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Hui Wang,
Xiaoguang Li, Xinying Yang,
Yanling Liu,
Nuoxi Gong,
Wenbo Yao,
Peizhan Chen,
Jiangjiang Qin,
Huizi Jin,
Jingquan Li,
Ruiai Chu,
Lei Shan,
Ruiwen Zhang,
Weidong Zhang
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ABSTRACT: PURPOSE: Nuclear factor-κB (NF-κB), a transcriptional regulator of diverse genes involved in cell survival, proliferation, adhesion, and apoptosis, has been implicated in various malignancies. We discover a potent natural NF-κB inhibitor, Japonicone A (JA), from traditional herb Inula japonica Thunb, evaluate its preclinical pharmacology and therapeutic activity, and investigate the underlying mechanisms of action for its anti-tumor activity. EXPERIMENTAL DESIGN: Various types of cancer and normal cells were exposed to JA for cytotoxicity screening, followed by determination of cell apoptosis and cell cycle arrest. Western blotting, immunostaining and gene reporter assay were used to analyze NF-κB activity. Two xenograft models were for therapeutic efficacy evaluation. RESULTS: JA killed cancer cells but had low cytotoxicity to normal cells. Burkitt's lymphoma (BL) cells were particularly sensitive. JA inhibited the growth and proliferation of Raji, BJAB, and NAMALWA lymphoma cells and resulted in G2/M phase arrest and apoptosis. Further, exposure of cells to JA caused inactivation of the TNFα-TAK1-IKK-NF-κB axis and inhibition of TNFα-stimulated NF-κB activity and nuclear translocation, followed by down-regulation of NF-κB target genes involved in cell apoptosis (bcl-2, bcl-XL, XIAP, TRAF2) and in the cell cycle and growth (cyclin D, c-Myc). Moreover, JA inhibited local growth and dissemination of cancer cells to multiple organs in vivo. CONCLUSIONS: JA exerts significant anticancer effects on BL cells in vitro and in vivo via targeting the NF-κB signaling cascade. These results highlight the potential of JA as a chemotherapeutic agent and warrant for development of it as a drug for therapy of lymphomas.
Clinical Cancer Research 04/2013; · 7.74 Impact Factor
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Xinying Yang,
Guojian Zhang,
Xuelian Tang,
Jieying Jiao,
Sung Yeon Kim,
Joo Young Lee,
Tianjiao Zhu,
Dehai Li,
Yong Gab Yun,
Qianqun Gu,
Hyun Park
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ABSTRACT: ACTG-toxin H (AH) originates from Alternaria sp. In this study, we explored the molecular mechanism underlying the anti-inflammatory properties of AH. Treatment with AH inhibited lipopolysaccharide (LPS)-induced interleukin-6, IL-1β, inducible nitric oxide synthase, and cyclooxygenase-2 expression and nitric oxide production. Furthermore, AH inhibited LPS-induced P38 MAPK and Akt activation in RAW264.7 cells. Electrophoretic mobility shift assays (EMSAs) showed that AH inhibited LPS-induced nuclear factor-κB (NFκB) DNA-binding activity. Using transfection assay and measurement of an NFκB-sensitive promoter region, we found that transfection of toll-like receptor 4 (TLR4) increased LPS-induced NFκB transcription activity in 293T cells. AH significantly blocked LPS-induced NFκB activation in TLR4-transfected cells. Taken together, our data indicated that anti-inflammatory properties of AH resulted from the inhibition of proinflammatory cytokines and enzyme production via the TLR4/NFκB signaling pathway.
