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Chen Y, Wang L, Liu X, Wang F, An Y, Zhao W, Tian J, Kong D, Zhang W, Xu Y, Ba Y, Zhou H. The Genus Broussonetia: An Updated Review of Phytochemistry, Pharmacology and Applications. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27165344. [PMID: 36014582 PMCID: PMC9414938 DOI: 10.3390/molecules27165344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 02/05/2023]
Abstract
The Broussonetia genus (Moraceae), recognized for its value in many Chinese traditional herbs, mainly includes Broussonetia papyrifera (L.) L’Hér. ex Vent. (BP), Broussonetia kazinoki Siebold (BK), and Broussonetia luzonica (Blanco) Bureau (BL). Hitherto, researchers have found 338 compounds isolated from BP, BK, and BL, which included flavonoids, polyphenols, phenylpropanoids, alkaloids, terpenoids, steroids, and others. Moreover, its active compounds and extracts have exhibited a variety of pharmacological effects such as antitumor, antioxidant, anti-inflammatory, antidiabetic, anti-obesity, antibacterial, and antiviral properties, and its use against skin wrinkles. In this review, the phytochemistry and pharmacology of Broussonetia are updated systematically, after its applications are first summarized. In addition, this review also discusses the limitations of investigations and the potential direction of Broussonetia. This review can help to further understand the phytochemistry, pharmacology, and other applications of Broussonetia, which paves the way for future research.
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Choi E, Han F, Park J, Lee IS. Microbial Transformation and Biological Activities of the Prenylated Aromatic Compounds from Broussonetia kazinoki. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27061879. [PMID: 35335241 PMCID: PMC8954733 DOI: 10.3390/molecules27061879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/11/2022] [Accepted: 03/12/2022] [Indexed: 11/16/2022]
Abstract
Broussonetia kazinoki has been used as a traditional medicine for the treatment of burns and acne, and its extracts have been found to show tyrosinase inhibitory and anticancer activities. In this study, the tyrosinase inhibitory and cytotoxic activities of B. kazinoki were explored, leading to the isolation of kazinol C (1), kazinol E (2), kazinol F (3), broussonol N (4), and kazinol X (5), of which the compounds 4 and 5 have not been previously reported. Microbial transformation has been recognized as an efficient tool to generate more active metabolites. Microbial transformation of the major compounds 1 and 3 was conducted with Mucor hiemalis, where four glucosylated metabolites (6-9) were produced from 1, while one hydroxylated (10) and one glucosylated (11) metabolites were obtained from 3. Structures of the isolated metabolites were determined by extensive spectroscopic analyses. All compounds were evaluated for their tyrosinase inhibitory and cytotoxic activities. Compound 3 and its metabolites, kazinol Y (10) and kazinol F-4″-O-β-d-glucopyranoside (11), exhibited the most potent tyrosinase inhibitory activities with the IC50 values ranging from 0.71 to 3.36 µM. Meanwhile, none of the metabolites, except for kazinol C-2',3″-di-O-β-d-glucopyranoside (7), showed moderate cytotoxic activities (IC50 17.80 to 24.22 µM) against A375P, B16F10 and B16F1 cell lines.
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Kim JH, Kim S, Han S, Ahn EK, Cho YR, Jeong W, Kim SJ, Bae GU, Oh JS, Seo DW. Broussonin A- and B-mediated inhibition of angiogenesis by blockade of VEGFR-2 signalling pathways and integrin β1 expression. J Cell Mol Med 2022; 26:1194-1205. [PMID: 34994065 PMCID: PMC8831976 DOI: 10.1111/jcmm.17173] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 11/28/2022] Open
Abstract
In the present study, we demonstrate the regulatory effects and mechanism of broussonin A and B, diphenylpropane derivatives isolated from Broussonetia kazinoki, on vascular endothelial growth factor‐A (VEGF‐A)–stimulated endothelial cell responses in vitro and microvessel sprouting ex vivo. Treatment with broussonin A or B suppressed VEGF‐A‐stimulated endothelial cell proliferation by regulating the expression of cell cycle–related proteins and the phosphorylation status of retinoblastoma protein. In addition, treatment with broussonin A or B abrogated VEGF‐A‐stimulated angiogenic responses including endothelial cell migration, invasion, tube formation and microvessel formation from rat aortic rings. These anti‐angiogenic activities of broussonin A and B were mediated through inactivation of VEGF‐A‐stimulated downstream signalling pathways, localization of vascular endothelial‐cadherin at cell‐cell contacts, and down‐regulation of integrin β1 and integrin‐liked kinase. Furthermore, treatment with broussonin A or B inhibited proliferation and invasion of non–small cell lung cancer and ovarian cancer cells. Taken together, our findings suggest the pharmacological potential of broussonin A and B in the regulation of angiogenesis, cancer cell growth and progression.
