Induction of apoptosis and inhibition of cell migration and tube-like formation by dihydroartemisinin in murine lymphatic endothelial cells.
ABSTRACT Dihydroartemisinin (DHA) is a semisynthesized agent from the artemisinin first extracted from the Chinese plant Artemisia annua. Previous studies have shown that artemisinin derivates, apart from their antimalarial activity, possess antitumor, antiangiogenic, and anti-inflammatory effects. In the present investigation, DHA was found to have a potent ability in influencing lymphatic endothelial cells (LECs) behavior. Murine LECs were isolated from benign lymphangiomas induced by intraperitoneal injection of incomplete Freund's adjuvant and identified by indirect immunofluorescence assay and fluorescence-activated cell sorting analysis to examine the expression of the specific marker VEGFR-3/Flt-4. When LECs were treated with DHA at 10 microg/ml, the growth of LECs was inhibited, and LECs showed typical apoptotic morphological features, with a higher apoptotic rate as compared with the controls. DHA also exerted a significant inhibitory effect on migration and tube-like formation of LECs in a dose-dependent manner. Quantitative RT-PCR further showed that DHA remarkably downregulated the expression of antiapoptotic bcl-2 mRNA, but upregulated that of the proapoptotic gene bax mRNA. In addition, DHA could strongly attenuate the mRNA and protein levels of VEGFR-3/Flt-4. In summary, these findings indicate that DHA may be useful as a potential lymphangiogenesis inhibitor under induction of cell apoptosis, inhibition of the migration, and formation of tube-like structures in LECs.
- SourceAvailable from: Suchandra GoswamiAntimicrobial Agents and Chemotherapy 06/2012; 56(9):4594. · 4.57 Impact Factor
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ABSTRACT: The antimalarial drug artemisinin from Artemisia annua demonstrated remarkably strong activity against Helicobacter pylori, the pathogen responsible for peptic ulcer diseases. In an effort to develop a novel antimicrobial chemotherapeutic agent containing such a sesquiterpene lactone endoperoxide, a series of analogues (2 natural and 15 semisynthetic molecules), including eight newly synthesized compounds, were investigated against clinical and standard strains of H. pylori. The antimicrobial spectrum against 10 H. pylori strains and a few other bacterial and fungal strains indicated specificity against the ulcer causing organism. Of five promising molecules, a newly synthesized ether derivative β-artecyclopropylmether was found to be the most potent compound, which exhibited MIC range, MIC(90), and minimum bactericidal concentration range values of 0.25 to 1.0 μg/ml, 1.0 μg/ml, and 1 to 16 μg/ml, respectively, against both resistant and sensitive strains of H. pylori. The molecule demonstrated strong bactericidal kinetics with extensive morphological degeneration, retained functional efficacy at stomach acidic pH unlike clarithromycin, did not elicit drug resistance unlike metronidazole, and imparted sensitivity to resistant strains. It is not cytotoxic and exhibits in vivo potentiality to reduce the H. pylori burden in a chronic infection model. Thus, β-artecyclopropylmether could be a lead candidate for anti-H. pylori therapeutics. Since the recurrence of gastroduodenal ulcers is believed to be mainly due to antibiotic resistance of the commensal organism H. pylori, development of a candidate drug from this finding is warranted.09/2012;
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ABSTRACT: Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has been demonstrated to possess a strong antiangiogenic activity. However, the molecular mechanisms underlying this effect remain unclear. Endothelial cell (EC) migration is an essential component of angiogenesis, and the p38 mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in the regulation of migration induced by vascular endothelial growth factor (VEGF). The aim of the present study was to investigate the effects of DHA on EC migration and the p38 MAPK signaling pathway. Human umbilical vein ECs (HUVECs) were treated with DHA and VEGF-induced migration was analyzed. The activation of p38 MAPK was detected by western blot analysis, and the migration assays were performed with a p38-specific inhibitor, SB203850. It was revealed that 20 μM DHA significantly reduced EC migration in the transwell migration assay, wound healing assay and electrical cell-substrate impedance sensing real-time analysis. However, DHA did not affect p38 MAPK phosphorylation or expression. In the absence or presence of SB203850, DHA induced a similar proportional reduction of EC migration in the three migration assays. Therefore, the present study demonstrated that DHA inhibits VEGF-induced EC migration via a p38 MAPK-independent pathway.Experimental and therapeutic medicine 12/2014; 8(6):1707-1712. · 0.34 Impact Factor