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Svolacchia F, Brongo S, Catalano A, Ceccarini A, Svolacchia L, Santarsiere A, Scieuzo C, Salvia R, Finelli F, Milella L, Saturnino C, Sinicropi MS, Fabrizio T, Giuzio F. Natural Products for the Prevention, Treatment and Progression of Breast Cancer. Cancers (Basel) 2023; 15:cancers15112981. [PMID: 37296944 DOI: 10.3390/cancers15112981] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
In this review, we summarize the most used natural products as useful adjuvants in BC by clarifying how these products may play a critical role in the prevention, treatment and progression of this disease. BC is the leading cancer, in terms of incidence, that affects women. The epidemiology and pathophysiology of BC were widely reported. Inflammation and cancer are known to influence each other in several tumors. In the case of BC, the inflammatory component precedes the development of the neoplasm through a slowly increasing and prolonged inflammation that also favors its growth. BC therapy involves a multidisciplinary approach comprising surgery, radiotherapy and chemotherapy. There are numerous observations that showed that the effects of some natural substances, which, in integration with the classic protocols, can be used not only for prevention or integration in order to prevent recurrences and induce a state of chemoquiescence but also as chemo- and radiosensitizers during classic therapy.
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Affiliation(s)
- Fabiano Svolacchia
- Department of Medical-Surgical Sciences and Biotechnologies, La Sapienza University, 00118 Rome, Italy
- Department of Medical Sciences, Policlinic Foundation Tor Vergata University, 00133 Rome, Italy
| | - Sergio Brongo
- Department of Plastic Surgery, University of Salerno, 84131 Campania, Italy
| | - Alessia Catalano
- Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", 70126 Bari, Italy
| | - Agostino Ceccarini
- U.O.C. Primary Care and Territorial Health, Social and Health Department, State Hospital, 47893 San Marino, San Marino
| | - Lorenzo Svolacchia
- Department of Medical-Surgical Sciences and Biotechnologies, La Sapienza University, 00118 Rome, Italy
| | - Alessandro Santarsiere
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- CNRS, UMR 7042-LIMA, ECPM, Université de Strasbourg, Université de Haute-Alsace, 67000 Strasbourg, France
| | - Carmen Scieuzo
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- Spinoff XFlies s.r.l., University of Basilicata, 85100 Potenza, Italy
| | - Rosanna Salvia
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- Spinoff XFlies s.r.l., University of Basilicata, 85100 Potenza, Italy
| | | | - Luigi Milella
- Department of Science, University of Basilicata, 85100 Potenza, Italy
| | - Carmela Saturnino
- Department of Science, University of Basilicata, 85100 Potenza, Italy
| | - Maria Stefania Sinicropi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Tommaso Fabrizio
- Department of Plastic Surgery, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy
| | - Federica Giuzio
- U.O.C. Primary Care and Territorial Health, Social and Health Department, State Hospital, 47893 San Marino, San Marino
- Department of Science, University of Basilicata, 85100 Potenza, Italy
- Spinoff TNcKILLERS s.r.l., University of Basilicata, 85100 Potenza, Italy
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Estrogenic flavonoids and their molecular mechanisms of action. J Nutr Biochem 2023; 114:109250. [PMID: 36509337 DOI: 10.1016/j.jnutbio.2022.109250] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/02/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
Flavonoids are a major group of phytoestrogens associated with physiological effects, and ecological and social impacts. Although the estrogenic activity of flavonoids was reported by researchers in the fields of medical, environmental and food studies, their molecular mechanisms of action have not been comprehensively reviewed. The estrogenic activity of the respective classes of flavonoids, anthocyanidins/anthocyanins, 2-arylbenzofurans/3-arylcoumarins/α-methyldeoxybenzoins, aurones/chalcones/dihydrochalcones, coumaronochromones, coumestans, flavans/flavan-3-ols/flavan-4-ols, flavanones/dihydroflavonols, flavones/flavonols, homoisoflavonoids, isoflavans, isoflavanones, isoflavenes, isoflavones, neoflavonoids, oligoflavonoids, pterocarpans/pterocarpenes, and rotenone/rotenoids, was summarized through a comprehensive literature search, and their structure-activity relationship, biological activities, signaling pathways, and applications were discussed. Although the respective classes of flavonoids contained at least one chemical mimicking estrogen, the mechanisms varied, such as those with estrogenic, anti-estrogenic, non-estrogenic, and biphasic activities, and additional activities through crosstalk/bypassing, which exert biological activities through cell signaling pathways. Such mechanistic variations of estrogen action are not limited to flavonoids and are observed among other broad categories of chemicals, thus this group of chemicals can be termed as the "estrogenome". This review article focuses on the connection of estrogen action mainly between the outer and the inner environments, which represent variations of chemicals and biological activities/signaling pathways, respectively, and form the basis to understand their applications. The applications of chemicals will markedly progress due to emerging technologies, such as artificial intelligence for precision medicine, which is also true of the study of the estrogenome including estrogenic flavonoids.
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The Anti-Inflammatory and Antithrombotic Properties of Bioactives from Orange, Sanguine and Clementine Juices and from Their Remaining By-Products. BEVERAGES 2022. [DOI: 10.3390/beverages8030039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The anti-oxidant properties of vitamin C and of phenolic compounds of citrus fruits are well established. However, the evaluation of the anti-inflammatory and antithrombotic potential of both vitamin C and of the more amphiphilic and lipophilic components of citrus fruits needs further attention. In this study, the anti-inflammatory and antithrombotic properties of vitamin C and of freshly squeezed juices and their lipid bioactives from the Navalina and Sanguine orange varieties and the Clementine variety of mandarins, as well as from their remaining by-products, were evaluated against the inflammatory and thrombotic pathways of the platelet-activating factor (PAF) and thrombin in platelets, as well as against PAF-biosynthesis in leukocytes. The non-oxidized juices of these citrus fruits and a vitamin C supplement showed stronger anti-PAF and antithrombin effects than their oxidized versions through their general anti-oxidant effect in platelets. The total lipids (TLs) and the HPLC-derived fractions of phenolic compounds and of polar lipid bioactives from both juices and their peels’ by-products showed a more specific stronger inhibitory effect against the inflammatory and thrombotic pathways of PAF and thrombin in platelets, while these bioactives strongly inhibited also the specific enzyme activities of the main biosynthetic enzymes of PAF in leukocytes. The stronger bioactivity of the dietary bioactives found in the juices of these citrus fruits against specific biochemical pathways of inflammation and thrombosis seems to act with synergy with the anti-oxidant potential of their vitamin C content, which further supports the notion that these juices are functional foods with anti-inflammatory protective health benefits. In addition, the presence of these dietary bioactive phenolic compounds and polar lipid bioactives in the remaining peels’ wastes further enhance the valorization of such food industry by-products as potential sources of anti-inflammatory bioactives to be used as ingredients for novel functional products.
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Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens. Int J Mol Sci 2022; 23:ijms23126813. [PMID: 35743256 PMCID: PMC9224163 DOI: 10.3390/ijms23126813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/31/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors. Thus, successful breast cancer therapy would need to target these BCSCs, as well the tumor bulk cells. Since the Women’s Health Initiative study reported an increased risk of breast cancer with the use of conventional hormone replacement therapy in postmenopausal women, many have turned their attention to phytoestrogens as a natural alternative. Phytoestrogens are plant compounds that share structural similarities with human estrogens and can bind to the estrogen receptors to alter the endocrine responses. Recent studies have found that phytoestrogens can also target BCSCs and have the potential to complement conventional therapy eradicating BCSCs. This review summarized the latest findings of different phytoestrogens and their effect on BCSCs, along with their mechanisms of action, including selective estrogen receptor binding and inhibition of molecular pathways used by BCSCs. The latest results of phytoestrogens in clinical trials are also discussed to further evaluate the use of phytoestrogen in the treatment and prevention of breast cancer.
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Abdelghffar EA, El-Nashar HAS, Al-Mohammadi AGA, Eldahshan OA. Orange fruit ( Citrus sinensis) peel extract attenuates chemotherapy-induced toxicity in male rats. Food Funct 2021; 12:9443-9455. [PMID: 34606555 DOI: 10.1039/d1fo01905h] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background: Cyclophosphamide (CYP) is a chemotherapy drug widely used in the treatment of several types of cancers and autoimmune disorders. Unfortunately, it causes severe side effects on many organs due to its oxidative stress effect. Objective: The present study aims to tentatively identify the phytochemical constituents of orange fruit (Citrus sinensis) peel extract (OFPE) and elucidate the chemopreventive effects of OFPE on CYP drug induced organ toxicity. Methods: The high performance liquid chromatography coupled with mass spectroscopy (HPLC-MS/MS) technique was used to identify the compounds. Thirty-five male rats were divided into five groups (GP; n = 7): GP1: normal control, GP2: OFPE 0.5 only, GP3: CYP-only, GP4: OFPE 0.25 + CYP, and GP5: OFPE 0.5 + CYP. Results: Twenty-nine compounds of polyphenolic nature, mainly flavonoids, anthocyanidins, phenolic acids and limonoids were characterized by HPLC-MS/MS analysis. Among these compounds, naringin, hesperidin, diosmin, rutin, neohesperidin and limonin were the predominant compounds in the examined extract. Serum cellular markers were found to be decreased significantly upon treatment with OFPE (especially high dose). Also, a significant prophylactic effect against liver, kidney, and heart injuries induced by CYP via decreasing inflammation (serum TNF-α, IL-1β & IL-6) and lipid peroxidation (MDA) was also revealed. Also, an increase in antioxidant levels (serum TAO, and cellular GSH & CAT in tissue homogenates) confirmed the protective efficacy of OFPE against CYP toxicity. Conclusions: The present study reveals some chemopreventive properties and beneficial effects of OFPE on CYP-induced organ toxicity via its antioxidant status and immunoregulatory activities.