Molecular and Cellular Biochemistry 11/2012; · 2.06 Impact Factor
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Tao Chen,
Yi Xu,
He Guo,
Yanling Liu,
Pingting Hu, Xinying Yang,
Xiaoguang Li,
Shichao Ge,
Sadanandan E Velu,
Dwayaja H Nadkarni,
Wei Wang,
Ruiwen Zhang,
Hui Wang
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ABSTRACT: The present study was designed to determine the biological effects of novel marine alkaloid analog 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) on human ovarian cancer cells for its anti-tumor potential and the underlying mechanisms as a novel chemotherapeutic agent. Human ovarian cancer cells (A2780 and OVCAR-3), and Immortalized non-tumorigenic human Ovarian Surface Epithelial cells (IOSE-144), were exposed to FBA-TPQ for initial cytotoxicity evaluation (via MTS assay kit, Promega). The detailed in-vitro (cell level) and in-vivo (animal model) studies on the antitumor effects and possible underlying mechanisms of action of the compounds were then performed. FBA-TPQ exerted potent cytotoxicity against human ovarian cancer A2780 and OVCAR-3 cells as an effective inhibitor of cell growth and proliferation, while exerting lesser effects on non-tumorigenic IOSE-144 cells. Further study in the more sensitive OVCAR-3 cell line showed that it could potently induce cell apoptosis (Annexin V-FITC assay), G2/M cell cycle arrest (PI staining analysis) and also dose-dependently inhibit OVCAR-3 xenograft tumors' growth on female athymic nude mice (BALB/c, nu/nu). Mechanistic studies (both in vitro and in vivo) revealed that FBA-TPQ might exert its activity through Reactive Oxygen Species (ROS)-associated activation of the death receptor, p53-MDM2, and PI3K-Akt pathways in OVCAR-3 cells, which is in accordance with in vitro microarray (Human genome microarrays, Agilent) data analysis (GEO accession number: GSE25317). In conclusion, FBA-TPQ exhibits significant anticancer activity against ovarian cancer cells, with minimal toxicity to non-tumorigenic human IOSE-144 cells, indicating that it may be a potential therapeutic agent for ovarian cancer.
PLoS ONE 01/2011; 6(6):e20729. · 4.09 Impact Factor
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ABSTRACT: Excessive release of proinflammatory cytokines by activated microglia can cause neurotoxicity in neurodegenerative diseases. We found that Brevicompanine E (BE), isolated from a deep ocean sediment derived fungus Penicillium sp., inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2) production in microglia. Moreover, electrophoretic mobility shift assay (EMSA) demonstrated that BE attenuated nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) DNA binding activity in LPS-induced microglia. Consistent with this finding, BE inhibited LPS-induced IkappaBalpha degradation, NF-kappaB nuclear translocation, and also Akt, c-Jun NH2-terminal kinase (JNK) phosphorylation. Thus, BE may be potentially useful for modulating neuroinflammation.
Journal of neuroimmunology 10/2009; 216(1-2):32-8. · 2.84 Impact Factor
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ABSTRACT: Five new diketopiperazine alkaloids, brevicompanines D-H (3-7), together with two known analogs, allo-brevicompanine B (1) and fructigenine B (2), were isolated from a deep ocean sediment derived fungus Penicillium sp. Their structures were established by spectroscopic methods including 2D NMR and chiral HPLC analysis. Compounds 4 and 7 inhibited lipopolysaccharide (LPS)-induced nitric oxide production in BV2 microglial cells.
CHEMICAL & PHARMACEUTICAL BULLETIN 09/2009; 57(8):873-6. · 1.59 Impact Factor
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Xiaonan Zhao,
Jia Chen,
Lei Lei,
Guangjing Hu,
Ying Xiong,
Jiajia Xu,
Qin Li, Xinying Yang,
Catherine Cy Chang,
Baoliang Song,
Tayuan Chang,
Boliang Li
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ABSTRACT: We have previously reported that human ACAT1 mRNAs produce the 50 kDa protein using the AUG(11397-1399) initiation codon, and also a minor 56 kDa isoform using the upstream in-frame GGC(1274-1276) initiation codon. The GGC(1274-1276) codon is located at the optional long 5'-untranslated region (5'-UTR, nt 1-1396) of the mRNAs. The DNA sequences corresponding to this 5'-UTR are located in two different chromosomes, 7 and 1. In the current work, we report that the optional long 5'-UTR significantly impairs the production of human ACAT1 protein initiated from the AUG(1397-1399)codon, mainly by promoting its mRNA decay. The western blot analyses indicated that the optional long 5'-UTR potently impaired the production of different proteins initiated from the AUG(1397-1399) codon, meaning that this impairing effect was not influenced by the 3'-UTR or the coding sequence of ACAT1 mRNA. The results of reverse transcription-quantitative polymerase chain reaction demonstrated that this 5'- UTR dramatically reduced the contents of its linked mRNAs. Analyses of the protein to mRNA ratios showed that this 5'-UTR mainly decreased its mRNA stability rather than altering its translational efficiency. We next performed the plasmid transfection experiments and used actinomycin D to inhibit transcription. The results showed that this 5'-UTR promoted its mRNA decay. Additional transfection and nucleofection experiments using RNAs prepared in vitro illustrated that, in both the cytoplasm and the nucleus of cells, the optional long 5'-UTR-linked mRNAs decayed faster than those without the link. Overall, our study brings new insight to the regulation of the human ACAT1 gene expression at the post-transcription level.
Acta Biochimica et Biophysica Sinica 02/2009; 41(1):30-41. · 1.38 Impact Factor
