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Duan X, Li Y, Xu F, Ding H. Study on the neuroprotective effects of Genistein on Alzheimer's disease. Brain Behav 2021; 11:e02100. [PMID: 33704934 PMCID: PMC8119804 DOI: 10.1002/brb3.2100] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 01/04/2021] [Accepted: 02/23/2021] [Indexed: 01/14/2023] Open
Abstract
Along with the aging of the world population, the incidence rate of Alzheimer's disease (AD) has been increasing. At present, AD has become one of the most serious problems faced by modern medicine. Studies have shown that estrogen has a positive effect on AD, but estrogen has the side effect of leading to tumors. Recent in vivo studies have shown that genistein, one of the selective estrogen receptor modulators (SERMs), can improve brain function through the blood-brain barrier (BBB), antagonize the toxicity of amyloid β-protein (Aβ), that is, to inhibit neurotoxicity due to aggregation of beta amyloid protein, and have neuroprotective effects. In addition, the use of Gen can avoid the risk of endometrial cancer and breast cancer caused by estrogen therapy while exerting an estrogen-like effect, which has some potential for the delay and treatment of AD.
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Affiliation(s)
- Xiaoying Duan
- Department of Acupuncture and Moxibustion, the Second Hospital of Jilin University, Changchun, China
| | - Yanshuang Li
- Department of Acupuncture and Moxibustion, the Second Hospital of Jilin University, Changchun, China
| | - Fei Xu
- Department of Acupuncture and Moxibustion, the Second Hospital of Jilin University, Changchun, China
| | - Hong Ding
- Department of Traditional Chinese Medicine, the Second Hospital of Jilin University, Changchun, China
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Ullah MF, Usmani S, Shah A, Abuduhier FM. Dietary molecules and experimental evidence of epigenetic influence in cancer chemoprevention: An insight. Semin Cancer Biol 2020; 83:319-334. [PMID: 33152485 DOI: 10.1016/j.semcancer.2020.10.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/26/2020] [Accepted: 10/27/2020] [Indexed: 12/17/2022]
Abstract
The world-wide rate of incidence of cancer disease has been only modestly contested by the past and current preventive and interventional strategies. Hence, the global effort towards novel ideas to contain the disease still continues. Constituents of human diets have in recent years emerged as key regulators of carcinogenesis, with studies reporting their inhibitory potential against all the three stages vis-a-vis initiation, promotion and progression. Unlike drugs which usually act on single targets, these dietary factors have an advantage of multi-targeted effects and pleiotropic action mechanisms, which are effective against cancer that manifest as a micro-evolutionary and multi-factorial disease. Since most of the cellular targets have been identified and their consumption considered relatively safe, these diet-derived agents often appear as molecules of interest in repurposing strategies. Currently, many of these molecules are being investigated for their ability to influence the aberrant alterations in cell's epigenome for epigenetic therapy against cancer. Targeting the epigenetic regulators is a new paradigm in cancer chemoprevention which acts to reverse the warped-up epigenetic alterations in a cancer cell, thereby directing it towards a normal phenotype. In this review, we discuss the significance of dietary factors and natural products as chemopreventive agents. Further, we corroborate the experimental evidence from existing literature, reflecting the ability of a series of such molecules to act as epigenetic modifiers in cancer cells, by interfering with molecular events that map the epigenetic imprints such as DNA methylation, histone acetylation and non-coding RNA mediated gene regulation.
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Affiliation(s)
- Mohammad Fahad Ullah
- Prince Fahad Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia.
