Cannabidiol (CBD) with 4',7-Isoflavandiol (Equol) Efficacy is Greater than CBD or Equol Treatment Alone via Human Skin Gene Expression Analysis.

BACKGROUND: While cannabidiol (CBD) and 4',7-isoflavandiol (Equol) have been examined individually in various skin studies, the present investigation tested whether topically applied CBD with Equol may yield enhanced effects on human skin biomarkers. METHODS: After 24 hours exposure human skin gene expression was measured by quantitative polymerase chain reaction-messenger ribonucleic acid (qPCR-mRNA) analysis across 9 functional skin categories covering 97 biomarkers. RESULTS: In general, among the biomarkers analyzed the CBD with Equol treatment displayed greater efficacy compared to CBD only or the Equol treatment alone (e.g., 4 out 5 for anti-acne, 15 out of 17 for anti-aging [e.g., collagen, elastin, calcium binding protein A7, tissue inhibitor of matrix metalloproteinase 1 (TIMP 1), etc.], 19 out of 21 for anti-inflammatory (pain), 10 out of 11 for antioxidants to protect against oxidative stress, 6 out of 6 for circadian rhythm regulation for cell repair/restoration, 10 out of 15 for anti-pigmentation properties, 4 out of 5 for skin hydration, 6 out of 6 for tissue integrity, and 11 out of 12 for wound healing properties). CONCLUSIONS: CBD with Equol displayed synergistic effects that may be an effective topical treatment for dermatology and cosmetic applications to improve human skin health and reduce photo-aging.

Overview of BPH: Symptom Relief with Dietary Polyphenols, Vitamins and Phytochemicals by Nutraceutical Supplements with Implications to the Prostate Microbiome.

Benign prostatic hyperplasia (BPH) is an age-related disorder, which is one of the most prevalent and costly benign neoplasms in men with over 94 million cases worldwide. Starting before or around 50 years of age, there is a linear increase in prostate volume and BPH symptoms, which are influenced by changes in hormonal, inflammatory, growth factors, cell receptor signaling, diet, physical activity, and the microbiome of the prostate that leads to cellular proliferation. While current pharmaceutical or surgical treatments are currently available, each treatment has serious side effects. This dilemma has motived men to seek treatment without negative side effects from medicinal plants such as botanicals, phytochemicals, and vitamins that have established safety records. This narrative overview focuses on several botanicals, phytochemicals and vitamins that are widely used in the treatment of BPH and emphasizes how, in some cases, combinations of these natural ingredients may provide better BPH symptom relief compared to utilization of a single medicinal plant product (monotherapy). Finally, this overview highlights in vitro, in vivo animal studies and mainly clinical data of journal reports published in the past 5 years from January 2018 to January 2023 on BPH and nutraceuticals. Notably, there is an evolving perspective or rethinking of the role that medicinal phytochemicals and natural vitamins usage play; that is, they may hold promise or are likely to alleviate BPH symptoms.

Factors Influencing Skin Aging and the Important Role of Estrogens and Selective Estrogen Receptor Modulators (SERMs).

The narrative for this overview focuses on updating the factors that influence skin aging and the important role estrogens and selective estrogen receptor modulators (SERMs) play in this process (mainly utilizing journal reports and reviews from the last four years). Estrogens have been known and studied for over a century. For many years, it has been recognized that estrogens are important in the maintenance of human skin. Women seek cosmetic and medical treatments to improve dermal health and physical characteristics to enhance their self-perception and inhibit skin aging, particularly in highly visible body areas. The goal: to retain estrogen's positive benefits while aging and especially at/after menopause where estrogen-deficient skin contributes to the dramatic decline in skin health. In this overview, both background information and recent novel findings are included that cover aging (general mechanisms), skin aging, and factors that influence skin aging (intrinsic, extrinsic, skin microbiome and gut microbiome.) Plus, estrogen's general role in maintaining skin health is presented through the classical estrogen receptors alpha (α) and beta (ß) and non-classical (or non-genomic) estrogen receptor (G protein-coupled seven transmembrane receptor). More importantly, the various benefits of 17ß-estradiol in skin health are examined (ie, skin collagen and elastin profiles that follow 17ß-estradiol levels during aging and at/after menopause). Finally, a revision of information for estrogenic skin topical applications involving isoflavonoid compounds that act as SERMs, but are classified as endocrine disruptors, and a topical estrogen analog are explored to update the known and unknown characteristics of these treatments. Further study is warranted to understand the biological and molecular mechanisms by which estrogens support and enhance dermal health and wellbeing.

