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Fu L, Zhao L, Li F, Wen F, Zhang P, Yang X, Wang Y. Pharmacological mechanism of quercetin in the treatment of colorectal cancer by network pharmacology and molecular simulation. J Biomol Struct Dyn 2024; 42:7065-7076. [PMID: 37464874 DOI: 10.1080/07391102.2023.2235589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 07/06/2023] [Indexed: 07/20/2023]
Abstract
Colorectal cancer is a serious threat to people's life due to its high incidence and high mortality. Quercetin can effectively treat colorectal carcinoma (CRC), but its exact mechanism of action is still unclear. Then quercetin-related target genes were obtained from Swiss Target Prediction database and Similarity Ensemble Approach (SEA) database, and CRC-related target genes were obtained from GeneCards database, respectively. Common target genes were obtained by FunRich software. String software was used to construct a protein-protein interaction (PPI) network. R package was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking, molecular dynamics (MD) simulation and post-dynamics simulation were used to explore the binding stability of quercetin to key targets. In total, 103 and 141 target information of quercetin were obtained from the Swiss Target Prediction database and SEA database, respectively. 1,649 CRC-related genes were obtained from GeneCards database. FunRich software was used to draw venny map and obtain 36 intersection targets of quercetin and CRC. String software was used to construct the PPI network. The core genes were AKT1, EGFR, MMP9, KDR, MET and PTK2. There were 532 items related to biological processes, 14 items related to cellular components, and 43 items related to molecular functions among the key target GO enrichment items. KEGG enrichment pathways of key targets involved cancer pathways, PI3K-Akt signal pathway, etc. The results of molecular docking, MD simulation and post-dynamics simulation showed they had a good affinity and formed a stable effect. So quercetin may play an important role in the treatment of CRC by acting on AKT1, EGFR, MMP9, KDR, MET and PTK2 to affect the development of CRC.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Le Fu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing University Qianjiang Hospital (Qianjiang Central Hospital of Chongqing), Chongqing, China
| | - Linan Zhao
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
- Chongqing University Qianjiang Hospital (Qianjiang Central Hospital of Chongqing), Chongqing, China
| | - Fei Li
- Chongqing University Qianjiang Hospital (Qianjiang Central Hospital of Chongqing), Chongqing, China
| | - Feng Wen
- Chongqing University Qianjiang Hospital (Qianjiang Central Hospital of Chongqing), Chongqing, China
| | - Peng Zhang
- Chongqing University Qianjiang Hospital (Qianjiang Central Hospital of Chongqing), Chongqing, China
| | - Xia Yang
- Chongqing University Qianjiang Hospital (Qianjiang Central Hospital of Chongqing), Chongqing, China
| | - Yuanqiang Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
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2
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Calabrese EJ, Hayes AW, Pressman P, Dhawan G, Kapoor R, Agathokleous E, Calabrese V. Quercetin induces its chemoprotective effects via hormesis. Food Chem Toxicol 2024; 184:114419. [PMID: 38142767 DOI: 10.1016/j.fct.2023.114419] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/20/2023] [Accepted: 12/20/2023] [Indexed: 12/26/2023]
Abstract
Quercetin is a polyphenol present in numerous fruits and vegetables and therefore widely consumed by humans with average daily dietary intakes of 10-20 mg/day. It is also a popular dietary supplement of 250-1000 mg/day. However, despite the widespread consumer interest in quercetin, due to its possible chemopreventive properties, the extensively studied quercetin presents a highly diverse and complex array of biological effects. Consequently, the present paper provides the first assessment of quercetin-induced hormetic concentration/dose responses, their quantitative features and mechanistic foundations, and their biological, biomedical, clinical, and public health implications. The findings indicate that quercetin-induced hormetic dose responses are widespread, being independent of biological model, cell type, and endpoint. These findings have the potential to enlighten future experimental studies with quercetin especially with respect to study design parameters and may also affect the appraisal of possible public health benefits and risks associated with highly diverse consumer consumption practices.
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Affiliation(s)
- Edward J Calabrese
- School of Public Health and Health Sciences, Department of Environmental Health, Morrill I-N344, University of Massachusetts, Amherst, MA, 01003, USA.
| | - A Wallace Hayes
- Center for Environmental Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL, USA.
| | - Peter Pressman
- University of Maine, 5728 Fernald Hall, Room 201, Orono, ME, 04469, USA.
| | - Gaurav Dhawan
- Sri Guru Ram Das (SGRD), University of Health Sciences, Amritsar, India.
| | - Rachna Kapoor
- Saint Francis Hospital and Medical Center, Hartford, CT, USA.
| | - Evgenios Agathokleous
- School of Ecology and Applied Meteorology, Nanjing University of Information Science & Technology, Nanjing, 210044, China.
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, School of Medicine University of Catania, Via Santa Sofia 97, Catania, 95123, Italy.
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3
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Dubey N, Dubey N, Bhadoria U, Shah K, Chauhan NS. Targeting colorectal cancer using dietary flavonols. CANCER INNOVATION 2024; 3:e99. [PMID: 38948535 PMCID: PMC11212334 DOI: 10.1002/cai2.99] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 08/25/2023] [Accepted: 09/03/2023] [Indexed: 07/02/2024]
Abstract
Colorectal cancer is among the well-known forms of cancer and a prominent cause of cancer demises worldwide. In vitro experiments reinforced by animal studies, as well as epidemiological studies of human colorectal cancer propose that the growth of this disease can be moderated by eating aspects. Dietary intake including green vegetables and fruits may result in the reduction of colon cancer chances. The finding suggests that the combinations of dietary nutrients may deliver additive or synergistic effects and might be a powerful method to avoid or eradicate colon cancer beginning and/or development. Flavonols are one of the most widespread dietary nutrients of the polyphenols-flavonoids and major constituent of Allium and Brassicaceae vegetables. Flavonols present in vegetables of Allium and Brassicaceae family are kaempferol, myricetin, quercetin, and isorhamnetin. These flavonols are claimed to have antiproliferative activity in vivo and in vitro against colorectal cancer. The objective of this review is to summarize the role of flavonols obtained from dietary sources in the prevention and treatment of colorectal cancer.
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Affiliation(s)
- Nitin Dubey
- IPS Academy College of PharmacyIndoreMadhya PradeshIndia
| | - Nidhi Dubey
- School of PharmacyDevi Ahilya VishwavidyalayaIndoreMadhya PradeshIndia
| | | | - Kamal Shah
- Institute of Pharmaceutical ResearchGLA UniversityMathuraUttar PradeshIndia
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4
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Parekh N, Garg A, Choudhary R, Gupta M, Kaur G, Ramniwas S, Shahwan M, Tuli HS, Sethi G. The Role of Natural Flavonoids as Telomerase Inhibitors in Suppressing Cancer Growth. Pharmaceuticals (Basel) 2023; 16:ph16040605. [PMID: 37111362 PMCID: PMC10143453 DOI: 10.3390/ph16040605] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/10/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Cancer is a complex and multifaceted group of diseases characterized by the uncontrolled growth and spread of abnormal cells. While cancer can be challenging and life-altering, advances in research and development have led to the identification of new promising anti-cancer targets. Telomerase is one such target that is overexpressed in almost all cancer cells and plays a critical role in maintaining telomere length, which is essential for cell proliferation and survival. Inhibiting telomerase activity can lead to telomere shortening and eventual cell death, thus presenting itself as a potential target for cancer therapy. Naturally occurring flavonoids are a class of compounds that have already been shown to possess different biological properties, including the anti-cancer property. They are present in various everyday food sources and richly present in fruits, nuts, soybeans, vegetables, tea, wine, and berries, to name a few. Thus, these flavonoids could inhibit or deactivate telomerase expression in cancer cells by different mechanisms, which include inhibiting the expression of hTERT, mRNA, protein, and nuclear translocation, inhibiting the binding of transcription factors to hTERT promoters, and even telomere shortening. Numerous cell line studies and in vivo experiments have supported this hypothesis, and this development could serve as a vital and innovative therapeutic option for cancer. In this light, we aim to elucidate the role of telomerase as a potential anti-cancer target. Subsequently, we have illustrated that how commonly found natural flavonoids demonstrate their anti-cancer activity via telomerase inactivation in different cancer types, thus proving the potential of these naturally occurring flavonoids as useful therapeutic agents.
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Affiliation(s)
- Neel Parekh
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM'S NMIMS, Vile Parle (W), Mumbai 400056, India
| | - Ashish Garg
- Department of P.G. Studies and Research in Chemistry and Pharmacy, Rani Durgavati University Jabalpur, Jabalpur 482001, India
| | - Renuka Choudhary
- Department of Biotechnology, Maharishi Markandeshwar, Deemed to be University, Ambala 133207, India
| | - Madhu Gupta
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi 110017, India
| | - Ginpreet Kaur
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM'S NMIMS, Vile Parle (W), Mumbai 400056, India
| | - Seema Ramniwas
- University Centre for Research and Development, University Institute of Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali 140413, India
| | - Moyad Shahwan
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman 346, United Arab Emirates
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab Emirates
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar, Deemed to be University, Ambala 133207, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
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5
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Yang Y, Shen X. Preparation and Application of Molecularly Imprinted Polymers for Flavonoids: Review and Perspective. Molecules 2022; 27:7355. [PMID: 36364181 PMCID: PMC9653670 DOI: 10.3390/molecules27217355] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/16/2022] [Accepted: 10/19/2022] [Indexed: 08/24/2023] Open
Abstract
The separation and detection of flavonoids from various natural products have attracted increasing attention in the field of natural product research and development. Depending on the high specificity of molecularly imprinted polymers (MIPs), MIPs are proposed as efficient adsorbents for the selective extraction and separation of flavonoids from complex samples. At present, a comprehensive review article to summarize the separation and purification of flavonoids using molecular imprinting, and the employment of MIP-based sensors for the detection of flavonoids is still lacking. Here, we reviewed the general preparation methods of MIPs towards flavonoids, including bulk polymerization, precipitation polymerization, surface imprinting and emulsion polymerization. Additionally, a variety of applications of MIPs towards flavonoids are summarized, such as the different forms of MIP-based solid phase extraction (SPE) for the separation of flavonoids, and the MIP-based sensors for the detection of flavonoids. Finally, we discussed the advantages and disadvantages of the current synthetic methods for preparing MIPs of flavonoids and prospected the approaches for detecting flavonoids in the future. The purpose of this review is to provide helpful suggestions for the novel preparation methods of MIPs for the extraction of flavonoids and emerging applications of MIPs for the detection of flavonoids from natural products and biological samples.
