44 results on '"Tse AK"'
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2. Corrigendum to "Comprehensive comparison on the anti-inflammatory effects of three species of Sigesbeckia plants based on NF-κB and MAPKs signal pathways in vitro" [J. Ethnopharmacol. 250, 25 March (2020), 112530].
- Author
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Linghu KG, Zhao GD, Xiong W, Sang W, Xiong SH, Wing Tse AK, Hu Y, Bian Z, Wang Y, and Yu H
- Published
- 2025
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3. Comparison of the colour accuracy of a single-lens reflex camera and a smartphone camera in a clinical context.
- Author
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Yung D, Tse AK, Hsung RT, Botelho MG, Pow EH, and Lam WY
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- Humans, Color, Calibration, Cuspid, Smartphone, Reflex
- Abstract
Objectives: This study aimed to investigate the colour accuracy of digital photographs captured by a single-lens reflex (SLR) camera and a smartphone camera in a clinical setting., Methods: Dentate subjects were recruited, and their maxillary anterior teeth were photographed along with a colour target and a dental shade guide. There were eight groups: Group 1: SLR camera with a 100 mm macro-lens and a ring-flash (SLRC); Group 2: SLRC with a polarizer; Group 3: SLRC with white-balance calibration; Group 4: SLRC with a polarizer and white-balance calibration. Groups 5 to 8 were similar to Groups 1 to 4, except a smartphone camera and an external light source (SC) were used. The CIE LAB coordinates of the colour target, shade guide, and centre of the maxillary right central incisor (tooth 11) in the digital photographs were retrieved. The colour difference ΔE=[(ΔL*)
2 +(Δa*)2 +(Δb*)2 ]1/2 to the reference colour coordinates or the reading of the dental spectrophotometer was calculated. The results were analysed by the Kruskal-Wallis test at α=0.05 with Bonferroni correction., Results: Thirty-nine subjects were photographed. SLRC with a polarizer showed the largest ΔE in this study (P<0.001). When capturing tooth 11, SLRC with calibrated white-balance resulted in the smallest ΔE in this study (P<0.001), and the use of a polarizer and/or calibrated white-balance did not result in a smaller ΔE than that of SC alone (P>0.001)., Conclusion: Calibration for white-balance is recommended for the SLRC. The use of a polarizer does not show an improvement in colour accuracy. SC alone may be sufficient for intraoral photography., Clinical Significance: When capturing intraoral photography using a single-lens reflex camera, it is recommended to calibrate the white-balance. The use of a polarizer does not significantly improve colour accuracy. However, a smartphone camera with an external light source can serve as a viable alternative., Competing Interests: Declaration of Competing Interest The study has been presented at the 2022 IADR/APR General Session & Exhibition., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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4. A BODIPY-based fluorescent sensor for the detection of Pt2+ and Pt drugs.
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Tang FK, Zhu J, Kong FK, Ng M, Bian Q, Yam VW, Tse AK, Tse YC, and Leung KC
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- A549 Cells, Cisplatin therapeutic use, Humans, Ligands, Lung Neoplasms drug therapy, Molecular Structure, Optical Imaging, Spectrometry, Fluorescence, Boron Compounds chemistry, Cisplatin analysis, Fluorescent Dyes chemistry, Lung Neoplasms diagnostic imaging, Platinum analysis
- Abstract
A BODIPY-based fluorescent sensor PS with an NO4S2 podand ligand was studied for the selective detection of Pt2+ over 21 cations as well as selected platinum drugs in aqueous medium. The platinum sensor PS shows 28-fold, 22-fold and 14-fold fluorescence turn-on enhancements to Pt2+, cisplatin and nedaplatin, and was thereby employed to detect platinum drugs in A-549 human lung cancer cells.
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- 2020
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5. Ribosome-Inactivating Protein α-Momorcharin Derived from Edible Plant Momordica charantia Induces Inflammatory Responses by Activating the NF-kappaB and JNK Pathways.
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Chen YJ, Zhu JQ, Fu XQ, Su T, Li T, Guo H, Zhu PL, Lee SK, Yu H, Tse AK, and Yu ZL
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- Animals, Cell Line, Cell Line, Tumor, Cell Survival drug effects, Cytokines biosynthesis, Gene Expression Regulation drug effects, Humans, Male, Mice, Mice, Inbred ICR, Microarray Analysis, Plants, Edible, Recombinant Proteins chemistry, Recombinant Proteins pharmacology, Ribosome Inactivating Proteins pharmacology, Inflammation chemically induced, MAP Kinase Signaling System drug effects, Momordica charantia chemistry, NF-kappa B drug effects, Ribosome Inactivating Proteins chemistry
- Abstract
Alpha-momorcharin (α-MMC), a member of the ribosome-inactivating protein (RIP) family, has been found in the seeds of Momordica charantia (bitter melon). α-MMC contributes a number of pharmacological activities; however, its inflammatory properties have not been well studied. Here, we aim to determine the inflammatory responses induced by recombinant α-MMC and identify the underlying mechanisms using cell culture and animal models. Recombinant α-MMC was generated in Rosetta™(DE3)pLysS and purified by the way of nitrilotriacetic acid (NTA) chromatography. Treatment of recombinant α-MMC at 40 μg/mL exerted sub-lethal cytotoxic effect on THP-1 monocytic cells. Transcriptional profiling revealed that various genes coding for cytokines and other proinflammatory proteins were upregulated upon recombinant α-MMC treatment in THP-1 cells, including MCP-1, IL-8, IL-1β, and TNF-α. Recombinant α-MMC was shown to activate IKK/NF-κB and JNK pathways and the α-MMC-induced inflammatory gene expression could be blocked by IKKβ and JNK inhibitors. Furthermore, murine inflammatory models further demonstrated that α-MMC induced inflammatory responses in vivo. We conclude that α-MMC stimulates inflammatory responses in human monocytes by activating of IKK/NF-κB and JNK pathways, raising the possibility that consumption of α-MMC-containing food may lead to inflammatory-related diseases., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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6. Synthesis and study of Au(iii)-indolizine derivatives: turn-on luminescence by photo-induced controlled release.
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Yang J, Zhu Y, Tse AK, Zhou X, Chen Y, Tse YC, Wong KM, and Ho CY
- Abstract
The photo- and structural properties of a series of Au(iii) indolizine complexes were determined. Controlled release of halogenated indolizine derivatives from the corresponding Au(iii) complexes was achieved by photoinduced C-X bond formation, which provided turn-on luminescence with an increase in emission intensity of up to 67 times.
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- 2019
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7. Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo .
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Zhu PL, Fu XQ, Li JK, Tse AK, Guo H, Yin CL, Chou JY, Wang YP, Liu YX, Chen YJ, Hossen MJ, Zhang Y, Pan SY, Zhao ZJ, and Yu ZL
- Abstract
Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is a common cause of cancer-related death worldwide. Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in HCC and has been proposed as a chemotherapeutic target for HCC. Antrodia camphorata (AC), a medicinal mushroom unique to Taiwan, is traditionally used for treating HCC. Whereas natural AC is scarce, cultured AC mycelia are becoming alternatives. In this study, we investigated the anti-HCC effects of the ethyl acetate fraction of an ethanolic extract of AC mycelia (EEAC), particularly exploring the involvement of STAT3 signaling in these effects. We found that EEAC reduced cell viability, induced apoptosis, and retarded migration and invasion in cultured HepG2 and SMMC-7721 cells. Immunoblotting results showed that EEAC downregulated protein levels of phosphorylated and total STAT3 and JAK2 (an upstream kinase of STAT3) in HCC cells. Real-time PCR analyses showed that STAT3, but not JAK2, mRNA levels were decreased by EEAC. EEAC also lowered the protein level of nuclear STAT3, decreased the transcriptional activity of STAT3, and downregulated protein levels of STAT3-targeted molecules, including anti-apoptotic proteins Bcl-xL and Bcl-2, and invasion-related proteins MMP-2 and MMP-9. Over-activation of STAT3 in HCC cells diminished the cytotoxic effects of EEAC. In SMMC-7721 cell-bearing mice, EEAC (100 mg/kg, i.g. for 18 days) significantly inhibited tumor growth. Consistent with our in vitro data, EEAC induced apoptosis and suppressed JAK2/STAT3 activation/phosphorylation in the tumors. Taken together, EEAC exerts anti-HCC effects both in vitro and in vivo ; and inhibition of STAT3 signaling is, at least in part, responsible for these effects. We did not observe significant toxicity of EEAC in normal human liver-derived cells, nude mice and rats. Our results provide a pharmacological basis for developing EEAC as a safe and effective agent for HCC management.
- Published
- 2018
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8. Comparison of the chemical profiles and inflammatory mediator-inhibitory effects of three Siegesbeckia herbs used as Herba Siegesbeckiae (Xixiancao).
- Author
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Guo H, Zhang Y, Cheng BC, Lau MY, Fu XQ, Li T, Su T, Zhu PL, Chan YC, Tse AK, Yi T, Chen HB, and Yu ZL
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- Animals, Cell Survival drug effects, Interleukin-6 analysis, Interleukin-6 metabolism, Macrophages drug effects, Mice, Nitric Oxide analysis, Nitric Oxide metabolism, RAW 264.7 Cells, Reproducibility of Results, Asteraceae chemistry, Drugs, Chinese Herbal chemistry, Drugs, Chinese Herbal pharmacology
- Abstract
Background: Herba Siegesbeckiae (HS, Xixiancao in Chinese) is a commonly used traditional Chinese medicinal herb for soothing joints. In ancient materia medica books, HS is recorded to be the aerial part of Siegesbeckia pubescens Makino (SP) which is also the only origin of HS in the 1963 edition of the Chinese Pharmacopeia (ChP). The aerial parts of Siegesbeckia orientalis L. (SO) and Siegesbeckia glabrescens Makino (SG) have been included as two additional origins for HS in each edition of ChP since 1977. However, chemical and pharmacological comparisons among these three species have not been conducted., Methods: An HPLC with diode array detector (HPLC-DAD) method combined with similarity analysis, hierarchical cluster analysis (HCA) and principal component analysis (PCA) was developed for comparing the fingerprint chromatograms of the three species. The inhibitory effects of the three species on NO production and IL-6 secretion in LPS-stimulated RAW264.7 macrophages were compared., Results: Fingerprint chromatograms of the three species showed different profiles, but had 13 common peaks. Results from HCA and PCA of the common peaks demonstrated that all 14 herbal samples of the three species tended to be grouped and separated species dependently. The extents of inhibition on NO production and IL-6 secretion of the three species were different, with SG being the most and SP the least potent., Conclusions: Both chemical profiles and inflammatory mediator-inhibitory effects of the three species were different. These findings provide a chemical and pharmacological basis for determining whether the three species can all serve as the origins of HS.
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- 2018
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9. An ethanolic extract of the aerial part of Siegesbeckia orientalis L. inhibits the production of inflammatory mediators regulated by AP-1, NF-κB and IRF3 in LPS-stimulated RAW 264.7 cells.
