Table 3.

Dietary phytoestrogens as epigenetic modulators—in vitro and in vivo studies.

Dietary Phytoestrogen	Concentration	Cell Line/In Vivo Models	Epigenetic Changes	Targeted Gene	Biological Activity	References
I. Isoflavones
Genistein	In vitro 0.5–1 μM	MCF-7	↓DNMT1, ↓CpG methylation at BRCA1, ESR1 promoter	↑BRCA1, p53, CYP1A1, ↓cyclin D1	-Anti-proiferative and chemopreventive effect in breast cancer cells with activated AhR.	[190]
	3.125 μM	MDA-MB-468,	↓CpG methylation at GSTP1 promoter	↑GSTP1	-Preventive effect, activates phaseI enzyme in TNBC cells.	[211]
	5 μM	MDA-MB-435, Hs578T	↓miR-155	↑FOXO3, PTEN, casein kinase, p27, ↓β-catenin	-Inhibits cells viability and induces apoptosis in TNBC cells.	[197]
	18.5 μM	MCF-7 MDA-MB-231	↓Global DNA methylation, ↓CpG methylation BRCA1, BRCA2, MeCP2 promoters; ↓H3K9me3, H3K4me3, H3K27me3; ↑H4K8ac, H3K4ac at promoters of EZH2,BRCA1, ERα, ERβ, SRC3, p300	↑BRCA1, ↑BRCA2; ↓EZH2, ↑p300, ↑SRC3	-Inhibition of breast cancer cells’ proliferation.	[191,195]
	10–20 μM	UACC-3199, KYSE 510, SiHa; DU145, LNCaP, PC-3, ARCaP-E, ARCaP-M	↓DNMT1, ↓CpG methylation of BRCA1, ESR1 promoters; ↓CpG methylation at RARβ2, p16, MGMT, ↓DNMTs; ↓DNA methylation at RARβ 2; ↑H3K9ac at promoters of APC, SOX7, SFRP1, SFRP2, DKK, WIF1, ↑HAT1	↑BRCA1, ER α, p53 CYP1A1, ↓cyclin D1 ↑RARβ2, p16, MGMT ↑RARβ2; ↑SOX7, SFRP1, BRCA1, BARD1, RAD23B, XRCC2, ↓BIRC7, SLUG, HES1, TGFBIII	-Anti-proiferative and chemopreventive effect in breast cancer cells with activated AhR; -Inhibition of esophageal squamous cell carcinoma growth; -Induces apoptosis in cervix squamous cells carcinoma; -Reduces proliferation and induces apoptosis in prostate cancer cells	[190,193,212,213]
	25 μM	MDA-MB-157, MDA-MB-231; A-498; 786-O; Caki-2; PC3, DU145, RWPE-1; 786-O, ACHN; PC-3, DU145	↑Ac-H3, ↓DNMT1, HDAC1; ↓miR-1260b; ↓CpG methylation at SFRP1 ↓H3K9me2, H2K9me3, H3K27me3 at SFRP1, Smad4 genes; ↓lnc HOTAIR, ↓EZH2, ↑miR-574-3p, ↑mir-34a	↑Erα; ↑SFRP1, Dkk2, Smad4; ↓ARID1A, EED SMARCB1, SNAIL, ↑ZO-1; ↓RAC1, ↓EGFR, ↓EP300 ↓MMP9, VEGF	-Inhibitits proliferation, invasion of TNBC, renal carcinoma and prostate cancer cells; -Enhances tamoxifen induced anticancer effect in TNBC cells; -Promotes apoptosis in renal carcinoma and prostate cancer cells; -Inhibits cell proliferation, migration and invasion in vitro and in vivo in prostate cancer;	[196,199,200,210,214,215]
	5–40 μM	SH, SHR	↑Global H3ac, ↑H3K4me3, ↓H3K27me3, H3K9me3 at p16, p21 promoters, ↑HMTs activities	↑p21, p16, ↓BMI1, c-MYC	-Inhibits growth of breast cancer cells, but no effect on normal cells; -Preventive effect on breast tumorigenesis in vivo.	[188]
	20–40 μM	U266	↑miR-29b	↓NF-κB	-Inhibits proliferation and induces apoptosis in multiple myeloma.	[216]
	40 µM	DU-145, PC-3 LNCaP	↓CpG methylation at BRCA1, GSTP1, EPHB2, RASSF1A promoters; altered methylation pattern of MAD1L1, TRAF7, KDM4B, hTERT genes; ↑miR-200c	↑ BRCA1, GSTP1, ↑EPHB2; Potential target genes SOX2, ZEB1	-Inhibits prostate cancer cells’ proliferation, clonogenic potential and induces apoptosis.	[187,217,218]
	50 µM	HeLa	↓DNA methylation at TP53, PTEN, CDH1, DAPK1, FHIT, RUNX3, SOCS1 promoters, ↓DNMTs, HDACs, HMTs	↑TP53, PTEN, CDH1, DAPK1, FHIT, RUNX3, SOCS1	-Anti-proliferative effect on cervical tumor cells.	[194]
	60–100 μM	MCF-7, MDA-MB-231	↓Global DNA methylation; ↓DNAmethylation at TSG promoters; ↓DNMT1	↑ATM, ↑APC,↑PTEN	-Reduced cellular viability and anti-proliferative effect on breast cancer cells;	[189]