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Affiliation(s)
| | - Xiantao Shen
- State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment and Health, Ministry of Education, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road #13, Wuhan 430030, China
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6
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Mirazimi SMA, Dashti F, Tobeiha M, Shahini A, Jafari R, Khoddami M, Sheida AH, EsnaAshari P, Aflatoonian AH, Elikaii F, Zakeri MS, Hamblin MR, Aghajani M, Bavarsadkarimi M, Mirzaei H. Application of Quercetin in the Treatment of Gastrointestinal Cancers. Front Pharmacol 2022; 13:860209. [PMID: 35462903 PMCID: PMC9019477 DOI: 10.3389/fphar.2022.860209] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/02/2022] [Indexed: 02/06/2023] Open
Abstract
Many cellular signaling pathways contribute to the regulation of cell proliferation, division, motility, and apoptosis. Deregulation of these pathways contributes to tumor cell initiation and tumor progression. Lately, significant attention has been focused on the use of natural products as a promising strategy in cancer treatment. Quercetin is a natural flavonol compound widely present in commonly consumed foods. Quercetin has shown significant inhibitory effects on tumor progression via various mechanisms of action. These include stimulating cell cycle arrest or/and apoptosis as well as its antioxidant properties. Herein, we summarize the therapeutic effects of quercetin in gastrointestinal cancers (pancreatic, gastric, colorectal, esophageal, hepatocellular, and oral).
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Affiliation(s)
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Tobeiha
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.,Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Shahini
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Raha Jafari
- Department of Medicine, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Mehrad Khoddami
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Amir Hossein Sheida
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.,Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Parastoo EsnaAshari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.,Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Amir Hossein Aflatoonian
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.,Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Fateme Elikaii
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.,Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Melika Sadat Zakeri
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.,Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Mohammad Aghajani
- Infectious Disease Research Center, School of Nursing and Midwifery, Kashan University of Medical Sciences, Kashan, Iran
| | - Minoodokht Bavarsadkarimi
- Clinical Research Development Center, Mahdiyeh Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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7
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Ansari B, Aschner M, Hussain Y, Efferth T, Khan H. Suppression of colorectal carcinogenesis by naringin. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 96:153897. [PMID: 35026507 DOI: 10.1016/j.phymed.2021.153897] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 12/13/2021] [Accepted: 12/18/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Colorectal cancer is the third most malignant cancer worldwide. Despite novel treatment options, the incidence and mortality rates of colon cancer continue to increase in most countries, especially in US, European and Asian countries. Colorectal carcinogenesis is multifactorial, including dietary and genetic factors, as well as lacking physical activity. Vegetables and fruits contain high amounts of secondary metabolites, which might reduce the risk for colorectal carcinogenesis. Flavonoids are important bioactive polyphenolic compounds. There are more than 4,000 different flavonoids, including flavanones, flavonoids, isoflavonoids, flavones, and catechins in a large variety of plant. HYPOTHESIS Among various other flavonoids, naringin in Citrus fruits has been a subject of intense scrutiny for its activity against many types of cancer, including colorectal cancer. We hypothesize that naringin is capable to inhibit the growth of transformed colonocytes and to induce programmed cell death in colon cancer cells. RESULTS We comprehensively review the inhibitory effects of naringin on colorectal cancers and address the underlying mechanistic pathways such as NF-κB/IL-6/STAT3, PI3K/AKT/mTOR, apoptosis, NF-κB-COX-2-iNOS, and β-catenin pathways. CONCLUSION Naringin suppresses colorectal inflammation and carcinogenesis by various signaling pathways. Randomized clinical trials are needed to determine their effectiveness in combating colorectal cancer.
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Affiliation(s)
- Bushra Ansari
- Department of Pharmacy, Abdul Wali Khan University Mardan 23200, Pakistan
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Yaseen Hussain
- College of Pharmaceutical Sciences, Soochow University, Jiangsu, 221400, P R China
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Staudinger Weg 5, 55128 Mainz, Germany
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan 23200, Pakistan
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8
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Benito I, Encío IJ, Milagro FI, Alfaro M, Martínez-Peñuela A, Barajas M, Marzo F. Microencapsulated Bifidobacterium bifidum and Lactobacillus gasseri in Combination with Quercetin Inhibit Colorectal Cancer Development in Apc Min/+ Mice. Int J Mol Sci 2021; 22:4906. [PMID: 34063173 PMCID: PMC8124226 DOI: 10.3390/ijms22094906] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/28/2021] [Accepted: 05/01/2021] [Indexed: 12/12/2022] Open
Abstract
Recent studies have suggested that flavonoids such as quercetin and probiotics such as Bifidobacterium bifidum (Bf) and Lactobacillus gasseri (Lg) could play a relevant role in inhibiting colon cancer cell growth. Our study investigated the role of dietary supplementation with microencapsulated probiotics (Bf and Lg) along with quercetin in the development of mouse colorectal cancer (CRC). Methods: Adenomatous polyposis coli/multiple intestinal neoplasia (ApcMin/+) mice were fed a standard diet or the same diet supplemented with microencapsulated probiotics (Bf and Lg strains, 107 CFU/100 g food) or both probiotics strains plus microencapsulated quercetin (15 mg/100 g food) for 73 days. Changes in body and organ weights, energy metabolism, intestinal microbiota, and colon tissue were determined. The expression of genes related to the Wnt pathway was also analyzed in colon samples. Results: Dietary supplementation with microencapsulated probiotics or microencapsulated probiotics plus quercetin reduced body weight loss and intestinal bleeding in ApcMin/+ mice. An improvement in energy expenditure was observed after 8 weeks but not after 10 weeks of treatment. A supplemented diet with microencapsulated Bf and Lg reduced the number of aberrant crypt foci (ACF) and adenomas by 45% and 60%, respectively, whereas the supplementation with Bf, Lg and quercetin decreased the number of ACF and adenomas by 57% and 80%, respectively. Microencapsulated Bf and Lg in combination with quercetin could exert inhibition of the canonical Wnt/β-catenin signaling pathway in the colon of ApcMin/+ mice Conclusions: The administration of microencapsulated Bf and Lg, individually or in combination with quercetin, inhibits the CRC development in ApcMin/+ mice.
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Affiliation(s)
- Iván Benito
- Laboratory of Animal Physiology and Nutrition, School of Agronomy, Public University of Navarre, Campus Arrosadia, 31006 Pamplona, Spain; (I.B.); (M.A.)
| | - Ignacio J. Encío
- Biochemistry Area, Department of Health Science, Public University of Navarre, 31008 Pamplona, Spain;
| | - Fermín I. Milagro
- Department of Nutrition, Food Sciences and Physiology, Center for Nutrition Research, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain;
- Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - María Alfaro
- Laboratory of Animal Physiology and Nutrition, School of Agronomy, Public University of Navarre, Campus Arrosadia, 31006 Pamplona, Spain; (I.B.); (M.A.)
| | | | - Miguel Barajas
- Biochemistry Area, Department of Health Science, Public University of Navarre, 31008 Pamplona, Spain;
| | - Florencio Marzo
- Laboratory of Animal Physiology and Nutrition, School of Agronomy, Public University of Navarre, Campus Arrosadia, 31006 Pamplona, Spain; (I.B.); (M.A.)
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9
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Ghanbari-Movahed M, Jackson G, Farzaei MH, Bishayee A. A Systematic Review of the Preventive and Therapeutic Effects of Naringin Against Human Malignancies. Front Pharmacol 2021; 12:639840. [PMID: 33854437 PMCID: PMC8039459 DOI: 10.3389/fphar.2021.639840] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 01/28/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Natural product-based cancer preventive and therapeutic entities, such as flavonoids and their derivatives, are shown to have a noticeable capability to suppress tumor formation and cancer cell growth. Naringin, a natural flavanone glycoside present in various plant species, has been indicated to modulate different signaling pathways and interact with numerous cell signaling molecules, which allows for an extensive variety of pharmacological actions, such as amelioration of inflammation, oxidative stress, metabolic syndromes, bone disorders, and cancer. The purpose of this systematic review is to present a critical and comprehensive assessment of the antitumor ability of naringin and associated molecular targets in various cancers. Methods: Studies were identified through systematic searches of Science Direct, PubMed, and Scopus as well as eligibility checks according to predefined selection criteria. Results: Eighty-seven studies were included in this systematic review. There was strong evidence for the association between treatment with naringin alone, or combined with other drugs and antitumor activity. Additionally, studies showed that naringin-metal complexes have greater anticancer effects compared to free naringin. It has been demonstrated that naringin employs multitargeted mechanisms to hamper cancer initiation, promotion, and progression through modulation of several dysregulated signaling cascades implicated in cell proliferation, autophagy, apoptosis, inflammation, angiogenesis, metastasis, and invasion. Conclusion: The results of our work show that naringin is a promising candidate for cancer prevention and treatment, and might offer substantial support for the clinical application of this phytocompound in the future. Nevertheless, further preclinical and clinical studies as well as drug delivery approaches are needed for designing novel formulations of naringin to realize the full potential of this flavonoid in cancer prevention and intervention.
