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Zhang C, Sui C, Ma X, Ma C, Sun X, Zhai C, Cao P, Zhang Y, Cheng J, Li T, Sai J. Therapeutic potential of Xihuang Pill in colorectal cancer: Metabolomic and microbiome-driven approaches. Front Pharmacol 2024; 15:1402448. [PMID: 39687297 PMCID: PMC11646767 DOI: 10.3389/fphar.2024.1402448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 11/07/2024] [Indexed: 12/18/2024] Open
Abstract
Introduction The Xihuang Pill (XHP), a venerated traditional Chinese medicine, has demonstrated significant anti-cancer capabilities. Despite its proven efficacy, the scarcity of comprehensive pharmacological studies limits the widespread application of XHP. This research endeavor seeks to demystify the therapeutic underpinnings of XHP, particularly in the realm of colorectal cancer (CRC) therapy. Methods In this study, mice harboring CT26 tumors were divided into four groups, each administered with either XHP monotherapy, 5-fluorouracil (5-FU), or a combination of both. The tumor growth trajectory was closely monitored to evaluate the effectiveness of these anti-neoplastic interventions. Advanced techniques, including 16S-rDNA gene sequencing and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), were harnessed to scrutinize the gut microbiota and serum metabolite profiles. Immunohistochemical assays were employed to gauge the expression levels of CD4, CD8, and Foxp3, thereby providing insights into the dynamics of tumor-infiltrating lymphocytes within the tumor microenvironment. Results Our findings indicate that XHP effectively suppresses the initiation and progression of colorectal tumors. The combinatorial therapy of XHP with 5-FU exhibited an enhanced inhibitory effect on tumor growth. Metabolic profiling revealed that XHP induced notable metabolic shifts, particularly impacting pathways such as steroid hormone synthesis, arachidonic acid metabolism, purine biosynthesis, and renin secretion. Notably, 17α-ethinyl estradiol and α-ergocryptine were identified as serum metabolites with the most substantial increase following XHP administration. Analysis of the gut microbiome suggested that XHP promoted the expansion of specific bacterial taxa, including Lachnospiraceae_NK4A136_group, Clostridiales, Desulfovibrionaceae, and Anaerotignum_sp., while suppressing the proliferation of others such as Ligilactobacilus, Lactobacillus_taiwanensis, and Candidatus_saccharimonas. Immunohistochemical staining indicated an upregulation of CD4 and CD8 post-XHP treatment. Conclusion This study delineates a potential mechanism by which XHP inhibits CRC tumorigenesis through modulating the gut microbiota, serum metabolites, and reshaping the tumor immune microenvironment in a murine CRC model. These findings contribute to a more profound understanding and potentially broaden the clinical utility of XHP in oncology.
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Affiliation(s)
- Chen Zhang
- Department of oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Conglu Sui
- Department of oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaona Ma
- Department of oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Chongyang Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Xinhui Sun
- Department of oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Changming Zhai
- Department of oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Peng Cao
- Department of oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yue Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Jinjun Cheng
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Tong Li
- Department of oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jiayang Sai
- Department of oncology, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
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Wang X, Guo J, Zang S, Liu B, Wu Y. Comparison of Flavonoid Content, Antioxidant Potential, Acetylcholinesterase Inhibition Activity and Volatile Components Based on HS-SPME-GC-MS of Different Parts from Matteuccia struthiopteris (L.) Todaro. Molecules 2024; 29:1142. [PMID: 38474653 DOI: 10.3390/molecules29051142] [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: 01/30/2024] [Revised: 02/22/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024] Open
Abstract
Matteuccia struthiopteris is one of the most globally consumed edible ferns and widely used in folk medicine. Reports mainly focus on young fronds and the rhizome which are common edible medicinal parts. However, there are few detailed reports on other parts. Therefore, the volatile components of different parts based on HS-SPME-GC-MS were identified, and total flavonoid contents, antioxidant activities and acetylcholinesterase inhibitory activities were compared in order to reveal the difference of volatile components and potential medicinal value of different parts. The results showed that total flavonoid contents, antioxidant activities and volatile components of different parts were obviously different. The crozier exhibited the strongest antioxidant activities, but only underground parts exhibited a dose-dependent inhibition potential against AChE. Common volatile compounds were furfural and 2-furancarboxaldehyde, 5-methyl-. In addition, it was found that some volatile components from adventitious root, trophophyll, sporophyll and petiole were important ingredients in food, cosmetics, industrial manufacturing and pharmaceutical applications.
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Affiliation(s)
- Xin Wang
- College of Life Science and Technology, Harbin Normal University, Harbin 150025, China
| | - Jiatao Guo
- College of Life Science and Technology, Harbin Normal University, Harbin 150025, China
| | - Siqi Zang
- College of Life Science and Technology, Harbin Normal University, Harbin 150025, China
| | - Baodong Liu
- College of Life Science and Technology, Harbin Normal University, Harbin 150025, China
| | - Yuhuan Wu
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China
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Zhou L, Lin XY, Xue RY, Yang JL, Zhang YS, Zhou D, Li HB. Mechanistic Insights into Effects of Different Dietary Polyphenol Supplements on Arsenic Bioavailability, Biotransformation, and Toxicity Based on a Mouse Model. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:15422-15431. [PMID: 37797956 DOI: 10.1021/acs.est.3c05556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
Arsenic (As) exposure has been related to many diseases, including cancers. Given the antioxidant and anti-inflammatory properties, the dietary supplementation of polyphenols may alleviate As toxicity. Based on a mouse bioassay, this study investigated the effects of chlorogenic acid (CA), quercetin (QC), tannic acid (TA), resveratrol (Res), and epigallocatechin gallate (EGCG) on As bioavailability, biotransformation, and toxicity. Intake of CA, QC, and EGCG significantly (p < 0.05) increased total As concentrations in liver (0.48-0.58 vs 0.27 mg kg-1) and kidneys (0.72-0.93 vs 0.59 mg kg-1) compared to control mice. Upregulated intestinal expression of phosphate transporters with QC and EGCG and proliferation of Lactobacillus in the gut of mice treated with CA and QC were observed, facilitating iAsV absorption via phosphate transporters and intestinal As solubility via organic acid metabolites. Although As bioavailability was elevated, serum levels of alpha fetoprotein and carcinoembryonic antigen of mice treated with all five polyphenols were reduced by 13.1-16.1% and 9.83-17.5%, suggesting reduced cancer risk. This was mainly due to higher DMAV (52.1-67.6% vs 31.4%) and lower iAsV contribution (4.95-10.7% vs 27.9%) in liver of mice treated with polyphenols. This study helps us develop dietary strategies to lower As toxicity.
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Affiliation(s)
- Lei Zhou
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Xin-Ying Lin
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Rong-Yue Xue
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Jin-Lei Yang
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Yao-Sheng Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Dongmei Zhou
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Hong-Bo Li
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of the Environment, Nanjing University, Nanjing 210023, China
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Zhao M, Lv D, Hu J, He Y, Wang Z, Liu X, Ran B, Hu J. Hybrid Broussonetia papyrifera Fermented Feed Can Play a Role Through Flavonoid Extracts to Increase Milk Production and Milk Fatty Acid Synthesis in Dairy Goats. Front Vet Sci 2022; 9:794443. [PMID: 35359682 PMCID: PMC8963508 DOI: 10.3389/fvets.2022.794443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 02/09/2022] [Indexed: 11/13/2022] Open
Abstract
In order to explore the effect of hybrid Broussonetia papyrifera fermented feed on milk production and milk quality of dairy goats, and to compare with alfalfa hay, three dairy goat diets were designed based on the principle of equal energy and equal protein. The goats in the control group were fed a basic TMR diet (CG group), and the other two groups were supplemented with 10% alfalfa hay (AH group) and 10% hybrid B. papyrifera fermented feed (BP group). The results showed that the dry matter intake and milk production of BP group increased significantly. The total amount of amino acids and the content of each amino acid in the milk of AH group and BP group were lower than those of CG group. The content of saturated fatty acids in the milk of BP group decreased while the content of unsaturated fatty acids increased. The contents of prolactin, estrogen and progesterone in BP goat serum were generally higher than those of AH goat and CG goat. Subsequently, this study separated and cultured mammary epithelial cells from breast tissue, and added flavone extracted from the leaves of hybrid B. papyrifera and alfalfa to their culture medium for comparison, which is one of their important bioactive components. The results showed that low-dose alfalfa flavone (AH) and hybrid B. papyrifera flavone (BP) can increase cell viability. They also can increase the accumulation of intracellular triglyceride and the formation of lipid droplets. Both AH flavone and BP flavone significantly up-regulated the expression of genes related to milk fat synthesis, including genes related to fatty acid de novo synthesis (ACACA, FASN, and SCD1), long-chain fatty acid activation and transport related genes (ACSL1), and genes related to transcription regulation (SREBP1). The three genes related to triglyceride synthesis (DGAT1, DGAT2, and GPAM) were all significantly increased by BP flavone. Both AH flavone and BP flavone significantly increased the protein expression of progesterone receptor and estrogen receptor in mammary epithelial cells but had no effect on prolactin receptor.