	In vivo 2 mg/day 50 mg /kg 250 mg/kg 270 mg/kg	Neuroblastoma xenografts, Eker rats, Avy female mice, tumor xenograft mice, 123/SvJ:C57BL/6J mice	↓DNTM3B, ↓CHD5 promoter methylation; ↓EZH2, ↓H3K27me3; ↑CpG methylation at Avy IAP gene; ↓DNMT1, HDAC1; ↓HDACs activity; ↑DNA methylation in repetitive elements; ↓HDAC6	↑CHD5; ↑PI3K/AKT pathways in uterus; ↓ectopic Agouti expression; ↑ERα, ↑PCNA in breast tissues; ↓p21, cyclin D1, PCNA, IGF2 expression in adult mice	-Decrease of tumor size and frequency. -Increases hypersensivity of ER-responsive genes in neonatal uteri and adult myometrium; -Reduces obesity offsprings, phenotypes changes; -Re-sensitizing ERα-negative breast cancer to therapy; -Prenatal exposure leads to long-term epigenetics changes.	[196,219,220,221,222]
	Soy based diet	Cynomolgus monkeys	↓DNA methylation at promoter of HOXA5, HOXA11, HOXB1, ABCG5	↑HOXA5, HOXA11, HOXB1, ABCG5	-Decrease in fasting insulin and HOMA index values.	[223]
Daidzein	20–50 μM	KYSE 510	↓DNA methylation at RARβ2 promoter; ↓DNMTs activity	↑RARβ2	-Dose-dependent inhibition of cells growth.	[193]
	78.5 μM	MCF-7, MDA-MB 231	↓Global DNA methylation, ↓CpG methylation at BRCA1, BRCA2 promoters, ↓MeCP2; ↓H3K9, H3K27, H3K4 (me3) ↑H4K8ac, H3K4ac at promoters of EZH2, BRCA1, ERα, ERβ, SRC3, p300	↑BRCA1, BRCA2; ↓EZH2, ↑p300, SRC3	-Inhibition of ER(-) and ER(+) breast cancer cells’ proliferation.	[191,195]
	110 µM	DU-145, PC-3 LNCaP	↓CpG methylation at BRCA1, GSTP1, EPHB2 promoters; altered methylation pattern of MAD1L1, TRAF7, KDM4B, hTERT	↑BRCA1, GSTP1, EPHB2	-Inhibits prostate cancer cells’ proliferation and induces apoptosis.	[187,218]
Biochanin A	2–6 μM	T47-D, MCF-7	↑miR-375	↑ERα, ↑Bcl -2	-Promotes proliferation of breast cancer cells.	[203]
	2.95 μM	MGC-803	↓LSD1, ↑H3K4me1/2, H3K9 me1/2	↓MAO-A/B, Bcl-2, ↑Bax	-Suppresses colony formation and migration and induces apoptosis in gastric cancer cells.	[201]
	20–50 μM	KYSE 510	↓CpG methylation at RARβ promoter, ↓DNMTs activity	↑RARβ	-Inhibits the growth of eosphageal squamous cells.	[193]
Formononetin	In vitro 2–6 μM	HUVEC	↑miR-375	↑ERα, Bcl-2, ↓RASD1	-Promotes cell proliferation and inhibits apoptosis.	[204]
	10–20 μM	GMCs	↑SIRT1	↑Nrf2/ARE ↓Fibronectin, ICAM-1	-Inhibits hyperglycemia-induced ROS overproduction in glomerular mesangial cells.	[224]
	40 μM	BT-549, MDA-MB-231	↓lncRNA AFAP1-AS1 ↑miR-545, miR-195	↓CDK4, Raf-1	-Inhibits proliferation, migration and invasion of TNBC cells.	[208]
	20–100 μM	SW1116, HCT116	↑miR-149	↓EphB3, cyclin D1, MMP2/9, ↓PI3K/AKT ↓STAT3	-Inhibits colon carcinoma cell proliferation and invasion.	[202]
	50–200 μM	T24	↓miR-21	↑PTEN, ↓p-Akt	-Inhibits proliferation, induces apoptosis and decreases invasiveness of bladder cancer.	[205]
	100 µM	U87MG	↓HDAC5	↓Vimentin ↑E-cadherin	-Enhances the cytotoxicity of doxorubicin in glioma cells.	[206]
	In vivo 4–8 mg/kg/day	Ovariectomized rats	↑miR-375	↑ERα, ↑Bcl-2, ↓RASD1	-Lower risk of postmenopausal breast cancer development.	[204]
	20–40 mg/kg	Diabetic type II rats	↑SIRT1 in pancreatic tissues and sciatic nerve tissue	↓MDA, ↑GSH, SOD; ↑NGF in sciatic nerve tissue.	-Reduces oxidative stress, risk of nephro-pathy and the level of triglyceride and cholesterol; -Protects from hyperglycemia induced neuronal damage.	[225,226]
	25–50 mg/kg	Diabetes mice model	↑SIRT1 in kidney tissues	↑Nrf2, ↓Fibronectin, ICAM 1	-Reduces renal fibrosis, improves renal function.	[207,224]
S-equol	In vitro 2 µM	MCF-7, MDA-MB-231	↓CpGmethylation at BRCA1, BRCA2 promoters	↑BRCA1, BRCA2	-Inhibits breast cancer cells’ proliferation.	[192]