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Affiliation(s)
- Maryam Ghanbari-Movahed
- Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Gloria Jackson
- Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
| | - Mohammad Hosein Farzaei
- Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
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10
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Antileishmanial Activity of Lignans, Neolignans, and Other Plant Phenols. PROGRESS IN THE CHEMISTRY OF ORGANIC NATURAL PRODUCTS 2021; 115:115-176. [PMID: 33797642 DOI: 10.1007/978-3-030-64853-4_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Secondary metabolites (SM) from organisms have served medicinal chemists over the past two centuries as an almost inexhaustible pool of new drugs, drug-like skeletons, and chemical probes that have been used in the "hunt" for new biologically active molecules with a "beneficial effect on human mind and body." Several secondary metabolites, or their derivatives, have been found to be the answer in the quest to search for new approaches to treat or even eradicate many types of diseases that oppress humanity. A special place among SM is occupied by lignans and neolignans. These phenolic compounds are generated biosynthetically via radical coupling of two phenylpropanoid monomers, and are known for their multitarget activity and low toxicity. The disadvantage of the relatively low specificity of phenylpropanoid-based SM turns into an advantage when structural modifications of these skeletons are made. Indeed, phenylpropanoid-based SM previously have proven to offer great potential as a starting point in drug development. Compounds such as Warfarin® (a coumarin-based anticoagulant) as well as etoposide and teniposide (podophyllotoxin-based anticancer drugs) are just a few examples. At the beginning of the third decade of the twenty-first century, the call for the treatment of more than a dozen rare or previously "neglected" diseases remains for various reasons unanswered. Leishmaniasis, a neglected disease that desperately needs new ways of treatment, is just one of these. This disease is caused by more than 20 leishmanial parasites that are pathogenic to humans and are spread by as many as 800 sandfly species across subtropical areas of the world. With continuing climate changes, the presence of Leishmania parasites and therefore leishmaniasis, the disease caused by these parasites, is spreading from previous locations to new areas. Thus, leishmaniasis is affecting each year a larger proportion of the world's population. The choice of appropriate leishmaniasis treatment depends on the severity of the disease and its form of manifestation. The success of current drug therapy is often limited, due in most cases to requiring long hospitalization periods (weeks to months) and the toxicity (side effects) of administered drugs, in addition to the increasing resistance of the parasites to treatment. It is thus important to develop new drugs and treatments that are less toxic, can overcome drug resistance, and require shorter periods of treatment. These aspects are especially important for the populations of developing countries. It was reported that several phenylpropanoid-based secondary metabolites manifest interesting antileishmanial activities and are used by various indigenous people to treat leishmaniasis. In this chapter, the authors shed some light on the various biological activities of phenylpropanoid natural products, with the main focus being on their possible applications in the context of antileishmanial treatment.
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11
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Dey M, Ghosh B, Giri TK. Enhanced intestinal stability and pH sensitive release of quercetin in GIT through gellan gum hydrogels. Colloids Surf B Biointerfaces 2020; 196:111341. [DOI: 10.1016/j.colsurfb.2020.111341] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/16/2020] [Accepted: 08/13/2020] [Indexed: 11/17/2022]
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12
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Fundamental insights into the interaction between telomerase/TERT and intracellular signaling pathways. Biochimie 2020; 181:12-24. [PMID: 33232793 DOI: 10.1016/j.biochi.2020.11.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 11/07/2020] [Accepted: 11/16/2020] [Indexed: 12/12/2022]
Abstract
Telomerase activity is critical for cancer cells to provide unrestricted proliferation and cellular immortality through maintaining telomeres. Telomerase enzymatic activity is regulatable at the level of DNA, mRNA, post translational modifications, cellular transport and enzyme assembly. More recent studies confirm the interaction of the telomerase with various intracellular signaling pathways including PI3K/AKT/mTOR, NF-κB and Wnt/β-catenin which mainly participating in inflammation, epithelial to mesenchymal transition (EMT) and tumor cell invasion and metastasis. Furthermore, hTERT protein has been detected in non-nuclear sites such as the mitochondria and cytoplasm in cells. Mitochondrial TERT indicates various non-telomere-related functions such as decreasing reactive oxygen species (ROS) generation, boosting the respiration rate, protecting mtDNA by direct binding, interacting with mitochondrial tRNAs and increasing mitochondrial membrane potential which can lead to higher chemoresistance rate in cancer cells during therapies. Understanding the molecular mechanisms of the TERT function and depended interactions in tumor cells can suggest novel therapeutic approaches. Hence, in this review we will explain the telomerase activity regulation in translational and post translational levels besides the established correlations with various cell signaling pathways with possible pathways for therapeutic targeting.
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13
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Bastin A, Sadeghi A, Nematollahi MH, Abolhassani M, Mohammadi A, Akbari H. The effects of malvidin on oxidative stress parameters and inflammatory cytokines in LPS-induced human THP-1 cells. J Cell Physiol 2020; 236:2790-2799. [PMID: 32914418 DOI: 10.1002/jcp.30049] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 08/25/2020] [Accepted: 08/27/2020] [Indexed: 01/29/2023]
Abstract
Malvidin is an anthocyanin which is involved in inhibiting inflammatory-related mediators in inflammatory diseases; however, its mechanism of action in THP-1 cells is not yet known. THP-1 is a human monocytic cell line that is derived from patients with acute monocytic leukemia. The present study aimed to investigate the effect of malvidin on inflammatory responses and oxidative stress in lipopolysaccharide (LPS)-induced THP-1 cells. THP-1 cells were stimulated with LPS (50 ng/ml) to induce inflammation in the presence or absence of malvidin. The anti/proinflammatory cytokines were evaluated by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Total protein levels/phosphorylation of c-Jun N-terminal kinase (JNK), P65-NF-κB, and IKKα/IKKβ were evaluated by western blot analysis. Malondialdehyde (MDA) and nitric oxide (NO) metabolite levels, ferric reducing antioxidant power (FRAP), total thiol (T-SH) content, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity were measured to evaluate the antioxidant activity of malvidin in THP-1 cells. Treatment of LPS-stimulated THP-1 cells with malvidin (100 and 200 μM) led to the significant inhibition of interleukin-6 (IL-6), tumor necrosis factor-α, and IL-1β messenger RNA (mRNA) expression and protein levels as well as a significant increase in the IL-10 mRNA expression and protein secretion. Moreover, 200 μM malvidin treatment reduced the phosphorylation of JNK, IKKα/IKKβ, and P65-NF-κB. These findings showed that malvidin not only decreased the MDA and NO metabolite levels but also increased the FRAP and T-SH content as well as SOD and GPx activities. The findings of the present study demonstrated the potential role of malvidin in blocking inflammation and oxidative stress induced by LPS in THP-1 cell line, suggesting that malvidin is likely to be a therapeutic agent for inflammatory diseases.
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Affiliation(s)
- Alireza Bastin
- Herbal and Traditional Medicine Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Asie Sadeghi
- Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran.,Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Hadi Nematollahi
- Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Moslem Abolhassani
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Abbas Mohammadi
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Hamed Akbari
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
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14
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Mazzoni L, Giampieri F, Alvarez Suarez JM, Gasparrini M, Mezzetti B, Forbes Hernandez TY, Battino MA. Isolation of strawberry anthocyanin-rich fractions and their mechanisms of action against murine breast cancer cell lines. Food Funct 2019; 10:7103-7120. [PMID: 31621765 DOI: 10.1039/c9fo01721f] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The aim of this study was the evaluation of the effects of strawberry anthocyanin extract treatment on two in vitro models of murine breast cancer cell lines, in an attempt to detect a specific pathway (AMP-activated protein kinase or AMPK) through which strawberries exert their anticancer activity. The anticancer activity of purified anthocyanin extracts from an Alba cultivar on two murine cancer cell lines, N202/1A (with high levels of the HER2/neu oncogene) and N202/1E (with low levels of the HER2/neu oncogene), was evaluated after 48 and 72 h of treatment. The cell viability and apoptosis, intracellular ROS rates, and cell oxidative damage were assessed. Western blot assays were performed to analyze the expression of several proteins related to apoptosis, autophagy, metastasis, the oxidative status, mitochondrial functionality, and the AMPK pathway. This study demonstrated that the anthocyanin extract of Alba strawberry shows an antiproliferative effect on cancer cells, through the induction of apoptosis and oxidative stress, by stimulating different molecular pathways. This study is one of the first studies that have tried to deepen the understanding of a candidate pathway for the explanation of the effects of strawberry on cancer cells. A relationship between the AMPK pathway and the anticancer effects of strawberries was demonstrated.
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Affiliation(s)
- Luca Mazzoni
- Department of Agricultural, Food and Environmental Sciences - Università Politecnica delle Marche, Via Brecce Bianche 10, 60131, Ancona, Italy
| | - Francesca Giampieri
- Dipartimento di Scienze Cliniche Specialistiche e Odontostomatologiche - Università Politecnica delle Marche, Via Ruggeri, 60130, Ancona, Italy.
| | - Jose Miguel Alvarez Suarez
- Facultad de Ingeniería y Ciencias Aplicadas. Grupo de Investigación en Biotecnología Aplicada a Biomedicina, Universidad de Las Américas (UDLA), Quito, Ecuador
| | - Massimiliano Gasparrini
- Department of Agricultural, Food and Environmental Sciences - Università Politecnica delle Marche, Via Brecce Bianche 10, 60131, Ancona, Italy
| | - Bruno Mezzetti
- Department of Agricultural, Food and Environmental Sciences - Università Politecnica delle Marche, Via Brecce Bianche 10, 60131, Ancona, Italy
| | - Tamara Yuliett Forbes Hernandez
- Nutrition and Food Science Group, Department of Analytical and Food Chemistry, CITACA, CACTI, University of Vigo - Vigo Campus, 32004 Ourense, Spain.
| | - Maurizio Antonio Battino
- Dipartimento di Scienze Cliniche Specialistiche e Odontostomatologiche - Università Politecnica delle Marche, Via Ruggeri, 60130, Ancona, Italy. and Nutrition and Food Science Group, Department of Analytical and Food Chemistry, CITACA, CACTI, University of Vigo - Vigo Campus, 32004 Ourense, Spain. and College of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
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15
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Afshari K, Haddadi NS, Haj-Mirzaian A, Farzaei MH, Rohani MM, Akramian F, Naseri R, Sureda A, Ghanaatian N, Abdolghaffari AH. Natural flavonoids for the prevention of colon cancer: A comprehensive review of preclinical and clinical studies. J Cell Physiol 2019; 234:21519-21546. [PMID: 31087338 DOI: 10.1002/jcp.28777] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/07/2019] [Accepted: 04/11/2019] [Indexed: 12/18/2022]
Abstract
Flavonoids comprise a group of natural polyphenols consisting of more than 5,000 subtypes mostly existing in fruits and vegetables. Flavonoids consumption could potentially attenuate the incidence and recurrence risk of colorectal cancers through their antiperoxidative, antioxidant, and anti-inflammatory effects. In addition, these compounds regulate the mitochondrial function, balance the bacterial flora and promote the apoptosis process in cancerous cells. However, some previous data failed to show the effectiveness of flavonoids in reducing the risk of colorectal cancer. In this study, we have reviewed the efficacy of different flavonoids subtypes on the risk of colon cancer and molecular mechanisms involved in this process in both clinical and animal studies. In addition, we tried to elucidate the potential synergy between these compounds and current colorectal cancer treatments.
