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1
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Raimondi MV, Rigogliuso S, Saiano F, Poma P, Labbozzetta M, Barreca M, Barbera M, Bivacqua R, Li Petri G, Buscemi S, Sardo I, Spanò V, Palumbo Piccionello A, Montalbano A, Barraja P, Notarbartolo M. Citrus wastewater as a source of value-added products: Quali-quantitative analysis and in vitro screening on breast cancer cell lines. Arch Pharm (Weinheim) 2024:e2400530. [PMID: 39363788 DOI: 10.1002/ardp.202400530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 09/09/2024] [Accepted: 09/11/2024] [Indexed: 10/05/2024]
Abstract
Citrus wastewater from industries is a source of bioactive compounds whose recovery could be a useful approach to convert processing waste into potential resources to be exploited in food, pharmaceutical, and chemical companies. Citrus wastewater, obtained from the industrial processing of Citrus sinensis, was freeze-dried and qualitative/quantitative evaluated using HPLC/MS Q-TOF analysis. Antiproliferative activity was investigated on MDA-MB-231 (triple-negative breast cancer cell line), MCF-7 (breast cancer cell line), and its multidrug-resistant variant MCF-7R. Fraction 8 emerged for its cytotoxicity toward MCF-7R cells. Its main component, the polymethoxylated flavone nobiletin (80%), is likely involved in increasing the number of G1-phase MCF-7R cells without inducing cell death. Notably, fraction 8 sensitizes MCF7-R cells to the antiproliferative effects of doxorubicin, thus contributing to overcoming MCF7-R multidrug resistance. Our studies highlighted the possibility of applying a sustainable strategy for citrus wastewater recycling to recover functional compounds as useful adjuvants for the prevention and treatment of malignancies.
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Affiliation(s)
- Maria Valeria Raimondi
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Salvatrice Rigogliuso
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Filippo Saiano
- Department of Agricultural, Food and Forestry Sciences (SAAF), University of Palermo, Palermo, Italy
| | - Paola Poma
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Manuela Labbozzetta
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Marilia Barreca
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Marcella Barbera
- Department of Earth and Marine Sciences (DiSTeM), University of Palermo, Palermo, Italy
| | - Roberta Bivacqua
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Giovanna Li Petri
- Istituto per lo Studio dei Materiali Nanostrutturati, CNR, Palermo, Italy
| | - Silvestre Buscemi
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Ignazio Sardo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Virginia Spanò
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Antonio Palumbo Piccionello
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Alessandra Montalbano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Paola Barraja
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Monica Notarbartolo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
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Almubarak A, Lee S, Yu IJ, Jeon Y. Effects of Nobiletin supplementation on the freezing diluent on porcine sperm cryo-survival and subsequent in vitro embryo development. Theriogenology 2024; 214:314-322. [PMID: 37956580 DOI: 10.1016/j.theriogenology.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 10/29/2023] [Accepted: 11/05/2023] [Indexed: 11/15/2023]
Abstract
Nobiletin (NOB) is a bioflavonoid compound isolated from citrus fruit peels. The present study aimed to elucidate whether NOB facilitates the porcine sperm cryosurvival and embryo development after in vitro fertilization (IVF). To this end, spermatozoa were diluted and cryopreserved in a freezing extender supplemented with 0 (control), 50, 100, 150, and 200 μM Nobiletin. The kinematic patterns of frozen-thawed (FT) sperm were assessed after 30 and 90 min incubation using a Sperm Class Analyzer (SCA). Viability, acrosome integrity, and mitochondrial membrane potential (MMP) were measured by fluorescence microscopy 30 min after thawing using SYBR-14/PI, PSA/FITC, and R123/PI, respectively. Lipid peroxidation was determined using MDA assay after incubation for 90 min. The addition of 100 μM and 150 μM NOB to the extender significantly improved sperm progressive motility, and acrosome integrity compared to the control group (P < 0.05). The proportion of viable spermatozoa was significantly higher in the 150 μM NOB group. MDA levels were less in 50 μM and 150 μM NOB treated groups compared to the control. In addition, IVF with FT sperm was used to assess the embryo developmental competence. Treatment with 150 μM NOB before cryopreservation increased the cleavage and blastocyst formation rates compared to the control group. Furthermore, the relative expression of POU5F1 and AMPK, genes related to pluripotency and cell differentiation were significantly upregulated in embryos resulting from NOB-treated sperm compared to the control group. These results suggest that Nobiletin is a functionally novel phytochemical to mitigate oxidative stress during the freezing-thawing of porcine spermatozoa as reflected by improved FT sperm quality and IVF outcome.
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Affiliation(s)
- Areeg Almubarak
- Department of Theriogenology and Reproductive Biotechnology, College of Veterinary Medicine and Bio-safety Research Institute, Jeonbuk National University, Iksan, 54596, South Korea; Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, Sudan University of Science and Technology, P.O. Box 204, Hilat Kuku, Khartoum North, 11111, Sudan
| | - Sanghoon Lee
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, 9 34134, South Korea
| | - Il-Jeoung Yu
- Department of Theriogenology and Reproductive Biotechnology, College of Veterinary Medicine and Bio-safety Research Institute, Jeonbuk National University, Iksan, 54596, South Korea
| | - Yubyeol Jeon
- Department of Theriogenology and Reproductive Biotechnology, College of Veterinary Medicine and Bio-safety Research Institute, Jeonbuk National University, Iksan, 54596, South Korea.
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3
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Peng Q, Zhang Y, Zhu M, Bao F, Deng J, Li W. Polymethoxyflavones from citrus peel: advances in extraction methods, biological properties, and potential applications. Crit Rev Food Sci Nutr 2022; 64:5618-5630. [PMID: 36530054 DOI: 10.1080/10408398.2022.2156476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Citrus peel, as an effective component of citrus by-products, contains a large number of natural active components, including pectin, vitamins, dietary fiber, essential oil, phenolic compounds, flavonoids, and so on. With the development of the circular economy, citrus peel has attracted extensive concern in the food industry. The exploitation of citrus peel would assist in excavating potential properties and alleviating the environmental burden. Polymethoxyflavones (PMFs) exist almost in citrus peel, which have remarkable biological activities including antioxidant, anti-inflammatory, anti-cancer, and anti-obesity. Therefore, PMFs from citrus peel have the potential to develop as dietary supplements in the near future. Collectively, it is essential to take action to optimize the extraction conditions of PMFs and make the most of the extracts. This review mainly compiles several extraction methods and bioactivities of PMFs from citrus peel and introduces different applications including food processing, pharmaceutical industry, and plant rhizosphere to develop better utilization of citrus PMFs.
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Affiliation(s)
- Qiong Peng
- National Engineering Research Center of Rice and Byproduct Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, China
| | - Yao Zhang
- National Engineering Research Center of Rice and Byproduct Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, China
| | - Mingxuan Zhu
- National Engineering Research Center of Rice and Byproduct Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, China
| | - Feng Bao
- National Engineering Research Center of Rice and Byproduct Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, China
| | - Jing Deng
- National Engineering Research Center of Rice and Byproduct Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, China
- College of Food Science and Engineering, Nanjing University of Finance, and Economics/Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing, Jiangsu, China
| | - Wen Li
- National Engineering Research Center of Rice and Byproduct Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, China
- College of Food Science and Engineering, Nanjing University of Finance, and Economics/Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing, Jiangsu, China
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Hussain H, Mamadalieva NZ, Hussain A, Hassan U, Rabnawaz A, Ahmed I, Green IR. Fruit Peels: Food Waste as a Valuable Source of Bioactive Natural Products for Drug Discovery. Curr Issues Mol Biol 2022; 44:1960-1994. [PMID: 35678663 PMCID: PMC9164088 DOI: 10.3390/cimb44050134] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/27/2022] [Accepted: 04/27/2022] [Indexed: 12/31/2022] Open
Abstract
Fruits along with vegetables are crucial for a balanced diet. These not only have delicious flavors but are also reported to decrease the risk of contracting various chronic diseases. Fruit by-products are produced in huge quantity during industrial processing and constitute a serious issue because they may pose a harmful risk to the environment. The proposal of employing fruit by-products, particularly fruit peels, has gradually attained popularity because scientists found that in many instances peels displayed better biological and pharmacological applications than other sections of the fruit. The aim of this review is to highlight the importance of fruit peel extracts and natural products obtained in food industries along with their other potential biological applications.
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Affiliation(s)
- Hidayat Hussain
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany
| | - Nilufar Z. Mamadalieva
- Institute of the Chemistry of Plant Substances of the Academy Sciences of Uzbekistan, Tashkent 100170, Uzbekistan;
| | - Amjad Hussain
- Department of Chemistry, University of Okara, Okara 56130, Pakistan;
| | - Uzma Hassan
- Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, Pakistan;
| | - Aisha Rabnawaz
- Department of Chemistry, University of Okara, Okara 56130, Pakistan;
| | - Ishtiaq Ahmed
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB3 0AS, UK;
| | - Ivan R. Green
- Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1, Matieland, Stellenbosch 7600, South Africa;
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Tajaldini M, Asadi J. The Use of Bio-Active Compounds of Citrus Fruits as Chemopreventive Agents and Inhibitor of Cancer Cells Viability. Anticancer Agents Med Chem 2021; 21:1058-1068. [PMID: 32698740 DOI: 10.2174/1871520620666200721105505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 05/13/2020] [Accepted: 05/24/2020] [Indexed: 11/22/2022]
Abstract
Common therapy of cancer, such as chemotherapy, has various side effects for the patients. In recent studies, new therapeutic approaches in cancer treatment are adjuvant therapy, along with a reduction in side effects of chemotherapy drugs. Treatment by herbal medicines may have some advantages over treatment with single purified chemicals, also in terms of side effects, the use of plants in cancer treatment is a more secure method. Citrus fruits are one of the most consumed natural products in the world due to the presence of various metabolites and bioactive compounds, such as phenols, flavonoids and, carotenoids. Bioactive compounds of citrus modulate signaling pathways and interact with signaling molecules such as apoptotic and cell cycle (P53, P21, etc.) and thus have a wide range of pharmacological activities, including anti-inflammatory, anti-cancer and oxidative stress. The findings discussed in this review strongly support their potential as anti-cancer agents. Therefore, the purpose of this review was to examine the effects of active compounds in citrus as a therapy agent in cancer treatment.