	12.8 μM	MCF-7, MDA-MB-231	↓H3K9, H3K27, H3K4(me3) ↑H3K4ac, H4K8ac at promoter of EZH2,BRCA1, ERα, ERβ, SRC3, p300 genes	↓EZH2, ↑p300, ↑SRC3	-	[195]
	50–150 µg/mL	MCF-7	↑miR-10a-5p	↓PI3K p110α, ↓ p-Akt	-Anti-proliferative and pro-apoptotic effect.	[209]
	In vivo 10–100 mg/day	Neonatal rats	↑DNA methylation of H-ras in pancreatic cells	-	-	[227]
II. Prenylflavonoids
6-PN 8-PN	1 μM 50–100 μM	MCF-7 SK-MEL-28	↓DNMT1 HDAC2,4,7,8 inhibition ↑H3 acetylation	↓ERα ↑P450 1A1 ↓pS6P, ↓pERK/pP90	-Activates AhR to attenuate inhibition of CYP1A1 and degradation of ERα; -Antiproliferative effects on melanoma cells.	[228,229]
Glabridin	In vitro 10 μM	MDA-MB-231 Hs-578T	↑miR-148a, ↓DNMT1 ↓DNMT3A,	↓TGFβ/SMAD2	-Inhibits the CSCs-like properties of breast cancer cells.	[167]
	10–20 μM	MDA-MB-231, Hs-578T; HepG2, Huh-7	↑miR-148a	↓Wnt/β-catenin ↓VEGF ↓SMAD2	-Attenuates angiogenes in breast cancer cells; -Inhibits the CSCs-like properties of HCC cells.	[166,230]
	In vivo 20 mg/kg/d	mouse xenograft	↑miR-148a, ↓DNMT1 ↓DNMT3A	↓TGFβ/SMAD2	-Attenuated the tumor growth, CSCs-like properties in vivo.	[167]
Icariin	1 nM	hMSCs	↓DNA methylation at ABCB1 promoter	↑ABCB1, MMP ↑P-gp protein	-Improves cellular viability, decreases oxidative stress and promotes osteogenesis of MSCs;	[231]
	10 nM	Mouse aortic ECs	↑SIRT6, ↓H3K9ac	↓NF-κB, TNF-α, ICAM-1, IL-2, IL-6	-Reduces inflammation in vitro and in vivo;	[232]
	5–10 μM	MDA-MB-231, 4T1	↑SIRT6 ↓H3K9ac	↓NF-κB p65, ↓MMP2, ↓N-cadherin ↓TNFα, ↑E-cadherin	-Suppresses migration, invasion, decreases ROS level in breast cancer cells;	[233]
	2–16 μM	IMR-90	↑SIRT6, SIRT1	↓NF-κB, ↓p-p53, p-p21, ↓Cav1	-Prevents D-gal-induced aging and cell-cycle arrest in lung fibroblast cells;	[234]
	25–50 μM	A2780	↓miR21	↑PTEN, RECK, ↓Bcl-2	-Regulates proliferation and apoptosis of ovarian cancer cells;	[235]
	In vivo 100 mg/kg	Rats	↑SIRT1, H4AcK16	↓TNF-α, IL-1β, and IL-6 ↓NF-κB(p65) phosphorylation	-Suppresses paclitaxel-induced neuroinflammation and mechanical allodynia;	[236]
	10−2 μM 100 mg/kg/day	FA HSPCs isolated from mice	↑SIRT6, ↓H3K9ac	↓NF-κB	-In vitro progenitor capacity; -In vivo repopulating ability of FA HSCs.	[237]
Icaritin	40 μM	CD4+T cells from SLE patients	↑H3K4me3 at Foxp3 gene ↑H3K9me3 at IL17a gene	↑Foxp3 ↓IL17a	-Reduced autoreactivity of CD4+Tcells.	[238]
III. Coumestans
Coumestrol	In vitro 1–10 μM	Muscle cells	↑SIRT1	↑NDUFA9, SDHA, UQCRC2, COX1, PGC1, Nrf1	-Increases mitochondria number, respiratory chain proteins and mitochondrial function;	[239]
	10–50 μM	ES2	↓DNMT3A phospho	↓CK2, PCNA, ERBB2, p-AKT, p70S6K, ERK1/2, JNK1/2, p90RSK	-Preventive effects on epithelial ovarian cancer cells;	[161]
	20–40 μM	HCT116	↓H3Tr3phos	↓Haspin kinase	-Suppresses colon cancer cells’ proliferation;	[162]
	In vivo 10–100 mg/day	Neonatal rats	↑DNA methylation of H-ras	-	-	[227]
Wedelolactone	0.1–10 μM	Mino	↓EZH2, PRC2, HTM ↓H3K27me3	↓PRC2, EZH2	-Inhibition of B cell non-Hodgkin’s lymphoma cells’ proliferation;	[240]
	50 μM	HepG2, THP1, K562	↓EZH2, PRC2	↑DAB2IP, ADRB2, CDKN2A, GADD45A	-Inhibits proliferation and migration, and induces apoptosis and cell-cycle arrest of PRC2-dependent cancers.	[241]
IV. Lignans
Arctigenin	In vitro 0.268 μM 0.5–1 μM 5 μM 20–100 μM	Rats’ neurons; SH-SY5Y; MDA-MB-231 H9C2, Rats cardiomyocyte	↑SIRT1 ↑miR-16 ↑miR-199a ↑H3K9 me3 at AP-1, Bcl-2 promoters ↑SIRT1	↓NLRP3 ↓IL-1β, ↓IL-18, ↓ASC ↓caspases-1 p20; ↓IKKα ↓IKKβ, ↓NF-κB ↓TNF-α ↓IL-6, ↑IL-10; ↓Bcl-2, ↑ phos ATF-2 ↑AMPK, ↑I-κB, ↓NFkB	-Protection against ischemic stroke, neuroprotection; -Induces anti-inflammatory, anti-apoptotic mechanisms to prevent secondary damage; -Supressed cardiomyocytes apoptosis, inflammation and oxidative stress;	[169,242,243,244]