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Affiliation(s)
- Khashayar Afshari
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nazgol-Sadat Haddadi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arvin Haj-Mirzaian
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Mojtaba Rohani
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Freshteh Akramian
- Department of Pharmacology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Rozita Naseri
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Antoni Sureda
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands, Palma de Mallorca, Spain.,CIBEROBN (Physiopathology of Obesity and Nutrition, CB12/03/30038), Instituto de Salud Carlos III, Madrid, Spain
| | - Negar Ghanaatian
- Department of Pharmacology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Amir Hossein Abdolghaffari
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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16
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Sen K, Banerjee S, Mandal M. Dual drug loaded liposome bearing apigenin and 5-Fluorouracil for synergistic therapeutic efficacy in colorectal cancer. Colloids Surf B Biointerfaces 2019; 180:9-22. [PMID: 31015105 DOI: 10.1016/j.colsurfb.2019.04.035] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/26/2019] [Accepted: 04/15/2019] [Indexed: 01/06/2023]
Abstract
Multidrug-based combinatorial therapeutic regiments which target multiple pathways simultaneously are being utilized as a therapeutic strategy of choice due to reduction in toxicity profile and enhancement of therapeutic index of the individual drugs. 5-Fluorouracil is a clinically approved drug which has limited response rate in the realm of colorectal cancer amelioration, hence our study aims to improve its efficacy by aiming the simultaneous delivery of 5-Flurouracil and apigenin which is naturally occurring flavone abundantly present in fruit and vegetables through a single liposome to combat and control colorectal cancer effectively in-vitro and in-vivo. The liposomal nanocarrier bearing the anti-tumorigenic agent apigenin was designed in this study in order to improve the bioavailability of the flavone while at the same time achieve combinatorial drug regime with 5- Fluorouracil. This study reports the synthesis and production of a relatively robust dual drug-loaded liposomal formulation by modified thin film hydration method which substantially entraps both the drugs. Even though there have been reports of the combinatorial regimen involving apigenin and 5-Flurouracil our study reports the optimal molar ratio for effective synergistic therapeutic application of this drug combination to alleviate colorectal cancer. The cytotoxicity and cellular effects of individual, combinatorial free drugs and their liposomal counterparts tested against two human colon cancer cell lines revealed significantly higher cytotoxicity of the dual-drug liposomes. The dual-drug liposomes demonstrated enhanced inhibition of angiogenesis, better reduction in cell proliferation and increased apoptotic potential. Cell signaling studies indicating a significant upregulation of pAMPK and activity against downstream targets by dual drug liposomes suggested its role in the reversal of Warburg effect. The formulation was tested in a preclinical setting in nude mice tumor xenograft model and was found to have greater anti-neoplastic and anti-tumorigenic effect. The study indicated that the increased chemotherapeutic potential in vivo was due to the passive targeting achieved by the liposomal drug loaded nano-carrier and the synergistic effect of apigenin in 5-Fluorouracil treatment offers a new attractive alternative to enhance the therapeutic potency of drugs and paves way for potential clinical applications.
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Affiliation(s)
- Kacoli Sen
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, 721302, India
| | - Shubhadeep Banerjee
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, 721302, India
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, 721302, India.
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17
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Ajayi AM, Diya OO, Adedapo ADA. Hypolipidemic Effect of Chrysophyllum albidum Peel Extract and Its Underlying Antioxidant Mechanisms in Normal and Triton-X-100-Induced Hyperlipidemic Rats. J Diet Suppl 2019; 17:365-383. [DOI: 10.1080/19390211.2019.1591563] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Abayomi M. Ajayi
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Nigeria
| | - Olubunmi O. Diya
- Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan, Nigeria
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18
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Di Gioia F, Petropoulos SA. Phytoestrogens, phytosteroids and saponins in vegetables: Biosynthesis, functions, health effects and practical applications. ADVANCES IN FOOD AND NUTRITION RESEARCH 2019; 90:351-421. [PMID: 31445599 DOI: 10.1016/bs.afnr.2019.02.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Phytoestrogens are non-steroidal secondary metabolites with similarities in structure and biological activities with human estrogens divided into various classes of compounds, including lignans, isoflavones, ellagitannins, coumestans and stilbenes. Similarly, phytosteroids are steroidal compounds of plant origin which have estrogenic effects and can act as agonists, antagonists, or have a mixed agonistic/antagonistic activity to animal steroid receptors. On the other hand, saponins are widely distributed plant glucosides divided into triterpenoid and steroidal saponins that contribute to plant defense mechanism against herbivores. They present a great variation from a structural point of view, including compounds from different classes. In this chapter, the main vegetable sources of these compounds will be presented, while details regarding their biosynthesis and plant functions will be also discussed. Moreover, considering the significant bioactive properties that these compounds exhibit, special focus will be given on their health effects, either beneficial or adverse. The practical applications of these compounds in agriculture and phytomedicine will be also demonstrated, as well as the future prospects for related research.
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Affiliation(s)
- Francesco Di Gioia
- Department of Plant Science, Pennsylvania State University, University Park, PA, United States
| | - Spyridon A Petropoulos
- Department of Crop Production and Rural Environment, University of Thessaly, Volos, Greece.
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19
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Ahmed W, Azmat R. Citrus: An Ancient Fruits of Promise for Health Benefits. CITRUS - HEALTH BENEFITS AND PRODUCTION TECHNOLOGY 2019. [DOI: 10.5772/intechopen.79686] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
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20
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Rescigno T, Tecce MF, Capasso A. Protective and Restorative Effects of Nutrients and Phytochemicals. Open Biochem J 2018; 12:46-64. [PMID: 29760813 PMCID: PMC5906970 DOI: 10.2174/1874091x01812010046] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 04/02/2018] [Accepted: 04/03/2018] [Indexed: 12/11/2022] Open
Abstract
Intoroduction: Dietary intake fundamentally provides reintegration of energy and essential nutrients to human organisms. However, its qualitative and quantitative composition strongly affects individual’s health, possibly being either a preventive or a risk factor. It was shown that nutritional status resulting from long-term exposition to specific diet formulations can outstandingly reduce incidences of most common and most important diseases of the developed world, such as cardiovascular and neoplastic diseases. Diet formulations result from different food combinations which bring specific nutrient molecules. Numerous molecules, mostly but not exclusively from vegetal foods, have been characterized among nutritional components as being particularly responsible for diet capabilities to exert risk reduction. These “bioactive nutrients” are able to produce effects which go beyond basic reintegration tasks, i.e. energetic and/or structural, but are specifically pharmacologically active within pathophysiological pathways related to many diseases, being able to selectively affect processes such as cell proliferation, apoptosis, inflammation, differentiation, angiogenesis, DNA repair and carcinogens activation. Conclusion: The present review was aimed to know the molecular mechanisms and pathways of activity of bioactive molecules; which will firstly allow search for optimal food composition and intake, and then use them as possible therapeutical targets and/or diagnostics. Also, the present review discussed the therapeutic effect of both nutrients and phytochemicals.
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Affiliation(s)
- Tania Rescigno
- Department of Pharmacy, University of Salerno, Fisciano (SA), Italy
| | - Mario F Tecce
- Department of Pharmacy, University of Salerno, Fisciano (SA), Italy
| | - Anna Capasso
- Department of Pharmacy, University of Salerno, Fisciano (SA), Italy
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21
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Darband SG, Kaviani M, Yousefi B, Sadighparvar S, Pakdel FG, Attari JA, Mohebbi I, Naderi S, Majidinia M. Quercetin: A functional dietary flavonoid with potential chemo-preventive properties in colorectal cancer. J Cell Physiol 2018; 233:6544-6560. [PMID: 29663361 DOI: 10.1002/jcp.26595] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 03/12/2018] [Indexed: 02/06/2023]
Abstract
Recently, an intense attention has been paid to the application of natural compounds as a novel therapeutic strategy for cancer treatment. Quercetin, a natural flavonol present in many commonly consumed food items, is widely demonstrated to exert inhibitory effects on cancer progression through various mechanisms. Since there is a strong association with diets containing abundant vegetables, fruits, and grains, and significant decline in the risk of colon cancer, accumulation studies have focused on the anticancer potential of quercetin in colorectal cancer. Cell cycle arrest, increase in apoptosis, antioxidant replication, modulation of estrogen receptors, regulation of signaling pathways, inhibition of and metastasis and angiogenesis are among various mechanisms underlying the chemo-preventive effects of quercetin in colorectal cancer. This review covers various therapeutic interactions of Quercetin as to how targets cellular involved in cancer treatment.
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Affiliation(s)
- Saber G Darband
- Danesh Pey Hadi Co., Health Technology, Development Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Mojtaba Kaviani
- School of Nutrition and Dietetics, Acadia University, Wolfville, Nova Scotia, Canada
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shirin Sadighparvar
- Neurophysiology Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Firouz G Pakdel
- Neurophysiology Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Javad A Attari
- Department of Neurosurgery, Urmia University of Medical Sciences, Urmia, Iran
| | - Iraj Mohebbi
- Social Determinants of Health Center, Occupational Medicine Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Somayeh Naderi
- Danesh Pey Hadi Co., Health Technology, Development Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
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22
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Polyphenols in Colorectal Cancer: Current State of Knowledge including Clinical Trials and Molecular Mechanism of Action. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4154185. [PMID: 29568751 PMCID: PMC5820674 DOI: 10.1155/2018/4154185] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 11/08/2017] [Accepted: 12/17/2017] [Indexed: 02/08/2023]
Abstract
Polyphenols have been reported to have wide spectrum of biological activities including major impact on initiation, promotion, and progression of cancer by modulating different signalling pathways. Colorectal cancer is the second most major cause of mortality and morbidity among females and the third among males. The objective of this review is to describe the activity of a variety of polyphenols in colorectal cancer in clinical trials, preclinical studies, and primary research. The molecular mechanisms of major polyphenols related to their beneficial effects on colorectal cancer are also addressed. Synthetic modifications and other future directions towards exploiting of natural polyphenols against colorectal cancer are discussed in the last section.
