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Phytoestrogens are naturally occurring nonsteroidal phenolic plant compounds that, due to their molecular structure and size, resemble vertebrate steroids estrogens. This review is focused on plant flavonoids isoflavones, which are ranked among the most estrogenic compounds. The main dietary sources of isoflavones for humans are soybean and soybean products, which contain mainly daidzein and genistein. When they are consumed, they exert estrogenic and/or antiestrogenic effects. Isoflavones are considered chemoprotective and can be used as an alternative therapy for a wide range of hormonal disorders, including several cancer types, namely breast cancer and prostate cancer, cardiovascular diseases, osteoporosis, or menopausal symptoms. On the other hand, isoflavones may also be considered endocrine disruptors with possible negative influences on the state of health in a certain part of the population or on the environment. This review deals with isoflavone classification, structure, and occurrence, with their metabolism, biological, and health effects in humans and animals, and with their utilization and potential risks.

ABSTRACT Equol is the isoflavone-derived metabolite with the greatest estrogenic and antioxidant activity. It is produced from daidzein by fastidious and oxygen-susceptible intestinal bacteria, which hinders their use at an industrial scale. Therefore, expressing the equol production machinery into easily-cultivable hosts would expedite the heterologous production of this compound. In this work, four genes (racemase, tdr, ddr and dzr) coding for key enzymes involved in equol production in Adlercreutzia equolifaciens DSM19450T were synthesized and cloned in a pUC-derived vector (pUC57-equol) that was introduced in Escherichia coli. Recombinant clones of E. coli produced equol in cultures supplemented with daidzein (equol precursor) and dihydrodaidzein (intermediate compound). To check whether equol genes were expressed in Gram-positive bacteria, the pUC57-equol construct was cloned into the low-copy-number vector pIL252, and the new construct (pIL252-pUC57-equol) introduced into model strains of Lacticaseibacillus casei and Lactococcus lactis. L. casei clones carrying pIL252-pUC57-equol produced a small amount of equol from dihydrodaidzein but not from daidzein, while L. lactis recombinant clones produced no equol from either of the substrates. This is the first time that A. equolifaciens equol genes have been cloned and expressed in heterologous hosts. E. coli clones harboring pUC57-equol could be used for biotechnological production of equol. Heterologous equol production from synthetic genes based on those of Adlercreutzia equolifaciens.

Isoflavonoids comprise a class of plant natural products with great nutraceutical, pharmaceutical and agricultural significance. Their low abundance in nature and structural complexity however hampers access to these phytochemicals through traditional crop-based manufacturing or chemical synthesis. Microbial bioproduction therefore represents an attractive alternative. Here, we engineer the metabolism of Saccharomyces cerevisiae to become a platform for efficient production of daidzein, a core chemical scaffold for isoflavonoid biosynthesis, and demonstrate its application towards producing bioactive glucosides from glucose, following the screening-reconstruction-application engineering framework. First, we rebuild daidzein biosynthesis in yeast and its production is then improved by 94-fold through screening biosynthetic enzymes, identifying rate-limiting steps, implementing dynamic control, engineering substrate trafficking and fine-tuning competing metabolic processes. The optimized strain produces up to 85.4 mg L −1 of daidzein and introducing plant glycosyltransferases in this strain results in production of bioactive puerarin (72.8 mg L −1 ) and daidzin (73.2 mg L −1 ). Our work provides a promising step towards developing synthetic yeast cell factories for de novo biosynthesis of value-added isoflavonoids and the multi-phased framework may be extended to engineer pathways of complex natural products in other microbial hosts. Isoflavonoids are a class of industrially important plant natural products, but their low abundance and structural complexity limits their availability. Here, the authors engineer Saccharomyces cerevisiae metabolism to become a platform for efficient production of daidzein which is core chemical scaffold for isoflavonoid biosynthesis, and show its application for production of bioactive glucosides from glucose.

Epidemiological data suggest that regular intake of isoflavones from soy reduces the incidence of estrogen-dependent and aging-associated disorders, such as menopause symptoms in women, osteoporosis, cardiovascular diseases and cancer. Equol, produced from daidzein, is the isoflavone-derived metabolite with the greatest estrogenic and antioxidant activity. Consequently, equol has been endorsed as having many beneficial effects on human health. The conversion of daidzein into equol takes place in the intestine via the action of reductase enzymes belonging to incompletely characterized members of the gut microbiota. While all animal species analyzed so far produce equol, only between one third and one half of human subjects (depending on the community) are able to do so, ostensibly those that harbor equol-producing microbes. Conceivably, these subjects might be the only ones who can fully benefit from soy or isoflavone consumption. This review summarizes current knowledge on the microorganisms involved in, the genetic background to, and the biochemical pathways of, equol biosynthesis. It also outlines the results of recent clinical trials and meta-analyses on the effects of equol on different areas of human health and discusses briefly its presumptive mode of action.

Isoflavones have gained popularity as an alternative treatment for menopausal symptoms for people who cannot or are unwilling to take hormone replacement therapy. However, there is still no consensus on the effects of isoflavones despite over two decades of vigorous research. This systematic review aims to summarize the current literature on isoflavone supplements, focusing on the active ingredients daidzein, genistein, and S-equol, and provide a framework to guide future research. We performed a literature search in Ovid Medline using the search terms “isoflavone” and “menopause”, which yielded 95 abstracts and 68 full-text articles. We found that isoflavones reduce hot flashes even accounting for placebo effect, attenuate lumbar spine bone mineral density (BMD) loss, show beneficial effects on systolic blood pressure during early menopause, and improve glycemic control in vitro. There are currently no conclusive benefits of isoflavones on urogenital symptoms and cognition. Due to the lack of standardized research protocols including isoflavone component and dosage, outcomes, and trial duration, it is difficult to reach a conclusion at this point in time. Despite these limitations, the evidence thus far favors the use of isoflavones due to their safety profile and benefit to overall health.