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Yazdani F, Shareghi B, Farhadian S, Momeni L. Structural insights into the binding behavior of flavonoids naringenin with Human Serum Albumin. J Mol Liq 2022. [DOI: 10.1016/j.molliq.2021.118431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Shi S, Li J, Zhao X, Liu Q, Song SJ. A comprehensive review: Biological activity, modification and synthetic methodologies of prenylated flavonoids. PHYTOCHEMISTRY 2021; 191:112895. [PMID: 34403885 DOI: 10.1016/j.phytochem.2021.112895] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/18/2021] [Accepted: 07/31/2021] [Indexed: 06/13/2023]
Abstract
Prenylated flavonoids, a unique class of flavonoids which combine a flavonoid skeleton and a lipophilic prenyl side-chain, possess great potential biological activities including cytotoxicity, anti-inflammation, anti-Alzheimer, anti-microbial, anti-oxidant, anti-diabetes, estrogenic, vasorelaxant and enzyme inhibition. Recently, prenylated flavonoids have become an indispensable anchor for the development of new therapeutic agents, and have received increasing from medicinal chemists. The prenylated flavonoids have been outstanding developed through isolation, semi or fully synthesis in a very short period of time, which proves the great value in medicinal chemistry researches. In this review, research progress of prenylated flavonoids including natural prenylated flavonoids, structural modification, synthetic methodologies and pharmacological activities was summarized comprehensively. Furthermore, the structure-activity relationships (SARs) of prenylated flavonoids were summarized which provided a basis for the selective design and optimization of multifunctional prenylated flavonoid derivatives for the treatment of multi-factorial diseases in clinic.
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Affiliation(s)
- Shaochun Shi
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Jichong Li
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xuemei Zhao
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Qingbo Liu
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China; Jilin Yizheng Pharmaceutical Group Co., Ltd., Jilin Province, Siping, 136001, China.
| | - Shao-Jiang Song
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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VEGFR-Mediated Cytotoxic Activity of Pulicaria undulata Isolated Metabolites: A Biological Evaluation and In Silico Study. Life (Basel) 2021; 11:life11080759. [PMID: 34440504 PMCID: PMC8398779 DOI: 10.3390/life11080759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/24/2021] [Accepted: 07/27/2021] [Indexed: 01/25/2023] Open
Abstract
Natural products play a remarkable role not only in the synthesis, design, and discovery of new drugs but also as the most prominent source of drugs and bioactive substances. Adding to the search for new sources of safe innovative antitumor drugs, here we reported a phytochemical study on Pulicaria undulata which revealed promising antiangiogenic agents. Six compounds were isolated and identified as xanthoxyline (1), stigmasterol (2), oleanolic acid (3), salvigenin (4), rhamnetin (5) and dihydroquercetin-4′-methyl ether (6) using nuclear magnetic resonance (NMR) spectroscopic techniques. Compound 3 and 4 are first reported in Pulicaria genus. Both the extract and isolated compounds were evaluated for in vitro antiproliferative activity against breast cancer cell line (MCF-7). In vivo antiproliferative activity against Ehrlich’s ascites carcinoma (EAC) were also assessed. The P. undulata extract and isolates showed significant reduction in tumor weight, decreased both serum vascular endothelial growth factor B (VEGF-B) levels and vascular endothelial growth factor receptor 2 (VEGFR-2) expression significantly compared to the control EAC group, suggesting an antiangiogenic activity through the inhibition of VEGF signaling. Besides, they displayed reduction in CD34 expression, confirming their antiangiogenic effect. Moreover, the potential affinity of isolated compounds to human estrogen nuclear receptor-alpha (hER-α), the most recognized modulator of VEGFR-2 expression, was virtually estimated through molecular modeling studies. The most promising activity profiles were assigned to the investigated flavonoids, compounds 4–6, as well as the alkyl-phenylketone, compound 1. Additionally, these four top active compounds showed respective high to intermediate docking scores while possessing preferential binding with hER-α critical pocket residues. Based on the provided data, these isolated compounds illustrated promising inhibitors of VEGF-stimulated angiogenesis, which could be a possible mechanism for their anticancer activity.
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Laadraoui J, Aboufatima R, El Gabbas Z, Ferehan H, Bezza K, Ait Laaradia M, Marhoume F, Wakrim EM, Chait A. Effect of Artemisia herba-alba consumption during pregnancy on fertility, morphological and behaviors of mice offspring. JOURNAL OF ETHNOPHARMACOLOGY 2018; 226:105-110. [PMID: 30118834 DOI: 10.1016/j.jep.2018.08.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 06/28/2018] [Accepted: 08/13/2018] [Indexed: 06/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pregnant women prefer herbal medicines more than pharmaceutical drugs due to the cultural belief that herbs are more suffer during pregnancy for an accurate foetus development. Artemisia herba-alba (Asteraceae) is one of the most used plants in the Mediterranean region to treat various diseases including diabetes, hypertension, spasmodic dysphonia and some bacterial infection. AIM OF THE STUDY The present study aimed to investigate the effect of Artemisia herba-alba consumption during pregnancy on fertility, physical and behavior developments of mice offspring from birth-to-weaning days. MATERIALS AND METHODS Female pregnant mice were divided into three groups and orally administrated with 80 and 150 mg/kg/day of the methanol extract of Artemisia h.a respectively, during the entire period of gestation. At birth, total fertility rate was counted. Body development; neuromotor reflex and behavior were also examined in mice offspring RESULTS: Artemisia h.a (Aha) exposure significantly decreased the fertility ratio in both Aha-treated groups and increased the weight and length of mice offspring in 80 mg/kg/day Aha-exposed group. Moreover, Aha administration prolonged the time of completing the reflex response of surface righting, negative geotaxis, cliff avoidance and jumping test of mice offspring in Aha-exposed groups. CONCLUSION The present study provides strong evidence that discourage the use of Artemisia h.a during gestation period.
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Affiliation(s)
- Jawad Laadraoui
- Laboratory of Pharmacology, Neurobiology and Behavior, Semlalia Faculty of Sciences, Cadi Ayyad University, Marrakech, Morocco
| | - Rachida Aboufatima
- Laboratory of Génie Biologique, Sultan Moulay Slimane University, Faculty of Sciences and Techniques, Béni Mellal, Morocco
| | - Zineb El Gabbas
- Laboratory of Pharmacology, Neurobiology and Behavior, Semlalia Faculty of Sciences, Cadi Ayyad University, Marrakech, Morocco
| | - Hind Ferehan
- Laboratory of Pharmacology, Neurobiology and Behavior, Semlalia Faculty of Sciences, Cadi Ayyad University, Marrakech, Morocco
| | - Kenza Bezza
- Laboratory of Pharmacology, Neurobiology and Behavior, Semlalia Faculty of Sciences, Cadi Ayyad University, Marrakech, Morocco
| | - Mehdi Ait Laaradia
- Laboratory of Pharmacology, Neurobiology and Behavior, Semlalia Faculty of Sciences, Cadi Ayyad University, Marrakech, Morocco
| | - Fatimazahra Marhoume
- Laboratory of Pharmacology, Neurobiology and Behavior, Semlalia Faculty of Sciences, Cadi Ayyad University, Marrakech, Morocco
| | - El Mehdi Wakrim
- Laboratory of Pharmacology, Neurobiology and Behavior, Semlalia Faculty of Sciences, Cadi Ayyad University, Marrakech, Morocco
| | - Abderrahman Chait
- Laboratory of Pharmacology, Neurobiology and Behavior, Semlalia Faculty of Sciences, Cadi Ayyad University, Marrakech, Morocco.
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Cipolletti M, Montalesi E, Nuzzo MT, Fiocchetti M, Ascenzi P, Marino M. Potentiation of paclitaxel effect by resveratrol in human breast cancer cells by counteracting the 17β-estradiol/estrogen receptor α/neuroglobin pathway. J Cell Physiol 2018; 234:3147-3157. [PMID: 30421506 DOI: 10.1002/jcp.27309] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 08/02/2018] [Indexed: 12/28/2022]
Abstract
Neuroglobin (NGB), an antiapoptotic protein upregulated by 17β-estradiol (E2), is part of E2/estrogen receptor α (ERα) pathway pointed to preserve cancer cell survival in presence of microenvironmental stressors including chemotherapeutic drugs. Here, the possibility that resveratrol (Res), an anticancer plant polyphenol, could increase the susceptibility of breast cancer cells to paclitaxel (Pacl) by affecting E2/ERα/NGB pathway has been evaluated. In MCF-7 and T47D (ERα-positive), but not in MDA-MB 231 (ERα-negative) nor in SK-N-BE (ERα and ERβ positive), Res decreases NGB levels interfering with E2/ERα-induced NGB upregulation and with E2-induced ERα and protein kinase B phosphorylation. Although Res treatment does not reduce cell viability by itself, this compound potentiates Pacl proapoptotic effects. Notably, the increase of NGB levels by NGB expression vector transfection prevents Pacl or Res/Pacl effects. Taken together, these findings indicate a new Res-based mechanism that acts on tumor cells impairing the E2/ERα/NGB signaling pathways and increasing cancer cell susceptibility to chemotherapeutic agent.
