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In this work, we propose a new approach for coordinating generated agents’ plans dynamically. The purpose is to take into consideration new conflicts introduced in new versions of agents’ plans. The approach consists in finding the best combination which contains one plan for each agent among its set of possible plans whose execution does not entail any conflict. This combination of plans is reconstructed dynamically, each time agents decide to change their plans to take into account unpredictable changes in the environment. This not only ensures that new conflicts are likely to be introduced in the new plans that are taken into account but also it allows agents to deal, solely, with the execution of their actions and not with the resolution of conflicts. For this, we use genetic algorithms where the proposed fitness function is defined based on the number of conflicts that agents can experience in each combination of plans. As part of our work, we used a concrete case to illustrate and show the usefulness of our approach.

La Presse Medicale - In Press.Proof corrected by the author Available online since mardi 15 novembre 2016

Rhein is an active component of rhubarb; a traditional Chinese medicine reported to induce apoptosis and cause liver toxicity. However, rhein's apoptotic-inducing effects, as well as its molecular mechanisms of action on hepatic cells need to be further explored. In the present study, rhein was found to trigger apoptosis in primary human hepatic HL-7702 cells as showed by annexin V/PI double staining assay and nuclear morphological changes demonstrated by Hoechst 33258 staining. Moreover, it was observed that the mechanism implicated in rhein-induced apoptosis was caspase-dependent, presumably via ER-stress associated pathways, as illustrated by up-regulation of glucose-regulated protein 78 (GRP 78), PKR-like ER kinase (PERK), C-Jun N-terminal kinase (JNK) and CCAAT/enhancer-binding protein homologous protein (CHOP). Meanwhile, caspase-4 as a hallmark of ER-stress, was also showed to be activated following by caspase-3 activation. Furthermore, rhein also promoted intracellular elevation of calcium that contributed in apoptosis induction. Interestingly, pre-treatment with calpain inhibitor I reduced the effects of rhein on apoptosis induction and JNK activation. These data suggested that rhein-induced apoptosis through ER-stress and elevated intracellular calcium level in HL-7702 cells.

Pristimerin is a naturally occurring triterpenoid that has a cytotoxic effect on several cancer cell lines. However, the cytotoxic effects of pristimerin as well as its molecular mechanisms of action against colorectal cancer have never been explored. In the present study, we investigated the anticancer potential of pristimerin, and examined the different signaling pathways affected by its action in three colon cancer cell lines namely HCT-116, COLO-205 and SW-620. Pristimerin was found to possess potent cytotoxic and proliferation inhibitory effects against these cell lines. Cell cycle analysis revealed G1 phase arrest, which was strongly associated with decreased expression of cyclin D1 and cyclin-dependent kinases (cdk4 and cdk6) with concomitant induction of p21. Pristimerin also induced apoptosis in a dose-dependent manner. Cell plasma membrane alterations studied by Annexin V/PI double staining, loss of mitochondrial membrane potential (ΔΨm), measurements of caspase activities and the inhibitory effect of Z-VAD-FMK (a caspase inhibitor) confirmed the apoptotic effect of pristimerin. Moreover, western blot data showed that apoptotic induction was associated with activated caspase-3 and -8, PARP-1 cleavage and modulation of the expression levels of Bcl-2 family proteins. Additionally, pristimerin treatment downregulated the phosphorylated forms of EGFR and HER2 proteins, and subsequently caused a decrease in the phosphorylated forms of Erk1/2, Akt, mTOR and NF-κB proteins. Taken together, these results suggest that pristimerin may have potential as a new targeting therapeutic strategy for the treatment of colon cancer.

Triptolide is the major bioactive component isolated from the Chinese Medicinal plant Tripterygium wilfordii. Despite the growing interest and the plethora of reports discussing the pharmacological activity of this diterpenoid, no clear consensus regarding its cellular targets and full mechanism of action has been reached. In the present work, a combined in vitro and in silico approach was used to evaluate the biological activity of Triptolide on Non-small cell lung cancer (NSCLC). In vitro, Triptolide treatment induced apoptosis in NSCLC cell lines and down-regulated the phosphorylation of AKT, mTOR, and p70S6K. Triptolide also impacted cellular glycolysis as well as the antioxidant response through the impairment of glucose utilization, HKII, glutathione, and NRF2 levels. Molecular docking results examined the possible interactions between Triptolide and AKT and predicted an allosteric binding to AKT-1 structure. Molecular dynamics simulations were further used to evaluate the stability of the complex formed by Triptolide's best conformer and AKT. These findings provide an insightful approach to the anticancer effect of Triptolide against NSCLC and highlight a possible new role for AKT/mTOR HKII inhibition.