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Affiliation(s)
- Jae Hyeon Kim
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Sunho Kim
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Surim Han
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Eun-Kyung Ahn
- Biocenter, Gyeonggi Business & Science Accelerator, Suwon, Republic of Korea
| | - Young-Rak Cho
- Biocenter, Gyeonggi Business & Science Accelerator, Suwon, Republic of Korea
| | - Wonsik Jeong
- Biocenter, Gyeonggi Business & Science Accelerator, Suwon, Republic of Korea
| | - Sung Joon Kim
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Gyu-Un Bae
- Department of Pharmacy, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
| | - Joa Sub Oh
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Dong-Wan Seo
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
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Vu NK, Ha MT, Kim CS, Gal M, Kim JA, Woo MH, Lee JH, Min BS. Structural characterization of prenylated compounds from Broussonetia kazinoki and their antiosteoclastogenic activity. PHYTOCHEMISTRY 2021; 188:112791. [PMID: 34082339 DOI: 10.1016/j.phytochem.2021.112791] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/12/2021] [Accepted: 04/17/2021] [Indexed: 06/12/2023]
Abstract
An undescribed 1,3-diphenylpropane derivative, kazinol V and six undescribed prenylated flavonoids, broussonols F-H and broussonols K-M were isolated from the roots of Broussonetia kazinoki Siebold, together with 12 known compounds. This is the first report of the isolation and structure determination of broussonol I from a natural source. The chemical structure of the undescribed compounds was determined using conventional NMR and HRMS data. Absolute configurations were assigned using time-dependent density functional theory calculations and Electronic Circular Dichroism (ECD) spectroscopy. The isolated compounds were screened for their effects on RANKL-induced osteoclast formation using RAW264.7 cells. Among them, broussonols F, G, and K showed strong, dose-dependent antiosteoclastogenic activities. Broussonol K exhibited the most potent inhibitory activity and possessed bone resorption suppressive activity.
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Affiliation(s)
- Ngoc Khanh Vu
- College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk, 38430, Republic of Korea
| | - Manh Tuan Ha
- College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk, 38430, Republic of Korea
| | - Chung Sub Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Minju Gal
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, 24341, Republic of Korea
| | - Jeong Ah Kim
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Mi Hee Woo
- College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk, 38430, Republic of Korea
| | - Jeong-Hyung Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, 24341, Republic of Korea
| | - Byung Sun Min
- College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk, 38430, Republic of Korea.
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Malaník M, Treml J, Leláková V, Nykodýmová D, Oravec M, Marek J, Šmejkal K. Anti-inflammatory and antioxidant properties of chemical constituents of Broussonetia papyrifera. Bioorg Chem 2020; 104:104298. [PMID: 33011537 DOI: 10.1016/j.bioorg.2020.104298] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/20/2020] [Accepted: 09/16/2020] [Indexed: 01/27/2023]
Abstract
Extensive phytochemical analysis of the CHCl3-soluble part of an ethanolic extract of branches and twigs of Broussonetia papyrifera led to the isolation of fourteen compounds, including a novel 5,11-dioxabenzo[b]fluoren-10-one derivative named broussofluorenone C (12). The isolated compounds 1-14 were characterized based on their NMR and HRMS data, and examined for their anti-inflammatory activities in LPS-stimulated THP-1 cells as well as for their cellular antioxidant effects. Compounds 7-10 and 12 showed inhibitory effects on NF-κB/AP-1 activation and compounds 7-9 were subsequently confirmed to suppress the secretion of both IL-1β and TNF-α in LPS-stimulated THP-1 cells more significantly than the prednisone used as a positive control. In the CAA assay, compound 10 exhibited the greatest antioxidant effect, greater than that of the quercetin used as a positive control. The results show possible beneficial effects and utilization of B. papyrifera wood in the treatment of inflammatory diseases as well as oxidative stress.
