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Table 2 Herbal medicine-induced epigenetic alterations on chronic diseases

From: Epigenetic effects of herbal medicine

Year

Extract/component

Studying model/cell line

Epigenetic targets

Dose characteristics

Gene modified/epigenetic alterations

Outcome

References

Brain tumor

2013

Curcumin

U87 and U251 cells

DNA

•30 μM curcumin for 4 days

•10, 20, and 40 μM curcumin for 4 days

•Curcumin induces hypomethylation at 17 CpG sites on the RANK promoter

•Curcumin inhibits the activity of DNMT1

Results in RANK gene activation in epigenetic modification in human glioblastoma cells

[31]

2014

Tetramethylpyrazine

SH-SY5Y cells

Histone

•80 μM tetramethylpyrazine for 3 or 5 days

•Tetramethylpyrazine enhances the recruitment of ac-H3 and ac-H4 to the TopoIIβ gene promoter region

Promotes SH-SY5Y cells to differentiate toward post-mitotic neurons

[52]

2018

Leonurus sibiricus transgenic roots extract

U87MG and grade IV glioma cells

DNA; Histone

•Treat the cells with the extraction for 24 h

•The extract downregulates the expression of UHRF1 and DNMT1

Influences epigenetic regulation

[65]

2018

Rhaponticum carthamoides transformed roots extract

U87MG and grade IV glioma cells

DNA; Histone

•Treat the cells with the extraction for 24 h

•The extract downregulates the expression of UHRF1 and DNMT1

Influences epigenetic regulation

[66]

2019

Calebin-A

STS26T, ST8814, T265, and S462-TY cells

Histone

•12.5 and 25 μM calebin-A

•Calebin-A for 8 or 24 h

•Calebin-A decreases H3 histone acetylation

•Reduces HAT activity

Epigenetic control of survivin and hTERT genes

[28]

Thoracic tumor

2008

Nordihydroguaiaretic acid

T47D and RKO cells

DNA

•0–100 μM nordihydroguaiaretic acid for 72 or 144 h

•Nordihydroguaiaretic acid reverses p161NK4a CpG island hypermethylation

Induces cell cycle arrest in the G1 phase and a senescence-like state in cells

[112]

2008

Nordihydroguaiaretic acid

SKBR3 and MDA-MB-435 cells

DNA

•0–100 μM nordihydroguaiaretic acid for 7 days

•Nordihydroguaiaretic acid reverses methylation-silenced E-cadherin gene hypermethylation

Reactivates the expression of E-cadherin

[44]

2012

Thymus serpyllum extract

MDA-MB-231 cells

DNA; Histone

•250 and 500 μg/mL extract for 72 h

•The extract inhibits the DNMT and HDAC activities

Influences epigenetic regulation

[113]

2012

Tanshinone I

MCF-7 cells

Histone

•3 μM tanshinone I for 48 h

•Tanshinone I reduces ac-H3 associated with the primer 4-amplified area in Aurora A gene DNA promoter

Downregulates Aurora A gene expression

[71]

2014

Kazinol Q

MDA-MB-231 cells

DNA

•1, 2.5, 5, and 10 μM kazinol Q for 48 h

•Kazinol Q inhibits DNMT1 activity and reactivates the expression of a DNA methylation-silenced gene, E-cadherin

Inhibits cell viability

[37]

2016

Tien-Hsien Liquid

MCF-7 cells

DNA

•0–6 mg/mL Tien-Hsien Liquid for 72 h

•Tien-Hsien Liquid downregulates the protein level of DNMT1 and DNMT3a

Influences epigenetic regulation

[114]

2016

Jinfukang

A549 cells

Histone

•Treat the cells with Jinfukang for 48 h

•Jinfukang downregulates the H3K4me3 modification levels at SUSD2, PTN, GLIS2, CCND2, MYC, EGFR, and TM4SF4 genes, whereas those at BCL2A1, IL31RA, WISP2, TNFAIP6, and TMEM158 genes are upregulated

Inhibits cell proliferation

[75]

2017

Z-ligustilide

MDA-MB-231 cells

Histone

•50 μM Z-ligustilide for 72 h

•Z-ligustilide increases the enrichment of ac-H3 (K9/14) in the ERα promoter, and significantly reduces HDAC1, HDAC2, and HDAC4/5/7 at the ERα promoter