- Author
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Guo H, Zhang Y, Cheng BC, Fu X, Zhu P, Chen J, Chan Y, Yin C, Wang Y, Hossen M, Amin A, Tse AK, and Yu ZL
- Subjects
- Animals, Cell Nucleus metabolism, Chromatography, High Pressure Liquid, Mice, Plant Extracts chemistry, Protein Transport drug effects, RAW 264.7 Cells, Reference Standards, Signal Transduction drug effects, Toll-Like Receptor 4 metabolism, Asteraceae chemistry, Ethanol chemistry, Inflammation Mediators metabolism, Interferon Regulatory Factor-3 metabolism, Lipopolysaccharides pharmacology, NF-kappa B metabolism, Plant Extracts pharmacology, Transcription Factor AP-1 metabolism
- Abstract
Herba Siegesbeckiae (HS, the dried aerial part of Siegesbeckia orientalis L.) is a commonly used traditional Chinese medicinal herb for treating inflammatory diseases. HS has been reported to exert anti-inflammatory effects by inhibiting the MAPKs and NF-κB pathways, the downstream effectors of TLR4 signalling. This study aims to further investigate the involvement of TLR4 signalling cascades in the effects of an ethanolic extract of HS (HS for short) on inflammatory mediators in murine macrophages. HS was extracted using 50% ethanol. Lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were used as the cell model. ELISA was used to detect cytokine/chemokine secretion. Real time-PCR and immunoblotting were used to examine mRNA and protein levels, respectively. We observed that HS dose-dependently inhibited the secretion of PGE
2 , MCP-1, MIP-1α and RANTES, and down-regulated mRNA levels of iNOS, COX-2, IL-1β, IL-6, TNF-α, mPGES-1, MCP-1, MIP-1α and RANTES in LPS-stimulated RAW264.7 cells. HS did not affect the protein levels of TAK1, TBK1, PI3K, Akt, IKK, c-Jun, c-Fos and IRF3, while, dose-dependently decreased levels of their phosphorylated forms. The protein levels of IRAK1 and IRAK4 were upregulated, while those of TRAF6 and TRAF3 were downregulated by HS. Moreover, the nuclear protein levels of AP-1, NF-κB and IRF3 were dose-dependently decreased by HS. These results indicate that suppression of the IRAK4/MAPKs/AP-1, IRAK4/MAPKs/NF-κB, IRAK4/PI3K/NF-κB and TRAF3/TBK1/IRF3 pathways is associated with the inhibitory effects of HS on inflammatory mediators in LPS-stimulated RAW264.7 cells. This study provides a pharmacological basis for the clinical application of this herb in the treatment of inflammatory disorders.- Published
- 2018
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10. Computational and experimental prediction of molecules involved in the anti-melanoma action of berberine.
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Liu B, Fu XQ, Li T, Su T, Guo H, Zhu PL, Tse AK, Liu SM, and Yu ZL
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- Antineoplastic Agents therapeutic use, Berberine therapeutic use, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dihydroorotate Dehydrogenase, Humans, Melanoma drug therapy, Molecular Docking Simulation, Oxidoreductases Acting on CH-CH Group Donors metabolism, Phosphorylation drug effects, Protein Serine-Threonine Kinases metabolism, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Receptors, Glucocorticoid metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Antineoplastic Agents pharmacology, Berberine pharmacology, Melanoma metabolism
- Abstract
Ethnopharmacologic Relevance: Berberine (BBR) is a naturally occurring alkaloid compound that can be found in Chinese medicinal herbs such as Rhizoma Coptidis and Phellodendri Cortex. These BBR containing herbs are commonly used by Chinese medicine doctors to treat cancers including melanoma. In this study, we explored proteins potentially involved in the anti-melanoma effects of BBR using computational and experimental approaches., Materials and Methods: Target proteins of BBR were predicted using the reverse pharmacophore screening, molecular docking and molecular dynamics. Anti-melanoma activities of BBR in melanoma cells were examined by MTT and EdU proliferation assays. Effects of BBR on activities of target proteins in melanoma cells were examined by Western blotting or fluorescence assay., Results: Ten proteins implicated in cancer and with high fit-score in the reverse pharmacophore screening were selected as potential targets of BBR. Molecular docking and molecular dynamics revealed that BBR could stably bind to four of the ten proteins, namely 3-phosphoinositide-dependent protein kinase 1 (PDK1), glucocorticoid receptor (GR), p38 mitogen-activated protein kinase (p38) and dihydroorotate dehydrogenase (DHODH). Cellular experiments showed that BBR inhibited cell proliferation, increased the phosphorylation of GR and p38, and inhibited the activity of DHODH in A375 human melanoma cells., Conclusions: These findings suggest that p38, GR and DHODH are potentially involved in the anti-melanoma action of BBR. This study provided a chemical and pharmacological justification for the clinical use of BBR-containing herbs in melanoma treatment., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2017
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11. Inhibiting STAT3 signaling is involved in the anti-melanoma effects of a herbal formula comprising Sophorae Flos and Lonicerae Japonicae Flos.
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Li T, Fu X, Tse AK, Guo H, Lee KW, Liu B, Su T, Wang X, and Yu Z
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- Allografts, Animals, Apoptosis drug effects, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Disease Models, Animal, Humans, Melanoma, Experimental, Mice, Protein Transport, Antineoplastic Agents, Phytogenic pharmacology, Drugs, Chinese Herbal pharmacology, STAT3 Transcription Factor metabolism, Signal Transduction drug effects
- Abstract
A herbal formula (SL) comprising Sophorae Flos and Lonicerae Japonicae Flos was traditionally used to treat melanoma. Constitutively active signal transducer and activator of transcription 3 (STAT3) has been proposed as a therapeutic target in melanoma. Here we investigated whether an ethanolic extract of SL (SLE) exerted anti-melanoma activities by inhibiting STAT3 signaling. B16F10 allograft model, A375 and B16F10 cells were employed to assess the in vivo and in vitro anti-melanoma activities of SLE. A375 cells stably expressing STAT3C, a constitutively active STAT3 mutant, were used to determine the role of STAT3 signaling in SLE's anti-melanoma effects. Intragastric administration of SLE (1.2 g/kg) potently inhibited melanoma growth in mice and inhibited STAT3 phosphorylation in the tumors. In cultured cells, SLE dramatically reduced cell viability, induced apoptosis, suppressed migration and invasion, and restrained STAT3 activation and nuclear localization. STAT3C overexpression in A375 cells diminished SLE's effects on cell viability, apoptosis and invasion. Collectively, SLE exerted potent anti-melanoma effects partially by inhibiting STAT3 signaling. This study provides pharmacological justification for the traditional use of this formula in treating melanoma, and suggests that SLE has the potential to be developed as a modern alternative and/or complimentary agent for melanoma treatment and prevention.
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- 2017
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12. Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition.
- Author
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Tse AK, Chen YJ, Fu XQ, Su T, Li T, Guo H, Zhu PL, Kwan HY, Cheng BC, Cao HH, Lee SK, Fong WF, and Yu ZL
- Subjects
- Alkylating Agents administration & dosage, Animals, Cell Line, Tumor, DNA Damage drug effects, Humans, I-kappa B Kinase antagonists & inhibitors, Melanoma metabolism, Melanoma pathology, Mice, Neoplasm Metastasis, Nitrosourea Compounds administration & dosage, Thiophenes administration & dosage, Xenograft Model Antitumor Assays, Cell Death drug effects, I-kappa B Kinase genetics, Melanoma drug therapy, Oxidative Stress drug effects
- Abstract
Nitrosourea represents one of the most active classes of chemotherapeutic alkylating agents for metastatic melanoma. Treatment with nitrosoureas caused severe systemic side effects which hamper its clinical use. Here, we provide pharmacological evidence that reactive oxygen species (ROS) induction and IKKβ inhibition cooperatively enhance nitrosourea-induced cytotoxicity in melanoma cells. We identified SC-514 as a ROS-inducing IKKβ inhibitor which enhanced the function of nitrosoureas. Elevated ROS level results in increased DNA crosslink efficiency triggered by nitrosoureas and IKKβ inhibition enhances DNA damage signals and sensitizes nitrosourea-induced cell death. Using xenograft mouse model, we confirm that ROS-inducing IKKβ inhibitor cooperates with nitrosourea to reduce tumor size and malignancy in vivo. Taken together, our results illustrate a new direction in nitrosourea treatment, and reveal that the combination of ROS-inducing IKKβ inhibitors with nitrosoureas can be potentially exploited for melanoma therapy., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
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13. The anticancer and antiobesity effects of Mediterranean diet.
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Kwan HY, Chao X, Su T, Fu X, Tse AK, Fong WF, and Yu ZL
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- Animals, Anti-Inflammatory Agents, Non-Steroidal analysis, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Anti-Obesity Agents analysis, Anti-Obesity Agents therapeutic use, Anticarcinogenic Agents analysis, Anticarcinogenic Agents therapeutic use, Food Quality, Greece epidemiology, Humans, Neoplasms epidemiology, Neoplasms etiology, Neoplasms immunology, Obesity epidemiology, Obesity immunology, Obesity physiopathology, Olive Oil chemistry, Olive Oil standards, Olive Oil therapeutic use, Overweight epidemiology, Overweight immunology, Overweight physiopathology, Patient Compliance, Risk, Wine adverse effects, Wine analysis, Diet, Healthy, Diet, Mediterranean, Evidence-Based Medicine, Neoplasms prevention & control, Obesity prevention & control, Overweight prevention & control
- Abstract
Cancers have been the leading cause of death worldwide and the prevalence of obesity is also increasing in these few decades. Interestingly, there is a direct association between cancer and obesity. Each year, more than 90,000 cancer deaths are caused by obesity or overweight. The dietary pattern in Crete, referred as the traditional Mediterranean diet, is believed to confer Crete people the low mortality rates from cancers. Nevertheless, the antiobesity effect of the Mediterranean diet is less studied. Given the causal relationship between obesity and cancer, the antiobesity effect of traditional Mediterranean diet might contribute to its anticancer effects. In this regard, we will critically review the anticancer and antiobesity effects of this diet and its dietary factors. The possible mechanisms underlying these effects will also be discussed.
- Published
- 2017
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14. Metabolomics reveals the mechanisms for the cardiotoxicity of Pinelliae Rhizoma and the toxicity-reducing effect of processing.
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Su T, Tan Y, Tsui MS, Yi H, Fu XQ, Li T, Chan CL, Guo H, Li YX, Zhu PL, Tse AK, Cao H, Lu AP, and Yu ZL
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- Animals, Drugs, Chinese Herbal toxicity, Free Radicals antagonists & inhibitors, Free Radicals blood, Gene Expression Regulation, Zingiber officinale chemistry, Male, Medicine, Chinese Traditional, Pinellia toxicity, Rats, Rats, Sprague-Dawley, Signal Transduction, TOR Serine-Threonine Kinases blood, TOR Serine-Threonine Kinases genetics, Transforming Growth Factor beta blood, Transforming Growth Factor beta genetics, Cardiotoxicity prevention & control, Drugs, Chinese Herbal chemistry, Metabolomics, Pinellia chemistry, Technology, Pharmaceutical methods
- Abstract
Pinelliae Rhizoma (PR) is a commonly used Chinese medicinal herb, but it has been frequently reported about its toxicity. According to the traditional Chinese medicine theory, processing can reduce the toxicity of the herbs. Here, we aim to determine if processing reduces the toxicity of raw PR, and to explore the underlying mechanisms of raw PR-induced toxicities and the toxicity-reducing effect of processing. Biochemical and histopathological approaches were used to evaluate the toxicities of raw and processed PR. Rat serum metabolites were analyzed by LC-TOF-MS. Ingenuity pathway analysis of the metabolomics data highlighted the biological pathways and network functions involved in raw PR-induced toxicities and the toxicity-reducing effect of processing, which were verified by molecular approaches. Results showed that raw PR caused cardiotoxicity, and processing reduced the toxicity. Inhibition of mTOR signaling and activation of the TGF-β pathway contributed to raw PR-induced cardiotoxicity, and free radical scavenging might be responsible for the toxicity-reducing effect of processing. Our data shed new light on the mechanisms of raw PR-induced cardiotoxicity and the toxicity-reducing effect of processing. This study provides scientific justifications for the traditional processing theory of PR, and should help in optimizing the processing protocol and clinical combinational application of PR.