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Affiliation(s)
- Milan Malaník
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Palackého třída 1946/1, 61200 Brno, Czech Republic.
| | - Jakub Treml
- Department of Molecular Pharmacy, Faculty of Pharmacy, Masaryk University, Palackého třída 1946/1, 61200 Brno, Czech Republic
| | - Veronika Leláková
- Department of Molecular Pharmacy, Faculty of Pharmacy, Masaryk University, Palackého třída 1946/1, 61200 Brno, Czech Republic
| | - Daniela Nykodýmová
- Department of Molecular Pharmacy, Faculty of Pharmacy, Masaryk University, Palackého třída 1946/1, 61200 Brno, Czech Republic
| | - Michal Oravec
- Global Change Research Institute of the Czech Academy of Sciences, Bělidla 986/4a, 60300 Brno, Czech Republic
| | - Jaromír Marek
- X-ray Diffraction and Bio-SAXS Core Facility, Central European Institute of Technology, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
| | - Karel Šmejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Palackého třída 1946/1, 61200 Brno, Czech Republic.
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Xue JJ, Lei C, Wang PP, Kim KY, Li JY, Li J, Hou AJ. Flavans and diphenylpropanes with PTP1B inhibition from Broussonetia kazinoki. Fitoterapia 2018; 130:37-42. [DOI: 10.1016/j.fitote.2018.08.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/01/2018] [Accepted: 08/03/2018] [Indexed: 01/10/2023]
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Kim JH, Kim JK, Ahn EK, Ko HJ, Cho YR, Lee CH, Kim YK, Bae GU, Oh JS, Seo DW. Marmesin is a novel angiogenesis inhibitor: Regulatory effect and molecular mechanism on endothelial cell fate and angiogenesis. Cancer Lett 2015; 369:323-30. [DOI: 10.1016/j.canlet.2015.09.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 09/16/2015] [Accepted: 09/18/2015] [Indexed: 12/27/2022]
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Lee CG, Koo JH, Kim SG. Phytochemical regulation of Fyn and AMPK signaling circuitry. Arch Pharm Res 2015; 38:2093-105. [PMID: 25951818 DOI: 10.1007/s12272-015-0611-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Accepted: 04/27/2015] [Indexed: 01/03/2023]
Abstract
During the past decades, phytochemical terpenoids, polyphenols, lignans, flavonoids, and alkaloids have been identified as antioxidative and cytoprotective agents. Adenosine monophosphate-activated protein kinase (AMPK) is a kinase that controls redox-state and oxidative stress in the cell, and serves as a key molecule regulating energy metabolism. Many phytochemicals directly or indirectly alter the AMPK pathway in distinct manners, exerting catabolic metabolism. Some of them are considered promising in the treatment of metabolic diseases such as type II diabetes, obesity, and hyperlipidemia. Another important kinase that regulates energy metabolism is Fyn kinase, a member of the Src family kinases that plays a role in various cellular responses such as insulin signaling, cell growth, oxidative stress and apoptosis. Phytochemical inhibition of Fyn leads to AMPK-mediated protection of the cell in association with increased antioxidative capacity and mitochondrial biogenesis. The kinases may work together to form a signaling circuitry for the homeostasis of energy conservation and expenditure, and may serve as targets of phytochemicals. This review is intended as a compilation of recent advancements in the pharmacological research of phytochemicals targeting Fyn and AMPK circuitry, providing information for the prevention and treatment of metabolic diseases and the accompanying tissue injuries.
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Affiliation(s)
- Chan Gyu Lee
- College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Korea.
| | - Ja Hyun Koo
- College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Korea.
| | - Sang Geon Kim
- College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Korea.
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Ji J, Zhu J, Hu X, Wang T, Zhang X, Hou AJ, Wang H. (2S)-7,4'-dihydroxy-8-prenylflavan stimulates adipogenesis and glucose uptake through p38MAPK pathway in 3T3-L1 cells. Biochem Biophys Res Commun 2015; 460:578-82. [PMID: 25797620 DOI: 10.1016/j.bbrc.2015.03.072] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 03/12/2015] [Indexed: 01/14/2023]
Abstract
Adipose tissue plays a key role in the development of obesity and diabetes. Natural products are one of the main sources for discovering new lead compounds. In the present study, (2S)-7,4'-dihydroxy-8-prenylflavan (DHPF), a natural prenylated flavan isolated from Morus yunnanensis, was found to significantly promote adipogenesis and increase glucose uptake in 3T3-L1 cells. Real-time PCR results showed that DHPF increased the expression of glucose and lipid metabolism-related genes (C/EBPα, PPARγ, aP2, GLUT4 and adiponectin) and decreased the expression of inflammatory cytokine TNF-α. Western blotting further revealed that DHPF activated p38 MAPK at the initial stage of 3T3-L1 preadipocyte differentiation. DHPF-induced activation of p38, adipogenesis and glucose uptake were effectively blocked by SB203580, a specific p38 inhibitor. These results indicate that DHPF could stimulate adipogenesis and increase glucose uptake through the p38 MAPK pathway, and DHPF may be useful for the prevention and treatment of obesity-associated disorders such as type 2 diabetes (T2D).