Estrogen Action and Gut Microbiome Metabolism in Dermal Health.

Emerging scientific advances in microbial research linking estrogens and the gut-skin microbiome in reference to dermal health are featured in this narrative review of journal reports and reviews from January 2018 through February 2022. Background information on advances in microbial research along with defining the microbiota and microbiome is presented in brief. The development of and factors that influence the gut microbiome in health and disease as well as the intrinsic and extrinsic factors influencing the skin microbiome and skin aging are summarized. New information on the development and changes of organ microbiomes have exposed similarities between skin and gut structure/function, microbial components/diversity/taxonomy and how they impact the immune response for combating disease and enhancing wellness. Estrogens promote health and support homeostasis in general and directly impact dermal health. Moreover, the gut, based upon the level of the microbial enzyme ß-glucuronidase, which regulates estrogen's enterohepatic recirculation, constitutes a gut-skin microbial axis. This axis revolves around the systemically available estrogen to support immune function, counteract inflammation and oxidative stress, and decrease the risk of hormone-dependent skin cancers. These data support the direct effect of estrogens on skin health and the interaction of diet on dermal health via effects on the gut microflora. Finally, the potential for bioactive botanicals containing phytoestrogens or selective estrogen receptor modulators (SERMs) to evade the effects of gut ß-glucuronidase expressing flora is proposed that may have a positive impact on skin.

Phytoestrogens (Resveratrol and Equol) for Estrogen-Deficient Skin-Controversies/Misinformation versus Anti-Aging In Vitro and Clinical Evidence via Nutraceutical-Cosmetics.

The overarching theme for this review is perspective. Superfoods (a marketing term for fruits and vegetables, etc.) have a positive connotation, while many superfoods contain phytoestrogens, a term that is alarming to the public and has a negative connotation because phytoestrogens are endocrine-disruptors, even though they are strong antioxidants that have many health benefits. To understand phytoestrogens, this paper provides a brief summary of the characteristics of: (a) estrogens, (b) estrogen receptors (ER), (c) estrogen-deficient skin, (d) how perspective(s) get off track, (e) phytoestrogen food sources, and (f) misconceptions of phytoestrogens and food safety, in general, that influence person(s) away from what is true. Finally, a brief history of cosmetics to nutraceuticals is covered plus the characteristics of phytoestrogens, resveratrol and equol on: (g) estrogen receptor binding, (h) topical and oral dosing, and (i) in vitro, molecular mechanisms and select clinical evidence, where both phytoestrogens (resveratrol and equol) demonstrate promising applications to improve skin health is presented along with future directions of nutraceuticals. Perspective is paramount in understanding the controversies associated with superfoods, phytoestrogens, and endocrine-disruptors because they have both positive and negative connotations. Everyone is exposed to and consumes these molecules everyday regardless of age, gender, or geographic location around the world, and how we understand this is a matter of perspective.

Menopause and the Skin: Old Favorites and New Innovations in Cosmeceuticals for Estrogen-Deficient Skin.