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Affiliation(s)
- Mahboubeh Tajaldini
- Ischimic Disorder Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Jahanbakhsh Asadi
- Metabolic Disorder Center, Golestan University of Medical Sciences, Gorgan, Iran
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Yamamoto K, Musou-Yahada A, Yoshimoto A, Sakamoto K, Hirose N, Ohta H. Multivariate Analysis and Characterization of Flavonoids and Volatile Components of Citrus Fruits Produced in Okinawa. J JPN SOC FOOD SCI 2021. [DOI: 10.3136/nskkk.68.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Kenta Yamamoto
- Department of Food Management, Faculty of Nutritional Sciences, Nakamura Gakuen University
| | - Ayumi Musou-Yahada
- Department of Nutritional Sciences, Faculty of Nutritional Sciences, Nakamura Gakuen University
| | - Ayami Yoshimoto
- Department of Food Management, Faculty of Nutritional Sciences, Nakamura Gakuen University
| | - Koji Sakamoto
- Department of Clinical Nutrition, Faculty of Health Science, Hiroshima International University
| | | | - Hideaki Ohta
- Department of Food Management, Faculty of Nutritional Sciences, Nakamura Gakuen University
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Ashrafizadeh M, Zarrabi A, Saberifar S, Hashemi F, Hushmandi K, Hashemi F, Moghadam ER, Mohammadinejad R, Najafi M, Garg M. Nobiletin in Cancer Therapy: How This Plant Derived-Natural Compound Targets Various Oncogene and Onco-Suppressor Pathways. Biomedicines 2020; 8:biomedicines8050110. [PMID: 32380783 PMCID: PMC7277899 DOI: 10.3390/biomedicines8050110] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 04/28/2020] [Accepted: 04/28/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer therapy is a growing field, and annually, a high number of research is performed to develop novel antitumor drugs. Attempts to find new antitumor drugs continue, since cancer cells are able to acquire resistance to conventional drugs. Natural chemicals can be considered as promising candidates in the field of cancer therapy due to their multiple-targeting capability. The nobiletin (NOB) is a ubiquitous flavone isolated from Citrus fruits. The NOB has a variety of pharmacological activities, such as antidiabetes, antioxidant, anti-inflammatory, hepatoprotective, and neuroprotective. Among them, the antitumor activity of NOB has been under attention over recent years. In this review, we comprehensively describe the efficacy of NOB in cancer therapy. NOB induces apoptosis and cell cycle arrest in cancer cells. It can suppress migration and invasion of cancer cells via the inhibition of epithelial-to-mesenchymal transition (EMT) and EMT-related factors such as TGF-β, ZEB, Slug, and Snail. Besides, NOB inhibits oncogene factors such as STAT3, NF-κB, Akt, PI3K, Wnt, and so on. Noteworthy, onco-suppressor factors such as microRNA-7 and -200b undergo upregulation by NOB in cancer therapy. These onco-suppressor and oncogene pathways and mechanisms are discussed in this review.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 5166616471, Iran;
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey;
| | - Sedigheh Saberifar
- Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz 6135783151, Iran;
| | - Farid Hashemi
- DVM. Graduated, Young Researcher and Elite Club, Kazerun Branch, Islamic Azad University, Kazeroon 7319846451, Iran;
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran 1417414418, Iran;
| | - Fardin Hashemi
- Student Research Committee, Department of Physiotherapy, Faculty of Rehabilitation, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715749, Iran;
| | - Ebrahim Rahmani Moghadam
- Student Research Committee, Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran;
| | - Reza Mohammadinejad
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7619813159, Iran
- Correspondence: (R.M.); (M.N.); (M.G.)
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
- Correspondence: (R.M.); (M.N.); (M.G.)
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida-201313, India
- Correspondence: (R.M.); (M.N.); (M.G.)
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Wei D, Zhang G, Zhu Z, Zheng Y, Yan F, Pan C, Wang Z, Li X, Wang F, Meng P, Zheng W, Yan Z, Zhai D, Lu Z, Yuan J. Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells. Front Pharmacol 2019; 10:690. [PMID: 31354472 PMCID: PMC6635658 DOI: 10.3389/fphar.2019.00690] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 05/27/2019] [Indexed: 12/12/2022] Open
Abstract
Nobiletin is a polymethoxy flavonoid isolated from Citrus depressa and Citrus reticulata. It has been reported that nobiletin can suppress tumors. We primarily explored the antitumor effects of nobiletin and the associated potential mechanisms in ACHN and Caki-2 renal carcinoma cells. A CCK-8 assay and cloning experiments were used to assess cell viability, and a transwell assay and scratch test were used to assess metastatic ability. The cell cycle was analyzed by flow cytometry, whereas apoptosis was analyzed using flow cytometry and a terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. Protein expression was examined by Western blot and immunofluorescence. Renal cancer cells were subcutaneously transplanted into nude mice for in vivo studies. The data showed that nobiletin administration significantly dose- and time-dependently suppressed renal cancer cell proliferation; moreover, nobiletin treatment induced cell cycle arrest in the G0/G1 phase and promoted apoptosis. Immunofluorescence analysis indicated that nobiletin decreased the nuclear localization of signal transducer and activator of transcription 3 (STAT3) and YY1-associated protein 1 (YY1AP1). Western blot showed that the levels of phosphorylated SRC, phosphorylated AKT serine/threonine kinase (AKT), and phosphorylated STAT3 were decreased, whereas that of phosphorylated YY1AP1 was increased. The results further showed that application of insulin-like growth factor 1 (IGF1) was able to reverse the nobiletin-induced changes in the levels of phosphorylated AKT, phosphorylated STAT3, and phosphorylated YY1AP1, and could also reverse the antitumor effects of nobiletin. The results of in vivo experiments showed that, compared to the control, tumor volume and weight were both reduced following nobiletin treatment. In conclusion, our study demonstrated that nobiletin can inhibit renal carcinoma cell viability and provides a novel therapeutic approach for the treatment of kidney cancer.
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Affiliation(s)
- Di Wei
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Geng Zhang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zheng Zhu
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yu Zheng
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Fei Yan
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Chongxian Pan
- Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, CA, United States
| | - Zhiyong Wang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xian Li
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Fuli Wang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Ping Meng
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Wanxiang Zheng
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhao Yan
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Dongsheng Zhai
- State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China
| | - Zifan Lu
- State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi'an, China
| | - Jianlin Yuan
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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Goh JXH, Tan LTH, Goh JK, Chan KG, Pusparajah P, Lee LH, Goh BH. Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention. Cancers (Basel) 2019; 11:E867. [PMID: 31234411 PMCID: PMC6627117 DOI: 10.3390/cancers11060867] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 06/18/2019] [Accepted: 06/19/2019] [Indexed: 12/19/2022] Open
Abstract
The search for effective methods of cancer treatment and prevention has been a continuous effort since the disease was discovered. Recently, there has been increasing interest in exploring plants and fruits for molecules that may have potential as either adjuvants or as chemopreventive agents against cancer. One of the promising compounds under extensive research is nobiletin (NOB), a polymethoxyflavone (PMF) extracted exclusively from citrus peel. Not only does nobiletin itself exhibit anti-cancer properties, but its derivatives are also promising chemopreventive agents; examples of derivatives with anti-cancer activity include 3'-demethylnobiletin (3'-DMN), 4'-demethylnobiletin (4'-DMN), 3',4'-didemethylnobiletin (3',4'-DMN) and 5-demethylnobiletin (5-DMN). In vitro studies have demonstrated differential efficacies and mechanisms of NOB and its derivatives in inhibiting and killing of colon cancer cells. The chemopreventive potential of NOB has also been well demonstrated in several in vivo colon carcinogenesis animal models. NOB and its derivatives target multiple pathways in cancer progression and inhibit several of the hallmark features of colorectal cancer (CRC) pathophysiology, including arresting the cell cycle, inhibiting cell proliferation, inducing apoptosis, preventing tumour formation, reducing inflammatory effects and limiting angiogenesis. However, these substances have low oral bioavailability that limits their clinical utility, hence there have been numerous efforts exploring better drug delivery strategies for NOB and these are part of this review. We also reviewed data related to patents involving NOB to illustrate the extensiveness of each research area and its direction of commercialisation. Furthermore, this review also provides suggested directions for future research to advance NOB as the next promising candidate in CRC chemoprevention.