	In vivo 100 µM/kg; 4 mg/kg/day; 20 mg/kg; 50–100 mg/kg	Rats—myocardial ischemia; xenograft mice; Rats—cerebral ischemia	↑SIRT1; ↑pho-p38; ↑SIRT1, ↑miR-96-5p ↓miR-126-5p, miR-21-5p, ↑miR-135a-5p, miR-205-5p, miR-22-3p, miR-455-5p	↑AMPK, ↑I-κB, ↓NFkB ↓Bcl-2; ↓NLRP3 IL-1β, IL-18; ↓ASC, caspases-1 p20 TIMP3, ZNF185 ↓VEGF, EGF, FGF-β, ↑Bax/Bcl-2 ratio	-Inhibition of oxidative Stress and inflammation after acute myocardial ischemia; -Protects against ischemic stroke; -Inhibited prostate tumor cell growth both in vitro and in vivo.	[169,242,244,245]
Arctiin	5 μM 10 μM	HaCaT NHDF	↑miR-125a-5p, -205-3p, -21-3p, -29b-1-5p ↓miR-3652, -494, -1246; ↑miR-602, -762, -150-3p, -4327, -584-5p, -874, -3665 ↓miR-3679-5p, -1290, -575	-Possible regulation of members of MAPK pathways and cell growth signaling pathways.	-Enhances wound healing, DNA repair in UVB-exposed keratinocytes; -Inhibits the UVB-mediated cell growth defect, apoptosis, DNA damage.	[246,247]
SGD	In vitro 50–100 µM	3T3L1	↓DNMTs, HDACs, MBD2	-	-Antioxidant effect, epigenetic modification in murine adipocytes.	[248]
	In vivo Flaxseed diet	Female mice Mice pneumonopathy	↑miR-30b, -324-5p ↓miR-382, -423; ↓miR-142-3p, -150 ↑miR-34a	Changes in mammary gland miRNome; ↓Bcl2, FGFR1	-Prevents breast cancer development during adulthood. -Antioxidant and anti-inflammatory effects.	[249,250]
Sesamin	10 µM	THP-1	↓H3/H4 acetylation at MDC promoter area, ↓CBP	↓MAPK-p38, NFkB-p65, MDC, IP-10	-Supresses allergy and asthma-related chemokines expression; -Anti-inflammatory effect.	[251]
ENL	20 μM	RWPE-1, WPE1-NA22, -NB14, -NB11, -NB26, LNCaP	↓miR-106b cluster (miR-106b, -93, -25)	↓GMNN, CDT1, MCM2, MCM 7 ↑PTEN	-Anti-proliferative effect on mid and late prostate cancers;	[252]
	50–100 µM	3T3L1	↓DNMTs, HDACs, MBD2;	-	-Antioxidant activities, downregulates epigenetic-modification-associated gene expression in murine adipocytes.	[248]
V. Stibenes
Resveratrol	In vitro 1 μM	HaCaT	↑ SIRT1, HDAC2, ↓H4K16Ac	↑eNOS	-Accelerates wound healing repair in vitro and in vivo skin-wound models;	[253]
	5 μM	Canine-bone tissue cells MC3T3-E1	↑ SIRT1 ↓p300	↓NF-κB acetylation, IκBα phosphorylation, IKK activity kinase activity, ↑Cbfa-1	-Anti-osteoclastogenic, activates the bone-tissue cells to osteoblast and osteogenesis;	[254]
	10 μM	MDA-MB-468 A2058, M223; HCT116, SW480; HUVEC; ARPE-19	↓CpG methylation at ERα promoter; ↑SIRT1 ↑DNMT1, ↑LINE-1 methylation	↓STAT3 acethylation ↑ERα expression; ↓NF-Κb, CXCR4, MMP9; ↑eNOS acetylation	-Anti-proliferative, reduces viability and induces mesenchymal to epithelial transition phenotype in breast cancer and CRC cells; -Regulates endothelial function during oxidative stress; -Ameliorates viability and ROS production in retinal pigment epithelia cells under oxidative and inflammatory conditions;	[255,256,257,258]
	14–15 μM	MCF10A, MCF7, HCC1806, MDA-MB-157	↑CpG methylation at KCNJ4, RNF169, BCHE, DAOA ↓CpG methylation of HOXA9, KRTAP2-1, TAGAP, RUNX3; ↓CpG methylation at PTEN promoter, ↓DNMT1; ↓SIRT1, DNMT3B, ↓DNMTs activity; ↑HDACs, HATs, ↑H3Ac, H4Ac, H3K9Ac at ERα promoter	↓KCNJ4, DAOA ↑BCHE, KRTAP2-1, TAGAP; ↑PTEN, p21; ↓γ-H2AX, ↓hTERT; ↑ERα	-No cytotoxic effect on normal mammary gland cells; -Antiproliferative effect on breast cancer cells; -Induces apoptosis and cell-cycle arrest on TNBC cells.	[259,260,261,262]