Estrogen is a pivotal signaling molecule; its production is regulated by the expression of the aromatase (CYP19A1) gene from ovarian and peripheral tissue sites, and it is transmitted via estrogen receptors to influence many important biological functions. However, the narrative for this overview focuses on the decline of 17ß-estradiol levels from ovarian sites after menopause. This estrogen-deficient condition is associated with a dramatic reduction in skin health and wellness by negatively impacting dermal cellular and homeostatic mechanisms, as well as other important biological functions. The changes include loss of collagen, elastin, fibroblast function, vascularity, and increased matrix metalloproteinase(s) enzymatic activities, resulting in cellular and extracellular degradation that leads to dryness, wrinkles, atrophy, impaired wound healing/barrier function, decreased antioxidant capacity [i.e., defense against reactive oxygen species (ROS) and oxidative stress], decreased attractiveness and psychological health, and increased perception of aging. While topical estrogen may reverse these changes, the effects of today's low-dose systemic hormone treatments are not well established, raising the need for more concentrated local administration of hormones or newer cosmeceutical agents such as selective estrogen receptor modulators (SERMs), including phytoestrogens that have become major active ingredients for skin care products, especially when addressing estrogen-deficient skin. Two example compounds are presented, an analog of resveratrol (i.e., 4'-acetoxy resveratrol) and the isoflavonoid equol, both of which are involved in a variety of biochemical/molecular actions and mechanisms, as demonstrated via in vitro and clinical studies that enhance human dermal health, especially in estrogen-deficient skin.

Estradiol levels decline to near zero after menopause. Estrogen deficiency adversely affects many physiological functions, including skin changes such as atrophy, wrinkles, hydration, poor wound healing/barrier function, decline in perceived facial attractiveness, and even psychological health. Women with menopausal skin changes seek cosmetic and medical treatments that enhance their self-perception and inhibit skin aging, particularly in exposed areas (face, neck, and hands). It is widely accepted that traditional treatments such as local hormone treatment are effective in reversing (estrogen-deficient) aging skin deterioration. But, the uncertainly of the effects of long-term systemic menopausal treatment and, more recently, aversion to systemic hormones has led to newer therapeutic agents that can send estrogen's important skin-health signals via selective estrogen receptor modulators (SERMs) other than estrogen itself. Many plant-derived compounds (phytoestrogens) that contain estrogen-agonist SERMs now play major roles in treatments for aging and estrogen-deficient skin. The targets are the estrogen receptor beta molecules that are abundant in skin (keratinocytes/fibroblasts). The variation in effect and the influence of coexisting influences such as environmental exposure, race, and aging are reviewed. While several botanicals are mentioned in this overview, two promising cosmeceuticals are examined, an analog of resveratrol [4'-acetoxy resveratrol (4AR)], which enjoys a high public profile in the health arena, and the isoflavonoid compound equol. Both 4AR and equol are SERMs that have peer-reviewed in vitro and clinical study results supporting improvement of estrogen-deficient menopausal skin.

Human scalp hair: Modulation by various factors and hormones do estrogens inhibit or stimulate-A perplexing perspective.

Several journal reports, reviews, and commentaries over the last 20-25 years have pointed out the controversy attached to 17ß-estradiol's inhibitory or stimulatory influence on hair follicle growth/cycling citing rodent (murine) and human results. While 17ß-estradiol is the most potent sex steroid hormone in the body and has almost equal affinity for estrogen receptor (ER) alpha (α) and beta (ß), there appears to be specific ER-mediated effects on scalp hair follicles/growth, etc. Additionally, the newly discovered G protein-coupled estrogen receptor (GPR30 or GPER) and the orphan receptor, estrogen-related receptor (ERR) gamma (γ), in skin and other tissue sites have potential impacts of how estrogens via these receptors may alter scalp hair characteristics, but this remains to be elucidated. Conversely, the negative impact of the 5α-reductase enzyme and its steroid product, 5α-dihydrotestosterone, on scalp hair growth is clear. Less clear is how 17ß-estradiol is stimulatory in some scalp hair studies, but inhibitory in others. This brief summary examines the potential influences of steroidogenesis via aromatase (estrogen biosynthesis) and 5α-reductase expression, their enzyme activities, and steroid products along with the concepts of how steroid acute regulatory protein (StAR) and estrone sulfate may be involved in the complex hormonal, cellular/molecular signaling cascade of the hair follicle in growth and cycling.

Enhancing Skin Health: By Oral Administration of Natural Compounds and Minerals with Implications to the Dermal Microbiome.

