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ABSTRACT: HQS-3 is a newly baicalein derivative with a benzene substitution. We investigated the anticancer effect of HQS-3 in vivo and in vitro. HQS-3 significantly decreased tumor growth in mice inoculated with Heps and HepG2 cells; and had little influence on the state and weight of animals. After treatment with 20 mg/kg HQS-3, the inhibitory rate of tumor weight in mice inoculated with Heps and HepG2 cells were 63.62% and 68.03%, respectively. Meanwhile, HQS-3 inhibited the viability of various kinds of tumor cells with IC50 values in the range of 22.98 to 54.32 μM after 48 h treatment measured by MTT-assay. HQS-3 remarkably inhibited viability of hepatoma cells in a concentration- and time-dependent manner and induced apoptosis in HepG2 cells by DAPI staining and Annexin V/PI double staining. The apoptosis-induction effect of HQS-3 was attributed to its ability to modulate the actvity of caspase-9, caspase-3 and PARP. Moreover, the expression of bax protein was increased while the bcl-2 protein was decreased, leading to an increase in Bax/Bcl-2 ratio. The accumulation of ROS induced by HQS-3 in HepG2 cells was also observed. The further results suggested that HQS-3 induced mitochondrial-mediated apoptosis by increasing ROS level and inhibiting the expression of anti-oxidative protein SOD2. HQS-3 exerted anti-tumor activity both in vitro and in vivo via inducing tumor cells apoptosis, and these results suggested that it deserves further investigation as a novel chemotherapy for human tumors.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 04/2013; · 2.61 Impact Factor
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ABSTRACT: AIM: To investigate the potential anticancer effects of the natural flavonoid wogonin on human hepatocellular carcinoma (HCC) cells and tumor xenografts and the contribution of the unfolded protein response (UPR) and AKT pathways to the cytotoxicity of wogonin. METHODS: The HCC cell lines HepG2, SMMC-7721 and Hep3B were treated with wogonin. 3-(4 5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide assays were used to evaluate the cell viability. Flow cytometry assays were used to identify the cell death types and measure the concentrations of intracellular H(2) O(2) and Ca(2+) . Western blotting assays were used to detect the protein expression levels of members in the UPR and AKT pathways. Relative quantitative real-time polymerase chain reaction assays were used to analysis the mRNA expression levels of chop and trb3. Furthermore, the male BALB/c nude mice with SMMC-7721 xenografts were treated with wogonin. The tumor volume, tumor weight and bodyweight were monitored during the tumorigenicity assays. RESULTS: Wogonin significantly inhibited the viability of HCC cells by inducing apoptosis and necrosis. This cytotoxicity was at least partially attributed to the activation of the UPR pathway and consequent inactivation of AKT signaling, which resulted from the production of intracellular H(2) O(2) and causal release of endoplasmic reticulum Ca(2+) . Moreover, wogonin evidently repressed the growth of xenografts but slightly influenced the bodyweight of mice. CONCLUSION: Wogonin is a prospect for improving the systemic chemotherapy strategy on HCC by concurrently rectifying the aberrant UPR and AKT signaling pathways, which are crucial to the biology of HCC.
Hepatology Research 12/2012; · 2.20 Impact Factor
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ABSTRACT: Tumor necrosis factor-α (TNF-α) is being used as an antineoplastic agent in treatment regimens of patients with locally advanced solid tumors, but TNF-α alone is only marginally active. In clinical use, it is usually combined with other chemical agents to increase its tumor response rate. Our previous studies reported that LYG-202 (5-hydroxy-8-methoxy-7-(4-(4-methylpiperazin-1-yl)butoxy)-2-phenyl-4H-chromen-4-one), a synthesized flavonoid with a piperazine substitution, has antiproliferative, antiangiogenic, and proapoptotic activities in multiple cancer cell lines. Here we evaluated the antineoplastic effect of TNF-α and analyzed the mechanism underlying its combination with LYG-202. Our results indicated that LYG-202 significantly increased the cytostatic and proapoptotic activity of TNF-α in HepG2 cells and heightened the protein level of apoptosis-related genes including caspase-3, caspase-8/9, cleaved poly(ADP-ribose) polymerase, and Bid. The fact that LYG-202 had a fitness score similar to that of the casein kinase 2 (CK2) inhibitor naphthyridine-8-carboxylate (CX-4945) implied to us that it may serve as a potential candidate for CK2 inhibitor, and the kinase activity assay suggested that LYG-202 significantly inhibited CK2 activity. Moreover, the electrophoretic mobility shift assay and luciferase assay showed that LYG-202 blocked the TNF-α-induced nuclear factor-κB (NF-κB) survival signaling pathway primarily by inactivating protein kinase CK2. In murine xenograft models, we also found that LYG-202 enhanced TNF-α antineoplastic activity and inhibited CK2 activity and NF-κB-regulated antiapoptotic gene expression. All these results showed that LYG-202 enhanced TNF-α-induced apoptosis by attenuating the CK2-dependent NF-κB pathway and probably is a promising agent in combination with TNF-α.