	10–20 μM	MCF-7; MDA-MB-231	↓DMNT1, MBD2, H3K9me3 at BRCA1 promoter ↑H4Ac, H3K9Ac at BRCA1 promoter ↓PRMT5, EZH2, KDACs, ↑KAT2A/3B ↑global H3K9ac, H3K27ac ↓H4R3me2s, H3K27me3 at BRCA1, p53, p21 promoters	↑BRCA-1 ↓AhR and ERα at BRCA1 promoters; ↑BRCA1, p53, p21	-Attenuates dioxin carcinogenic chemicals-dependent repression of BRCA-1 and induction of DNA damage; -Inhibits breast cancer cells’ proliferation.	[263,264]
	25 μM	C2C12; A549	↑SIRT1; ↓lncAK001796	↑AMPK ↓LKB1ac, ↓PGC-1α ac ↑Nrf-1, Nrf-2, NDUFS8, SDHb, Uqcrc1, COX5b, ATP5a1 ↑BIRC5, TFDP2, CDC6 ↓ATR, CCNB1, CKS2	-Increase mitochondrial membrane potential, cellular ATP content in mouse mioblasts; -Inhibits lung cancer cells’ proliferation.	[265,266]
	20–30 μM	PANC-1, MIA PaCa-2, AsPC1; THP1	↓SIRT1, SIRT2, SIRT3; ↑miR-663, ↓miR-155	↑PTEN, p-JNK, FOXO ↓Ras, p-AKT, p-ERK, AKT kinase activity ↑caspase-3; ↓AP-1, ↑cMaf	-Induces cell-cycle arrest and apoptosis in pancreatic cancer cells; -Inhibits pancreatic tumor growth in vivo;	[267,268]
	20–50 μM	A549, BGC-823, SGC-7901 U266, LP1	↓CpG methylation at ZFP36 promoter; ↓DNMT1; ↑SIRT1; ↓lnc NEAT1	↑ZFP36, ↓CCND1, MYC, VEGFA; ↓cyclin D1, CDK4, CDK6 ↑p21, p16; ↑β-catenin cytoplasm, ↓c-Myc, MMP7, Survivin	-Inhibits migration and cell proliferation in non-small-cell lung cancer cells; -Inhibits gastric cancer cells’ proliferation and induces cell-cycle arrest; -Inhibits the tumor growth of xenografts; -Inhibits the proliferation, migration and invasion of multiple myeloma cells;	[269,270,271]
	50 µM	MCF-10A, MCF-7, MDA-MB-231 LNCaP, DU145, 22Rv1 SW480	↓CpG methylation at Nrf2, ↓miR-93; ↓HDAC activity, ↓HDAC2 at ATP2A3 promoter ↑global H3Ac, H3K27ac ↓DNMTs activity, ↓MeCP2, MBD2; ↓miRs-17-92, -106ab clusters ↓miRs-7, -17, -18b ↑miRs-150, -296-5p ↓miRs-17, -20a, -106a, -106b; ↓HDACs, NuRD complex, ↑p300; ↑miR-663, ↓miR-17, -21, -25, -92a-2	↑Nrf2; ↑ATP2A3, SERCA3; ↑PTEN; ↑PTENac, p53, ↓MTA1, PI3K-Akt; ↓TGFβ1, ↑PTEN, PDCD4, SMAD7	-Protective role against E2-induced mammary carcinogenesis; -Pro-apoptosis effect and changes in Ca2+ homeostasis; -Induces apoptosis and inhibits cell growth, angiogenesis and metastasis in prostate cancer cells; -Induces tumor regression in orthotopic prostate cancer xenografts; -Induces apoptosis, inhibits colon cancer cells growth.	[272,273,274,275,276,277]
	In vivo 7 ppm mixed AIN-76A diet	Pregnant female Sprague–Dawley rats	↓CpG methylation at BRCA1 promoter ↓DNMT1 at BRCA-1 promoter	↑BRCA1, AhR	-Reduces the risk of breast tumorigenesis in the offspring;	[278]
	diet with 0.4% resveratrol	Wild-type mouse	↑SIRT1	↑p-AMPK, NAD+, LKB1 acetylation	-Improves mitochondrial function and increases cellular ATP in skeletal muscle;	[265]
	5–25 mg/kg/day	Female rats bearing breast cancer	↑miRs -21, -129, -204, -489 ↓DNMT3B in tumor tissues; ↓miRs -21, -129, -204, -489 ↑DNMT3B in normal tissues		-Inhibits breast tumor formation in vivo;	[279]
	25–50 mg/kg	Mice bearing human melanoma	↓DNMT1 ↓CpG methylation at PTPN6, CDKN2A, SOCS3 promoters	↓STAT3 acetylation	-Tumor-growth inhibition;	[255]
	50 mg subcutaneous pellet/month	Female ACI rats	↓CpG methylation at Nrf2 promoter ↓miR-93	↑Nrf2, NQO1, SOD3 OGG1, FMO1, AOX1 ↓MTA1, pAkt	-Decreases tumor incidence and chemoprevention;	[272]
	extract containing resveratrol/ 1 year	Peripheral blood male with type-2 diabetes	↑miR-21, -181b, -663, -30c2 ↓miR-155, -34a	↓IL-6, CCL3, IL-1β, TNF-α ↑LRRFIP-1	-Beneficial immunomodulatory effect on hypertensive patients with type 2 diabeties.	[280]
Pterostilbene	2.5–10 μM	MCF-7 MDA-MB-231 in coculture with TAM	↑miR488	↓NF-κB, Twist1, vimentin ↑E-cadherin	-Suppresses breast EMT and/or generation of CSCs;	[173]
