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Zhang L, Ma C, Gu R, Zhang M, Wang X, Yang L, Liu Y, Zhou Y, He S, Zhu D. Paeonol regulates hypoxia-induced proliferation of pulmonary artery smooth muscle cells via EKR 1/2 signalling. Eur J Pharmacol 2018; 834:257-265. [DOI: 10.1016/j.ejphar.2018.07.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 07/11/2018] [Accepted: 07/12/2018] [Indexed: 01/08/2023]
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Ramachandhiran D, Vinothkumar V, Babukumar S. Paeonol exhibits anti-tumor effects by apoptotic and anti-inflammatory activities in 7,12-dimethylbenz(a)anthracene induced oral carcinogenesis. Biotech Histochem 2018; 94:10-25. [PMID: 30101628 DOI: 10.1080/10520295.2018.1493221] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We investigated the preventive potential of paeonol on 7,12-dimethylbenz(a)anthracene (DMBA) induced oral carcinogenesis. Oral tumors were developed in the buccal pouches of Syrian golden hamsters using topical application of 0.5% DMBA three times/week for 10 weeks. DMBA treated hamsters developed hyperplasia, dysplasia and well-differentiated squamous cell carcinoma. The animals also exhibited increased lipid oxidation, decreased antioxidant status and altered levels of detoxification agents. Paeonol treatment of DMBA treated hamsters for 14 weeks decreased tumor incidence, volume and burden Paeonol treatment also increased antioxidant activity and decreased lipid oxidation to near normal levels. Histomorphology and the expression patterns of mutant p53, cyclo-oxygenase (COX-2) and caspase-9 were investigated in the oral buccal mucosa. Paeonol exhibited protective effects against DMBA induced oral carcinogenesis owing to its antitumor, antioxidant, anti-inflammatory and apoptosis inducing properties.
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Affiliation(s)
- Duraisamy Ramachandhiran
- a Department of Biochemistry and Biotechnology, Faculty of Science , Annamalai University , Annamalainagar , India
| | - Veerasamy Vinothkumar
- a Department of Biochemistry and Biotechnology, Faculty of Science , Annamalai University , Annamalainagar , India
| | - Sukumar Babukumar
- a Department of Biochemistry and Biotechnology, Faculty of Science , Annamalai University , Annamalainagar , India
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Ding LQ, Qiu TY, Liu ZX, Chen LX, Oppong MB, Zhang DQ, Zhang BL, Bai G, Qiu F. Systematic characterization of the metabolites of paeonol in rats using ultra performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry with an integrative strategy. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1065-1066:70-78. [PMID: 28946128 DOI: 10.1016/j.jchromb.2017.09.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 09/05/2017] [Accepted: 09/10/2017] [Indexed: 02/05/2023]
Abstract
Paeonol, an active constituent in the root bark of Paeonia suffruticosa Andrews, is used to treat inflammation, headache and other diseases in clinic. Though the data on pharmacological researches of paeonol abounds, its metabolic profile is not so clear. It is essential to systematically characterize the in vivo metabolites in order to better understand its mechanism of action. In this study, ultra performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q/TOF-MS) with an integrative strategy was developed for analysis of paeonol metabolites. As a result, based on seven reference substances isolated or synthesized, twenty-five metabolites were detected and identified in urine, feces, bile and plasma of rats after oral administration of paeonol. To the best of our knowledge, 14 of these metabolites have not been reported previously. In addition, the dominating metabolic fates were oxidation, demethylation, hydrogenation, glucuronic acid and sulfate conjugations, and hydrogenation of paeonol was reported for the first time. This research provides scientific and reliable support for full understanding of the metabolic profiling of paeonol.
