臺灣博碩士論文加值系統

Background: β-amyloid (Aβ) formation in the brain is one of the characteristics of Alzheimer’s disease (AD). This peptide is the central role in the pathogenesis of AD with apoptosis comes out as the result. The effects of estrogen replacement therapy (ERT) on AD have been recognized, although associated with increased incidence of estrogen related cancer such as breast cancer. Equol is the metabolite form of daidzein, one of the major isoflavones in soybean product. By acting like estrogen, equol may have the same neuroprotective effect with estrogen that prevents the neuron cell apoptosis process.
Aim: This study investigated the neuroprotective effects of equol on cell apoptosis by regulating the cell cycle event and protein related through possible mechanism.
Methods: The SH-SY5Y neuroblastoma cells were exposed by 1 μM Aβ (25-35) for 24 h. To know the neuroprotective effect of equol and estradiol, either 1 μM S-equol or 10 nM 17β-estradiol was treated to cells 24 h prior to Aβ (25-35) exposure. Apoptotic cell death and cell cycle distributions were detected by flow cytometry, while Western blot was used to analyse the protein expression such as cyclin D1, estrogen receptor, SRC-1, and ERK 1/2. 1 μM of ICI 182,780 as estrogen receptor inhibitor was treated to the cells 1 h before estrogen or equol exposure to investigate the involvement of estrogen receptor in the mechanism.
Results: Following a 24 h exposure of the cells to amyloid β-peptide fragment 25-35 (Aβ 25-35), a significant reduction in cell survival and re-entry of cell cycle process which may lead to cell apoptosis were observed. However, pre-treatment of the cells with equol or estradiol prior to Aβ (25-35) exposure elevated the cell survival and prevent the cells to re-enter its cycle. As one of the marker of cell cycle re-entry, cyclin D1, was also decreased in the cells with equol or estradiol pre-treatment. The expression of phosphorylated form of ERK 1/2 was elevated as Aβ (25-35) treatment group. Regulated activation of ERK 1/2 seems to also regulate the expression of cyclin D1 thus modulate the cell cycle event. Group of cells with ICI 182,780 pre-treatment had no expression in estrogen receptor protein. Exposure to (Aβ 25-35) also decreased the expression of SRC-1 as estrogen receptor coactivator while pre-treatment with equol and estradiol could reverse this effect. These results indicated that the neuroprotective effect of equol and estradiol through estrogen receptor pathway and SRC-1 was involved in this mechanism.
Conclusion: Phytoestrogen equol may effectively antagonize Aβ (25-35)-induced cell toxicity by preventing the cell cycle re-entry and apoptotic cell through ERK 1/2 and estrogen receptor pathway, in a manner similar to estradiol. Our results suggested that equol was effective as a potential substitute of estrogen for Alzheimer’s disease.

Background: β-amyloid (Aβ) formation in the brain is one of the characteristics of Alzheimer’s disease (AD). This peptide is the central role in the pathogenesis of AD with apoptosis comes out as the result. The effects of estrogen replacement therapy (ERT) on AD have been recognized, although associated with increased incidence of estrogen related cancer such as breast cancer. Equol is the metabolite form of daidzein, one of the major isoflavones in soybean product. By acting like estrogen, equol may have the same neuroprotective effect with estrogen that prevents the neuron cell apoptosis process.
Aim: This study investigated the neuroprotective effects of equol on cell apoptosis by regulating the cell cycle event and protein related through possible mechanism.
Methods: The SH-SY5Y neuroblastoma cells were exposed by 1 μM Aβ (25-35) for 24 h. To know the neuroprotective effect of equol and estradiol, either 1 μM S-equol or 10 nM 17β-estradiol was treated to cells 24 h prior to Aβ (25-35) exposure. Apoptotic cell death and cell cycle distributions were detected by flow cytometry, while Western blot was used to analyse the protein expression such as cyclin D1, estrogen receptor, SRC-1, and ERK 1/2. 1 μM of ICI 182,780 as estrogen receptor inhibitor was treated to the cells 1 h before estrogen or equol exposure to investigate the involvement of estrogen receptor in the mechanism.