The history of cosmetics goes back to early Egyptian times for hygiene and health benefits while the history of topical applications that provide a medicinal treatment to combat dermal aging is relatively new. For example, the term cosmeceutical was first coined by Albert Kligman in 1984 to describe topical products that afford both cosmetic and therapeutic benefits. However, beauty comes from the inside. Therefore, for some time scientists have considered how nutrition reflects healthy skin and the aging process. The more recent link between nutrition and skin aging began in earnest around the year 2000 with the demonstrated increase in peer-reviewed scientific journal reports on this topic that included biochemical and molecular mechanisms of action. Thus, the application of: (a) topical administration from outside into the skin and (b) inside by oral consumption of nutritionals to the outer skin layers is now common place and many journal reports exhibit significant improvement for both on a variety of dermal parameters. Therefore, this review covers, where applicable, the history, chemical structure, and sources such as biological and biomedical properties in the skin along with animal and clinical data on the oral applications of: (a) collagen, (b) ceramide, (c) ß-carotene, (d) astaxanthin, (e) coenzyme Q10, (f) colostrum, (g) zinc, and (h) selenium in their mode of action or function in improving dermal health by various quantified endpoints. Lastly, the importance of the human skin microbiome is briefly discussed in reference to the genomics, measurement, and factors influencing its expression and how it may alter the immune system, various dermal disorders, and potentially be involved in chemoprevention.

A review of the role of estrogen in dermal aging and facial attractiveness in women.

Estrogens are known to have protective and favorable influences on skin health; conversely, androgens oppose the actions of estrogens. Estrogen's chemical messages are transmitted via the classical nuclear hormone estrogen receptors (ER) alpha and beta and the rapid-acting G-coupled membrane estrogen receptor. Androgens [both testosterone and 5α-dihydrotestosterone (5α-DHT)] bind the same androgen receptor. Estrogen levels peak in the mid- to late 20s in women and then decline by 50% by 50 years of age and dramatically decrease further after menopause. The loss of estrogens with aging contributes to diminished dermal health, whereas estrogen hormone therapy [eg, oral conjugated equine estrogens (CEE)] restores skin health. Several reports suggest positive correlations between the levels of circulating estrogens and: (1) perceived age, (2) attractiveness, (3) enhanced skin health, and (4) facial coloration in women. Based upon a psychological dermato-endocrine perspective, the positive correspondence of high estrogens levels with perceived age and facial attractiveness in women especially with aging demonstrates the importance of hormonal influences on observed dermal health and youthful appearance.

Human skin gene expression doesn't correlate with protein expression? Unless both parameters are quantified.

Many cosmetic companies utilize in vitro gene array studies to display significant stimulation or inhibition of various human skin biomarkers to validate in vivo actions that are reported to enhance dermal health. This follows the central dogma of DNA-to-RNA results in protein expression; however, gene and protein expressions do not usually correlate. Unless both gene and protein expressions are quantified which require further investigational time and investment. Where data are available, this short commentary displays the in vitro comparison of four human skin biomarkers for the gene and protein expressions of the stimulation of collagen type I and elastin and the inhibition of matrix metalloproteinases 1 and 3, when equol was tested. The results demonstrate a good correspondence between gene and protein expressions for the human skin biomarkers tested.

Human skin gene expression: Natural (trans) resveratrol versus five resveratrol analogs for dermal applications.