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Affiliation(s)
- Jun Ji
- Department of Pharmacognosy, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Pudong, Shanghai 201203, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China
| | - Jingjie Zhu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China
| | - Xiao Hu
- Department of Pharmacognosy, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Pudong, Shanghai 201203, China
| | - Ting Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China
| | - Xiaodong Zhang
- Department of Biochemistry and Molecular Biology, Mayo Clinic, 13400 East Shea Boulevard Scottsdale, AZ 85259, USA
| | - Ai-Jun Hou
- Department of Pharmacognosy, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Pudong, Shanghai 201203, China.
| | - Heyao Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China.
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Kim HS, Lim J, Lee DY, Ryu JH, Lim JS. Kazinol C from Broussonetia kazinoki activates AMP-activated protein kinase to induce antitumorigenic effects in HT-29 colon cancer cells. Oncol Rep 2014; 33:223-9. [PMID: 25394483 DOI: 10.3892/or.2014.3601] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 07/21/2014] [Indexed: 11/05/2022] Open
Abstract
Kazinol C is a 1,3-diphenylpropane, obtained from Broussonetia kazinoki, that has been employed in folk medicine as an edema suppressant. It exerts beneficial effects in oxidative stress-related diseases, such as cancer. However, the molecular mechanism involved in the anticancer effects remains to be determined. AMP-activated protein kinase (AMPK) has emerged as a possible anticancer target molecule. The present study investigated the effect of kazinol C on AMPK activation as well as subsequent HT-29 colon cancer cell viability, apoptosis and migration. Kazinol C markedly induced AMPK phosphorylation and significantly attenuated HT-29 colon cancer cell growth and viability. Compound C, as a well‑known AMPK inhibitor, blocked the kazinol C-induced cell death, and stable transduction of dominant-negative (DN) AMPK in colon cancer cells also inhibited kazinol C-induced cell apoptosis. In addition, kazinol C inhibited HT-29 cell migration and anchorage-independent growth. AMPK inhibition using stable transduction with DN AMPK significantly abrogated the kazinol C-induced inhibition of cancer cell migration. Thus, AMPK is a critical and novel regulator of kazinol C-mediated cancer cell apoptosis and inhibition of migration, suggesting that AMPK is a prime cancer target.
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Affiliation(s)
- Hak-Su Kim
- Department of Biological Science and the Research Center for Women's Diseases, Sookmyung Women's University, Yongsan-Gu, Seoul 140-742, Republic of Korea
| | - Jihyun Lim
- Department of Biological Science and the Research Center for Women's Diseases, Sookmyung Women's University, Yongsan-Gu, Seoul 140-742, Republic of Korea
| | - Da Yeon Lee
- Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Yongsan-Gu, Seoul 140-742, Republic of Korea
| | - Jae-Ha Ryu
- Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Yongsan-Gu, Seoul 140-742, Republic of Korea
| | - Jong-Seok Lim
- Department of Biological Science and the Research Center for Women's Diseases, Sookmyung Women's University, Yongsan-Gu, Seoul 140-742, Republic of Korea
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Cho YR, Kim JH, Kim JK, Ahn EK, Ko HJ, In JK, Lee SJ, Bae GU, Kim YK, Oh JS, Seo DW. Broussonetia kazinoki modulates the expression of VEGFR-2 and MMP-2 through the inhibition of ERK, Akt and p70S6K‑dependent signaling pathways: Its implication in endothelial cell proliferation, migration and tubular formation. Oncol Rep 2014; 32:1531-6. [PMID: 25109823 DOI: 10.3892/or.2014.3380] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Accepted: 07/22/2014] [Indexed: 11/06/2022] Open
Abstract
Broussonetia kazinoki (BK) has been used as a traditional medicine to improve vision, as well as for inflammatory and infectious diseases. In the present study, we investigated the effects and molecular mechanism of the ethanolic extract of BK on cell proliferation, migration and tubular formation in vascular endothelial growth factor-A (VEGF-A)-treated human umbilical vein endothelial cells. BK treatment inhibited VEGF-A-stimulated endothelial cell proliferation through the downregulation of cell cycle-related proteins including cyclin-dependent kinases and cyclins. Moreover, BK treatment suppressed cell migration and tubular formation in response to VEGF-A. These anti-angiogenic activities of BK were associated with the inactivation of mitogenic signaling pathways including extracellular signal-regulated kinase, Akt and p70S6K, and the subsequent downregulation of VEGFR-2 and matrix metalloproteinase-2. Taken together, these findings suggest further evaluation and development of BK as a potential therapeutic agent for the treatment and prevention of angiogenesis-related diseases including cancer.