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Affiliation(s)
- Joanna Xuan Hui Goh
- Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
| | - Loh Teng-Hern Tan
- Novel Bacteria and Drug Discovery (NBDD) Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
| | - Joo Kheng Goh
- School of Science, Monash University Malaysia, Jalan Lagoon Selatan, 47500, Bandar Sunway, Selangor Darul Ehsan, Malaysia.
| | - Kok Gan Chan
- Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia.
- International Genome Centre, Jiangsu University, Zhenjiang 212013, China.
| | - Priyia Pusparajah
- Medical Health and Translational Research Group, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia.
| | - Learn-Han Lee
- Novel Bacteria and Drug Discovery (NBDD) Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
- Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway 47500, Malaysia.
| | - Bey-Hing Goh
- Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
- Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway 47500, Malaysia.
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Endothelium-independent vasodilator effects of nobiletin in rat aorta. J Pharmacol Sci 2019; 140:48-53. [PMID: 31088764 DOI: 10.1016/j.jphs.2019.04.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/26/2019] [Accepted: 04/10/2019] [Indexed: 12/31/2022] Open
Abstract
Nobiletin is a one of the polymethoxyflavones contained in the peel of citrus fruits, such as Citrus depressa. In this study, the effect of nobiletin-induced relaxation on phenylephrine (PE)-induced contraction of endothelium-denuded rat aorta was investigated. Nobiletin inhibited PE- or KCl-induced contractions in a concentration-dependent manner in endothelium-intact and -denuded aortas. However, this relaxation was stronger in PE-induced contractions than in KCl-induced contractions; moreover, the nobiletin-induced relaxation was significantly increased on PE-induced contraction in endothelium-intact aorta. ODQ significantly inhibited the nobiletin-induced relaxation in endothelium-denuded aorta; however, SQ22536 did not affect the relaxation. In addition, IBMX synergistically enhanced the nobiletin-induced relaxation. Nobiletin increased cGMP levels in aorta. Also, IBMX significantly increased cGMP content in aorta, and ODQ significantly reduced cGMP levels. Nobiletin-induced relaxation was significantly inhibited by the Ca2+-activated K+ (BK) channel inhibitor iberiotoxin (IbTX) and the ATP-sensitive K+ (KATP) channel inhibitor glybenclamide. Sodium nitroprusside-induced relaxation was suppressed by IbTX, but not by glybenclamide. These results suggest that nobiletin inhibits PE-induced contractions of endothelium-denuded rat aorta by increasing cGMP levels via GC activation. Moreover, the present findings indicate the possibility that nobiletin opened BK channels by a cGMP-related signal, but KATP channels were opened by a cGMP-nonrelated signal in rat aorta.
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Sun Y, Han Y, Song M, Charoensinphon N, Zheng J, Qiu P, Wu X, Xiao H. Inhibitory effects of nobiletin and its major metabolites on lung tumorigenesis. Food Funct 2019; 10:7444-7452. [DOI: 10.1039/c9fo01966a] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The present study demonstrated that the oral administration of nobiletin significantly inhibited lung carcinogenesis in mice, and these chemopreventive effects could be attributed to its metabolites that showed potent anti-cancer effects.
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Affiliation(s)
- Yue Sun
- Anhui Engineering Laboratory for Agro-products Processing
- State Key Laboratory of Tea Plant Biology and Utilization
- International Joint Laboratory on Tea Chemistry and Health Effects
- Anhui Agricultural University
- Hefei
| | - Yanhui Han
- Department of Food Science
- University of Massachusetts
- Amherst
- USA
| | - Mingyue Song
- Department of Food Science
- University of Massachusetts
- Amherst
- USA
- College of Food Science
| | | | - Jinkai Zheng
- Department of Food Science
- University of Massachusetts
- Amherst
- USA
- Institute of Agro-Products Processing Science and Technology
| | - Peiju Qiu
- Department of Food Science
- University of Massachusetts
- Amherst
- USA
- School of Pharmacy
| | - Xian Wu
- Department of Food Science
- University of Massachusetts
- Amherst
- USA
- Department of Kinesiology and Health
| | - Hang Xiao
- Department of Food Science
- University of Massachusetts
- Amherst
- USA
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12
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Hirose N, Maeda G, Onda S, Shoda M, Miyagi K, Wada K, Ohta H. Development of Vinegar Extract from the Waste Peels of Shiikuwasha. J JPN SOC FOOD SCI 2017. [DOI: 10.3136/nskkk.64.81] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Naoto Hirose
- Okinawa Prefectural Agricultural Research Center
| | - Goki Maeda
- Okinawa Prefectural Agricultural Research Center
| | - Satoshi Onda
- Okinawa Prefectural Agricultural Research Center
| | | | - Kazuna Miyagi
- Faculity of Education and Graduate School of Education, University of the Ryukyus
| | - Koji Wada
- Faculty of Agriculture, University of the Ryukyus
| | - Hideaki Ohta
- Department of Nutritional Sciences, Nakamura Gakuen University
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13
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Chen J, Chen AY, Huang H, Ye X, Rollyson WD, Perry HE, Brown KC, Rojanasakul Y, Rankin GO, Dasgupta P, Chen YC. The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway. Int J Oncol 2015; 46:2629-38. [PMID: 25845666 PMCID: PMC4441297 DOI: 10.3892/ijo.2015.2946] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 03/19/2015] [Indexed: 11/24/2022] Open
Abstract
Despite its importance, the death rate of ovarian cancer has remained unchanged over the past five decades, demanding an improvement in prevention and treatment of this malignancy. With no known carcinogens, targeted prevention is currently unavailable, and efforts in early detection of this malignancy by screening biomarkers have failed. The inhibition of angiogenesis, also known as angioprevention, is a promising strategy to limit the growth of solid tumors, including ovarian cancers. Nobiletin, a polymethoxy flavonoid compound isolated from the tiansheng plant, has been shown to inhibit the growth of multiple types of human cancers. However, there are no reports involving the effect on nobiletin on human ovarian cancer. The present report shows that nobiletin potently decreases the viability of ovarian cancer cells in vitro. However, nobiletin does not affect the viability of normal ovarian epithelial cells at <40 μM. The antitumor activity of nobiletin was also observed in athymic mouse models and in chicken chorioallantoic membrane (CAM) models. The anti-neoplastic activity of nobiletin was due to its ability to inhibit angiogenesis. We also studied the molecular mechanisms by which nobiletin suppresses angiogenesis. We observed that nobiletin inhibits secretion of the key angiogenesis mediators, Akt, HIF-1α, NF-κB and vascular epithelial growth factor (VEGF) by ovarian cancer cells. Transient transfection experiments showed that nobiletin inhibits production of HIF-1α by downregulation of Akt. Such decreased levels of HIF-1α were responsible for nobiletin-induced suppression of VEGF. Our data suggest that nobiletin may be a promising anti-angiogenic agent relevant for therapy of ovarian cancers.
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Affiliation(s)
- Jianchu Chen
- College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, P.R. China
| | - Allen Y Chen
- Department of Pharmaceutical Science, West Virginia University, Morgantown, WV 26506, USA
| | - Haizhi Huang
- College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, P.R. China
| | - Xingqian Ye
- College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, P.R. China
| | - William D Rollyson
- Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Haley E Perry
- Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Kathleen C Brown
- Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Yon Rojanasakul
- Department of Pharmaceutical Science, West Virginia University, Morgantown, WV 26506, USA
| | - Gary O Rankin
- Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Piyali Dasgupta
- Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Yi Charlie Chen
- College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA
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14
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KOTANI A, NAGAMI K, MINO C, SUGAWARA Y, TAKAHASHI K, KUSU F, HAKAMATA H. Determination of Nobiletin in Rat Plasma after Ingestion of Citrus depressa Juice by Capillary Liquid Chromatography with Electrochemical Detection Using Boron-doped Diamond Electrode. ELECTROCHEMISTRY 2015. [DOI: 10.5796/electrochemistry.83.363] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Akira KOTANI
- Department of Analytical Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
| | - Kota NAGAMI
- Department of Analytical Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
| | - Chika MINO
- Department of Analytical Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
| | - Yasuhito SUGAWARA
- Department of Analytical Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
| | - Kouji TAKAHASHI
- Department of Analytical Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
| | - Fumiyo KUSU
- Department of Analytical Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
| | - Hideki HAKAMATA
- Department of Analytical Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
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15
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Zheng J, Li Y, Song M, Fang X, Cao Y, McClements DJ, Xiao H. Improving intracellular uptake of 5-demethyltangeretin by food grade nanoemulsions. Food Res Int 2014. [DOI: 10.1016/j.foodres.2014.02.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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16
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Jaganathan SK, Vellayappan MV, Narasimhan G, Supriyanto E. Role of pomegranate and citrus fruit juices in colon cancer prevention. World J Gastroenterol 2014; 20:4618-4625. [PMID: 24782614 PMCID: PMC4000498 DOI: 10.3748/wjg.v20.i16.4618] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 11/13/2013] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Recent studies prove that though chemotherapeutic agents are being used for the treatment of colon cancer, they become non-effective when the cancer progresses to an invasive stage. Since consumption of certain dietary agents has been linked with various cancers, fruit juices have been investigated for their consistently protective effect against colon cancer. The unique biochemical composition of fruit juices is responsible for their anticancer properties. In this review, the chemo-preventive effect of fruit juices such as pomegranate and citrus juices against colon cancer are discussed. For this purpose, the bioavailability, in vitro and in vivo effects of these fruit juices on colorectal cancer are highlighted. Moreover, there is a scarcity of studies involving human trials to estimate the preventive nature of these juices against colon cancer. This review will support the need for more preclinical tests with these crude juices and their constituents in different colorectal cancer cell lines and also some epidemiological studies in order to have a better understanding and promote pomegranate and citrus juices as crusaders against colon cancer.