- Published
- 2016
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15. Iciartin, a novel FASN inhibitor, exerts anti-melanoma activities through IGF-1R/STAT3 signaling.
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Wu J, Du J, Fu X, Liu B, Cao H, Li T, Su T, Xu J, Tse AK, and Yu ZL
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- Cell Survival drug effects, Fatty Acid Synthase, Type I antagonists & inhibitors, Flavonoids chemistry, Humans, Melanoma metabolism, Melanoma pathology, Molecular Docking Simulation, Receptor, IGF Type 1, Receptors, Somatomedin metabolism, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, Tumor Cells, Cultured, Antineoplastic Agents, Phytogenic pharmacology, Flavonoids pharmacology, Melanoma drug therapy
- Abstract
Icaritin (IT) is a flavonoid isolated from Herba Epimedii. In this study, we evaluated the anti-melanoma activities of IT, and determined its cytotoxic mechanism. We found that IT exerted cytotoxicity to melanoma cells. Furthermore, IT induced melanoma cell apoptosis, which was accompanied with PARP cleavage. Mechanistically, IT suppressed p-STAT3 (tyr705) level in parallel with increases of p-STAT3 (ser727), p-ERK and p-AKT. IT significantly inhibited STAT3 nuclear translocation and reduced the levels of STAT3 -targeted genes. IT also inhibited IGF-1-induced STAT3 activation through down-regulation of total IGF-1R level. No dramatic changes in IGF-1R mRNA levels were observed in IT-treated cells, suggesting that IT acted primarily at a post-transcriptional level. Using molecular docking analysis, IT was identified as a novel fatty acid synthase (FASN) inhibitor. We found that IT reduced the level of total IGF-1R via FASN inhibition. In summary, we reported that IT exerted anti-melanoma activities, and these effects were partially due to inhibition of FASN/IGF-1R/STAT3 signaling., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
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16. Icariside II overcomes TRAIL resistance of melanoma cells through ROS-mediated downregulation of STAT3/cFLIP signaling.
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Du J, Wu J, Fu X, Tse AK, Li T, Su T, and Yu ZL
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- CASP8 and FADD-Like Apoptosis Regulating Protein drug effects, CASP8 and FADD-Like Apoptosis Regulating Protein metabolism, Cell Line, Tumor, Down-Regulation, Humans, Reactive Oxygen Species, STAT3 Transcription Factor drug effects, STAT3 Transcription Factor metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Drug Resistance, Neoplasm drug effects, Flavonoids pharmacology, Melanoma, Signal Transduction drug effects, TNF-Related Apoptosis-Inducing Ligand pharmacology
- Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, many melanoma cells show weak responses to TRAIL. Here, we investigated whether Icariside II (IS), an active component of Herba Epimedii, could potentiate antitumor effects of TRAIL in melanoma cells. Melanoma cells were treated with IS and/or TRAIL and cell death, apoptosis and signal transduction were analyzed. We showed that IS promoted TRAIL-induced cell death and apoptosis in A375 melanoma cells. Mechanistically, IS reduced the expression levels of cFLIP in a phospho-STAT3 (pSTAT3)-dependent manner. Ectopic expression of STAT3 abolished IS-induced cFLIP down-regulation and the associated potentiation of TRAIL-mediated cell death. Moreover, IS-induced reactive oxygen species (ROS) production preceded down-regulation of pSTAT3/cFLIP via activating AKT, and the consequent sensitization of cells to TRAIL. We also found that IS treatment down-regulated cFLIP via ROS-mediated NF-κB pathway. In addition, IS converted TRAIL-resistant melanoma MeWo and SK-MEL-28 cells into TRAIL-sensitive cells. Taken together, our results indicated that IS potentiated TRAIL-induced apoptosis through ROS-mediated down-regulation of STAT3/cFLIP signaling., Competing Interests: There are no conflicts of interest.
- Published
- 2016
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17. Inhibition of the STAT3 signaling pathway contributes to apigenin-mediated anti-metastatic effect in melanoma.
- Author
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Cao HH, Chu JH, Kwan HY, Su T, Yu H, Cheng CY, Fu XQ, Guo H, Li T, Tse AK, Chou GX, Mo HB, and Yu ZL
- Subjects
- Animals, Cell Line, Tumor, Cell Movement drug effects, Down-Regulation drug effects, Epithelial-Mesenchymal Transition drug effects, Humans, Immunoblotting, Lung Neoplasms pathology, Lung Neoplasms secondary, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Melanoma metabolism, Melanoma pathology, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Neoplasm Invasiveness prevention & control, Phosphorylation drug effects, RNA Interference, RNA, Small Interfering metabolism, Real-Time Polymerase Chain Reaction, STAT3 Transcription Factor antagonists & inhibitors, STAT3 Transcription Factor genetics, Twist-Related Protein 1 antagonists & inhibitors, Twist-Related Protein 1 genetics, Twist-Related Protein 1 metabolism, Vascular Endothelial Growth Factor A metabolism, Apigenin pharmacology, STAT3 Transcription Factor metabolism, Signal Transduction drug effects
- Abstract
Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in human melanoma, and promotes melanoma metastasis. The dietary flavonoid apigenin is a bioactive compound that possesses low toxicity and exerts anti-metastatic activity in melanoma. However, the anti-metastasis mechanism of apigenin has not been fully elucidated. In the present study, we showed that apigenin suppressed murine melanoma B16F10 cell lung metastasis in mice, and inhibited cell migration and invasion in human and murine melanoma cells. Further study indicated that apigenin effectively suppressed STAT3 phosphorylation, decreased STAT3 nuclear localization and inhibited STAT3 transcriptional activity. Apigenin also down-regulated STAT3 target genes MMP-2, MMP-9, VEGF and Twist1, which are involved in cell migration and invasion. More importantly, overexpression of STAT3 or Twist1 partially reversed apigenin-impaired cell migration and invasion. Our data not only reveal a novel anti-metastasis mechanism of apigenin but also support the notion that STAT3 is an attractive and promising target for melanoma treatment.
- Published
- 2016
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18. A herbal formula comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos, attenuates collagen-induced arthritis and inhibits TLR4 signalling in rats.
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Cheng BC, Yu H, Guo H, Su T, Fu XQ, Li T, Cao HH, Tse AK, Wu ZZ, Kwan HY, and Yu ZL
- Subjects
- Animals, Arthritis, Experimental chemically induced, Arthritis, Experimental metabolism, Cell Proliferation drug effects, Chemokines metabolism, Collagen toxicity, Cytokines metabolism, Flow Cytometry, Immunoblotting, Male, Rats, Rats, Wistar, Toll-Like Receptor 4 metabolism, Arthritis, Experimental prevention & control, Fruit chemistry, Lonicera chemistry, Plant Extracts pharmacology, Rosa chemistry, Signal Transduction drug effects, Toll-Like Receptor 4 antagonists & inhibitors
- Abstract
RL, a traditional remedy for Rheumatoid arthritis (RA), comprises two edible herbs, Rosae Multiflorae Fructus and Lonicerae Japonicae Flos. We have reported that RL could inhibit the production of inflammatory mediators in immune cells. Here we investigated the effects and the mechanism of action of RL in collagen-induced arthritis (CIA) rats. RL significantly increased food intake and weight gain of CIA rats without any observable adverse effect; ameliorated joint erythema and swelling; inhibited immune cell infiltration, bone erosion and osteophyte formation in joints; reduced joint protein expression levels of TLR4, phospho-TAK1, phospho-NF-κB p65, phospho-c-Jun and phospho-IRF3; lowered levels of inflammatory factors (TNF-α, IL-6, IL-1β, IL-17A and MCP-1 in sera and TNF-α, IL-6, IL-1β and IL-17A in joints); elevated serum IL-10 level; reinvigorated activities of antioxidant SOD, CAT and GSH-Px in the liver and serum; reduced Th17 cell proportions in splenocytes; inhibited splenocyte proliferation and activation; and lowered serum IgG level. In conclusion, RL at nontoxic doses inhibited TLR4 signaling and potently improved clinical conditions of CIA rats. These findings provide further pharmacological justifications for the traditional use of RL in RA management.
- Published
- 2016
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19. Comparison of the toxicities, activities and chemical profiles of raw and processed Xanthii Fructus.
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Su T, Cheng BC, Fu XQ, Li T, Guo H, Cao HH, Kwan HY, Tse AK, Yu H, Cao H, and Yu ZL
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Antineoplastic Agents, Phytogenic chemistry, Cooking, Cytotoxins chemistry, Cytotoxins pharmacology, Drug Screening Assays, Antitumor, Drugs, Chinese Herbal chemistry, Fruit chemistry, Humans, Lipopolysaccharides, Mice, Tumor Cells, Cultured, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Drugs, Chinese Herbal pharmacology, Xanthium chemistry
- Abstract
Background: Although toxic, the Chinese medicinal herb Xanthii Fructus (XF) is commonly used to treat traditional Chinese medicine (TCM) symptoms that resemble cold, sinusitis and arthritis. According to TCM theory, stir-baking (a processing method) can reduce the toxicity and enhance the efficacy of XF., Methods: Cytotoxicities of raw XF and processed XF (stir-baked XF, SBXF) were determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay in normal liver derived MIHA cells. Nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) mRNA expression were measured by the Griess reagent and quantitative real-time PCR, respectively. The chemical profiles of XF and SBXF were compared using an established ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) method., Results: SBXF was less toxic than XF in MIHA cells. Both XF and SBXF had anti-inflammatory effects as demonstrated by their abilities to reduce nitric oxide production as well as inducible nitric oxide synthase mRNA expression in lipopolysaccharide-stimulated RAW 264.7 macrophages. Interestingly, the anti-inflammatory effects of SBXF were more potent than that of XF. By comparing the chemical profiles, we found that seven peaks were lower, while nine other peaks were higher in SBXF than in XF. Eleven compounds including carboxyatractyloside, atractyloside and chlorogenic acid corresponding to eleven individual changed peaks were tentatively identified by matching with empirical molecular formulae and mass fragments, as well as literature data., Conclusion: Our study showed that stir-baking significantly reduced the cytotoxicity and enhanced the anti-inflammatory effects of XF; moreover, with a developed ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry method we differentiated XF and SBXF by their chemical profiles. Further studies are warranted to establish the relationship between the alteration of chemical profiles and the changes of medicinal properties caused by stir-baking.
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- 2016
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20. Ultrasound determination of rotator cuff tear repairability.