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Affiliation(s)
- Eman A Abdelghffar
- Department of Biology, Collage of Science, Taibah University, Saudi Arabia. .,Department of Zoology, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Heba A S El-Nashar
- Pharmacognosy Department, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt.,Center for Drug Discovery Research and Development, Ain Shams University, Egypt
| | | | - Omayma A Eldahshan
- Pharmacognosy Department, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt.,Center for Drug Discovery Research and Development, Ain Shams University, Egypt
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Tajaldini M, Asadi J. The Use of Bio-Active Compounds of Citrus Fruits as Chemopreventive Agents and Inhibitor of Cancer Cells Viability. Anticancer Agents Med Chem 2021; 21:1058-1068. [PMID: 32698740 DOI: 10.2174/1871520620666200721105505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 05/13/2020] [Accepted: 05/24/2020] [Indexed: 11/22/2022]
Abstract
Common therapy of cancer, such as chemotherapy, has various side effects for the patients. In recent studies, new therapeutic approaches in cancer treatment are adjuvant therapy, along with a reduction in side effects of chemotherapy drugs. Treatment by herbal medicines may have some advantages over treatment with single purified chemicals, also in terms of side effects, the use of plants in cancer treatment is a more secure method. Citrus fruits are one of the most consumed natural products in the world due to the presence of various metabolites and bioactive compounds, such as phenols, flavonoids and, carotenoids. Bioactive compounds of citrus modulate signaling pathways and interact with signaling molecules such as apoptotic and cell cycle (P53, P21, etc.) and thus have a wide range of pharmacological activities, including anti-inflammatory, anti-cancer and oxidative stress. The findings discussed in this review strongly support their potential as anti-cancer agents. Therefore, the purpose of this review was to examine the effects of active compounds in citrus as a therapy agent in cancer treatment.
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Affiliation(s)
- Mahboubeh Tajaldini
- Ischimic Disorder Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Jahanbakhsh Asadi
- Metabolic Disorder Center, Golestan University of Medical Sciences, Gorgan, Iran
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Jain A, Madu CO, Lu Y. Phytochemicals in Chemoprevention: A Cost-Effective Complementary Approach. J Cancer 2021; 12:3686-3700. [PMID: 33995644 PMCID: PMC8120178 DOI: 10.7150/jca.57776] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 04/21/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer is one of the leading causes of death across the world. Although conventional cancer treatments such as chemotherapy and radiotherapy have effectively decreased cancer progression, they come with many dose-limiting side-effects. Phytochemicals that naturally occur in spices, fruits, vegetables, grains, legumes, and other common foods are surprisingly effective complements to conventional cancer treatments. These biologically active compounds demonstrate anticancer effects via cell signaling pathway interference in cancerous cells. In addition, phytochemicals protect non-cancerous cells from chemotherapy-induced side-effects. This paper addresses the not only the potential of phytochemicals quercetin, isoflavones, curcumin, catechins, and hesperidin in terms of cancer treatment and protection against side-effects of chemotherapy, but also methods for increasing phytochemical bioavailability.
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Affiliation(s)
- Aayush Jain
- Departments of Biological Sciences, University of Memphis, Memphis, TN 38152. USA
| | - Chikezie O. Madu
- Departments of Biological Sciences, University of Memphis, Memphis, TN 38152. USA
| | - Yi Lu
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN 38163. USA
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Gerçek E, Zengin H, Erdem Erişir F, Yılmaz Ö. Biochemical changes and antioxidant capacity of naringin and naringenin against malathion toxicity in Saccharomyces cerevisiae. Comp Biochem Physiol C Toxicol Pharmacol 2021; 241:108969. [PMID: 33412300 DOI: 10.1016/j.cbpc.2020.108969] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/18/2020] [Accepted: 12/24/2020] [Indexed: 11/18/2022]
Abstract
Flavonoids are rich in seeds, citrus fruits, olive oil, tea and red wine. Citrus flavonoids constitute an important type of flavonoids. Naringin and naringenin belong to flavonoids with known antioxidant and were found to display antioxidant activities. Malathion is an organophosphorus pesticide that has been broadly used throughout the world to control weeds and pests. It has also been used in public health for mosquito control and fruit fly eradication programs. Malathion, naringin, and naringenin were added to be in 40, 80, and 160 mg doses in Saccharomyces cerevisiae cultures mainly used to determine the antioxidant capacity, it is known that they have shown similar results to man. At the end of the experiment, total protein, malondialdehyde (MDA), reduced glutathione (GSH), oxidized glutathione (GSSG), vitamin K, vitamin E, vitamin D, ergosterol, stigmasterol, β-Sitosterol, and fatty acids were analyzed by HPLC (high performance liquid chromatography) and GC (gas chromatography) devices in the tested S. cerevisiae samples. The contents of the yeast cell of octanoic acid (C8:0), lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), palmitoleic acid (C16:1n-7), heptadecanoic acid (C17:0), stearic acid (C18:0), oleic acid (C18:1n-9), and linoleic acid (C18:2n-6) were identified. There were statistically significant changes in total protein, MDA, GSH, GSSG, vitamin K, vitamin E, vitamin D, phytosterol and fatty acid levels. It was determined that naringin and naringenin showed statistically significant decreases against malathion toxicity on these parameters. From this study it is found that, the mitigating effect of naringin against DPPH stable free radical was higher than that of naringenin. Citrus flavonoid, naringin showed promising antioxidant activity which can be used as effective protecting agents against oxidative stress.
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Affiliation(s)
- Ezgi Gerçek
- Department of Biology, Faculty of Science, Firat University, Elazig, Turkey.
| | - Hatayi Zengin
- Department of Mathematics and Science Education, Faculty of Education, Cumhuriyet University, Sivas, Turkey
| | - Figen Erdem Erişir
- Department of Biology, Faculty of Science, Firat University, Elazig, Turkey
| | - Ökkeş Yılmaz
- Department of Biology, Faculty of Science, Firat University, Elazig, Turkey
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Goudarzi M, Kalantar M, Sadeghi E, Karamallah MH, Kalantar H. Protective effects of apigenin on altered lipid peroxidation, inflammation, and antioxidant factors in methotrexate-induced hepatotoxicity. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:523-531. [PMID: 33057777 DOI: 10.1007/s00210-020-01991-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
Methotrexate (MTX) is used as an effective chemotherapeutic agent against autoimmune diseases and tumors. Oxidative stress and inflammation are involved in the pathogenesis of MTX-induced damage. This study aimed at examining the ameliorating effects of apigenin (API) as a natural antioxidant on MTX-induced hepatotoxicity. The rats were classified into four groups: group I: normal saline-treated, group II: MTX-treated (20 mg/kg, ip, single dose at day 7), group III: MTX + API-treated (20 mg/kg, po), and group IV: API-treated. API was administrated for 9 days. Alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) were used as biochemical factors of MTX-induced hepatic injury. In hepatic tissues, the levels of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), and activities of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) as oxidative stress markers along with inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) were assessed. Our results showed that MTX administration significantly increased ALP, ASP, ALT, MDA, NO, TNF-α, and IL-1β levels and significantly decreased antioxidant factors such as GSH, CAT, GPx, and SOD. The API pretreatment group showed a significant rise in hepatic antioxidant markers, besides significant reductions in the serum levels of AST, ALT, and ALP and hepatic content of MDA, TNF-α, NO, and IL-1β. In addition, the hepatoprotective effect of API was confirmed by histological evaluation of the liver. API can prevent MTX-induced hepatotoxicity through mitigation of oxidative stress and inflammation.
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Affiliation(s)
- Mehdi Goudarzi
- Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mojtaba Kalantar
- Faculty of Medicine, Shoushtar University of Medical Sciences, Shoushtar, Iran
| | - Elahe Sadeghi
- Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Hadi Kalantar
- Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Khan M, Rauf W, Habib FE, Rahman M, Iqbal M. Screening and identification of bioactive compounds from citrus against non-structural protein 3 protease of hepatitis C virus genotype 3a by fluorescence resonance energy transfer assay and mass spectrometry. World J Hepatol 2020; 12:976-992. [PMID: 33312423 PMCID: PMC7701965 DOI: 10.4254/wjh.v12.i11.976] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/03/2020] [Accepted: 09/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis C virus genotype 3a (HCV G3a) is highly prevalent in Pakistan. Due to the elevated cost of available Food and Drug Administration-approved drugs against HCV, medicinal natural products of potent antiviral activity should be screened for the cost-effective treatment of the disease. Furthermore, from natural products, active compounds against vital HCV proteins like non-structural protein 3 (NS3) protease could be identified to prevent viral proliferation in the host. AIM To develop cost-effective HCV genotype 3a NS3 protease inhibitors from citrus fruit extracts. METHODS Full-length NS3 without co-factor non-structural protein 4A (NS4A) and codon optimized NS3 protease in fusion with NS4A were expressed in Escherichia coli. The expressed protein was purified by metal ion affinity chromatography and gel filtration. Citrus fruit extracts were screened using fluorescence resonance energy transfer (FRET) assay against the protease and polyphenols were identified as potential inhibitors using electrospray ionization-mass spectrometry (MS)/MS technique. Among different polyphenols, highly potent compounds were screened using molecular modeling approaches and consequently the most active compound was further evaluated against HCV NS4A-NS3 protease domain using FRET assay. RESULTS NS4A fused with NS3 protease domain gene was overexpressed and the purified protein yield was high in comparison to the lower yield of the full-length NS3 protein. Furthermore, in enzyme kinetic studies, NS4A fused with NS3 protease proved to be functionally active compared to full-length NS3. So it was concluded that co-factor NS4A fusion is essential for the purification of functionally active protease. FRET assay was developed and validated by the half maximal inhibitory concentration (IC50) values of commercially available inhibitors. Screening of citrus fruit extracts against the native purified fused NS4A-NS3 protease domain showed that the grapefruit mesocarp extract exhibits the highest percentage inhibition 91% of protease activity. Among the compounds identified by LCMS analysis, hesperidin showed strong binding affinity with the protease catalytic triad having S-score value of -10.98. CONCLUSION Fused NS4A-NS3 protease is functionally more active, which is effectively inhibited by hesperidin from the grapefruit mesocarp extract with an IC50 value of 23.32 µmol/L.