Molecular pharmacology 08/2012; 82(5):958-71. · 4.53 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is a refractory malignancy with a high incidence and large mortality. Current strategy for the chemotherapy of HCC focuses on developing agents with better efficacy and lower toxicity. In this study, we demonstrated that the natural flavonoid oroxylin A preferentially inhibited the viability of HCC cell line HepG2 but not the normal hepatic cell line L02. In HepG2 but not L02 cells, oroxylin A induced substantial production of intracellular H₂O₂ and inordinate activation of the PERK-eIF2α-ATF4-CHOP branch of the unfolded protein response (UPR) pathway, which resulted in the induction of TRB3 and causal reduction of p-AKT1/2/3 (Ser473). Moreover, these effects were eliminated by either the stable knockdown of CHOP or the pretreatment and then co-incubation with the specific H₂O₂ scavenger catalase. These results indicated that the H₂O₂-triggered overactivation of the UPR pathway and causal inactivation of AKT signaling contributed to the preferential cytotoxicity of oroxylin A in malignant HepG2 cells. Therefore, present study proposed an underlying molecular mechanism that implicated the selective antitumor effect of oroxylin A and recommended oroxylin A as a prospect for improving the current chemotherapeutic strategy for the treatment of HCC.
Toxicology Letters 05/2012; 212(2):113-25. · 3.23 Impact Factor
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ABSTRACT: Genotypic differences in acquiring immobile P exist among species or cultivars within one species. We investigated the P-efficiency
mechanisms of rapeseed (Brassica napus L.) in low P soil by measuring plant growth, P acquisition and rhizosphere properties. Two genotypes with different P efficiencies
were grown in a root-compartment experiment under low P (P15: 15mg P kg−1) and high P (P100: 100mg P kg−1) treatments. The P-efficient genotype produced more biomass, and had a high seed yield and high P acquisition efficiency
under low P treatment. Under both P treatments, both genotypes decreased inorganic P (Pi) and organic P (Po) fractions in
the rhizosphere soil. However there was no decrease in NaHCO3-Po at P100. For the P15 treatment, the concentrations of NaHCO3-Po and NaOH-Po were negatively correlated with soil acid phosphatase activity. The P-efficient genotype 102 differed from
the P-inefficient genotype 105 in the following ways. In the rhizosphere the soil pH was lower, acid phosphatase activity
was higher, and depletion of P was greater. Further the depletion zones were wider. These results suggested that improving
P efficiency based on the character of P efficiency acquisition in P-efficient genotype would be a potential approach for
maintaining rapeseed yield potential in soils with low P bioavailability.
Plant and Soil 04/2012; 320(1):91-102. · 2.73 Impact Factor
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ABSTRACT: It has been well characterized that flavonoids possess pronounced anticancer potentials including anti-angiogenesis, anti-metastasis, and pro-apoptosis. Herein, we report, for the first time, that VI-14, a novel flavonoid derivative, possesses anti-cancer properties. The purpose of this study is to investigate the anti-migration and anti-invasion activities of VI-14 in breast cancer cells. Our data indicate that VI-14 inhibits adhesion, migration and invasion of MDA-MB-231 and MDA-MB-435 human breast cancer cells. MDA-MB-231 cells treated with VI-14 display reduced activities and expressions of ECM degradation-associated proteins including matrix metalloproteinase 2 (MMP-2) and 9 (MMP-9) at both the protein and mRNA levels. Meanwhile, VI-14 treatment induces an up-regulated expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and 2 (TIMP-2) in MDA-MB-231 cells. Western blotting results show that phosphorylation levels of critical components of the MAPK signaling pathway, including ERK, JNK and P38, are dramatically decreased in VI-14-treated MDA-MB-231 cells. Furthermore, treatment of VI-14 significantly decreases the nuclear levels and the binding ability of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). Taken together, our data suggest that VI-14 treatment suppresses migration and motility of breast cancer cells, and VI-14 may be a potential compound for cancer therapy.