Resveratrol (RV) is a polyphenolic compound naturally produced by plants. Polyphenolic compounds incorporated into medicinal products are beneficial but, RV is rapidly metabolized with an associated decline in biological activity. This study tested RV as the standard and compared five structurally modified RV analogs: butyrate, isobutyrate, palmitoate, acetate, and diacetate (to improve functionality) at 1% concentration(s) for 24 h in epiderm full thickness cultures by gene array/qPCR mRNA analysis. When silent mating type information regulation 2 homolog 1, extracellular elements (collagen1A1, 3A1, 4A1; elastin, tissue inhibitor of matrix metalloproteinase 1, fibrillin 1 laminin beta1 and matrix metalloproteinase 9), anti-aging and aging genes, inflammatory biomarkers (interleukin-1A [IL1A], IL1R2, IL-6 and IL-8), nerve growth factor, and the antioxidants (proliferating cell nuclear antigen, catalase, superoxide dismutase and metallothionein 1H/2H) were evaluated, ranking each from highest-to-lowest for gene expression: butyrate > isobutyrate > diacetate > acetate > palmitoate. This study showed that the butyrate and isobutyrate analogs are more biologically active compared to resveratrol and have potential use in topical applications to improve dermal and other health applications. Impact statement Resveratrol has been reported to have a wide variety of health benefits but its rapid metabolism especially after oral ingestion results in very low bioavailability. Notably, the first human skin gene expression study of resveratrol was not published until 2014. The purpose of this study was to determine if increased stability and biological activity could be obtained by modifying the chemical structure of natural (trans) resveratrol and quantifying human gene expression by qPCR of skin biomarkers that enhance dermal health. Five resveratrol analogs were synthesized that increased their lipophilic index to enhance tissue penetration and augment biological activities on the measured parameters that expand the current knowledge of structure/function relationships. The butyrate and isobutyrate modifications displayed gene expression values significantly above resveratrol and suggest that oral application of these and potentially other resveratrol analogs may yield similar results to improve stability and biological activity to benefit/address various disorders/diseases.

Resveratrol, 4' Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health.

Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best-known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17ß-estradiol. Human skin gene expression was reviewed for 28 different biomarkers when resveratrol, 4' acetoxy resveratrol (4AR), R-equol, racemic equol or S-equol were tested. Sirtuin 1 activator (SIRT 1) was stimulated by resveratrol and 4AR only. Resveratrol, R-equol and racemic equol were effective on the aging biomarkers proliferating cell nuclear factor (PCNA), nerve growth factor (NGF), 5α-reductase and the calcium binding proteins S100 A8 and A9. Racemic equol and 4AR displayed among the highest levels for the collagens, elastin and tissue inhibitor of the matrix metalloproteinase 1 (TIMP 1). S-equol displayed the lowest level of effectiveness compared to the other compounds. The 4AR analog was more effective compared to resveratrol by 1.6-fold. R-equol and racemic equol were almost equal in potency displaying greater inhibition vs. resveratrol or its 4' analog for the matrix metalloproteinases (MMPs), but among the inflammatory biomarkers, resveratrol, 4AR, R-equol and racemic equol displayed high inhibition. Thus, these cosmeceuticals display promise to improve dermal health; however, further study is warranted to understand how phytochemicals protect/enhance the skin.

Skin aging and oxidative stress: Equol's anti-aging effects via biochemical and molecular mechanisms.

Oxygen in biology is essential for life. It comes at a cost during normal cellular function, where reactive oxygen species (ROS) are generated by oxidative metabolism. Human skin exposed to solar ultra-violet radiation (UVR) dramatically increases ROS production/oxidative stress. It is important to understand the characteristics of human skin and how chronological (intrinsic) aging and photo-aging (extrinsic aging) occur via the impact of ROS production by cascade signaling pathways. The goal is to oppose or neutralize ROS insults to maintain good dermal health. Botanicals, as active ingredients, represent one of the largest categories used in dermatology and cosmeceuticals to combat skin aging. An emerging botanical is equol, a polyphenolic/isoflavonoid molecule found in plants and food products and via gastrointestinal metabolism from precursor compounds. Introductory sections cover oxygen, free radicals (ROS), oxidative stress, antioxidants, human skin aging, cellular/molecular ROS events in skin, steroid enzymes/receptors/hormonal actions and genetic factors in aging skin. The main focus of this review covers the characteristics of equol (phytoestrogenic, antioxidant and enhancement of extracellular matrix properties) to reduce skin aging along with its anti-aging skin influences via reducing oxidative stress cascade events by a variety of biochemical/molecular actions and mechanisms to enhance human dermal health.

Synthesis and skin gene analysis of 4'-acetoxy-resveratrol (4AR), therapeutic potential for dermal applications.