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23
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Patil VM, Masand N. Anticancer Potential of Flavonoids: Chemistry, Biological Activities, and Future Perspectives. STUDIES IN NATURAL PRODUCTS CHEMISTRY 2018. [DOI: 10.1016/b978-0-444-64179-3.00012-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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24
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Ganesan K, Xu B. Telomerase Inhibitors from Natural Products and Their Anticancer Potential. Int J Mol Sci 2017; 19:ijms19010013. [PMID: 29267203 PMCID: PMC5795965 DOI: 10.3390/ijms19010013] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 12/10/2017] [Accepted: 12/19/2017] [Indexed: 12/25/2022] Open
Abstract
Telomeres and telomerase are nowadays exploring traits on targets for anticancer therapy. Telomerase is a unique reverse transcriptase enzyme, considered as a primary factor in almost all cancer cells, which is mainly responsible to regulate the telomere length. Hence, telomerase ensures the indefinite cell proliferation during malignancy—a hallmark of cancer—and this distinctive feature has provided telomerase as the preferred target for drug development in cancer therapy. Deactivation of telomerase and telomere destabilization by natural products provides an opening to succeed new targets for cancer therapy. This review aims to provide a fundamental knowledge for research on telomere, working regulation of telomerase and its various binding proteins to inhibit the telomere/telomerase complex. In addition, the review summarizes the inhibitors of the enzyme catalytic subunit and RNA component, natural products that target telomeres, and suppression of transcriptional and post-transcriptional levels. This extensive understanding of telomerase biology will provide indispensable information for enhancing the efficiency of rational anti-cancer drug design.
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Affiliation(s)
- Kumar Ganesan
- Food Science and Technology Program, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai 519087, China.
| | - Baojun Xu
- Food Science and Technology Program, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai 519087, China.
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25
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Phytochemicals Targeting Estrogen Receptors: Beneficial Rather Than Adverse Effects? Int J Mol Sci 2017; 18:ijms18071381. [PMID: 28657580 PMCID: PMC5535874 DOI: 10.3390/ijms18071381] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 06/19/2017] [Accepted: 06/24/2017] [Indexed: 12/31/2022] Open
Abstract
In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERα and ERβ. These proteins are members of the nuclear receptor family, characterized by distinct structural and functional domains, and participate in the regulation of different biological processes, including cell growth, survival and differentiation. The two estrogen receptor (ER) subtypes are generated from two distinct genes and have partially distinct expression patterns. Their activities are modulated differently by a range of natural and synthetic ligands. Some of these ligands show agonistic or antagonistic effects depending on ER subtype and are described as selective ER modulators (SERMs). Accordingly, a few phytochemicals, called phytoestrogens, which are synthesized from plants and vegetables, show low estrogenic activity or anti-estrogenic activity with potentially anti-proliferative effects that offer nutraceutical or pharmacological advantages. These compounds may be used as hormonal substitutes or as complements in breast cancer treatments. In this review, we discuss and summarize the in vitro and in vivo effects of certain phytoestrogens and their potential roles in the interaction with estrogen receptors.
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26
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27
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Chaudhary PR, Bang H, Jayaprakasha GK, Patil BS. Variation in Key Flavonoid Biosynthetic Enzymes and Phytochemicals in 'Rio Red' Grapefruit (Citrus paradisi Macf.) during Fruit Development. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:9022-9032. [PMID: 27808514 DOI: 10.1021/acs.jafc.6b02975] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
In the current study, the phytochemical contents and expression of genes involved in flavonoid biosynthesis in Rio Red grapefruit were studied at different developmental and maturity stages for the first time. Grapefruit were harvested in June, August, November, January, and April and analyzed for the levels of carotenoids, vitamin C, limonoids, flavonoids, and furocoumarins by HPLC. In addition, genes encoding for phenylalanine ammonia-lyase (PAL), chalcone synthase (CHS), chalcone isomerase (CHI), and 1,2-rhamnosyltransferase (2RT) were isolated, and their expression in grapefruit juice vesicles was studied. Fruit maturity had significant influence on the expression of the genes, with PAL, CHS, and CHI having higher expression in immature fruits (June), whereas 2RT expression was higher in mature fruits (November and January). The levels of flavonoids (except naringin and poncirin), vitamin C, and furocoumarins gradually decreased from June to April. Furthermore, limonin levels sharply decreased in January. Lycopene decreased whereas β-carotene gradually increased with fruit maturity. Naringin did not exactly follow the pattern of 2RT or of PAL, CHS, and CHI expression, indicating that the four genes may have complementary effects on the level of naringin. Nevertheless, of the marketable fruit stages, early-season grapefruits harvested in November contained more beneficial phytochemicals as compared to mid- and late-season fruits harvested in January and April, respectively.
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Affiliation(s)
- Priyanka R Chaudhary
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University , College Station, Texas 77845, United States
| | - Haejeen Bang
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University , College Station, Texas 77845, United States
| | | | - Bhimanagouda S Patil
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University , College Station, Texas 77845, United States
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28
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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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Rodriguez GC, Walmer DK, Cline M, Krigman H, Lessey BA, Whitaker RS, Dodge R, Hughes CL. Effect of Progestin on the Ovarian Epithelium of Macaques: Cancer Prevention Through Apoptosis? ACTA ACUST UNITED AC 2016. [DOI: 10.1177/107155769800500508] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Gustavo C. Rodriguez
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham; Division of Reproductive Endocrinology. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham and Laboratory of Reproductive and Development Toxicology. National Institute for Environmental Health Science, National Institutes of Health, Research Triangle Park: Department of Comparative Medicine, Bowman Gray School of Medicine, Winston-Salem: Department of Pathology,
| | | | | | | | | | | | | | - Claude L. Hughes
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham; Division of Reproductive Endocrinology. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham and Laboratory of Reproductive and Development Toxicology. National Institute for Environmental Health Science, National Institutes of Health, Research Triangle Park: Department of Comparative Medicine, Bowman Gray School of Medicine, Winston-Salem: Department of Pathology,
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Wang B, Wang J, Zhao XH. In vitroActivities of the Four Structurally Similar Flavonols Weakened by the Prior Thermal and Oxidative Treatments to a Human Colorectal Cancer Line. J Food Biochem 2016. [DOI: 10.1111/jfbc.12310] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Bo Wang
- Key Laboratory of Dairy Science, Ministry of Education; Northeast Agricultural University; Harbin 150030 PR China
- College of Pharmacy, Heilongjiang University of Chinese Medicine; Harbin PR China
| | - Jing Wang
- Key Laboratory of Dairy Science, Ministry of Education; Northeast Agricultural University; Harbin 150030 PR China
| | - Xin-Huai Zhao
- Key Laboratory of Dairy Science, Ministry of Education; Northeast Agricultural University; Harbin 150030 PR China
- Synergetic Innovation Center of Food Safety and Nutrition; Northeast Agricultural University; Harbin 150030 PR China
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Vaidya B, Cho SY, Oh KS, Kim SH, Kim YO, Jeong EH, Nguyen TT, Kim SH, Kim IS, Kwon J, Kim D. Effectiveness of Periodic Treatment of Quercetin against Influenza A Virus H1N1 through Modulation of Protein Expression. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:4416-4425. [PMID: 27157719 DOI: 10.1021/acs.jafc.6b00148] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Kimchi, a traditional fermented food regularly consumed in Korea, contains various types of antimicrobial compounds. Among the tested compounds present in common spices used in Kimchi, quercetin showed the highest selectivity index against influenza A virus (IAV) H1N1. In this study, the effect of pretreatment and periodic treatment with quercetin against IAV in Madin-Darby canine kidney cells was observed. Compared to pretreatment, periodic treatment resulted in significantly higher cell viability but lower relative expression of the IAV PA gene and total apoptosis and cell death. To explain the mechanisms underlying the antiviral effects of quercetin treatment, a comparative proteomic analysis was performed in four samples (mock, quercetin-treated, IAV-infected, and quercetin-treated IAV-infected). Among the 220 proteins, 56 proteins were classified nonhierarchically into three clusters and were differentially modulated by quercetin treatment in IAV-infected cells. Post-translational modifications were identified in 68 proteins. In conclusion, periodic treatment with quercetin is effective in reducing IAV infection, and differentially regulates the expression of key proteins, including heat shock proteins, fibronectin 1, and prohibitin to reduce IAV replication.
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Affiliation(s)
- Bipin Vaidya
- Department of Food Science and Technology, BK21 Plus Program, and Foodborne Virus Research Center, Chonnam National University , Gwangju 61186, South Korea
- Bioenergy Research Center, Chonnam National University , Gwangju 61186, South Korea
| | - Se-Young Cho
- Department of Food Science and Technology, BK21 Plus Program, and Foodborne Virus Research Center, Chonnam National University , Gwangju 61186, South Korea
| | - Kyung-Seo Oh
- Department of Food Science and Technology, BK21 Plus Program, and Foodborne Virus Research Center, Chonnam National University , Gwangju 61186, South Korea
| | - Song Hak Kim
- Department of Food Science and Technology, BK21 Plus Program, and Foodborne Virus Research Center, Chonnam National University , Gwangju 61186, South Korea
| | - Yeong O Kim
- Department of Food Science and Technology, BK21 Plus Program, and Foodborne Virus Research Center, Chonnam National University , Gwangju 61186, South Korea
| | - Eun-Hye Jeong
- Department of Food Science and Technology, BK21 Plus Program, and Foodborne Virus Research Center, Chonnam National University , Gwangju 61186, South Korea
| | - Thoa Thi Nguyen
- Department of Food Science and Technology, BK21 Plus Program, and Foodborne Virus Research Center, Chonnam National University , Gwangju 61186, South Korea
| | - Sung Hyun Kim
- Hygienic Safety and Analysis Center, World Institute of Kimchi , Gwangju 61755, South Korea
| | - In Seon Kim
- Division of Applied Bioscience and Biotechnology, Institute of Environmentally-Friendly Agriculture, Chonnam National University , Gwangju 61186, South Korea
| | - Joseph Kwon
- Korea Basic Science Institute , Daejeon 34133, South Korea
| | - Duwoon Kim
- Department of Food Science and Technology, BK21 Plus Program, and Foodborne Virus Research Center, Chonnam National University , Gwangju 61186, South Korea
- Bioenergy Research Center, Chonnam National University , Gwangju 61186, South Korea
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Refolo MG, D'Alessandro R, Malerba N, Laezza C, Bifulco M, Messa C, Caruso MG, Notarnicola M, Tutino V. Anti Proliferative and Pro Apoptotic Effects of Flavonoid Quercetin Are Mediated by CB1 Receptor in Human Colon Cancer Cell Lines. J Cell Physiol 2015; 230:2973-80. [PMID: 25893829 DOI: 10.1002/jcp.25026] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 04/16/2015] [Indexed: 01/15/2023]
Abstract
Quercetin, the major constituent of flavonoid and widely present in fruits and vegetables, is an attractive compound for cancer prevention due to its beneficial anti proliferative effects, showing a crucial role in the regulation of apoptosis and cell cycle signaling. In vitro studies have demonstrated that quercetin specifically influences colon cancer cell proliferation. Our experiments, using human colon adenocarcinoma cells, confirmed the anti proliferative effect of quercetin and gave intriguing new insight in to the knowledge of the mechanisms involved. We observed a significant increase in the expression of the endocannabinoids receptor (CB1-R) after quercetin treatment. CB1-R can be considered an estrogen responsive receptor and quercetin, having a structure similar to that of the estrogens, can interact with CB1-R leading to the regulation of cell growth. In order to clarify the contribution of the CB1-R to the quercetin action, we investigated some of the principal molecular pathways that are inhibited or activated by this natural compound. In particular we detected the inhibition of the major survival signals like the PI3K/Akt/mTOR and an induction of the pro apoptotic JNK/JUN pathways. Interestingly, the metabolism of β-catenin was modified by flavonoid both directly and through activated CB1-R. In all the experiments done, the quercetin action has proven to be reinforced by anandamide (Met-F-AEA), a CB1-R agonist, and partially counteracted by SR141716, a CB1-R antagonist. These findings open new perspectives for anticancer therapeutic strategies.