	5 μM	HCC1806 MDA-MB-157	↓SIRT1, ↓DNMTs activity ↑HDACs, HATs ↑H3Ac, H4Ac, H3K9Ac at ERα promoter	↓γ-H2AX, hTERT ↑ERα	-Induces apoptosis and cell-cycle arrest in breast cancer cell lines;	[261,262]
	50 μM	DU145, 22Rv1	↓miRs-17, -20a, -106a, -106b	↑PTEN ↓PI3K-Akt	-Promotes apoptosis, inhibits cell proliferation both in vitro and in vivo, and downregulates circulating tumor-derived oncomiRs in vivo.	[275]
Piceatannol	In vitro 1 μM	U937	↓miR-183	↓ADAM17, Sp1, Foxp3, TNFα/NFkB ↑ β-TrCP	-InhibitsTNF α-mediated signaling pathway in leukemia cell line;	[281]
	10 μM	THP-1, Raw264.7	↑SIRT1 ↓miR-183	↑HO-1	-Attenuates osteoclastogenesis in bone-marrow-derived macrophages;	[282]
	30 μM	RAW264.7, A2058, WM266-4, HCT116	↑miR-200a ↑miR-181a ↑miR-129	↑Nrf2 ↓NLRP3, IL-18, IL-1β, caspase1 ↑Bax, caspase 3, ↓Bcl-2	-Attenuates oxLDL-induced lipid storage by inhibiting pyroptosis in human macrophage cells; -Induces apoptosis of melanoma cells and CRC cells;	[283,284]
	In vivo 50 mg/kg/day	Renal fibrosis mice model	↓HDAC4, HDAC5	↓p38-MAPK, ECM	-Ameliorates renal fibrosis.	[285]
Resveratrol + Pterostibene	In vitro 15 μM + 5 μM	HCC1806 MDA-MB-157	↓SIRT1, ↓DNMTs, ↓Global DNA methylation ↑HDACs, HATs ↑ H3Ac, H4Ac, H3K9Ac at ERα promoter	↓γ-H2AX, hTERT, ↑ERα	-Induces apoptosis and cell-cycle arrest; -Retrieves responsiveness to E2 and 4-hydroxytamoxifen treatments in resensitized breast cancer cells.	[261,262]
	15 µM + 7 μM	MCF10A MCF10CA1h MCF10CA1a	↑CpG methylation at MAML2, GLI2 promoters; ↑DNMT3B	↓MAML2 ↓NOTCH	-Inhibition of growth of cancer cells with low and high invasive properties;	[286]
	In vivo 5–25 mg/kg/day	Rats bearing estrogen-dependent breast tumors	↓DNMT3B, ↑miR10a,−21, −129, −204, −489	-	-Delay in mammary tumor formation; -Different pattern of epigenetic changes tumor versus normal tissues;	[279]
	CSAA diet + REV 1.2 g or with PTS, 1.34 g/kg/day	Rats	DNA methylation ↓RUNX3, ↑ KCNJ4	↑RUNX3, ↓KCNJ4	-Changes theDNA methylation pattern on long-term dietary exposures.	[259]

Note: 5-mC, 5 methyl cytosine; 6-PN, 6-prenylnaringenin; 8-PN, 8-prenylnaringenin; ABCB1, ATP-binding cassette sub-family B member 1; ABCG5, ATP Binding Cassette Subfamily G Member 5; ADAM17, ADAM Metallopeptidase Domain 17; AhR, Aryl hydrocarbon receptor; AIF, Apoptosis Inducing Factor; AMPK-5’, Adenosine Monophosphate-Activated Protein Kinase; AOX1, Aldehyde Oxidase1; APC, Adenomatous Polyposis Coli; ARE, Antioxidant Responsive Element; ARID1A, AT-Rich Interaction Domain 1A; ATM, Ataxia Telangiectasia Mutated Protein; ATP5a1, ATP Synthase F1 Subunit Alpha; BARD1, BRCA1-Associated RING Domain 1; Bax, BCL2 Associated X, Apoptosis Regulator; BCHE, Butyrylcholinesterase; Bcl-2, B-cell lymphoma/leukemia protein; BIRC7, Baculoviral IAP Repeat Containing 7; BMI1, Polycomb complex protein; BRCA1,2, breast cancer type 1,2 susceptibility protein; Cav1, Caveolin 1; CCND1, cyclin D1 protein; CDK4, cyclin-dependent kinase 4; CDH1, cadherin 1; CDT1, chromatin licensing and DNA replication Factor 1; CK2, protein casein kinase 2; COX1, Cyclooxygenase-1; COX5b, Cytochrome C Oxidase Subunit 5B; CYP1A1, Cytochrome P450, family 1, subfamily A, polypeptide 1; DAOA, D-amino acid oxidase activator; DAPK1, Death Associated Protein Kinase 1; Dkk2, Dickkopf WNT Signaling Pathway Inhibitor 2; DNMT1, 3A, 3B DNA Methyltransferase 1, 3A, 3B; EED, Embryonic Ectoderm Development; EGFR, Epidermal Growth Factor Receptor; ERK1/2 extracellular signal-regulated protein kinase ½; EP300/p300 E1A Binding Protein P300; EPHB2 Ephrin type-B receptor 2; ERα, ERβ Estrogen receptor