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Tse AK, Lam PH, Walton JR, Hackett L, and Murrell GA
- Abstract
Background: Rotator cuff repair aims to reattach the torn tendon to the greater tuberosity footprint with suture anchors. The present study aimed to assess the diagnostic accuracy of ultrasound in predicting rotator cuff tear repairability and to assess which sonographic and pre-operative features are strongest in predicting repairability., Methods: The study was a retrospective analysis of measurements made prospectively in a cohort of 373 patients who had ultrasounds of their shoulder and underwent rotator cuff repair. Measurements of rotator cuff tear size and muscle atrophy were made pre-operatively by ultrasound to enable prediction of rotator cuff repairability. Tears were classified following ultrasound as repairable or irreparable, and were correlated with intra-operative repairability., Results: Ultrasound assessment of rotator cuff tear repairability has a sensitivity of 86% (p < 0.0001) and a specificity of 67% (p < 0.0001). The strongest predictors of rotator cuff repairability were tear size (p < 0.001) and age (p = 0.004). Sonographic assessments of tear size ≥4 cm(2) or anteroposterior tear length ≥25 mm indicated an irreparable rotator cuff tear., Conclusions: Ultrasound assessment is accurate in predicting rotator cuff tear repairability. Tear size or anteroposterior tear length and age were the best predictors of repairability.
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- 2016
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21. A herbal formula comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos inhibits the production of inflammatory mediators and the IRAK-1/TAK1 and TBK1/IRF3 pathways in RAW 264.7 and THP-1 cells.
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Cheng BC, Yu H, Su T, Fu XQ, Guo H, Li T, Cao HH, Tse AK, Kwan HY, and Yu ZL
- Subjects
- Animals, Anti-Inflammatory Agents isolation & purification, Anti-Inflammatory Agents pharmacology, Cell Line, Dose-Response Relationship, Drug, Humans, Inflammation Mediators antagonists & inhibitors, Inflammation Mediators metabolism, Interferon Regulatory Factor-3 biosynthesis, Interleukin-1 Receptor-Associated Kinases biosynthesis, MAP Kinase Kinase Kinases biosynthesis, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred BALB C, Monocytes drug effects, Monocytes metabolism, Plant Extracts isolation & purification, Plant Extracts pharmacology, Plant Preparations isolation & purification, Plant Preparations pharmacology, Protein Serine-Threonine Kinases biosynthesis, Interferon Regulatory Factor-3 antagonists & inhibitors, Interleukin-1 Receptor-Associated Kinases antagonists & inhibitors, Lonicera, MAP Kinase Kinase Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Rosa
- Abstract
Ethnopharmacological Relevance: As documented in the Chinese Materia Medica Grand Dictionary (), a herbal formula (RL) consisting of Rosae Multiflorae Fructus (multiflora rose hips) and Lonicerae Japonicae Flos (Japanese honeysuckle flowers) has traditionally been used in treating inflammatory disorders. RL was previously reported to inhibit the expression of various inflammatory mediators regulated by NF-κB and MAPKs that are components of the TLR4 signalling pathways., Aim of the Study: This study aims to provide further justification for clinical application of RL in treating inflammatory disorders by further delineating the involvement of the TLR4 signalling cascades in the effects of RL on inflammatory mediators., Materials and Methods: RL consisting of Rosae Multiflorae Fructus and Lonicerae Japonicae Flos (in 5:3 ratio) was extracted using absolute ethanol. We investigated the effect of RL on the production of cytokines and chemokines that are regulated by three key transcription factors of the TLR4 signalling pathways AP-1, NF-κB and IRF3 in LPS-stimulated RAW264.7 cells using the multiplex biometric immunoassay. Phosphorylation of AP-1, NF-κB, IRF3, IκB-α, IKKα/β, Akt, TAK1, TBK1, IRAK-1 and IRAK-4 were examined in LPS-stimulated RAW264.7 cells and THP-1 cells using Western blotting. Nuclear localizations of AP-1, NF-κB and IRF3 were also examined using Western blotting., Results: RL reduced the secretion of various pro-inflammatory cytokines and chemokines regulated by transcription factors AP-1, NF-κB and IRF3. Phosphorylation and nuclear protein levels of these transcription factors were decreased by RL treatment. Moreover, RL inhibited the activation/phosphorylation of IκB-α, IKKα/β, TAK1, TBK1 and IRAK-1., Conclusions: Suppression of the IRAK-1/TAK1 and TBK1/IRF3 signalling pathways was associated with the effect of RL on inflammatory mediators in LPS-stimulated RAW264.7 and THP-1 cells. This provides further pharmacological basis for the clinical application of RL in the treatment of inflammatory disorders., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
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- 2015
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22. Centipeda minima (Ebushicao) extract inhibits PI3K-Akt-mTOR signaling in nasopharyngeal carcinoma CNE-1 cells.
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Guo YQ, Sun HY, Chan CO, Liu BB, Wu JH, Chan SW, Mok DK, Tse AK, Yu ZL, and Chen SB
- Abstract
Background: Centipeda minima (Ebushicao) has been used for the treatment of various diseases, such as nasal allergies, rhinitis and sinusitis, nasopharyngeal carcinoma, cough, and headache. This study aims to investigate the anticancer activities of Centipeda minima ethanol extracts (CME) against nasopharyngeal carcinoma cell CNE-1 and their underlying mechanism., Methods: CNE-1 cells were treated with different concentrations (15-50 μg/mL) of CME for different time intervals (24, 48, and 72 h). Cytotoxicity of CME was determined by MTT assay. Cell morphological changes were observed by fluorescence microscopy after HO 33258 staining. Cell cycle status was evaluated by flow cytometry following propidium iodide staining. Apoptosis was detected by flow cytometry following annexin V-FITC/PI staining. The levels of apoptosis-associated and PI3K-Akt-mTOR signaling related proteins were measured by western blotting analysis., Results: CME (15-50 μg/mL) significantly inhibited the proliferation of CNE-1 in a dose- and time-dependent manner (P = 0.026 for 15 μg/mL, P < 0.001 for 25, 30, 40, and 50 μg/mL, respectively); the IC50 values (μg/mL) were 41.57 ± 0.17, 30.34 ± 0.06 and 24.98 ± 0.08 for 24, 48 and 72 h treatments, respectively. Significant morphological changes of CNE-1 cells displaying apoptosis were observed after CME treatment. CME showed low cytotoxicity toward normal LO2 cells. CNE-1 cells were arrested in the G2/M phase while treated with 15, 25, 40 μg/mL of CME, respectively (P = 0.032, P = 0.0053, P < 0.001). CME (15, 25, 40 μg/mL) down-regulated Bcl-2 expression (P = 0.032, P = 0.0074, P < 0.001), and up-regulated Bax (P = 0.026, P = 0.0056, P < 0.001) with activation of caspase-3, caspase-8, caspase-9, and PARP observed in CNE-1 cells (P = 0.015, P = 0.0067, P < 0.001 for caspase 3; P = 0.210, 0.028, < 0.001 for caspase 8; P = 0.152, 0.082, 0.0080 for caspase 9; P = 0.265, 0.0072, < 0.001 for PARP). CME suppressed the activation of the PI3K-AKT-mTOR pathway (P = 0.03, 0.0007, 0.004, 0.006, 0.022 for p-PI3K, p-Akt-Ser(473), p-Akt-Thr(308), p-mTOR-Ser(2448), p-mTOR-Ser(2481), respectively after 40 μg/mL of CME treated for 24 h)., Conclusion: CME inhibited the proliferation of CNE-1 cells and activation of the PI3K-AKT-mTOR signaling pathway.
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- 2015
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23. ERK/GSK3β signaling is involved in atractylenolide I-induced apoptosis and cell cycle arrest in melanoma cells.
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Ye Y, Chao XJ, Wu JF, Cheng BC, Su T, Fu XQ, Li T, Guo H, Tse AK, Kwan HY, Du J, Chou GX, and Yu ZL
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- Animals, Apoptosis drug effects, Cell Cycle Checkpoints drug effects, Cell Proliferation drug effects, Gene Expression Regulation, Neoplastic drug effects, Glycogen Synthase Kinase 3 genetics, Glycogen Synthase Kinase 3 beta, Humans, Melanoma, Experimental genetics, Melanoma, Experimental pathology, Mice, Mitogen-Activated Protein Kinase 3 genetics, Neoplasm Proteins biosynthesis, Signal Transduction drug effects, Glycogen Synthase Kinase 3 biosynthesis, Lactones administration & dosage, Melanoma, Experimental drug therapy, Mitogen-Activated Protein Kinase 3 biosynthesis, Sesquiterpenes administration & dosage
- Abstract
Novel agents need to be developed to overcome the limitations of the current melanoma therapeutics. Atractylenolide I (AT-I) is a sesquiterpene compound isolated from atractylodis macrocephalae rhizoma. Previous findings demonstrated that AT-I exhibited cytotoxic action in melanoma cells. However, the molecular mechanisms of AT‑1's anti-melanoma properties remain to be elucidated. In the present study, the cell cycle-arrest and apoptosis-promoting effects as well as the ERK/GSK3β signaling-related mechanism of action of AT-I were examined. B16 melanoma cells were treated with various concentrations of AT-1 (50, 75 and 100 µM) for 48 or 72 h. Cell cycle and apoptosis were analyzed by flow cytometry. Protein expression levels were detected by western blot analysis. AT-I treatment induced G1 phase arrest, which was accompanied by increased p21 and decreased CDK2 protein expression levels. Apoptosis was observed after AT-I treatment for 72 h, which was accompanied by activated caspase‑3 and ‑8. AT-I treatment significantly decreased phospho-ERK, phospho-GSK3β, c-Jun and increased p53 protein expression levels. Lithium chloride (LiCl, 5 mM), a GSK3β inhibitor, treatment alone did not increase the apoptosis of B16 cells, while pretreatment with LiCl markedly reversed AT-I-induced apoptosis. Additionally, AT-I-induced G1 phase arrest was partially reversed by LiCl pretreatment. In conclusion, ERK/GSK3β signaling was involved in the apoptotic and G1 phase arrest effects of AT-I in melanoma cells.
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- 2015
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24. Quercetin inhibits HGF/c-Met signaling and HGF-stimulated melanoma cell migration and invasion.
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Cao HH, Cheng CY, Su T, Fu XQ, Guo H, Li T, Tse AK, Kwan HY, Yu H, and Yu ZL
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- Animals, Cell Line, Tumor, Enzyme Activation drug effects, Fatty Acid Synthases antagonists & inhibitors, Fatty Acid Synthases metabolism, Focal Adhesion Protein-Tyrosine Kinases metabolism, Hepatocyte Growth Factor metabolism, Humans, Neoplasm Invasiveness, Phosphorylation drug effects, Protein Multimerization drug effects, p21-Activated Kinases metabolism, Cell Movement drug effects, Hepatocyte Growth Factor pharmacology, Melanoma metabolism, Melanoma pathology, Proto-Oncogene Proteins c-met metabolism, Quercetin pharmacology, Signal Transduction drug effects
- Abstract
Background: Melanoma is notorious for its propensity to metastasize, which makes treatment extremely difficult. Receptor tyrosine kinase c-Met is activated in human melanoma and is involved in melanoma progression and metastasis. Hepatocyte growth factor (HGF)-mediated activation of c-Met signaling has been suggested as a therapeutic target for melanoma metastasis. Quercetin is a dietary flavonoid that exerts anti-metastatic effect in various types of cancer including melanoma. In a previous report, we demonstrated that quercetin inhibited melanoma cell migration and invasion in vitro, and prevented melanoma cell lung metastasis in vivo. In this study, we sought to determine the involvement of HGF/c-Met signaling in the anti-metastatic action of quercetin in melanoma., Methods: Transwell chamber assay was conducted to determine the cell migratory and invasive abilities. Western blotting was performed to determine the expression levels and activities of c-Met and its downstream molecules. And immunoblotting was performed in BS(3) cross-linked cells to examine the homo-dimerization of c-Met. Quantitative real-time PCR analysis was carried out to evaluate the mRNA expression level of HGF. Transient transfection was used to overexpress PAK or FAK in cell models. Student's t-test was used in analyzing differences between two groups., Results: Quercetin dose-dependently suppressed HGF-stimulated melanoma cell migration and invasion. Further study indicated that quercetin inhibited c-Met phosphorylation, reduced c-Met homo-dimerization and decreased c-Met protein expression. The effect of quercetin on c-Met expression was associated with a reduced expression of fatty acid synthase. In addition, quercetin suppressed the phosphorylation of c-Met downstream molecules including Gab1 (GRB2-associated-binding protein 1), FAK (Focal Adhesion Kinase) and PAK (p21-activated kinases). More importantly, overexpression of FAK or PAK significantly reduced the inhibitory effect of quercetin on the migration of the melanoma cells., Conclusions: Our findings suggest that suppression of the HGF/c-Met signaling pathway contributes to the anti-metastatic action of quercetin in melanoma.