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Affiliation(s)
- Maria Grazia Refolo
- Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases S. de Bellis, Bari, Italy
| | - Rosalba D'Alessandro
- Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases S. de Bellis, Bari, Italy
| | - Natascia Malerba
- Nutritional Biochemistry, National Institute for Digestive Diseases S. de Bellis, Bari, Italy
| | - Chiara Laezza
- Institute of Endocrinology and Experimental Oncology-CNR, Napoli, Italy.,Department of Biology and Cellular Pathology, University Federico II, Napoli, Italy
| | - Maurizio Bifulco
- Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy
| | - Caterina Messa
- Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases S. de Bellis, Bari, Italy
| | - Maria Gabriella Caruso
- Nutritional Biochemistry, National Institute for Digestive Diseases S. de Bellis, Bari, Italy
| | - Maria Notarnicola
- Nutritional Biochemistry, National Institute for Digestive Diseases S. de Bellis, Bari, Italy
| | - Valeria Tutino
- Nutritional Biochemistry, National Institute for Digestive Diseases S. de Bellis, Bari, Italy
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Vidak M, Rozman D, Komel R. Effects of Flavonoids from Food and Dietary Supplements on Glial and Glioblastoma Multiforme Cells. Molecules 2015; 20:19406-32. [PMID: 26512639 PMCID: PMC6332278 DOI: 10.3390/molecules201019406] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/21/2015] [Accepted: 10/14/2015] [Indexed: 11/24/2022] Open
Abstract
Quercetin, catechins and proanthocyanidins are flavonoids that are prominently featured in foodstuffs and dietary supplements, and may possess anti-carcinogenic activity. Glioblastoma multiforme is the most dangerous form of glioma, a malignancy of the brain connective tissue. This review assesses molecular structures of these flavonoids, their importance as components of diet and dietary supplements, their bioavailability and ability to cross the blood-brain barrier, their reported beneficial health effects, and their effects on non-malignant glial as well as glioblastoma tumor cells. The reviewed flavonoids appear to protect glial cells via reduction of oxidative stress, while some also attenuate glutamate-induced excitotoxicity and reduce neuroinflammation. Most of the reviewed flavonoids inhibit proliferation of glioblastoma cells and induce their death. Moreover, some of them inhibit pro-oncogene signaling pathways and intensify the effect of conventional anti-cancer therapies. However, most of these anti-glioblastoma effects have only been observed in vitro or in animal models. Due to limited ability of the reviewed flavonoids to access the brain, their normal dietary intake is likely insufficient to produce significant anti-cancer effects in this organ, and supplementation is needed.
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Affiliation(s)
- Marko Vidak
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia.
| | - Damjana Rozman
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia.
| | - Radovan Komel
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia.
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Song L, Li Y, He B, Gong Y. Development of Small Molecules Targeting the Wnt Signaling Pathway in Cancer Stem Cells for the Treatment of Colorectal Cancer. Clin Colorectal Cancer 2015; 14:133-145. [PMID: 25799881 DOI: 10.1016/j.clcc.2015.02.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 01/13/2015] [Accepted: 02/06/2015] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) was ranked third in morbidity and mortality in the United States in 2013. Although substantial progress has been made in surgical techniques and postoperative chemotherapy in recent years, the prognosis for colon cancer is still not satisfactory, mainly because of cancer recurrence and metastasis. The latest studies have shown that cancer stem cells (CSCs) play important roles in cancer recurrence and metastasis. Drugs that target CSCs might therefore have great therapeutic potential in prevention of cancer recurrence and metastasis. The wingless-int (Wnt) signaling pathway in CSCs has been suggested to play crucial roles in colorectal carcinogenesis, and has become a popular target for anti-CRC therapy. Dysregulation of the Wnt signaling pathway, mostly by inactivating mutations of the adenomatous polyposis coli tumor suppressor or oncogenic mutations of β-catenin, has been implicated as a key factor in colorectal tumorigenesis. Abnormal increases of β-catenin levels represents a common pathway in Wnt signaling activation and is also observed in other human malignancies. These findings highlight the importance of developing small-molecule drugs that target the Wnt pathway. Herein we provide an overview on the current development of small molecules that target the Wnt pathway in colorectal CSCs and discuss future research directions.
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Affiliation(s)
- Lele Song
- Department of Radiotherapy, the PLA 309 Hospital, Beijing, China; BioChain (Beijing) Science and Technology, Inc, Beijing, China.
| | - Yuemin Li
- Department of Radiotherapy, the PLA 309 Hospital, Beijing, China.
| | - Baoming He
- Department of Nuclear Medicine, the PLA 309 Hospital, Beijing, China
| | - Yuan Gong
- Department of Gastroenterology, the PLA General Hospital, Beijing, China
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Preliminary in vitro evaluation of genistein chemopreventive capacity as a result of esterification and cyclodextrin encapsulation. Anal Cell Pathol (Amst) 2015; 2015:262930. [PMID: 26161301 PMCID: PMC4460206 DOI: 10.1155/2015/262930] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 05/16/2015] [Accepted: 05/17/2015] [Indexed: 01/02/2023] Open
Abstract
The present study focuses on the synthesis and analysis of a genistein ester derivative with myristic acid followed by beta cyclodextrin encapsulation; physicochemical analysis using consecrated techniques such as FTIR, MS, DSC, and SEM revealed both a successful esterification and inclusion inside the cyclodextrin cavity. Cytotoxic effects were measured in vitro on three human cell lines: HeLa (cervix adenocarcinoma), A2780 (ovary carcinoma), and A431 (skin epidermoid carcinoma). The in vitro biological analysis exhibited rather poor antiproliferative results on all three tested cancer cell lines, behavior that may be due to the high stability of the complex within the in vitro environment.
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36
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Quercetin Enhances Chemosensitivity to Gemcitabine in Lung Cancer Cells by Inhibiting Heat Shock Protein 70 Expression. Clin Lung Cancer 2015; 16:e235-43. [PMID: 26050647 DOI: 10.1016/j.cllc.2015.05.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 05/10/2015] [Accepted: 05/12/2015] [Indexed: 11/22/2022]
Abstract
UNLABELLED Quercetin is a bioflavonoid known for antioxidation and antiproliferation activities. We demonstrated that quercetin inhibited cancer cell growth and sensitized cancer cells to gemcitabine treatment by promoting apoptosis via inhibiting heat shock protein 70 expression. Our results suggest that quercetin might have potential to increase sensitivity to chemotherapy and that heat shock protein 70 could be a new target for lung cancer treatment. BACKGROUND Quercetin is a bioflavonoid with antiproliferative and proapoptotic activity in various cancer cells. However, little is known about the mechanism by which quercetin inhibits cancer growth or its potential role as a chemosensitizer in lung cancer cells. We investigated whether quercetin-induced inhibition of heat shock protein 70 (HSP70) is involved in its anticancer activity and whether it could modulate the responsiveness of lung cancer cells to chemotherapy. MATERIALS AND METHODS Various concentrations of quercetin and gemcitabine, either alone or in combination, were applied to lung cancer cells (A549 and H460 cells). We evaluated cell viability with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide salt assay, apoptotic activity by determining caspase-3 and caspase-9 activities, and HSP70 expression using Western blot analysis after treatment. RESULTS Quercetin reduced cell viability and suppressed HSP70 expression in both cell lines dose-dependently. Adding a fixed quercetin dose enhanced gemcitabine-induced cell death, which was related to increased caspase-3 and caspase-9 activities. Combination treatment with quercetin and gemcitabine downregulated HSP70 expression more prominently than treatment with quercetin or gemcitabine alone. CONCLUSION Quercetin-induced HSP70 inhibition was involved in growth inhibition and sensitization to chemotreatment in lung cancer cells. Quercetin might have potential as a chemosensitizer in lung cancer treatment.
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Dian L, Yu E, Chen X, Wen X, Zhang Z, Qin L, Wang Q, Li G, Wu C. Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles. NANOSCALE RESEARCH LETTERS 2014; 9:2406. [PMID: 26088982 PMCID: PMC4493852 DOI: 10.1186/1556-276x-9-684] [Citation(s) in RCA: 134] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/09/2014] [Indexed: 05/04/2023]
Abstract
To improve its poor aqueous solubility and stability, the potential chemotherapeutic drug quercetin was encapsulated in soluplus polymeric micelles by a modified film dispersion method. With the encapsulation efficiency over 90%, the quercetin-loaded polymeric micelles (Qu-PMs) with drug loading of 6.7% had a narrow size distribution around mean size of 79.00 ± 2.24 nm, suggesting the complete dispersibility of quercetin in water. X-ray diffraction (XRD) patterns illustrated that quercetin was in amorphous or molecular form within PMs. Fourier transform infrared spectroscopy (FTIR) indicated that quercetin formed intermolecular hydrogen bonding with carriers. An in vitro dialysis test showed the Qu-PMs possessed significant sustained-release property, and the formulation was stable for at least 6 months under accelerated conditions. The pharmacokinetic study in beagle dogs showed that absorption of quercetin after oral administration of Qu-PMs was improved significantly, with a half-life 2.19-fold longer and a relative oral bioavailability of 286% as compared to free quercetin. Therefore, these novel soluplus polymeric micelles can be applied to encapsulate various poorly water-soluble drugs towards a development of more applicable therapeutic formulations.