Results: Following a 24 h exposure of the cells to amyloid β-peptide fragment 25-35 (Aβ 25-35), a significant reduction in cell survival and re-entry of cell cycle process which may lead to cell apoptosis were observed. However, pre-treatment of the cells with equol or estradiol prior to Aβ (25-35) exposure elevated the cell survival and prevent the cells to re-enter its cycle. As one of the marker of cell cycle re-entry, cyclin D1, was also decreased in the cells with equol or estradiol pre-treatment. The expression of phosphorylated form of ERK 1/2 was elevated as Aβ (25-35) treatment group. Regulated activation of ERK 1/2 seems to also regulate the expression of cyclin D1 thus modulate the cell cycle event. Group of cells with ICI 182,780 pre-treatment had no expression in estrogen receptor protein. Exposure to (Aβ 25-35) also decreased the expression of SRC-1 as estrogen receptor coactivator while pre-treatment with equol and estradiol could reverse this effect. These results indicated that the neuroprotective effect of equol and estradiol through estrogen receptor pathway and SRC-1 was involved in this mechanism.
Conclusion: Phytoestrogen equol may effectively antagonize Aβ (25-35)-induced cell toxicity by preventing the cell cycle re-entry and apoptotic cell through ERK 1/2 and estrogen receptor pathway, in a manner similar to estradiol. Our results suggested that equol was effective as a potential substitute of estrogen for Alzheimer’s disease.

ABSTRACT i
Acknowledgement ii
Table of Contents iv
List of Figures vi
1. INTRODUCTION 1
1.1 Background 1
1.2 Aim of the Study 6
1.3 Objectives 6
2. LITERATURE REVIEW 7
2.1 Alzheimer’s Disease 7
2.2 Beta amyloid (Aβ) 7
2.3 Apoptosis 9
2.4 Cell Cycle 11
2.5 Cyclin D1 14
2.6 ERK 1/2 16
2.7 Steroid Receptor Coactivator-1 (SRC-1) 19
2.8 Estrogen receptor 20
2.9 Estrogen 24
2.10 Equol 26
3. HYPOTHESIS AND RESEARCH INNOVATION 30
3.1 Hypothesis 30
3.2 Research Innovation 31
4. PRELIMINARY STUDY 32
4.1 Aβ(25-35) 32
4.2 S-Equol 34
4.4 17β-Estradiol 36
4.5 ICI 182,780 37
5. MATERIALS AND METHODS 39
5.1 Flow Chart 39
5.2 Materials 41
5.3 Methods 41
5.3.1 Cell Culture 41
5.3.2 Treatments 42
5.3.3 Apoptotic Cells Analysis 42
5.3.4 Cell Cycle Analysis 43
5.3.5 Cell Viability 43
5.3.6 Protein Extraction and Quantification 44
5.3.7 Western blot analysis 44
5.3.8 Cell Morphology 45
5.4 Statistical analysis 45
6. RESULTS 46
6.1 Cell Viability 46
6.3 Cell Apoptosis 47
6.4 Cell Cycle 49
6.5 Cyclin D1 Protein Expression 51
6.6 Activation of ERK 1/2 52
6.7 SRC-1 Protein Expression 53
6.8 Estrogen Receptor Protein Expression 54
6.9 Cell Morphology 55
7. DISCUSSION 58
7.1 Activation of cell cycle in response to Aβ(25-35) is related to neuronal death 59
7.2 ERK 1/2 signalling controls cyclin D1 expression to regulate cell cycle re-entry 61
7.3 Estrogen receptor and SRC-1 are required for equol to regulates the downstream pathway 62
8. SIGNIFICANCE AND LIMITATION OF THIS STUDY 64
9. CONCLUSION 65
10. REFERENCES 66

ABIRU, Y., KUMEMURA, M., UENO, T., UCHIYAMA, S. & MASAKI, K. 2012. Discovery of an S-equol rich food stinky tofu, a traditional fermented soy product in Taiwan. Int J Food Sci Nutr, 63, 964-70.
AKAZA, H., MIYANAGA, N., TAKASHIMA, N., NAITO, S., HIRAO, Y., TSUKAMOTO, T., FUJIOKA, T., MORI, M., KIM, W. J., SONG, J. M. & PANTUCK, A. J. 2004. Comparisons of percent equol producers between prostate cancer patients and controls: case-controlled studies of isoflavones in Japanese, Korean and American residents. Jpn J Clin Oncol, 34, 86-9.
ANDERSON, N. B., BULATAO, R. A. & COHEN, B. 2004. Critical Perspectives on Racial and Ethnic Differences in Health in Late Life, Washington, D.C, The National Academic Press.