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Affiliation(s)
| | | | | | | | - Paolo Ascenzi
- Department of Science, Roma Tre University, Rome, Italy
| | - Maria Marino
- Department of Science, Roma Tre University, Rome, Italy
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Choe U, Yu LL, Wang TTY. The Science behind Microgreens as an Exciting New Food for the 21st Century. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:11519-11530. [PMID: 30343573 DOI: 10.1021/acs.jafc.8b03096] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Chronic diseases are a major health problem in the United States. Accumulated data suggest that consumption of vegetables can significantly reduce the risk of many chronic diseases. Dietary guidelines for 2015-2020 from the U.S. Department of Agriculture and the U.S. Department of Health and Human Services recommend 1-4 cups of vegetables per day for males and 1-3 cups of vegetables per day for females, depending on their age. However, the average intake of vegetables is below the recommended levels. Microgreens are young vegetable greens. Although they are small, microgreens have delicate textures, distinctive flavors, and various nutrients. In general, microgreens contain greater amounts of nutrients and health-promoting micronutrients than their mature counterparts. Because microgreens are rich in nutrients, smaller amounts may provide similar nutritional effects compared to larger quantities of mature vegetables. However, literature on microgreens remains limited. In this Review, we discuss chemical compositions, growing conditions, and biological efficacies of microgreens. We seek to stimulate interest in further study of microgreens as a promising dietary component for potential use in diet-based disease prevention.
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Affiliation(s)
- Uyory Choe
- Department of Nutrition and Food Science , University of Maryland , College Park , Maryland 20742 , United States
- Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, ARS , U.S. Department of Agriculture , 10300 Baltimore Avenue , Beltsville , Maryland 20705 , United States
| | - Liangli Lucy Yu
- Department of Nutrition and Food Science , University of Maryland , College Park , Maryland 20742 , United States
| | - Thomas T Y Wang
- Diet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, ARS , U.S. Department of Agriculture , 10300 Baltimore Avenue , Beltsville , Maryland 20705 , United States
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Cipolletti M, Solar Fernandez V, Montalesi E, Marino M, Fiocchetti M. Beyond the Antioxidant Activity of Dietary Polyphenols in Cancer: the Modulation of Estrogen Receptors (ERs) Signaling. Int J Mol Sci 2018; 19:E2624. [PMID: 30189583 PMCID: PMC6165334 DOI: 10.3390/ijms19092624] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 08/31/2018] [Accepted: 09/03/2018] [Indexed: 02/07/2023] Open
Abstract
The potential "health benefits" of dietary polyphenols have been ascribed to their direct antioxidant activity and their impact on the regulation of cell and tissue redox balance. However, because of the relative poor bioavailability of many of these compounds, their effects could not be easily explained by the antioxidant action, which may occur only at high circulating and tissue concentrations. Therefore, many efforts have been put forward to clarify the molecular mechanisms underlining the biological effect of polyphenols in physiological and pathological conditions. Polyphenols' bioavailability, metabolism, and their effects on enzyme, membrane, and/or nuclear receptors and intracellular transduction mechanisms may define the overall impact of these compounds on cancer risk and progression, which is still debated and not yet clarified. Polyphenols are able to bind to estrogen receptor α (ERα) and β (ERβ), and therefore induce biological effects in human cells through mimicking or inhibiting the action of endogenous estrogens, even at low concentrations. In this work, the role and effects of food-contained polyphenols in hormone-related cancers will be reviewed, mainly focusing on the different polyphenols' mechanisms of action with particular attention on their estrogen receptor-based effects, and on the consequences of such processes on tumor progression and development.
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Affiliation(s)
- Manuela Cipolletti
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
| | | | - Emiliano Montalesi
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
| | - Maria Marino
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
| | - Marco Fiocchetti
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
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Put "gender glasses" on the effects of phenolic compounds on cardiovascular function and diseases. Eur J Nutr 2018; 57:2677-2691. [PMID: 29696400 DOI: 10.1007/s00394-018-1695-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 04/19/2018] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The influence of sex and gender is particularly relevant in cardiovascular diseases (CVD) as well as in several aspects of drug pharmacodynamics and pharmacokinetics. Anatomical and physiological differences between the sexes may influence the activity of many drugs, including the possibility of their interaction with other drugs, bioactive compounds, foods and beverages. Phenolic compounds could interact with our organism at organ, cellular, and molecular levels triggering a preventive action against chronic diseases, including CVD. RESULTS This article will review the role of sex on the activity of these bioactive molecules, considering the existence of sex differences in oxidative stress. It describes the pharmacokinetics of phenolic compounds, their effects on vessels, on cardiovascular system, and during development, including the role of nuclear receptors and microbiota. CONCLUSIONS Although there is a large gap between the knowledge of the sex differences in the phenolic compounds' activity and safety, and the urgent need for more research, available data underlie the possibility that plant-derived phenolic compounds could differently influence the health of male and female subjects.
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Song X, Liu B, Cui L, Zhou B, Liu L, Liu W, Yao G, Xia M, Hayashi T, Hattori S, Ushiki-Kaku Y, Tashiro SI, Ikejima T. Estrogen Receptors Are Involved in the Neuroprotective Effect of Silibinin in Aβ 1-42-Treated Rats. Neurochem Res 2018; 43:796-805. [PMID: 29397533 DOI: 10.1007/s11064-018-2481-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 01/18/2018] [Accepted: 01/19/2018] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by a cascade of pathologic changes. A widely discussed theory indicates that amyloid β (Aβ) peptides are the causative agents of AD. Silibinin, a flavonoid derived from milk thistle, is well known for its hepato-protective activities and we have reported the neuroprotective effects of silibinin. In this study, we investigated the role of estrogen receptors (ERs) in silibinin's neuroprotective effect on Aβ1-42-injected rats. Results of Morris water maze and novel object-recognition tests demonstrated that silibinin significantly attenuated Aβ1-42-induced memory impairment. Silibinin attenuated ERs and PI3K-Akt pathways, as well as modulated mitogen-activated protein kinases in the hippocampus of Aβ1-42-injected rats. Taken together, silibinin is a potential candidate in the treatment of Alzheimer's disease.
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Affiliation(s)
- Xiaoyu Song
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.,Medical Research Center, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Bo Liu
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Lingyu Cui
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Biao Zhou
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Lu Liu
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Weiwei Liu
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Guodong Yao
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.,School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mingyu Xia
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Toshihiko Hayashi
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China
| | - Shunji Hattori
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan
| | - Yuko Ushiki-Kaku
- Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan
| | - Shin-Ichi Tashiro
- Department of Medical Education & Primary Care, Kyoto Prefectural University of Medicine, Kajiicho 465, Kamikyo-ku, Kyoto City, Kyoto, 602-8566, Japan
| | - Takashi Ikejima
- China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
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14
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Song X, Liu B, Cui L, Zhou B, Liu W, Xu F, Hayashi T, Hattori S, Ushiki-Kaku Y, Tashiro SI, Ikejima T. Silibinin ameliorates anxiety/depression-like behaviors in amyloid β-treated rats by upregulating BDNF/TrkB pathway and attenuating autophagy in hippocampus. Physiol Behav 2017; 179:487-493. [DOI: 10.1016/j.physbeh.2017.07.023] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/15/2017] [Accepted: 07/18/2017] [Indexed: 02/07/2023]
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15
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Marcoccia D, Pellegrini M, Fiocchetti M, Lorenzetti S, Marino M. Food components and contaminants as (anti)androgenic molecules. GENES AND NUTRITION 2017; 12:6. [PMID: 28239427 PMCID: PMC5312591 DOI: 10.1186/s12263-017-0555-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 01/23/2017] [Indexed: 01/14/2023]
Abstract
Androgens, the main male sex steroids, are the critical factors responsible for the development of the male phenotype during embryogenesis and for the achievement of sexual maturation and puberty. In adulthood, androgens remain essential for the maintenance of male reproductive function and behavior. Androgens, acting through the androgen receptor (AR), regulate male sexual differentiation during development, sperm production beginning from puberty, and maintenance of prostate homeostasis. Several substances present in the environment, now classified as endocrine disruptors (EDCs), strongly interfere with androgen actions in reproductive and non-reproductive tissues. EDCs are a heterogeneous group of xenobiotics which include synthetic chemicals used as industrial solvents/lubricants, plasticizers, additives, agrochemicals, pharmaceutical agents, and polyphenols of plant origin. These compounds are even present in the food as components (polyphenols) or food/water contaminants (pesticides, plasticizers used as food packaging) rendering the diet as the main route of exposure to EDCs for humans. Although huge amount of literature reports the (anti)estrogenic effects of different EDCs, relatively scarce information is available on the (anti)androgenic effects of EDCs. Here, the effects and mechanism of action of phytochemicals and pesticides and plasticizers as possible modulators of AR activities will be reviewed taking into account that insight derived from principles of endocrinology are required to estimate EDC consequences on endocrine deregulation and disease.