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Affiliation(s)
- Linghui Dian
- />School of Pharmaceutical Sciences, Guangdong Medical College, Xincheng Road 1, Dongguan, 523808 Guangdong People’s Republic of China
- />School of Pharmaceutical Sciences, Sun Yat-Sen University, Waihuan Road 132, Guangzhou, Guangdong 510006 People’s Republic of China
| | - Enjiang Yu
- />School of Pharmaceutical Sciences, Guangdong Medical College, Xincheng Road 1, Dongguan, 523808 Guangdong People’s Republic of China
| | - Xiaona Chen
- />School of Pharmaceutical Sciences, Sun Yat-Sen University, Waihuan Road 132, Guangzhou, Guangdong 510006 People’s Republic of China
| | - Xinguo Wen
- />School of Pharmaceutical Sciences, Sun Yat-Sen University, Waihuan Road 132, Guangzhou, Guangdong 510006 People’s Republic of China
| | - Zhengzan Zhang
- />School of Pharmaceutical Sciences, Sun Yat-Sen University, Waihuan Road 132, Guangzhou, Guangdong 510006 People’s Republic of China
| | - Lingzhen Qin
- />School of Pharmaceutical Sciences, Sun Yat-Sen University, Waihuan Road 132, Guangzhou, Guangdong 510006 People’s Republic of China
| | - Qingqing Wang
- />School of Pharmaceutical Sciences, Sun Yat-Sen University, Waihuan Road 132, Guangzhou, Guangdong 510006 People’s Republic of China
| | - Ge Li
- />R&D Center of Pharmaceutical Engineering, Sun Yat-sen University, Waihuan Road 132, Guangzhou, 510006 Guangdong People’s Republic of China
| | - Chuanbin Wu
- />School of Pharmaceutical Sciences, Sun Yat-Sen University, Waihuan Road 132, Guangzhou, Guangdong 510006 People’s Republic of China
- />R&D Center of Pharmaceutical Engineering, Sun Yat-sen University, Waihuan Road 132, Guangzhou, 510006 Guangdong People’s Republic of China
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Antunes-Ricardo M, Moreno-García BE, Gutiérrez-Uribe JA, Aráiz-Hernández D, Alvarez MM, Serna-Saldivar SO. Induction of apoptosis in colon cancer cells treated with isorhamnetin glycosides from Opuntia ficus-indica pads. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2014; 69:331-336. [PMID: 25186940 DOI: 10.1007/s11130-014-0438-5] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
(OFI) contains health-promoting compounds like flavonoids, being the isorhamnetin glycosides the most abundant. We evaluated the effect of OFI extracts with different isorhamnetin glycosides against two different human colon cancer cells (HT-29 and Caco2). The extracts were obtained by alkaline hydrolysis with NaOH at 40 °C during 15, 30 or 60 min. Tri and diglycosides were the most abundant isorhamnetin glycosides, therefore these compounds were isolated to compare their cytotoxic effect with the obtained from the extracts. The OFI extracts and purified isorhamnetin glycosides were more cytotoxic against HT-29 cells than Caco2 cells. OFI-30 exhibited the lowest IC50 value against HT-29 (4.9 ± 0.5 μg/mL) and against Caco2 (8.2 ± 0.3 μg/mL). Isorhamnetin diglycosides IG5 and IG6 were more cytotoxic than pure isorhamnetin aglycone or triglycosides when they were tested in HT-29 cells. Bioluminescent analysis revealed increased activity of caspase 3/7 in OFI extracts-treated cells, particularly for the extract with the highest concentration of isorhamnetin triglycosides. Flow cytometry analysis confirmed that OFI extract and isorhamnetin glycosides induced a higher percentage of apoptosis in HT-29 than in Caco2, while isorhamnetin was more apoptotic in Caco2. This research demonstrated that glycosilation affected antiproliferative effect of pure isorhamnetin glycosides or when they are mixed with other phytochemicals in an extract obtained from OFI.
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Affiliation(s)
- Marilena Antunes-Ricardo
- Centro de Biotecnología-FEMSA., Tecnológico de Monterrey-, Av. Eugenio Garza Sada 2501 Sur, C.P. 64849, Monterrey, N.L., México
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Yoon H. Effects of aging on the phenolic content and antioxidant activities of magnolia (Magnolia denudata) flower extracts. Food Sci Biotechnol 2014. [DOI: 10.1007/s10068-014-0234-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Pampaloni B, Palmini G, Mavilia C, Zonefrati R, Tanini A, Brandi ML. In vitro effects of polyphenols on colorectal cancer cells. World J Gastrointest Oncol 2014; 6:289-300. [PMID: 25132926 PMCID: PMC4133796 DOI: 10.4251/wjgo.v6.i8.289] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 05/30/2014] [Accepted: 06/27/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the effects of quercetin and genistein on colon cancer cell proliferation and their estrogen receptor β (ERβ) expression.
METHODS: Colon cancer cells were stably transfected with a mammalian expression vector to overexpress ERβ (HCT8-β8-expressing cells) or a control vector (HCT8-pSV2neo-expressing cells). The proliferation of these cells was examined after treatment with quercetin or genistein (5-100 μmol/L), or 10 nmol/L 17β-estradiol (17β-E2). Cell viability was examined by acridine orange staining following treatments for 48 or 144 h. Effects of quercetin and genistein on ERβ transcriptional transactivation were examined by luciferase activity in HCT8-β8-expressing cells transiently transfected with a pEREtkLUC reporter vector. In addition, the regulation of ERβ transcription by phytoestrogens and 17β-E2 was examined by quantitative polymerase chain reaction.
RESULTS: Proliferation of HCT8-β8-expressing cells was not reduced low doses (5 μmol/L) of quercetin and genistein, while it was reduced at 25-50 μmol/L with an effect similar to 10 nmol/L 17β-E2. Treatment with doses of phytoestrogens ≥ 75 μmol/L completely blocked cell growth and reduced overall cell counts, however no effects at any dose were observed in HCT8-pSV2neo-expressing cells. These results were supported by viability staining that revealed acridine orange-stained lysosomes with high doses or extended treatment periods. Genistein and quercetin (50 μmol/L) significantly increased ER-responsive luciferase activity similar to 10 nmol/L 17β-E2 (P < 0.05). Furthermore, genistein and quercetin (50 μmol/L), as well as 10 nmol/L 17β-E2 significantly increased ERβ mRNA levels in HCT8-β8-expressing cells (P < 0.05). In addition, treatment of HCT8-pSV2neo-expressing cells with 50 µmol/L quercetin or 10 nmol/L 17β-E2 significantly increased ERβ mRNA levels compared to untreated controls (P < 0.05), though the absolute levels were much lower than in HCT8-β8-expressing cells.
CONCLUSION: The antitumorigenic effects of the phytoestrogenic compounds quercetin and genistein on colon cancers cells occur through ERβ activity and expression.
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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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Kurzeja E, Stec M, Synowiec-Wojtarowicz A, Jowsa A, Pawłowska-Góral K. Studies on the effect of quercetin and nitrates on the redox homeostasis using in vitro model. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2014; 38:24-30. [PMID: 24860958 DOI: 10.1016/j.etap.2014.04.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 04/15/2014] [Accepted: 04/21/2014] [Indexed: 06/03/2023]
Abstract
Antioxidants are widely considered to be a preventive measure for many diseases and beneficial for health. However, an increasing number of reports suggest a lack of any influence by antioxidants on health or even harmful pro-oxidative effects of antioxidants. In most cases, the research was conducted with respect to a chosen antioxidant, without considering the presence of other chemical substances present in food, with which these compounds may react. The aim of this work was to determine whether and to what extent the simultaneous presence of quercetin and sodium nitrate influences oxidative-reductive homeostasis in fibroblast cultures. Superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and nitric oxide synthase (NOS) activities were measured together with nitric oxide (NO) concentration and total antioxidant status (TAS). An increase in the activity of all the enzymes measured and in the NO concentration was determined compared with the control culture. The most prominent changes were observed at the highest quercetin concentration. These results indicate that the simultaneous presence of quercetin and sodium nitrate disrupts the oxidative-reductive homeostasis in fibroblasts.
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Affiliation(s)
- Ewa Kurzeja
- Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Food and Nutrition, 8 Jednosci Street, 41-200 Sosnowiec, Poland.
| | - Małgorzata Stec
- Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Food and Nutrition, 8 Jednosci Street, 41-200 Sosnowiec, Poland
| | - Agnieszka Synowiec-Wojtarowicz
- Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Food and Nutrition, 8 Jednosci Street, 41-200 Sosnowiec, Poland
| | - Andrzej Jowsa
- Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Food and Nutrition, 8 Jednosci Street, 41-200 Sosnowiec, Poland
| | - Katarzyna Pawłowska-Góral
- Medical University of Silesia, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Department of Food and Nutrition, 8 Jednosci Street, 41-200 Sosnowiec, Poland
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Zhou C, Lin Y. Osteogenic differentiation of adipose-derived stem cells promoted by quercetin. Cell Prolif 2014; 47:124-32. [PMID: 24617900 DOI: 10.1111/cpr.12097] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Accepted: 11/09/2013] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES The present study aimed to investigate overall effect of quercetin on proliferation and osteogenic differentiation of mouse adipose stem cells (mASCs) in vitro. MATERIALS AND METHODS Mouse adipose stem cells were isolated from subcutaneous fat pads and induced into the osteogenic lineage. Effects of quercetin on cell proliferation were assessed using MTT assay. Then they were treated by quercetin for 3, 7 and 11 days in a range of concentrations. Finally, effects of quercetin on osteogenic differentiation of mASCs were analysed by real-time PCR. RESULTS Data of MTT assay showed that quercetin did not enhance mASC proliferation in a dose-dependent or time-dependent manner. Results of qPCR indicated that quercetin promoted expressions of Osx, Runx2, BMP-2, Col-1, OPN and OCN at the mRNA level in the presence of osteo-induction medium. CONCLUSIONS Our data demonstrated that quercetin was not active in terms of enhancing mASCs proliferation; however, it increased osteogenesis of mASCs by up-regulation of genes including Osx, Runx2, BMP-2, Col-1, OPN and OCN.