Induces cell cycle arrest and apoptosis

[115]

2018

Nimbolide

MDA-MB-231 and MCF-7 cells

Histone

•0–2.5 μM nimbolide for 48 h

•Nimbolide decreases HDAC2 and increases H3K27ac

Induces apoptosis, autophagy, cytoplasmic vacuolization and formation of autophagosomes

[43]

2019

Cucurbitacin B

MDA-MB-231, MCF-10A, and MCF-7 cells

DNA

•0–5 μM cucurbitacin B for 48 h

•Cucurbitacin upregulates DNMT1, as well as increases methylation in c-Myc, cyclin D1, and survivin promoters

Downregulates the expression of oncogenes, c-Myc, cyclin D1, and survivin

[30]

2020

Luteolin

MCF7-TamR cells

Histone

•10 and 20 μM luteolin

•Luteolin increases the expression of MLL3, increases the global level of H3K4me1, decreases the global level of H3K4ac, and increases the monomethylation level of H3K4 in the Ras gene enhancer and promoter region

Inactivates PI3K/AKT/mTOR pathway through repression of the Ras gene and thus causes apoptosis in tamoxifen-resistant breast cancer cells

[74]

2020

Cotinus coggygria Scop. extract

MCF-7 cells

DNA

•40.6 μg/mL Cotinus coggygria Scop. extract for 3, 24, 48, or 72 h

•Inhibits the expression of DNMT1 and DNMT3a

Causes S phase cell cycle arrest and triggers apoptosis, reduces colony formation, induces DNA damage, affects cellular thermodynamic parameters

[116]

2021

Valeric acid

MCF-7 cells

DNA; Histone

•0–10 μM valeric acid for 48 h

•Reduces HDAC activity and a global DNA hypomethylation

Decreases the breast cancer cell proliferation

[54]

2021

Luteolin

BT-20 and MDA-MB-231 cells

Histone

•10, 20 and 30 μM luteolin

•Luteolin decreases the level of H3K27ac and H3K56ac in the MMP-9 promoter region 2 and 3 in the BT-20 cells, and increases H3K27ac and H3K56ac on the MMP-2 and MMP-9 promoter region in MDA-MB-231 cells

Inhibits the proliferation and metastasis of androgen receptor-positive triple-negative breast cancer cells

[73]

Digestive system tumor

2010

N-butylidenephthalide

HepG2 and J5 HCC cells

DNA

•50 μg/mL of n-butylidenephthalide for 48 h

•25 μg/mL n-butylidenephthalide combined with 6.25–25 μM 1,3-bis(2-chloroethyl)-1-nitrosourea for 48 h

•N-butylidenephthalide downregulates the mRNA and protein level of MGMT

•The combination treatment enhances methylation of the MGMT promoter

Inhibits the expression of MGMT and enhances apoptosis

[42]

2019

Ginkgo biloba extract

B6C3F1/N mice

DNA

•0, 200, 600, and 2000 mg/kg Ginkgo biloba extract, 5 days a week for 104 weeks

•The Ginkgo biloba extract-exposed affects the methylation of the hepatocellular carcinoma gene promoter

Influences epigenetic regulation

[117]

2019

Aged citrus peel extract

AML-12 cells

DNA; Histone

•0–100 μg/mL aged citrus peel extract for 72 h

•50–1000 μg/mL aged citrus peel extract

•Aged citrus peel extract decreases the protein expression of HDAC8, DNMT1 and DNMT3a, enhances the protein expression of JMJD3 and UTX, and demethylates Nrf2 promoter

•Inhibits CpG methyltransferase activity

Attenuates APAP-induced hepatic injury through the reactivation of NRF2 pathway in mouse AML-12 hepatocytes

[118]

2019

Supercritical CO2 extract of Azadirachta indica; Nimbolide

HCT116 and HT29

DNA; Histone

•40 and 75 μg/mL supercritical CO2 extract of Azadirachta indica for 48 or 96 h

•5 and 10 μM nimbolide for 48 or 96 h

•Inhibits HDAC and DNMT activity and expression in both cell lines

•Increases acetylation of H3K9, H3K14, H3K18, and H3K27 in the p16 promoter region and decreases methylation levels of H3K9me3 and H3K27me3 in HCT116 cells