alpha, beta; ERBB-4, Erb-B2 Receptor Tyrosine Kinase 4; ESR1, 2 Estrogen receptor 1, 2; EZH2 Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit; FHIT (Fragile Histidine Triad Diadenosine Triphosphatase; FMO1 Flavin Containing Dimethylaniline Monoxygenase 1; FOXO3 Forkhead Box O3; GSH Glutathione; GSTP1 Glutathione S-Transferase Pi 1; HES1 Hes Family BHLH Transcription Factor 1; H3K9me3, Histone 3 lysine 9 trimethylation; H3K27me3 Histone 3 lysine 9 trimethylation; H3K4ac Histone H3 acetylated at lysine 4; H4K8ac Histone H4 acetylated at lysine 8; HDAC1, 2, 5 Histone Deacetylase 1, 2, 5; HOXA5, A9, A11, B1 Homeobox proteins; HO-1 heme oxygenase-1; hTERT Telomerase reverse transcriptase; ICAM 1 Intercellular Adhesion Molecule 1; IL-1β2,6, Interleukin-1β,2, 6; IX, isoxanthohumol; JAK/STAT, Janus kinase/signal transducer and activator of transcription; JNK1/2, c-Jun N-terminal kinases ½; KAT2A/3B, (Lysine Acetyltransferase 2A/3B); KCNJ4, Potassium Inwardly Rectifying Channel Subfamily J Member 4; KDACs, Lysine (K) deacetylases; KDM4B, Lysine Demethylase 4B; KRTAP2-1, keratin-associated protein 2-1; LSD1, Lysine-specific histone demethylase 1A; LKB1, Liver Kinase B1; MAD1L1 mitotic arrest deficient 1–like 1; MBD2, Methyl-CpG-binding domain protein 2; MCM7, Minichromosome Maintenance Complex Component 7; MeCP2, Methyl-CpG Binding Protein 2; MGMT O-6-Methylguanine-DNA Methyltransferase; MMP2,7,9 matrix metallopeptidase 2,7,9; NF-Κb Nuclear factor-kappa B; NGF Nerve growth factor; Nrf1 Nuclear Respiratory Factor 1; Nrf2 Nuclear Factor Erythroid 2–like 2; NDUFA9 NADH:Ubiquinone Oxidoreductase Subunit A9; NDUFS8 NADH:Ubiquinone Oxidoreductase Core Subunit S8; NOTCH Notch Receptor; O-DMA O-demethylangolensin; OGG1 oxidative DNA damage repair gene; p16 multiple tumor-suppressor 1 or cyclin-dependent kinase inhibitor 2A; p27 Cyclin-dependent kinase inhibitor 1B;p53/ TP53 transformation-related protein 53; p65 nuclear factor NF-kappa-B; p70S6K phosphorylated ribosomal protein S6 kinase; p90RSK phosphorylated Serine/threonine-protein kinase; P450 1A1 Cytochrome P450, Family 1, Subfamily A, Polypeptide 1; p-AKT phosphorylated Protein kinase B; PCNA Proliferating Cell Nuclear Antigen; pS6P phosphorylated (Ser240/244) S6 ribosomal protein; pERK PKR-like ER kinase;PI3K p110α phosphatidylinositol 3-kinase P110 Subunit Alpha;PcG polycomb-group proteins;P-gp P-glycoprotein 1; PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-α; PRC2 Polycomb repressive complex 2; PRMT5 Protein Arginine Methyltransferase 5; PTEN Phosphatase and Tensin Homolog; RAC1 Rac Family Small GTPase 1; RAD23B UV Excision Repair Protein RAD23 Homolog B; Raf1 Proto-Oncogene Serine/Threonine Protein Kinase; RASD1 Ras Related Dexamethasone Induced 1; RARβ2 retinoic acid receptor beta2; RECK Reversion Inducing Cysteine Rich Protein with Kazal Motifs; REPS2 RALBP1-associated Eps domain containing 2; RNF169 ring finger protein 169; RUNX3 runt-related transcription factor 3; SDHb Succinate Dehydrogenase Complex Iron Sulfur Subunit B; SFRP1 Secreted Frizzled Related Protein 1; Smad 2,4 SMAD Family Member 2,4; SDHA Succinate Dehydrogenase Complex Flavoprotein Subunit A; SIRT1,6, silent mating type information regulation 2 homolog 1,6; SLUG/SNAIL, Snail Family Transcriptional Repressor 2; SMARCB1, SWI/SNF-Related Matrix-Associated Protein; SOCS1, Suppressor of Cytokine Signaling 1; SOD, Superoxide Dismutase; SOX7, SRY-Box Transcription Factor 7; SRC3, Nuclear Receptor Coactivator 3; TAGAP, T-cell activation RhoGTPase-activating