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Affiliation(s)
- Daniele Marcoccia
- Dpt. of Food Safety and Veterinary Public Health, Food and Veterinary Toxicology Unit, Istituto Superiore di Sanità - ISS, Viale Regina Elena 299, I-00161 Rome, Italy.,Present address: Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia-Romagna, via A. Bianchi 9, 25124 Brescia, Italy
| | - Marco Pellegrini
- Department of Science, University Roma Tre, Viale G. Marconi 446, I-00146 Rome, Italy.,Present address: Department of Molecular Medicine, University of Padova, Via Ugo Bassi, 58/b, 35131 Padova, Italy
| | - Marco Fiocchetti
- Department of Science, University Roma Tre, Viale G. Marconi 446, I-00146 Rome, Italy
| | - Stefano Lorenzetti
- Dpt. of Food Safety and Veterinary Public Health, Food and Veterinary Toxicology Unit, Istituto Superiore di Sanità - ISS, Viale Regina Elena 299, I-00161 Rome, Italy
| | - Maria Marino
- Department of Science, University Roma Tre, Viale G. Marconi 446, I-00146 Rome, Italy
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16
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Kim MJ, Kwon SB, Kim MS, Jin SW, Ryu HW, Oh SR, Yoon DY. Trifolin induces apoptosis via extrinsic and intrinsic pathways in the NCI-H460 human non-small cell lung-cancer cell line. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2016; 23:998-1004. [PMID: 27444344 DOI: 10.1016/j.phymed.2016.05.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 05/04/2016] [Accepted: 05/27/2016] [Indexed: 06/06/2023]
Abstract
BACKGROUND Trifolin (kaempferol-3-O-galactoside), which is a galactose-conjugated flavonol, exhibits antifungal and anticancer effects. However, the mechanisms underlying its anticancer activities have not yet been examined. PURPOSE In this study, the anticancer effects of trifolin were examined in human lung cancer cells. METHODS Cytotoxicity was determined by evaluating cell viability. Apoptosis was analyzed through flow cytometry and western blotting analysis. Death receptors and inhibitors of apoptosis were evaluated through RT-PCR. RESULTS Trifolin induced apoptosis in NCI-H460 human non-small cell lung cancer (NSCLC) cells by inhibiting the survival pathway and inducing the intrinsic and extrinsic apoptosis pathways. Trifolin decreased levels of Akt/p-Akt, whereas levels of expression of phosphatidylinositide 3-kinase (PI3K), cyclin D1, cyclin E, and cyclin A were not altered. Trifolin initiated cytochrome c release by inducing mitochondrial outer membrane permeabilization (MOMP). Trifolin increased Bcl-2-associated X protein (Bax) levels and decreased b-cell lymphoma 2 (Bcl-2) levels, while the levels of Bcl-xL were not altered. In addition, trifolin increased the levels of the death receptor involving the Fas/Fas ligand (FasL) and Fas-associated protein with the death domain (FADD), which consequently activated caspase-8, caspase-9, caspase-3, and the proteolytic cleavage of poly (ADP-ribose) polymerase (PARP). CONCLUSION These results suggested that trifolin induced apoptosis via death receptor-dependent and mitochondria-dependent pathways and that trifolin can be used as a therapeutic agent in human lung cancer.
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Affiliation(s)
- Min-Je Kim
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Sae-Bom Kwon
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Man-Sub Kim
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Seung Won Jin
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hyung Won Ryu
- Natural Medicine Research Center, KRIBB, Cheongwon-gu, Cheongju-si, Republic of Korea
| | - Sei-Ryang Oh
- Natural Medicine Research Center, KRIBB, Cheongwon-gu, Cheongju-si, Republic of Korea
| | - Do-Young Yoon
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Gwangjin-gu, Seoul 05029, Republic of Korea.
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17
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Wang X, Cao J, Wu Y, Wang Q, Xiao J. Flavonoids, Antioxidant Potential, and Acetylcholinesterase Inhibition Activity of the Extracts from the Gametophyte and Archegoniophore of Marchantia polymorpha L. Molecules 2016; 21:360. [PMID: 26999088 PMCID: PMC6273606 DOI: 10.3390/molecules21030360] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 03/03/2016] [Accepted: 03/10/2016] [Indexed: 02/05/2023] Open
Abstract
Marchantia polymorpha L. is a representative bryophyte used as a traditional Chinese medicinal herb for scald and pneumonia. The phytochemicals in M. polymorpha L. are terpenoids and flavonoids, among which especially the flavonoids show significant human health benefits. Many researches on the gametophyte of M. polymorpha L. have been reported. However, as the reproductive organ of M. polymorpha L., the bioactivity and flavonoids profile of the archegoniophore have not been reported, so in this work the flavonoid profiles, antioxidant and acetylcholinesterase inhibition activities of the extracts from the archegoniophore and gametophyte of M. polymorpha L. were compared by radical scavenging assay methods (DPPH, ABTS, O(2-)), reducing power assay, acetylcholinesterase inhibition assay and LC-MS analysis. The results showed that the total flavonoids content in the archegoniophore was about 10-time higher than that of the gametophyte. Differences between the archegoniophore and gametophyte of M. polymorpha L. were observed by LC-MS analysis. The archegoniophore extracts showed stronger bio-activities than those of the gametophyte. The archegoniophore extract showed a significant acetylcholinesterase inhibition, while the gametophyte extract hardly inhibited it.
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Affiliation(s)
- Xin Wang
- Insititute of Applied Ecology, Chinese Academy of Sciences, Shenyang 110016, China.
- University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
| | - Jianguo Cao
- College of Life and Environmental Sciences, Shanghai Normal University, Shanghai 200234, China.
| | - Yuhuan Wu
- Insititute of Applied Ecology, Chinese Academy of Sciences, Shenyang 110016, China.
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China.
| | - Quanxi Wang
- College of Life and Environmental Sciences, Shanghai Normal University, Shanghai 200234, China.
- Shanghai Key Laboratory of Plant Functional Genomics and Resources, Chinese Academy of Sciences, Shanghai Chenshan Botanical Garden, Shanghai 200234, China.
| | - Jianbo Xiao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau.
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18
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Souza CS, Paulsen BS, Devalle S, Lima Costa S, Borges HL, Rehen SK. Commitment of human pluripotent stem cells to a neural lineage is induced by the pro-estrogenic flavonoid apigenin. ACTA ACUST UNITED AC 2015. [DOI: 10.3402/arb.v2.29244] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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19
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Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, Marino M, Martinez-Chantar ML, Nawroth R, Sanchez-Garcia I, Sharma D, Saxena NK, Singh N, Vlachostergios PJ, Guo S, Honoki K, Fujii H, Georgakilas AG, Bilsland A, Amedei A, Niccolai E, Amin A, Ashraf SS, Boosani CS, Guha G, Ciriolo MR, Aquilano K, Chen S, Mohammed SI, Azmi AS, Bhakta D, Halicka D, Keith WN, Nowsheen S. Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol 2015; 35 Suppl:S25-S54. [PMID: 25892662 PMCID: PMC4898971 DOI: 10.1016/j.semcancer.2015.02.006] [Citation(s) in RCA: 464] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 02/20/2015] [Accepted: 02/23/2015] [Indexed: 02/08/2023]
Abstract
Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.