Restores the expression p16

[80]

2020

Silibinin

RT4, 5637, and T24 cells

DNA

•50 μM silibinin for 24 h

•Silibinin induces global DNA hypomethylation

Influences epigenetic regulation

[50]

2020

Valeric acid

Hep3B, SNU-449, and HepG2 cells

Histone

•850 μM valeric acid for 24, 48, or 72 h

•Valeric acid inhibits HDAC1, HDAC2 and HDAC3 activity

Suppresses liver cancer development

[119]

2021

Oleanolic acid

MKN-45 cells

DNA

•0–40 μM oleanolic acid for 24 h

•Oleanolic acid selectively reduced the expression of TET3 in IL-1β-treated MKN-45 cells

Leads to DNA hypomethylation

[45]

2021

Hesperetin

Nude mice with MKN45 cells

MKN-45 and HGC-27 cells

Histone

•Mice: 50 mg/kg hesperetin for 1 week

•Cell: 0–100 μM hesperetin for 48 h

•Hesperetin decreases H3K79me2 and H3K79me3 levels in mice

•Inhibits H3K79 methylation and reduces the abundance of Dot1L protein in the cells

Decreases the mobility of gastric cancer cells and inhibits the abundance of DOT1L

[78]

2021

Curcumol

HepG2 and SMMC-7721 cells

Histone

•60 μM curcumol for 48 h

•Curcumol increases the expression of H3K27me3 and H3K9me3 in HepG2 cells, decreases H3K27me3 expression in SMMC-7721 cells, and downregulates EZH2

Downregulates lncRNA Hotair in turn downregulated EZH2, thereby disrupting trimethylation of H3K9 and H3K27 specifically catalyzed by EZH2, and regulating histone modification to inhibit tumor growth and metastasis

[32]

2022

Baicalin

BALB/c nude mouse and HepG2 cells

DNA

•Mice: 20 or 50 mg/kg baicalin for 28 days

•Cell: 50 mg/L baicalin for 24 h

•Baicalin downregulates the m6A/A, SAM/SAH, and m6A (2854) levels of HKDC1 in the tumor tissue of the BALB/c mice

•Downregulates the total DNA 5mC and RNA m6A levels, upregulates SAM/SAH, and suppresses the RNA m6A (2854) of HKDC1 in HepG2 cells

Inhibits the progression of T2D-induced liver tumors by regulating the HKDC1/JAK2/STAT1/caspase-3 pathway

[27]

2022

Phyllanthus debilis methanolic extract

HT-29 cells

DNA

•0.1 mg/mL Phyllanthus debilis methanolic extract for 24 h

•Phyllanthus debilis extract increases the Alu DNA methylation and LINE-1 methylation

Anticancer effects

[120]

Urogenital tumor

2012

Trichosanthin

HeLa and CaSki cells

DNA

•0, 20, 40, and 80 μg/mL for 48 h

•Trichosanthin inhibits DNMT1 enzyme activity and DNMT1 expression

Induces gene demethylation of both HeLa and CaSki cells

[121]

2012

Triptolide

Du145

Histone

•0, 25, 50, 100 nM triptolide for 24 h

•Triptolide decreases histone H3K27me3 methylation and downregulates EZH2

Influences epigenetic regulation

[122]

2013

Z-Ligustilide; Radix Angelicae Sinensis

TRAMP C1 cells

DNA

•50 µM Z-Ligustilide or 8.5 µg/mL Radix Angelicae Sinensis for 3 days

•Z-Ligustilide or Radix Angelicae Sinensis treatment reduces the methylation levels of the first five CpG of the NRF2 promoter and inhibits DNA methyltransferase in vitro

Results in the re-expression of NRF2 and NRF2 target genes

[90]

2013

Triptolide

PC-3 cells

Histone

•0–1 µM triptolide for 24 h

•Triptolide decreases the expression of EZH2

Results in increased mRNA levels of target genes (ADRB2, CDH1, CDKN2A, and DAB2IP), and decreased mRNA levels of gene (cyclinD1)

[83]

