We investigated the catechin content in green tea leaf (GTL) and green tea seed (GTS), the antiproliferative and detoxifying phase II enzyme-inducing activities of the methanolic (80%, v/v) extracts from GTL and GTS. GTL and GTS contained $8,685{\pm}1,061$ and $108{\pm}32\;{\mu}g/g$ epigallocatechin gallate (EGCG), $11,486{\pm}506$ and $116{\pm}72\;{\mu}g/g$ epigallocatechin (EGC), $3,535{\pm}308$ and $821{\pm}95\;{\mu}g/g$ epicatechin gallate (ECG), and $1,429{\pm}177$ and $37{\pm}44\;{\mu}g/g$ epicatechin (EC), respectively. The methanolic extract of GTS showed a greater increase in quinone reductase activity and antiproliferation potential against mouse hepatoma cells than GTL extract did. GTS treatment resulted in the accumulation at sub-G1 phase of mouse hepatoma hepa1c1c7 cells as assessed by flow cytometry. Enhancement of phase II enzyme activity by GTS extract was shown to be mediated, directly or indirectly, via interaction with the antioxidant response element (ARE) sequence in the genes encoding the phase enzymes. As the catechin content in GTS was significantly lower than that in GTL, components other than catechins appear to be responsible for the anticarcinogenic activity of the seed. In summary, these results suggest that the 80% methanolic extract of GTS deserves further study to evaluate its potential as an anticarcinogenic agent and to investigate its mechanism of action.
Background: The human protein methyl-transferase DOT1L catalyzes the methylation of histone H3 on lysine 79 (H3K79) at homeobox genes and is also involved in a number of significant processes ranging from gene expression to DNA-damage response and cell cycle progression. Inhibition of DOT1L activity by shRNA or small-molecule inhibitors has been established to prevent proliferation of various MLL-rearranged leukemia cells in vitro, establishing DOT1L an attractive therapeutic target for mixed lineage leukemia (MLL). Most of the drugs currently in use for the MLL treatment are reported to have low efficacy, hence this study focused on various natural compounds which exhibit minimal toxic effects and high efficacy for the target receptor. Materials and Methods: Structures of human protein methyl-transferase DOT1L and natural compound databases were downloaded from various sources. Virtual screening, molecular docking, dynamics simulation and drug likeness studies were performed for those natural compounds to evaluate and analyze their anti-cancer activity. Results: The top five screened compounds possessing good binding affinity were identified as potential high affinity inhibitors against DOT1L's active site. The top ranking molecule amongst the screened ligands had a Glide g-score of -10.940 kcal/mol and Glide e-model score of -86.011 with 5 hydrogen bonds and 12 hydrophobic contacts. This ligand's behaviour also showed consistency during the simulation of protein-ligand complex for 20000 ps, which is indicative of its stability in the receptor pocket. Conclusions: The ligand obtained out of this screening study can be considered as a potential inhibitor for DOT1L and further can be treated as a lead for the drug designing pipeline.
Objective : This study was designed to investigate the anti-cancer effects of bee venom on melanoma in C57BL mice. Materials and Methods : For the induction of melanoma, C57BL mice were treated by DMBA(7, 12-dimethylbenz[a]anthracene). Each group of C57BL mouse was treated with DMBA $50{\mu}g$, $75{\mu}g$, $100{\mu}g$ respectively once a week for 15 weeks. Tumor generation in each group of 10 mice was observed. Cumulative curves were showed in the density and frequency of skin tumor generation. To know the effects of pre-treatment of bee venom on tumor generation by DMBA treatment(frequency of tumor generation), Each group of C57BL mouse was pretreated and treated with bee venom $5{\mu}{\ell}$, $25{\mu}{\ell}$, $50{\mu}{\ell}$ respectively once a week for 3 weeks, whereafter each mouse was treated with DMBA $100{\mu}g$ once a week for 15 weeks. Results and Conclusion (1) There was chemotherapeutic effect, but not chemopreventive effect. (2) Cpp32 activity was increased by $50{\mu}{\ell}$ bee venom treatment. (3) Bee venom treatment inhibited expression of cell-cycle regulating, growth-promoting genes such as c-Jun, c-Fos, and Cyclin Dl, and increased tumor suppressors p53 and p21/Wafl. (4) Bee venom treatment activated expression of a representative apoptosis-inducing gene Bax.
Chelidonium majus (CM) contains several isoquinoline alkaloids that have been reported to have various biological activities such as anti-inflammatory, antimicrobial, antioxidant, immune-modulatory, and antitumoral. It has been reported that the extract of CM had an antioxidant potential, however the mechanism has not been verified. In this study, we found that CM extract activated FOXO3a. FOXO3a is a transcription factor that involved in various biological processes such as cell cycle arrest, apoptosis, DNA repair, and ROS detoxification. Transcriptional activities of FOXO3a were regulated by post-translational modifications including phosphorylation, acetylation, and ubiquitination. Protein level of FOXO3a was increased by CM extract. Promoter activities of FOXO-transcriptional target genes such as MnSOD, p27 and GADD45 were activated by CM extract in a dose dependent manner. In addition, protein level of MnSOD, major antioxidant enzyme, was increased by CM extract. Thereby ROS level was decreased by CM in old HEF cells. These results suggest that CM extract has an antioxidant activity through FOXO activation.