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Affiliation(s)
- Mark A Feitelson
- Department of Biology, Temple University, Philadelphia, PA, United States.
| | - Alla Arzumanyan
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Rob J Kulathinal
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Stacy W Blain
- Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, NY, United States
| | - Randall F Holcombe
- Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, United States
| | - Jamal Mahajna
- MIGAL-Galilee Technology Center, Cancer Drug Discovery Program, Kiryat Shmona, Israel
| | - Maria Marino
- Department of Science, University Roma Tre, V.le G. Marconi, 446, 00146 Rome, Italy
| | - Maria L Martinez-Chantar
- Metabolomic Unit, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Technology Park of Bizkaia, Bizkaia, Spain
| | - Roman Nawroth
- Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Isidro Sanchez-Garcia
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Dipali Sharma
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Neeraj K Saxena
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States
| | - Neetu Singh
- Tissue and Cell Culture Unit, CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow, India
| | | | - Shanchun Guo
- Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Zografou 15780, Athens, Greece
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - S Salman Ashraf
- Department of Chemistry, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - Chandra S Boosani
- Department of BioMedical Sciences, Creighton University, Omaha, NE, United States
| | - Gunjan Guha
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Maria Rosa Ciriolo
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Sophie Chen
- Department of Research and Development, Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey GU2 7YG, United Kingdom
| | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - Asfar S Azmi
- Department of Pathology, Karmonas Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States
| | - Dipita Bhakta
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Dorota Halicka
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY, United States
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Somaira Nowsheen
- Mayo Graduate School, Mayo Medical School, Mayo Clinic Medical Scientist Training Program, Rochester, MN, United States
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Suganya J, Radha M, Naorem DL, Nishandhini M. In Silico docking studies of selected flavonoids--natural healing agents against breast cancer. Asian Pac J Cancer Prev 2015; 15:8155-9. [PMID: 25338999 DOI: 10.7314/apjcp.2014.15.19.8155] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Breast cancer is the serious health concern in India causing the highest mortality rate in females, which occurs due to uncontrolled cell division and can be metastasize to other parts of the human body. Interactions with estrogen receptor (ER) alpha are mainly responsible for the malignant tumors with regulation of the transcription of various genes as a transcription factor. Most of the drugs currently used for the breast cancer treatment produce various side effects and hence we focused on natural compounds which do not exhibit any toxic effect against normal human cells. MATERIALS AND METHODS Structure of human ER was retrieved from the Protein Data Bank and the structures of flavonoid compounds have been collected from PubChem database. Molecular docking and drug likeness studies were performed for those natural compounds to evaluate and analyze the anti-breast cancer activity. RESULTS Finally two compounds satisfying the Lipinski's rule of five were reported. The two compounds also exhibited highest binding affinity with human ER greater than 10.5 Kcal/mol. CONCLUSIONS The results of this study can be implemented in the drug designing pipeline.
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Affiliation(s)
- Jeyabaskar Suganya
- Department of Bioinformatics, School of Life Sciences, Vels University, Pallavaram, Chennai, Tamil Nadu, India E-mail : ,
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Pellegrini M, Bulzomi P, Galluzzo P, Lecis M, Leone S, Pallottini V, Marino M. Naringenin modulates skeletal muscle differentiation via estrogen receptor α and β signal pathway regulation. GENES AND NUTRITION 2014; 9:425. [PMID: 25156241 DOI: 10.1007/s12263-014-0425-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 07/29/2014] [Indexed: 01/13/2023]
Abstract
Several experiments sustain healthful benefits of the flavanone naringenin (Nar) against chronic diseases including its protective effects against estrogen-related cancers. These experiments encourage Nar use in replacing estrogen treatment in post-menopausal women avoiding the serious side effects ascribed to this hormone. However, at the present, scarce data are available on the impact of Nar on E2-regulated cell functions. This study was aimed at determining the impact of Nar on the estrogen receptor (ERα and β)-dependent signals important for 17β-estradiol (E2) effect in muscle cells (rat L6 myoblasts, mouse C2C12 myoblasts, and mouse skeletal muscle satellite cells). Dietary relevant concentration of Nar delays the appearance of skeletal muscle differentiation markers (i.e., GLUT4 translocation, myogenin, and both fetal and slow MHC isoforms) and impairs E2 effects specifically hampering ERα ability to activate AKT. Intriguingly, Nar effects are specific for E2-initiating signals because IGF-I-induced AKT activation, and myoblast differentiation markers were not affected by Nar treatment. Only 7 days after Nar stimulation, early myoblast differentiation markers (i.e., myogenin, and fetal MHC) start to be accumulated in myoblasts. On the other hand, Nar stimulation activates, via ERβ, the phosphorylation of p38/MAPK involved in reducing the reactive oxygen species formation in skeletal muscle cells. As a whole, data reported here strongly sustain that although Nar action mechanisms include the impairment of ERα signals which drive muscle cells to differentiation, the effects triggered by Nar in the presence of ERβ could balance this negative effect avoiding the toxic effects produced by oxidative stress .
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Affiliation(s)
- Marco Pellegrini
- Department of Sciences, Biomedical and Technology Science Section, University Roma Tre, Viale G. Marconi 446, 00146, Roma, Italy
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Induction of hepatic apolipoprotein A-I gene expression by the isoflavones quercetin and isoquercetrin. Life Sci 2014; 110:8-14. [DOI: 10.1016/j.lfs.2014.06.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 06/02/2014] [Accepted: 06/10/2014] [Indexed: 02/06/2023]
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23
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Marino M. Xenoestrogens challenge 17β-estradiol protective effects in colon cancer. World J Gastrointest Oncol 2014; 6:67-73. [PMID: 24653796 PMCID: PMC3955780 DOI: 10.4251/wjgo.v6.i3.67] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 01/10/2014] [Accepted: 02/18/2014] [Indexed: 02/05/2023] Open
Abstract
Several epidemiological, cellular, and molecular studies demonstrate the role of environmental chemicals with endocrine disrupting activities, typical of Westernized societies, in the pathogenesis of numerous diseases including cancer. Nonetheless this information, the design and execution of studies on endocrine disruptors are not yet cognizant that the specific actions of individual hormones often change with development and ageing, they may be different in males and females and may be mediated by different receptors isoforms expressed in different tissues or at different life stages. These statements are particularly true when assessing the hazard of endocrine disruptors against 17β-estradiol (E2) actions in that this hormone is crucial determinant of sex-related differences in anatomical, physiological, and behavioral traits which characterize male and female physiology. Moreover, E2 is also involved in carcinogenesis. The oncogenic effects of E2 have been investigated extensively in breast and ovarian cancers where hormone-receptor modulators are now an integral part of targeted treatment. Little is known about the E2 preventive signalling in colorectal cancer, although this disease is more common in men than women, the difference being more striking amongst pre-menopausal women and age-matched men. This review aims to dissect the role and action mechanisms of E2 in colorectal cancer evaluating the ability of estrogen disruptors (i.e., xenoestrogens) in impair these E2 actions. Data discussed here lead to define the possible role of xenoestrogens in the impairment and/or activation of E2 signals important for colorectal cancer prevention.
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Comparative binding affinities of flavonoid phytochemicals with bovine serum albumin. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2014; 13:1019-28. [PMID: 25276204 PMCID: PMC4177624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Dietary flavonoids show beneficial effects in the prevention of chronic diseases. However, flavonoid bioavailability is poor, probably due to their interaction with serum albumins. In the current work, the binding interactions of eight related flavonoids, sharing a similar core structure, with bovine serum albumin (BSA) were investigated by fluorescence spectroscopy. The binding affinities of the flavonoids with BSA were in the order hesperetin (KA=5.59 × 10(5))> quercetin (4.94 × 10(5)) > naringenin (3.04 × 10(5)) > isoquercitrin (4.66 × 10(4)) > icariin (3.60 × 10(4)) > rutin (1.65 × 10(4)) > hesperidin (2.50 × 10(3)) > naringin (8.70 × 10(2)). The associations of specific structural components of the flavonoids with their binding properties to BSA were also explored and hydrophobicity, functional group substituents, steric hindrance effects and the spatial arrangements of substituents seem to be the key factors for the affinities of flavonoids towards BSA. The results from the current work contribute to a better understanding of the transport of flavonoids in plasma and helping predict their physiological functions based on their intrinsic structures.
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Rietjens IMCM, Sotoca AM, Vervoort J, Louisse J. Mechanisms underlying the dualistic mode of action of major soy isoflavones in relation to cell proliferation and cancer risks. Mol Nutr Food Res 2013; 57:100-13. [PMID: 23175102 DOI: 10.1002/mnfr.201200439] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Revised: 09/25/2012] [Accepted: 10/08/2012] [Indexed: 12/12/2022]
Abstract
Isoflavones are phytoestrogens that have been linked to both beneficial as well as adverse effects in relation to cell proliferation and cancer risks. The present article presents an overview of these seemingly contradicting health effects and of mechanisms that could be involved in this dualistic mode of action. One mechanism relates to the different ultimate cellular effects of activation of estrogen receptor (ER) α, promoting cell proliferation, and of ERβ, promoting apoptosis, with the major soy isoflavones genistein and daidzein activating especially ERβ. A second mode of action includes the role of epigenetics, including effects of isoflavones on DNA methylation, histone modification and miRNA expression patterns. The overview presented reveals that we are only at the start of unraveling the complex underlying mode of action for effects of isoflavones, both beneficial or adverse, on cell proliferation and cancer risks. It is evident that whatever model system will be applied, its relevance to human tissues with respect to ERα and ERβ levels, co-repressor and co-activator characteristics as well as its relevance to human exposure regimens, needs to be considered and defined.