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Affiliation(s)
- Young-Rak Cho
- College of Pharmacy, Dankook University, Cheonan 330-714, Republic of Korea
| | - Jae Hyeon Kim
- College of Pharmacy, Dankook University, Cheonan 330-714, Republic of Korea
| | - Jin-Kyu Kim
- Natural Products Research Institute, Gyeonggi Institute of Science and Technology Promotion, Suwon 443-270, Republic of Korea
| | - Eun-Kyung Ahn
- Natural Products Research Institute, Gyeonggi Institute of Science and Technology Promotion, Suwon 443-270, Republic of Korea
| | - Hye-Jin Ko
- Natural Products Research Institute, Gyeonggi Institute of Science and Technology Promotion, Suwon 443-270, Republic of Korea
| | - Jae Kyung In
- College of Pharmacy, Dankook University, Cheonan 330-714, Republic of Korea
| | - Sang-Jin Lee
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea
| | - Gyu-Un Bae
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea
| | - Yong Kee Kim
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea
| | - Joa Sub Oh
- College of Pharmacy, Dankook University, Cheonan 330-714, Republic of Korea
| | - Dong-Wan Seo
- College of Pharmacy, Dankook University, Cheonan 330-714, Republic of Korea
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Weng JR, Lai IL, Yang HC, Lin CN, Bai LY. Identification of kazinol Q, a natural product from Formosan plants, as an inhibitor of DNA methyltransferase. Phytother Res 2013; 28:49-54. [PMID: 23447335 DOI: 10.1002/ptr.4955] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Revised: 01/14/2013] [Accepted: 01/25/2013] [Indexed: 11/12/2022]
Abstract
DNA methylation plays a pivotal role in the epigenetic regulation of the transcription of a number of cancer-related genes, thereby representing an important target for cancer prevention and treatment. In our search for DNA methyltransferase (DNMT) inhibitors from Formosan plants, by screening against a library consisting of 12 structurally distinct natural products, we identified kazinol Q {4-[6-(1,1-dimethyl-allyl)-7-hydroxy-chroman-2-yl]-3,6-bis-(3-methyl-but-2-enyl)-benzene-1,2-diol} as an inhibitor of recombinant DNMT1 with IC50 of 7 μM. The effect of kazinol Q on DNMT inhibition was validated by its ability to reactivate the expression of a DNA methylation-silenced gene, E-cadherin, in MDA-MB-231 breast cancer cells. Moreover, kazinol Q suppressed the proliferation of MCF-7 breast and LNCaP prostate cancer cells, in part, through apoptosis induction. The role of DNMT1 inhibition in mediating kazinol Q's antiproliferative effect was supported by the protective effect of ectopic expression of DNMT1 on kazinol Q-induced cell death. Molecular modeling analysis suggests that kazinol Q inhibited DNMT activity by competing with cytosine binding, a mechanism similar to that described for (-)-epigallocatechin-3-gallate (EGCG). Relative to EGCG, kazinol Q exhibits several desirable features for drug development, including chemical stability and increased hydrophobicity, and might have therapeutic relevance to cancer treatment.