ASCENZI, P., BOCEDI, A. & MARINO, M. 2006. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol Aspects Med, 27, 299-402.
ASO, T., UCHIYAMA, S., MATSUMURA, Y., TAGUCHI, M., NOZAKI, M., TAKAMATSU, K., ISHIZUKA, B., KUBOTA, T., MIZUNUMA, H. & OHTA, H. 2012. A natural S-equol supplement alleviates hot flushes and other menopausal symptoms in equol nonproducing postmenopausal Japanese women. J Womens Health (Larchmt), 21, 92-100.
ATKINSON, C., FRANKENFELD, C. L. & LAMPE, J. W. 2005. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Exp Biol Med (Maywood), 230, 155-70.
AUGER, A. P., TETEL, M. J. & MCCARTHY, M. M. 2000. Steroid receptor coactivator-1 (SRC-1) mediates the development of sex-specific brain morphology and behavior. Proc Natl Acad Sci U S A, 97, 7551-5.
BANG, O. Y., HONG, H. S., KIM, D. H., KIM, H., BOO, J. H., HUH, K. & MOOK-JUNG, I. 2004. Neuroprotective effect of genistein against beta amyloid-induced neurotoxicity. Neurobiol Dis, 16, 21-8.
BEHL, C. 1999. Alzheimer''s disease and oxidative stress: implications for novel therapeutic approaches. Prog Neurobiol, 57, 301-23.
BEHL, C., WIDMANN, M., TRAPP, T. & HOLSBOER, F. 1995. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun, 216, 473-82.
BELCHER, S. M. & ZSARNOVSZKY, A. 2001. Estrogenic actions in the brain: estrogen, phytoestrogens, and rapid intracellular signaling mechanisms. J Pharmacol Exp Ther, 299, 408-14.
BERRIDGE, M. J. 2012a. Cell Cycle and Proliferation.
BERRIDGE, M. J. 2012b. Cell Signalling Pathway.
BLANC, F., POISBEAU, P., SELLAL, F., TRANCHANT, C., DE SEZE, J. & ANDRE, G. 2010. [Alzheimer disease, memory and estrogen]. Rev Neurol (Paris), 166, 377-88.
BORRAS, C., GAMBINI, J., GOMEZ-CABRERA, M. C., SASTRE, J., PALLARDO, F. V., MANN, G. E. & VINA, J. 2005. 17beta-oestradiol up-regulates longevity-related, antioxidant enzyme expression via the ERK1 and ERK2[MAPK]/NFkappaB cascade. Aging Cell, 4, 113-8.
BROOKMEYER, R., JOHNSON, E., ZIEGLER-GRAHAM, K. & ARRIGHI, H. M. 2007. Forecasting the global burden of Alzheimer''s disease. Alzheimers Dement, 3, 186-91.
BYRNES, K. R., STOICA, B. A., FRICKE, S., DI GIOVANNI, S. & FADEN, A. I. 2007. Cell cycle activation contributes to post-mitotic cell death and secondary damage after spinal cord injury. Brain, 130, 2977-92.
CHEUNG, E. C. & SLACK, R. S. 2004. Emerging role for ERK as a key regulator of neuronal apoptosis. Sci STKE, 2004, Pe45.
CHONG, Y. H., SHIN, Y. J., LEE, E. O., KAYED, R., GLABE, C. G. & TENNER, A. J. 2006. ERK1/2 activation mediates Abeta oligomer-induced neurotoxicity via caspase-3 activation and tau cleavage in rat organotypic hippocampal slice cultures. J Biol Chem, 281, 20315-25.
CHOW, V. W., MATTSON, M. P., WONG, P. C. & GLEICHMANN, M. 2010. An overview of APP processing enzymes and products. Neuromolecular Med, 12, 1-12.
CLEMENTI, M. E., MARINI, S., COLETTA, M., ORSINI, F., GIARDINA, B. & MISITI, F. 2005. Abeta(31-35) and Abeta(25-35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Role of the redox state of methionine-35. FEBS Lett, 579, 2913-8.
COPANI, A., CONDORELLI, F., CARUSO, A., VANCHERI, C., SALA, A., GIUFFRIDA STELLA, A. M., CANONICO, P. L., NICOLETTI, F. & SORTINO, M. A. 1999. Mitotic signaling by beta-amyloid causes neuronal death. FASEB J, 13, 2225-34.
COSGROVE, D. 2000. Estrogen as a treatment for Alzheimer disease. JAMA, 284, 307; author reply 308.