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Pang G, Xie J, Chen Q, Hu Z. How functional foods play critical roles in human health. FOOD SCIENCE AND HUMAN WELLNESS 2012. [DOI: 10.1016/j.fshw.2012.10.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Xu H, Su ZR, Huang W, Choi RCY, Zheng YZ, Lau DTW, Dong TTX, Wang ZT, Tsim KWK. Er Zhi Wan, an ancient herbal decoction for woman menopausal syndrome, activates the estrogenic response in cultured MCF-7 cells: an evaluation of compatibility in defining the optimized preparation method. JOURNAL OF ETHNOPHARMACOLOGY 2012; 143:109-115. [PMID: 22710293 DOI: 10.1016/j.jep.2012.06.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 05/29/2012] [Accepted: 06/06/2012] [Indexed: 06/01/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Er Zhi Wan (EZW), a Chinese medicinal preparation, has been used clinically for treating menopausal syndrome for its kidney-invigorating function, which contains simply two herbs, Ecliptae Herba (EH) and Ligustri Lucidi Fructus (LLF). Although this herbal extract has been used for many years, there is no scientific basis about its effectiveness on menopausal symptom. Here, we aimed to evaluate the estrogenic activities of EZW and to study the compatibilities of two herbs including different processed-LLF in single and mixed preparation of EZW. Moreover, the weight ratio of EH to LLF in EZW was determined according to their estrogenic activities. MATERIALS AND METHODS The extractions of LLF, processed-LLF and EH were prepared separately by extracting the powders with water, 50% alcohol or 95% alcohol. Steamed-LLF and EH were extracted separately, or together, in preparing EZW extracts. A promoter-reporter construct (pERE-Luc) containing three repeats of estrogen responsive elements (ERE) was stably transfected into MCF-7 cells, and this stable breast cancer cell line was used to determine the estrogenic property. The cell proliferation was measured by MTT assay. RESULTS The results showed that EZW could significantly induce the expression of luciferase driven by an estrogen responsive element in a pERE-Luc vector. The proliferation of MCF-7 cells was not altered by this herbal treatment. The best preparation of EZW was from: (i) LLF was firstly steamed over water and then dried to make steamed-LLF; and (ii) steamed-LLF and EH were extracted separately by 95% alcohol and then mixed together according to a weight ratio of 1:1. CONCLUSIONS Under the optimized extracting method, EZW possessed robust effect in activating the estrogenic activity, but which did not alter the proliferation of cultured MCF-7 cells. Thus, EZW is an effective and safe estrogenic herbal extract.
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Affiliation(s)
- Hong Xu
- Division of Life Science, Center for Chinese Medicine and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay Road, Hong Kong, China
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Marino M, Pellegrini M, La Rosa P, Acconcia F. Susceptibility of estrogen receptor rapid responses to xenoestrogens: Physiological outcomes. Steroids 2012; 77:910-7. [PMID: 22410438 DOI: 10.1016/j.steroids.2012.02.019] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 02/13/2012] [Accepted: 02/24/2012] [Indexed: 02/06/2023]
Abstract
17β-Estradiol (E2) binding induces rapid modification in the conformation of its cognate receptors (i.e., ERα and ERβ). These allosteric changes allow the association of ERs with cell specific transcriptional cofactors, thus determining cellular contexts specific variations in gene expression. In addition, E2-ER complexes could also interact with membrane and cytosolic signal molecules triggering extra-nuclear signalling pathways. The synergy between these mechanisms is necessary for E2-induced pleiotropic actions in target tissues. Besides E2, the ER ligand binding domains can accommodate many other natural and synthetic ligands. Several of these compounds act as agonist or antagonist of ER transcriptional activity due to their ability to modify the interactions between ERs and transcriptional co-regulators. However, the ability of natural or manmade ER ligands to affect the extra-nuclear interactions of the ERs has been rarely evaluated. Here, the ability of two diet-derived flavonoids (i.e., naringenin and quercetin) and of the synthetic food-contaminant bisphenol A to modulate specifically ER extra-nuclear signalling pathways will be reported. All the tested compounds bind to both ER subtypes even if lesser than E2 activating divergent signal transduction pathways. In fact, in the presence of ERα, both naringenin and quercetin decouple ERα activities by specifically interfering with ERα membrane initiating signals. On the other hand, bisphenol A, but not flavonoids, maintains ERβ at the membrane thus impairing the activation of the downstream kinases. As a whole, extra-nuclear ER signals are highly susceptible to different ligands that, by unbalancing E2-induced cell functions drive cells to different functional endpoints.
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Affiliation(s)
- Maria Marino
- Department of Biology, University Roma TRE, viale G. Marconi, 446, I-00146 Rome, Italy.
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Bulzomi P, Bolli A, Galluzzo P, Acconcia F, Ascenzi P, Marino M. The naringenin-induced proapoptotic effect in breast cancer cell lines holds out against a high bisphenol a background. IUBMB Life 2012; 64:690-6. [PMID: 22692793 DOI: 10.1002/iub.1049] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 04/17/2012] [Indexed: 12/19/2022]
Abstract
Fruit and vegetable consumption has generally been associated with the prevention or suppression of cancer. However, food could contain a multitude of chemicals (e.g., bisphenol A; BPA) that could synergize or antagonize the effects of diet-derived compounds. Remarkably, food containers (e.g., water and infant bottles) are the largest source of exposure to BPA for human beings. Here, the effects of the coexposure of naringenin (Nar, 1.0 × 10(-9) M to 1.0 × 10(-4) M) and BPA (1.0 × 10(-5) M) in estrogen-dependent breast cancer cell lines expressing (i.e., MCF-7 and T47D) or not expressing (i.e., MDA-MB-231) estrogen receptor α (ERα) are reported. Although both Nar and BPA bind to ERα, they induce opposite effects on breast cancer cell growth. BPA induces cell proliferation, whereas Nar only decreases the number of ERα-positive cells (i.e., MCF-7 and T47D). Notably, even in the presence of BPA, Nar impairs breast cancer cell proliferation by activating caspase-3. The molecular pathways involved require p38 activation, whereas, the BPA-induced AKT activation is completely prevented by the Nar treatment. As a whole, Nar maintains its proapoptotic effects even in the presence of the food contaminant BPA, thus, enlarging the chemopreventive potential of this flavanone.
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Affiliation(s)
- Pamela Bulzomi
- Department of Biology, University Roma Tre, Viale G. Marconi 446, I-00146 Roma, Italy
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Leung YK, Lee MT, Lam HM, Tarapore P, Ho SM. Estrogen receptor-beta and breast cancer: translating biology into clinical practice. Steroids 2012; 77:727-37. [PMID: 22465878 PMCID: PMC3356459 DOI: 10.1016/j.steroids.2012.03.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Revised: 03/15/2012] [Accepted: 03/16/2012] [Indexed: 02/07/2023]
Abstract
Estrogen receptor (ER) β was discovered over a decade ago. The design of most studies on this receptor was based on knowledge of its predecessor, ERα. Although breast cancer (BCa) has been a main focus of ERβ research, its precise roles in breast carcinogenesis remain elusive. Data from in vitro models have not always matched those from observational or clinical studies. Several inherent factors may contribute to these discrepancies: (a) several ERβ spliced variants are expressed at the protein level, and isoform-specific antibodies are unavailable for some variants; (b) post-translational modifications of the receptor regulate receptor functions; (c) the role of the receptor differs significantly depending on the type of ligands, cis-elements, and co-regulators that interact with the receptor; and (d) the diversity of distribution of the receptor among intracellular organelles of BCa cells. This review addresses the gaps in knowledge in ERβ research as it pertains to BCa regarding the following questions: (1) is ERβ a tumor suppressor in BCa?; (2) do ERβ isoforms play differential roles in breast carcinogenesis?; (3) do nuclear signaling and extranuclear ERβ signaling differ in BCa?; (4) what are the consequences of post-translational modifications of ERβ in BCa?; (5) how do co-regulators and interacting proteins increase functional diversity of ERβ?; and (6) how do the types of ligand and regulatory cis-elements affect the action of ERβ in BCa?. Insights gained from these key questions in ERβ research should help in prevention, diagnosis/prognosis, and treatment of BCa.