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Affiliation(s)
- Mahim Khan
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad 38000, Punjab, Pakistan
| | - Waqar Rauf
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad 38000, Punjab, Pakistan
| | - Fazal-E- Habib
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad 38000, Punjab, Pakistan
| | - Moazur Rahman
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad 38000, Punjab, Pakistan
| | - Mazhar Iqbal
- Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad 38000, Punjab, Pakistan.
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Khodavandi A, Alizadeh F, Razis AFA. Association between dietary intake and risk of ovarian cancer: a systematic review and meta-analysis. Eur J Nutr 2020; 60:1707-1736. [PMID: 32661683 DOI: 10.1007/s00394-020-02332-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 07/07/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE It is unclear how dietary intake influences the ovarian cancer. The present paper sets out to systematically review and meta-analyze research on dietary intake to identify cases having high- or low-risk ovarian cancer. METHODS Scopus, PubMed, and Wiley Online Libraries were searched up to the date November 24, 2019. Two reviewers were requested to independently extract study characteristics and to assess the bias and applicability risks with reference to the study inclusion criteria. Meta-analyses were performed to specify the relationship between dietary intake and the risk of ovarian cancer identifying 97 cohort studies. RESULTS No significant association was found between dietary intake and risk of ovarian cancer. The results of subgroup analyses indicated that green leafy vegetables (RR = 0.91, 95%, 0.85-0.98), allium vegetables (RR = 0.79, 95% CI 0.64-0.96), fiber (RR = 0.89, 95% CI 0.81-0.98), flavonoids (RR = 0.83, 95% CI 0.78-0.89) and green tea (RR = 0.61, 95% CI 0.49-0.76) intake could significantly reduce ovarian cancer risk. Total fat (RR = 1.10, 95% CI 1.02-1.18), saturated fat (RR = 1.11, 95% CI 1.01-1.22), saturated fatty acid (RR = 1.19, 95% CI 1.04-1.36), cholesterol (RR = 1.13, 95% CI 1.04-1.22) and retinol (RR = 1.14, 95% CI 1.00-1.30) intake could significantly increase ovarian cancer risk. In addition, acrylamide, nitrate, water disinfectants and polychlorinated biphenyls were significantly associated with an increased risk of ovarian cancer. CONCLUSION These results could support recommendations to green leafy vegetables, allium vegetables, fiber, flavonoids and green tea intake for ovarian cancer prevention.
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Affiliation(s)
- Alireza Khodavandi
- Department of Biology, Gachsaran Branch, Islamic Azad University, Gachsaran, Iran
| | - Fahimeh Alizadeh
- Department of Microbiology, Yasooj Branch, Islamic Azad University, Yasooj, Iran
| | - Ahmad Faizal Abdull Razis
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia. .,Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia. .,Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
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Nagaprashantha LD, Singhal J, Chikara S, Gugiu G, Horne D, Awasthi S, Salgia R, Singhal SS. 2′-Hydroxyflavanone induced changes in the proteomic profile of breast cancer cells. J Proteomics 2019; 192:233-245. [DOI: 10.1016/j.jprot.2018.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 09/03/2018] [Accepted: 09/10/2018] [Indexed: 12/12/2022]
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Kirsanov KI, Vlasova OA, Fetisov TI, Zenkov RG, Lesovaya EA, Belitsky GA, Gurova K, Yakubovskaya MG. Influence of DNA-binding compounds with cancer preventive activity on the mechanisms of gene expression regulation. ADVANCES IN MOLECULAR ONCOLOGY 2019. [DOI: 10.17650/2313-805x-2018-5-4-41-63] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- K. I. Kirsanov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; Peoples’ Friendship University of Russia
| | - O. A. Vlasova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - T. I. Fetisov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - R. G. Zenkov
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - E. A. Lesovaya
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia; I.P. Pavlov Ryazan State Medical University
| | - G. A. Belitsky
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | | | - M. G. Yakubovskaya
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
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14
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Tan YQ, Chiu-Leung LC, Lin SM, Leung LK. The citrus flavonone hesperetin attenuates the nuclear translocation of aryl hydrocarbon receptor. Comp Biochem Physiol C Toxicol Pharmacol 2018; 210:57-64. [PMID: 29763690 DOI: 10.1016/j.cbpc.2018.05.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 05/03/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023]
Abstract
The environmental polycyclic aromatic hydrocarbons (PAH) and dioxins are carcinogens and their adverse effects have been largely attributed to the activation of AhR. Hesperetin is a flavonone found abundantly in citrus fruits and has been shown to be a biologically active agent. In the present study, the effect of hesperetin on the nuclear translocation of AhR and the downstream gene expression was investigated in MCF-7 cells. Confocal microscopy indicated that 7, 12-dimethylbenz[α]anthracene (DMBA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) -induced nuclear translocation of AhR was deterred by hesperetin treatment. The reduced nuclear translocation could also be observed in Western analysis. Reporter-gene assay further illustrated that the induced XRE transactivation was weakened by the treatment of hesperetin. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay demonstrated that the gene expressions of CYP1A1, 1A2, and 1B1 followed the same pattern of AhR translocation. These results suggested that hesperetin counteracted AhR transactivation and suppressed the downstream gene expression.
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MESH Headings
- 9,10-Dimethyl-1,2-benzanthracene/antagonists & inhibitors
- 9,10-Dimethyl-1,2-benzanthracene/toxicity
- Active Transport, Cell Nucleus/drug effects
- Antineoplastic Agents, Phytogenic/metabolism
- Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Breast Neoplasms/chemically induced
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Breast Neoplasms/prevention & control
- Carcinogens, Environmental/chemistry
- Carcinogens, Environmental/toxicity
- Cytochrome P-450 CYP1A1/antagonists & inhibitors
- Cytochrome P-450 CYP1A1/chemistry
- Cytochrome P-450 CYP1A1/genetics
- Cytochrome P-450 CYP1A1/metabolism
- Cytochrome P-450 CYP1A2/chemistry
- Cytochrome P-450 CYP1A2/genetics
- Cytochrome P-450 CYP1A2/metabolism
- Cytochrome P-450 CYP1B1/antagonists & inhibitors
- Cytochrome P-450 CYP1B1/chemistry
- Cytochrome P-450 CYP1B1/genetics
- Cytochrome P-450 CYP1B1/metabolism
- Dietary Supplements
- Down-Regulation
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Genes, Reporter/drug effects
- Hesperidin/metabolism
- Humans
- MCF-7 Cells
- Microscopy, Confocal
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Polychlorinated Dibenzodioxins/antagonists & inhibitors
- Polychlorinated Dibenzodioxins/chemistry
- Receptors, Aryl Hydrocarbon/antagonists & inhibitors
- Receptors, Aryl Hydrocarbon/metabolism
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Affiliation(s)
- Yan Qin Tan
- Food and Nutritional Sciences Programme, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
| | | | - Shu-Mei Lin
- Department of Food Science, National Chiayi University, Chiayi City, Taiwan
| | - Lai K Leung
- Food and Nutritional Sciences Programme, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
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15
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Nagaprashantha LD, Singhal J, Li H, Warden C, Liu X, Horne D, Awasthi S, Salgia R, Singhal SS. 2'-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer. Oncotarget 2018; 9:18053-18068. [PMID: 29719590 PMCID: PMC5915057 DOI: 10.18632/oncotarget.24720] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 03/06/2018] [Indexed: 11/25/2022] Open
Abstract
Breast cancer (BC) is the most common cancer in women. Estrogen, epidermal growth factor receptor 2 (ERBB2, HER2), and oxidative stress represent critical mechanistic nodes associated with BC. RLIP76 is a major mercapturic acid pathway transporter whose expression is increased in BC. In the quest of a novel molecule with chemopreventive and chemotherapeutic potential, we evaluated the effects of 2'-Hydroxyflavanone (2HF) in BC. 2HF enhanced the inhibitory effects of RLIP76 depletion and also inhibited RLIP76-mediated doxorubicin transport in BC cells. RNA-sequencing revealed that 2HF induces strong reversal of the gene expression pattern in ER+MCF7, HER2+ SKBR3 and triple-negative MDA-MB-231 BC cells with minimal effects on MCF10A normal breast epithelial cells. 2HF down regulated ERα and enhanced inhibitory effects of imatinib mesylate/Gleevec in MCF7 cells. 2HF also down regulated ERα and HER2 gene networks in MCF7 and SKBR3 cells, respectively. 2HF activated TP53 and inhibited TGFβ1 canonical pathway in MCF7 and MDA-MB-231 BC cells. 2HF also regulated the expression of a number of critical prognostic genes of MammaPrint panel and their upstream targets including TP53, CDKN2A and MYC. The collective findings from this study provide a comprehensive, direct and integrated evidence for the benefits of 2HF in targeting major and clinically relevant mechanistic regulators of BC.