DONG, Y., YANG, N., LIU, Y., LI, Q. & ZUO, P. 2011. The neuroprotective effects of phytoestrogen alpha-zearalanol on beta-amyloid-induced toxicity in differentiated PC-12 cells. Eur J Pharmacol, 670, 392-8.
FIOCCHETTI, M., ASCENZI, P. & MARINO, M. 2012. Neuroprotective effects of 17beta-estradiol rely on estrogen receptor membrane initiated signals. Front Physiol, 3, 73.
FRASCA, G., CHIECHIO, S., VANCHERI, C., NICOLETTI, F., COPANI, A. & ANGELA SORTINO, M. 2004. Beta-amyloid-activated cell cycle in SH-SY5Y neuroblastoma cells: correlation with the MAP kinase pathway. J Mol Neurosci, 22, 231-6.
FRIEDLANDER, R. M. 2003. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med, 348, 1365-75.
GARCIA-SEGURA, L. M., AZCOITIA, I. & DONCARLOS, L. L. 2001. Neuroprotection by estradiol. Prog Neurobiol, 63, 29-60.
GONZALEZ-ARENAS, A., HANSBERG-PASTOR, V., HERNANDEZ-HERNANDEZ, O. T., GONZALEZ-GARCIA, T. K., HENDERSON-VILLALPANDO, J., LEMUS-HERNANDEZ, D., CRUZ-BARRIOS, A., RIVAS-SUAREZ, M. & CAMACHO-ARROYO, I. 2012. Estradiol increases cell growth in human astrocytoma cell lines through ERalpha activation and its interaction with SRC-1 and SRC-3 coactivators. Biochim Biophys Acta, 1823, 379-86.
GROSS, A., MCDONNELL, J. M. & KORSMEYER, S. J. 1999. BCL-2 family members and the mitochondria in apoptosis. Genes Dev, 13, 1899-911.
HERRUP, K. 2010. The involvement of cell cycle events in the pathogenesis of Alzheimer''s disease. Alzheimers Res Ther, 2, 13.
HOIKKALA, A., MUSTONEN, E., SAASTAMOINEN, I., JOKELA, T., TAPONEN, J., SALONIEMI, H. & WAHALA, K. 2007. High levels of equol in organic skimmed Finnish cow milk. Mol Nutr Food Res, 51, 782-6.
JOHNSON, A. B. & O''MALLEY, B. W. 2012. Steroid receptor coactivators 1, 2, and 3: critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy. Mol Cell Endocrinol, 348, 430-9.
JUNG, M. E., GATCH, M. B. & SIMPKINS, J. W. 2005. Estrogen neuroprotection against the neurotoxic effects of ethanol withdrawal: potential mechanisms. Exp Biol Med (Maywood), 230, 8-22.
KANDUC, D., MITTELMAN, A., SERPICO, R., SINIGAGLIA, E., SINHA, A. A., NATALE, C., SANTACROCE, R., DI CORCIA, M. G., LUCCHESE, A., DINI, L., PANI, P., SANTACROCE, S., SIMONE, S., BUCCI, R. & FARBER, E. 2002. Cell death: apoptosis versus necrosis (review). Int J Oncol, 21, 165-70.
KASTEN, M. M. & GIORDANO, A. 1998. pRb and the cdks in apoptosis and the cell cycle. Cell Death Differ, 5, 132-40.
KATO, S., ENDOH, H., MASUHIRO, Y., KITAMOTO, T., UCHIYAMA, S., SASAKI, H., MASUSHIGE, S., GOTOH, Y., NISHIDA, E., KAWASHIMA, H., METZGER, D. & CHAMBON, P. 1995. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science, 270, 1491-4.
KRANENBURG, O., VAN DER EB, A. J. & ZANTEMA, A. 1996. Cyclin D1 is an essential mediator of apoptotic neuronal cell death. Embo j, 15, 46-54.
KREIJKAMP-KASPERS, S., KOK, L., BOTS, M. L., GROBBEE, D. E., LAMPE, J. W. & VAN DER SCHOUW, Y. T. 2005. Randomized controlled trial of the effects of soy protein containing isoflavones on vascular function in postmenopausal women. Am J Clin Nutr, 81, 189-95.
LAFERLA, F. M., GREEN, K. N. & ODDO, S. 2007. Intracellular amyloid-beta in Alzheimer''s disease. Nat Rev Neurosci, 8, 499-509.