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Affiliation(s)
- Li-Qin Ding
- Tianjin Key Laboratory of TCM Chemistry and Analysis, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tian-Yi Qiu
- Tianjin Key Laboratory of TCM Chemistry and Analysis, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhao-Xi Liu
- Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang, China; College of Pharmacy, Nankai University, Tianjin, China
| | - Li-Xia Chen
- Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang, China
| | - Mahmood Brobbey Oppong
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - De-Qin Zhang
- Tianjin Key Laboratory of TCM Chemistry and Analysis, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Bo-Li Zhang
- Tianjin Key Laboratory of TCM Chemistry and Analysis, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Gang Bai
- College of Pharmacy, Nankai University, Tianjin, China
| | - Feng Qiu
- Tianjin Key Laboratory of TCM Chemistry and Analysis, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
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He RX, Ye X, Li R, Chen W, Ge T, Huang TQ, Nie XJ, Chen HJT, Peng DY, Chen WD. PEGylated niosomes-mediated drug delivery systems for Paeonol: preparation, pharmacokinetics studies and synergistic anti-tumor effects with 5-FU. J Liposome Res 2016; 27:161-170. [DOI: 10.1080/08982104.2016.1191021] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Rui-Xi He
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
| | - Xi Ye
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
| | - Rui Li
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
| | - Wei Chen
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
| | - Tao Ge
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
| | - Tian-Qing Huang
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
| | - Xiang-Jiang Nie
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
| | - He-Jun-Tao Chen
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
| | - Dai-Yin Peng
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
| | - Wei-Dong Chen
- Anhui University of Chinese Medicine, Hefei, Anhui, PR China
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Ou Y, Li Q, Wang J, Li K, Zhou S. Antitumor and Apoptosis Induction Effects of Paeonol on Mice Bearing EMT6 Breast Carcinoma. Biomol Ther (Seoul) 2014; 22:341-6. [PMID: 25143814 PMCID: PMC4131527 DOI: 10.4062/biomolther.2013.106] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 06/11/2014] [Accepted: 06/16/2014] [Indexed: 11/05/2022] Open
Abstract
Paeonol is a major phenolic micromolecular component of Moutan cortex Radicis, a traditional Chinese Medicine. It has shown antitumor effects in previous studies; however, the underlying mechanisms remain unknown. This study investigated the mechanism by giving treatments of placebo, cyclophosphamide, paeonol of 150 and 300 mg/kg to 4 groups of mice bearing EMT6 breast cancer. Apoptosis in tumor cells were confirmed by morphology analysis, including hematoxylin, eosin staining and TUNEL staining. The results showed that the weight of EMT6 breast tumor was significantly reduced in the groups treated with both 150 and 300 mg/kg of paeonol. Immunohistochemical and Western blot results showed that the expression of Bcl-2 was down-regulated while the expression of Bax, caspase 8 and caspase 3 was up-regulated respectively. These results suggest that paeonol exhibits antitumor effects and the mechanism of the inhibition is via induction of apoptosis, regulation of Bcl-2 and Bax expression, and activation of caspase 8 and caspase 3.
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Affiliation(s)
- Yetao Ou
- Department of Biological Engineering, College of Environment and Chemical Engineering, Yanshan University, Qinghuangdao 066004 ; College of Basic Medicine, Jiamusi University, Jiamusi 154007, P. R China
| | - Qingwang Li
- Department of Biological Engineering, College of Environment and Chemical Engineering, Yanshan University, Qinghuangdao 066004 ; College of Animal Science, Northwest A&F University, Yangling 712100
| | - Jianjie Wang
- College of Basic Medicine, Jiamusi University, Jiamusi 154007, P. R China
| | - Kun Li
- Department of Biological Engineering, College of Environment and Chemical Engineering, Yanshan University, Qinghuangdao 066004
| | - Shaobo Zhou
- Department of Life Science, Institute of Biomedical and Environmental Science and Technology, University of Bedfordshire, Luton, LU1 3JU, UK