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Affiliation(s)
- Lokesh Dalasanur Nagaprashantha
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Jyotsana Singhal
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA.,Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Hongzhi Li
- Department of Computational Therapeutics, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Charles Warden
- Department of Genomic Core, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Xueli Liu
- Department of Information Sciences & Biostatistics, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - David Horne
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sanjay Awasthi
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ravi Salgia
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sharad S Singhal
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
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16
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Dalasanur Nagaprashantha L, Adhikari R, Singhal J, Chikara S, Awasthi S, Horne D, Singhal SS. Translational opportunities for broad-spectrum natural phytochemicals and targeted agent combinations in breast cancer. Int J Cancer 2017; 142:658-670. [PMID: 28975625 DOI: 10.1002/ijc.31085] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 08/18/2017] [Accepted: 09/12/2017] [Indexed: 12/17/2022]
Abstract
Breast cancer (BC) prevention and therapy in the context of life-style risk factors and biological drivers is a major focus of developmental therapeutics in oncology. Obesity, alcohol, chronic estrogen signaling and smoking have distinct BC precipitating and facilitating effects that may act alone or in combination. A spectrum of signaling events including enhanced oxidative stress and changes in estrogen-receptor (ER)-dependent and -independent signaling drive the progression of BC. Breast tumors modulate ERα/ERβ ratio, upregulate proliferative pathways driven by ERα and HER2 with a parallel loss and/or downregulation of tumor suppressors such as TP53 and PTEN which together impact the efficacy of therapeutic strategies and frequently lead to emergence of drug resistance. Natural phytochemicals modulate oxidative stress, leptin, integrin, HER2, MAPK, ERK, Wnt/β-catenin and NFκB signaling along with regulating ERα and ERβ, thereby presenting unique opportunities for both primary and combinatorial interventions in BC. In this regard, this article focuses on critical analyses of the evidence from multiple studies on the efficacy of natural phytochemicals in BC. In addition, areas in which the combinations of such effective natural phytochemicals with approved and/or developing anticancer agents can be translationally beneficial are discussed to derive evidence-based inference for addressing challenges in BC control and therapy.
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Affiliation(s)
| | | | - Jyotsana Singhal
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA
| | - Shireen Chikara
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA
| | - Sanjay Awasthi
- Texas Tech University Health Sciences Center, Lubbock, TX
| | - David Horne
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA
| | - Sharad S Singhal
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA
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17
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Singhal J, Nagaprashantha L, Chikara S, Awasthi S, Horne D, Singhal SS. 2'-Hydroxyflavanone: A novel strategy for targeting breast cancer. Oncotarget 2017; 8:75025-75037. [PMID: 29088842 PMCID: PMC5650397 DOI: 10.18632/oncotarget.20499] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 07/12/2017] [Indexed: 11/25/2022] Open
Abstract
Breast cancer is the most common cancer in women that is driven by cross-talk with hormonal and cellular signaling pathways. The natural phytochemicals, due to broad-spectrum anti-inflammatory and anti-cancerous properties, present with novel opportunities for targeting breast cancer. Intake of citrus fruits is known to reduce the risk for incidence of breast cancer. Hence, we tested the efficacy of citrus flavonoid 2'-hydroxyflavanone (2HF) in breast cancer. 2HF inhibited survival, clonogenic ability, cell cycle progression and induced apoptosis in breast cancer cells. 2HF also decreased VEGF levels and inhibited migratory capacity of breast cancer cells. Administration of 2HF led to regression of triple-negative MDA-MB-231 tumors in the mice xenograft model. 2HF decreased the levels of RLIP76 both in vitro studies and in vivo MDA-MB-231 xenograft model of breast cancer. Western blot and histopathological analyses of resected tumors showed a decline in the levels of survival and proliferation markers Ki67, pAkt, survivin, and cell cycle proteins CDK4 and cyclin B1. 2HF treatment led to inhibition of angiogenesis as determined by decreased VEGF levels in vitro and angiogenesis marker CD31 in vivo. 2HF reversed the pro-/anti-apoptotic ratio of BAX/BCL-2 by decreasing anti-apoptotic protein BCL-2 and increasing pro-apoptotic proteins BAX and BIM in vivo. 2HF also decreased the mesenchymal markers vimentin and fibronectin along with causing a parallel increase in pro-differentiation protein E-cadherin. Collectively, the ability of 2HF to decrease RLIP76, VEGF and regulate critical proliferative, apoptotic and differentiation proteins together provides strong rationale to further develop 2HF based interventions for targeting breast cancer.
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Affiliation(s)
- Jyotsana Singhal
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Lokesh Nagaprashantha
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Shireen Chikara
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sanjay Awasthi
- Department of Medical Oncology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - David Horne
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sharad S. Singhal
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
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18
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Cirmi S, Ferlazzo N, Lombardo GE, Maugeri A, Calapai G, Gangemi S, Navarra M. Chemopreventive Agents and Inhibitors of Cancer Hallmarks: May Citrus Offer New Perspectives? Nutrients 2016; 8:E698. [PMID: 27827912 PMCID: PMC5133085 DOI: 10.3390/nu8110698] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 10/11/2016] [Accepted: 10/13/2016] [Indexed: 12/12/2022] Open
Abstract
Fruits and vegetables have long been recognized as potentially important in the prevention of cancer risk. Thus, scientific interest in nutrition and cancer has grown over time, as shown by increasing number of experimental studies about the relationship between diet and cancer development. This review attempts to provide an insight into the anti-cancer effects of Citrus fruits, with a focus on their bioactive compounds, elucidating the main cellular and molecular mechanisms through which they may protect against cancer. Scientific literature was selected for this review with the aim of collecting the relevant experimental evidence for the anti-cancer effects of Citrus fruits and their flavonoids. The findings discussed in this review strongly support their potential as anti-cancer agents, and may represent a scientific basis to develop nutraceuticals, food supplements, or complementary and alternative drugs in a context of a multi-target pharmacological strategy in the oncology.
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Affiliation(s)
- Santa Cirmi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98168, Italy.
| | - Nadia Ferlazzo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98168, Italy.
| | - Giovanni E Lombardo
- Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro I-88100, Italy.
| | - Alessandro Maugeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98168, Italy.
| | - Gioacchino Calapai
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina I-98125, Italy.
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, University of Messina, Messina I-98125, Italy.
- Institute of Applied Sciences and Intelligent Systems (ISASI), National Research Council (CNR), Pozzuoli I-80078, Italy.
| | - Michele Navarra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98168, Italy.
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19
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Dourado GKZS, Stanilka JM, Percival SS, Cesar TB. Chemopreventive Actions of Blond and Red-Fleshed Sweet Orange Juice on the Loucy Leukemia Cell Line. Asian Pac J Cancer Prev 2016; 16:6491-9. [PMID: 26434864 DOI: 10.7314/apjcp.2015.16.15.6491] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Red-fleshed sweet orange juice (ROJ) comes from a new variety of citrus cultivated in Brazil that contains high levels of β-carotene and lycopene, and similar amounts of hesperidin (HSP) and nutrients, equivalently to blond orange juice (BOJ). Such bioactive compounds are associated with chemopreventive actions in several cancer cell lines. The purpose of this study was to examine the cytotoxicity, cell cycle, apoptosis, and cytokine secretion after BOJ, ROJ, and HSP treatment of a novel T acute lymphoblastic leukemia cell line, Loucy. MATERIALS AND METHODS Loucy cells were incubated for 24-h with BOJ, ROJ, and HSP, and the viability was measured using trypan blue. Cell cycling and apoptosis were assessed by propidium iodide (PI) and annexin V-FITC/PI flow cytometry, respectively. Secretion of cytokines IL-1α, IL1-β, IL-2, IL-4, IL-6, IL-10, IL-17A, IFNγ, TNFα, TGFβ, MIPα, and MIPβ was determined by ELISA array. RESULTS BOJ and ROJ treatments promoted Loucy cell cytotoxicity. Additionally, BOJ induced cell cycle arrest in the G0/G1 phase, and decreased the cell accumulation in the G2/M. ROJ decreased only the G0/G1 fraction, while HSP did not change the cell cycle. BOJ led to apoptosis in a different fashion of ROJ, while the first treatment induced apoptosis by increase of late apoptosis and primary necrotic fractions, the second increased early and late apoptosis, and primary necrotic fraction compared to positive controls. HSP had no effect on apoptosis. IL-6 and IL-10 were abrogated by all treatments. CONCLUSIONS Taking together, these results suggest potential chemopreventive effects of BOJ and ROJ on Loucy cells.
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Affiliation(s)
- Grace K Z S Dourado
- Food and Nutrition, Pharmaceutical School, Universidade Estadual Paulista, Araraquara, Brazil E-mail :
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20
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Granchi C, Fortunato S, Minutolo F. Anticancer agents interacting with membrane glucose transporters. MEDCHEMCOMM 2016; 7:1716-1729. [PMID: 28042452 DOI: 10.1039/c6md00287k] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The altered metabolism observed in cancer cells generally consists in increased glucose uptake and glycolytic activity. This is associated with an overexpression of glucose transporter proteins (GLUTs), which facilitate glucose uptake across the plasma membrane and play a crucial role in the survival of cancer cells. Therefore GLUTs are considered as suitable targets for the treatment of cancer. Herein we review some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents.