| | - Shazia Usmani
- Faculty of Pharmacy, Integral University, Lucknow, India
| | - Aaliya Shah
- Department of Biochemistry, SKIMS Medical College, Srinagar, India
| | - Faisel M Abuduhier
- Prince Fahad Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia
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Koudoufio M, Desjardins Y, Feldman F, Spahis S, Delvin E, Levy E. Insight into Polyphenol and Gut Microbiota Crosstalk: Are Their Metabolites the Key to Understand Protective Effects against Metabolic Disorders? Antioxidants (Basel) 2020; 9:E982. [PMID: 33066106 PMCID: PMC7601951 DOI: 10.3390/antiox9100982] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
Lifestyle factors, especially diet and nutrition, are currently regarded as essential avenues to decrease modern-day cardiometabolic disorders (CMD), including obesity, metabolic syndrome, type 2 diabetes, and atherosclerosis. Many groups around the world attribute these trends, at least partially, to bioactive plant polyphenols given their anti-oxidant and anti-inflammatory actions. In fact, polyphenols can prevent or reverse the progression of disease processes through many distinct mechanisms. In particular, the crosstalk between polyphenols and gut microbiota, recently unveiled thanks to DNA-based tools and next generation sequencing, unravelled the central regulatory role of dietary polyphenols and their intestinal micro-ecology metabolites on the host energy metabolism and related illnesses. The objectives of this review are to: (1) provide an understanding of classification, structure, and bioavailability of dietary polyphenols; (2) underline their metabolism by gut microbiota; (3) highlight their prebiotic effects on microflora; (4) discuss the multifaceted roles of their metabolites in CMD while shedding light on the mechanisms of action; and (5) underscore their ability to initiate host epigenetic regulation. In sum, the review clearly documents whether dietary polyphenols and micro-ecology favorably interact to promote multiple physiological functions on human organism.
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Affiliation(s)
- Mireille Koudoufio
- Research Centre, Sainte-Justine University Health Center, Montreal, QC H3T 1C5, Canada; (M.K.); (F.F.); (S.S.); (E.D.)
- Department of Nutrition, Université de Montréal, Montreal, QC H3T 1J4, Canada
- Institute of Nutrition and Functional Foods, Laval University, Quebec City, QC G1V 0A6, Canada;
| | - Yves Desjardins
- Institute of Nutrition and Functional Foods, Laval University, Quebec City, QC G1V 0A6, Canada;
| | - Francis Feldman
- Research Centre, Sainte-Justine University Health Center, Montreal, QC H3T 1C5, Canada; (M.K.); (F.F.); (S.S.); (E.D.)
- Department of Nutrition, Université de Montréal, Montreal, QC H3T 1J4, Canada
- Institute of Nutrition and Functional Foods, Laval University, Quebec City, QC G1V 0A6, Canada;
| | - Schohraya Spahis
- Research Centre, Sainte-Justine University Health Center, Montreal, QC H3T 1C5, Canada; (M.K.); (F.F.); (S.S.); (E.D.)
- Department of Nutrition, Université de Montréal, Montreal, QC H3T 1J4, Canada
- Institute of Nutrition and Functional Foods, Laval University, Quebec City, QC G1V 0A6, Canada;
| | - Edgard Delvin
- Research Centre, Sainte-Justine University Health Center, Montreal, QC H3T 1C5, Canada; (M.K.); (F.F.); (S.S.); (E.D.)
- Department of Biochemistry, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Emile Levy
- Research Centre, Sainte-Justine University Health Center, Montreal, QC H3T 1C5, Canada; (M.K.); (F.F.); (S.S.); (E.D.)
- Department of Nutrition, Université de Montréal, Montreal, QC H3T 1J4, Canada
- Institute of Nutrition and Functional Foods, Laval University, Quebec City, QC G1V 0A6, Canada;
- Department of Pediatrics, Université de Montréal, Montreal, QC H3T 1J4, Canada
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Curcumin Inhibits Hepatocellular Carcinoma via Regulating miR-21/TIMP3 Axis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:2892917. [PMID: 32724322 PMCID: PMC7382716 DOI: 10.1155/2020/2892917] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 05/22/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022]
Abstract
Background/Aim Curcumin exhibits anticancer effects against various types of cancer including hepatocellular carcinoma (HCC). miR-21 has been reported to be involved in the malignant biological properties of HCC. However, whether miR-21 plays a role in curcumin-mediated treatment of HCC is unknown. The purpose of this study was to identify the potential functions and mechanisms of miR-21 in curcumin-mediated treatment of HCC. Methods The anticancer effects of curcumin were assessed in vivo and in vitro. The underlying mechanism of miR-21 in curcumin-mediated treatment of HCC was assessed by quantitative real-time PCR (RT-qPCR), western blot, and Dual-Luciferase Reporter assays. Results The present study revealed that curcumin suppressed HCC growth in vivo and inhibited HCC cell proliferation and induced cell apoptosis in a dose-dependent manner in vitro. Meanwhile, the curcumin treatment can downregulate miR-21 expression, upregulate TIMP3 expression, and inhibit the TGF-β1/smad3 signaling pathway. miR-21 inhibition enhanced the effect of curcumin on cell proliferation inhibition, apoptosis, and TGF-β1/smad3 signaling pathway inhibition in HepG2 and HCCLM3 cells. It demonstrated that TIMP3 was a direct target gene of miR-21. Interestingly, the effect of miR-21 inhibition on cell proliferation, apoptosis, and TGF-β1/smad3 signaling pathway in HepG2 and HCCLM3 cells exposed to curcumin was attenuated by TIMP3 silencing. Conclusion Taken together, the present study suggests that miR-21 is involved in the anticancer activities of curcumin through targeting TIMP3, and the mechanism possibly refers to the inhibition of TGF-β1/smad3 signaling pathway.
