(2017) conducted a meta-analysis with 21 case-control studies and two cohort studies, with a total number of 11,346 cases and 140,177 controls [77]. In soybeans, the three most abundant isoflavones are present in four chemical forms: aglycone, glycoside, acetylglycoside and malonylglucoside (Table 1 and Figure 2). This fact was not taken into account in previous meta-analyses, and thus it may justify the discrepancies amongst them. government site. and J.T. Since hepatic lipase and lipoprotein lipase hydrolyze triglycerides into their constituents glycerol and fatty acids, their activation results in the delivery of the fatty acids to tissues such as muscle and adipose tissue. Vlachopoulos C., Aznaouridis K., Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: A systematic review and meta-analysis. They performed a separated meta-analysis for each of the interventions, including dietary soy isoflavones (including four studies), supplements and extracts of soy isoflavones (including six studies) and red clover isoflavones (including seven studies). Estradiol, which has proven efficacy on hot flushes, needs 3.09 weeks to achieve half of its peak activity, while isoflavones require 13.4 weeks, suggesting that 12 weeks of treatment is not enough for soy isoflavones to exert a beneficial effect. Reproductive and developmental toxicity studies have stated that 1 g and 2 g of equol per day is safe [96], although further studies are required [92]. Man B., Cui C., Zhang X., Sugiyama D., Barinas-Mitchell E., Sekikawa A. Due to the high prevalence of colorectal cancer, three meta-analyses addressing this issue are included in the present review. Mace T.A., Ware M.B., King S.A., Loftus S., Farren M.R., McMichael E., Scoville S., Geraghty C., Young G., Carson W.E., et al. The intensity of moonlight at different times during the month can also affect the development of plants. This difference could explain the slow effect of isoflavones in alleviating hot flushes. Isoflavones are found in several vegetables, mainly in legumes (Fabaceae family) such as soy, white and red clover, alfalfa and beans [9,10]. Sfakianos J., Coward L., Kirk M., Barnes S. Intestinal uptake and biliary excretion of the isoflavone genistein in rats. Chang H.H., Robinson A.R., Common R.H. Excretion of radioactive diadzein and equol as monosulfates and disulfates in the urine of the laying hen. Some authors label equol as an isoflavone; however, since it is a daidzein-derived bacterial metabolite and not a naturally occurring isoflavone, this classification is not correct [10]. Zhong X.S., Ge J., Chen S.W., Xiong Y.Q., Ma S.J., Chen Q. The authors suggested that further studies grouping subjects by isoflavone intake or by the circulating isoflavone levels might enhance this association. A systematic review and meta-analysis of the effects of isoflavone formulations against estrogen-deficient bone resorption in peri- and postmenopausal women. Nevertheless, the results do not seem entirely conclusive, as there are discrepancies among the studies included in the systematic reviews and in the meta-analyses, probably related to their experimental designs. Regarding the mechanisms by which isoflavones act to alleviate vasomotor symptoms, is has been proposed that they bind to estrogen receptors and activate endothelial nitric oxide synthase (eNOS) transcription, leading to eNOS synthesis and nitric oxide production, the main mediator of vasodilatation, which allows cutaneous heat dissipation [91] (Figure 6). In this sense, Micek et al. (2019) conducted a meta-analysis where 23 prospective studies with a total of 330,826 participants were included. ; WritingReview and Editing, M.P.P., S.G.-Z., I.E. They observed that it was dose-dependent at low to moderate soybean consumption. Hua X., Yu L., You R., Yang Y., Liao J., Chen D. Association among Dietary Flavonoids, Flavonoid Subclasses and Ovarian Cancer Risk: A Meta-Analysis. This study was supported by Instituto de Salud Carlos III (CIBERobn) under Grant CB12/03/30007, Basque Government under Grant PA20/04 and the University of the Basque Country under Grant GIU18-173. However, the authors pointed out several limitations of this study, such as the important source of heterogeneity in their study. In the meta-analysis reported by Chen et al. Li L., Lv Y., Xu L., Zheng Q. Quantitative efficacy of soy isoflavones on menopausal hot flashes. Perna et al. Science is Knowledge Space & Physics The Effects of Moonlight May 22, 1858 Professor Piazza Smyth, the Astronomer Royal for Scotland, in his interesting account of a recent scientific. However, the intake of specific isoflavones, genistein and daidzein, was indeed significantly associated with a reduced risk of this type of cancer. U.S. Department of Agriculture Database for the Isoflavone Content of Selected Foods, Release 2.0. Kelly G.E., Nelson C., Waring M.A., Joannou G.E., Reeder A.Y. In some cases the purported effect may depend on external cues, such as the amount of moonlight. In this section, 16 meta-analyses have been revised: Nachvack