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Affiliation(s)
- C Granchi
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
| | - S Fortunato
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
| | - F Minutolo
- Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
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21
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Razavi-Azarkhiavi K, Iranshahy M, Sahebkar A, Shirani K, Karimi G. The Protective Role of Phenolic Compounds Against Doxorubicin-induced Cardiotoxicity: A Comprehensive Review. Nutr Cancer 2016; 68:892-917. [PMID: 27341037 DOI: 10.1080/01635581.2016.1187280] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Although doxorubicin (DOX) is among the most widely used anticancer agents, its clinical application is hampered owing to its cardiotoxicity. Adjuvant therapy with an antioxidant has been suggested as a promising strategy to reduce DOX-induced adverse effects. In this context, many phenolic compounds have been reported to protect against DOX-induced cardiotoxicity. The cardioprotective effects of phenolic compounds are exerted via multiple mechanisms including inhibition of reactive oxygen species generation, apoptosis, NF-κB, p53, mitochondrial dysfunction, and DNA damage. In this review, we present a summary of the in vitro, in vivo, and clinical findings on the protective mechanisms of phenolic compounds against DOX-induced cardiotoxicity.
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Affiliation(s)
- Kamal Razavi-Azarkhiavi
- a Department of Pharmacodynamy and Toxicology , Faculty of Pharmacy, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Milad Iranshahy
- b Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Amirhossein Sahebkar
- c Biotechnology Research Center, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Kobra Shirani
- d Department of Pharmacodynamy and Toxicology , Faculty of Pharmacy, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Gholamreza Karimi
- e Department of Pharmacodynamy and Toxicology , Faculty of Pharmacy, Mashhad University of Medical Sciences , Mashhad , Iran.,f Pharmaceutical Research Center and Pharmacy School, Mashhad University of Medical Sciences
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22
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Chattopadhyay D, Sen S, Chatterjee R, Roy D, James J, Thirumurugan K. Context- and dose-dependent modulatory effects of naringenin on survival and development of Drosophila melanogaster. Biogerontology 2015; 17:383-93. [PMID: 26520643 DOI: 10.1007/s10522-015-9624-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 10/28/2015] [Indexed: 12/19/2022]
Abstract
Naringenin, the predominant bioflavonoid found in grapefruit and tomato has diverse bioactive properties that encompass anti-carcinogenic, anti-inflammatory, anti-atherogenic, anti-estrogenic, anti-hyperlipidemic and anti-hyperglycemic characteristics. Naringenin has not been explored for its pro-longevity traits in fruit flies. Therefore, the current study explores its influence on longevity, fecundity, feeding rate, larval development, resistance to starvation stress and body weight in male and female wild-type Drosophila melanogaster Canton-S flies. Flies were fed with normal and high fat diets respectively. The results implied hormetic effects of naringenin on longevity and development in flies. In flies fed with standard and high fat diets, lower concentrations of naringenin (200 and 400 µM) augmented mean lifespan while higher concentrations (600 and 800 µM) were consistently lethal. However, enhanced longevity seen at 400 µM of naringenin was at the expense of reduced fecundity and food intake in flies. Larvae reared on standard diet having 200 µM of naringenin exhibited elevated pupation and emergence as flies. Eclosion time was hastened in larvae reared on standard diet having 200 µM of naringenin. Female flies fed with a standard diet having 200 and 400 µM of naringenin were more resistant to starvation stress. Reduction in body weight was observed in male and female flies fed with a high fat diet supplemented with 200 and 400 µM of naringenin respectively. Collectively, the results elucidated a context- and dose-dependent hormetic efficacy of naringenin that varied with gender, diet and stage of lifecycle in flies.
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Affiliation(s)
- Debarati Chattopadhyay
- 206, Structural Biology Lab, Centre for Biomedical Research, VIT University, Vellore, Tamil Nadu, India
| | - Soumadeep Sen
- 206, Structural Biology Lab, Centre for Biomedical Research, VIT University, Vellore, Tamil Nadu, India
| | - Rishita Chatterjee
- 206, Structural Biology Lab, Centre for Biomedical Research, VIT University, Vellore, Tamil Nadu, India
| | - Debasish Roy
- 206, Structural Biology Lab, Centre for Biomedical Research, VIT University, Vellore, Tamil Nadu, India
| | - Joel James
- 206, Structural Biology Lab, Centre for Biomedical Research, VIT University, Vellore, Tamil Nadu, India
| | - Kavitha Thirumurugan
- 206, Structural Biology Lab, Centre for Biomedical Research, VIT University, Vellore, Tamil Nadu, India.
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23
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Levitsky DO, Dembitsky VM. Anti-breast Cancer Agents Derived from Plants. NATURAL PRODUCTS AND BIOPROSPECTING 2014; 5:1-16. [PMID: 25466288 PMCID: PMC4327996 DOI: 10.1007/s13659-014-0048-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 11/11/2014] [Indexed: 05/28/2023]
Abstract
Upon emergence of modern anticancer therapy, medical community is divided into two opposite camps, one of them claiming absolute necessity of using isolated or synthesized chemical compounds for efficient patient treatment and another one advocating alternative cancer therapies, in particular those based on natural sources, including extracts from plants. It seems, in reality, that the two camps are reconcilable: while natural sources, plant extracts or juices play both curative and protective role, drugs represent the ultimate possibility to inhibit or reverse tumor development. In this paper we tried to analyze anti-breast cancer potencies of quite a few extracts from different plant sources and to compare their anti-proliferative efficiency of crude extracts with actions of their purified ingredients.
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Affiliation(s)
- Dmitri O. Levitsky
- Unité Fonctionalité et Ingénierie des Protéines (UFIP), Faculté des Sciences et des Techniques, Université de Nantes/CNRS, 44322 Nantes Cedex 03, France
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24
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The inhibition of RANKL-induced osteoclastogenesis through the suppression of p38 signaling pathway by naringenin and attenuation of titanium-particle-induced osteolysis. Int J Mol Sci 2014; 15:21913-34. [PMID: 25464380 PMCID: PMC4284685 DOI: 10.3390/ijms151221913] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 10/30/2014] [Accepted: 11/24/2014] [Indexed: 12/25/2022] Open
Abstract
The aim of this study was to assess the effect of naringenin on osteoclastogenesis and titanium particle-induced osteolysis. Osteolysis from wear-induced particles and aseptic loosening are the most frequent late complications of total joint arthroplasty leading to revision of the prosthesis. Osteolysis during aseptic loosening is most likely due to increased bone resorption by osteoclasts. Through in vitro studies, we demonstrated that naringenin, a naturally occurring flavanone in grapefruit and tomatoes, exerts potent inhibitory effects on the ligand of the receptor activator of nuclear factor-κB (RANKL)-induced osteoclastogenesis and revealed that the mechanism of action of naringenin, which inhibited osteoclastogenesis by suppression of the p38 signaling pathway. Through in vivo studies, we proved that naringenin attenuated titanium particle-induced osteolysis in a mouse calvarial model. In general, we demonstrated that naringenin inhibited osteoclastogenesis via suppression of p38 signaling in vitro and attenuated titanium particle-induced osteolysis in vivo. This study also suggested that naringenin has significant potential for the treatment of osteolysis-related diseases caused by excessive osteoclast formation and activity.
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25
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Sak K. Cytotoxicity of dietary flavonoids on different human cancer types. Pharmacogn Rev 2014; 8:122-146. [PMID: 25125885 PMCID: PMC4127821 DOI: 10.4103/0973-7847.134247] [Citation(s) in RCA: 305] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Revised: 03/27/2014] [Accepted: 06/10/2014] [Indexed: 02/06/2023] Open
Abstract
Flavonoids are ubiquitous in nature. They are also in food, providing an essential link between diet and prevention of chronic diseases including cancer. Anticancer effects of these polyphenols depend on several factors: Their chemical structure and concentration, and also on the type of cancer. Malignant cells from different tissues reveal somewhat different sensitivity toward flavonoids and, therefore, the preferences of the most common dietary flavonoids to various human cancer types are analyzed in this review. While luteolin and kaempferol can be considered as promising candidate agents for treatment of gastric and ovarian cancers, respectively, apigenin, chrysin, and luteolin have good perspectives as potent antitumor agents for cervical cancer; cells from main sites of flavonoid metabolism (colon and liver) reveal rather large fluctuations in anticancer activity probably due to exposure to various metabolites with different activities. Anticancer effect of flavonoids toward blood cancer cells depend on their myeloid, lymphoid, or erythroid origin; cytotoxic effects of flavonoids on breast and prostate cancer cells are highly related to the expression of hormone receptors. Different flavonoids are often preferentially present in certain food items, and knowledge about the malignant tissue-specific anticancer effects of flavonoids could be purposely applied both in chemoprevention as well as in cancer treatment.
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Affiliation(s)
- Katrin Sak
- Non Government Organization Praeventio, Tartu, Estonia
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Park M, Kim K, Lee YM, Rhyu MR, Kim HY. Naringenin stimulates cholecystokinin secretion in STC-1 cells. Nutr Res Pract 2014; 8:146-50. [PMID: 24741397 PMCID: PMC3988502 DOI: 10.4162/nrp.2014.8.2.146] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 12/04/2013] [Accepted: 12/05/2013] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND/OBJECTIVES Cholecystokinin (CCK), a hormone or neuropeptide, is secreted in response to intraluminal nutrients by enteroendocrine I-cells of the intestine and has important physiological actions related to appetite regulation and satiety. The stimulation on CCK secretion from the intestine is of potential relevance for body weight management. Naringenin (4',5,7-trihydroxyflavanone) and its glycoside naringin (naringenin 7-rhamnoglucoside) have been reported to have many biological functions. In the current study, we investigated the question of whether naringenin and naringin could stimulate CCK secretion and then examined the mechanisms involved in CCK release. MATERIALS/METHODS STC-1 cells were used as a model of enteroendocrine cells. CCK release and changes in intracellular Ca(2+) ([Ca(2+)]i) were measured after incubation of cells with naringenin and naringin for 1 h. RESULTS Naringenin caused significant (P < 0.05) stimulation of CCK secretion, but naringin did not. In addition, regarding the secretory mechanisms, naringenin-induced CCK secretion involved increases in [Ca(2+)]i, influx of extracellular Ca(2+), at least in part, and activation of TRP channels, including TRPA1. CONCLUSION Findings of this study suggest that naringenin could have a role in appetite regulation and satiety.