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- 2015
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25. Dietary lipids and adipocytes: potential therapeutic targets in cancers.
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Kwan HY, Chao X, Su T, Fu XQ, Liu B, Tse AK, Fong WF, and Yu ZL
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- Adipogenesis, Adipose Tissue metabolism, Animals, Cachexia metabolism, Carcinogenesis, Cell Line, Tumor, Cell Transformation, Neoplastic, Fatty Acids biosynthesis, Humans, Tumor Microenvironment, Adipocytes metabolism, Dietary Fats metabolism, Neoplasms metabolism
- Abstract
Lipids play an important role to support the rapid growth of cancer cells, which can be derived from both the endogenous synthesis and exogenous supplies. Enhanced de novo fatty acid synthesis and mobilization of stored lipids in cancer cells promote tumorigenesis. Besides, lipids and fatty acids derived from diet or transferred from neighboring adipocytes also influence the proliferation and metastasis of cancer cells. Indeed, the pathogenic roles of adipocytes in the tumor microenvironment have been recognized recently. The adipocyte-derived mediators or the cross talk between adipocytes and cancer cells in the microenvironment is gaining attention. This review will focus on the impacts of lipids on cancers and the pathogenic roles of adipocytes in tumorigenesis and discuss the possible anticancer therapeutic strategies targeting lipids in the cancer cells., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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26. Lipidomic-based investigation into the regulatory effect of Schisandrin B on palmitic acid level in non-alcoholic steatotic livers.
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Kwan HY, Niu X, Dai W, Tong T, Chao X, Su T, Chan CL, Lee KC, Fu X, Yi H, Yu H, Li T, Tse AK, Fong WF, Pan SY, Lu A, and Yu ZL
- Subjects
- Animals, Cyclooctanes administration & dosage, Cyclooctanes pharmacology, Diet, High-Fat, Disease Models, Animal, Fasting, Fatty Acid Synthases genetics, Fatty Acid Synthases metabolism, Fatty Acids metabolism, Lignans administration & dosage, Lipids blood, Lipolysis, Liver drug effects, Liver metabolism, Liver Cirrhosis etiology, Male, Metabolic Networks and Pathways, Mice, NF-E2-Related Factor 2 metabolism, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease genetics, Polycyclic Compounds administration & dosage, Sterol Regulatory Element Binding Protein 1 genetics, Sterol Regulatory Element Binding Protein 1 metabolism, Tumor Necrosis Factor-alpha metabolism, Lignans pharmacology, Lipid Metabolism drug effects, Metabolomics, Non-alcoholic Fatty Liver Disease metabolism, Palmitic Acid metabolism, Polycyclic Compounds pharmacology
- Abstract
Schisandrin B (SchB) is one of the most abundant bioactive dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis. Here, we investigated the potential therapeutic effects of SchB on non-alcoholic fatty-liver disease (NAFLD). In lipidomic study, ingenuity pathway analysis highlighted palmitate biosynthesis metabolic pathway in the liver samples of SchB-treated high-fat-diet-fed mice. Further experiments showed that the SchB treatment reduced expression and activity of fatty acid synthase, expressions of hepatic mature sterol regulatory element binding protein-1 and tumor necrosis factor-α, and hepatic level of palmitic acid which is known to promote progression of steatosis to steatohepatitis. Furthermore, the treatment also reduced hepatic fibrosis, activated nuclear factor-erythroid-2-related factor-2 which is known to attenuate the progression of NASH-related fibrosis. Interestingly, in fasting mice, a single high-dose SchB induced transient lipolysis and increased the expressions of adipose triglyceride lipase and phospho-hormone sensitive lipase. The treatment also increased plasma cholesterol levels and 3-hydroxy-3-methylglutaryl-CoA reductase activity, reduced the hepatic low-density-lipoprotein receptor expression in these mice. Our data not only suggest SchB is a potential therapeutic agent for NAFLD, but also provided important information for a safe consumption of SchB because SchB overdosed under fasting condition will have adverse effects on lipid metabolism.
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- 2015
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27. Inhibition of STAT3 signalling contributes to the antimelanoma action of atractylenolide II.
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Fu XQ, Chou GX, Kwan HY, Tse AK, Zhao LH, Yuen TK, Cao HH, Yu H, Chao XJ, Su T, Cheng BC, Sun XG, and Yu ZL
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- Animals, Anticarcinogenic Agents chemistry, Apoptosis, Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Melanoma, Experimental, Mice, Mice, Inbred C57BL, STAT3 Transcription Factor antagonists & inhibitors, Signal Transduction, Xenograft Model Antitumor Assays, Lactones chemistry, Melanoma drug therapy, Melanoma metabolism, STAT3 Transcription Factor metabolism, Sesquiterpenes chemistry, Skin Neoplasms drug therapy, Skin Neoplasms metabolism
- Abstract
Our previous studies showed that atractylenolide II (AT-II) has antimelanoma effects in B16 melanoma cells. In this study, we investigated the involvement of STAT3 signalling in the antimelanoma action of AT-II. Daily administration of AT-II (12.5, 25 mg/kg, i.g.) for 14 days significantly inhibited tumor growth in a B16 xenograft mouse model and inhibited the activation/phosphorylation of STAT3 and Src in the xenografts. In B16 and A375 cells, AT-II (20, 40 μm) treatment for 48 h dose-dependently reduced protein expression levels of phospho-STAT3, phospho-Src, as well as STAT3-regulated Mcl-1 and Bcl-xL. Overexpression of a constitutively active variant of STAT3, STAT3C in A375 cells diminished the antiproliferative and apoptotic effects of AT-II. These data suggest that inhibition of STAT3 signalling contributes to the antimelanoma action of AT-II. Our findings shed new light on the mechanism of action underlying the antimelanoma effects of AT-II and provide further pharmacological basis for developing AT-II as a novel melanoma chemopreventive/chemotherapeutic agent., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2014
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28. Indomethacin sensitizes TRAIL-resistant melanoma cells to TRAIL-induced apoptosis through ROS-mediated upregulation of death receptor 5 and downregulation of survivin.
- Author
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Tse AK, Cao HH, Cheng CY, Kwan HY, Yu H, Fong WF, and Yu ZL
- Subjects
- Anti-Inflammatory Agents, Non-Steroidal pharmacology, Apoptosis drug effects, Apoptosis physiology, Cell Line, Tumor, Down-Regulation drug effects, Drug Resistance, Neoplasm physiology, Humans, Melanoma metabolism, Melanoma pathology, Reactive Oxygen Species metabolism, Skin Neoplasms metabolism, Skin Neoplasms pathology, Survivin, Up-Regulation drug effects, Indomethacin pharmacology, Inhibitor of Apoptosis Proteins metabolism, Melanoma drug therapy, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, Skin Neoplasms drug therapy, TNF-Related Apoptosis-Inducing Ligand metabolism
- Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted considerable attention owing to its selective killing of tumor cells but not normal cells. Melanoma shows weak response to TRAIL because of its low level of TRAIL death receptors. Here, we investigated whether indomethacin, a nonsteroidal anti-inflammatory drug, can potentiate TRAIL-induced apoptosis in melanoma cells. We showed that indomethacin was capable of promoting TRAIL-induced cell death and apoptosis in A375 melanoma cells. Mechanistically, indomethacin induced cell surface expression of death receptor 5 (DR5) in melanoma cells and also in various types of cancer cells. DR5 knockdown abolished the enhancing effect of indomethacin on TRAIL responses. Induction of the DR5 by indomethacin was found to be p53 independent but dependent on the induction of CCAAT/enhancer-binding protein homologous protein (CHOP). Knockdown of CHOP abolished indomethacin-induced DR5 expression and the associated potentiation of TRAIL-mediated cell death. In addition, indomethacin-induced reactive oxygen species (ROS) production preceded upregulation of CHOP and DR5, and consequent sensitization of cells to TRAIL. We also found that indomethacin treatment downregulated survivin via ROS and the NF-κB-mediated signaling pathways. Interestingly, indomethacin also converted TRAIL-resistant melanoma MeWo and SK-MEL-5 cells into TRAIL-sensitive cells. Taken together, our results indicate that indomethacin can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of survivin.
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- 2014
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29. Quercetin exerts anti-melanoma activities and inhibits STAT3 signaling.
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Cao HH, Tse AK, Kwan HY, Yu H, Cheng CY, Su T, Fong WF, and Yu ZL
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- Animals, Cell Line, Tumor, Cell Movement, Cell Survival drug effects, Humans, Male, Mice, Mice, Nude, Neoplasms, Experimental, Random Allocation, STAT3 Transcription Factor genetics, Antineoplastic Agents pharmacology, Gene Expression Regulation, Neoplastic physiology, Melanoma drug therapy, Quercetin pharmacology, STAT3 Transcription Factor metabolism
- Abstract
Melanoma is highly resistant to chemotherapy, and the mortality rate is increasing rapidly worldwide. STAT3 signaling has been implicated in the pathogenesis of melanoma and constitutive activated STAT3 has been validated can as a target for melanoma therapy. Quercetin, a noncarcinogenic dietary flavonoid with low toxicity, has been shown to exert anti-melanoma activity. However, the anti-melanoma mechanisms of quercetin are not fully understood. In this study, we sought to test the involvement of STAT3 signaling in the inhibitory effects of quercetin on melanoma cell growth, migration and invasion. Our results showed that exposure to quercetin resulted in inhibition of proliferation of melanoma cells, induction of cell apoptosis, and suppression of migratory and invasive properties. Mechanistic study indicated that quercetin inhibited the activation of STAT3 signaling by interfering with STAT3 phosphorylation, and reducing STAT3 nuclear localization. This inhibited STAT3 transcription activity and down-regulated STAT3 targeted genes Mcl-1, MMP-2, MMP-9 and VEGF, which are involved in cell growth, migration and invasion. Importantly, overexpression of constitutively active STAT3 partially rescued the growth inhibiting effects induced by quercetin. Furthermore, quercetin suppressed A375 tumor growth and STAT3 activities in xenografted mice model, and inhibited murine B16F10 cells lung metastasis in an animal model. Overall, these results indicate that the antitumor activity of quercetin is at least partially due to inhibition of STAT3 signaling in melanoma cells. Our findings provided new insight into the action of quercetin potently inhibits the STAT3 signaling pathway, suggesting it has a potential role in the prevention and treatment of melanoma., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2014
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30. The herbal compound cryptotanshinone restores sensitivity in cancer cells that are resistant to the tumor necrosis factor-related apoptosis-inducing ligand.