Resveratrol (RV) 1, a plant polyphenol, has proven effective in commercial products yet drawbacks include low bioavailability due to rapid metabolism. Structural modifications have led to a 4'-acetoxy analog 2 (4AR) now produced using a selective one-step esterification reaction. The one-step synthesis is shown together with expression of skin genes using human dermal models to establish 4AR 2 benefits to skin health. 4AR 2 at 1% in qPCR experiments using a human skin model significantly increased gene expression of the anti-aging factor, SIRT 1 by over 3.3-fold, extracellular matrix proteins collagen III, IV, elastin and tissue inhibitors of metalloproteinases (TIMP 1, 2), anti-oxidants CAT, LOX, superoxide dismutase (SOD 1, 2), metallothioneins (MT1H, MT1H), skin aging biomarkers fibrillin (FBN1), laminin (LAMB1), proliferating cell nuclear antigen (PCNA), skin growth factors (HBEGF, IGF1, NGF and TGF). 4AR 2 also decreased gene expression of inflammatory and skin-aging molecules (IL-1, IL-6, IL-8, COX-2, TNGRSF) and S100 calcium binding proteins A8, A9. These findings suggest that 4AR 2 has potential for topically treatment and prevention of skin aging.

Prenatal exposure to soy and selenium reduces prostate cancer risk factors in TRAMP mice more than exposure beginning at six weeks.

BACKGROUND: Diets high in soy and selenium (Se) decrease prostate cancer risk factors in healthy rats. The purpose of this study was to determine whether treatment with high levels of soy and/or supplemental Se would decrease prostate cancer risk factors in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mouse, and whether timing of the introduction of these nutrients would affect risk reduction. METHODS: Male hemizygous [C57BL/6 × FVB]F1 TRAMP mice were exposed to stock diets high or devoid of soy, with or without a supplement of Se-methylselenocysteine (MSC) starting at conception (10 mg Se/L in drinking water of pregnant/nursing dams; daily bolus of 4 mg Se/kg body weight to pups after weaning) or at 6 weeks of age in a 2 × 2 factorial design. Mice were killed at 12 weeks (n per dietary treatment = 20-30). RESULTS: Liver and serum Se concentrations were increased by MSC supplementation (P < 0.001), high-soy diet (P < 0.05), and initiation of dietary treatments at conception (P < 0.05). MSC supplementation had greater effects in mice fed the zero-soy basal diet, compared to the high-soy formulation (Pinteraction < 0.01). These same three interventions, individually and interactively, decreased body weight and epididymal fat pad weights, and steady state levels of mRNA for Cyp19a1 (aromatase) and Srd5a1 (5α-reductase). In contrast, MSC was the only treatment that decreased urogenital tract weights (P < 0.001), serum IGF-1 levels (P < 0.002), and Gleason scores (P < 0.05). CONCLUSIONS: Supplemental MSC reduces risk of prostate cancer in TRAMP mice. Basal diet composition (zero- vs. high-soy) can modify MSC's chemopreventive effects. Initiation of dietary treatments from conception maximizes chemopreventive effects of MSC. Prenatal Se status may have long-lasting effects on development and progression of prostate cancer.

Modulation of Aromatase by Phytoestrogens.

The aromatase enzyme catalyzes the conversion of androgens to estrogens in many human tissues. Estrogens are known to stimulate cellular proliferation associated with certain cancers and protect against adverse symptoms during the peri- and postmenopausal intervals. Phytoestrogens are a group of plant derived naturally occurring compounds that have chemical structures similar to estrogen. Since phytoestrogens are known to be constituents of animal/human food sources, these compounds have received increased research attention. Phytoestrogens may contribute to decreased cancer risk by the inhibition of aromatase enzyme activity and CYP19 gene expression in human tissues. This review covers (a) the aromatase enzyme (historical descriptions on function, activity, and gene characteristics), (b) phytoestrogens in their classifications and applications to human health, and (c) a chronological coverage of aromatase activity modulated by phytoestrogens from the early 1980s to 2015. In general, phytoestrogens act as aromatase inhibitors by (a) decreasing aromatase gene expression, (b) inhibiting the aromatase enzyme itself, or (c) in some cases acting at both levels of regulation. The findings presented herein are consistent with estrogen's impact on health and phytoestrogen's potential as anticancer treatments, but well-controlled, large-scale studies are warranted to determine the effectiveness of phytoestrogens on breast cancer and age-related diseases.