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Weis KE, Raetzman LT. Genistein inhibits proliferation and induces senescence in neonatal mouse pituitary gland explant cultures. Toxicology 2019; 427:152306. [PMID: 31593742 DOI: 10.1016/j.tox.2019.152306] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/26/2019] [Accepted: 10/02/2019] [Indexed: 12/27/2022]
Abstract
Genistein is an isoflavone abundant in soybean and infants are exposed to high levels of genistein in soy-based formula. It is known that genistein mediates estrogen receptor (ER) signaling, and exposure during neonatal development could cause acute and long term endocrine effects. We assayed genistein's impact on the neonatal mouse pituitary gland because it is an endocrine signaling hub and is sensitive to endocrine disruption during critical periods. Pituitary explant cultures, which actively proliferate and differentiate, were exposed to 0.06 μM-36 μM genistein and assayed for mRNA and protein changes. Genistein induced mRNA expression of the ERα regulated gene, Cckar, to the same magnitude as estradiol (E2) but with less potency. Interestingly, 36 μM genistein strongly inhibited pituitary proliferation, measured by a reduction in mKi67 mRNA and phospho-Histone H3 immunostaining. Examining cell cycle dynamics, we found that 36 μM genistein decreased Ccnb1 (Cyclin B1) mRNA; while mRNA for the cyclin dependent kinase inhibitor Cdkn1a (p21) was upregulated, correlated with an apparent increase in p21 immunostained cells. Strikingly, we observed a robust onset of cellular senescence, permanent cell cycle exit, in 36 μM genistein treated pituitaries by increased senescence activated β-galactosidase staining. We also found that 36 μM genistein decreased Bcl2 mRNA levels, a gene protective against apoptosis. Taken together these data suggest that genistein exposure during the neonatal period could initiate senescence and halt proliferation during a time when the proper numbers of endocrine cells are being established for mature gland function.
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Affiliation(s)
- Karen E Weis
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois, 61801, USA
| | - Lori T Raetzman
- Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois, 61801, USA.
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Sanaei M, Kavoosi F. Effect of DNA Methyltransferase in Comparison to and
in Combination with Histone Deacetylase Inhibitors on
Hepatocellular Carcinoma HepG2 Cell Line. Asian Pac J Cancer Prev 2019; 20:1119-1125. [PMID: 31030484 PMCID: PMC6948907 DOI: 10.31557/apjcp.2019.20.4.1119] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Background: DNA demethylating agents and histone deacetylase inhibitors can affect reactivation of gene expression and apoptosis induction by DNA acetylation and demethylation. The aim of the present study was to analyze the effects of DNA demethylating agent genistein (GE) and histone deacetylase inhibitor valproic acid VPA), alone and combined, on hepatocellular carcinoma Hep G2 cell line. Methods: The cells were treated with various doses of genistein and valproic acid (alone and combined) and the MTT assay and flow cytometry were used to determine cell viability and apoptosis. Results: Genistein and valproic acid inhibited the growth of HepG 2 cells significantly. Result of flow cytometry demonstrated that genistein and valproic acid (alone and combined) induce apoptosis significantly in a timedependent manner. Conclusions: Genistein and valproic acid can significantly inhibit proliferation and induce apoptosis in HepG2 cell line. The apoptotic effects of GE in combination with VPA were more significant that of each compound alone.