Although soy consumption is associated with breast cancer prevention, the low bioavailability and the extensive metabolism of soy-active components limit their clinical application. Here, the impact of daidzein (D) and its metabolites on estrogen-dependent anti-apoptotic pathway has been evaluated in breast cancer cells. In estrogen receptor α-positive breast cancer cells treated with D and its metabolites, single or in mixture, ERα activation and Neuroglobin (NGB) levels, an anti-apoptotic estrogen/ERα-inducible protein, were evaluated. Moreover, the apoptotic cascade activation, as well as the cell number after stimulation was assessed in the absence/presence of paclitaxel to determine the compound effects on cell susceptibility to a chemotherapeutic agent. Among the metabolites, only D-4′-sulfate maintains the anti-estrogenic effect of D, reducing the NGB levels and rendering breast cancer cells more prone to the paclitaxel treatment, whereas other metabolites showed estrogen mimetic effects, or even estrogen independent effects. Intriguingly, the co-stimulation of D and gut metabolites strongly reduced D effects. The results highlight the important and complex influence of metabolic transformation on isoflavones physiological effects and demonstrate the need to take biotransformation into account when assessing the potential health benefits of consumption of soy isoflavones in cancer.

Isoflavones are phytoestrogens of plant origin, mostly found in the members of the Fabaceae family, that exert beneficial effects in various degenerative disorders. Having high similarity to 17-β-estradiol, isoflavones can bind estrogen receptors, scavenge reactive oxygen species, activate various cellular signal transduction pathways and modulate growth and transcription factors, activities of enzymes, cytokines, and genes regulating cell proliferation and apoptosis. Due to their pleiotropic activities isoflavones might be considered as a natural alternative for the treatment of estrogen decrease-related conditions during menopause. This review will focus on the effects of isoflavones on inflammation and chronic degenerative diseases including cancer, metabolic, cardiovascular, neurodegenerative diseases, rheumatoid arthritis and adverse postmenopausal symptoms.

Soybeans are rich in proteins and lipids and have become a staple part of the human diet. Besides their nutritional excellence, they have also been shown to contain various functional components, including isoflavones, and have consequently received increasing attention as a functional food item. Isoflavones are structurally similar to 17-β-estradiol and bind to estrogen receptors (ERα and ERβ). The estrogenic activity of isoflavones ranges from a hundredth to a thousandth of that of estrogen itself. Isoflavones play a role in regulating the effects of estrogen in the human body, depending on the situation. Thus, when estrogen is insufficient, isoflavones perform the functions of estrogen, and when estrogen is excessive, isoflavones block the estrogen receptors to which estrogen binds, thus acting as an estrogen antagonist. In particular, estrogen antagonistic activity is important in the breast, endometrium, and prostate, and such antagonistic activity suppresses cancer occurrence. Genistein, an isoflavone, has cancer-suppressing effects on estrogen receptor-positive (ER+) cancers, including breast cancer. It suppresses the function of enzymes such as tyrosine protein kinase, mitogen-activated kinase, and DNA polymerase II, thus inhibiting cell proliferation and inducing apoptosis. Genistein is the most biologically active and potent isoflavone candidate for cancer prevention. Furthermore, among the various physiological functions of isoflavones, they are best known for their antioxidant activities. S-Equol, a metabolite of genistein and daidzein, has strong antioxidative effects; however, the ability to metabolize daidzein into S-equol varies based on racial and individual differences. The antioxidant activity of isoflavones may be effective in preventing dementia by inhibiting the phosphorylation of Alzheimer’s-related tau proteins. Genistein also reduces allergic responses by limiting the expression of mast cell IgE receptors, which are involved in allergic responses. In addition, they have been known to prevent and treat various diseases, including cardiovascular diseases, metabolic syndromes, osteoporosis, diabetes, brain-related diseases, high blood pressure, hyperlipidemia, obesity, and inflammation. Further, it also has positive effects on menstrual irregularity in non-menopausal women and relieving menopausal symptoms in middle-aged women. Recently, soybean consumption has shown steep increasing trend in Western countries where the intake was previously only 1/20–1/50 of that in Asian countries. In this review, Ihave dealt with the latest research trends that have shown substantial interest in the biological efficacy of isoflavones in humans and plants, and their related mechanisms.

Broiler chicks are fast-growing and susceptible to dietary selenium (Se) deficiency. This study sought to reveal the underlying mechanisms of how Se deficiency induces key organ dysfunctions in broilers. Day-old male chicks ( n =6 cages/diet, 6 chicks/cage) were fed with a Se-deficient diet (Se-Def, 0.047 mg Se/kg) or the Se-Def+0.3 mg Se/kg (Control, 0.345 mg Se/kg) for 6 weeks. The serum, liver, pancreas, spleen, heart, and pectoral muscle of the broilers were collected at week 6 to assay for Se concentration, histopathology, serum metabolome, and tissue transcriptome. Compared with the Control group, Se deficiency induced growth retardation and histopathological lesions and reduced Se concentration in the five organs. Integrated transcriptomics and metabolomics analysis revealed that dysregulation of immune and redox homeostasis related biological processes and pathways contributed to Se deficiency-induced multiple tissue damage in the broilers. Meanwhile, four metabolites in the serum, daidzein, epinephrine, L-aspartic acid and 5-hydroxyindoleacetic acid, interacted with differentially expressed genes with antioxidative effects and immunity among all the five organs, which contributed to the metabolic diseases induced by Se deficiency. Overall, this study systematically elucidated the underlying molecular mechanisms in the pathogenesis of Se deficiency-related diseases, which provides a better understanding of the significance of Se-mediated heath in animals.