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

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 S-equol 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, 5α-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 mirror-image 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.

A new synthesis of 4'-resveratrol esters and evaluation of the potential for anti-depressant activity.

The 4'-ester analog of the disease preventative resveratrol 1 (RV), 4'-acetyl-RV 2 along with 4'-pivaloate 13 and benzoate 14 RV were synthesized. The previously developed palladium catalyzed decarbonylative Heck coupling was used to assemble the stilbene core together with 3,5-dibenzyl protected phenol intermediates that allowed for efficient coupling and deprotection using boron trifluoride etherate. Studies with Long-Evans rats were performed to establish safety, toxicity, and behavioral parameters. In addition, the Porsalt forced-swim test was used to demonstrate anti-depressant activity.

Combination effects of dietary soy and methylselenocysteine in a mouse model of prostate cancer.

BACKGROUND: High dietary intake of soy or selenium (Se) is associated with decreased risk of prostate cancer. Soy constituents and various chemical forms of Se have each been shown to downregulate expression of the androgen receptor (AR) and AR-regulated genes in the prostate. We hypothesized that downregulation of AR and AR-regulated genes by the combination of these dietary components would inhibit tumorigenesis in the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mouse. METHODS: Male mice were exposed from conception to stock diets high or low in soy, with or without a supplement of Se-methylseleno-L-cysteine (MSC) in a 2 × 2 factorial design. Mice were sacrificed at 18 weeks. Prostate histopathology, urogenital tract (UGT) weight, hepatic activity of androgen-metabolizing enzymes, and expression of AR, AR-regulated, and AR-associated FOX family genes, in the dorsolateral prostate were examined. RESULTS: High soy intake decreased activity of hepatic aromatase and 5α-reductase, expression of AR, AR-regulated genes, FOXA1, UGT weight, and tumor progression, and upregulated protective FOXO3. Supplemental MSC upregulated AKR1C14, which reduces 5α-dihydrotestosterone. CONCLUSIONS: Soy is an effective pleiotropic dietary agent for prevention of prostate cancer. The finding of effects of soy on FOX family gene expression in animals is novel. Combination effects of supplemental MSC may depend upon the soy content of the basal diet to which it is added.

Biochemical investigation and gene analysis of equol: a plant and soy-derived isoflavonoid with antiaging and antioxidant properties with potential human skin applications.

The purpose of this study was to investigate the effects of equol, a plant and intestinal flora derived isoflavonoid molecule on the expression of skin genes and proteins using human dermal models. As equol has been shown to mimic 17ß-estradiol and bind specifically to 5α-dihydrotestostone (5α-DHT), these agents were used (in addition to equol) to determine whether equol may play important and beneficial roles in the extracellular matrix (ECM). Equol at 0.3 or 1.2% in qPCR experiments using a human skin barrier model examined ECM gene expression. Equol, 5α-DHT, and 17ß-estradiol at 10 nM were studied in human monolayer fibroblasts cultures (hMFC) for ECM protein expression. Human fibroblast three-dimensional organotypic cultures revealed equol's influence (@ 10 nM) on ECM proteins via fluorescent-activated cell sorting (FACS) analysis. In qPCR experiments, equol significantly increased collagen, elastin (ELN), and tissue inhibitor of metalloprotease and decreased metalloproteinases (MMPs) gene expression and caused significant positive changes in skin antioxidant and antiaging genes. In hMFC, equol significantly increased collagen type I (COL1A1), whereas, 5α-DHT significantly decreased cell viability that was blocked by equol. FACS analysis showed equol and 17ß-estradiol significantly stimulated COL1A1, collagen type III (COL3A1), and ELN while MMPs were significantly decreased compared with control values. Finally, tamoxifen blocked the positive influences of equol on ECM proteins via FACS analysis. These findings suggest that equol has the potential to be used topically for the treatment and prevention of skin aging, by enhancing ECM components in human skin.