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Lei Y, Li HX, Jin WS, Peng WR, Zhang CJ, Bu LJ, Du YY, Ma T, Sun GP. The radiosensitizing effect of Paeonol on lung adenocarcinoma by augmentation of radiation-induced apoptosis and inhibition of the PI3K/Akt pathway. Int J Radiat Biol 2013; 89:1079-86. [PMID: 23875954 DOI: 10.3109/09553002.2013.825058] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE To investigate the radiosensitizing effect and mechanism of action by the natural product Paeonol on lung adenocarcinoma both in vitro and in vivo. MATERIALS AND METHODS Two lung adenocarcinoma cell lines (human lung adenocarcinoma cell line A549 and mouse Lewis lung carcinoma (LLC) cell line) were chosen for this research. In order to select the experimental concentrations of Paeonol, cytotoxicity was determined using a MTT (3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide) assay. A clonogenic assay was performed to measure the radiosensitizing effects. Apoptosis was determined by the Tunel (terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling) assay and flow cytometry. Protein expression was analyzed by Western blotting. To test the radiosensitizing effect in vivo, a transplanted tumor model was established. RESULTS The MTT assay showed that Paeonol inhibited proliferation of cells. Paeonol concentration ranged from an IC5 (5% inhibiting concentration) to an IC20 and was used at non-toxic concentrations for subsequent experiments. The clonogenic assay showed that Paeonol enhanced the radiosensitivity of cells. Data from the Tunel assay and flow cytometry verified that Paeonol enhanced radiation-induced apoptosis. Paeonol inhibited the activation of the PI3K/AKT (Phosphatidylinositol 3-kinase/ Protein Kinase B) pathway and down-regulated the expression of COX-2 (Cyclooxygenase-2) and Survivin. Paeonol (1718 mg/kg) combined with 10 Gy irradiation inhibited the growth of a transplanted tumor model in vivo, resulting in the longest tumor growth time, tumor growth delay and the highest inhibition ratio when compared with the radiotherapy alone group. CONCLUSIONS It is reported for the first time that Paeonol has a radiosensitizing effect on lung adenocarcinoma both in vitro and in vivo. This effect could be related to the augmentation of radiation-induced apoptosis and the inhibition of the PI3K/Akt signalling pathway and its downstream proteins: COX-2 and Survivin.
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Affiliation(s)
- Yu Lei
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University , Hefei
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Ju Z, Li G, Wang J, Ye Y, Yang F, Zhao Y. Highly Regioselective Synthesis of Novel 4-O-Phosphorylated Paeonol Analogs. PHOSPHORUS SULFUR 2012. [DOI: 10.1080/10426507.2011.627901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Fan TWM, Lorkiewicz PK, Sellers K, Moseley HNB, Higashi RM, Lane AN. Stable isotope-resolved metabolomics and applications for drug development. Pharmacol Ther 2012; 133:366-91. [PMID: 22212615 PMCID: PMC3471671 DOI: 10.1016/j.pharmthera.2011.12.007] [Citation(s) in RCA: 160] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 12/06/2011] [Indexed: 12/14/2022]
Abstract
Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), during the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly cancer. The metabolome is the functional readout of the genome, functional genome, and proteome; it is also an integral partner in molecular regulations for homeostasis. The interrogation of the metabolome, or metabolomics, is now being applied to numerous diseases, largely by metabolite profiling for biomarker discovery, but also in pharmacology and therapeutics. Recent advances in stable isotope tracer-based metabolomic approaches enable unambiguous tracking of individual atoms through compartmentalized metabolic networks directly in human subjects, which promises to decipher the complexity of the human metabolome at an unprecedented pace. This knowledge will revolutionize our understanding of complex human diseases, clinical diagnostics, as well as individualized therapeutics and drug response. In this review, we focus on the use of stable isotope tracers with metabolomics technologies for understanding metabolic network dynamics in both model systems and in clinical applications. Atom-resolved isotope tracing via the two major analytical platforms, NMR and MS, has the power to determine novel metabolic reprogramming in diseases, discover new drug targets, and facilitates ADME studies. We also illustrate new metabolic tracer-based imaging technologies, which enable direct visualization of metabolic processes in vivo. We further outline current practices and future requirements for biochemoinformatics development, which is an integral part of translating stable isotope-resolved metabolomics into clinical reality.
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Affiliation(s)
- Teresa W-M Fan
- Department of Chemistry, University of Louisville, KY 40292, USA.
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Li N, Fan LL, Sun GP, Wan XA, Wang ZG, Wu Q, Wang H. Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo. World J Gastroenterol 2010; 16:4483-90. [PMID: 20845518 PMCID: PMC2941074 DOI: 10.3748/wjg.v16.i35.4483] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the anti-tumor effects of paeonol in gastric cancer cell proliferation and apoptosis in vitro and in vivo.
METHODS: Murine gastric cancer cell line mouse forestomach carcinoma (MFC) or human gastric cancer cell line SGC-7901 was cultured in the presence or absence of paeonol. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell cycle and apoptosis by flow cytometry and TUNEL staining. Tumor growth after subcutaneous implantation of MFC cells in mice was monitored, and the effects of treatment with paeonol were determined.