Toxicology and Applied Pharmacology 04/2012; 261(2):217-26. · 4.45 Impact Factor
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ABSTRACT: NAD-dependent l- and d-lactate dehydrogenases coexist in Lactobacillus genomes and may convert pyruvic acid into l-lactic acid and d-lactic acid, respectively. Our findings suggest that the relative catalytic efficiencies of ldhL- and ldhD-encoded products are crucial for the optical purity of lactic acid produced by Lactobacillus strains.
Applied and environmental microbiology 02/2012; 78(9):3480-3. · 3.69 Impact Factor
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ABSTRACT: Genotypic variations in the adaptive response to low-phosphorus (P) stress and P-uptake efficiency have been widely reported in many crops. We conducted a pot experiment to evaluate the P-acquisition ability of two rapeseed (Brassica napus) genotypes supplied with two sparingly soluble sources of P, Al-P and Fe-P. Then, the root morphology, proton concentrations, and carboxylate content were investigated in a solution experiment to examine the genotypic difference in P-acquisition efficiency. Both genotypes produced greater biomass and accumulated more P when supplied with Al-P than when supplied with Fe-P. The P-efficient genotype 102 showed a significantly greater ability to deplete sparingly soluble P from the rhizosphere soil because of its greater biomass and higher P uptake compared with those of the P-inefficient genotype 105. In the solution experiment, the P-efficient genotype under low-P conditions developed dominant root morphological traits, and it showed more intensive rhizosphere acidification because of greater H(+) efflux, higher H(+)-ATPase activity, and greater exudation of carboxylates than the P-inefficient genotype. Thus, a combination of morphological and physiological mechanisms contributed to the genotypic variation in the utilization of different sparingly soluble P sources in B. napus.
Science China. Life sciences 12/2011; 54(12):1134-42. · 2.02 Impact Factor
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Chenglin Li,
Na Lu,
Qi Qi,
Fanni Li,
Yun Ling,
Yan Chen,
Yansu Qin,
Zhiyu Li, Haiwei Zhang,
Qidong You,
Qinglong Guo
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ABSTRACT: Cell adhesion plays an important role in the steps of cancer metastasis. Regulation of cell-cell (intercellular) and cell-matrix adhesion is a promising strategy for cancer progression. Gambogic acid is a xanthone derived from the resin of the Chinese plant Garciania hanburyi, with potent anti-metastasis activity on highly metastatic cells. The aim of this study was to investigate the function and mechanism of gambogic acid on tumor adhesion. We found that gambogic acid strongly inhibited the adhesion of human cancer cells to fibronectin. This inhibition was associated with the deformation of focal adhesion complex, which was mediated by suppressing the expression of integrin β1 and integrin signaling pathway. In vitro, cell lipid rafts clustering was inhibited following treatment of gambogic acid, which induced the suppression of integrin β1 and focal adhesion complex proteins colocalization within rafts. Moreover, gambogic acid significantly decreased cellular cholesterol content, whereas cholesterol replenishment lessened the inhibitory effect of gambogic acid on cell adhesion. Real-time PCR analysis showed that gambogic acid reduced mRNA levels of hydroxymethylglutaryl-CoA reductase and sterol regulatory element binding protein-2, while increased acetyl-CoA acetyltransferase-1/2. Taken together, these results demonstrate that gambogic acid inhibits cell adhesion via suppressing integrin β1 abundance and cholesterol content as well as the membrane lipid raft-associated integrin function, which provide new evidence for the anti-cancer activity of gambogic acid.
Biochemical pharmacology 09/2011; 82(12):1873-83. · 4.25 Impact Factor
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ABSTRACT: Phenyllactic acid (PLA), a novel antimicrobial compound with broad and effective antimicrobial activity against both bacteria and fungi, can be produced by many microorganisms, especially lactic acid bacteria. However, the concentration and productivity of PLA have been low in previous studies. The enzymes responsible for conversion of phenylpyruvic acid (PPA) into PLA are equivocal.