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Affiliation(s)
- Min Park
- Division of Metabolism and Functionality Research, Korea Food Research Institute, 62 Road-1201 Anyang-Pangyo-Ro, Bundang, Sungnam, Gyeonggi 463-746, Korea
| | - Kyong Kim
- Division of Metabolism and Functionality Research, Korea Food Research Institute, 62 Road-1201 Anyang-Pangyo-Ro, Bundang, Sungnam, Gyeonggi 463-746, Korea
| | - Yu Mi Lee
- Division of Metabolism and Functionality Research, Korea Food Research Institute, 62 Road-1201 Anyang-Pangyo-Ro, Bundang, Sungnam, Gyeonggi 463-746, Korea
| | - Mee Ra Rhyu
- Division of Metabolism and Functionality Research, Korea Food Research Institute, 62 Road-1201 Anyang-Pangyo-Ro, Bundang, Sungnam, Gyeonggi 463-746, Korea
| | - Hye Young Kim
- Division of Metabolism and Functionality Research, Korea Food Research Institute, 62 Road-1201 Anyang-Pangyo-Ro, Bundang, Sungnam, Gyeonggi 463-746, Korea
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Madej A, Popłoński J, Huszcza E. Improved oxidation of naringenin to carthamidin and isocarthamidin by Rhodotorula marina. Appl Biochem Biotechnol 2014; 173:67-73. [PMID: 24615525 PMCID: PMC4007024 DOI: 10.1007/s12010-014-0787-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 02/10/2014] [Indexed: 01/08/2023]
Abstract
A novel single-step microbial transformation process for the efficient production of carthamidin and isocarthamidin from naringenin by yeast Rhodotorula marina in an aerated bioreactor was described. The biotransformation led to the total product concentration of 233 mg/l. The highest conversion efficiency observed for carthamidin was 0.31 mg/mg of naringenin and for isocarthamidin 0.47 mg/mg of naringenin.
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Affiliation(s)
- Anna Madej
- Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375, Wrocław, Poland
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Abstract
Food-derived flavonoid quercetin, widely distributed in onions, apples, and tea, is able to inhibit growth of various cancer cells indicating that this compound can be considered as a good candidate for anticancer therapy. Although the exact mechanism of this action is not thoroughly understood, behaving as antioxidant and/or prooxidant as well as modulating different intracellular signalling cascades may all play a certain role. Such inhibitory activity of quercetin has been shown to depend first of all on cell lines and cancer types; however, no comprehensive site-specific analysis of this effect has been published. In this review article, cytotoxicity constants of quercetin measured in various human malignant cell lines of different origin were compiled from literature and a clear cancer selective action was demonstrated. The most sensitive malignant sites for quercetin revealed to be cancers of blood, brain, lung, uterine, and salivary gland as well as melanoma whereas cytotoxic activity was higher in more aggressive cells compared to the slowly growing cells showing that the most harmful cells for the organism are probably targeted. More research is needed to overcome the issues of poor water solubility and relatively low bioavailability of quercetin as the major obstacles limiting its clinical use.
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Rech Franke SI, Guecheva TN, Henriques JAP, Prá D. Orange Juice and Cancer Chemoprevention. Nutr Cancer 2013; 65:943-53. [DOI: 10.1080/01635581.2013.817594] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Li F, Chow S, Cheung WH, Chan FL, Chen S, Leung LK. The citrus flavonone hesperetin prevents letrozole-induced bone loss in a mouse model of breast cancer. J Nutr Biochem 2013; 24:1112-6. [DOI: 10.1016/j.jnutbio.2012.08.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 08/03/2012] [Accepted: 08/13/2012] [Indexed: 11/16/2022]
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Swarnkar G, Sharan K, Siddiqui JA, Mishra JS, Khan K, Khan MP, Gupta V, Rawat P, Maurya R, Dwivedi AK, Sanyal S, Chattopadhyay N. A naturally occurring naringenin derivative exerts potent bone anabolic effects by mimicking oestrogen action on osteoblasts. Br J Pharmacol 2012; 165:1526-42. [PMID: 21864313 DOI: 10.1111/j.1476-5381.2011.01637.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Naringenin and its derivatives have been assessed in bone health for their oestrogen-'like' effects but low bioavailability impedes clinical potential. This study was aimed at finding a potent form of naringenin with osteogenic action. EXPERIMENTAL APPROACH Osteoblast cultures were harvested from mouse calvaria to study differentiation by naringenin, isosakuranetin, poncirin, phloretin and naringenin-6-C-glucoside (NCG). Balb/cByJ ovariectomized (OVx) mice without or with osteopenia were given naringenin, NCG, 17β-oestradiol (E2) or parathyroid hormone (PTH). Efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of new bone formation by fluorescent labelling of bone. Plasma levels of NCG and naringenin were determined by HPLC. KEY RESULTS NCG stimulated osteoblast differentiation more potently than naringenin, while isosakuranetin, poncirin or phloretin had no effect. NCG had better oral bioavailability than naringenin. NCG increased the mRNA levels of oestrogen receptors (ERs) and bone morphogenetic protein (an ER responsive gene) in vivo, more than naringenin. In OVx mice, NCG treatment in a preventive protocol increased bone formation rate (BFR) and improved trabecular microarchitecture more than naringenin or E2. In osteopenic mice, NCG but not naringenin, in a therapeutic protocol, increased BFR and improved trabecular microarchitecture, comparable with effects of PTH treatment. Stimulatory effects of NCG on osteoblasts were abolished by an ER antagonist. NCG transactivated ERβ but not ERα. NCG exhibited no uterine oestrogenicity unlike naringenin. CONCLUSIONS AND IMPLICATIONS NCG is a potent derivative of naringenin that has bone anabolic action through the activation of osteoblast ERs and exhibited substantial oral bioavailability.
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Affiliation(s)
- Gaurav Swarnkar
- Division of Endocrinology, CSIR-Central Drug Research Institute, Chattar Manzil, Lucknow, India
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Alshatwi AA, Ramesh E, Periasamy VS, Subash-Babu P. The apoptotic effect of hesperetin on human cervical cancer cells is mediated through cell cycle arrest, death receptor, and mitochondrial pathways. Fundam Clin Pharmacol 2012; 27:581-92. [PMID: 22913657 DOI: 10.1111/j.1472-8206.2012.01061.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2012] [Revised: 06/13/2012] [Accepted: 06/25/2012] [Indexed: 01/04/2023]
Abstract
Hesperetin, a flavonoid from citrus fruits, has several bioactivities such as anti-inflammatory, antihypertensive, antiatherogenic effects. However, studies elucidating the role and the mechanism(s) of action of hesperetin in cervical cancer are sparse. In this study, we investigated the mechanism of the antiproliferative and apoptotic actions exerted by hesperetin on human cervical cancer SiHa cells. The viability of SiHa cells was evaluated using the MTT assay, apoptosis by acridine orange/ethidium bromide, propidium iodide, TUNEL assay, and Annexin V-Cy3, cell cycle distribution and mitochondrial transmembrane potential using flow cytometry, and apoptotic marker genes using quantitative real-time PCR. The treatment of SiHa cells with hesperetin (IC50, 650 μm) showed a marked concentration- and time-dependent inhibition of proliferation and induced the G2/M phase in a dose-dependent manner after 24 h. There was an attenuation of mitochondrial membrane potential with increased expression of caspase-3, caspase-8, caspase-9, p53, Bax, and Fas death receptor and its adaptor protein Fas-associated death domain-containing protein (FADD), indicating the participation of both death receptor- and mitochondria-related mechanisms. Furthermore, hesperetin-induced apoptosis was confirmed by TUNEL and Annexin V-Cy3. This study shows that hesperetin exhibits a potential anticancer activity against human cervical cancer cell lines in vitro through the reduction in cell viability and the induction of apoptosis. Altogether, these data sustain our contention that hesperetin has anticancer properties and merits further investigation as a potential therapeutic agent.
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Affiliation(s)
- Ali A Alshatwi
- Department of Food Science and Nutrition, King Saud University, Riyadh, 11451, Saudi Arabia
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Aranganathan S, Nalini N. Antiproliferative efficacy of hesperetin (citrus flavanoid) in 1,2-dimethylhydrazine-induced colon cancer. Phytother Res 2012; 27:999-1005. [PMID: 22899565 DOI: 10.1002/ptr.4826] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2010] [Revised: 07/23/2012] [Accepted: 07/25/2012] [Indexed: 12/12/2022]
Abstract
Cancer is the second leading cause of death worldwide and is increasing at an alarming rate. The present study was to evaluate the antiproliferative effects of hesperetin, a flavonoid commonly found in many herbal medicines and foods, on aberrant crypt foci (ACF), argyrophylic nucleolar organizer regions (AgNORs) and proliferating cell nuclear antigen (PCNA) in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats. Rats were given subcutaneous injections of DMH (20 mg/kg body weight) weekly for 15 weeks to induce carcinogenesis, and hesperetin was administered orally at the dose of 20 mg/kg body weight. DMH exposure alone produced a high incidence of ACF and showed positive staining for PCNA and AgNORs in colonic tissues. Supplementation with hesperetin lowered the PCNA labeling index and suppressed the formation of ACF in the rats with colon cancer. These results clearly reveal that dietary hesperetin possesses antiproliferative ability against chemically induced colon tumourigenesis.