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Affiliation(s)
- Masumeh Sanaei
- Research Center for Non-Communicable Diseases, Jahrom University of Medical Sciences, Jahrom, Iran.
| | - Fraidoon Kavoosi
- Research Center for Non-Communicable Diseases, Jahrom University of Medical Sciences, Jahrom, Iran.
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Soleimani A, Pashirzad M, Avan A, Ferns GA, Khazaei M, Hassanian SM. Role of the transforming growth factor-β signaling pathway in the pathogenesis of colorectal cancer. J Cell Biochem 2018; 120:8899-8907. [PMID: 30556274 DOI: 10.1002/jcb.28331] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 11/28/2018] [Indexed: 12/22/2022]
Abstract
The transforming growth factor-β (TGF-β) signaling pathway plays an important role in cancer cell proliferation, growth, metastasis, and apoptosis. It has been shown that TGF-β acts as a tumor suppressor in the early stages of the disease, and as a tumor promoter in its late stages. Mutations in the TGF-β signaling components, the TGF-β receptors and cytoplasmic signaling transducers, are frequently observed in colorectal carcinomas. Exploiting specific TGF-β receptor agonist and antagonist with antitumor properties may be a way of controlling cancer progression. This review summarizes the regulatory role of TGF-β signaling in the pathogenesis of colorectal cancer.
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Affiliation(s)
- Atena Soleimani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Pashirzad
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Brighton, UK
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Tiwari A, Saraf S, Verma A, Panda PK, Jain SK. Novel targeting approaches and signaling pathways of colorectal cancer: An insight. World J Gastroenterol 2018; 24:4428-4435. [PMID: 30357011 PMCID: PMC6196338 DOI: 10.3748/wjg.v24.i39.4428] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 08/24/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer of mortality in the world. Chemotherapy based treatment leads to innumerable side effects as it delivers the anticancer drug to both normal cells besides cancer cells. Sonic Hedgehog (SHH), Wnt wingless-type mouse mammary tumor virus/β-catenin, transforming growth factor-β/SMAD, epidermal growth factor receptor and Notch are the main signaling pathways involved in the progression of CRC. Targeted therapies necessitate information regarding the particular aberrant pathways. Advancements in gene therapies have resulted in the recognition of novel therapeutic targets related with these signal-transduction cascades. CRC is a step-wise process where mutations occur over the time and activation of oncogenes and deactivation of tissue suppressor genes takes place. Genetic changes which are responsible for the induction of carcinogenesis include loss of heterozygosity in tumor suppressor genes such as adenomatous polyposis coli, mutation or deletion of genes like p53 and K-ras. Therefore, many gene-therapy approaches like gene correction, virus-directed enzyme-prodrug therapy, immunogenetic manipulation and virotherapy are currently being explored. Development of novel strategies for the safe and effective delivery of drugs to the cancerous site is the need of the hour. This editorial accentuates different novel strategies with emphasis on gene therapy and immunotherapy for the management of CRC.
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Affiliation(s)
- Ankita Tiwari
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Shivani Saraf
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Amit Verma
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Pritish Kumar Panda
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
| | - Sanjay K Jain
- Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar 470003, India
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Cai X, Wang L, Wang X, Hou F. Silence of IGFBP7 suppresses apoptosis and epithelial mesenchymal transformation of high glucose induced-podocytes. Exp Ther Med 2018; 16:1095-1102. [PMID: 30112052 PMCID: PMC6090473 DOI: 10.3892/etm.2018.6298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 02/16/2018] [Indexed: 12/15/2022] Open
Abstract
Insulin-like growth factor-binding protein 7 (IGFBP7) has been identified as a secreted protein associated with a number of cellular processes. However, the specific regulatory mechanisms of IGFBP7 on podocytes of diabetic nephropathy (DN) are yet to be elucidated. In the present study, podocytes were identified initially via an immunofluorescence assay using an anti-synaptopodin antibody. It was subsequently demonstrated that glucose promoted podocyte proliferation in a time- and dose-dependent manner via MTT assay. In addition, IGFBP7 expression was silenced in podocytes via siRNA, the effects of which were evaluated using western blotting and reverse transcription-quantitative polymerase chain reaction. It was demonstrated that silencing IGFBP7 inhibited apoptosis and epithelial mesenchymal transformation (EMT) of podocytes mediated by high glucose (HG). Transforming growth factor (TGF)-β1/mothers against decapentaplegic homolog (Smad) signaling was associated with proliferation, apoptotic activities and EMT. Therefore, the expression levels of TGF-β1/Smad pathway were detected, and it was observed that silencing IGFBP7 suppressed the TGF-β1/Smad pathway in podocytes induced by HG. These findings suggested that IGFBP7 may serve as a potential therapeutic target for DN.
