Transcriptional activity of estrogen-related receptor γ (ERRγ) is stimulated by the phytoestrogen equol

Hirvonen, Johanna; Rajalin, Ann-Marie; Wohlfahrt, Gerd; Adlercreutz, Herman; Wähälä, Kristiina; Aarnisalo, Piia

doi:10.1016/j.jsbmb.2010.11.001

Cited by 38 publications

(30 citation statements)

References 57 publications

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“…For instance, equol can act as a selective androgen modulator by binding 5a-DHT locally and inhibiting the SRD5A1 enzyme in dermal fibroblasts since it is known that androgens decrease skin health by increasing the production of metalloproteinases (MMPs) that break down COL1A1 and ELN and decrease wound healing (Ashcroft & Mills, 2002;Gopaul, et al, 2012;Kohl, 2011). Conversely, equol can act as a selective estrogen receptor modulator and bind to estrogen-related receptor gamma in keratinocytes and fibroblasts to stimulate positive influences on skin such as increasing COL1A1 and ELN, decreasing MMPs and slowing down neoplastic growth (Hirvonen et al, 2011;Krahn-Bertil et al, 2008;Lephart, 2013b;Verdier-Sevrain et al, 2006). Or other important dermal components may be stimulated by Requol via unknown mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of equol and their polyphenolic isomers against dermal aging: Microarray/protein evidence with clinical implications and unique delivery into human skin

Lephart¹

2013

Pharmaceutical Biology

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Context: Equol is a polyphenolic/isoflavonoid molecule that can be expressed as isomers. However, the characteristics of the equol isomers on dermal gene/protein expression and human skin percutaneous absorption remain unknown. Objective: Perform a comprehensive investigation on equol as: R-equol, racemic equol or Sequol to determine their differential expression of skin-related genes, quantify collagen expression and determine percutaneous absorption in human skin. Methods: Quantified: (i) gene expression/mRNA levels via gene array technology using human skin equivalents with equol exposure at 1.2% in qPCR experiments, (ii) in vitro collagen expression in human fibroblasts, and (iii) percutaneous absorption by Franz cell techniques. Results: In the qPCR studies, only three genes displayed the greatest significant expression by S-equol, whereas 16 genes displayed the greatest significant levels (either stimulation or inhibition) by R-equol and/or racemic equol, such as extracellular matrix proteins (i.e., collagen and elastin), nerve growth factor, aging genes [FOS, 100 A8 and A9 calcium-binding proteins, 5a-reductase type 1, and matrix metalloproteinases (1, 3, and 9)], and inflammatory genes (e.g., interleukin-1 alpha, interleukin-6, and cyclooxygenase-1). Collagen type I expression in fibroblasts was greater with racemic versus S-equol treatment at 1 and 10 nM. Percutaneous absorption demonstrated high sequestering in keratinocytes with subsequent accumulation/ release over time. Discussion and conclusion: Overall, these results illustrate the significant differences in mirrorimage molecules or isomers of equol where R-equol and/or racemic equol are better molecules for skin gene expression compared to S-equol and the percutaneous absorption of equol represents a unique epidermal reservoir delivery mechanism.

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Section: Discussionmentioning

confidence: 99%

Protective effects of equol and their polyphenolic isomers against dermal aging: Microarray/protein evidence with clinical implications and unique delivery into human skin

Lephart¹

2013

Pharmaceutical Biology

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“…The presence of ERR-γ during prostate cancer is indicative of a favorable prognosis, and ERR-γ has been shown to slow proliferation in prostate and breast cancer cell lines [3]. Using in vitro cultures examining PC-3 cells, equol has been shown to increase the transcriptional activity of ERR-γ [26], thereby enhancing the inhibitory actions of ERR-γ on neoplastic growth [3]. The concentrations of equol required to stimulate ERR-γ are relatively high but not out of physiological range [26] if equol were applied topically or consumed orally.…”