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Affiliation(s)
- C Zhou
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
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Su KY, Yu CY, Chen YP, Hua KF, Chen YLS. 3,4-Dihydroxytoluene, a metabolite of rutin, inhibits inflammatory responses in lipopolysaccharide-activated macrophages by reducing the activation of NF-κB signaling. Altern Ther Health Med 2014. [PMID: 24417898 DOI: 10.1186/1472-6882-14-21.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND Saussurea involucrata (Kar. et Kir.) (S. involucrate), is a rare traditional Chinese medicinal herb. Rutin and hispidulin as well as their metabolites are flavonoids of the flavonol type that abound in S. involucrata, which has been reported to inhibit nonoxidative advanced glycation end products which was involved in physiological inflammation. This study aims to investigate the role of 3,4-dihydroxytoluene (DHT), a metabolite of rutin, in inflammatory inhibition and its involved mechanism. METHODS This study utilized lipopolysaccharide (LPS) stimulated murine macrophage cell line RAW 264.7 as inflammatory model. The inhibitory effects of DHT were evaluated by the expression level of several inflammation markers such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 after LPS treatment. In addition, underlying mechanisms, the activation of mitogen-activated protein kinases (MAPKs) and NF-κB, were also investigated. RESULTS Our results showed that DHT significantly suppressed the LPS-induced production of nitric oxide (NO), iNOS, and COX-2 in a dose-dependent manner without cytotoxicity. DHT also reduced the generation of proinflammatory cytokines majorly in tumor necrosis factor (TNF)-α and minor in interleukin (IL)-1β and IL-6. In addition, LPS-stimulated I-κBα phosphorylation and degradation followed by translocation of the nuclear factor κB (NF-kB)-p65 from the cytoplasm to the nucleus were attenuated after DHT treatment. CONCLUSIONS Combined, the results suggest that DHT might exert anti-inflammatory effects in vitro in LPS stimulated RAW 264.7 macrophages and is potential in adjuvant treatment in inflammation disease.
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Affiliation(s)
| | | | | | | | - Yi-Lin Sophia Chen
- Department of Biotechnology and Animal Science, National Ilan University, Shen-Lung Road, Ilan 260, Taiwan.
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Su KY, Yu CY, Chen YP, Hua KF, Chen YLS. 3,4-Dihydroxytoluene, a metabolite of rutin, inhibits inflammatory responses in lipopolysaccharide-activated macrophages by reducing the activation of NF-κB signaling. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 14:21. [PMID: 24417898 PMCID: PMC3900474 DOI: 10.1186/1472-6882-14-21] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2013] [Accepted: 01/10/2014] [Indexed: 01/01/2023]
Abstract
Background Saussurea involucrata (Kar. et Kir.) (S. involucrate), is a rare traditional Chinese medicinal herb. Rutin and hispidulin as well as their metabolites are flavonoids of the flavonol type that abound in S. involucrata, which has been reported to inhibit nonoxidative advanced glycation end products which was involved in physiological inflammation. This study aims to investigate the role of 3,4-dihydroxytoluene (DHT), a metabolite of rutin, in inflammatory inhibition and its involved mechanism. Methods This study utilized lipopolysaccharide (LPS) stimulated murine macrophage cell line RAW 264.7 as inflammatory model. The inhibitory effects of DHT were evaluated by the expression level of several inflammation markers such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 after LPS treatment. In addition, underlying mechanisms, the activation of mitogen-activated protein kinases (MAPKs) and NF-κB, were also investigated. Results Our results showed that DHT significantly suppressed the LPS-induced production of nitric oxide (NO), iNOS, and COX-2 in a dose-dependent manner without cytotoxicity. DHT also reduced the generation of proinflammatory cytokines majorly in tumor necrosis factor (TNF)-α and minor in interleukin (IL)-1β and IL-6. In addition, LPS-stimulated I-κBα phosphorylation and degradation followed by translocation of the nuclear factor κB (NF-kB)-p65 from the cytoplasm to the nucleus were attenuated after DHT treatment. Conclusions Combined, the results suggest that DHT might exert anti-inflammatory effects in vitro in LPS stimulated RAW 264.7 macrophages and is potential in adjuvant treatment in inflammation disease.
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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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Yuenyongsawad S, Bunluepuech K, Wattanapiromsakul C, Tewtrakul S. Anti-cancer activity of compounds from Bauhinia strychnifolia stem. JOURNAL OF ETHNOPHARMACOLOGY 2013; 150:765-769. [PMID: 24120967 DOI: 10.1016/j.jep.2013.09.025] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 09/04/2013] [Accepted: 09/07/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The stem and root of Bauhinia strychnifolia Craib (Fabaceae family) have been traditionally used in Thailand to treat fever, alcoholic toxication, allergy and cancer. An EtOH extract of Bauhinia strychnifolia showed good inhibitory activity against several cancer cell lines including HT-29, HeLa, MCF-7 and KB. As there has been no previous reports on chemical constituents of Bauhinia strychnifolia, this study is aimed to isolate the pure compounds with anti-cancer activity. MATERIALS AND METHODS Five pure compounds were isolated from EtOH extract of Bauhinia strychnifolia stem using silica gel, dianion HP-20 and sephadex LH-20 column chromatography and were tested for their cytotoxic effects against HT-29, HeLa, MCF-7 and KB cell lines using the Sulforhodamine B (SRB) assay. RESULTS Among five compounds, 3,5,7,3',5'-pentahydroxyflavanonol-3-O-α-l-rhamnopyranoside (2) possessed very potent activity against KB (IC₅₀=0.00054μg/mL), HT-29 (IC₅₀=0.00217 μg/mL), MCF-7 (IC₅₀=0.0585 μg/mL) and HeLa cells (IC₅₀=0.0692 μg/mL). 3,5,7-Trihydroxychromone-3-O-α-l-rhamnopyranoside (3) also showed good activity against HT-29 (IC₅₀=0.02366 μg/mL), KB (IC₅₀=0.0412 μg/mL) and MCF-7 (IC₅₀=0.297 μg/mL), respectively. The activity of 2 (IC₅₀=0.00054 μg/mL) against KB cell was ten times higher than that of the positive control, Camptothecin (anti-cancer drug, IC₅₀=0.0057 μg/mL). All compounds did not show any cytotoxicity with normal cells at the concentration of 1 μg/mL. CONCLUSION This is the first report of compounds 2 and 3 on anti-cancer activity and based on the anti-cancer activity of extracts and pure compounds isolated from Bauhinia strychnifolia stem, it might be suggested that this plant could be useful for treatment of cancer.
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Affiliation(s)
- Supreeya Yuenyongsawad
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand.
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Padma VV, Poornima P, Prakash C, Bhavani R. Oral treatment with gallic acid and quercetin alleviates lindane-induced cardiotoxicity in rats. Can J Physiol Pharmacol 2013; 91:134-40. [DOI: 10.1139/cjpp-2012-0279] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Lindane is a man-made organochlorine pesticide used for agricultural purposes. Since lindane-induced toxicity is mediated by free radical generation, this investigation was carried out to study the protective effects of gallic acid and quercetin against lindane-induced cardiotoxicity. Lindane (100 mg·(kg body mass)−1) was administered orally to rats for 30 days. Histological analysis revealed pathological changes in the heart of lindane-treated rats. Biochemical analysis of the lindane-treated animals showed elevated activity for serum marker enzymes, lipid peroxidation (LPO), and membrane-bound Ca2+ ATPase, with a concomitant decrease in the level of non-enzymic antioxidant (GSH), enzymic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase (GPx), and glutathione-S-transferase (GST), and membrane-bound ATPases like Na+/K+ ATPase and Mg2+ ATPase in heart tissue. The results suggest that gallic acid and quercetin offer protection against lindane-induced myocardial damage, possibly through maintaining levels of endogenous antioxidant enzymes and membrane bound ATPase activity, as well as inhibiting lipid peroxidation.
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Affiliation(s)
- Viswanadha Vijaya Padma
- Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore 641046, India
| | - Paramasivan Poornima
- Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore 641046, India
| | - Chermakani Prakash
- Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore 641046, India
| | - Ramachandran Bhavani
- Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore 641046, India
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Zhao Y, Zhu L, Yu S, Zhao Z. HPLC-UV-ESI-MS methods for flavonoid profiling of sugarcane juice extract. SUGAR INDUSTRY-ZUCKERINDUSTRIE 2013. [DOI: 10.36961/si14371] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
An efficient method combining liquid chromatography coupled to electrospray ionization mass spectrometry in tandem mode with negative ion detection was described for the qualitative analysis of flavonoids in sugarcane juice. The analyses were carried out on a Shim-pack C18 column (150mm×4.6mmI.D.,5µm), with a mobile phase composed by methanol: 5% aqueous acetic acid by linear gradient elution (0–20min, methanol 15–25%; 20–60min, methanol 25–33%; 60–90min, methanol 33–48%). Nine phenolic compounds were identified on the basis of their mass spectra in full scan mode and the pattern of their fragmentation. The diagnostic fragmentation patterns of the compounds during collision induced dissociation (CID) elucidated structural information of the compounds analysed. This is the first time that vitexin-rhamnosyl glucoside (8-glucopyranosyl-7-[6-O-(6-deoxy-mannopyranosyl)-glucopyranosyl]-5-hydroxy-2-(4-hydroxyphenyl)-4H-1-Benzopyran-4-one) has been detected or identified in sugarcane juice.
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Toxicological aspects of the use of phenolic compounds in disease prevention. Interdiscip Toxicol 2012; 4:173-83. [PMID: 22319251 PMCID: PMC3274725 DOI: 10.2478/v10102-011-0027-5] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Revised: 11/30/2011] [Accepted: 12/01/2011] [Indexed: 12/22/2022] Open
Abstract
The consumption of a diet low in fat and enhanced by fruits and vegetables, especially rich in phenolic compounds, may reduce risks of many civilization diseases. The use of traditional medicines, mainly derived from plant sources, has become an attractive segment in the management of many lifestyle diseases. Concerning the application of dietary supplements (based on phenolic compounds) in common practice, the ongoing debate over possible adverse effects of certain nutrients and dosage levels is of great importance. Since dietary supplements are not classified as drugs, their potential toxicities and interactions have not been thoroughly evaluated. First, this review will introduce phenolic compounds as natural substances beneficial for human health. Second, the potential dual mode of action of flavonoids will be outlined. Third, potential deleterious impacts of phenolic compounds utilization will be discussed: pro-oxidant and estrogenic activities, cancerogenic potential, cytotoxic effects, apoptosis induction and flavonoid-drug interaction. Finally, future trends within the research field will be indicated.
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