2014

Zyflamend

CWR22Rv1 cells

Histone

•200 µg/mL zyflamend for 0–60 min

•200 μg/ml zyflamend for 24 h

•Zyflamend downregulates the expression of all class I and II HDACs, and upregulates the histone acetyltransferase complex CBP/ p300

•Increases histone 3 acetylation

Promotes the increased expression of the tumor suppressor p21 gene

[123]

2015

Allicin

MIA PaCa-2 cells

Histone

•100 and 200 µM allicin for 24 h

•Allicin reduces the level of H3K9me, and increases the level of H3S10ph and H3K14ac

Modulates apoptosis and represses gene expression

[26]

2017

Triptolide

PC-3 cells

Histone

•0–100 nM triptolide for 24 h or 100 nM triptolide for 0–24 h

•Triptolide enhances H3K27me3 levels by downregulating JMJD3 and UTX and enhances H3K9me3 level through upregulation of SUV39H1

Influences epigenetic regulation

[86]

2019

Oldenlandia diffusa extract

A2780cis cells

Histone

•40 µg/mL and 160 µg/mL for 48 h

•Oldenlandia diffusa extract downregulates the epigenetic regulator KDM1B

Overcomes resistance to cisplatin in CRC by modulating epigenetic regulation

[92]

Blood tumor

2010

Triptolide

U266 cells

Histone

•20, 80, and 160 nM triptolide for 48 h

•20, 80, and 160 nM triptolide for 24 h

•Triptolide decreases the expression of histone H3K4me3, H3K27me3 and H3K36me3

•Decreases histone methyltransferases SMYD3, EZH2 and NSD1

Induces epigenetic alterations

[53]

2010

Triptolide

RPMI8226 cells

Histone

•0–160 nM triptolide for 48 h

•Triptolide decreases histone H3K9me3 and H3K27me3 and downregulates histone methyltransferase SUV39H1 and EZH2

Induces epigenetic alterations by regulating histone lysine methylation

[124]

2011

Tien-Hsien Liquid

NB4 cells

DNA

•0–3 mg/mL Tien-Hsien Liquid for 72 h

•Tien-Hsien Liquid downregulates DNMT1

Influences epigenetic regulation

[125]

2012

Triptolide

RPMI8226 cells

Histone

•50, 100, and 150 nM triptolide for 48 h

•Triptolide suppresses the expression of H3K4me2, H3K9me2 and H3K36me2 and alters the expression of histone demethylase LSD1 and JMJD2B

Restores epigenetic changes by regulating the histone demethylases LSD1 and JMJD2B

[98]

2015

Triptolide

KM3 cells

Histone

•0–160 nM triptolide for 48 h

•Triptolide blocks the accumulation of H3K4me3 on c-Myc and VEGFA promoters

Decreases the expression of c-Myc and VEGFA genes

[102]

2016

Acanthopanax senticosus

HL-60 and HL60/ADM cells

Histone

•100 μg/mL Acanthopanax senticosus for 6 h

•100 μg/mL Acanthopanax senticosus for 0–24 h

•Acanthopanax senticosus decreases HDAC enzyme activity

•Increases histone ac-H3

Induces apoptosis of leukemia cells, cell cycle arrest, and FasL expression by promoting histone H3 acetylation

[126]

2020

Zaluzanin D

PMA differentiated human monocytic THP-1 cells

DNA

•0.35 mM zaluzanin D for 24 h

•Zaluzanin D reduces hypomethylation of the MMP9 gene promoter region caused by PMA activation

Influences the epigenetic machinery

[55]

2021

Z-ligustilide

Acute myeloid leukemia cells

Histone

•50 μM Z-ligustilide for 1 h

•50 μM Z-ligustilide for 6 h

•Z-ligustilide increases the enrichment of ac-H3 (K9/14) in the Nur77 and NOR-1 promoters

•Increases p300 acetyltransferase and decreases HDACs, including HDAC1 and HDAC4/5/7 and MTA1, recruitment to the Nur77 promoter region

Restores the expression of both Nur77 and NOR-1

[56]

Other chronic diseases

2012

Parthenolide

JB6P + cells

Histone

•5 and 10 μM parthenolide for 24 h

•Parthenolide inhibits HDAC1 and increases dimethylation level of H3 (K9/K4) on p21 and cyclin D1 promoters