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17
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Yasuda M, Kawabata K, Miyashita M, Okumura M, Yamamoto N, Takahashi M, Ashida H, Ohigashi H. Inhibitory effects of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide-induced inflammatory responses in RAW264 macrophages. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2014; 62:462-467. [PMID: 24369884 DOI: 10.1021/jf404175t] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
The Japanese herb, Ashitaba (Angelica keiskei Koidzumi), contains two prenylated chalcones, 4-hydroxyderricin and xanthoangelol, which are considered to be the major active compounds of Ashitaba. However, their effects on inflammatory responses are poorly understood. In the present study, we investigated the effects and underlying molecular mechanisms of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264 mouse macrophages. LPS-mediated production of nitric oxide (NO) was markedly reduced by 4-hydroxyderricin (10 μM) and xanthoangelol (5 μM) compared with their parent compound, chalcone (25 μM). They also inhibited LPS-induced secretion of tumor necrosis factor-alpha (TNF-α) and expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Although chalcone decreased the DNA-binding activity of both activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB), 4-hydroxyderricin and xanthoangelol suppressed only AP-1 and had no effect on NF-κB. On the other hand, all of the tested chalcones reduced the phosphorylation (at serine 536) level of the p65 subunit of NF-κB. 4-Hydroxyderricin and xanthoangelol may be promising for the prevention of inflammatory diseases.
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Affiliation(s)
- Michiko Yasuda
- Organization of Advanced Science and Technology, Kobe University , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
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18
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19
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Kimura O, Ohta C, Koga N, Haraguchi K, Kato Y, Endo T. Carrier-mediated uptake of nobiletin, a citrus polymethoxyflavonoid, in human intestinal Caco-2 cells. Food Chem 2013; 154:145-50. [PMID: 24518326 DOI: 10.1016/j.foodchem.2013.12.069] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/17/2013] [Accepted: 12/17/2013] [Indexed: 11/18/2022]
Abstract
The mechanism of intestinal absorption of nobiletin (NBL) was investigated using Caco-2 cells. The uptake of NBL from the apical membranes of Caco-2 cells was rapid and temperature-dependent and the presence of metabolic inhibitors, NaN3 and carbonylcyanide p-trifluoromethoxyphenylhydrazone, did not cause a decrease in NBL uptake. The relationship between the initial uptake of NBL and its concentration was saturable, suggesting the involvement of a carrier-mediated process. The Km and uptake clearance (Vmax/Km) values for NBL were 50.6 and 168.1μl/mg protein/min, respectively. This clearance value was about 9-fold greater than that of the non-saturable uptake clearance (Kd: 18.5μl/mg protein/min). The presence of structurally similar compounds, such as quercetin and luteolin, competitively inhibited NBL uptake. These results suggest that uptake of NBL from the apical membranes of Caco-2 cells is mainly mediated by an energy-independent facilitated diffusion process.
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Affiliation(s)
- Osamu Kimura
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
| | - Chiho Ohta
- Faculty of Nutritional Sciences, Nakamura Gakuen University, Jonan-Ku, Fukuoka 814-0198, Japan
| | - Nobuyuki Koga
- Faculty of Nutritional Sciences, Nakamura Gakuen University, Jonan-Ku, Fukuoka 814-0198, Japan
| | - Koichi Haraguchi
- Daiichi College of Pharmaceutical Sciences, Minami-Ku, Fukuoka 815-8511, Japan
| | - Yoshihisa Kato
- Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
| | - Tetsuya Endo
- School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, 1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
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20
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Ting Y, Li CC, Pan MH, Ho CT, Huang Q. Effect of a labile methyl donor on the transformation of 5-demethyltangeretin and the related implication on bioactivity. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2013; 61:8090-8097. [PMID: 23915315 DOI: 10.1021/jf400562p] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Polymethoxyflavones (PMFs) belong to a subgroup of flavonoids that particularly exist in the peels of citrus fruits. Despite their many health-beneficial biofunctionalities, the lipophilic nature of PMFs limits their water solubility and oral bioavailability. To investigate the effect of the delivery system on the improvement of PMF bioavailibility, a lecithin-based emulsion was formulated for the delivery of two PMF compounds, tangeretin and 5-demethyltangeretin. While the emulsion system improved the digestion kinetics and the total solubilized PMF concentrations in in vitro lipolysis studies, the concentration of 5-demethyltangeretin decreased due to chemical transformation to its permethoxylated counterpart, tangeretin. The emulsifier lecithin used in this emulsion formulation contained a choline headgroup as a labile methyl group donor. The presence of a methyl donor potentially caused the transformation of 5-demethyltangeretin and reduced its anti-cancer-cell-proliferation activities. Moreover, this is the first report in the literature of the transformation from 5-demethyltangeretin to tangeretin in a lecithin-based emulsion during lipolysis, and the mechanism underlying this phenomenon has also been proposed for the first time.
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Affiliation(s)
- Yuwen Ting
- Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick, New Jersey 08901, USA
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21
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YAMAMOTO K, YAHADA A, SASAKI K, FUNAKOSHI-YOSHIDA A, OHTA C, KOGA N, OHTA H. Detection of Adulterated Shiikuwasha Juice by Sensory Evaluation, Colorimetric Value and Volatile Components. FOOD SCIENCE AND TECHNOLOGY RESEARCH 2013. [DOI: 10.3136/fstr.19.843] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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22
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Li Y, Xiao H, McClements DJ. Encapsulation and Delivery of Crystalline Hydrophobic Nutraceuticals using Nanoemulsions: Factors Affecting Polymethoxyflavone Solubility. FOOD BIOPHYS 2012; 7:341-353. [PMID: 23646037 PMCID: PMC3640569 DOI: 10.1007/s11483-012-9272-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Polymethoxyflavones (PMF) isolated from citrus peel have potent anti-cancer activity, however their utilization as functional ingredients in foods is currently limited because of their high melting point and poor water-solubility. The influence of oil type and concentration, hydrophilic polymer addition, and simulated intestinal conditions on PMF (5-hydroxytangeretin) solubility in solutions and nanoemulsions was examined. The saturation concentration of PMF in water was relatively low (0.93 µM), but could be increased appreciably by adding certain hydrophilic polymers: polyethylene glycol (PEG) and β-cyclodextrin (CD) were ineffective at increasing solubility, but poly(vinyl alcohol) (PVA) and hydroxypropyl methylcellulose (HPMC) greatly enhanced solubility (e.g., > 6 µM for 0.5 % polymer). PMF was more soluble in medium chain triglycerides (MCT, 6.1 mM) than long chain triglycerides (LCT, 4.2 mM). The encapsulation efficiency of PMF in oil-in-water nanoemulsions was higher when MCT was used as the oil phase rather than LCT, and could be increased by increasing the oil droplet content. The solubility of PMF in simulated small intestinal fluids was increased by solubilization in bile micelles and mixed micelles formed during lipid digestion. These results have important implications for the development of functional foods fortified with bioactive hydrophobic components aimed at improving human health and wellness.
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Affiliation(s)
- Yan Li
- Biopolymers and Colloids Research Laboratory, Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA
| | - Hang Xiao
- Biopolymers and Colloids Research Laboratory, Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA
| | - David Julian McClements
- Biopolymers and Colloids Research Laboratory, Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA
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23
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Yamamoto K, Yahada A, Sasaki K, Ogawa K, Koga N, Ohta H. Chemical markers of shiikuwasha juice adulterated with calamondin juice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2012; 60:11182-11187. [PMID: 23043313 DOI: 10.1021/jf303374g] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Detection of shiikuwasha (Citrus depressa Hayata) juice adulterated with calamondin (Citrus madurensis Lour.) juice was investigated by the analyses of (1) phloretin dihydrochalcone glucoside, 3',5'-di-C-β-glucopyranosylphloretin (PD) detected by thin-layer chromatography and high-performance liquid chromatography (HPLC), (2) polymethoxylated flavones (PMFs), included nobiletin, tangeretin, and sinensetin, detected by HPLC, and (3) γ-terpinene peak percentage obtained by headspace solid-phase microextraction gas chromatography with cryofocusing. PD was detected in calamondin juice (25.5 mg/100 mL) but not in shiikuwasha juice. Shiikuwasha juice contained higher levels of nobiletin (48.8 mg/100 mL) than calamondin juice (2.4 mg/100 mL). Shiikuwasha juice was characterized by containing a higher percentage of γ-terpinene (12.3%) than calamondin juice (0.7%). A discrimination function obtained by a linear discriminant analysis with PMFs and a peak ratio of [nobiletin/tangeretin] and γ-terpinene detected the adulteration with accuracies of 91.7%. These three chemical markers were useful to detect shiikuwasha juice that is suspected of being adulterated with calamondin juice.