- Author
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Tse AK, Chow KY, Cao HH, Cheng CY, Kwan HY, Yu H, Zhu GY, Wu YC, Fong WF, and Yu ZL
- Subjects
- Blotting, Western, Cell Line, Tumor, Cell Survival drug effects, Drug Synergism, Gene Expression Regulation, Neoplastic, HCT116 Cells, HT29 Cells, Humans, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, RNA Interference, Reactive Oxygen Species metabolism, Receptors, TNF-Related Apoptosis-Inducing Ligand genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, Reverse Transcriptase Polymerase Chain Reaction, Salvia miltiorrhiza chemistry, Transcription Factor CHOP genetics, Transcription Factor CHOP metabolism, Up-Regulation drug effects, Apoptosis drug effects, Drug Resistance, Neoplasm drug effects, Drugs, Chinese Herbal pharmacology, Phenanthrenes pharmacology, TNF-Related Apoptosis-Inducing Ligand pharmacology
- Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells but not normal cells. However, TRAIL resistance due to low level of TRAIL receptor expression is widely found in cancer cells and hampers its development for cancer treatment. Thus, the agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are urgently needed. We investigated whether tanshinones, the major bioactive compounds of Salvia miltiorrhiza (danshen), can up-regulate TRAIL receptor expression. Among the major tanshinones being tested, cryptotanshinone (CT) showed the best ability to induce TRAIL receptor 2 (DR5) expression. We further showed that CT was capable of promoting TRAIL-induced cell death and apoptosis in A375 melanoma cells. CT-induced DR5 induction was not cell type-specific, as DR5 induction was observed in other cancer cell types. DR5 knockdown abolished the enhancing effect of CT on TRAIL responses. Mechanistically, induction of the DR5 by CT was found to be p53-independent but dependent on the induction of CCAAT/enhancer-binding protein-homologous protein (CHOP). Knockdown of CHOP abolished CT-induced DR5 expression and the associated potentiation of TRAIL-mediated cell death. In addition, CT-induced ROS production preceded up-regulation of CHOP and DR5 and consequent sensitization of cells to TRAIL. Interestingly, CT also converted TRAIL-resistant lung A549 cancer cells into TRAIL-sensitive cells. Taken together, our results indicate that CT can potentiate TRAIL-induced apoptosis through up-regulation of DR5.
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- 2013
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31. 1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through microRNA-498.
- Author
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Kasiappan R, Shen Z, Tse AK, Jinwal U, Tang J, Lungchukiet P, Sun Y, Kruk P, Nicosia SV, Zhang X, and Bai W
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis, Cell Line, Tumor, Female, Genome, Humans, Mice, Mice, Nude, MicroRNAs physiology, Mutagenesis, Oligonucleotide Array Sequence Analysis, RNA, Untranslated metabolism, Calcitriol pharmacology, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, MicroRNAs biosynthesis, Neoplasms metabolism, Telomerase antagonists & inhibitors, Telomerase biosynthesis
- Abstract
Telomerase is an essential enzyme that counteracts the telomere attrition accompanying DNA replication during cell division. Regulation of the promoter activity of the gene encoding its catalytic subunit, the telomerase reverse transcriptase, is established as the dominant mechanism conferring the high telomerase activity in proliferating cells, such as embryonic stem and cancer cells. This study reveals a new mechanism of telomerase regulation through non-coding small RNA by showing that microRNA-498 (miR-498) induced by 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) decreases the mRNA expression of the human telomerase reverse transcriptase. MiR-498 was first identified in a microarray analysis as the most induced microRNA by 1,25(OH)(2)D(3) in ovarian cancer cells and subsequently validated by quantitative polymerase chain reaction assays in multiple human cancer types. A functional vitamin D response element was defined in the 5-prime regulatory region of the miR-498 genome, which is occupied by the vitamin D receptor and its coactivators. Further studies showed that miR-498 targeted the 3-prime untranslated region of human telomerase reverse transcriptase mRNA and decreased its expression. The levels of miR-498 expression were decreased in malignant human ovarian tumors as well as human ovarian cancer cell lines. The ability of 1,25(OH)(2)D(3) to decrease human telomerase reverse transcriptase mRNA and to suppress ovarian cancer growth was compromised when miR-498 was depleted using the sponges in cell lines and mouse tumor models. Taken together, our studies define a novel mechanism of telomerase regulation by small non-coding RNAs and identify miR-498 as an important mediator for the anti-tumor activity of 1,25(OH)(2)D(3).
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- 2012
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32. 20(S)-Protopanaxadiol, a metabolite of ginsenosides, induced cell apoptosis through endoplasmic reticulum stress in human hepatocarcinoma HepG2 cells.
- Author
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Zhu GY, Li YW, Tse AK, Hau DK, Leung CH, Yu ZL, and Fong WF
- Subjects
- Extracellular Signal-Regulated MAP Kinases metabolism, Hep G2 Cells, Humans, MAP Kinase Signaling System drug effects, Mitochondria drug effects, Mitochondria metabolism, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, Transcription Factor CHOP metabolism, Unfolded Protein Response drug effects, Up-Regulation drug effects, Vacuoles drug effects, Vacuoles metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Apoptosis drug effects, Endoplasmic Reticulum Stress drug effects, Ginsenosides metabolism, Liver Neoplasms pathology, Sapogenins metabolism, Sapogenins pharmacology
- Abstract
20(S)-Protopanaxadiol (PPD), a metabolite of ginsenosides, has been demonstrated to possess cytotoxic effects on several cancer cell lines. The molecular mechanism is, however, not well understood. In this study, we have shown that PPD inhibits cell growth and induces apoptosis in human hepatocarcinoma HepG2 cells. PPD-treated cells showed a massive cytoplasmic vacuolization and a dramatic change of endoplasmic reticulum (ER) morphology. The induction of ER stress is associated with the upregulation of ER stress-associated genes and proteins. PPD activates the unfolded protein response (UPR) through the phosphorylation of PERK and eIF2α, the splicing of XBP1 mRNA, and the cleavage of AFT6. PPD also induces the intrinsic and extrinsic apoptotic pathways. It activates DR5, caspase-8, -9, -3, and promotes the cleavage of PARP while it downregulates Bcl-2, Bcl-x(L) and mitochondrial membrane potential. Knockdown of one of the three UPR limbs by specific siRNAs did not affect PPD-induced apoptosis, which was however, significantly suppressed by the downregulation of CHOP. Western blot analysis showed that PPD-stimulated downregulation of Bcl-2 protein, increase of DR5 protein, activation of caspase-8 and cleavage of PARP were significantly inhibited in CHOP siRNA-transfected cells. Taken together, we have identified ER as a molecular target of PPD and our data support the hypothesis that PPD induces HepG2 cell apoptosis through the ER stress pathway., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
- Full Text
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33. Inhibition of cytochrome P450 3A4 activity by schisandrol A and gomisin A isolated from Fructus Schisandrae chinensis.
- Author
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Wan CK, Tse AK, Yu ZL, Zhu GY, Wang H, and Fong DW
- Subjects
- Cyclooctanes isolation & purification, Cytochrome P-450 CYP3A, Dioxoles isolation & purification, Drug Resistance, Multiple, Fruit, Hep G2 Cells, Herb-Drug Interactions, Humans, Inhibitory Concentration 50, Lignans isolation & purification, Plant Extracts chemistry, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Cyclooctanes pharmacology, Cytochrome P-450 CYP3A Inhibitors, Dioxoles pharmacology, Glutathione metabolism, Lignans pharmacology, Plant Extracts pharmacology, Schisandra chemistry
- Abstract
We studied the effects of schisandrol A (SCH) and gomisin A (GOM), two of the main bioactive components of Fructus Schisandrae chinensis, on cytochrome P450-3A4 (CYP3A4) activity and cellular glutathione (GSH) level. In a cell-free system both SCH and GOM inhibited CYP3A4 activity with IC(50) values of 32.02 microM and 1.39 microM, respectively. SCH or GOM at concentrations up to 100 microM did not alter cellular GSH level in regular HepG2 cells and P-glycoprotein overexpressing HepG2-DR cells. Since SCH and GOM may reverse multidrug resistance (MDR) by impeding the activity of P-glycoprotein, a membrane xenobiotic exporter, SCH or GOM could affect cellular drug metabolism in addition to drug uptake., ((c) 2009 Elsevier GmbH. All rights reserved.)
- Published
- 2010
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34. 1alpha,25-Dihydroxyvitamin D3 inhibits transcriptional potential of nuclear factor kappa B in breast cancer cells.
- Author
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Tse AK, Zhu GY, Wan CK, Shen XL, Yu ZL, and Fong WF
- Subjects
- Acetylation drug effects, Animals, Blotting, Western, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Down-Regulation genetics, Female, HeLa Cells, Histone Deacetylases genetics, Histone Deacetylases metabolism, Humans, I-kappa B Proteins genetics, I-kappa B Proteins metabolism, NF-KappaB Inhibitor alpha, NF-kappa B genetics, NF-kappa B p50 Subunit genetics, NF-kappa B p50 Subunit metabolism, Nuclear Receptor Co-Repressor 2 genetics, Nuclear Receptor Co-Repressor 2 metabolism, Phosphorylation drug effects, RNA Interference, Receptors, Calcitriol genetics, Receptors, Calcitriol metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha pharmacology, Vitamins pharmacology, Calcitriol pharmacology, NF-kappa B metabolism, Transcriptional Activation drug effects
- Abstract
1alpha,25-Dihydroxyvitamin D(3) (VD(3)), the biologically active form of vitamin D, may have either pro- or anti-inflammatory activities because of its diverse actions on nuclear factor kappa B (NF-kappaB). Previous studies indicated that VD(3) can either activate or inhibit NF-kappaB via Akt-induced I kappaB alpha phosphorylation and increase in I kappaB alpha synthesis respectively. At present, the relevant contribution of each mechanism has not been fully explored. We observed a VD(3)-mediated NF-kappaB inhibitory effect in vitamin D receptor (VDR)-positive MCF-7 breast cancer cells. We showed that VD(3) induced VDR-dependent I kappaB alpha expression but still able to lead on transient NF-kappaB p65 nuclear translocation through Akt-induced I kappaB alpha phosphorylation. Upon TNFalpha stimulation, VD(3) was not capable to inhibit I kappaB alpha degradation, p65 nuclear translocation and p65/p50-DNA binding. Here, we found that VD(3) strongly repressed p65 transactivation in MCF-7 cells using Gal4-p65 chimeras system. VDR was required for the VD(3)-mediated transrepression and mutations in VDR affected its suppressive ability. We also demonstrated that neither inhibition of p65 phosphorylation nor acetylation was responsible for the transrepression. In fact, we found that treatment of MCF-7 cells with histone deacetylase inhibitors abrogated VD(3)-induced p65 transrepression. In addition, knockdown of two nuclear corepressors HDAC3 and SMRT relieved p65 transactivation and particular TNFalpha-triggered gene expression. In conclusion, the reduction of gene activation by VD(3) in breast cancer cells was caused by the interference of the transactivation potential of NF-kappaB p65 subunit. Our studies provide a scientific background for rational use of vitamin D in the prevention and treatment of inflammatory diseases., ((c) 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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35. Influence of Magnolol on the bystander effect induced by alpha-particle irradiation.