RESULTS: In vitro, paeonol caused dose-dependent inhibition on cell proliferation and induced apoptosis. Cell cycle analysis revealed a decreased proportion of cells in G0/G1 phase, with arrest at S. Paeonol treatment in gastric cancer cell line MFC and SGC-790 cells significantly reduced the expression of Bcl-2 and increased the expression of Bax in a concentration-related manner. Administration of paeonol to MFC tumor-bearing mice significantly lowered the tumor growth and caused tumor regression.
CONCLUSION: Paeonol has significantly growth-inhibitory and apoptosis-inducing effects in gastric cancer cells both in vitro and in vivo.
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Hu S, Shen G, Zhao W, Wang F, Jiang X, Huang D. Paeonol, the main active principles of Paeonia moutan, ameliorates alcoholic steatohepatitis in mice. JOURNAL OF ETHNOPHARMACOLOGY 2010; 128:100-106. [PMID: 20051254 DOI: 10.1016/j.jep.2009.12.034] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Revised: 08/27/2009] [Accepted: 12/28/2009] [Indexed: 05/27/2023]
Abstract
AIM OF STUDY Paeonol, a major phenolic component of Moutan Cortex, is traditionally used as a Chinese herbal medicine in various diseases including hepatitis. Evidence shows that paeonol has anti-inflammatory, anti-tumor, and anti-atherosclerosis effects. However, the effect of paeonol on alcoholic liver injury remains obscure. The present investigation was designed to determine the effects of paeonol on alcohol-induced hepatic injury in mice. MATERIALS AND METHODS The degree of alcoholic liver injury was evaluated biochemically by measuring serum markers and pathological examination. Real-time PCR and ELISA methods were used to check the expression of cytokines. Western blotting was used to check CYP 450 expression. RESULTS Treatment with paeonol significantly attenuated the level of serum aminotransferase, reduced the severe extent of hepatic cell damage, steatosis, and the infiltration of inflammatory cells in a model of alcoholic liver injury (P<0.05). Interestingly, paeonol markedly decreased hepatic mRNA expression of lipogenic genes (P<0.05) while had no effect on protein expression of hepatic CYP2E1. Furthermore, paeonol significantly decreased serum and tissue inflammatory cytokine levels, tissue lipid peroxidation, neutrophil infiltration and inhibited the apoptosis of hepatocytes (P<0.05). Kupffer cells isolated from ethanol-fed mice produced high amounts of tumor necrosis factor alpha, whereas Kupffer cells from paeonol treatment ethanol-fed mice produced less tumor necrosis factor alpha (P<0.05). CONCLUSIONS These findings suggest that paeonol may represent a novel, protective strategy against alcoholic liver injury by attenuating hepatic steatosis, inflammatory response and apoptosis.
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Affiliation(s)
- Shilian Hu
- Department of Geriatrics, Anhui Evidence-based Medicine Center, Anhui Geriatrics Institute, Anhui Provincial Hospital, Hefei 230001, China.