Epigenetically modulates p21 and cyclin D1 expression

[47]

2019

Moringa isothiocyanate

JB6P + cells

DNA

•2.5 μM Moringa isothiocyanate and/or 10 ng/mL 12-O-tetradecanoylphorbol-13-acetate for 5 days

•Moringa isothiocyanate reverses methylation changes in those genes (hyper- or hypomethylation) that occur in response to TPA

Affects the progression of skin carcinogenesis

[40]

2015

Esculetin

Type 2 diabetic rats

Histone

•50 and 100 mg/kg/day esculetin for 2 weeks

•Inhibits H3K4me2, H3K36me2, H3K79me2, H3S10ph, H3S28ph, H3T3ph, H3K27ac and H3K56ac, and decreases H2AK119ub and H2BK120ub in hearts of IR and type 2 diabetic rats

Restores normal levels of allowed PTHMs and H2A/H2Bub in the hearts of IR and diabetic hearts

[106]

2017

Esculetin

Type 2 diabetic rats

Histone

•50 and 100 mg/kg/day esculetin for 2 weeks

•Esculetin reverses the modification in H2BK120ub and decreases the mRNA levels of Usp16 and Usp22

Intervenes H2Bub system

[33]

2017

Esculetin

Type 2 diabetic rats

Histone

•50 mg/kg/day esculetin for 6 weeks

•Esculetin reduces H3K9ac, H2AK119ub and H2BK120ub level

Influences epigenetic regulation

[107]

2021

Naringenin and Hesperetin

INS-1 cells and C57BLKS/Leprdb mice

Histone

•Cell: 100 μM naringenin or hesperetin for 24 h

•Mice: 50 mg/kg/day naringenin or 50 mg/kg/day hesperetin for 6 weeks

•Naringenin and hesperetin suppress the acetylation of H3K18 and H3K27 and inhibit the activity of p300, and hesperetin suppresses H3K27 acetylation in the transcriptional regulatory region of Txnip gene in INS-1 cells

•Inhibit the acetylation of H3K18 and H3K27 in the islets of the C57BLKS/Leprdb mouse

Reduces the expression of TXNIP

[41]

2020

Hesperetin

RAW 264.7 cells

Histone

•100 μM hesperetin overnight

•Suppresses the acetylation of RelA/p65 by inducing SIRT1 expression

Reduces NF-κB activity

[127]

2022

Kaempferol

3T3-L1 cells

Histone

•100 μM kaempferol

•Kaempferol decreases H3K27me3 deposition in the promoter region of Adipoq, Fabp4, and Lpl genes

Suppresses the expression of PPARγ target genes (Adipoq, Fabp4, and Lpl)

[38]

2020

Bacopa monniera extraction

Male Swiss albino mice

DNA; Histone

•120 mg/kg Bacopa monniera extract

•Reduces the expression of HDACs, and decreases the activity of DNMT and HDAC enzyme and global DNA methylation

Reverses epigenetic changes in scopolamine induced amnesia as well as able to recover levels of synaptic proteins

[128]

2019

Piperine

3T3-L1 cells

Histone

•50 μM for piperine 8 days

•Piperine decreases the enrichment of H3K27me3 PPARγ, and H3K9ac, and increase EZH2

Augments the expression of Ezh2-associated lipolytic genes

[48]

2021

Sophora flavescens (SF)-F2

PBMCs

DNA

•22.5 μg/mL Sophora flavescens (SF)-F2 for 3 days

•Sophora flavescens (SF)-F2 combination with dexamethasone downregulates the Foxp3 promoter methylation at CpG

Counteracts dexamethasone-induced immuno-suppression

[129]

2021

Hydroxysafflor yellow A

hBMSCs

Histone

•10 μM hydroxysafflor yellow A for 48 h

•Hydroxysafflor yellow A increases the protein level of KDM7A and decreases the occupancy of H3K27me2 on beta-catenin promoter

Increases β-catenin expression

[35]

2020

Astragalus polysaccharide

Specific pathogen-free

Female Sprague–Dawley rats

DNA

•150 mg/kg/day astragalus polysaccharide for 8 weeks

•Astragalus polysaccharide alters the DNA methylation group of the colon epithelium and induces promoter DNA methylation changes in genes involved in calcium homeostasis, osteocast/osteoblast balance, Wnt signaling, and hormone-related processes

