Deoxyelephantopin, a sesquiterpene lactone extracted and purified from Elephantopus scaber, has been shown to exhibit antitumor and hepatoprotective activities. The purpose of this study was to investigate the antiproliferative and apoptosis-inducing properties of deoxyelephantopin in SiHa cells and to elucidate the underlying molecular mechanisms. Deoxyelephantopin inhibited growth of SiHa cells and triggered apoptosis. Apoptosis was accompanied by sequential activation of caspases (8, 9, 3, and 7) and reactive oxygen species (ROS) production. Downregulation of antiapoptotic proteins (Bcl2 and Bcl-xL) and upregulation of apoptotic protein (bax) were also detected. Our results demonstrated that deoxyelephantopin-induced G2/M phase arrest was associated with a marked increase in the levels of p53 and p21 and a decrease in phospho-signal transducer and activator of transcription 3 (pSTAT3-Tyr705), cyclin-dependent kinase 1 (cdc2), and cyclin B1. The expression of p-Akt and p-mTOR was downregulated. p-ERK was inhibited while p-JNK and p-p38 was activated on deoxyelephantopin treatment. Our findings provided the first evidence that STAT3/p53/p21 signaling, MAPK pathway, PI3k/Akt/mTOR pathway, caspase cascades, and ROS play critical roles in deoxyelephantopin-induced G2/M phase arrest and apoptosis of SiHa cells.
In this study, we focused on the in vitro anti-metastatic effects of deoxyelephantopin (DOE), a sesquiterpene lactone from Elephantopus scaber on lung cancer A549 cells. DOE significantly decreased the metastatic potential of A549 cells as demonstrated by transwell invasion and migration assay. DOE inhibited the expression of matrix metalloproteinase-2 (MMP-2), MMP-9, urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor at transcript level. Tissue inhibitors of metalloproteinase-2 (TIMP-2) mRNA levels was up-regulated in A549 tumour cells without any change in TIMP-1 expression after DOE treatment. DOE inhibited the protein levels of p-ERK1/2 and p-Akt in A549 cells but it activated p-JNK, p-p38 protein expression. NF-κB and IκBα expressions were down-regulated in DOE-treated cells. All these results demonstrated that DOE has shown anti-metastatic activity against A549 tumour cells.
The shortage of effective drugs against wound infecting pathogens poses a serious public health threat. Combination treatment may represent a good choice for treating infections caused by these pathogens. The aim of the present study was to evaluate the in vitro efficacy of nimbolide, desacetylnimbin isolated from Azadirachta indica and the amide derivatives of nimbolide in combination with first generation cephalosporin antibiotics against major wound associated bacterial pathogens. The antibacterial activity of the compounds and antibiotics were studied by calculating minimum inhibitory concentration and minimum bactericidal concentration. The checkerboard and time-kill assay were used to evaluate the interactions between the compounds and antibiotics. Nimbolide recorded highest antimicrobial activity against all tested strains followed by desacetylnimbin but the amide derivatives of nimbolide were found to be less active. The MICs of test compounds ranged from 64 to 2000 µg/mL. In the checkerboard test, nimbolide and its derivatives markedly reduced the MIC values of the antibiotics. Significant synergistic effect was recorded by nimbolide as well as desacetylnimbin in combination with antibiotics and this combination recorded significant reduction of the colony forming units (CFUs) in time kill assay and the maximum reduction was recorded between 4 to 12 h. The above combination was also found to be effective against methicillin-resistant Staphylococcus aureus (MRSA), an important drug resistant bacterium. The cytotoxicity of the compounds was tested against H9c2 and recorded no toxicity up to 200 µM. In summary, the combination of nimbolide/desacetylnimbin and antibiotics demonstrated synergistic activity against the major wound associated bacteria tested in this study. Furthermore, these compounds may potentially widen the therapeutic window of antibiotics, suggesting that these combinations could be used clinically to control infections caused by wound pathogens after in vivo experiments.
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