A novel thermophilic strain, Bacillus coagulans SDM, was isolated for production of PLA. When the solubility and dissolution rate of PPA were enhanced at a high temperature, whole cells of B. coagulans SDM could effectively convert PPA into PLA at a high concentration (37.3 g l(-1)) and high productivity (2.3 g l(-1) h(-1)) under optimal conditions. Enzyme activity staining and kinetic studies identified NAD-dependent lactate dehydrogenases as the key enzymes that reduced PPA to PLA.
Taking advantage of the thermophilic character of B. coagulans SDM, a high yield and productivity of PLA were obtained. The enzymes involved in PLA production were identified and characterized, which makes possible the rational design and construction of microorganisms suitable for PLA production with metabolic engineering.
PLoS ONE 01/2011; 6(4):e19030. · 4.09 Impact Factor
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Yinyuan Wu,
Yanquan Zhang, Haiwei Zhang,
Xi Yang,
Yinyin Wang,
Fangli Ren,
Huitu Liu,
Yonggong Zhai,
Baoqing Jia,
Jun Yu,
Zhijie Chang
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ABSTRACT: The formation of a β-catenin·TCF4 complex in the nucleus of cells is well known as a prerequisite for the transcription of Wnt target genes. Although many co-factors have been identified to regulate the activity of the β-catenin·TCF4 complex, it remains unclear how the complex association is negatively regulated. In this study, we report that p15RS, a negative regulator of the cell cycle, blocks β-catenin·TCF4 complex formation and inhibits Wnt signaling. We observed that p15RS interacts with β-catenin and TCF4. Interestingly, whereas the interaction of p15RS with β-catenin is increased, its interaction with TCF4 is decreased upon Wnt1 stimulation. Moreover, overexpression of p15RS reduces the interaction of β-catenin with TCF4, whereas the depletion of p15RS enhances their interaction. We further demonstrate that overexpression of p15RS suppresses canonical Wnt signaling and results in retarded cell growth, whereas depletion of p15RS shows an enhanced effect on Wnt signaling. We analyzed that inhibition of Wnt signaling by p15RS leads to decreased expression of CYCLIN D1 and c-MYC, two Wnt targeted genes critical for cell growth. Our data suggest that p15RS inhibits Wnt signaling by interrupting β-catenin·TCF4 complex formation and that Wnt signaling initiates downstream gene expression by removing p15RS from promoters.
Journal of Biological Chemistry 11/2010; 285(45):34621-31. · 4.77 Impact Factor
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Haiwei Zhang,
Hui Zhang,
Yanquan Zhang,
Ser Sur Ng,
Fangli Ren,
Yingying Wang,
Yaqi Duan,
Lin Chen,
Yonggong Zhai,
Qinglong Guo,
Zhijie Chang
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ABSTRACT: The TCF4/beta-catenin complex, the executor of canonical Wnt/beta-catenin signaling, is regulated by a variety of factors. Among these, Dishevelled (Dvl) is a critical regulator that releases beta-catenin from degradation and stabilizes TCF4/beta-catenin complex. Here, we report that DDIP (Dishevelled-DEP domain Interacting Protein, also named as Spats1, spermatogenesis associated, serine-rich 1), a novel protein that interacts with Dvl, regulates Wnt signaling. We provide evidence that DDIP suppresses Lef-1 luciferase reporter activity stimulated by Wnt1, Dvl2 or beta-catenin, interacts with the TCF4/beta-catenin complex, and disrupts the interaction of TCF4 and beta-catenin by promoting TCF4 degradation through the proteasome pathway. Our results indicate that DDIP is a negative regulator of the canonical Wnt signaling.
Cellular signalling 11/2010; 22(11):1753-60. · 4.09 Impact Factor
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ABSTRACT: To understand whether genotypic variation in acid phosphatase (APase) activity in rapeseed (Brassica napus L.) induced by phosphorus (P) deficiency has impact on P efficiency, soil APase activity in the rhizosphere for rapeseed P-efficient genotype 102 and P-inefficient genotype 105 was measured against organic and inorganic P sources in the pot experiment, and the activities of root-secreted APase and leaf intracellular APase were investigated in different P-starvation periods in the nutrient solution. Higher activity of root-secreted APase in B. napus was induced under low P conditions. However, P nutrition and P uptake efficiency of the plants supplied with organic P were not directly related to the activity of root-secreted APase due to several confounding factors affecting APase availability. The higher activity of leaf APase improved P remobilization in plants and played important roles in enhancing P use efficiency, shown by the significant correlation between leaf APase activity and P use efficiency in a rapeseed recombinant inbred population of 135 lines.