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Affiliation(s)
- Jing-Ru Weng
- Department of Biological Science and Technology, China Medical University, Taichung, 40402, Taiwan
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George VC, Kumar DN, Suresh P, Kumar RA. Apoptosis-Induced Cell Death due to Oleanolic Acid in HaCaT Keratinocyte Cells -a Proof-of-Principle Approach for Chemopreventive Drug Development. Asian Pac J Cancer Prev 2012; 13:2015-20. [DOI: 10.7314/apjcp.2012.13.5.2015] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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14
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Wang GW, Huang BK, Qin LP. The Genus Broussonetia: A Review of its Phytochemistry and Pharmacology. Phytother Res 2011; 26:1-10. [DOI: 10.1002/ptr.3575] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2010] [Revised: 04/16/2011] [Accepted: 04/30/2011] [Indexed: 11/11/2022]
Affiliation(s)
- Guo-Wei Wang
- Department of Pharmacognosy, School of Pharmacy; Second Military Medical University; Shanghai; China
| | - Bao-Kang Huang
- Department of Pharmacognosy, School of Pharmacy; Second Military Medical University; Shanghai; China
| | - Lu-Ping Qin
- Department of Pharmacognosy, School of Pharmacy; Second Military Medical University; Shanghai; China
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Kazinol Q from Broussonetia kazinoki enhances cell death induced by Cu(II) through increased reactive oxygen species. Molecules 2011; 16:3212-21. [PMID: 21499221 PMCID: PMC6260624 DOI: 10.3390/molecules16043212] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 04/08/2011] [Accepted: 04/12/2011] [Indexed: 11/17/2022] Open
Abstract
The ability of the flavan kazinol Q (KQ) to induce DNA breakage in the presence of Cu(II) was examined by agarose gel electrophoresis using supercoiled plasmid DNA. In KQ-mediated DNA breakage reaction, the involvement of reactive oxygen species (ROS), H2O2 and O2- was established by the inhibition of DNA breakage by catalase and revealed DNA breakage by superoxide dismutase (SOD). The cell viability of gastric carcinoma SCM-1 cells treated with various concentrations of KQ was significantly decreased by cotreatment with Cu(II). Treatment of SCM-1 cells with 300 μM Cu(II) enhanced the necrosis induced by 100 μM KQ. Treatment of SCM-1 cells with 100 μM KQ in the presence of 300 μM Cu(II) increased the generation of H2O2. Taken together, the above finding suggested that KQ cotreatment with Cu(II) produced increased amounts of H2O2, thus enhancing subsequent cell death due to necrosis.
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Bae UJ, Lee DY, Song MY, Lee SM, Park JW, Ryu JH, Park BH. A Prenylated Flavan from Broussonetia kazinoki Prevents Cytokine-Induced .BETA.-Cell Death through Suppression of Nuclear Factor-.KAPPA.B Activity. Biol Pharm Bull 2011; 34:1026-31. [DOI: 10.1248/bpb.34.1026] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Ui-Jin Bae
- Department of Biochemistry, Research Institute for Endocrine Sciences, and Diabetes Research Center, Chonbuk National University Medical School
| | - Da Yeon Lee
- College of Pharmacy, Sookmyung Women's University
| | - Mi-Young Song
- Department of Biochemistry, Research Institute for Endocrine Sciences, and Diabetes Research Center, Chonbuk National University Medical School
| | - Sang-Myeong Lee
- Division of Biotechnology, College of Environmental and Bioresource Sciences, Chonbuk National University
| | - Jin-Woo Park
- Department of Biochemistry, Research Institute for Endocrine Sciences, and Diabetes Research Center, Chonbuk National University Medical School
| | - Jae-Ha Ryu
- College of Pharmacy, Sookmyung Women's University
| | - Byung-Hyun Park
- Department of Biochemistry, Research Institute for Endocrine Sciences, and Diabetes Research Center, Chonbuk National University Medical School
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Baek YS, Ryu YB, Curtis-Long MJ, Ha TJ, Rengasamy R, Yang MS, Park KH. Tyrosinase inhibitory effects of 1,3-diphenylpropanes from Broussonetia kazinoki. Bioorg Med Chem 2009; 17:35-41. [DOI: 10.1016/j.bmc.2008.11.022] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2008] [Revised: 11/08/2008] [Accepted: 11/11/2008] [Indexed: 11/26/2022]
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Martín R, Carvalho-Tavares J, Carvalho J, Ibeas E, Hernández M, Ruiz-Gutierrez V, Nieto ML. Acidic Triterpenes Compromise Growth and Survival of Astrocytoma Cell Lines by Regulating Reactive Oxygen Species Accumulation. Cancer Res 2007; 67:3741-51. [PMID: 17440087 DOI: 10.1158/0008-5472.can-06-4759] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Several studies have shown how pentacyclic triterpenes can inhibit proliferation and induce apoptosis of some tumor cell lines; however, its effect on astrocytic tumors, one of the most malignant forms of cancer, has rarely been reported. The aim of this study was to examine how the pentacyclic triterpenes, oleanolic acid and maslinic acid, isolated from olive juice, affected astrocytoma cell morphology and survival. Cell proliferation was inhibited in 1321N1 astrocytoma cells by using 1 to 50 micromol/L of either oleanolic acid or maslinic acid, with an average IC(50) of 25 micromol/L. Growth inhibition led to morphologic and cytoskeletal alterations associated with the loss of stellate morphology and characterized by a retraction of the cytoplasm and collapse of actin stress fibers. Using 4',6-diamidino-2-phenylindole and Annexin V, we showed that astrocytoma cell death induced by oleanolic acid or maslinic acid were mainly due to apoptotic events. Furthermore, we showed that caspase-3 is activated as a consequence of triterpene treatment. Finally, we found that exposure of the cells to oleanolic acid or maslinic acid resulted in a significant increase of intracellular reactive oxygen species, followed by loss of mitochondrial membrane integrity. Importantly, enzymatic scavengers, such as catalase, or phenolic antioxidants, such as butylated hydroxytoluene, rescued cells from the triterpene-mediated apoptosis, suggesting that the potential therapeutic effect of these acidic triterpenes is dependent on oxidative stress. Our data show that acidic triterpenes play a major role in 1321N1 astrocytoma morphology and viability and support the conclusion that oleanolic acid and maslinic acid may thus be promising new agents in the management of astrocytomas.