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Affiliation(s)
- Kenta Yamamoto
- Graduate School of Health and Nutrition Sciences, Nakamura Gakuen University, 5-7-1, Befu, Fukuoka 814-0198, Japan
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24
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Ohta H. Physiological Function and Variety Differentiation of Shiikuwasha Fruit (Citrus depressa, Hayata) Produced in Okinawa. J JPN SOC FOOD SCI 2012. [DOI: 10.3136/nskkk.59.357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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25
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Kanazawa K. Bioavailability of non-nutrients for preventing lifestyle-related diseases. Trends Food Sci Technol 2011. [DOI: 10.1016/j.tifs.2011.06.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Nanoemulsion-based delivery systems for poorly water-soluble bioactive compounds: Influence of formulation parameters on Polymethoxyflavone crystallization. Food Hydrocoll 2011; 27:517-528. [PMID: 22685367 DOI: 10.1016/j.foodhyd.2011.08.017] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Polymethoxyflavones (PMFs) extracted from citrus peel exhibit potent anti-cancer activity, but are highly hydrophobic molecules with poor solubility in both water and oil at ambient and body temperature, which limits their bioavailability. The possibility of encapsulating PMFs within nanoemulsion-based delivery systems to facilitate their application in nutraceutical and pharmaceutical products was investigated. The influence of oil type (corn oil, MCT, orange oil), emulsifier type (β-lactoglobulin, lyso-lecithin, Tween, and DTAB), and neutral cosolvents (glycerol and ethanol) on the formation and stability of PMF-loaded nanoemulsions was examined. Nanoemulsions (r < 100 nm) could be formed using high pressure homogenization for all emulsifier types, except DTAB. Lipid droplet charge could be altered from highly cationic (DTAB), to near neutral (Tween), to highly anionic (β-lactoglobulin, lyso-lecithin) by varying emulsifier type. PMF crystals formed in all nanoemulsions after preparation, which had a tendency to sediment during storage. The size, morphology, and aggregation of PMF crystals depended on preparation method, emulsifier type, oil type, and cosolvent addition. These results have important implications for the development of delivery systems for bioactive components that have poor oil and water solubility at application temperatures.
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27
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Koga N, Ohta C, Kato Y, Haraguchi K, Endo T, Ogawa K, Ohta H, Yano M. In vitro metabolism of nobiletin, a polymethoxy-flavonoid, by human liver microsomes and cytochrome P450. Xenobiotica 2011; 41:927-33. [PMID: 21726170 DOI: 10.3109/00498254.2011.593208] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Cytochrome P450 enzymes (CYPs) in the liver metabolize drugs prior to excretion, with different enzymes acting at different molecular motifs. At present, the human CYPs responsible for the metabolism of the flavonoid, nobiletin (NBL), are unidentified. We investigated which enzymes were involved using human liver microsomes and 12 cDNA-expressed human CYPs. Human liver microsomes metabolized NBL to three mono-demethylated metabolites (4'-OH-, 7-OH- and 6-OH-NBL) with a relative ratio of 1:4.1:0.5, respectively, by aerobic incubation with nicotinamide adenine dinucleotide phosphate (NADPH). Of 12 human CYPs, CYP1A1, CYP1A2 and CYP1B1 showed high activity for the formation of 4'-OH-NBL. CYP3A4 catalyzed the formation of 7-OH-NBL with the highest activity and of 6-OH-NBL with lower activity. CYP3A5 also catalyzed the formation of both metabolites but considerably more slowly than CYP3A4. In contrast, seven CYPs (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1) were inactive for NBL. Both ketoconazole and troleandomycin (CYP3A inhibitors) almost completely inhibited the formation of 7-OH- and 6-OH-NBL. Similarly, α-naphthoflavone (CYP1A1 inhibitor) and furafylline (CYP1A2 inhibitor) significantly decreased the formation of 4'-OH-NBL. These results suggest that CYP1A2 and CYP3A4 are the key enzymes in human liver mediating the oxidative demethylation of NBL in the B-ring and A-ring, respectively.
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Affiliation(s)
- Nobuyuki Koga
- Faculty of Nutritional Sciences, Nakamura Gakuen University, Johnan-ku, Fukuoka, Japan.
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28
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Miyake Y, Ito C, Itoigawa M. Characteristics of Flavonoids and Coumarins in Meyer Lemon (Citrus meyerii). J JPN SOC FOOD SCI 2011. [DOI: 10.3136/nskkk.58.178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Kunimasa K, Ikekita M, Sato M, Ohta T, Yamori Y, Ikeda M, Kuranuki S, Oikawa T. Nobiletin, a citrus polymethoxyflavonoid, suppresses multiple angiogenesis-related endothelial cell functions and angiogenesis in vivo. Cancer Sci 2010; 101:2462-9. [PMID: 20670297 PMCID: PMC11158917 DOI: 10.1111/j.1349-7006.2010.01668.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Nobiletin is a citrus polymethoxyflavonoid that suppresses tumor growth and metastasis, both of which depend on angiogenesis. We recently identified nobiletin as a cell differentiation modulator. Because cell differentiation is a critical event in angiogenesis, it might be possible that nobiletin could exhibit antiangiogenic activity, resulting in suppression of these tumor malignant properties. To verify this possibility, we examined the antiangiogenic effects of nobiletin in vitro and in vivo. Nobiletin had concentration-dependent inhibitory effects on multiple functions of angiogenesis-related endothelial cells (EC); it suppressed the proliferation, migration and tube formation on matrigel of human umbilical vein EC (HUVEC) stimulated with endothelial cell growth supplement (ECGS), a mixture of acidic and basic fibroblast growth factors (FGFs). Gelatin zymography and northern blotting revealed that nobiletin suppressed pro-matrix metalloproteinase-2 (proMMP-2) production and MMP-2 mRNA expression in ECGS-stimulated HUVEC. Nobiletin also downregulated cell-associated plasminogen activator (PA) activity and urokinase-type PA mRNA expression. Furthermore, nobiletin inhibited angiogenic differentiation induced by vascular endothelial growth factor and FGF, an in vitro angiogenesis model. This inhibition was accompanied by downregulation of angiogenesis-related signaling molecules, such as extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase, and transcriptional factors (c-Jun and signal transducer and activator of transcription 3), and activation of the caspase pathway. In a chick embryo chorioallantoic membrane assay, nobiletin showed an antiangiogenic activity, the ID(50) value being 10μg (24.9nmol) per egg. These results indicate that nobiletin is a novel antiangiogenic compound that exhibits its activity through combined inhibition of multiple angiogenic EC functions.
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Affiliation(s)
- Kazuhiro Kunimasa
- Department of Applied Biological Science, Tokyo University of Science, Chiba Institute for World Health Development, Mukogawa Women's University, Hyogo Tokyo, Japan
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Akachi T, Shiina Y, Ohishi Y, Kawaguchi T, Kawagishi H, Morita T, Mori M, Sugiyama K. Hepatoprotective effects of flavonoids from shekwasha (Citrus depressa) against D-galactosamine-induced liver injury in rats. J Nutr Sci Vitaminol (Tokyo) 2010; 56:60-7. [PMID: 20354348 DOI: 10.3177/jnsv.56.60] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
We attempted to isolate the constituent(s) responsible for the suppressive effect of the juice of shekwasha, a citrus produced in Okinawa Prefecture, on D-galactosamine (GalN)-induced liver injury in rats. Liver injury-suppressive activity, as assessed by plasma alanine aminotransferase and aspartate aminotransferase activities, was found only in the fraction that was extracted with n-hexane when three fractions were added to the diet and fed to rats. Of five compounds isolated from the n-hexane-soluble fraction by silica gel column chromatography, three compounds had liver injury-suppressive effects when five compounds were singly force-fed to rats at a level of 300 mg/kg body wt 4 h before the injection with GalN. The structures of the three active compounds were determined as 3',4',5,6,7,8-hexamethoxyflavanone (citromitin), 4',5,6,7,8-pentamethoxyflavone (tangeretin) and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), which are known flavonoids mainly existing in citrus. Nobiletin, the most important compound in the n-hexane-soluble fraction, also had suppressive effects on liver injuries induced by carbon tetrachloride, acetaminophen and GalN/lipopolysaccharide (LPS) in addition to liver injury induced GalN. Nobiletin suppressed GalN/LPS-induced increases in plasma tumor necrosis factor (TNF)-alpha and nitric oxide (NO) concentrations and hepatic mRNA levels for inducible NO synthase and DNA fragmentation. These results suggest that nobiletin suppressed GalN/LPS-induced liver injury at least by suppressing the production of both TNF-alpha and NO. The results obtained here indicate that the hepatoprotective effect of shekwasha juice is mainly ascribed to several polymethoxy flavonoids included in the juice.
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Affiliation(s)
- Toshiyuki Akachi
- The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan.