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Affiliation(s)
- Selvaraj Aranganathan
- Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar--608002, Tamilnadu, India
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Bayomi SM, El-Kashef HA, El-Ashmawy MB, Nasr MNA, El-Sherbeny MA, Badria FA, Abou-zeid LA, Ghaly MA, Abdel-Aziz NI. Synthesis and biological evaluation of new curcumin derivatives as antioxidant and antitumor agents. Med Chem Res 2012. [DOI: 10.1007/s00044-012-0116-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Ye L, Chan FL, Chen S, Leung LK. The citrus flavonone hesperetin inhibits growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice. J Nutr Biochem 2011; 23:1230-7. [PMID: 22209285 DOI: 10.1016/j.jnutbio.2011.07.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Revised: 06/02/2011] [Accepted: 07/12/2011] [Indexed: 11/16/2022]
Abstract
Aromatase is responsible for the rate-determining reaction in estrogen synthesis and is a prime target for treating estrogen-receptor-positive breast cancer. Previous in vitro study has demonstrated that apigenin (APG), naringenin (NGN) and hesperetin (HSP) are three of the most potent natural aromatase inhibitors. Because the enzyme inhibition could potentially block breast cancer development, we employed an established postmenopausal breast cancer model to examine the chemopreventive effect of these flavonoids in vivo. Athymic mice were ovariectomized and transplanted with aromatase-overexpressing MCF-7 cells. Dietary administration of HSP at 1000 ppm and 5000 ppm significantly deterred the xenograft growth, while a null effect was observed in mice treated with APG or NGN. Further study illustrated that plasma estrogen in HSP-treated mice was reduced. Messenger RNA expression of the estrogen-responsive gene pS2 was also decreased in the tumors of mice treated with 1000 and 5000 ppm HSP. On the other hand, western analysis indicated that cyclin D1, CDK4 and Bcl-x(L) were reduced in the tumors. This study suggested that HSP could be a potential chemopreventive agent against breast carcinogenesis through aromatase inhibition.
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Affiliation(s)
- Lan Ye
- Biochemistry Programme, School of Life Sciences, Faculty of Science, the Chinese University of Hong Kong
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36
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Wise LA, Radin RG, Palmer JR, Kumanyika SK, Boggs DA, Rosenberg L. Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata. Am J Clin Nutr 2011; 94:1620-31. [PMID: 22071705 PMCID: PMC3252555 DOI: 10.3945/ajcn.111.016600] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Accepted: 09/19/2011] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND US black women have higher rates of uterine leiomyomata (UL) and lower intakes of fruit and vegetables than do white women. Whether fruit and vegetable intake is associated with UL in black women has not been studied. OBJECTIVE We assessed the association of dietary intake of fruit, vegetables, carotenoids, folate, fiber, and vitamins A, C, and E with UL in the Black Women's Health Study. DESIGN In this prospective cohort study, we followed 22,583 premenopausal women for incident UL (1997-2009). Diet was estimated by using food-frequency questionnaires in 1995 and 2001. Cox regression was used to derive incidence rate ratios (IRRs) and 95% CIs for the association between each dietary variable (in quintiles) and UL. RESULTS There were 6627 incident cases of UL diagnosed by ultrasonography (n = 4346) or surgery (n = 2281). Fruit and vegetable intake was inversely associated with UL (≥4 compared with <1 serving/d; IRR: 0.90; 95% CI: 0.82, 0.98; P-trend = 0.03). The association was stronger for fruit (≥2 servings/d compared with <2 servings/wk; IRR: 0.89; 95% CI: 0.81, 0.98; P-trend = 0.07) than for vegetables (≥2 servings/d compared with <4 servings/wk: IRR: 0.97; 95% CI: 0.89, 1.05; P-trend = 0.51). Citrus fruit intake was inversely associated with UL (≥3 servings/wk compared with <1 serving/mo: IRR: 0.92; 95% CI: 0.86, 1.00; P-trend = 0.01). The inverse association for dietary vitamin A (upper compared with lower quintiles: IRR: 0.89; 95% CI: 0.83, 0.97; P-trend = 0.01) appeared to be driven by preformed vitamin A (animal sources), not provitamin A (fruit and vegetable sources). UL was not materially associated with dietary intake of vitamins C and E, folate, fiber, or any of the carotenoids, including lycopene. CONCLUSION These data suggest a reduced risk of UL among women with a greater dietary intake of fruit and preformed vitamin A.
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Affiliation(s)
- Lauren A Wise
- Slone Epidemiology Center at Boston University, MA 02215, USA.
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Shiromwar SS, Chidrawar VR. Combined effects of p-coumaric acid and naringenin against doxorubicin-induced cardiotoxicity in rats. Pharmacognosy Res 2011; 3:214-9. [PMID: 22022172 PMCID: PMC3193624 DOI: 10.4103/0974-8490.85012] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Revised: 04/18/2011] [Accepted: 09/16/2011] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Doxorubicin (DOX) is the most active cytotoxic agents having efficacy in malignancies either alone or combined with other cytocidal agents. The clinical usefulness of the anthracycline drug has been precluded by cardiac toxicity. Many therapeutic interventions have been attempted to improve the therapeutic benefits of the drug. This study is based on the possible protective effects of combination of p-coumaric acid (PC) and naringenin (NR) on DOX induced cardiac toxicity in male Swiss albino rats. METHODS Total nine groups of Swiss albino rats were used, Group I (vehicle control) receive saline solution daily and Group II (disease control) receive saline solution daily up to 29(th) day and at 30(th) day a single dose of DOX (15 mg/kg i.p.) is given. PC alone (100 mg/kg/day p.o.) and (200 mg/kg/day p.o.) also NR alone (15 mg/kg/day) orally administer for 30 days. Similarly a standard drug Vit. E (100 mg/kg/day) administers alone for 30 days. Group PC/DOX and PC and NR/DOX receive PC (200 mg/kg/day) and combine PC (200 mg/kg/day). RESULTS Doxorubicin induced marked biochemical alterations characteristic of cardiac toxicity including increase in MDA level and decrease SOD, CAT & GSH level but prior administration of combination of PC & NR ahead of doxorubicin challenge ameliorated all these biochemical markers. CONCLUSION The study proves the beneficial effects of combination of PC and NR in protecting animal against DOX induced cardiotoxicity.
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Affiliation(s)
- Shruti S. Shiromwar
- Department of Pharmacology, Sudhakarrao Naik Institute of Pharmacy, Pusad, Yavatmal, Maharashtra, India
| | - Vijay R. Chidrawar
- Department of Pharmacology, Shree H. N. Shukla Institute of Pharmaceutical Education and Research, Rajkot, Gujarat, India
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Chidambara Murthy KN, Jayaprakasha GK, Patil BS. Apoptosis mediated cytotoxicity of citrus obacunone in human pancreatic cancer cells. Toxicol In Vitro 2011; 25:859-67. [DOI: 10.1016/j.tiv.2011.02.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Revised: 01/30/2011] [Accepted: 02/12/2011] [Indexed: 01/11/2023]
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Cardioprotective Effects of Hesperetin against Doxorubicin-Induced Oxidative Stress and DNA Damage in Rat. Cardiovasc Toxicol 2011; 11:215-25. [DOI: 10.1007/s12012-011-9114-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Hesperetin protects testicular toxicity of doxorubicin in rat: Role of NFκB, p38 and caspase-3. Food Chem Toxicol 2011; 49:838-47. [DOI: 10.1016/j.fct.2010.12.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Revised: 11/17/2010] [Accepted: 12/03/2010] [Indexed: 11/19/2022]
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Adepoju GKA, Adeyemi T. Evaluation of the effect of lime fruit juice on the anticoagulant effect of warfarin. J Young Pharm 2010; 2:269-72. [PMID: 21042484 PMCID: PMC2964779 DOI: 10.4103/0975-1483.66808] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
AIM Citrus aurantifolia (Family Rutaceae) is commonly known as a familiar food and medicine, and s therapeutic effectiveness in a variety of diseases has been suggested in traditional medicine. Various complementary and alternative medicines (CAM) have been shown to interact with orthodox medicines. Hence, the aim of this study is to investigate such a phenomenon particularly the interaction of lime fruit juice with warfarin. MATERIALS AND METHOD Wistar strain albino rats of both sexes weighing between 190 and 230g were administered with oral doses of the respective drugs used depending on the groups of animals. Effects on the anticoagulant activity of warfarin were determined by standard laboratory methods. RESULT Lime fruit juice caused a reduction in the anticoagulant activity of warfarin. CONCLUSION This finding has shown that CAM can interact with orthodox medicines hence, warfarin prescribers need to be aware of the usage of CAM and monitor the international normalized ratio (INR) of their patients more frequently.