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Affiliation(s)
- Yuet-Kin Leung
- Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
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Bak Y, Kim H, Kang JW, Lee DH, Kim MS, Park YS, Kim JH, Jung KY, Lim Y, Hong J, Yoon DY. A synthetic naringenin derivative, 5-hydroxy-7,4'-diacetyloxyflavanone-N-phenyl hydrazone (N101-43), induces apoptosis through up-regulation of Fas/FasL expression and inhibition of PI3K/Akt signaling pathways in non-small-cell lung cancer cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2011; 59:10286-97. [PMID: 21877710 DOI: 10.1021/jf2017594] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Naringenin, a well-known naturally occurring flavonone, demonstrates cytotoxicity in a variety of human cancer cell lines; its inhibitory effects on tumor growth have spurred interest in its therapeutic application. In this study, naringenin was derivatized to produce more effective small-molecule inhibitors of cancer cell proliferation, and the anticancer effects of its derivative, 5-hydroxy-7,4'-diacetyloxyflavanone-N-phenyl hydrazone (N101-43), in non-small-cell lung cancer (NSCLC) cell lines NCI-H460, A549, and NCI-H1299 were investigated. Naringenin itself possesses no cytotoxicity against lung cancer cells. In contrast, N101-43 inhibits proliferation of both NCI-H460 and A549 cell lines; this capacity is lost in p53-lacking NCI-H1299 cells. N101-43 induces apoptosis via sub-G1 cell-cycle arrest in NCI-H460 and via G0/G1 arrest in A549 cells. Expression of apoptosis and cell-cycle regulatory factors is altered: Cyclins A and D1 and phospho-pRb are down-regulated, but expression of CDK inhibitors such as p21, p27, and p53 is enhanced by N101-43 treatment; N101-43 also increases expression levels of the extrinsic death receptor Fas and its binding partner FasL. Furthermore, N101-43 treatment diminishes levels of cell survival factors such as PI3K and p-Akt dose-dependently, and N101-43 additionally induces cleavage of the pro-apoptotic factors caspase-3, caspase-8, and poly ADP-ribose polymerase (PARP). Cumulatively, these investigations show that the naringenin derivative N101-43 induces apoptosis via up-regulation of Fas/FasL expression, activation of caspase cascades, and inhibition of PI3K/Akt survival signaling pathways in NCI-H460 and A549 cells. In conclusion, these data indicate that N101-43 may have potential as an anticancer agent in NSCLC.
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Affiliation(s)
- Yesol Bak
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea
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Sotoca AM, Gelpke MDS, Boeren S, Ström A, Gustafsson JÅ, Murk AJ, Rietjens IMCM, Vervoort J. Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics 2010; 10:M110.002170. [PMID: 20884965 DOI: 10.1074/mcp.m110.002170] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The present study addresses, by transcriptomics and quantitative stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics, the estrogen receptor α (ERα) and β (ERβ)-mediated effects on gene and protein expression in T47D breast cancer cells exposed to the phytoestrogen genistein. Using the T47D human breast cancer cell line with tetracycline-dependent ERβ expression (T47D-ERβ), the effect of a varying intracellular ERα/ERβ ratio on genistein-induced gene and protein expression was characterized. Results obtained reveal that in ERα-expressing T47D-ERβ cells with inhibited ERβ expression genistein induces transcriptomics and proteomics signatures pointing at rapid cell growth and migration by dynamic activation of cytoskeleton remodeling. The data reveal an interplay between integrins, focal adhesion kinase, CDC42, and actin cytoskeleton signaling cascades, occurring upon genistein treatment, in the T47D-ERβ breast cancer cells with low levels of ERα and no expression of ERβ. In addition, data from our study indicate that ERβ-mediated gene and protein expression counteracts ERα-mediated effects because in T47D-ERβ cells expressing ERβ and exposed to genistein transcriptomics and proteomics signatures pointing at a clear down-regulation of cell growth and induction of cell cycle arrest and apoptosis were demonstrated. These results suggest that ERβ decreases cell motility and metastatic potential as well as cell survival of the breast cancer cell line. It is concluded that the effects of genistein on proteomics and transcriptomics end points in the T47D-ERβ cell model are comparable with those reported previously for estradiol with the ultimate estrogenic effect being dependent on the relative affinity for both receptors and on the receptor phenotype (ERα/ERβ ratio) in the cells or tissue of interest.
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Affiliation(s)
- Ana M Sotoca
- Toxicology section, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
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Bolli A, Marino M, Rimbach G, Fanali G, Fasano M, Ascenzi P. Flavonoid binding to human serum albumin. Biochem Biophys Res Commun 2010; 398:444-9. [PMID: 20599706 DOI: 10.1016/j.bbrc.2010.06.096] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 06/24/2010] [Indexed: 12/24/2022]
Abstract
Dietary flavonoid may have beneficial effects in the prevention of chronic diseases. However, flavonoid bioavailability is often poor probably due to their interaction with plasma proteins. Here, the affinity of daidzein and daidzein metabolites as well as of genistein, naringenin, and quercetin for human serum albumin (HSA) has been assessed in the absence and presence of oleate. Values of the dissociation equilibrium constant (K) for binding of flavonoids and related metabolites to Sudlow's site I range between 3.3x10(-6) and 3.9x10(-5)M, at pH 7.0 and 20.0 degrees C, indicating that these flavonoids are mainly bound to HSA in vivo. Values of K increase (i.e., the flavonoid affinity decreases) in the presence of saturating amounts of oleate by about two folds. Present data indicate a novel role of fatty acids as allosteric inhibitors of flavonoid bioavailability, and appear to be relevant in rationalizing the interference between dietary compounds, food supplements, and drugs.
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Affiliation(s)
- Alessandro Bolli
- Department of Biology, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
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Wu Y, Wang Y, Zhang A, Yu H, Wang L. Three-Dimensional Quantitative Structure-Activity Relationships of flavonoids and estrogen receptors based on docking. CHINESE SCIENCE BULLETIN-CHINESE 2010. [DOI: 10.1007/s11434-010-3048-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Bulzomi P, Bolli A, Galluzzo P, Leone S, Acconcia F, Marino M. Naringenin and 17beta-estradiol coadministration prevents hormone-induced human cancer cell growth. IUBMB Life 2010; 62:51-60. [PMID: 19960539 DOI: 10.1002/iub.279] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Flavonoids have been described as health-promoting, disease-preventing dietary components. In vivo and in vitro experiments also support a protective effect of flavonoids to reduce the incidence of certain hormone-responsive cancers. In particular, our previous results indicate that the flavanone naringenin (Nar), decoupling estrogen receptor alpha (ERalpha) action mechanisms, drives cancer cells to apoptosis. Because these studies were conducted in the absence of the endogenous hormone 17beta-estradiol (E2), the physiological relevance of these findings is not clear. We investigate whether the antiproliferative Nar effect persists in the presence of physiological E2 concentration (i.e. 10 nM), using both ERalpha-transfected (HeLa cells) and ERalpha-containing (HepG2 cells) cancer cell lines. Ligand saturation experiments indicate that Nar decreases the binding of E2 to ERalpha without impairing the estrogen response element (ERE)-driven reporter plasmid activity. In contrast, Nar stimulation prevents E2-induced extracellular regulated kinases (ERK1/2) and AKT activation and still induces the activation of p38, the proapoptotic member of mitogen-activating protein kinase (MAPK) family. As a consequence, Nar stimulation impedes the E2-induced transcription of cyclin D1 promoter and reverts the E2-induced cell proliferation, driving cancer cell to apoptosis. Thus, these results suggest that coexposure to this low-affinity, low-potency ligand for ERalpha specifically antagonizes the E2-induced ERalpha-dependent rapid signals by reducing the effect of the endogenous hormone in promoting cellular proliferation. As a whole, these data indicate that Nar is an excellent candidate as a chemopreventive agent in E2-dependent cancers.
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Affiliation(s)
- Pamela Bulzomi
- Department of Biology, University Roma Tre, Viale G. Marconi, I-00146 Roma, Italy
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Galluzzo P, Martini C, Bulzomi P, Leone S, Bolli A, Pallottini V, Marino M. Quercetin-induced apoptotic cascade in cancer cells: Antioxidantversusestrogen receptor α-dependent mechanisms. Mol Nutr Food Res 2009; 53:699-708. [DOI: 10.1002/mnfr.200800239] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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di Masi A, De Marinis E, Ascenzi P, Marino M. Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects. Mol Aspects Med 2009; 30:297-343. [PMID: 19427329 DOI: 10.1016/j.mam.2009.04.002] [Citation(s) in RCA: 221] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Accepted: 04/28/2009] [Indexed: 12/31/2022]
Abstract
Nuclear receptors (NRs) are ligand-activated transcription factors sharing a common evolutionary history and having similar sequence features at the protein level. Selective ligand(s) for some NRs is not known, therefore these NRs have been named "orphan receptors". Whenever ligands have been recognized for any of the orphan receptor, it has been categorized and grouped as "adopted" orphan receptor. This group includes the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). They function as sensors of toxic byproducts derived from endogenous metabolites and of exogenous chemicals, in order to enhance their elimination. This unique function of CAR and PXR sets them apart from the steroid hormone receptors. The broad response profile has established that CAR and PXR are xenobiotic sensors that coordinately regulate xenobiotic clearance in the liver and intestine via induction of genes involved in drug and xenobiotic metabolism. In the past few years, research has revealed new and mostly unsuspected roles for CAR and PXR in modulating hormone, lipid, and energy homeostasis as well as cancer and liver steatosis. The purpose of this review is to highlight the structural and molecular bases of CAR and PXR impact on human health, providing information on mechanisms through which diet, chemical exposure, and environment ultimately impact health and disease.