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Affiliation(s)
- Xiaojun Cai
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang 150036, P.R. China
| | - Lei Wang
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang 150036, P.R. China
| | - Xuling Wang
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang 150036, P.R. China
| | - Fengyan Hou
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang 150036, P.R. China
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Peng Y, Jiang B, Wu H, Dai R, Tan L. Effects of genistein on neuronal apoptosis, and expression of Bcl-2 and Bax proteins in the hippocampus of ovariectomized rats. Neural Regen Res 2014; 7:2874-81. [PMID: 25317139 PMCID: PMC4190945 DOI: 10.3969/j.issn.1673-5374.2012.36.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Accepted: 08/01/2012] [Indexed: 11/18/2022] Open
Abstract
Genistein is one of several isoflavones that has a structure similar to 17β-estradiol, has a strong antioxidant effect, and a high affinity to estrogen receptors. At 15 weeks after ovariectomy, the expression of Bcl-2 in the hippocampus of rats decreased and Bax expression increased, with an obvious upregulation of apoptosis. However, intraperitoneal injection of genistein or 17β-estradiol for 15 consecutive weeks from the second day after operation upregulated Bcl-2 protein expression, downregulated Bax protein expression, and attenuated hippocampal neuron apoptosis. Our experimental findings indicate that long-term intervention with genistein can lead to a decrease in apoptosis in hippocampal neurons following ovariectomy, upregulate the expression of Bcl-2, and downregulate the expression of Bax. In addition, genistein and 17β-estradiol play equal anti-apoptotic and neuroprotective roles.
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Affiliation(s)
- Yun Peng
- Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Bo Jiang
- Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Huiling Wu
- Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Ruchun Dai
- Institute of Endocrinology and Metabolism, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Liming Tan
- Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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XUE JIAPENG, WANG GENG, ZHAO ZONGBIN, WANG QUN, SHI YUN. Synergistic cytotoxic effect of genistein and doxorubicin on drug-resistant human breast cancer MCF-7/Adr cells. Oncol Rep 2014; 32:1647-53. [DOI: 10.3892/or.2014.3365] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 07/11/2014] [Indexed: 11/05/2022] Open
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Schiller V, Wichmann A, Kriehuber R, Schäfers C, Fischer R, Fenske M. Transcriptome alterations in zebrafish embryos after exposure to environmental estrogens and anti-androgens can reveal endocrine disruption. Reprod Toxicol 2013; 42:210-23. [PMID: 24051129 DOI: 10.1016/j.reprotox.2013.09.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Revised: 08/13/2013] [Accepted: 09/07/2013] [Indexed: 12/16/2022]
Abstract
Exposure to environmental chemicals known as endocrine disruptors (EDs) is in many cases associated with an unpredictable hazard for wildlife and human health. The identification of endocrine disruptive properties of chemicals certain to enter the aquatic environment relies on toxicity tests with fish, assessing adverse effects on reproduction and sexual development. The demand for quick, reliable ED assays favored the use of fish embryos as alternative test organisms. We investigated the application of a transcriptomics-based assay for estrogenic and anti-androgenic chemicals with zebrafish embryos. Two reference compounds, 17α-ethinylestradiol and flutamide, were tested to evaluate the effects on development and the transcriptome after 48h-exposures. Comparison of the transcriptome response with other estrogenic and anti-androgenic compounds (genistein, bisphenol A, methylparaben, linuron, prochloraz, propanil) showed commonalities and differences in regulated pathways, enabling us to classify the estrogenic and anti-androgenic potencies. This demonstrates that different mechanism of ED can be assessed already in fish embryos.
