological effects of the DOX-CS-MNPs on U251 glioblastoma cells, particularly cytotoxicity, cell viability, actin cytoskeleton and apoptosis rate, are subsequently investigated. The data show that the prepared DOX-CS-MNPs are spherical in shape with average diameter of 60 nm approximately. The fabricated DOX-CS-MNPs also exhibit specific properties including low aggregation, high saturation magnetization, satisfactory magnetic-responsive aggregation, and redispersion in water, etc. The biological assays show that the DOX-CS-MNPs can efficiently enter the cells, reduce cell viability, and inhibit cell proliferation in a dose-dependent manner, and a high rate of cell apoptosis is induced in U251 glioblastoma cells after DOX-CS-MNPs treatment. Therefore, the present results indicate that the constructed DOX-CS-MNPs may be a promising vehicle for efficiently inhibiting proliferation of human U251 glioblastoma cells.