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Gao X, Yu Z, Zhao Y, Men L, Wang Q, Wang Z, Chen X, Xiao W, Bi K. Development of an LC Method for Simultaneous Analysis of Cinnamic Acid and Paeonol in Rat Plasma, and Its Application to a Pharmacokinetic Study after Intragastric Administration of Guizhi–Fuling Capsule. Chromatographia 2009. [DOI: 10.1365/s10337-009-1188-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Mutlib AE. Application of stable isotope-labeled compounds in metabolism and in metabolism-mediated toxicity studies. Chem Res Toxicol 2008; 21:1672-89. [PMID: 18702535 DOI: 10.1021/tx800139z] [Citation(s) in RCA: 136] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Stable isotope-labeled compounds have been synthesized and utilized by scientists from various areas of biomedical research during the last several decades. Compounds labeled with stable isotopes, such as deuterium and carbon-13, have been used effectively by drug metabolism scientists and toxicologists to gain better understanding of drugs' disposition and their potential role in target organ toxicities. The combination of stable isotope-labeling techniques with mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, which allows rapid acquisition and interpretation of data, has promoted greater use of these stable isotope-labeled compounds in absorption, distribution, metabolism, and excretion (ADME) studies. Examples of the use of stable isotope-labeled compounds in elucidating structures of metabolites and delineating complex metabolic pathways are presented in this review. The application of labeled compounds in mechanistic toxicity studies will be discussed by providing an example of how strategic placement of a deuterium atom in a drug molecule mitigated specific-specific renal toxicity. Other examples from the literature demonstrating the application of stable isotope-labeled compounds in understanding metabolism-mediated toxicities are presented. Furthermore, an example of how a stable isotope-labeled compound was utilized to better understand some of the gene changes in toxicogenomic studies is discussed. The interpretation of large sets of data produced from toxicogenomics studies can be a challenge. One approach that could be used to simplify interpretation of the data, especially from studies designed to link gene changes with the formation of reactive metabolites thought to be responsible for toxicities, is through the use of stable isotope-labeled compounds. This is a relatively unexplored territory and needs to be further investigated. The employment of analytical techniques, especially mass spectrometry and NMR, used in conjunction with stable isotope-labeled compounds to establish and understand mechanistic link between reactive metabolite formation, genomic, and proteomic changes and onset of toxicity is proposed. The use of stable isotope-labeled compounds in early human ADME studies as a way of identifying and possibly quantifying all drug-related components present in systemic circulation is suggested.
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Affiliation(s)
- Abdul E Mutlib
- Biotransformation Department, Drug Safety and Metabolism, Wyeth Research, Collegeville, Pennsylvania 19426, USA.
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Sun GP, Wang H, Xu SP, Shen YX, Wu Q, Chen ZD, Wei W. Anti-tumor effects of paeonol in a HepA-hepatoma bearing mouse model via induction of tumor cell apoptosis and stimulation of IL-2 and TNF-alpha production. Eur J Pharmacol 2008; 584:246-52. [PMID: 18329639 DOI: 10.1016/j.ejphar.2008.02.016] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2007] [Revised: 01/19/2008] [Accepted: 02/06/2008] [Indexed: 11/26/2022]
Abstract
Paeonol, a phenolic component from the root bark of Paeonia moutan, is traditionally used as a Chinese herbal medicine to activate the blood flow and remove blood stasis. Evidence shows that paeonol have anti-tumor, anti-inflammatory, and analgesic effects; however, the underlying mechanisms remain unknown. In this study, we investigated the molecular mechanisms by which paeonol exerts the anti-tumor effects by using a murine model of hepatoma established by in vivo injection of mouse HepA-hepatoma cells. Treatment of mice with 100, 200, or 400 mg/kg/day of paeonol significantly inhibited the growth of the HepA tumor in mice, induced HepA cell apoptosis as demonstrated by light microscopy and electron microscopy analyses, decreased the expression of Bcl-2 and increased the expression of Bax in HepA tumor tissues in a dose-related manner. Administration of paeonol in vivo also elevated serum levels of IL-2 and TNF-alpha in tumor-bearing mice. Moreover, splenocytes and macrophages isolated from paeonol-treated HepA tumor-bearing mice produced higher levels of IL-2 and TNF-alpha in response to concanavalin A and lipopolysaccharide stimulation, respectively, compared to these isolated from non-treated HepA tumor-bearing mice. In vitro treatment with paeonol was able to directly stimulate IL-2 and TNF-alpha production in splenocytes and macrophages from tumor-bearing mice, respectively. In conclusion, paeonol has the anti-tumor effect against hepatoma cells, which are likely mediated via induction of tumor cell apoptosis and stimulation of IL-2 and TNF-alpha production. Paeonol could be a promising drug to treat hepatocellular carcinoma.
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Affiliation(s)
- Guo-Ping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University; Hefei, 230032, China.
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Xu SP, Sun GP, Shen YX, Wei W, Peng WR, Wang H. Antiproliferation and apoptosis induction of paeonol in HepG 2 cells. World J Gastroenterol 2007; 13:250-6. [PMID: 17226904 PMCID: PMC4065953 DOI: 10.3748/wjg.v13.i2.250] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the antiproliferative effect of paeonol (Pae) used alone or in combination with chemotherapeutic agents [cisplatin (CDDP), doxorubicin (DOX) and 5-fluorouracil (5-FU)] on human hepatoma cell line HepG2 and the possible mechanisms.