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Affiliation(s)
- Alessandra di Masi
- Department of Biology, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
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Sotoca AM, Ratman D, van der Saag P, Ström A, Gustafsson JA, Vervoort J, Rietjens IMCM, Murk AJ. Phytoestrogen-mediated inhibition of proliferation of the human T47D breast cancer cells depends on the ERalpha/ERbeta ratio. J Steroid Biochem Mol Biol 2008; 112:171-8. [PMID: 18955141 DOI: 10.1016/j.jsbmb.2008.10.002] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2008] [Revised: 09/17/2008] [Accepted: 10/02/2008] [Indexed: 02/07/2023]
Abstract
This study investigates the importance of the intracellular ratio of the two estrogen receptors ERalpha and ERbeta for the ultimate potential of the phytoestrogens genistein and quercetin to stimulate or inhibit cancer cell proliferation. This is of importance because (i) ERbeta has been postulated to play a role in modulating ERalpha-mediated cell proliferation, (ii) genistein and quercetin may be agonists for both receptor types and (iii) the ratio of ERalpha to ERbeta is known to vary between tissues. Using human osteosarcoma (U2OS) ERalpha or ERbeta reporter cells it was shown that compared to estradiol (E2), genistein and quercetin have not only a relatively greater preference for ERbeta but also a higher maximal potential for activating ERbeta-mediated gene expression. Using the human T47D breast cancer cell line with tetracycline-dependent ERbeta expression (T47D-ERbeta), the effect of a varying intracellular ERalpha/ERbeta ratio on E2- or pythoestrogen-induced cell proliferation was characterised. E2-induced proliferation of cells in which ERbeta expression was inhibited was similar to that of the T47D wild type cells, whereas this E2-induced cell proliferation was no longer observed when ERbeta expression was increased. With increased expression of ERbeta the phytoestrogen-induced cell proliferation was also reduced. These results point at the importance of the cellular ERalpha/ERbeta ratio for the ultimate effect of (phyto)estrogens on cell proliferation.
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Affiliation(s)
- A M Sotoca
- Toxicology Section, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
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Virgili F, Marino M. Regulation of cellular signals from nutritional molecules: a specific role for phytochemicals, beyond antioxidant activity. Free Radic Biol Med 2008; 45:1205-16. [PMID: 18762244 DOI: 10.1016/j.freeradbiomed.2008.08.001] [Citation(s) in RCA: 133] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2008] [Revised: 07/21/2008] [Accepted: 08/01/2008] [Indexed: 10/21/2022]
Abstract
Phytochemicals (PhC) are a ubiquitous class of plant secondary metabolites. A "recommended" human diet should warrant a high proportion of energy from fruits and vegetables, therefore providing, among other factors, a huge intake of PhC, in general considered "health promoting" by virtue of their antioxidant activity and positive modulation, either directly or indirectly, of the cellular and tissue redox balance. Diet acts through multiple pathways and the association between the consumption of specific food items and the risk of degenerative diseases is extremely complex. Recent literature suggests that molecules having a chemical structure compatible with a putative antioxidant capacity can actually "perform" activities and roles independent of such capacity, interacting with cellular functions at different levels, such as affecting enzyme activities, binding to membrane or nuclear receptors as either an elective ligand or a ligand mimic. Inductive or signaling effects may occur at concentrations much lower than that required for effective antioxidant activity. Therefore, the "antioxidant hypothesis" is to be considered in some cases an intellectual "shortcut" possibly biasing the real understanding of the molecular mechanisms underlying the beneficial effects of various classes of food items. In the past few years, many exciting new indications elucidating the mechanisms of polyphenols have been published. Here, we summarize the current knowledge of the mechanisms by which specific molecules of nutritional interest, and in particular polyphenols, play a role in cellular response and in preventing pathologies. In particular, their direct interaction with nuclear receptors and their ability to modulate the activity of key enzymes involved in cell signaling and antioxidant responses are presented and discussed.
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Affiliation(s)
- Fabio Virgili
- National Institute for Food and Nutrition Research, Via Ardeatina, 546, I-00178 Roma, Italy.
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40
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Sotoca AMC, van den Berg H, Vervoort J, van der Saag P, Ström A, Gustafsson JA, Rietjens I, Murk AJ. Influence of cellular ERalpha/ERbeta ratio on the ERalpha-agonist induced proliferation of human T47D breast cancer cells. Toxicol Sci 2008; 105:303-11. [PMID: 18644836 PMCID: PMC2527638 DOI: 10.1093/toxsci/kfn141] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Breast cancer cells show overexpression of estrogen receptor (ER) alpha relative to ERbeta compared to normal breast tissues. This observation has lead to the hypothesis that ERbeta may modulate the proliferative effect of ERalpha. This study investigated how variable cellular expression ratios of the ERalpha and ERbeta modulate the effects on cell proliferation induced by ERalpha or ERbeta agonists, respectively. Using human osteosarcoma (U2OS) ERalpha or ERbeta reporter cells, propyl-pyrazole-triol (PPT) was shown to be a selective ERalpha and diarylpropionitrile (DPN) a preferential ERbeta modulator. The effects of these selective estrogen receptor modulators (SERMs) and of the model compound E2 on the proliferation of T47D human breast cancer cells with tetracycline-dependent expression of ERbeta (T47D-ERbeta) were characterized. E2-induced cell proliferation of cells in which ERbeta expression was inhibited was similar to that of the T47D wild-type cells, whereas this E2-induced cell proliferation was no longer observed when ERbeta expression in the T47D-ERbeta cells was increased. In the T47D-ERbeta cell line, DPN also appeared to be able to suppress cell proliferation when levels of ERbeta expression were high. In the T47D-ERbeta cell line, PPT was unable to suppress cell proliferation at all ratios of ERalpha/ERbeta expression, reflecting its ability to activate only ERalpha and not ERbeta. It is concluded that effects of estrogen-like compounds on cell proliferation are dependent on the actual ERalpha/ERbeta expression levels in these cells or tissues and the potential of the estrogen agonists to activate ERalpha and/or ERbeta.
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Affiliation(s)
- Ana M Covaleda Sotoca
- Toxicology Section, Wageningen University, Tuinlaan 5, 6703 HE, Wageningen, The Netherlands.
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Galluzzo P, Ascenzi P, Bulzomi P, Marino M. The nutritional flavanone naringenin triggers antiestrogenic effects by regulating estrogen receptor alpha-palmitoylation. Endocrinology 2008; 149:2567-75. [PMID: 18239068 DOI: 10.1210/en.2007-1173] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Naringenin (Nar) is a component of fruits and vegetables associated with healthful benefits, such as in osteoporosis, cancer, and cardiovascular diseases. These protective effects have been linked with Nar antiestrogenic as well as estrogenic activities. Previous studies indicate that Nar impaired estrogen receptor (ER) alpha signaling by interfering with ERalpha-mediated activation of ERK and phosphoinositide 3-kinase signaling pathways in the absence of effects at the transcriptional level. The present studies evaluated the hypothesis that these Nar antagonistic effects occur at the level of the plasma membrane. Our results indicate that Nar induces ERalpha depalmitoylation faster than 17beta-estradiol, which results in receptor rapid dissociation from caveolin-1. Furthermore, Nar impedes ERalpha to bind adaptor (modulator of nongenomic actions of the ER) and signaling (c-Src) proteins involved in the activation of the mitogenic signaling cascades (i.e. ERK and phosphoinositide 3-kinase). On the other hand, Nar induces the ER-dependent, but palmitoylation-independent, activation of p38 kinase, which in turn is responsible for Nar-mediated antiproliferative effects in cancer cells. Altogether, these data highlight new ER-dependent mechanisms on the root of antiproliferative and antiestrogenic effects of Nar. Moreover, the different modulation of ERalpha palmitoylation exerted by different ligands represents a pivotal mechanism that drives cancer cell to proliferation or apoptosis.
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Affiliation(s)
- Paola Galluzzo
- Department of Biology, University Roma Tre, Viale G. Marconi, 446, I-00146 Roma, Italy
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Marino M, Galluzzo P. Are flavonoids agonists or antagonists of the natural hormone 17β-estradiol? IUBMB Life 2008; 60:241-4. [DOI: 10.1002/iub.34] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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