LAHAD, A. & ISHAY, L. 2003. Estrogen replacement and risk of Alzheimer disease. JAMA, 289, 1100-1; author reply 1101-2.
LEE, K. Y., KOH, S. H., NOH, M. Y., KIM, S. H. & LEE, Y. J. 2008. Phosphatidylinositol-3-kinase activation blocks amyloid beta-induced neurotoxicity. Toxicology, 243, 43-50.
LEVIN, E. R. 2005. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol, 19, 1951-9.
LI, Y. P., BUSHNELL, A. F., LEE, C. M., PERLMUTTER, L. S. & WONG, S. K. 1996. Beta-amyloid induces apoptosis in human-derived neurotypic SH-SY5Y cells. Brain Res, 738, 196-204.
LU, Q., PALLAS, D. C., SURKS, H. K., BAUR, W. E., MENDELSOHN, M. E. & KARAS, R. H. 2004. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha. Proc Natl Acad Sci U S A, 101, 17126-31.
LU, Z. & XU, S. 2006. ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life, 58, 621-31.
LUO, S., LAN, T., LIAO, W., ZHAO, M. & YANG, H. 2012. Genistein inhibits Abeta(2)(5)(-)(3)(5) -induced neurotoxicity in PC12 cells via PKC signaling pathway. Neurochem Res, 37, 2787-94.
MALIK, B., CURRAIS, A., ANDRES, A., TOWLSON, C., PITSI, D., NUNES, A., NIBLOCK, M., COOPER, J., HORTOBAGYI, T. & SORIANO, S. 2008. Loss of neuronal cell cycle control as a mechanism of neurodegeneration in the presenilin-1 Alzheimer''s disease brain. Cell Cycle, 7, 637-46.
MARINO, M., GALLUZZO, P. & ASCENZI, P. 2006. Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics, 7, 497-508.
MATHEY, J., LAMOTHE, V., COXAM, V., POTIER, M., SAUVANT, P. & BENNETAU-PELISSERO, C. 2006. Concentrations of isoflavones in plasma and urine of post-menopausal women chronically ingesting high quantities of soy isoflavones. J Pharm Biomed Anal, 41, 957-65.
MCBRIDE, H. M., NEUSPIEL, M. & WASIAK, S. 2006. Mitochondria: more than just a powerhouse. Curr Biol, 16, R551-60.
MCSHEA, A., WAHL, A. F. & SMITH, M. A. 1999. Re-entry into the cell cycle: a mechanism for neurodegeneration in Alzheimer disease. Med Hypotheses, 52, 525-7.
MEIJER, O. C., STEENBERGEN, P. J. & DE KLOET, E. R. 2000. Differential expression and regional distribution of steroid receptor coactivators SRC-1 and SRC-2 in brain and pituitary. Endocrinology, 141, 2192-9.
MILLUCCI, L., GHEZZI, L., BERNARDINI, G. & SANTUCCI, A. 2010. Conformations and biological activities of amyloid beta peptide 25-35. Curr Protein Pept Sci, 11, 54-67.
MISITI, S., SCHOMBURG, L., YEN, P. M. & CHIN, W. W. 1998. Expression and hormonal regulation of coactivator and corepressor genes. Endocrinology, 139, 2493-500.
MODI, P. K., KOMARAVELLI, N., SINGH, N. & SHARMA, P. 2012. Interplay between MEK-ERK signaling, cyclin D1, and cyclin-dependent kinase 5 regulates cell cycle reentry and apoptosis of neurons. Mol Biol Cell, 23, 3722-30.
MOLENDA, H. A., GRIFFIN, A. L., AUGER, A. P., MCCARTHY, M. M. & TETEL, M. J. 2002. Nuclear receptor coactivators modulate hormone-dependent gene expression in brain and female reproductive behavior in rats. Endocrinology, 143, 436-44.
MOLTENI, A., BRIZIO-MOLTENI, L. & PERSKY, V. 1995. In vitro hormonal effects of soybean isoflavones. J Nutr, 125, 751S-756S.
MORTON, M. S., ARISAKA, O., MIYAKE, N., MORGAN, L. D. & EVANS, B. A. 2002. Phytoestrogen concentrations in serum from Japanese men and women over forty years of age. J Nutr, 132, 3168-71.