Shin, Jong-Il;Jeon, Yong-Joon;Lee, Sol;Lee, Yoon Gyeong;Kim, Ji Beom;Lee, Kyungho
Molecules and Cells
/
v.42
no.3
/
pp.252-261
/
2019
The omega-3 fatty acid docosahexaenoic acid (DHA) is known to induce apoptosis and cell cycle arrest via the induction of reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress in many types of cancers. However, the roles of DHA in drug-resistant cancer cells have not been elucidated. In this study, we investigated the effects of DHA in cisplatin-resistant gastric cancer SNU-601/cis2 cells. DHA was found to induce ROS-dependent apoptosis in these cells. The inositol 1,4,5-triphosphate receptor ($IP_3R$) blocker 2-aminoethyl diphenylboninate (2-APB) reduced DHA-induced ROS production, consequently reducing apoptosis. We also found that G-protein-coupled receptor 120 (GPR120), a receptor of long-chain fatty acids, is expressed in SNU-601/cis2 cells, and the knockdown of GPR120 using specific shRNAs alleviated DHA-mediated ROS production and apoptosis. GPR120 knockdown reduced the expression of ER stress response genes, similar to the case for the pre-treatment of the cells with N-acetyl-L-cysteine (NAC), an ROS scavenger, or 2-APB. Indeed, the knockdown of C/EBP homologous protein (CHOP), a transcription factor that functions under ER stress conditions, markedly reduced DHA-mediated apoptosis, indicating that CHOP plays an essential role in the anti-cancer activity of DHA. These results suggest that GPR120 mediates DHA-induced apoptosis by regulating $IP_3R$, ROS, and ER stress levels in cisplatin-resistant cancer cells, and that GPR120 is an effective chemotherapeutic target for cisplatin resistance.
Although reactive oxygen species (ROS) are inevitable by-products of many redox reactions in eukaryotic cells, they play a crucial role as signaling molecules in many cellular processes for development and defense response to abiotic stresses. The biphasic ROS production which was peaked twice in a first transient phase and a second massive phase was occurred after treatment of abiotic stress such as oxidative stress, high salinity. This biphasic generation of ROS was followed by the biphasic production of stress hormone, ethylene. The mechanism of interactions between ROS and ethylene biosynthesis is studied in tobacco (Nicotiana tabaccum L.) plants under the abiotic stresses. The stress-induced ethylene production was significantly inhibited in RbohD-AS and RbohF-AS, in which antisense expression of NADPH oxidase genes was performed. The accumulation of ROS, which was determined by DAB and DCFH-DA staining, was significantly decreased after abiotic stresses in transgenic plants. The suppression of signaling with ethylene and ROS induced more tolerance in response to abiotic stress. The transgenic plants were more tolerant in MS medium supplemented with salinity stress in contrast with wild-type. Stress-induced cell damage determined by DNA fragmentation was decreased at phase II in those transgenic plants. Therefore, the first burst of ROS is more responsible for making a role as a signaling molecule during stress-induced response. These results suggested that ethylene and ROS act in a positive feedback cycle that results in mutual enhancement of ethylene and ROS production during stress-induced cell death.
Oral squamous carcinoma (OSC) cells present resistance to chemotherapeutic agents-mediated apoptosis in the late stages of malignancy. Advances in the understanding of bacterial toxins have produced new strategies for the treatment of cancers. It was demonstrated here that Pseudomonas aeruginosa exotoxin A (PEA) significantly decreased the viability of chemoresistant YD-9 cells in the apoptosis mechanism. Apoptotic manifestations were evident through changes in nuclear morphology and generation of DNA fragmentation. PEA treatment induced caspase-3, -6 and -9 cleavage, and activation. These events preceded proteolysis of the caspase substrates poly (ADP-ribose) polymerase (PARP), DNA fragmentation factor 45 (DFF45), and lamin A in YD-9 cells. The reduction of mitochondrial membrane potential, release of cytochrome c and SmacjDlABLO from mitochondria to cytosol, andtranslocation of AlF into nucleus were shown. While p53, p21 and $14-3-3{\gamma}$ were upregulated, cyclin Band cdc2 were downregulated by PEA treatment. Taken together, PEA induces apoptosis in chemoresistant YD-9 cells via activation of caspases, mitochondrial events and regulation of cell cycle genes.