Section: Discussionmentioning

confidence: 99%

“…Using in vitro cultures examining PC-3 cells, equol has been shown to increase the transcriptional activity of ERR-γ [26], thereby enhancing the inhibitory actions of ERR-γ on neoplastic growth [3]. The concentrations of equol required to stimulate ERR-γ are relatively high but not out of physiological range [26] if equol were applied topically or consumed orally. Also, it is known that equol (particularly S-equol) has relatively high affinity for ER-β where it can act as a selective estrogen receptor modulator or SERM [19,25].…”

Section: Discussionmentioning

confidence: 99%

“…Also, equol has the unique characteristic to bind specifically 5α-DHT (to decrease negative androgen impact in the prostate) by sequestering 5α-DHT from the androgen receptor (AR), thus altering growth and physiological hormone responses regulated by 5α-DHT [19,24,25]. It also has affinity for ERR-γ and ER-β (to increase positive estrogen-like influences in the prostate) [3,4,25,26] and can be found as R-equol and S-equol isomers [18,25]. Equol is currently used in skin treatments and has many positive influences on dermal gene and protein expression (e.g., anti-aging, anti-inflammatory and anti-oxidant properties) [27], but a recent proposal suggests equol may have beneficial applications for improvement in prostate health [25].…”

Section: Introductionmentioning

confidence: 99%

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Severe & Moderate BPH Symptoms in Mid-Aged Men Improve with Isoflavonoid-Equol Treatment: Pilot Intervention Study

Lephart¹

2013

OJU

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Benign prostatic hyperplasia (BPH) is the pathological cellular progression of glandular proliferation associated with aging. Current available treatment options for BPH have limitations and various adverse effects. Equol is a polyphenolic/isoflavonoid molecule derived from intestinal metabolism, dairy and dietary plant sources. It has the unique characteristic to bind specifically 5α-dihydrotestosterone (5α-DHT) by sequestering 5α-DHT from the androgen receptor, thus decreasing androgen hormone actions to improve prostate health by acting as a selective androgen modulator (SAM). It also has affinity for estrogen related receptor gamma (ERR-γ) and estrogen receptor beta (ER-β) within the prostate that is known to improve male health via selective estrogen receptor modulatory (SERM) activities to decrease inflammation, cellular proliferation and carcinogenesis. We investigated the possible clinical efficacy of equol on the symptoms associated with benign prostatic hyperplasia (BPH) in this study. Materials and Methods: We performed a pilot intervention study evaluating the effects of low dose oral equol supplement (6 mg, twice a day with meals) for 4 weeks in a total of 18 men (49 -60 years old) with moderate or severe BPH. Subjects included in the study: gave informed consent, underwent a physical examination and verified their BPH symptoms as measured by the International Prostate Symptom Scores (IPSS) and then were assigned to the moderate or severe BPH groups based upon their total IPSS index. All adverse events were reported. The primary efficacy measure was the IPSS parameters comparing baseline to 2 and 4 week IPSS indices. Blood samples were collected at the baseline and 4th week visits that served as secondary efficacy parameters that included testosterone, 5α-DHT and general blood chemistries along with cardiac and hepatic function panels. Results: Low dose equol positively improved moderate to severe BPH symptoms according to the IPSS indices. In moderately symptomatic men (n = 10) 5 out of 7 of the IPSS parameters significantly improved by 4 weeks of equol treatment. In severely symptomatic men (n = 8) all 7 of the IPSS parameters significantly improved with 4 weeks of equol treatment. There were no significant changes in androgen levels, general blood chemistries or cardiac and hepatic function parameters. Although, 5α-DHT levels declined by 21% in severely symptomatic men (from baseline vs 4 week values). Conclusion: These findings suggest that equol may provide a well tolerated and rapid beneficial therapy for BPH that can be used alone or in combination with current pharmaceutical therapies. The beneficial clinical efficacy of equol observed in this study may be due to the multiple positive biological actions that are not present in current pharmaceutical treatments.