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Lai CS, Tsai ML, Cheng AC, Li S, Lo CY, Wang Y, Xiao H, Ho CT, Wang YJ, Pan MH. Chemoprevention of colonic tumorigenesis by dietary hydroxylated polymethoxyflavones in azoxymethane-treated mice. Mol Nutr Food Res 2010; 55:278-90. [DOI: 10.1002/mnfr.201000224] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Revised: 06/03/2010] [Accepted: 06/22/2010] [Indexed: 12/21/2022]
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Leonardi T, Vanamala J, Taddeo SS, Davidson LA, Murphy ME, Patil BS, Wang N, Carroll RJ, Chapkin RS, Lupton JR, Turner ND. Apigenin and naringenin suppress colon carcinogenesis through the aberrant crypt stage in azoxymethane-treated rats. Exp Biol Med (Maywood) 2010; 235:710-7. [PMID: 20511675 PMCID: PMC2885760 DOI: 10.1258/ebm.2010.009359] [Citation(s) in RCA: 100] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Epidemiological evidence suggests that a diet abundant in fruits and vegetables may protect against colon cancer. Bioactive compounds, including flavonoids and limonoids, have been shown to possess antiproliferative and antitumorigenic effects in various cancer models. This experiment investigated the effects of four citrus flavonoids and one limonoid mixture at the promotion stage of chemically induced colon cancer in rats. Male Sprague-Dawley rats (n = 10 rats/group) were randomly allocated to one of six diets formulated to contain 0.1% apigenin, 0.02% naringenin, 0.1% hesperidin, 0.01% nobiletin, 0.035% limonin glucoside/obacunone glucoside mixture or a control diet (0% flavonoid/limonoid). Rats received experimental diets for 10 weeks and were injected with azoxymethane (15 mg/kg) at weeks 3 and 4. Excised colons were evaluated for aberrant crypt foci (ACF) formation, colonocyte proliferation (proliferating cell nuclear antigen assay), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay) and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) (immunoblotting). When compared with the control diet, apigenin lowered the number of high multiplicity ACF (HMACF >4 aberrant crypts/focus) by 57% (P < 0.05), while naringenin lowered both the number of HMACF by 51% (P < 0.05) and the proliferative index by 32% (P < 0.05). Both apigenin and naringenin increased apoptosis of luminal surface colonocytes (78% and 97%, respectively; P < 0.05) when compared with the control diet. Hesperidin, nobiletin and the limonin glucoside/obacunone glucoside mixture did not affect these variables. The colonic mucosal protein levels of iNOS or COX-2 were not different among the six diet groups. The ability of dietary apigenin and naringenin to reduce HMACF, lower proliferation (naringenin only) and increase apoptosis may contribute toward colon cancer prevention. However, these effects were not due to mitigation of iNOS and COX-2 protein levels at the ACF stage of colon cancer.
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Affiliation(s)
- Tety Leonardi
- Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2253
| | - Jairam Vanamala
- Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2253
- Vegetable and Fruit Improvement Center, Texas A&M University, College Station, TX 77843-2119
| | - Stella S. Taddeo
- Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2253
| | - Laurie A. Davidson
- Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2253
| | - Mary E. Murphy
- Department of Statistics, Texas A&M University, College Station, TX 77843-3143
| | - Bhimanagouda S. Patil
- Vegetable and Fruit Improvement Center, Texas A&M University, College Station, TX 77843-2119
| | - Naisyin Wang
- Department of Statistics, Texas A&M University, College Station, TX 77843-3143
| | - Raymond J. Carroll
- Department of Statistics, Texas A&M University, College Station, TX 77843-3143
| | - Robert S. Chapkin
- Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2253
- Vegetable and Fruit Improvement Center, Texas A&M University, College Station, TX 77843-2119
| | - Joanne R. Lupton
- Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2253
| | - Nancy D. Turner
- Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2253
- Vegetable and Fruit Improvement Center, Texas A&M University, College Station, TX 77843-2119
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Chemistry and health effects of polymethoxyflavones and hydroxylated polymethoxyflavones. J Funct Foods 2009. [DOI: 10.1016/j.jff.2008.09.003] [Citation(s) in RCA: 183] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Miyamoto S, Yasui Y, Tanaka T, Ohigashi H, Murakami A. Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice. Carcinogenesis 2008; 29:1057-63. [PMID: 18375960 DOI: 10.1093/carcin/bgn080] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Adipocytokines are a group of adipocyte-secreted proteins that have significant effects on the metabolism of lipids and carbohydrates, as well as numerous other processes. A number of recent studies have indicated that some adipocytokines may significantly influence the proliferation of malignant cells in vitro, whereas it remains unclear whether they have similar roles in vivo. In this study, we determined serum levels of adipocytokines in mice with azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colon carcinogenesis. Five-week-old ICR mice were given a single intraperitoneal injection of AOM followed by 1% DSS in drinking water for 7 days. Nobiletin (NOB), a citrus flavonoid, was given in the diet (100 p.p.m) for 17 weeks. Thereafter, the incidence and number of colon tumors and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was six times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin and interleukin-6. Feeding with NOB abolished colonic malignancy and notably decreased the serum leptin level by 75%. Further, NOB suppressed the leptin-dependent, but not independent, proliferation of HT-29 colon cancer cells and decreased leptin secretion through inactivation of mitogen-activated protein kinase/extracellular signaling-regulated protein kinase, but not that of adiponectin in differentiated 3T3-L1 mouse adipocytes in a dose-dependent manner. Taken together, our results suggest that higher levels of leptin in serum promote colon carcinogenesis in mice, whereas NOB has chemopreventive effects against colon carcinogenesis, partly through regulation of leptin levels.
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Affiliation(s)
- Shingo Miyamoto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
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Koga N, Matsuo M, Ohta C, Haraguchi K, Matsuoka M, Kato Y, Ishii T, Yano M, Ohta H. Comparative study on nobiletin metabolism with liver microsomes from rats, Guinea pigs and hamsters and rat cytochrome p450. Biol Pharm Bull 2008; 30:2317-23. [PMID: 18057719 DOI: 10.1248/bpb.30.2317] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In vitro metabolism of nobiletin, a polymethoxy-flavonoid abundantly present in citrus peels, was studied using liver microsomes of rats, hamsters and guinea pigs and ten cDNA-expressed rat cytochrome P450 (P450). The effects of P450 inducers on nobiletin metabolism were also investigated. Aerobical incubation with NADPH and animal liver microsomes transformed nobiletin to five metabolites, M-1, M-2, M-3, M-4 and M-5. From LC-MS and (1)H-NMR data and a time-course study, these were assumed to be 4'-hydroxy (OH)-, 7-OH-, 6-OH-, 3',4'-diOH- and 6,7-diOH-metabolites, respectively. Pretreatment of animals with phenobarbital increased M-2 and M-3 to about 2-fold that in untreated animals. Pretreatment with 3-methylcholanthrene (MC) resulted in remarkable increases of both M-1 and M-4 (3 to 9-fold that of untreated). Males had 2-3 times higher M-2 and M-3 formation activities in rats, and for M-2 in hamsters than did females. Immunoinhibition study using antiserum against P450 revealed the involvement of hamster CYP1A2 in the formation of M-1 and M-4 in hamster liver. Of ten rat P450s, CYP2C11, CYP3A1, CYP3A2 and CYP2D1 had high activities for the formation of M-1, M-2 and M-3. Another P450s (CYP1A1, CYP2C12 and CYP1A2) also showed activity for the formation of M-1. Only CYP1A1 produced 3',4'-diOH-metabolites (M-4). However, CYP2A1, CYP2B1 and CYP2E1 had no activity for nobiletin. These results suggested that constitutive P450s such as CYP2C11, CYP2D1, CYP3A1, CYP3A2 and CYP2C12 are responsible for the demethylation at the 6-, 7-, 3'- and 4'-positions; whereas, MC-inducible P450s, CYP1A1 and CYP1A2, preferentially catalyzed demethylation at the 3'-and 4'-positions.
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Affiliation(s)
- Nobuyuki Koga
- Faculty of Nutritional Sciences, Nakamura Gakuen University, 5-7-1 Befu, Johnan-ku, Fukuoka 814-0198, Japan.
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Abe S, Fan K, Ho CT, Ghai G, Yang K. Chemopreventive effects of orange peel extract (OPE). II: OPE inhibits atypical hyperplastic lesions in rodent mammary gland. J Med Food 2007; 10:18-24. [PMID: 17472462 DOI: 10.1089/jmf.2006.0215] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cancer chemoprevention via the ingestion of natural substances is a current topic of considerable interest. Flavonoids are a family of biologically active phytochemicals having a variety of biological effects. Orange peel extract (OPE) is an abundant source of polymethoxyflavones (PMFs) with potential chemopreventive properties. The OPE used here was a mixture containing tangeretin (19.0%), heptamethoxyflavone (15.24%), tetramethoxyflavone (13.6%), nobiletin (12.49%), hexamethoxyflavone (11.06%), and sinensitin (9.16%). C57Bl/6 mice were fed a new "Western-style" diet (NWD), which had previously induced atypical hyperplasias in mammary gland, and NWD supplemented with a standardized OPE containing 30% PMFs. Mice were fed one of four diets: (1) AIN-76A diet (control); (2) NWD; 0.25% OPE in NWD; or (4) 0.5% OPE in NWD. After 3 months of feeding, atypical hyperplasias developed in mammary glands of mice fed NWD, but not in controls. After feeding OPE in NWD, atypical hyperplasias per mouse decreased in frequency compared to feeding NWD alone (P < .05 in mice fed 0.25% OPE). Apoptosis increased in OPE-treated groups (P < .01) with no inhibition of mitosis. Thus, a standardized preparation of OPE with 30% PMFs decreased development of an atypical hyperplastic lesion and increased apoptosis in ductal epithelial cells of mouse mammary gland.