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Affiliation(s)
- Rubén Martín
- Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, C/Sanz y Forés s/n, 47003 Valladolid, Spain
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Huang D, Ding Y, Li Y, Zhang W, Fang W, Chen X. Anti-tumor activity of a 3-oxo derivative of oleanolic acid. Cancer Lett 2005; 233:289-96. [PMID: 16154686 DOI: 10.1016/j.canlet.2005.03.019] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2005] [Revised: 03/10/2005] [Accepted: 03/14/2005] [Indexed: 11/19/2022]
Abstract
Oleanolic acid (3beta-hydroxy-olea-12-en-28-oic acid, OA) exists widely in plant kingdom and possesses various pharmacological activities. In recent years, it was found that it had marked anti-tumor effects and exhibited cytotoxic activity towards many cancer cell lines in culture. In this article, the anti-tumor and differentiation-inducing effects of a derivative of OA modified at C-3, 3-oxo oleanolic acid (3-oxo-olea-12-en-28-oic acid, 3-oxo-OA, 3-7-1) was reported. In vitro, 3-7-1 were found to inhibit significantly the growth of cancer cells derived from different tissues. And 3-7-1 had inhibitory effect on melanoma in vivo. This selection may relate to the differentiation induced by 3-7-1. The inhibition of 3-7-1 on B16-BL6 suggests that 3-7-1 may be a useful anti-cancer agent for melanoma.
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Affiliation(s)
- Dan Huang
- Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China
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Nam NH, Kim Y, You YJ, Hong DH, Kim HM, Ahn BZ. New constituents fromCrinum latifoliumwith inhibitory effects against tube-like formation of human umbilical venous endothelial cells. Nat Prod Res 2004; 18:485-91. [PMID: 15595606 DOI: 10.1080/1057563031000122103] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Six compounds (1-6) were isolated from the methanol extract of Crinum latifolium by bioassay-guided separation. Among the six isolates, compounds 2 and 6 were new metabolites. Their structures were established as 4-senecioyloxymethyl-3,4-dimethoxycoumarin (2) and 5,6,3'-trihydroxy-7,8,4'-trimethoxyflavone (6) based on spectroscopic analyses. Compound 2 was found to be strongly inhibitory against the in vitro tube-like formation of human umbilical venous endothelial cells (HUVECs) while manifesting no cytotoxicity in tumor cell lines (B16F10, HCT116). Significant inhibitory activity (inhibition percentage, 53.5%) was still observed at concentrations as low as 1 microg/mL. Compound 6 showed a modest inhibitory effect on the tube-like formation of HUVECs. Other compounds, including cycloartenol (1), 4',7-dihydroxy-3'-methoxyflavan (3), 4',7-dihydroxyflavan (4), and 2',4',7-trihydroxydihydrochalcone (5) were found to be nearly inactive.
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Affiliation(s)
- Nguyen-Hai Nam
- College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea.