The notion of absence of the frontal sinuses in human individuals presenting a persistence of the metopic suture is considered as classical in many treatises of reference; however, precise studies are very rare and even controversial. The purpose of this study was thus to provide original data to confirm or refute this classical affirmation with the perspective of some original insights into biological significance of the frontal sinuses and the factors influencing their exceptional polymorphism. The material consisted of 143 dry skulls of adult individuals (European Homo sapiens), distributed in two groups: 80 skulls presenting a complete frontal closure with total disappearance of the metopic suture, and 63 skulls presenting a complete persistence of the metopic suture. Each skull was radiographed in oblique projection using the occipitomental view. A simple morphological quantification of the sinus size was defined with four categories: (1) aplasia, (2) hypoplasia, (3) medium size, (4) hyperplasia. Statistically significant difference in frontal sinusal size was found between both groups of skulls. Absent and small sinuses were considerably more frequent in skulls with persistence of the metopic suture (57.9 vs. 11.9%): small frontal sinuses (hypoplasia) were much more frequent (50.8 vs. 9.4%), although the frequency of absence of frontal sinuses (aplasia) was only slightly higher (7.1 vs. 2.5%). Am J Phys Anthropol 154:621–627, 2014. © 2014 Wiley Periodicals, Inc.

Isoniazid (INH) remains the core drug in tuberculosis management, but serious hepatotoxicity and potentially fatal liver injury continue to accompany INH consumption. Among numerous theories that have been established to explain INH-induced liver injury, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. Inflammatory stress usually sensitizes tissues to a drug's toxic consequences. Therefore, the present study was conducted to verify whether bacterial lipopolysaccharide (LPS)-induced inflammation may have a role in enhancing INH hepatotoxicity. While single INH or LPS administration showed no major toxicity signs, INH-LPS cotreatment intensified liver toxicity. Both blood biomarkers and histological evaluations clearly showed positive signs of severe liver damage accompanied by massive necrosis, inflammatory infiltration, and hepatic steatosis. Furthermore, elevated serum levels of bile acid associated with the repression of bile acid synthesis and transport regulatory parameters were observed. Moreover, the principal impact of cytochrome P450 2E1 (CYP2E1) on INH toxicity could be anticipated, as its protein expression showed enormous increases in INH-LPS-cotreated animals. Furthermore, the crucial role of CYP2E1 in the production of reactive oxygen species (ROS) was clearly obvious in the repression of hepatic antioxidant parameters. In summary, these results confirmed that this LPS-induced inflammation model might prove valuable in revealing the hepatotoxic mechanisms of INH and the crucial role played by CYP2E1 in the initiation and propagation of INH-induced liver damage, information which could be very useful to clinicians in understanding the pathogenesis of drug-induced liver injury.

The evolution of genomic research enabled the genetic and molecular profiling of breast cancer and revealed the profound complexity and heterogeneity of this disease. Subtypes of breast cancer characterized by mutations and/or amplifications of some proto-oncogenes are associated with an increased rate of recurrence and poor prognosis. They represent a challenge in the clinic with limited arsenal to attack them. Nowadays, metabolic reprogramming is firmly established as a hallmark of cancer. An increased rate of lipid and protein syntheses in cancerous tissues, a direct consequence of alterations in key metabolic enzymes involved in these pathways, is now recognized as an important aspect of the rewired metabolism of neoplastic cells. Over the past several years, accumulating evidence has revealed that mutations or amplifications of some proto-oncogenes are primarily involved in this metabolic dysregulation. It is thus critically important to dissect the molecular mechanisms tumors use to link metabolic reprogramming with upstream altered signaling. In this article, we review the recent findings that support the importance of lipid and protein biosyntheses in breast tumorigenesis, discuss the crosstalk between growth factor signal transduction and key metabolic enzymes involved in these processes, and point out the potentials of developing new strategies and therapeutics to target these key parameters in order to help breast cancer patients by providing new therapeutic opportunities.

The aryltetralin-type lignan podophyllotoxin, the main agent present in the resin extracted from the rhizomes of different podophyllum species, possesses important antineoplastic and antiviral properties and has been widely used in diverse cultures since ancient times for medicinal purposes as a cathartic and antihelminthic agent. Today, podophyllotoxin serves as the starting material for the preparation of the well-known cytostatic agents: etoposide and teniposide which are used in combination therapies with other drugs for the treatment of a variety of malignancies. The present review focuses on the lead compound, that is, podophyllotoxin and summarizes its structural characteristics, natural sources, biological activities, novel derivatives, medicinal applications and future perspectives.

Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer.