- Author
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Wong TP, Law YL, Tse AK, Fong WF, and Yu KN
- Subjects
- Alpha Particles, Animals, Bystander Effect radiation effects, CHO Cells, Cricetinae, Cricetulus, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Radiation-Protective Agents administration & dosage, Biphenyl Compounds administration & dosage, Bystander Effect drug effects, Chromosome Aberrations drug effects, Chromosome Aberrations radiation effects, Lignans administration & dosage, Radiation Tolerance drug effects
- Abstract
In this work, the influence of Magnolol on the bystander effect in alpha-particle irradiated Chinese hamster ovary (CHO) cells was examined. The bystander effect was studied through medium transfer experiments. Cytokinesis-block micronucleus (CBMN) assay was performed to quantify the chromosome damage induced by alpha-particle irradiation. Our results showed that the alpha-particle induced micronuclei (MN) frequencies were suppressed with the presence of Magnolol., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
36. Increased epidermal growth factor receptor (EGFR) expression in malignant mammary phyllodes tumors.
- Author
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Tse GM, Lui PC, Vong JS, Lau KM, Putti TC, Karim R, Scolyer RA, Lee CS, Yu AM, Ng DC, Tse AK, and Tan PH
- Subjects
- Adolescent, Adult, Aged, Biomarkers, Tumor, Cell Proliferation, Female, Humans, Immunohistochemistry methods, In Situ Hybridization, Fluorescence, Ligands, Middle Aged, Breast Neoplasms metabolism, ErbB Receptors biosynthesis, Gene Expression Regulation, Neoplastic, Phyllodes Tumor metabolism
- Abstract
Mammary phyllodes tumors are uncommon stromal-epithelial neoplasms, and are divided into benign, borderline malignant and frankly malignant groups on the basis of their histological features. Accumulating evidence shows that epidermal growth factor receptor (EGFR) is involved in the pathogenesis and progression of many malignancies. This study investigated 453 phyllodes tumors (296 benign, 98 borderline, 59 malignant) for EGFR expression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for gene amplification. The staining was correlated to tumor margin status, degree of malignancy, stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. Cases with strong positive IHC staining were selected for FISH. The overall positive rate for EGFR was 16.2% (48/296), 30.6% (30/98) and 56% (33/59) for benign, borderline malignant and frankly malignant phyllodes tumors, respectively. FISH demonstrated egfr gene amplification in 8% of immunohistochemically positive cases. The results of this study provide strong evidence that EGFR overexpression is involved in the pathogenesis of phyllodes tumors, although gene amplification may not be the major underlying mechanism for overexpression.
- Published
- 2009
- Full Text
- View/download PDF
37. Methoxylation of 3',4'-aromatic side chains improves P-glycoprotein inhibitory and multidrug resistance reversal activities of 7,8-pyranocoumarin against cancer cells.
- Author
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Fong WF, Shen XL, Globisch C, Wiese M, Chen GY, Zhu GY, Yu ZL, Tse AK, and Hu YJ
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Adenosine Triphosphatases antagonists & inhibitors, Adenosine Triphosphatases metabolism, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Survival drug effects, Coumarins chemistry, Humans, Molecular Structure, Neoplasms enzymology, Pyrans chemistry, Sensitivity and Specificity, Structure-Activity Relationship, Substrate Specificity, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Antineoplastic Agents chemistry, Drug Resistance, Multiple drug effects, Neoplasms pathology, Oxygen chemistry, Pyranocoumarins chemistry, Pyranocoumarins pharmacology
- Abstract
The overexpression of P-glycoprotein (Pgp), an ATP-driven membrane exporter of hydrophobic xenobiotics, is one of the major causes of multidrug resistance (MDR) in cancer cells. Through extensive screening we have found that the extracts of Peucedanum praeruptorum Dunn. and one of the major components (+/-)-praeruptorin A (PA) may reverse Pgp-mediated multidrug resistance. Studies on novel PA derivatives have shown that (+/-)-3'-O,4'-O-dicinnamoyl-cis-khellactone (DCK) is more active than PA or verapamil and is a non-competitive inhibitor of Pgp. Here, we report that methoxylation of the cinnamoyl groups on DCK may further enhance its bioactivity. The structure-activity relationship is demonstrated by comparing two new pyranocoumarins (+/-)-3'-O,4'-O-bis(3,4-dimethoxycinnamoyl)-cis-khellactone (DMDCK) and (+/-)-3'-O,4'-O-bis(4-methoxycinnamoyl)-cis-khellactone (MMDCK). While the co-existence of 3- and 4-methoxy groups on cinnamoyl remarkably enhanced the Pgp-inhibitory activity, the lone existence of the 4-methoxy group on cinnamoyl reduced the activity. Contrary to DCK, DMDCK promoted the binding of UIC2 antibody to Pgp which signifies a conformational change of Pgp similar to that induced by transport substrates. While DCK moderately stimulated the basal Pgp-ATPase activity, DMDCK inhibited the activity. A pharmacophore search with verapamil-based template revealed that four functional groups of DMDCK could be simultaneously involved in interaction with Pgp whereas for DCK or MMDCK only three groups were involved. It is speculated that the additional 3-methoxy group on cinnamoyl allows DMDCK to interact more efficiently with Pgp substrate site(s). If DMDCK was tightly bind to Pgp substrate site(s) the complexes could be inactive with regard to transportation and ATP hydrolysis could also be inhibited.
- Published
- 2008
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38. 1,25-dihydroxyvitamin D3 induces biphasic NF-kappaB responses during HL-60 leukemia cells differentiation through protein induction and PI3K/Akt-dependent phosphorylation/degradation of IkappaB.
- Author
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Tse AK, Wan CK, Shen XL, Zhu GY, Cheung HY, Yang M, and Fong WF
- Subjects
- CD11b Antigen metabolism, HL-60 Cells, Humans, I-kappa B Proteins antagonists & inhibitors, Interleukin-1beta metabolism, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System physiology, NF-kappa B antagonists & inhibitors, NF-kappa B biosynthesis, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Signal Transduction, Transcription Factor RelA antagonists & inhibitors, Transcription Factor RelA metabolism, Tumor Necrosis Factor-alpha metabolism, Up-Regulation, bcl-X Protein metabolism, Calcitriol pharmacology, Cell Differentiation, I-kappa B Proteins metabolism, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases physiology, Proto-Oncogene Proteins c-akt physiology
- Abstract
1,25-dihydroxyvitamin D(3) (VD(3)) induces differentiation in a number of leukemia cell lines and under various conditions is able to either stimulate or inhibit nuclear factor kappa B (NF-kappaB) activity. Here we report a time-dependent biphasic regulation of NF-kappaB in VD(3)-treated HL-60 leukemia cells. After VD(3) treatment there was an early approximately 4 h suppression and a late 8-72 h prolonged reactivation of NF-kappaB. The reactivation of NF-kappaB was concomitant with increased IKK activities, IKK-mediated IkappaBalpha phosphorylation, p65 phosphorylation at residues S276 and S536, p65 nuclear translocation and p65 recruitment to the NF-kappaB/vitamin D responsive element promoters. In parallel with NF-kappaB stimulation, there was an up-regulation of NF-kappaB controlled inflammatory and anti-apoptotic genes such as TNFalpha, IL-1beta and Bcl-xL. VD(3)-triggered reactivation of NF-kappaB was associated with PI3K/Akt phosphorylation. PI3K/Akt antagonists suppressed VD(3)-stimulated IkappaBalpha phosphorylation as well as NF-kappaB-controlled gene expression. The early approximately 4 h VD(3)-mediated NF-kappaB suppression coincided with a prolonged increase of IkappaBalpha protein which require de novo protein synthesis, lasted for as least 72 h and was insensitive to MAPK, IKK or PI3K/Akt inhibitors. Our data suggest a novel biphasic regulation of NF-kappaB in VD(3)-treated leukemia cells and our results may have provided the first molecular explanation for the contradictory observations reported on VD(3)-mediated immune-regulation.
- Published
- 2007
- Full Text
- View/download PDF
39. Magnolol suppresses NF-kappaB activation and NF-kappaB regulated gene expression through inhibition of IkappaB kinase activation.
- Author
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Tse AK, Wan CK, Zhu GY, Shen XL, Cheung HY, Yang M, and Fong WF
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Cytokines genetics, Dimerization, Down-Regulation, Humans, I-kappa B Kinase metabolism, Lipopolysaccharides pharmacology, Matrix Metalloproteinase 9 genetics, NF-kappa B metabolism, NF-kappa B p50 Subunit antagonists & inhibitors, NF-kappa B p50 Subunit metabolism, Phosphorylation drug effects, Transcription Factor RelA antagonists & inhibitors, Transcription Factor RelA metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha pharmacology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Biphenyl Compounds pharmacology, Gene Expression Regulation drug effects, I-kappa B Kinase antagonists & inhibitors, Lignans pharmacology, NF-kappa B drug effects
- Abstract
The mis-regulation of nuclear factor-kappa B (NF-kappaB) signal pathway is involved in a variety of inflammatory diseases that leds to the production of inflammatory mediators. Our studies using human U937 promonocytes cells suggested that magnolol, a low molecular weight lignan isolated from the medicinal plant Magnolia officinalis, differentially down-regulated the pharmacologically induced expression of NF-kappaB-regulated inflammatory gene products MMP-9, IL-8, MCP-1, MIP-1alpha, TNF-alpha. Pre-treatment of magnolol blocked TNF-alpha-induced NF-kappaB activation in different cell types as evidenced by EMSA. Magnolol did not directly affect the binding of p65/p50 heterodimer to DNA. Immunoblot analysis demonstrated that magnolol inhibited the TNF-alpha-stimulated phosphorylation and degradation of the cytosolic NF-kappaB inhibitor IkappaBalpha and the effects were dose-dependent. Mechanistically, a non-radioactive IkappaB kinases (IKK) assay using immunoprecipitated IKKs protein demonstrated that magnolol inhibited both intrinsic and TNF-alpha-stimulated IKK activity, thus suggesting a critical role of magnolol in abrogating the phosphorylation and degradation of IkappaBalpha. The involvement of IKK was further verified in a HeLa cell NF-kappaB-dependent luciferase reporter system. In this system magnolol suppressed luciferase expression stimulated by TNF-alpha and by the transient transfection and expression of NIK (NF-kappaB-inducing kinase), wild type IKKbeta, constitutively active IKKalpha and IKKbeta, or the p65 subunit. Magnolol was also found to inhibit the nuclear translocation and phosphorylation of p65 subunit of NF-kappaB. In line with the observation that NF-kappaB activation may up-regulate anti-apoptotic genes, it was shown in U937 cells that magnolol enhanced TNF-alpha-induced apoptotic cell death. Our results suggest that magnolol or its derivatives may have potential anti-inflammatory actions through IKK inactivation.