Park, Cheol;Jin, Cheng-Yun;Choi, Byung-Tae;Lee, Won-Ho;Choi, Yung-Hyun
Journal of Life Science
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v.18
no.3
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pp.336-343
/
2008
Histone deacetylases (HDACs) inhibitors have emerged as the accessory therapeutic agents for various human cancers, since they can block the activity of specific HDACs, restore the expression of some tumor suppressor genes and induce cell differentiation, cell cycle arrest and apoptosis in vitro and in vivo. In the present study, we investigated that the effect of trichostatin A (TSA), an HDAC inhibitor, on the cell growth and apoptosis, and its effect on the nuclear factor-kappaB $(NF-{\kappa}B)$ activity in 267B1 human prostate epithelial cells. Exposure of 267B1 cells to TSA resulted in growth inhibition and apoptosis induction in and dose-dependent manners as measured by fluorescence microscopy, agarose gel electrophoresis and flow cytometry analysis. TSA treatment inhibited the levels of IAP family members such as c-IAP-1 and c-IAP-2 and induced the proteolytic activation of caspase-3, -8 and -9, which were associated with concomitant degradation of poly (ADP-ribose)-polymerase, ${\beta}-catenin$ and laminin B proteins. The increase in apoptosis by TSA was connected with the translocation of $NF-{\kappa}B$ from cytosol to nucleus, increase of the DNA binding as well as promoter activity of $NF-{\kappa}B$, and degradation of cytosolic inhibitor of KappaB $(I{\kappa}B)-{\alpha}$ protein. We therefore concluded that TSA demonstrated anti-proliferative and apoptosis-inducing effects on 267B1 cells in vitro, and that the activation of caspases and $NF-{\kappa}B$ may play important roles in its mechanism of action. Although further studies are needed, these findings provided important insights into the possible molecular mechanisms of the anti-cancer activity of TSA.
The nuclear phosphoprotein p53 is expressed in all normal cells and appears to function in cell cycle regulation. Abnormally high levels of the protein are found in many different types of cancer. In human cancer overexpression of p53 is associated with point mutations within highly conserved regions of p53 gene. These altered genes encode stable p53 proteins that can detected by standard immunocytochemical techniques unable to detect rapidly degraded wild-type protein. Using of a monoclonal antibody to p53 antigen, immunocytochemical analysis of 29 squamous cell carcinomas of tongue(n= 19) and tonsil(n= 10) was performed. Non-tumor nuclei showed all negative reactivity. Positive reactivity was found in 4/29(13.8%)of SCCs of tongue and tonsil. In sizes of primary tumor, the cases over 4cm showed more positive reactivity than the cases under 4cm(p < 0.05). There was no stastical correlation between the reactivity and histopathologic grades, the primary sites of tumor or the presence of cervical metastasis.
Hwang, Eunmi;Kim, Gye Won;Song, Ki Duk;Lee, Hak-Kyo;Kim, Sung-Jo
Asian-Australasian Journal of Animal Sciences
/
v.32
no.11
/
pp.1776-1788
/
2019
Objective: The demands for measures to improve disease resistance and productivity of livestock are increasing, as most countries prohibit the addition of antibiotics to feed. This study therefore aimed to uncover functional feed additives to help enhance livestock immunity and disease resistance, using Acanthopanax sessiliflorus fruit extract (ASF). Methods: ASF was extracted with 70% EtOH, and total polyphenolic and catechin contents were measured by the Folin-Ciocalteu and vanillin assay, respectively. The 3D4/31 porcine macrophage cells ($M{\Phi}$) were activated by phorbol 12-myristate 13-acetate (PMA), and cell survival and growth rate were measured with or without ASF treatment. Flow-cytometric analysis determined the lysosomal activity, reactive oxygen species levels (ROS), and cell cycle distribution. Nuclear factor kappa B ($NF-{\kappa}B$) and superoxide dismutase (SOD) protein expression levels were quantified by western blotting and densitometry analysis. Quantitative polymerase chain reaction was applied to measure the lipid metabolism-related genes expression level. Lastly, the antibacterial activity of 3D4/31 $M{\Phi}$ cells was evaluated by the colony forming unit assay. Results: ASF upregulated the cell viability and growth rate of 3D4/31 $M{\Phi}$, with or without PMA activation. Moreover, lysosomal activity and intracellular ROS levels were increased after ASF exposure. In addition, the antioxidant enzyme SOD2 expression levels were proportionately increased with ROS levels. Both ASF and PMA treatment resulted in upregulation of $NF-{\kappa}B$ protein, tumor necrosis factor $(TNF){\alpha}$ mRNA expression levels, lipid synthesis, and fatty acid oxidation metabolism. Interestingly, co-treatment of ASF with PMA resulted in recovery of $NF-{\kappa}B$, $TNF{\alpha}$, and lipid metabolism levels. Finally, ASF pretreatment enhanced the in vitro bactericidal activity of 3D4/31 $M{\Phi}$ against Escherichia coli. Conclusion: This study provides a novel insight into the regulation of $NF-{\kappa}B$ activity and lipid metabolism in $M{\Phi}$, and we anticipate that ASF has the potential to be effective as a feed additive to enhance livestock immunity.
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