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Affiliation(s)
- Viktoria Schiller
- Fraunhofer Institute for Molecular Biology and Applied Ecology, 52074 Aachen, Germany.
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Li YS, Wu LP, Li KH, Liu YP, Xiang R, Zhang SB, Zhu LY, Zhang LY. Involvement of nuclear factor κB (NF-κB) in the downregulation of cyclooxygenase-2 (COX-2) by genistein in gastric cancer cells. J Int Med Res 2012; 39:2141-50. [PMID: 22289529 DOI: 10.1177/147323001103900610] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Genistein induces growth inhibition in various human cancer cell lines but its mechanism of action remains unknown. This study determined whether the effect of genistein is mediated via suppression of cyclo-oxygenase (COX)-2 protein, and elucidated the mechanism of action of this effect in the human gastric cancer cell line BGC-823. Genistein treatment inhibited cell proliferation and induced apoptosis in a dose- and time-dependent manner; Western blotting analysis indicated a significant dose-dependent decrease in COX-2 protein levels. Genistein treatment exerted a significant inhibitory effect on activation of the transcription factor nuclear factor κB (NF-κB). Additionally, the NF-κB inhibitor pyrrolidine dithiocarbamate caused a reduction in COX-2 protein levels and NF-κB activation, similar to the effect of genistein. Suppression of COX-2 protein may be important for the antiproliferative and proapoptotic effects of genistein in BGC-823 cells, and these effects may be partly mediated through the NF-κB pathway.
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Affiliation(s)
- Y-S Li
- Department of Orthopaedics, Xiangya Hospital, Shenzhen, China
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Lin JH, Morikawa T, Chan AT, Kuchiba A, Shima K, Nosho K, Kirkner G, Zhang SM, Manson JE, Giovannucci E, Fuchs CS, Ogino S. Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression. Cancer Res 2012; 72:3020-8. [PMID: 22511578 DOI: 10.1158/0008-5472.can-11-2619] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell-cycle regulators. However, epidemiologic studies evaluating hormone therapy use and colorectal cancer risk by the status of cell-cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between hormone therapy use and colorectal cancer risk differs by the molecular pathologic status of microsatellite instability (MSI) and expression of cell-cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between hormone therapy use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105,520 postmenopausal women. We found a difference between hormone therapy use and colorectal cancer risk according to CDKN1A expression (P(heterogeneity) = 0.01). Current hormone therapy use was associated with a reduced risk for CDKN1A-nonexpressed [multivariate relative risk (RR), 0.61; 95% confidence interval (CI), 0.46-0.82] but not for CDKN1A-expressed (RR, 1.32; 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A-nonexpressed but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between hormone therapy use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular pathological epidemiology findings suggest a preventive effect of hormone therapy against colorectal carcinogenesis that depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.
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Affiliation(s)
- Jennifer H Lin
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.