Science China. Life sciences 06/2010; 53(6):709-17. · 2.02 Impact Factor
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Ying Gao,
Na Lu,
Yun Ling,
Yan Chen,
Ling Wang,
Qing Zhao,
Qi Qi,
Wei Liu, Haiwei Zhang,
Qidong You,
Qinglong Guo
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ABSTRACT: In this study, we examined the antiangiogenic effect of oroxylin A in vitro and in vivo and explored the potential mechanisms for this effect.
Transwell assay and tube formation assay were used to evaluate the effects of oroxylin A on vascular endothelial growth factor (VEGF)-induced migration and tube formation of human umbilical vein endothelial cells (HUVECs). Rat aortic ring assay was also employed to assess the effect of oroxylin A on microvessel outgrowth from rat aorta. Human tumor xenografts model in nude mice was further used to investigate the antiangiogenic activity of oroxylin A in vivo. Western blot analysis was used to investigate the related mechanism.
Oroxylin A remarkably suppressed the VEGF-stimulated migration and tube formation of HUVECs. It also inhibited microvessel sprouting from rat aortic ring in vitro. In addition, it suppressed the angiogenesis of xenograft tumor in nude mice, which concurred with the inhibition of tumor growth. Moreover, oroxylin A blocked VEGF-induced phosphorylation of KDR/Flk-1 and related downstream signaling molecules, including p38 mitogen-activated protein kinase, extracellular signal-regulated kinase and Akt.
Oroxylin A possessed antiangiogenic activities in vitro and in vivo, which could be an underlying mechanism of its anticancer effect.
Journal of Cancer Research and Clinical Oncology 11/2009; 136(5):667-75. · 2.56 Impact Factor
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ABSTRACT: Varp, a novel protein containing a VPS9 domain and ankyrin repeats, can function as a guanine nucleotide exchange factor (GEF) of Rab21. We previously reported that Varp plays an important role in the regulation of endosome dynamics. To further investigate the function of Varp, a yeast two-hybrid screen was performed and Rab38 was identified as a Varp-associated protein. We demonstrate that Varp physically interacts with Rab38, and preferentially binds to the active GTP-bound form of Rab38 both in vitro and in vivo. Furthermore, Varp was shown to be recruited to Rab38-positive organelles in an ankyrin-repeat 1 (ANK1)-dependent manner. Our data demonstrate that Varp is a potential effector of Rab38. Together with our previous study, we propose Varp serves as both an effector and a GEF by interacting with different Rabs in mammalian cells.
Biochemical and Biophysical Research Communications 08/2008; 372(1):162-7. · 2.48 Impact Factor
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Na Lu,
Yun Ling,
Ying Gao,
Yan Chen,
Rong Mu,
Qi Qi,
Wei Liu, Haiwei Zhang,
Hongyan Gu,
Sen Wang,
Yong Yang,
Qinglong Guo
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ABSTRACT: Endostar, a novel recombinant human endostatin expressed and purified in Escherichia coli with an additional nine-amino acid sequence forming another his-tag structure, was approved by the State Food and Drug Administration of China (SFDA) in 2005 for the treatment of non-small-cell lung cancer. However, the molecular mechanism of its potent anticancer activity remains poorly understood and warrants further investigations. In this study, we examined the anti-invasive activities of endostar in vitro. The results showed that endostar suppressed MDA-MB-435 cell adhesion to the fibronectin-coated substrate in a concentration-dependent manner. It could inhibit the wound healing migration of MDA-MB-435 cells and invasion of MDA-MB-435 cells through reconstituted ECM (matrigel). Zymography revealed that endostar decreased the secretion of MMP-2 and MMP-9. Endostar could also inhibit the expressions of MMP-2 and MMP-9 in MDA-MB-435 cells. Additionally, endostar exerted an inhibitory effect on the phosphorylation of ERK1/2. Collectively, these data provided a molecular basis for the anti-invasive effects of endostar.
Experimental Biology and Medicine 06/2008; 233(8):1013-20. · 2.64 Impact Factor