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Kromann H, Larsen M, Boesen T, Schønning K, Nielsen SF. Synthesis of prenylated benzaldehydes and their use in the synthesis of analogues of licochalcone A. Eur J Med Chem 2004; 39:993-1000. [PMID: 15501549 DOI: 10.1016/j.ejmech.2004.07.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2004] [Revised: 07/19/2004] [Accepted: 07/30/2004] [Indexed: 11/21/2022]
Abstract
In this paper, a general applicable synthesis of prenylated aromatic compounds exemplified by prenylated benzaldehydes starting from readily available acetophenones is described. The synthesized benzaldehydes are used to prepare a number of novel analogues of Licochalcone A, a known antibacterial compound, and for the exploration of the pharmacophoric elements that are essential for the antibacterial activity. It is shown that the hydroxyl group in the A ring is essential for the activity and that the hydroxyl group in the B ring has no influence on the antibacterial effect of Licochalcone A. Furthermore, it is shown that the prenyl group at the position 5 of the B ring also has a dominating influence on the activity. This aliphatic group can be replaced by other lipophilic long chained substituents in order to maintain the activity.
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Affiliation(s)
- Hasse Kromann
- Lica Pharmaceuticals A/S, Symbion Science Park, Fruebjergvej 3, DK-2100 Copenhagen, Denmark
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Ryu JH, Ahn H, Jin Lee H. Inhibition of nitric oxide production on LPS-activated macrophages by kazinol B from Broussonetia kazinoki. Fitoterapia 2003; 74:350-4. [PMID: 12781805 DOI: 10.1016/s0367-326x(03)00062-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The ethyl acetate soluble fraction of Broussonetia kazinoki at 50 microg/ml showed a significant inhibition (78.2%) of nitric oxide (NO) in lipopolysaccharide activated macrophages. Kazinol B, an isoprenylated flavan, was identified as the active principle. It inhibits the NO synthesis with an IC(50) of 21.6 microM.
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Affiliation(s)
- Jae-Ha Ryu
- College of Pharmacy, Sookmyung Women's University, Seoul 140-742, South Korea.
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Bioactive Compounds from the Genus Broussonetia. ACTA ACUST UNITED AC 2003. [DOI: 10.1016/s1572-5995(03)80137-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Li J, Guo WJ, Yang QY. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. World J Gastroenterol 2002; 8:493-5. [PMID: 12046077 PMCID: PMC4656428 DOI: 10.3748/wjg.v8.i3.493] [Citation(s) in RCA: 143] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2001] [Revised: 01/13/2002] [Accepted: 02/07/2002] [Indexed: 02/06/2023] Open
Abstract
AIM Ursolic acid (UA) and oleanolic acid (OA) are triperpene acids having a similar chemical structure and are distributed wildly in plants all over the world. In recent years, it was found that they had marked anti-tumor effects. There is little literature currently available regarding their effects on colon carcinoma cells. The present study was designed to investigate their inhibitory effects on human colon carcinoma cell line HCT15. METHODS HCT15 cells were cultured with different drugs. The treated cells were stained with hematoxylin-eosin and their morphologic changes observed under a light microscope. The cytotoxicity of these drugs was evaluated by tetrazolium dye assay. Cell cycle analysis was performed by flow cytometry (FCM). Data were expressed as means +/-SEM and Analysis of variance and Student' t-test for individual comparisons. RESULTS Twenty-four to 72 h after UA or OA 60 micromol/L treatment, the numbers of dead cells and cell fragments were increased and most cells were dead at the 72nd hour. The cytotoxicity of UA was stronger than that of OA. Seventy-eight hours after 30 micromol/L of UA or OA treatment, a number of cells were degenerated, but cell fragments were rarely seen. The IC(50) values for UA and OA were 30 and 60 micromol/L, respectively. Proliferation assay showed that proliferation of UA and OA-treated cells was slightly increased at 24h and significantly decreased at 48 h and 60 h, whereas untreated control cells maintained an exponential growth curve. Cell cycle analysis by FCM showed HCT15 cells treated with UA 30 and OA 60 for 36 h and 72 h gradually accumulated in G(0)/G(1) phase (both drugs P<0.05 for 72 h), with a concomitant decrease of cell populations in S phase (both drugs P<0.01 for 72 h) and no detectable apoptotic fraction. CONCLUSION UA and OA have significant anti-tumor activity. The effect of UA is stronger than that of OA. The possible mechanism of action is that both drugs have an inhibitory effect on tumor cell proliferation through cell-cycle arrest.
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Affiliation(s)
- Jie Li
- Department of Oncology, Cancer Center, Xin Hua Hospital, Shanghai Second Medical University, Shanghai 200092, China.
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Cytotoxicity of flavonoids on cancer cell lines. Structure-activity relationship. BIOACTIVE NATURAL PRODUCTS (PART H) 2002. [DOI: 10.1016/s1572-5995(02)80050-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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