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15
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Giroux V, Bernatchez G, Carrier JC. Chemopreventive effect of ERβ-Selective agonist on intestinal tumorigenesis in Apc(Min/+) mice. Mol Carcinog 2010; 50:359-69. [PMID: 21480389 DOI: 10.1002/mc.20719] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Revised: 11/02/2010] [Accepted: 11/03/2010] [Indexed: 12/17/2022]
Abstract
Epidemiological and experimental evidence suggests that estrogen replacement therapy reduces the risk of colon cancer in postmenopausal women. Estrogen receptor beta (ERβ) is thought to be the principal mediator of the estrogen effect in the colon. Recent studies by our team suggested positive regulation of the transforming growth factor (TGF)β pathway by estrogen in mice colonocytes. We therefore wanted to investigate the effects of ERβ agonist treatment on intestinal tumorigenesis in Apc(Min/+) mice. Weaned Apc(Min/+) mice were injected subcutaneously three times a week for 12 wk with vehicle or ERβ-selective agonist, diarylpropionitrile (DPN, 5 mg/kg). DPN administration resulted in a significant reduction in small intestinal polyp multiplicity in both Apc(Min/+) male and female mice. Furthermore, the mean diameter of small intestinal polyps was lower in DPN-treated than vehicle-treated males, along with lower BrdU incorporation indices in jejunal and colon epithelial cells of both sexes. DPN treatment also increased apoptosis in colon epithelium as measured by TUNEL assay and cleaved caspase 3 quantification. The effect of DPN on various components of the TGFβ pathway was also studied in colonocytes. DPN treatment increased expression of TGFβ1 and TGFβ3 transcripts, levels of nuclear and phosphorylated Smad2 as well as p27 cell-cycle inhibitor, a TGFβ pathway target gene. Our results demonstrate that DPN treatment reduces intestinal tumorigenesis in Apc(Min/+) mice. Furthermore, we suggest that positive regulation of the TGFβ pathway by ERβ activation could contribute to the protective role of estrogen in intestinal tumor development.
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Affiliation(s)
- Véronique Giroux
- Faculty of Medicine and Health Sciences, Department of Medicine and Anatomy and Cellular Biology, CIHR Team on Digestive Epithelium, Université de Sherbrooke, Sherbrooke, Québec, Canada
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16
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Effects of genistein on secretion of extracellular matrix components and transforming growth factor beta in high-glucose-cultured rat mesangial cells. J Artif Organs 2009; 12:242-6. [DOI: 10.1007/s10047-009-0479-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2008] [Accepted: 10/14/2009] [Indexed: 01/08/2023]
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17
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Song H, Guo B, Zhang J, Song C. Transforming Growth Factor-β Suppressed Id-1 Expression in a smad3-Dependent Manner in LoVo Cells. Anat Rec (Hoboken) 2009; 293:42-7. [DOI: 10.1002/ar.21012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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18
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Cross HS, Kallay E. Regulation of the colonic vitamin D system for prevention of tumor progression: an update. Future Oncol 2009; 5:493-507. [DOI: 10.2217/fon.09.22] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A compromised vitamin D status and nutritional calcium deficit are linked with sporadic colorectal cancer incidence. 25(OH)D3 serum concentration is a major determinant of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) synthesis in colonic mucosa, which expresses the vitamin D receptor and both the synthesizing (CYP27B1) and catabolic (CYP24A1) hydroxylases. Receptor-bound, 1,25(OH)2D3 regulates proliferation, differentiation and apoptosis in an autocrine/paracrine manner. During early malignancy 1,25(OH)2D3 synthesis is often enhanced to counteract hyperproliferation. In many advanced tumors, vitamin D catabolism surpasses synthesis. In vivo, expression and activity of CYP27B1 and vitamin D receptor are stimulated by (phyto)estrogens. Conversely, low nutritional calcium and folate enhance vitamin D catabolism. These insights could explain the lower colorectal cancer incidence in females, the chemopreventive potency of vitamin D and calcium against colorectal cancer, and the benefit of nutritional folate as a methyl donor for epigenetic regulation of the vitamin D system.
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Affiliation(s)
- Heide S Cross
- Department of Pathophysiology, Medical University of Vienna, Waehringerguertel 18–20, A-1090 Vienna, Austria
| | - Enikoe Kallay
- Department of Pathophysiology, Medical University of Vienna, Waehringerguertel 18–20, A-1090 Vienna, Austria
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19
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Kim YS, Young MR, Bobe G, Colburn NH, Milner JA. Bioactive food components, inflammatory targets, and cancer prevention. Cancer Prev Res (Phila) 2009; 2:200-8. [PMID: 19258539 DOI: 10.1158/1940-6207.capr-08-0141] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Various dietary components may modify chronic inflammatory processes at the stage of cytokine production, amplification of nuclear factor-kappaB-mediated inflammatory gene expression, and the release of anti-inflammatory cytokine, transforming growth factor-beta. This review provides a synopsis of the strengths and weaknesses of the evidence that specific bioactive food components influence inflammation-related targets linked to cancer. A target repeatedly surfacing as a site of action for several dietary components is transforming growth factor beta. Whereas the use of dietary intervention strategies offers intriguing possibilities for maintaining normal cell function by modifying a process that is essential for cancer development and progression, more information is needed to characterize the minimum quantity of the bioactive food components required to bring about a change in inflammation-mediated cancer, the ideal time for intervention, and the importance of genetics in determining the response. Unquestionably, the societal benefits of using foods and their components to prevent chronic inflammation and associated complications, including cancer, are enormous.