MULNARD, R. A., COTMAN, C. W., KAWAS, C., VAN DYCK, C. H., SANO, M., DOODY, R., KOSS, E., PFEIFFER, E., JIN, S., GAMST, A., GRUNDMAN, M., THOMAS, R. & THAL, L. J. 2000. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer''s Disease Cooperative Study. JAMA, 283, 1007-15.
OWENS, C. T. 2002. Estrogen replacement therapy for Alzheimer disease in postmenopausal women. Ann Pharmacother, 36, 1273-6.
PAGANINI-HILL, A. & HENDERSON, V. W. 1996. Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med, 156, 2213-7.
PIKE, C. J., CARROLL, J. C., ROSARIO, E. R. & BARRON, A. M. 2009. Protective actions of sex steroid hormones in Alzheimer''s disease. Front Neuroendocrinol, 30, 239-58.
PIKE, C. J., WALENCEWICZ-WASSERMAN, A. J., KOSMOSKI, J., CRIBBS, D. H., GLABE, C. G. & COTMAN, C. W. 1995. Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25-35 region to aggregation and neurotoxicity. J Neurochem, 64, 253-65.
PRINCE, M., BRYCE, R., ALBANESE, E., WIMO, A., RIBEIRO, W. & FERRI, C. P. 2013. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement, 9, 63-75 e2.
PUCCI, B., KASTEN, M. & GIORDANO, A. 2000. Cell cycle and apoptosis. Neoplasia, 2, 291-9.
RAPOPORT, M. & FERREIRA, A. 2000. PD98059 prevents neurite degeneration induced by fibrillar beta-amyloid in mature hippocampal neurons. J Neurochem, 74, 125-33.
RICHARDSON, T. E. & SIMPKINS, J. W. 2012. R- and S-equol have equivalent cytoprotective effects in Friedreich''s ataxia. BMC Pharmacol Toxicol, 13, 12.
ROSENBERG, L. 2003. Estrogen replacement and risk of Alzheimer disease. JAMA, 289, 1101; author reply 1101-2.
ROSENFELD, M. G., LUNYAK, V. V. & GLASS, C. K. 2006. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev, 20, 1405-28.
SAITOH, S., SATO, T., HARADA, H. & MATSUDA, T. 2004. Biotransformation of soy isoflavone-glycosides in laying hens: intestinal absorption and preferential accumulation into egg yolk of equol, a more estrogenic metabolite of daidzein. Biochim Biophys Acta, 1674, 122-30.
SETCHELL, K. D. 1998. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr, 68, 1333S-1346S.
SETCHELL, K. D., BROWN, N. M. & LYDEKING-OLSEN, E. 2002. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr, 132, 3577-84.
SETCHELL, K. D. & CASSIDY, A. 1999. Dietary isoflavones: biological effects and relevance to human health. J Nutr, 129, 758S-767S.
SETCHELL, K. D. & CLERICI, C. 2010a. Equol: history, chemistry, and formation. J Nutr, 140, 1355S-62S.
SETCHELL, K. D. & CLERICI, C. 2010b. Equol: pharmacokinetics and biological actions. J Nutr, 140, 1363S-8S.
SETCHELL, K. D., CLERICI, C., LEPHART, E. D., COLE, S. J., HEENAN, C., CASTELLANI, D., WOLFE, B. E., NECHEMIAS-ZIMMER, L., BROWN, N. M., LUND, T. D., HANDA, R. J. & HEUBI, J. E. 2005. S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin Nutr, 81, 1072-9.
SETCHELL, K. D., ZHAO, X., JHA, P., HEUBI, J. E. & BROWN, N. M. 2009. The pharmacokinetic behavior of the soy isoflavone metabolite S-(-)equol and its diastereoisomer R-(+)equol in healthy adults determined by using stable-isotope-labeled tracers. Am J Clin Nutr, 90, 1029-37.
SHAH, R. S., LEE, H. G., XIONGWEI, Z., PERRY, G., SMITH, M. A. & CASTELLANI, R. J. 2008. Current approaches in the treatment of Alzheimer''s disease. Biomed Pharmacother, 62, 199-207.
SHINKARUK, S., CARREAU, C., FLOURIOT, G., BENNETAU-PELISSERO, C. & POTIER, M. 2010. Comparative effects of R- and S-equol and implication of transactivation functions (AF-1 and AF-2) in estrogen receptor-induced transcriptional activity. Nutrients, 2, 340-54.
SINGH, M., SETALO, G., JR., GUAN, X., WARREN, M. & TORAN-ALLERAND, C. D. 1999. Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J Neurosci, 19, 1179-88.