METHODS: The cytotoxic effect of drugs on HepG2 cells was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetra-zolium bromide (MTT) assay. Morphologic changes were observed by acridine orange (AO) fluorescence staining. Cell cycle and apoptosis rate were detected by flow cytometry (FCM). Drug-drug interactions were analyzed by the coefficient of drug interaction (CDI).
RESULTS: Pae (7.81-250 mg/L) had an inhibitory effect on the proliferation of HepG2 cells in a dose-dependent manner, with the IC50 value of (104.77 ± 7.28) mg/L. AO fluorescence staining and FCM assays showed that Pae induced apoptosis and arrested cell cycle at S phase in HepG2 cells. Further, different extent synergisms were observed when Pae (15.63, 31.25, 62.5 mg/L) was combined with CDDP (0.31-2.5 mg/L), DOX (0.16-1.25 mg/L), or 5-FU (12.5-100 mg/L) at appropriate concentrations. The IC50 value of the three drugs decreased dramatically when combined with Pae (p < 0.01). Of the three different combinations, the sensitivity of cells to drugs was considerably different.
CONCLUSION: Pae had a significant growth-inhibitory effect on the human hepatoma cell line HepG2, which may be related to apoptosis induction and cell cycle arrest. It also can enhance the cytotoxicity of chemotherapeutic agents on HepG2 cells, and the S phase arrest induced by Pae may be one of the mechanisms of these interactions.
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Affiliation(s)
- Shu-Ping Xu
- Institute of Clinical Pharmacology of Anhui Medical University, Key Laboratory of Antiinflammatory and Immunological Pharmacology in Anhui Province, Hefei 230032, Anhui Province, China
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Hamm S, Von Unruh GE, Paar WD, Dengler HJ. Isotope Effects During Metabolism of (±)-Tramadol Isotopomers by Human Liver Microsomes. ACTA ACUST UNITED AC 2006. [DOI: 10.1080/00211919408046722] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- S. Hamm
- a Medizinische Universitätsklinik, Allgemeine Innere Medizin , Universität Bonn
| | - G. E. Von Unruh
- a Medizinische Universitätsklinik, Allgemeine Innere Medizin , Universität Bonn
| | - W. D. Paar
- a Medizinische Universitätsklinik, Allgemeine Innere Medizin , Universität Bonn
| | - H. J. Dengler
- a Medizinische Universitätsklinik, Allgemeine Innere Medizin , Universität Bonn
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Riley CM, Ren TC. Simple method for the determination of paeonol in human and rabbit plasma by high-performance liquid chromatography using solid-phase extraction and ultraviolet detection. JOURNAL OF CHROMATOGRAPHY 1989; 489:432-7. [PMID: 2753967 DOI: 10.1016/s0378-4347(00)82926-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- C M Riley
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045-2504
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Abstract
This paper focuses on stable isotope labeling of drugs, in combination with mass spectrometry (MS)-based methods, to facilitate the recognition and identification of metabolites and the employment of stable isotope-labeled derivatization reagents (e.g., bis-trimethylsilylacetamide-d18) in the structure elucidation of metabolites from unlabeled drugs via gas-liquid chromatography-MS techniques. In both cases, it is the so-called isotope peak shift that permits generation of data useful for metabolite identification. Furthermore, judicious labeling of a drug permits characterization of drug-related species (metabolites) by MS-based recognition of isotope cluster signatures. Studies using stable isotope-labeled drugs are exemplified by work on aminopyrine and isopropylantipyrine metabolism; examples of the derivatization peak shift approach include those from studies of timolol and cyproheptadine.
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Baillie TA, Rettenmeier AW. Recent advances in the use of stable isotopes in drug metabolism research. J Clin Pharmacol 1986; 26:481-4. [PMID: 3734140 DOI: 10.1002/j.1552-4604.1986.tb03562.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Pohl LR, Gillette JR. Determination of toxic pathways of metabolism by deuterium substitution. Drug Metab Rev 1984; 15:1335-51. [PMID: 6398777 DOI: 10.3109/03602538409029963] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Chapter 27. Stable Isotopes in Drug Metabolism and Disposition. ANNUAL REPORTS IN MEDICINAL CHEMISTRY 1984. [DOI: 10.1016/s0065-7743(08)60703-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register]
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