- Published
- 2007
- Full Text
- View/download PDF
40. Alpha-particle radiobiological experiments using thin CR-39 detectors.
- Author
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Chan KF, Siu SY, McClella KE, Tse AK, Lau BM, Nikezic D, Richardson BJ, Lam PK, Fong WF, and Yu KN
- Subjects
- Alpha Particles, Cells, Cultured, Comet Assay methods, DNA chemistry, DNA ultrastructure, Equipment Design, Equipment Failure Analysis, HeLa Cells, Humans, Radiobiology instrumentation, Radiobiology methods, Radiometry methods, Reproducibility of Results, Sensitivity and Specificity, Comet Assay instrumentation, DNA genetics, DNA radiation effects, DNA Damage, Radiometry instrumentation, Transducers
- Abstract
The present paper studied the feasibility of applying comet assay to evaluate the DNA damage in individual HeLa cervix cancer cells after alpha-particle irradiation. We prepared thin CR-39 detectors (<20 microm) as cell-culture substrates, with UV irradiation to shorten the track formation time. After irradiation of the HeLa cells by alpha particles, the tracks on the underside of the CR-39 detector were developed by chemical etching in (while floating on) a 14 N KOH solution at 37 degrees C. Comet assay was then applied. Diffusion of DNA out of the cells could be generally observed from the images of stained DNA. The alpha-particle tracks corresponding to the comets developed on the underside of the CR-39 detectors could also be observed by just changing the focal plane of the confocal microscope.
- Published
- 2006
- Full Text
- View/download PDF
41. Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation.
- Author
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Tse AK, Wan CK, Shen XL, Yang M, and Fong WF
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis drug effects, Biphenyl Compounds chemistry, Cell Line, Tumor, Electrophoretic Mobility Shift Assay methods, Gene Expression drug effects, Genes, Reporter physiology, Humans, I-kappa B Kinase antagonists & inhibitors, I-kappa B Kinase drug effects, Lignans chemistry, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides pharmacology, Luciferases antagonists & inhibitors, Luciferases drug effects, Luciferases genetics, Lymphotoxin-alpha metabolism, NF-kappa B metabolism, NF-kappa B p50 Subunit drug effects, NF-kappa B p50 Subunit metabolism, Phosphorylation, Reverse Transcriptase Polymerase Chain Reaction methods, Tetradecanoylphorbol Acetate antagonists & inhibitors, Tetradecanoylphorbol Acetate pharmacology, Transcription Factor AP-1 antagonists & inhibitors, Transcription Factor AP-1 drug effects, Transcription Factor RelA drug effects, Transcription Factor RelA metabolism, Tumor Necrosis Factor-alpha drug effects, Tumor Necrosis Factor-alpha metabolism, Biphenyl Compounds pharmacology, I-kappa B Kinase metabolism, Lignans pharmacology, NF-kappa B antagonists & inhibitors, NF-kappa B genetics, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Honokiol, a small molecular weight lignan originally isolated from Magnolia officinalis, shows anti-angiogenic, anti-invasive and anti-proliferative activities in a variety of cancers. In this study, we investigated whether honokiol affects the transcription factor nuclear factor-kappa B (NF-kappaB) which controls a large number of genes involved in angiogenesis, metastasis and cell survival. We observed that the tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activation was blocked by honokiol in four different cancer cell lines as evidenced by EMSA. Honokiol did not directly affect the NF-kappaB-DNA binding. Immunoblot experiments demonstrated that honokiol inhibited the TNF-alpha-stimulated phosphorylation and degradation of the cytosolic NF-kappaB inhibitor IkappaBalpha. Furthermore, honokiol suppressed the intrinsic and TNF-alpha-stimulated upstream IkappaB kinases (IKKs) activities measured by a non-radioactive kinase assay using immunoprecipitated IKKs, suggesting a critical role of honokiol in abrogating the phosphorylation and degradation of IkappaBalpha. In a HeLa cell NF-kappaB-dependent luciferase reporter system, honokiol suppressed luciferase expression stimulated by TNF-alpha and by the transient transfection and expression of NIK (NF-kappaB-inducing kinase), wild type IKKbeta, constitutively active IKKalpha and IKKbeta, or the p65 subunit. Honokiol was also found to inhibit the nuclear translocation and phosphorylation of p65 subunit of NF-kappaB. RT-PCR results showed that honokiol suppressed NF-kappaB-regulated inflammatory and carcinogenic gene products including MMP-9, TNF-alpha, IL-8, ICAM-1 and MCP-1. In line with the observation that NF-kappaB activation may up-regulate anti-apoptotic genes, it was shown that honokiol enhanced TNF-alpha-induced apoptotic cell death. In summary, our results demonstrate that honokiol suppresses NF-kappaB activation and NF-kappaB-regulated gene expression through the inhibition of IKKs, which provides a possible mechanism for its anti-tumor actions.
- Published
- 2005
- Full Text
- View/download PDF
42. Magnolol and honokiol enhance HL-60 human leukemia cell differentiation induced by 1,25-dihydroxyvitamin D3 and retinoic acid.
- Author
-
Fong WF, Tse AK, Poon KH, and Wang C
- Subjects
- CD11b Antigen biosynthesis, G1 Phase drug effects, HL-60 Cells, Humans, Lipopolysaccharide Receptors biosynthesis, MAP Kinase Signaling System drug effects, Resting Phase, Cell Cycle drug effects, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Biphenyl Compounds pharmacology, Calcitriol pharmacology, Calcium Channel Agonists pharmacology, Cell Differentiation drug effects, Lignans pharmacology, Tretinoin pharmacology
- Abstract
Magnolol (MG) and honokiol (HK), two lignans showing anti-inflammatory and anti-oxidant properties and abundantly available in the medicinal plants Magnolia officinalis and M. obovata, were found to enhance HL-60 cell differentiation initiated by low doses of 1,25-dihydroxyvitamin D3 (VD3) and all-trans-retinoic acid (ATRA). Cells expressing membrane differentiation markers CD11b and CD14 were increased from 4% in non-treated control to 8-16% after being treated with 10-30 microM MG or HK. When added to 1 nM VD3, MG or HK increased markers expressing cells from approximately 30% to 50-80%. When either MG or HK was added to 20 nM ATRA, only CD11b, but not CD14, expressing cells were increased from 9% to 24-70%. Under the same conditions, adding MG or HK to VD3 or ATRA treatment further enlarged the G0/G1 cell population and increased the expression of p27(Kip1), a cyclin-dependent kinase inhibitor. Pharmacological studies using PD098059 (a MEK inhibitor), SB203580 (a p38 MAPK inhibitor) and SP600125 (a JNK inhibitor) suggested that the MEK pathway was important for VD3 and ATRA-induced differentiation and also its enhancement by MG or HK, the p38 MAPK pathway had a inhibitory effect and the JNK pathway had little influence. It is evident that MG and HK are potential differentiation enhancing agents which may allow the use of low doses of VD3 and ATRA in the treatment for acute promyelocytic leukemia.
- Published
- 2005
- Full Text
- View/download PDF
43. Reversal of P-glycoprotein-mediated multidrug resistance by Alisol B 23-acetate.
- Author
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Wang C, Zhang JX, Shen XL, Wan CK, Tse AK, and Fong WF
- Subjects
- Adenosine Triphosphatases metabolism, Doxorubicin pharmacokinetics, Doxorubicin pharmacology, Drug Resistance, Multiple, Drug Resistance, Neoplasm physiology, Gene Expression drug effects, Humans, Iodine Radioisotopes, K562 Cells, Photoaffinity Labels metabolism, Rhodium metabolism, Tumor Cells, Cultured, Vinblastine pharmacology, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Cholestenones pharmacology, Drug Resistance, Neoplasm drug effects
- Abstract
Herbal drugs were screened for their activity in reversing multidrug resistance (MDR) in P-glycoprotein (P-gp) over-expressing cancer cells. Through bio-assay guided fractionation an active compound was isolated from Rhizoma Alismatis, the underground part of Alisma orientale and the chemical structure of the isolate compound was confirmed by HPLC, LC-MS and NMR as Alisol B 23-acetate (ABA). ABA restored the sensitivity of MDR cell lines HepG2-DR and K562-DR to anti-tumor agents that have different modes of action but are all P-gp substrates. It restored the activity of vinblastine, a P-gp substrate, in causing G2/M arrest in MDR cells. In a dose-dependent manner, ABA increased doxorubicin accumulation and slowed down the efflux of rhodamin-123 from MDR cells. ABA inhibited the photoaffinity labeling of P-gp by [125I]iodoarylazidoprazosin and stimulated the ATPase activity of P-gp in a concentration-dependent manner, suggesting that it could be a transporter substrate for P-gp. In addition, ABA was also a partial non-competitive inhibitor of P-gp when verapamil was used as a substrate. Our results suggest that ABA may be a potential MDR reversal agent and could serve as a lead compound in the development of novel drugs.
- Published
- 2004
- Full Text
- View/download PDF
44. Betulinic acid enhances 1alpha,25-dihydroxyvitamin D3-induced differentiation in human HL-60 promyelocytic leukemia cells.
- Author
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Poon KH, Zhang J, Wang C, Tse AK, Wan CK, and Fong WF
- Subjects
- Apoptosis drug effects, CD11b Antigen biosynthesis, CD11b Antigen genetics, Cell Differentiation drug effects, Cell Division drug effects, Dose-Response Relationship, Drug, Drug Synergism, Enzyme Activation drug effects, Enzyme Activation genetics, Enzyme Activation physiology, Flavonoids pharmacology, G1 Phase drug effects, G1 Phase physiology, Gene Expression drug effects, Gene Expression genetics, Humans, Lipopolysaccharide Receptors biosynthesis, Lipopolysaccharide Receptors genetics, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinase Kinases drug effects, Mitogen-Activated Protein Kinase Kinases metabolism, Monocytes cytology, Monocytes drug effects, Pentacyclic Triterpenes, Triterpenes antagonists & inhibitors, Triterpenes chemistry, Betulinic Acid, Calcitriol pharmacology, HL-60 Cells cytology, Triterpenes pharmacology
- Abstract
Betulinic acid (BA) is a pentacyclic triterpene found in a number of medicinal plants and has been shown to cause apoptosis in a number of cell lines. We report here that BA may also have an effect on HL-60 cell differentiation. BA was cytotoxic to HL-60 cells with an IC50 of 5.7 microM after a 72-h treatment. Flow cytometry analysis showed that after exposure to 1-12 microM of BA for 72 h, approximately 10% of viable cells were in the sub-G1, presumably apoptotic, phase. At the same time differentiation was induced in approximately 10% (at 1 microM BA) to a maximum of 20% (at 6 microM BA) of cells as judged by the NBT-reduction test, and the expression of membrane markers CD11b and CD14. On the other hand, at 1 and 5 nM, 1alpha,25-dihydroxyvitamin D3 (DHD3) induced differentiation in approximately 10 and 70% of cells, respectively. At 1 nM DHD3, the addition of 1 microM BA increased differentiated cells from 10 to 43% and with 3 microM BA the increase was to 80%. BA also enhanced the effects of DHD3 in the expansion of the G1 cell population with a concomitant decrease of S phase cells. The effects of DHD3 and BA on CD11b and CD14 expression were inhibited by PD98059, a MEK inhibitor. Our results suggest that BA may enhance the effect of DHD3 in inducing mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase-mediated HL-60 cell differentiation.
- Published
- 2004
- Full Text
- View/download PDF
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