SOSA-ORTIZ, A. L., ACOSTA-CASTILLO, I. & PRINCE, M. J. 2012. Epidemiology of dementias and Alzheimer''s disease. Arch Med Res, 43, 600-8.
SPITZER, P., SCHIEB, H., KAMROWSKI-KRUCK, H., OTTO, M., CHIASSERINI, D., PARNETTI, L., HERUKKA, S. K., SCHUCHHARDT, J., WILTFANG, J. & KLAFKI, H. W. 2011. Evidence for Elevated Cerebrospinal Fluid ERK1/2 Levels in Alzheimer Dementia. Int J Alzheimers Dis, 2011, 739847.
STANCIU, M., WANG, Y., KENTOR, R., BURKE, N., WATKINS, S., KRESS, G., REYNOLDS, I., KLANN, E., ANGIOLIERI, M. R., JOHNSON, J. W. & DEFRANCO, D. B. 2000. Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J Biol Chem, 275, 12200-6.
STUCHBURY, G. & MUNCH, G. 2005. Alzheimer''s associated inflammation, potential drug targets and future therapies. J Neural Transm, 112, 429-53.
SUMREJKANCHANAKIJ, P., TAMAMORI-ADACHI, M., MATSUNAGA, Y., ETO, K. & IKEDA, M. A. 2003. Role of cyclin D1 cytoplasmic sequestration in the survival of postmitotic neurons. Oncogene, 22, 8723-30.
THIES, W., BLEILER, L. & ALZHEIMER''S, A. 2013. 2013 Alzheimer''s disease facts and figures. Alzheimers Dement, 9, 208-45.
USUI, T. 2006. Pharmaceutical prospects of phytoestrogens. Endocr J, 53, 7-20.
VALLES, S. L., BORRAS, C., GAMBINI, J., FURRIOL, J., ORTEGA, A., SASTRE, J., PALLARDO, F. V. & VINA, J. 2008. Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38. Aging Cell, 7, 112-8.
VERGNE, S., TITIER, K., BERNARD, V., ASSELINEAU, J., DURAND, M., LAMOTHE, V., POTIER, M., PEREZ, P., DEMOTES-MAINARD, J., CHANTRE, P., MOORE, N., BENNETAU-PELISSERO, C. & SAUVANT, P. 2007. Bioavailability and urinary excretion of isoflavones in humans: effects of soy-based supplements formulation and equol production. J Pharm Biomed Anal, 43, 1488-94.
WAKELING, A. E. 2000. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer, 7, 17-28.
WANG, Y. & ZHANG, Y. 2010. [Advances on the study of equol metabolism in human]. Wei Sheng Yan Jiu, 39, 787-9.
WOOD, C. E., APPT, S. E., CLARKSON, T. B., FRANKE, A. A., LEES, C. J., DOERGE, D. R. & CLINE, J. M. 2006. Effects of high-dose soy isoflavones and equol on reproductive tissues in female cynomolgus monkeys. Biol Reprod, 75, 477-86.
WU, J., OKA, J., EZAKI, J., OHTOMO, T., UENO, T., UCHIYAMA, S., TODA, T., UEHARA, M. & ISHIMI, Y. 2007. Possible role of equol status in the effects of isoflavone on bone and fat mass in postmenopausal Japanese women: a double-blind, randomized, controlled trial. Menopause, 14, 866-74.
YAMAMOTO, S., SOBUE, T., KOBAYASHI, M., SASAKI, S., TSUGANE, S. & JAPAN PUBLIC HEALTH CENTER-BASED PROSPECTIVE STUDY ON CANCER CARDIOVASCULAR DISEASES, G. 2003. Soy, isoflavones, and breast cancer risk in Japan. J Natl Cancer Inst, 95, 906-13.
YU, H. L., LI, L., ZHANG, X. H., XIANG, L., ZHANG, J., FENG, J. F. & XIAO, R. 2009. Neuroprotective effects of genistein and folic acid on apoptosis of rat cultured cortical neurons induced by beta-amyloid 31-35. Br J Nutr, 102, 655-62.
ZHANG, D., GUO, Q., BIAN, C., ZHANG, J., LIN, S. & SU, B. 2011. Alterations of steroid receptor coactivator-1 (SRC-1) immunoreactivities in specific brain regions of young and middle-aged female Sprague-Dawley rats. Brain Res, 1382, 88-97.