et al. Daidzein, genistein and glycitein occur naturally in the aglycone form, and thus their absorption is faster than that of others. Diversely, Liu et al. The gravitational attraction between the Earth and the Moon produces two bulges in the ocean on opposite sides of the Earth. and transmitted securely. (2016) conducted a meta-analysis of 18 studies involving 16,917 colorectal cancer cases in 559,486 participants [78]. Their meta-analysis included five studies with a total of 728 menopausal women between 50.5 and 58.5 years old and concluded that women who are not able to produce equol could benefit from equol supplementation. With regard to the published meta-analysis, the studies included were restricted to randomized controlled trials. Regarding cancer, scientific evidence suggests that isoflavones could be useful in reducing the risk of suffering from some types of cancer, such as breast and endometrial cancer, although further studies are needed to confirm these results. van Erp-Baart M.A., Brants H.A., Kiely M., Mulligan A., Turrini A., Sermoneta C., Kilkkinen A., Valsta L.M. That's what behavioral ecologist Jenny York learned while studying white-browed sparrow weavers . On the contrary, a systematic review and meta-analysis reported by Man et al. Further, Chalvon-Demersay et al. Another meta-analysis, conducted by Zhao et al. (2019), included 16 prospective cohort studies involving 11,169 breast cancer cases and 648,913 participants [70]. In Japanese men, pre-diagnostic circulating levels of genistein, daidzein and equol did not significantly affect prostate cancer risk. When a group receiving hormone replacement therapy was included in the study, significant differences between the effects of hormone replacement therapy and soy were found, being the effect of the former superior to that of isoflavones. Perna S., Peroni G., Miccono A., Riva A., Morazzoni P., Allegrini P., Preda S., Baldiraghi V., Guido D., Rondanelli M. Multidimensional Effects of Soy Isoflavone by Food or Supplements in Menopause Women: A Systematic Review and Bibliometric Analysis. The mean age of women ranged from 49 to 58.3 and 48 to 60.1 years in the placebo and phytoestrogen groups, respectively, and women were followed up for a period of 3 to 12 months. Moreover, the number of publications grouping women according to pre- or post-diagnosis intake criteria is small. They found that the use of dietary isoflavones or supplements and extracts was associated with an improvement in hot flushes, but not with a reduction in the frequency of night sweats. Zhong et al. Inverse association between isoflavone consumption and colorectal cancer risk in case-control studies, but not in cohort studies. Isoflavone content in soy-derived products is usually lower than in soybeans [17]. Daily J.W., Ko B.S., Ryuk J., Liu M., Zhang W., Park S. Equol Decreases Hot Flashes in Postmenopausal Women: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Overall, evidence regarding the use of isoflavones in cancer prevention suggests that they may be useful in reducing the risk of suffering from some types of cancer, such as breast and endometrial cancer, two of the types for which the association between isoflavone intake and cancer risk has been studied more in-depth. The Effects and Action Mechanisms of Phytoestrogens on Vasomotor Symptoms During Menopausal Transition: Thermoregulatory Mechanism. Although the mechanisms of action of isoflavones are not completely understood, it seems that isoflavones not only reduce the rate of bone resorption but also increase the rate of bone formation. Specifically, the time to achieve half of the efficacy was 11.6 weeks for soy isoflavones, while for the rest of the compounds, the onset time was near 0 weeks. Collison M.W. Lastly, Zhang et al. Ingram D., Sanders K., Kolybaba M., Lopez D. Case-control study of phyto-oestrogens and breast cancer. Regarding cancer, scientific evidence suggests that isoflavones could be useful in reducing the risk of suffering some types of cancer, such as breast and endometrial cancer, but further studies are needed to confirm these results. In addition, genistein and glycitein are transformed into dihydrogenistein and dihydroglycitein, respectively, before being further converted into other metabolites. It is also important to mention that isoflavones could act as potential anticancer compounds due to their antioxidant role in malignant cell proliferation and differentiation (Figure 5). Lastly, Abshirini et al. For this reason, the results should be interpreted with caution, and more randomized clinical trials are imperative. After an extensive bibliographical review, the expert panel concluded that the results of observational studies do not support the hypothesis of an increased risk of breast cancer after isoflavone-rich food supplement intake [93]. HRT: hormone replacement therapy, RCT: randomized controlled trial, VSM: vasomotor symptoms. The four chemical forms of the three most abundant isoflavones. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: A meta-analysis of prospective studies. Considering the isoflavone chemical structure, potential health adverse effects of these compounds related to their estrogenic activity have been postulated, despite the scientific opinion offered by EFSA indicating that isoflavone intake was safe. Kurzer M.S., Xu X. Dietary phytoestrogens. The improvement was greater in treatments lasting more than one year and in subjects with normal weight, probably because subjects with excessive body weight have a lesser risk of bone loss. Further, Chalvon-Demersay et al. Endometrial cancer (Table 4), as well as breast cancer, is an estrogen-dependent cancer type related to high circulating estradiol concentrations. (2016) suggested that a daily intake of soy isoflavones, ranging from 20 to 100 mg/day, reduced total cholesterol and triglyceride plasma concentrations, as well as some markers of oxidative stress (nitric oxide and malonaldehyde), thus reducing cardiovascular risk [52]. Association between Dietary Isoflavones in Soy and Legumes and Endometrial Cancer: A Systematic Review and Meta-Analysis. Chen L.R., Ko N.Y., Chen K.H. For their meta-analysis, Jiang et al. In view of the results gathered in the present review, we can conclude that there is scientific evidence that reveals the beneficial effect of isoflavones on bone health and thus in the prevention and treatment of osteoporosis in postmenopausal women. The authors reported that neither soy food intake nor circulating isoflavones were associated with a reduced risk of prostate cancer. In this systematic review, 123 studies were included, with a total number of 516,330 participants. Daily et al. Li L., Xu L., Wu J., Dong L., Zhao S., Zheng Q. Explore our digital archive back to 1845, including articles by more than 150 Nobel Prize winners. ; Project Administration, M.P.P. Some gardening folklore suggests that planting crops according to the phases of the moon will give you a better harvest, but there is little scientific evidence to back this up. Moreover, the authors suggested that ethnicity could have had influenced this association, but studies with larger sample sizes are needed to confirm this hypothesis. For this purpose, 23 studies with 2167 patients were included in this meta-analysis, which showed that a daily dose of more than 54 mg could decrease the endometrial thickness in North American women, whereas the contrary effect was observed in the Asian sample. According to the results gathered in the present review, it can be stated that there is scientific evidence showing the beneficial effect of isoflavones on bone health and thus in the prevention and treatment of osteoporosis on postmenopausal women, although the results do not seem entirely conclusive as there are discrepancies among the studies, probably related to their experimental designs. Metabolism of intraruminally administered [4-. Despite the positive effect of isoflavones, the authors emphasized that the effects took a long time to appear. The latter is the most common form in foodstuffs, with the exception of fermented soy products, such as miso and tempeh. After this, each metabolite undergoes its own metabolic pathway [40]. The light of the moon also influences animals that are active in daytime. After the consumption of around 17 mg of isoflavones per day, the median plasma concentrations of genistein, glycitein, daidzein and equol were 245.3 ng/mL, 9.8 ng/mL, 86.8 ng/mL and 12.7 ng/mL, respectively. Gruber C.J., Tschugguel W., Schneeberger C., Huber J.C. Production and actions of estrogens. These two associations were significant for postmenopausal participants. However, the results do not seem entirely conclusive, for there are discrepancies among the studies, probably related to their experimental designs. However, the authors acknowledged several limitations to their study, such as the small sample size in the meta-analysis (middle-aged 276 women and 209 men), and recognized that a large number of subjects as well as a lengthier intervention are needed to investigate whether supplementation of soy isoflavones actually improves these outcomes. Indeed, some authors speculate that hepatic and lipoprotein lipase activity may have been altered after variable isoflavone intake from soybean, although no experimental data were provided [67]. Opposite effect in Asian women, Prospective studies (3) Case-control studies (5), Isoflavone consumption (>45 mg/day among the Asian population, and >1 mg/day among the non-Asian population), Potential reduction risk associated with isoflavone consumption, Prospective cohort study (5) Case-control study (7), Cohort prospective study (2 studies from Japan and 5 studies from Europe), 241 cases and 503 controls (from Japanese studies), and 2828 cases and 5593 controls (from European studies), Circulating isoflavone concentrations (nmol/L): Daidzein (Japanese: 115166; European: 2.843.96), Genistein, daidzein and equol did not affect prostate cancer risk in both Japanese and European men, Case-control study (15) Cohort study (8) Nested case-control study (7), 266,699 (21,612 patients with prostate cancer), Isoflavones were not associated with a reduction of prostate cancer risk, Daidzein, genistein, and equol (dose not defined), 19% reduction in prostate cancer risk was found at high concentrations of daidzein, but not with genistein or equol, Participants: 11,346 cases and 140,177 controls, Daidzein and genistein intakes were associated with a reduction of prostate cancer risk (no effect with equol), 559,486 (among them 16,917 colorectal cancer cases), Foods rich in isoflavones (dose not defined), Soy foods (30 mg/day170 g/day) and isoflavones (0.01460 mg/day). Dong J.Y., Qin L.Q. In contrast, red clover was not associated with changes in the hot flush frequency. Moreover, five studies reported side-effect data, and after the analysis, no significant differences were observed between the two groups. Focusing on the overall intake of isoflavones in humans, several studies have reported varied results. This meta-analysis included 266,699 participants (21,612 patients with prostate cancer among them). Grosso G., Godos J., Lamuela-Raventos R., Ray S., Micek A., Pajak A., Sciacca S., DOrazio N., Del Rio D., Galvano F. A comprehensive meta-analysis on dietary flavonoid and lignan intake and cancer risk: Level of evidence and limitations. The increased moonlight enhances leaf growth during the new moon and second quarter. . In general terms, it has been observed that in Asian countries where there is high consumption of soy and its derived foodstuffs, isoflavone intake is high, ranging from 15 to 60 mg/day [20,21], whereas, in western countries, it is notably lower, around 12 mg/day [22,23,24]. In general, evidence regarding the use of isoflavones on vasomotor symptoms suggests that they could be useful in reducing hot flushes. Rienks et al. Circulating isoflavone and lignan concentrations and prostate cancer risk: A meta-analysis of individual participant data from seven prospective studies including 2,828 cases and 5,593 controls. In this study, five prospective cohort studies and seven case-control studies, with 6275 cases and 393,776 controls, were included. Rossi M., Amaretti A., Roncaglia R., Leonardi A., Raimondi S. Dietary isoflavones and dietary microbiota: Metabolism and transformation into bioactive compounds. By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. Thirty-seven articles presenting evidence of the physiological effects of viewing nature were selected. In this sense, soy isoflavones have been proposed as beneficial because, in theory, they may contribute to the maintenance of good bone health (mass, mineral density and bone structure) in women who are at this stage in their life. Before Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. (2018) showed no effect of soy isoflavones on plasma concentrations of lipoprotein a (Lpa), a low-density lipoprotein associated with increased cardiovascular risk due to its pro-thrombotic and atherogenic properties [63]. Soy Consumption and the Risk of Prostate Cancer: An Updated Systematic Review and Meta-Analysis. Schmidt M., Arjomand-Wlkart K., Birkhuser M.H., Genazzani A.R., Gruber D.M., Huber J., Klbl H., Kreft S., Leodolter S., Linsberger D., et al. (2015) concluded that soy isoflavones have both a slight and slow effect in attenuating menopausal hot flushes [87]. This result has implications for granivory and perhaps plant demography in invaded and restored coastal habitats. Lu L.J., Anderson K.E. Furthermore, among the four studies of breast cancer recurrence, three studies found that isoflavone intake decreased the risk of breast cancer recurrence, although further studies are required to confirm this finding [82]. . That aluminum may be harmful to plants as well as animals. ; WritingOriginal Draft Preparation, S.G.-Z., M.G.-A., A.F.-Q., I.E. Due to the presence of biologically active compounds, walnut was used in the . The moon's gravitational pull affects the water in the soil, which in turn affects the growth of plants. Liu J., Yuan F., Gao J., Shan B., Ren Y., Wang H., Gao Y. Prez-Cornago et al. The same results were reported in another meta-analysis published by the same authors a year later (Li et al., 2016), when they compared the efficacy of several non-hormonal drugs on hot flushes, including selective serotonin reuptake inhibitors (SSRIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), gabapentin, clonidine and soy isoflavones [88]. Dietary polyphenol intake in Europe: The European Prospective Investigation into Cancer and Nutrition (EPIC) study. Received 2020 Nov 30; Accepted 2020 Dec 15. The authors found, in a small number of studies (17 studies including 337 healthy, diabetic or hypercholesterolemic individuals), that a soy protein-based diet (rich in isoflavones) as compared to animal protein-based diets (meat, milk, casein, whey) resulted in reduced total cholesterol or LDL-cholesterol concentrations, increased HDL cholesterol concentrations, improved LDL:HDL cholesterol ratio, and decreased triglycerides. 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