// Mounia Guerram 1 , Zhen-Zhou Jiang 1, 2 , Bashir Alsiddig Yousef 1 , Aida Mejda Hamdi 1 , Hozeifa Mohamed Hassan 1 , Zi-Qiao Yuan 1 , Hou-Wei Luo 3 , Xiong Zhu 4 , Lu-Yong Zhang 1, 5 1 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China 2 Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China 3 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China 4 Medical and Chemical Institute, China Pharmaceutical University, Nanjing 210009, China 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China Correspondence to: Zhen-Zhou Jiang, e-mail: beaglejiang@cpu.edu.cn Lu-Yong Zhang, e-mail: lyzhang@cpu.edu.cn Keywords: ATA, breast cancer, metabolism, HER2, signaling pathways Received: February 15, 2015 Accepted: May 14, 2015 Published: May 28, 2015 ABSTRACT Increased lipogenesis and protein synthesis is a hallmark of cancer cell proliferation, survival, and metastatic progression and is under intense investigation as a potential antineoplastic target. Acetyltanshinone IIA (ATA) is a compound that was obtained from chemical modifications of tanshinone IIA (TIIA), a potent anticancer agent extracted from the dried roots of the Chinese herbal medicine Salvia miltiorrhiza Bunge. A previous investigation indicated that ATA is more effective in inhibiting the growth of breast cancer especially cells with HER2 overexpression. However, the molecular mechanism(s) mediating this cytotoxic effect on HER2-positive breast cancer remained undefined. Studies described here report that ATA induced G1/S phase arrest and apoptosis in the HER2-positive MDA-MB-453, SK-BR-3, and BT-474 breast cancer cell lines. Mechanistic investigations revealed that the ATA-induced apoptosis effect is associated with remarkably down-regulation of receptor tyrosine kinases (RTKs) EGFR/HER2 and inhibition of their downstream pro-survival signaling pathways. Interestingly, ATA was found to trigger oxidative and endoplasmic reticulum (ER) stresses and to activate AMP activated protein kinase (AMPK) leading to inactivation of key enzymes involved in lipid and protein biogenesis. Intraperitoneal administration of ATA significantly inhibited the growth of MDA-MB-453 xenografts in athymic mice without causing weight loss and any other side effects. Additionally, transwell migration, invasion, and wound healing assays revealed that ATA could suppress tumor angiogenesis in vitro . Taken together, our data suggest that ATA may have broad utility in the treatment of HER2-overexpressed breast cancers.

This work reports the phytochemical profile phenolic content and flavonoid, in vitro antioxidant against DPPH, s-carotene radical and total antioxidant activity of methanolic leaves extract from Tamarix gallica and Tamarix articulata. Formore, HPLC analysis for identification of individual polyphenols was identification in different phenolic groups and the quantification are also described. The quantification of total phenolic and flavonoids content realized by spectrophotometric methods. The antiradical capacities of extracts were evaluated against DPPH free radical and phosphomolybdenum method. Total phenolic contents and flavonoid from an extract of Tamarix gallica were founded high against Tamarix articulata, 334.19±8.47, 395.62±6.23 mg GAE/g DW for phenolic content and 159.73±6.28, 117.47±4.04 mg CE/g DW respectively. The HPLC analysis showed that at least 6 considerable phenolic compounds of leaves extract exist for the two extracts, the major ones being vanillic acid, naringin, and caffeic acid. Similar results for antioxidant activity leaves extract from Tamarix gallica exhibited strong inhibition of free radical against DPPH against Tamarix articulata IC50=5.70±0.18, 7.69±0.11 µg/ml and total antioxidant activity 341.69±9.28, 287.64±8.72 mg GAE/g DW respectively. The obtained results suggest that Tamarix gallica and Tamarix articulata could be a promising source for new drugs because of its antioxidant properties and phenolic compounds.

Background Deoxypodophyllotoxin (DPT) is a semi-synthetic compound derived from the extract of Dysosma versipellis (Hance) M. Cheng, one of the most popular Chinese herbal medicines. The present study evaluates the in vitro cytotoxicity of DPT on a wide panel of human cancer cell lines and investigates its molecular mechanism of action on high grade glioma U-87 MG and SF126 cells. Methods The growth inhibitory effect of DPT on different types of human cancer cells was measured by the Cell Counting Kit-8 (CCK-8) assay. For the elucidation of the nature of the cellular response to DPT-treatment; flow cytometry-based assays, light and fluorescent microscopy, caspase colorimetric and inhibition assays, and Western blot analysis were performed. Results Our data show that DPT possesses a potent growth-inhibitory action, with IC 50 values in nanomolar ranges. Cell cycle analysis revealed G2/M phase arrest in a dose- and time-dependent manner before cell death occurred. Additional studies indicated that DPT induced G2 arrest in U-87 MG cells by decreasing the expression of Cdc2, cyclin B1, and Cdc25C proteins. In contrast, DPT failed to down-regulate these cell cycle regulatory molecules in SF126 glioblastoma cells and stopped the cell cycle at M phase. Interestingly, morphological changes and biochemical markers such as phosphatydylserine externalization, DNA fragmentation, and caspase activation, confirmed that DPT-treatment resulted in an induction of apoptosis in both examined cell lines via caspase-dependent pathways. Conclusions Taken together, our data demonstrated that DPT possesses a potent in vitro cytotoxic activity and exerts its effect via G2/M arrest and apoptosis.