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“…Genistein also increased Sex Hormone Binding Globulin (SHBG) and, thus, decreased the bioavailability of free androgens and estrogens in addition to its independent effects on androgen and estrogen signaling pathways [34]. Hiroven et al [35] showed that equol stimulated transcriptional activity of ERR Gamma (Estrogen related receptor) in prostate cancer PC3 cell lines causing growth inhibition. Several effects of isoflavones upon molecular targets were discussed in a comprehensive review by Banerjee et al [28] and de Souza et al [29].…”

Section: Studies Addressing Phytoestrogen Mechanisms Of Actionmentioning

confidence: 99%

Phytoestrogens and their Potential Role in Prostate Cancer Prevention and Treatment

Kolukula¹

2011

J Cancer Sci Ther

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Phytoestrogens are hormonally active compounds present in plant foods that are being studied extensively for their potential roles in hormonally-sensitive neoplasms such as prostate cancer. We postulate that the evidence for a protective role of phytoestrogens is not conclusive enough for a general recommendation for their use as dietary supplements, but phytoestrogens can be considered for therapeutic use in prostate cancer patients under certain circumstances. A literature review was performed to study the evidence regarding the chemopreventive role of phytoestrogens in healthy men, the protective role in early prostate cancer, and a possible therapeutic role in advanced prostate cancer patients. Dietary supplementation with phytoestrogens for chemoprevention of prostate cancer is still a debatable subject. Numerous pre-clinical in vitro studies have been promising, and novel molecular mechanisms of action for phytoestrogens continue to be identified. However, human clinical trials including studies done on prostate biomarkers and on the effects of phytoestrogens on steroid hormones are complicated by the possibility of local paracrine effects in prostatic tissue by phytoestrogens that are steroid-like in structure. Their interaction with multiple enzymes represents a paradigm for the complexity of phytoestrogen effects and a window into a potential reason that study results are inconsistent or difficult to explain. A final outcome of the phytoestrogen effect in the intact human may be difficult to discern because these agents can inhibit or induce enzymes, destroy cancer cells, yet will have intrinsic estrogenic effects themselves. Larger multi-center, multi-national, randomized controlled trials are needed before definitive recommendations can be made on the usefulness of phytoestrogens for chemoprevention and therapy for prostate cancer. However, combinations of phytoestrogens with radiation therapy and other antioxidants in advanced or metastatic prostate cancer can be considered because there are limited effective therapy options for this group of patients.

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Transcriptional activity of estrogen-related receptor γ (ERRγ) is stimulated by the phytoestrogen equol

Cited by 38 publications

References 57 publications

Protective effects of equol and their polyphenolic isomers against dermal aging: Microarray/protein evidence with clinical implications and unique delivery into human skin

Protective effects of equol and their polyphenolic isomers against dermal aging: Microarray/protein evidence with clinical implications and unique delivery into human skin

Severe & Moderate BPH Symptoms in Mid-Aged Men Improve with Isoflavonoid-Equol Treatment: Pilot Intervention Study

Phytoestrogens and their Potential Role in Prostate Cancer Prevention and Treatment

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Transcriptional activity of estrogen-related receptor γ (ERRγ) is stimulated by the phytoestrogen equol

Cited by 38 publications

References 57 publications

Protective effects of equol and their polyphenolic isomers against dermal aging: Microarray/protein evidence with clinical implications and unique delivery into human skin

Protective effects of equol and their polyphenolic isomers against dermal aging: Microarray/protein evidence with clinical implications and unique delivery into human skin

Severe &amp; Moderate BPH Symptoms in Mid-Aged Men Improve with Isoflavonoid-Equol Treatment: Pilot Intervention Study

Phytoestrogens and their Potential Role in Prostate Cancer Prevention and Treatment

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Product

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Severe & Moderate BPH Symptoms in Mid-Aged Men Improve with Isoflavonoid-Equol Treatment: Pilot Intervention Study