Table 2.

Glyceollins effects in noncancer diseases.

Diseases or Functions	Cell Line/Animal Model	Treatment	Major Effects	References
Osteoporosis	Adipose-derived stromal cells and bone marrow stromal cell line	GI 1 and GII 2	- GI and GII: Increase calcium deposition - GII: Stronger than E2 and GI, increase the expression of genes involved in osteogenic differentiation in a similar manner to E2	Bateman et al. 2017 [76]
Glucose and lipid metabolism	Enteroendocrine NCI-H716 cell line	Glyceollin mixture 3	- Enhance GLP-1 4 secretion to increase insulinotropic actions	Park et al. 2010 [79]
	3T3-L1 adipocyte cell line	Glyceollin mixture	- Increase both insulin-stimulated and basal glucose uptake - Increase glucose transporter GLUT4 5 level - Decrease triacylglycerol accumulation	Boué et al. 2012 [41], Park et al. 2010 [79]
	Insulima Min6 cell line	Glyceollin mixture	- Decrease apoptosis - Enhance insulinotropic actions	Park et al. 2010 [79]
	Diabetic male C57BL6J mouse	Fermented soybeans containing glyceollins	- Decrease blood glucose level - Increase hepatic glycogen accumulation - Decrease triglyceride storage	Park et al. 2012 [42]
	Prediabetic male ZDSD/Pco rat	Glyceollin mixture	- Decrease blood glucose level	Boué et al. 2012 [41]
	Male golden Syrian hamster	Diet containing glyceollins	- Reduce plasma VLDL 6, hepatic cholesterol esters, total lipid content - Alter expression of the genes related to cholesterol in liver	Huang et al. 2013 [80]
	Female monkey (Macaca fascicularis)	Diet containing glyceollins	- Decrease serum total cholesterol, specifically LDL 7 and VLDL, increase serum triglycerides - Upregulate genes expression of PPAR 8-γ, adiponectin, leptin, liptin 1, lipoprotein lipase and triglyceride	Wood et al. 2012 [81]
Oxidative stress	Tests in vitro	Glyceollin mixture	- Have ferric-reducing antioxidant power, radical scavenging activities	Kim et al. 2010 [82]
	Hepa1c1c7/ BPRc1 cell line	Glyceollin mixture	- Inhibit H2O2-induced ROS 9 production - Induce Nrf2-mediated phase 2 detoxifying enzymes - Activate Nrf2-signaling pathway under oxidative stress	Kim et al. 2010 [82], Kim et al. 2011 [83] Jung et al. 2013 [84]
	Female C57BL/6J mouse	Glyceollin mixture	- Increase NAD(P)H:quinone oxidoreductase 1activity in kidney, liver, and large intestine	Kim et al. 2015 [72]
	Rat	Glyceollin mixture	- Inhibit lipid peroxidation in liver, kidney, and brain tissue extracts	Kim et al. 2010 [82]
Central nervous system	Breast cancer MCF-7 cell line	Glyceollins mixture	- Increase nerve growth factor receptor gene expression	Zimmermann et al. 2010 [28]
	Glutamate-sensitive murine hippocampal HT22 cell line	Glyceollin mixture	- Attenuate glutamate-induced neurotoxicity - Suppress glutamate-induced intracellular ROS - Act through Nrf2 signaling pathway, activate hem oxygenase-1 enzyme	Seo et al. 2018 [85]
	Primary cortical neurons from wild-type and Nrf2 knockout male C57BL/6J mouse	Glyceollin mixture	- Suppress glutamate-induce cytotoxicity in primary cortical neurons of wild-type mice, but not cells from Nrf2 knockout.	Seo et al. 2018 [85]
	Wild-type and Nrf2 knockout male C57BL/6J mouse	Glyceollin mixture	-Improve cognitive deficits caused by scopolamine in wild-type mice, but no effect in Nrf2 knockout mice - Inhibit acetylcholine esterase activity in neurons from the cortex, but not in cells from the hippocampus	Seo et al. 2018 [85]
	Ovariectomized adult female CFW mouse	Glyceollin mixture	- Upregulate genes involved in neurogenesis, synaptic plasticity, tissue development and transcripts involved in signal transduction pathways, regulation of nerve impulse, cytoskeletal remodeling, and hormone signaling - Downregulate genes involved in neurodegeneration apoptosis and transcripts involved in developmental neurogenesis, synaptogenesis, and cell adhesion - Act through ER 10-dependent or ER-independent mechanisms depending on the target genes	Bamji et al. 2015 [86], Bamji et al. 2018 [87]
Inflammation	Murine macrophage RAW264.7 cell line	Glyceollin mixture	- Inhibit nitric oxide production and inflammatory mediators release through the NF-κB pathway	Kim et al. 2011 [88], Yoon et al. 2012 [89]
	Human umbilical vein endothelial cell line	Glyceollin mixture	- Reduce HMGB1 11 protein level induced by LPS 12 - Decrease HMGB1-induced vascular barrier disruption - Decrease HMGB1-mediated pro-inflammatory and inflammatory response	Lee et al. 2014 [90]
	ICR mouse	Glyceollin mixture	- Reduce mouse ear swelling caused by 12-O-tetradecanoylphorbol-13-acetate	Kim et al. 2011 [88]
	Male C57BL/6 mouse that underwent cecal ligation and puncture	Glyceollin mixture	- Reduce serum HMGB1 level, decrease HMGB1-induced vascular barrier disruption - Reduce HMGB1-induced mortality	Lee et al. 2014 [90]
Cardiovascular diseases	Human aortic smooth muscle cell line	Glyceollin mixture	- Inhibit the cell proliferation and migration induced by PDGF-BB 13	Kim et al. 2012 [91]
	Aortic rings from male Sprague-Dawley rat	GI	- Reduce vascular contraction partly through the inhibition of the RhoA/Rho-kinase signaling pathway	Song et al. 2010 [92]
Melanogenesis	B16/B16F10 cell lines	Glyceollin mixture	- Inhibit melanin synthesis by decreasing melanogenic enzymes and other factors	Lee et al. 2010 [93], Shin et al. 2013 [94]
	Standard AB strain zebrafish (Danio rerio) embryos	Glyceollin mixture	- Decrease the pigmentation of the embryos, melanin synthesis and tyrosinase activity - Decrease Sox10, a pigment cell-specific gene	Shin et al. 2013 [94]

¹ Glyceollin I, ² Glyceollin II, ³ Glyceollin mixture contains glyceollin I, glyceollin II, and glyceollin III, ⁴ glucagon-like peptide 1, ⁵ glucose transporter 4, ⁶ very low-density lipoprotein, ⁷ low-density lipoprotein, ⁸ peroxisome proliferator-activated receptor, ⁹ reactive oxygen species, ¹⁰ estrogen receptor, ¹¹ high mobility group box 1, ¹² lipopolysaccharide, ¹³ platelet-derived growth factor BB.