protein; TGFβ, Transforming Growth Factor-Beta; TGFBIII, Transforming Growth Factor Beta Induced; TNFα, Tumor Necrosis Factor; TRAF7, TNF Receptor Associated Factor 7; Uqcrc1,2, Ubiquinol-Cytochrome C Reductase Core Protein 1,2; VEGFA, Vascular Endothelial Growth Factor A; ZFP36, ZFP36 Ring Finger Protein; ZO-1, Tight junction protein-1; XN, Xanthohumol; XRCC2, X-Ray Repair Cross Complementing 2. Cell lines: 22Rv1 human prostate carcinoma epithelial; 3T3L1 mouse fibroblast-cell line capable of differentiating into adipocytes; 4T1 mouse breast cancer epithelial, resistant to 6-thioguanine; 786-O human renal adenocarcinoma; A2058 human melanoma; A2780 human ovarian carcinoma; A-498 human renal carcinoma; A549 human adenocarcinoma alveolar basal epithelial cells; ACHN human papillary renal cell carcinoma; ARCaP-E, ARCaP-M human prostate cancer cells; ARPE-19, spontaneously arising retinal pigment epithelia (RPE) cells; AsPC-1 human pancreatic adenocarcinoma; BGC-823 human-papillomavirus-related endocervical adenocarcinoma; BT-474 human invasive ductal carcinoma; BT-549 human ductal carcinoma; Caki-2 human renal carcinoma; C2C12 immortalized mouse myoblast; DU145-human prostate cancer (AR+); ES2 human ovarian carcinoma; Ecs mouse aortic endothelial cells; FA HSPCs human Fanconi anemia hematopoietic stem cells; GMCs, human glomerular mesangial cells; H9C2 rat myoblast cells; HaCaT, human aneuploid immortal keratinocyte; HCC1806 human breast cancer (ER-, PR-); HCT116 human colorectal carcinoma; HeLa human cervical cancer; HepG2 human hepatocellular carcinoma; HMECs normal human mammary epithelial; hMSCs, Human Mesenchymal Stem Cells; Hs578T human breast carcinoma (ER-); HT29 human recto-sigmoid adenocarcinoma; Huh-7 human hepatocellular carcinoma; HUVEC, Human Umbilical Vein Endothelial Cells; IMR-90 human embryonic lung fibroblasts; K562 human erythroleukemia; KYSE-510 human eosphageal squamous cell carcinoma; LAPC-4 human prostate cancer (AR+, PSA+); LNCaP, Lymph Node Carcinoma of the Prostate cell line (AR+, ER+); LP-1 human myeloma; M223 human etastatic melanoma; MC3T3-E1 mouse pre-osteoblastic cells; MCF7 human breast adenocarcinoma (ER+); MCF10Ahuman breast non-tumorigenic epithelial cells; MCF10CA1h human malignant breast cells; MCF10CA1a human pre-neoplastic mammary gland cells; MDA-MB-157, MDA-MB-231, MDA-MB-435 and MDA-MB-468 human metastatic breast carcinoma cells (ER-, PR-, Her2-); MGC-803 human gastric cancer cells; Mino human mantle cell lymphoma; NHDF human dermal fibroblast cells; MIA PaCa-2 human pancreatic carcinoma; PANC-1 human pancreatic epithelioid carcinoma; PC-3-human prostate adenocarcinoma; RAW264.7 murine macrophage cells; RWPE-1 human immortalized, normal prostate cells; SGC-7901 human gastric cancer cells; SH human precancerous breast cells expressing hTERT; SHR human completely transformed, breast cancer cells; SH-SY5Yhuman neuroblastoma; SiHa human cervix squamous carcinoma; SKBR3 human breast adenocarcinoma; SK-MEL-28 human melanoma; SW1116 human colorectal adenocarcinoma; SW480 human colon adenocarcinoma; SW620 human metastatic colon adenocarcinoma; T24 human bladder cancer; T-47D human breast carcinoma; TAM tumor-associated macrophages; THP-1 human monocytic leukemia; UACC-3199 human mammary gland ductal carcinoma c (ERα-); U-87MG human glioblastoma; U266 human B lymphocyte myeloma; U937 human monocyte histiocytic lymphoma; WM266-4 human metastatic melanoma; WPE1–human prostate cells with different grade of malignancy, increasing from NA22, NB11, NB14, to NB26.