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Affiliation(s)
- GKA Adepoju
- Department of Clinical Pharmacy and Biopharmacy, Faculty of Pharmacy, Olabisi Onabanjo University, Sagamu, Ogun State, Nigeria
| | - T Adeyemi
- Department of Clinical Pharmacy and Biopharmacy, Faculty of Pharmacy, Olabisi Onabanjo University, Sagamu, Ogun State, Nigeria
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Zygmunt K, Faubert B, MacNeil J, Tsiani E. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochem Biophys Res Commun 2010; 398:178-83. [PMID: 20558145 DOI: 10.1016/j.bbrc.2010.06.048] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2010] [Accepted: 06/10/2010] [Indexed: 11/25/2022]
Abstract
Naringenin, a flavonoid found in high concentrations in grapefruit, has been reported to have antioxidant, antiatherogenic, and anticancer effects. Effects on lipid and glucose metabolism have also been reported. Naringenin is structurally similar to the polyphenol resveratrol, that has been reported to activate the SIRT1 protein deacetylase and to have antidiabetic properties. In the present study we examined the direct effects of naringenin on skeletal muscle glucose uptake and investigated the mechanism involved. Naringenin stimulated glucose uptake in L6 myotubes in a dose- and time-dependent manner. Maximum stimulation was seen with 75 microM naringenin for 2 h (192.8+/-24%, p<0.01), a response comparable to maximum insulin response (190.1+/-13%, p<0.001). Similar to insulin, naringenin did not increase glucose uptake in myoblasts indicating that GLUT4 glucose transporters may be involved in the naringenin-stimulated glucose uptake. In addition, naringenin did not have a significant effect on basal or insulin-stimulated Akt phosphorylation while significantly increased AMPK phosphorylation/activation. Furthermore, silencing of AMPK, using siRNA approach, abolished the naringenin-stimulated glucose uptake. The SIRT1 inhibitors nicotinamide and EX527 did not have an effect on naringenin-stimulated AMPK phosphorylation and glucose uptake. Our data show that naringenin increases glucose uptake by skeletal muscle cells in an AMPK-dependent manner.
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Affiliation(s)
- Katarzyna Zygmunt
- Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada L2S 3A1
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Brett GM, Hollands W, Needs PW, Teucher B, Dainty JR, Davis BD, Brodbelt JS, Kroon PA. Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion. Br J Nutr 2009; 101:664-75. [PMID: 18710603 PMCID: PMC3508427 DOI: 10.1017/s000711450803081x] [Citation(s) in RCA: 113] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Oranges are rich sources of flavonoids that are bioactive and may protect against age-related diseases. The absorption of orange flavanones may be affected by factors such as processing and subject anthropometric variables, and the bioactivity of the absorbed phytochemicals depends on how they are metabolised during absorption. In a randomised cross-over study, twenty subjects consumed a single portion of orange fruit (150 g) or juice (300 g) that contained the flavanones narirutin and hesperidin, and an additional 109 subjects across a broad age range (18-80 years) consumed the juice. Flavanone metabolites were measured in regularly collected samples of plasma and urine. After consumption of fruit or juice, flavanone conjugates, but not the aglycones, were detected in plasma and urine. The flavanone conjugates were shown to include the 7- and 4'-O-monoglucuronides of naringenin, the 7- and 3'-O-monoglucuronides of hesperetin, two hesperetin diglucuronides and a hesperetin sulfo-glucuronide, but no aglycones or rutinosides. Analysis of the plasma pharmacokinetic and urinary excretion data on a dose-adjusted basis indicated no difference in absorption or excretion of either flavanone between the fruit and juice matrices. In the extended urinary excretion dataset the individual variation was very large (range 0-59 % urinary yield). There was a small but significant (P < 0.05) decrease in the excretion of hesperetin (but not naringenin) with increasing age (P < 0.05), but the effects of sex, BMI and contraceptive pill use were shown not to be associated with the variation in flavanone excretion.
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Affiliation(s)
- Gary M. Brett
- Institute of Food Research, Colney Lane, Norwich, Norfolk NR4 7UA, UK
| | - Wendy Hollands
- Institute of Food Research, Colney Lane, Norwich, Norfolk NR4 7UA, UK
| | - Paul W. Needs
- Institute of Food Research, Colney Lane, Norwich, Norfolk NR4 7UA, UK
| | - Birgit Teucher
- Institute of Food Research, Colney Lane, Norwich, Norfolk NR4 7UA, UK
- Elsie Widdowson Laboratory, MRC Human Nutrition Research, Fulbourn Road, Cambridge CB1 9NL, UK
| | - Jack R. Dainty
- Institute of Food Research, Colney Lane, Norwich, Norfolk NR4 7UA, UK
| | - Barry D. Davis
- Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
| | - Jennifer S. Brodbelt
- Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
| | - Paul A. Kroon
- Institute of Food Research, Colney Lane, Norwich, Norfolk NR4 7UA, UK
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Dwyer J, Peterson J, Winters B, Liu W, Mitchell DC, Atkinson K. Do flavonoid intakes of postmenopausal women with breast cancer vary on very low fat diets? Nutr Cancer 2008; 60:450-60. [PMID: 18584478 DOI: 10.1080/01635580802143828] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
In the Women's Intervention Nutrition Study (WINS), a very low-fat eating pattern decreased breast cancer recurrence. We assessed whether the women's flavonoid intakes varied on the very low fat diet. A total of 550 randomly selected WINS participants who had been treated with conventional therapy (surgery, chemotherapy, and/or radiation) for primary breast cancer were randomized to either a very low fat diet (15% of calories from fat, N = 218) or their usual diets (30% calories from fat, N = 332). We compared their intakes of total flavonoids and 6 flavonoid classes (isoflavones, flavones, flavanones, flavonols, flavan-3-ols, and anthocyanins) for these 2 groups using the U.S. Department of Agriculture food flavonoid database and a flavonoid dietary supplement database on three 24-h dietary recalls at baseline and 12 mo after randomization. At baseline, neither mean fat intakes (31.7% +/- 6.8 SD of calories, n = 332 in the usual diet group and 31.6% +/- 6.8 SD of calories, n = 218 in the very low fat diet group; P = NS) nor flavonoid intakes (218 +/- 283 SD mg/day, n = 332 in the usual diet group and 236 +/- 393 SD mg/day, n = 218 in the very low fat diet group; P = NS) differed. Over half of the women's flavonoid intakes were from the flavan-3-ols. After 12 months of intervention, with 39 participants lost to follow-up, dietary fat intakes were 30.7 +/- 8.4 SD calories (n = 316) among those on their usual diets but were significantly lower among those on the very low fat diet intervention: 21.4 +/- 8.3 SD calories (n = 195), P = <0.05. However, flavonoid intakes remained similar in both groups (201 +/- 252 SD mg/day, n = 316 in the usual diet group vs. 235 +/- 425 SD mg/day, n = 195 in the very low fat group; P = NS). In this random sample of WINS participants, neither total flavonoid intakes nor intakes of subclasses of flavonoids differed between those who had dramatically decreased their fat intakes and those who had not. Flavonoid intakes are therefore unlikely to account for WINS results on differences between the groups in cancer recurrence.
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Affiliation(s)
- Johanna Dwyer
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts 02111, USA.
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Impact of naringenin on glycoprotein levels in N-methyl-N′-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats. Anticancer Drugs 2008; 19:885-90. [DOI: 10.1097/cad.0b013e32830ea1bc] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Antioxidant capacity of pummelo and navel oranges: Extraction efficiency of solvents in sequence. Lebensm Wiss Technol 2008. [DOI: 10.1016/j.lwt.2007.03.017] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Kiani J, Imam SZ. Medicinal importance of grapefruit juice and its interaction with various drugs. Nutr J 2007; 6:33. [PMID: 17971226 PMCID: PMC2147024 DOI: 10.1186/1475-2891-6-33] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2007] [Accepted: 10/30/2007] [Indexed: 02/07/2023] Open
Abstract
Grapefruit juice is consumed widely in today's health conscious world as a protector against cardiovascular diseases and cancers. It has however, been found to be an inhibitor of the intestinal cytochrome P - 450 3A4 system, which is responsible for the first pass metabolism of many drugs. The P - glycoprotein pump, found in the brush border of the intestinal wall which transports many of these cytochrome P - 450 3A4 substrates, has also been implicated to be inhibited by grapefruit juice. By inhibiting these enzyme systems, grapefruit juice alters the pharmacokinetics of a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on the calcium channel antagonist and the statin group of drugs. In the case of many drugs, the increased serum concentration has been found to be associated with increased frequency of dose dependent adverse effects. In this review, we have discussed the phytochemistry of grapefruit juice, the various drugs involved in the drug - grapefruit juice reaction with their mechanisms of action and have presented the clinical implications of these interactions.
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Affiliation(s)
- Jawad Kiani
- Medical College, Aga Khan University, Stadium Road, Karachi, Pakistan.
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Choi EJ. Hesperetin Induced G1-Phase Cell Cycle Arrest in Human Breast Cancer MCF-7 Cells: Involvement of CDK4 and p21. Nutr Cancer 2007; 59:115-9. [DOI: 10.1080/01635580701419030] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Camarda L, Di Stefano V, Del Bosco SF, Schillaci D. Antiproliferative activity of Citrus juices and HPLC evaluation of their flavonoid composition. Fitoterapia 2007; 78:426-9. [PMID: 17628348 DOI: 10.1016/j.fitote.2007.02.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2006] [Accepted: 02/28/2007] [Indexed: 11/24/2022]
Abstract
The antiproliferative activity of fresh fruit juices extracted from Citrus sinensis (cv. Washington Navel and cv. Sanguinello), C. deliciosa cv. Avana, C. clementina cv. Nules, C. aurantium subsp. myrtifolia , was evaluated against K562 (human chronic myelogenous leukemia), HL-60 (human leukemia) and MCF-7 (human breast adenocarcinoma) cell lines. All the juices tested showed antiproliferative activity. Moreover, the pattern of the main flavanone compounds in the juices has been determined by HPLC analysis.
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Affiliation(s)
- Lorenzo Camarda
- Dipartimento di Chimica e Tecnologie Farmaceutiche, Università degli Studi di Palermo, via Archirafi 32, 90123, Palermo, Italy.
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