Influences epigenetic regulation

[130]

2011

Multiglycosides of Tripterygium wilfordii Hook f extract

68 days male mice

Histone

•7.5–22.5 mg/kg/day multiglycosides of Tripterygium wilfordii Hook f extract for 40 days

•Reduces the dimethylation levels of histone H3K9 in germ cells

Inhibits the process of spermatogenesis

[131]

2020

Qian Yang Yu Yin Granule

The renal damage model of spontaneously hypertensive rats

HEK293T cells

DNA; Histone

•Mice: 2.1 or 8.4 g/kg/d Qian Yang Yu Yin Granule for 8 weeks

•Cell: 0.5 or 10 μg/mL

•Qian Yang Yu Yin Granule suppresses protein expression of NNMT and ac-cortactin and increased protein expression of H3K4me3

•Inhibits the production of NNMT and SAH mRNA, and promotes the production of SAM and SIRT1, and upregulates DNA methylation

Protects against hypertension-induced renal injury in spontaneously hypertensive rats and inhibited cells proliferation induced by Ang II

[132]

2021

Juglanin

High fat diet-fed mice

Histone

•7.5–30 mg/kg juglanin for 16 weeks

•Juglanin suppresses the expression of HDAC3 from mRNA and protein levels

Suppresses the activation of NF-κB/HDAC3 signaling in kidney of HFD-challenged mice

[36]

2012

Yang-Gan-Wan

Hepatic stellate cells isolated from C57Bl/6 and Coll-GFP mice

Histone

•Yang-Gan-Wan for 7 days

•Yang-Gan-Wan suppresses the expression of PRC2 components, EZH2, SUZ12, and EED, and increases H3K4me2 and H3ac at the PPARγ promoter locus

Prevents and reverses hepatic stellate cell activation

[133]

2020

Sennoside A

HSC-T6 cells

DNA

•10 μM sennoside A for 48 h

•Sennoside A blunts the activity of DNMT1 in TGF-β1-treated HSC-T6 cells

Inhibits activation and proliferation of HSC-T6 cells by targeting DNMT1

[109]

2021

Sennoside A

RAW264.7 cells

DNA

•Sennoside A 20 nM for 24 h

•Sennoside A decreases the activity of DNMT1 in LPS-treated RAW264.7 cells and inhibits SOCS1 hypermethylation mediated by DNMT1

Enhances SOCS1 expression

[49]

2014

Luteolin

THP-1 cells

Histone

•3, 6 and 10 μM luteolin for 48 h

•Luteolin downregulates HAT activity, upregulates HDAC activity and decreases the levels of acetyl CBP/p300 in high-glucose conditions

Affects NF-κB and p65 activation and interaction between p300 and NF-κB under hyperglycemic conditions in monocytes

[39]

2017

Osthole

PDLSCs

Histone

•10 μM osthole for 7 days

•Osthole increases the expression of KAT5, MOZ, MORF and ELP3, and increases the level of acetylation of H3K9 and H3K14

Reverses defective osteogenesis of P-PDLSCs

[46]

2013

Cannabidiol and cannabigerol

HaCaT cells

DNA

•0.5 μM cannabidiol or 0.5 μM cannabigerol for 5 days

•Cannabidiol and cannabigerol enhance DNMT1 expression

Increase global DNA methylation levels and decrease the expression of all the genes examined in the differentiated HaCaT cells by increasing the DNA methylation of the keratin 10 gene

[29]

2021

Cannabidiol, luteolin, and piceatannol

CPEK cells

DNA

•10 μM cannabidiol, 25 μM luteolin, and 25 μM piceatannol for 8 h

•Increase the percentage of methylation in ccl2 CpG sites

Manage chronic inflammation through nutraceuticals that modulate DNA methylation

[134]

2022

Cooked rhubarb

Young male Sprague–Dawley rats

DNA

•3 g/kg/day cooked rhubarb for 8 weeks

•Regulates the level of DNA methylation and expression of IL-1α and IL-10 genes

Reduces pathological tissue damage caused by chronic alcohol exposure

[135]