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Affiliation(s)
- Sadanori Abe
- Strang Cancer Prevention Center at The Rockefeller University, New York, New York 10021, USA
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Fan K, Kurihara N, Abe S, Ho CT, Ghai G, Yang K. Chemopreventive effects of orange peel extract (OPE). I: OPE inhibits intestinal tumor growth in ApcMin/+ mice. J Med Food 2007; 10:11-7. [PMID: 17472461 DOI: 10.1089/jmf.2006.0214] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Orange peel is a rich source of flavonoids with polymethoxyflavones as major constituents, compounds associated with potential antioxidant, anti-inflammatory, and antitumor activities. We studied the effect of an orange peel extract (OPE) on intestinal tumor growth in Apc(Min/+) mice, a mouse model for human familial adenomatous polyposis (FAP). The OPE contained 30% polymethoxyflavones, a mixture that included tangeretin (19.0%), heptamethoxyflavone (15.24%), tetramethoxyflavone (13.6%), nobiletin (12.49%), hexamethoxyflavone (11.06%), and sinensitin (9.16%). Apc(Min/+) mice were fed one of four diets: (1) AIN-76A control diet; (2) a new Western-style diet (NWD), i.e., AIN-76A diet modified with decreased calcium, vitamin D, and methyl-donor nutrients and increased lipid content); (3) NWD with 0.25% OPE; and (4) NWD with 0.5% OPE, with all additives premixed in the diet. After 9 weeks of feeding NWD to the Apc(Min/+) mice, tumors increased mainly in the colon, with tumor multiplicity increasing 5.3-fold and tumor volume increasing 6.7-fold. After feeding 0.5% OPE in NWD, the development of tumors markedly decreased, with multiplicity decreasing 49% in the small intestine and 38% in the colon. NWD also led to increased apoptosis in intestinal tumors, and 0.5% OPE in NWD further increased apoptosis in tumors of the small and large intestine. Findings indicated that OPE inhibited tumorigenesis in this preclinical mouse model of FAP, and increased apoptosis may have contributed to this effect.
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Affiliation(s)
- Kunhua Fan
- Strang Cancer Prevention Center at The Rockefeller University, New York, New York 10021, USA
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Tanaka T, Sugie S. Inhibition of Colon Carcinogenesis by Dietary Non-Nutritive Compounds. J Toxicol Pathol 2007. [DOI: 10.1293/tox.20.215] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Murakami A, Song M, Katsumata SI, Uehara M, Suzuki K, Ohigashi H. Citrus nobiletin suppresses bone loss in ovariectomized ddY mice and collagen-induced arthritis in DBA/1J mice: possible involvement of receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis regulation. Biofactors 2007; 30:179-92. [PMID: 18525112 DOI: 10.1002/biof.5520300305] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Bone resorption is known to accelerate during the onset of several disorders, including osteoporosis (OP) and rheumatoid arthritis (RA). Some epidemiological surveys have suggested that a high intake of vegetables and fruits has an inverse relation to such disease incidence, though the number of active constituents elucidated thus far is limited. In the present study, we examined the efficacy of various food phytochemicals using two animal models. First, female ddY mice were ovariectomized (OVX) or sham-operated (sham), after which five different compounds (phenethyl isothiocyanate, zerumbone, auraptene, 1'-acetoxychavicol acetate, and nobiletin) were administered separately to OVX mice with a mini-osmotic pump at doses of 0.25 or 0.5 mg/day for 4 weeks, with 17beta-estradiol (E_{2}, 0.03 microg/day) used as a positive control. Nobiletin, in contrast to the other tested phytochemicals, significantly (P<0.05) suppressed the reduction of whole bone mineral density by 61%, which was comparable to or higher than the efficacy of E_{2}. Next, nobiletin given as an i.p. administration at 20 mg/kg of body weight, but not 2 mg/kg, to male DBA/1J mice every 2 days for 12 days led to a marked decrease in type II collagen-induced arthritis by 45% (P < 0.05). Furthermore, the flavonoid (4-50 microM) attenuated receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis of RAW264.7 cells, as detected by tartarate-resistant acid phosphatase activity and microscopic observations. Of note, nobiletin also suppressed RANKL-activated extracellular signal-regulated kinase1/2, c-Jun N-terminal kinase1/2, and p38 mitogen-activated protein kinase activities, and thereby regulated the promoter activation of nuclear factor kappaB (NFkappaB) and activator protein-1, key transcription factors for differentiation. Together, our results suggest that nobiletin is a promising phytochemical for the prevention or treatment of osteoclastogenesis-related disorders, including OP and RA, with reasonable action mechanisms.
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Affiliation(s)
- Akira Murakami
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
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Murakami A, Ohigashi H. Cancer-preventive anti-oxidants that attenuate free radical generation by inflammatory cells. Biol Chem 2006; 387:387-92. [PMID: 16606336 DOI: 10.1515/bc.2006.052] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Abstract
Active inflammatory leukocytes are a major endogenous source of reactive oxygen and nitrogen oxide species (RONS). We have recently established novel bioassay systems, in which either phorbol ester-stimulated, differentiated HL-60 human leukemia cells or lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages were co-cultured with AS52 Chinese hamster ovary cells. Extensive screening of extracts from Asian vegetables and fruits led to the identification of 1′-acetoxychavicol acetate (ACA), auraptene, nobiletin, and zerumbone, all of which were found to be highly anti-mutagenic in the above co-culture systems. Pretreatment of RAW264.7 macrophages with LPS led to the activation of mitogen-activated protein kinases (MAPKs) and Akt, together with the degradation of IκB-α protein, and the resultant activation of the AP-1, NF-κB, and CREB transcription factors. ACA abrogated ERK1/2 and JNK1/2, but not p38 activation, as well as the activation and transcriptional activation of NF-κB and CREB, whereas nobiletin allowed phosphorylation of these MAPKs, while it suppressed AP-1, NF-κB, and CREB activation. Interestingly, zerumbone did not have any effects on the latter transcription factors, although it did attenuate iNOS mRNA expression. In addition, auraptene suppressed iNOS protein production, but not mRNA expression, implying that it targets the translation step. Our model systems may be useful for identifying potentially anti-carcinogenic inhibitors of RONS generation.
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Affiliation(s)
- Akira Murakami
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
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Li S, Wang Z, Sang S, Huang MT, Ho CT. Identification of nobiletin metabolites in mouse urine. Mol Nutr Food Res 2006; 50:291-9. [PMID: 16521176 DOI: 10.1002/mnfr.200500214] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Nobiletin, a major component of citrus polymethoxyflavones, has many potential significant health benefits. While the biological activities of nobiletin have been widely reported, its in vitro and in vivo metabolic fate has been rarely studied. To explore the biotransformation mechanism of nobiletin we conducted an investigation into its metabolic profile in mouse urine, by various analytical techniques. Due to sample amount limitations for isolating and characterizing an individual metabolite, two possible nobiletin metabolites were prepared in a similar multi-step organic synthetic route: 3'-hydroxy-5,6,7,8,4'-pentamethoxyflavone (3'-demethylnobiletin) and 4'-hydroxy-5,6,7,8,3'-pentamethoxyflavone (4'-demethylnobiletin). Normal phase (silica gel) and C(18) reverse phase chromatography, as well as liquid chromatography-mass spectrometry-mass spectrometry, were employed in the separation of 3'-demethylnobiletin and 4'-demethylnobiletin, however, without success due to the structural similarities of these mono-demethylated nobiletins. Using a chiral packed column eluted under supercritical fluid chromatography (SFC) conditions, a clear separation was achieved. Thus, by comparing the SFC profiles of metabolite mixtures with the synthesized standard compounds, the major nobiletin metabolite of mouse urine is identified as 4'-demethylnobiletin, whereas 3'-demethylnobiletin is a minor metabolite. In this study, the concentration of 4'-demethylnobiletin in mouse urine is 28.9 microg/mL.
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Affiliation(s)
- Shiming Li
- Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA
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Ikeda M, Masumura KI, Matsui K, Kohno H, Sakuma K, Tanaka T, Nohmi T. Chemopreventive Effects of Nobiletin against Genotoxicity Induced by 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the Lung of gpt delta Transgenic Mice. Genes Environ 2006. [DOI: 10.3123/jemsge.28.84] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Murakami A, Shigemori T, Ohigashi H. Zingiberaceous and citrus constituents, 1'-acetoxychavicol acetate, zerumbone, auraptene, and nobiletin, suppress lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 murine macrophages through different modes of action. J Nutr 2005; 135:2987S-2992S. [PMID: 16317159 DOI: 10.1093/jn/135.12.2987s] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
In the present study, we explored the suppressive activities of 1'-acetoxychavicol acetate (ACA), auraptene, nobiletin, and zerumbone toward LPS-induced cyclooxygenase (COX)-2 mRNA expression in mouse macrophages and the underlying molecular mechanisms. Pretreatment of RAW264.7 cells with LPS led to the activation of mitogen-activated protein kinase (MAPK)s [p38, extracellular signal-regulated kinase (ERK)1/2, c-Jun NH2-terminal kinase (JNK)1/2] and Akt, together with degradation of the inhibitor of nuclear factor-kappaB (IkappaB)-alpha protein and nuclear translocation of nuclear factor (NF)-kappaB p65, and the resultant activation of activator protein (AP)-1, NF-kappaB, and cAMP-responsive element-binding protein (CREB) transcription factors. ACA abrogated ERK1/2 and JNK1/2, but not p38 MAPK, as well as the activation of those transcription factors. Although it allowed LPS-triggered phosphorylation of those MAPKs and NF-kappaB nuclear translocation, nobiletin suppressed the activation of AP-1, NF-kappaB, and CREB. Zerumbone had no effect on those transcription factors, though it attenuated COX-2 mRNA expression, suggesting that it disrupts the stabilization of COX-2 mRNA. Conversely, zerumbone significantly accelerated spontaneous COX-2 mRNA decay, the potency of which was comparable with that of SB203580, an inhibitor of p38 MAPK, whose activation has key roles in the proinflammatory mRNA stabilization processes. Because SB203580 but not zerumbone suppressed LPS-induced p38 MAPK activation, the molecular targets of zerumbone may be MAPK-activated protein kinase-2 or located downstream. However, auraptene suppressed the expression of COX-2 protein but not mRNA, implying that it targets translation. We propose that these phytochemicals are promising chemopreventive agents for inflammation-associated carcinogenesis. Their use in combination may enhance their efficacy because of their different modes of action.
