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Previous studies have demonstrated antiestrogenic and antiproliferative effects of these molecules in breast cancer cells. Notably, we have reported that pure synthetic glyceollins I and II act through various pathways, including ERα, FOXM1, AhR, and HIF pathways to inhibit cell proliferation and migration. In this study, the potential antitumor activity of glyceollins enriched in crude soybean extracts, obtained by solid fermentation with Aspergillus sojae, was investigated in vivo on MCF‐7 breast cancer cells implanted in the chorioallantoic membrane of the chick egg and on ovariectomized nude mice. The first trial showed a substantial reduction in the migration of MCF‐7 cells treated with the natural extracts. However, the natural extracts significantly reduced the estrogen‐dependent growth of transplanted tumors in orally fed nude mice. Our results showed that natural soybean extracts slightly but significantly reduced estrogen‐dependent growth of the transplanted tumors in orally fed nude mice. These results were confirmed by immunohistochemistry of Ki‐67 and histone H3S10 phosphorylation (H3S10P), revealing lower expression of these proliferation markers in the transplanted tumors from mice fed with the fermented extracts. Additionally, compared to the control animals, we observed a lower expression of angiogenesis markers such as CD31 and CD34. Surprisingly, transcriptomic analysis of RNA from transplanted MCF‐7 cells revealed no differential gene expression. These results may suggest that orally consumed natural glyceollins exert biological effects throughout the body, acting indirectly to reduce tumor angiogenesis and consequently tumor volume. Overall, our results indicate that glyceollins, elicited components of the soy origin, hold potential therapeutic applications for the prevention and treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Xenohormesis proposes that phytochemicals produced to combat stressors in the host plant exert biochemical effects in animal cells lacking cognate receptors. Xenohormetic phytochemicals such as flavonoids and phytoalexins modulate a range of human cell signaling mechanisms but functional correlations with human pathophysiology are lacking. Here, potent inhibitory effects of grapefruit‐derived Naringenin (Nar) and soybean‐derived Glyceollins (Gly) in human microphysiological models of bulk tissue vasculogenesis and tumor angiogenesis are reported. Despite this interference of vascular morphogenesis, Nar and Gly are not cytotoxic to endothelial cells and do not prevent cell cycle entry. The anti‐vasculogenic effects of Glyceollin are significantly more potent in sex‐matched female (XX) models. Nar and Gly do not decrease viability or expression of proangiogenic genes in triple negative breast cancer (TNBC) cell spheroids, suggesting that inhibition of sprouting angiogenesis by Nar and Gly in a MPS model of the (TNBC) microenvironment are mediated via direct effects in endothelial cells. The study supports further research of Naringenin and Glyceollin as health‐promoting agents with special attention to mechanisms of action in vascular endothelial cells and the role of biological sex, which can improve the understanding of dietary nutrition and the pharmacology of phytochemical preparations. [ABSTRACT FROM AUTHOR]

Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70–85 years) with obesity. Whole green soybean pods grown under controlled conditions were processed to flour (WGS) at the United States Department of Agriculture using common cooking techniques such as slicing and heat treatment. WGS incorporated into food products was consumed at 10 g, 20 g, and 30 g/day for one week at each dose. The gastrointestinal outcomes, clinical biomarkers, and adverse events were evaluated. We explored the stimulation of phytoalexin (glyceollin) production in live viable soybean seeds (LSS-G). We compared the compositions of WGS and LSS-G with commercial soybean flour and its fermented and enzymatically hydrolyzed forms. We found that although 30 g WSG was well-tolerated, and it made participants feel full. Our processing produced glyceollins (267 µg/g) in LSS-G. Processing soybean flour decreased the iron content, but reduced the oligosaccharides, which could attenuate flatulence. Providing soybean flour at <30 g/day may be prudent for overall health and to prevent the exclusion of other food groups and nutrients in older adults with obesity. [ABSTRACT FROM AUTHOR]

Glyceollins, isoflavonoid-derived antimicrobial metabolites, are the major phytoalexins in soybean (Glycine max). They play essential roles in providing resistance to the soil-borne pathogen Phytophthora sojae and have unconventional anticancer and neuroprotective activities that render them desirable for pharmaceutical development. Our previous studies revealed that the transcription factors GmMYB29A2 and GmNAC42-1 have essential roles in activating glyceollin biosynthesis, yet each cannot activate the transcription of all biosynthesis genes in the absence of a pathogen elicitor treatment. Here, we report that co-overexpressing both transcription factors is also insufficient to activate glyceollin biosynthesis. To understand this insufficiency, we compared the transcriptome profiles of hairy roots overexpressing each transcription factor with glyceollin-synthesizing roots treated with wall glucan elicitor (WGE) from P. sojae. GmMYB29A2 upregulated most of the WGE-regulated genes that encode enzymatic steps spanning from primary metabolism to the last step of glyceollin biosynthesis. By contrast, GmNAC42-1 upregulated glyceollin biosynthesis genes only when overexpressed in the presence of WGE treatment. This is consistent with our recent discovery that, in the absence of WGE, GmNAC42-1 is bound by GmJAZ1 proteins that inhibit its transactivation activity. WGE, and not GmMYB29A2 or GmNAC42-1, upregulated the heat shock family gene GmHSF6-1, the homolog of Arabidopsis HSFB2a that directly activated the transcription of several glyceollin biosynthesis genes. Our results provide important insights into what biosynthesis genes will need to be upregulated to activate the entire glyceollin biosynthetic pathway. [ABSTRACT FROM AUTHOR]

Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70–85 years) with obesity. Whole green soybean pods grown under controlled conditions were processed to flour (WGS) at the United States Department of Agriculture using common cooking techniques such as slicing and heat treatment. WGS incorporated into food products was consumed at 10 g, 20 g, and 30 g/day for one week at each dose. The gastrointestinal outcomes, clinical biomarkers, and adverse events were evaluated. We explored the stimulation of phytoalexin (glyceollin) production in live viable soybean seeds (LSS-G). We compared the compositions of WGS and LSS-G with commercial soybean flour and its fermented and enzymatically hydrolyzed forms. We found that although 30 g WSG was well-tolerated, and it made participants feel full. Our processing produced glyceollins (267 µg/g) in LSS-G. Processing soybean flour decreased the iron content, but reduced the oligosaccharides, which could attenuate flatulence. Providing soybean flour at

Glyceollins, isoflavonoid-derived antimicrobial metabolites, are the major phytoalexins in soybean (Glycine max). They play essential roles in providing resistance to the soil-borne pathogen Phytophthora sojae and have unconventional anticancer and neuroprotective activities that render them desirable for pharmaceutical development. Our previous studies revealed that the transcription factors GmMYB29A2 and GmNAC42-1 have essential roles in activating glyceollin biosynthesis, yet each cannot activate the transcription of all biosynthesis genes in the absence of a pathogen elicitor treatment. Here, we report that co-overexpressing both transcription factors is also insufficient to activate glyceollin biosynthesis. To understand this insufficiency, we compared the transcriptome profiles of hairy roots overexpressing each transcription factor with glyceollin-synthesizing roots treated with wall glucan elicitor (WGE) from P. sojae. GmMYB29A2 upregulated most of the WGE-regulated genes that encode enzymatic steps spanning from primary metabolism to the last step of glyceollin biosynthesis. By contrast, GmNAC42-1 upregulated glyceollin biosynthesis genes only when overexpressed in the presence of WGE treatment. This is consistent with our recent discovery that, in the absence of WGE, GmNAC42-1 is bound by GmJAZ1 proteins that inhibit its transactivation activity. WGE, and not GmMYB29A2 or GmNAC42-1, upregulated the heat shock family gene GmHSF6-1, the homolog of Arabidopsis HSFB2a that directly activated the transcription of several glyceollin biosynthesis genes. Our results provide important insights into what biosynthesis genes will need to be upregulated to activate the entire glyceollin biosynthetic pathway.

The WRKYs are a group of plant-specific transcription factors that play important roles in defense responses. In this study, we silenced 2 GmWRKY33B homologous genes using a bean pod mosaic virus (BPMV) vector carrying a single fragment from the conserved region of the GmWRKY33B genes. Silencing GmWRKY33B did not result in morphological changes. However, significantly reduced resistances to Pseudomonas syringae pv. glycinea ( Psg ) and soybean mosaic virus (SMV) were observed in the GmWRKY33B -silenced plants, indicating a positive role of the GmWRKY33B genes in disease resistance. Kinase assay showed that silencing the GmWRKY33B genes significantly reduced the activation of Gm MPK6, but not Gm MPK3, in response to flg22 treatment. Reverse transcriptase PCR (RT-PCR) analysis of the genes encoding prenyltransferases (PTs), which are the key enzymes in the biosynthesis of glyceollin, showed that the Psg -induced expression of these genes was significantly reduced in the GmWRKY33B -silenced plants compared with the BPMV-0 empty vector plants, which correlated with the presence of the W-boxes in the promoter regions of these genes. Taken together, our results suggest that Gm WRKY33Bs are involved in soybean immunity through regulating the activation of the kinase activity of Gm MPK6 as well as through regulating the expression of the key genes encoding the biosynthesis of glyceollins.

Apart from the physiological effects of glyceollins, information regarding their tissue distribution is scarce in the literature. Thus, the aim of this study is to clarify the distribution of glyceollins in rat organs. Glyceollins I and III were orally administered to Sprague-Dawley rats (1.0 mg/kg) with daidzein as control, and their accumulations in organs were investigated by liquid chromatography-time-of-flight/mass spectrometry (LC-TOF/MS). Glyceollins accumulated in intact and conjugated forms in circulatory organs with a T of 0.5 h, in the following order of descending preference: liver, kidney, heart, lung, soleus muscle, and abdominal aorta. The accumulation of hydrophobic glyceollin I was more than 1.5 times higher than that of III. In contrast, daidzein and hydroxy equol were detected only in the liver and kidneys at lower concentrations (1/100 times) than those of glyceollins. In conclusion, prenylated isoflavones, glyceollins, were preferentially distributed in circulatory organs as intact, sulfated, or glucuronidated forms up to 6 h after the intake.max of 0.5 h, in the following order of descending preference: liver, kidney, heart, lung, soleus muscle, and abdominal aorta. The accumulation of hydrophobic glyceollin I was more than 1.5 times higher than that of III. In contrast, daidzein and hydroxy equol were detected only in the liver and kidneys at lower concentrations (1/100 times) than those of glyceollins. In conclusion, prenylated isoflavones, glyceollins, were preferentially distributed in circulatory organs as intact, sulfated, or glucuronidated forms up to 6 h after the intake.