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Affiliation(s)
- Young S Kim
- Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
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20
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Production of apoptosis-inducing substances from soybean protein by Clostridium butyricum: characterization of their toxic effects on human colon carcinoma cells. Cancer Lett 2009; 277:190-8. [PMID: 19147278 DOI: 10.1016/j.canlet.2008.12.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2008] [Revised: 12/02/2008] [Accepted: 12/03/2008] [Indexed: 11/21/2022]
Abstract
Microbial metabolism of soybean constituents is known to produce novel active substances as a chemopreventive agent during the fermentation, and enterobacteria are expected to produce chemopreventive agents as a consequence of metabolizing soybean constituents in the intestinal tract. Then, the conditioned medium was prepared by culturing an enterobacterium Clostridium butyricum (C. butyricum) with soybean protein, and its direct effect on human colon carcinoma HCT116 cells was examined. The conditioned medium was shown to induce the cell death, and suggested to contain novel apoptosis-inducing substances. Thus, enterobacteria are predicted to produce anti-tumor substances from food-derived proteins within the intestinal tract.
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21
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Craft CS, Xu L, Romero D, Vary CPH, Bergan RC. Genistein induces phenotypic reversion of endoglin deficiency in human prostate cancer cells. Mol Pharmacol 2008; 73:235-42. [PMID: 17951357 DOI: 10.1124/mol.107.038935] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2025] Open
Abstract
Genistein has been shown to inhibit human prostate cancer (PCa) cell motility. Endoglin has been identified as an important suppressor of PCa cell motility, and its expression is lost during PCa progression. It is therefore important to determine whether endoglin loss affects genistein's efficacy and, if so, by what mechanism. In the current study, genistein was shown to induce reversion of endoglin-deficient cells to a low motility, endoglin-replete phenotype. Because endoglin suppresses PCa cell motility in an activin-like kinase receptor-2 (ALK2)- and Smad1-dependent manner, we sought to determine whether genistein was activating the ALK2-Smad1 pathway. Although treatment with genistein or overexpression of Smad1 or ALK2 all increased Smad1-responsive promoter activity and decreased cell motility, genistein's efficacy was abrogated by either Smad1 or ALK2 knockdown. Furthermore, transfection of cells with a kinase dead mutant of ALK2 abrogated genistein's efficacy. Together, these findings demonstrate that genistein therapeutically induces reversion to a low-motility phenotype in aggressive endoglin-deficient PCa cells. It does so by activating ALK2-Smad1 endoglin-associated signaling. These findings support the notion that individuals with low endoglin-expressing PCa will benefit from genistein treatment.
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Affiliation(s)
- Clarissa S Craft
- Division of Hematology/Oncology, Department of Medicine, Northwestern University, Olson 8321, 710 North Fairbanks, Chicago, IL 60610-3008, USA
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Abstract
Phytoestrogens are estrogen-like substances produced by plants that account for some of the constituents present in vegetation that may be responsible for the health benefits of a diet rich in fruit and vegetables. Phytoestrogens have a plethora of different actions that they are capable of exerting on cellular metabolism. This review will focus on some of the major non-estrogen receptor-mediated cellular effects used by phytoestrogens and will draw attention to the fact that while they may have a number of beneficial effects, particularly in offering a protective effect against some hormone-dependent cancers, such as breast and prostate cancer, they may also have possible unfavorable effects by interfering with the functioning of normal cellular activities such as receptor-mediated signal transduction and DNA replication, as well as being genotoxic, mutagenic and promoting the proliferation of some cancer cells.
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Affiliation(s)
- Jan H J Martin
- University of Wolverhampton, Research Institute of Healthcare Science, Wulfruna Street, Wolverhampton, UK.
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