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Affiliation(s)
- Akira Murakami
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan
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Nozawa H, Nakao W, Zhao F, Kondo K. Dietary supplement of isohumulones inhibits the formation of aberrant crypt foci with a concomitant decrease in prostaglandin E2 level in rat colon. Mol Nutr Food Res 2005; 49:772-8. [PMID: 15968705 DOI: 10.1002/mnfr.200500027] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Male Fischer 344 rats were subcutaneously injected with azoxymethane (AOM) twice weekly at a dose of 15 mg/kg and were fed with freeze-dried (FD) samples of beer brewed without hops (non-hops beer), beer with hops at 4 times the amount of regular lager beer (x 4-hops beer), and isomerized hop extract (IHE) for the whole experimental period (I/PI) or for the post-initiation period (PI) only. Feeding FD beer samples at a dose of 1% significantly decreased the number of aberrant cryp foci (ACF) in the PI protocol over five weeks.x4-hops beer showed stronger inhibitory effects on the development of the numbers of aberrant crypts per focus and large ACF with four or more crypts than non-hops beer. Feeding IHE to rats at a dose of 0.01% or 0.05% in either the I/PI or PI experiment significantly reduced the numbers of ACF. Prostaglandin E2 (PGE2) levels in colonic mucosa of AOM-treated rats were significantly reduced by feeding of IHE. PGE2 production induced by lipopolysaccharide/interferon-gamma (LPS/IFN-gamma) in RAW264.7 cells was also reduced by treatment with IHE and isohumulone in a dose-dependent manner. These observations suggest that isohumulones show chemopreventive effects on ACF formation in rat colon by inhibiting the production of PGE2.
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Affiliation(s)
- Hajime Nozawa
- Applied Bioresearch Center, Kirin Brewery Co., Ltd., Takasaki-shi Gunma, Japan.
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Suzuki M, Sasaki K, Yoshizaki F, Oguchi K, Fujisawa M, Cyong JC. Anti-hepatitis C virus effect of citrus unshiu peel and its active ingredient nobiletin. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2005; 33:87-94. [PMID: 15844836 DOI: 10.1142/s0192415x05002680] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
We investigated the effects of water and ethyl acetate extracts of Citrus unshiu peel (Aurantii Nobilis pericarpium) on hepatitis C virus (HCV) absorption in MOLT-4 cells (a human lymphoblastoid leukemia cell line). By reverse transcription polymerase chain reaction (RT-PCR), we showed that both the ethyl acetate layer of Citrus unshiu peel extract and fraction 7 decreased HCV absorption in MOLT-4 cells. Furthermore, we demonstrated that 3',4',5,6,7,8-hexamethoxyflavone (nobiletin) is the active ingredient that markedly inhibited HCV infection in MOLT-4 cells.
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Affiliation(s)
- Megumi Suzuki
- Department of Pharmacology, School of Medicine, Showa University, Japan
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Li S, Yu H, Ho CT. Nobiletin: efficient and large quantity isolation from orange peel extract. Biomed Chromatogr 2005; 20:133-8. [PMID: 15999338 DOI: 10.1002/bmc.540] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
It is known that nobiletin possesses anticancer, antiviral and anti-inflammatory activities. Recently, the demand for nobiletin in large quantities and high purity has increased. However, conventional normal-phase silica gel chromatography and C(18)-reverse-phase separation methods cannot satisfy the requirement of pure and gram scale nobiletin in a timely manner. In exploring the composition and the biological activities of polymethoxyflavones from sweet orange (Citrus sinensis) peel, we developed an efficient isolation method for nobiletin. By employing this methodology, pure nobiletin, in gram quantities, was obtained in only one purification cycle. The orange peel extract was loaded onto a silica gel flash column and eluted by a mixed solvent system of ethyl acetate and hexanes, and the fractions collected. Upon combination of the eluted fractions, mainly containing nobiletin and 5,6,7,4'-tetramethoxyflavone, and concentration under reduced pressure, the resultant residue was loaded onto a Regis chiral column. Gram amounts of nobiletin and 5,6,7,4'-tetramethoxyflavone were then eluted with ethanol and hexanes, respectively.
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Affiliation(s)
- Shiming Li
- Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick, NJ 08901-8520, USA
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Yoshimizu N, Otani Y, Saikawa Y, Kubota T, Yoshida M, Furukawa T, Kumai K, Kameyama K, Fujii M, Yano M, Sato T, Ito A, Kitajima M. Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation. Aliment Pharmacol Ther 2004; 20 Suppl 1:95-101. [PMID: 15298613 DOI: 10.1111/j.1365-2036.2004.02082.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIM To demonstrate the antitumour effects of nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), a citrus flavonoid extracted from Citrus depressa Hayata, on human gastric cancer cell lines TMK-1, MKN-45, MKN-74 and KATO-III. MATERIALS AND METHODS 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the TdT-mediated dUTP biotin nick-end labelling (TUNEL) method and cell-cycle analysis revealed that nobiletin acted on these cells in several ways, namely by direct cytotoxicity, induction of apoptosis and modulation of cell cycle. The efficacy of combined treatment of nobiletin with a conventional anticancer drug, CDDP, was also examined. Treatment with nobiletin 24 h prior to CDDP administration showed a synergistic effect compared to the control. CONCLUSIONS Although the effective dose and administration route of nobiletin require further investigation, our study represents a potential successful linking of this compound with the treatment of gastric cancer.
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Affiliation(s)
- N Yoshimizu
- Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
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Hokaiwado N, Asamoto M, Tsujimura K, Hirota T, Ichihara T, Satoh T, Shirai T. Rapid analysis of gene expression changes caused by liver carcinogens and chemopreventive agents using a newly developed three-dimensional microarray system. Cancer Sci 2004; 95:123-30. [PMID: 14965361 PMCID: PMC11159649 DOI: 10.1111/j.1349-7006.2004.tb03192.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2003] [Revised: 11/28/2003] [Accepted: 12/11/2003] [Indexed: 12/26/2022] Open
Abstract
We investigated changes of gene expression in livers of rats treated with carcinogens and tumor promoters using a novel three-dimensional microarray system developed by Olympus Optical Co., Ltd., to assess the feasibility of predicting modifying effects on hepatocarcinogenesis on the basis of changes in the patterns. For this purpose, two genotoxic carcinogens, two nongenotoxic carcinogens (promoters) and seven candidate chemopreventive agents were examined. Six-week-old male F344 rats were treated for 2 weeks with the 11 chemicals (0.05% phenobarbital, 0.3% clofibrate, 0.01% N-diethylnitrosamine (DEN), 0.01% 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 1% catechol, 1% caffeic acid, 0.05% nobiletin, 0.05% garcinol, 0.05% auraptene, 0.05% zermbone and 0.05% 1'-acetoxychavicol acetate (ACA). Test chemicals were mixed in food with the exception of DEN, which was administered in drinking water. RNAs from liver were then analyzed using two kinds of customized microarrays (PamChip(\xa8) microarray A spotted for 28 genes of drug-metabolizing enzymes in duplicate, and PamChip microarray B spotted for 131 genes which are known to be up- or down-regulated in hepatocarcinoma cells). Hybridization and subsequent analysis were usually completed within 2 h and the data obtained were highly reproducible. Carcinogens were classified into genotoxic and nongenotoxic substances by clustering analysis. We could also divide test chemicals into carcinogens and chemopreventive agents from their effects on gene expression. In this study, we have thus shown that it is feasible to predict the modifying effects of chemicals on the basis of changes of gene expression patterns after only 2 weeks of exposure, using our novel three-dimensional microarrays.
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Affiliation(s)
- Naomi Hokaiwado
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan.
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Suzuki R, Kohno H, Murakami A, Koshimizu K, Ohigashi H, Yano M, Tokuda H, Nishino H, Tanaka T. Citrus nobiletin inhibits azoxymethane-induced large bowel carcinogenesis in rats. Biofactors 2004; 22:111-4. [PMID: 15751122 DOI: 10.1002/biof.552210121] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The inhibitory effects of dietary feeding of citrus nobiletin on azoxymethane (AOM)-induced rat colon carcinogenesis using a long-term bioassay were investigated. Five-week old male F344 rats were initiated with two weekly subcutaneous injections of AOM (20 mg/kg bw) to induce colonic tumors. They were also given the diets containing 0.01% or 0.05% nobiletin for 34 weeks, starting one week after the last dosing of AOM. At the end of the study, the incidence of colonic adenocarcinoma were 67% in the AOM alone group, 55% in the AOM-->0.01% nobiletin group, 35% (p<0.05) in the AOM-->0.05% nobiletin group. Also, nobiletin feeding reduced the cell-proliferation activity, increased the apoptotic index, and decreased the prostaglandin E2 content in colonic adenocarcinoma and/or colonic mucosa. These findings might suggest that citrus nobiletin has chemopreventive ability against AOM-induced rat colon carcinogenesis.
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Affiliation(s)
- Rikako Suzuki
- The First Department of Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
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