Epigenetic effects of herbal medicine
Clinical Epigenetics volume 15, Article number: 85 (2023)
Epigenetic memory is essential for life that governs the predefined functional features of cells. Recent evidence has indicated that the epigenetic modification provides a potential link to gene expression changes that may be involved in the development of various chronic diseases, and targeting the epigenome becomes a plausible method for treating diseases. Traditional herbal medicine has gradually entered the vision of researchers due to its low toxicity and its effectiveness in treating diseases. As a matter of fact, researchers found that the possessed epigenetic modification capacity of herbal medicine had the ability to combat the progression of the disease, such as various types of cancer, diabetes, inflammation, amnesia, liver fibrosis, asthma, and hypertension-induced renal injury. Studies on the epigenetic effects of herbal medicine will provide valuable insights into the molecular mechanisms of human diseases, which may lead to new therapeutic approaches and diagnoses. Thus, this review summarized the impact of herbal medicine and its bioactive components on disease epigenome as examples of how utilization of epigenetic plasticity could be useful as the basis for the future development of targeted therapies in chronic diseases.
Chronic diseases have now become a major health problem threatening to developing and developed countries, and if the situation is not effectively improved, the pandemic of chronic diseases will become a great burden to the global healthcare systems . Sadly, most chronic diseases are difficult to cure, and patients can only take drugs to prevent the aggravation of the disease and delay the progress of the disease, such as cancer, coronary heart disease, diabetes and so on [2,3,4]. However, these drugs have more or less side effects, so understanding the pathogenesis of chronic diseases and finding appropriate therapeutic agents are urgently needed.
Epigenetic mechanisms play an important role in promoting the development of chronic diseases . Epigenetic modifications mainly include DNA methylation, noncoding RNA, as well as histone modifications . It has been found that noncoding RNA regulates gene transcription by inducing DNA methylation and histone modifications [7, 8]. DNA methylation and histone modifications are involved in many cellular processes and multiple human diseases . Many substances can cause damage to the body by affecting the epigenetic state, resulting in the occurrence of chronic diseases. E-cigarettes ingredients (nicotine, tobacco-specific nitrosamines, volatile organic compounds, carbonyl compounds and toxic metals) can influence the occurrence of chronic bronchitis, facilitate cancer, neurodegeneration, etc., through DNA methylation, histone modifications or noncoding RNA expression . Besides, epigenetic changes associated with cancer risk factors may play an important causal role in the development of cancer . At the same time, disrupting the balance of epigenetic modifications within the body may lead to multiple pathologies, such as obesity and type 2 diabetes mellitus (T2D) . Thus, a compromised epigenetic state plays a pivotal role in contracting various diseases, while the reversal of aberrant epigenetic modifications provides an exciting opportunity for the development of clinically relevant therapies .
Traditional Chinese Medicine (TCM) has a long history in China and TCM is an important category of complementary and alternative medicine, its use has increased in place in western countries over the past decade and the typical TCM therapies include acupuncture, herbal medicine and qigong exercises . The three most common diseases of TCM users were tumors (33.2%), respiratory diseases (32.9%) and infectious diseases (8.86%), while the most commonly used TCM therapy is the Chinese herbal medicine and patients with comorbid diseases such as allergic rhinitis, indigestion, menstrual disorders, musculoskeletal system and connective tissue disorders tend to visit TCM clinics . Studies have also indicated that herbal medicine can influence the progression of diseases through epigenetic modifications, including cancer, Alzheimer's disease, male infertility, etc. [16,17,18].
Understanding the regulation of the human epigenome by herbal medicine can help to elucidate the discovery of plant pharmacology and epigenetic drugs . Therefore, this review mainly combines the relevant literature of nearly 10 years to discuss the epigenetic modification of chronic diseases through DNA and histone modifications by herbal medicine, in order to provide ideas for future disease research and treatment.
Bioactive compounds from herbal medicine
Herbal medicine has been serving the Chinese people since ancient times and plays an important role in today's medical care . According to a 1995 survey, there are 12,807 Chinese medicinal resources in China, including 11,146 medicinal plants . TCM is mainly composed of botanical medicine (root, stem, leaf, and fruit) and mineral medicine. Because plant medicine accounts for the majority of TCM, TCM is also called herbal medicine. Although Western medicine has achieved remarkable results in the treatment of many diseases, the main challenges remain: infectious diseases that rapidly evolve to develop drug resistance to drugs, new diseases, especially new diseases caused by viruses, and ineffective long-term treatment of chronic and non-communicable diseases. TCM can provide complementary treatment based on personalized interventions to address the impact of disease on the whole body . Most of the TCM preparations are oral preparations, such as decoction, pills, powder and other TCM dosage forms, as well as modern dosage forms such as granules, tablets and capsules. The oral preparations of TCM are the same as the chemical drug preparations containing one or more active ingredients, which first need to be absorbed through the gastrointestinal tract. TCM is rich in various components, leading to the complex absorption mechanism of drugs in the gastrointestinal tract, which is also one of the main differences between TCM and chemical drugs . Although each herbal medicine contains hundreds or even thousands of components, only a few compounds can produce the drug and/or toxic effects . Table 1 shows the active components with epigenetic modification effects as well as plants that are currently known to acquire these components. The active ingredients are rich in different herbs, which give these plants the characteristics to treat different diseases. Based on the efficacy of many bioactive compounds first discovered in herbal extracts, such as paclitaxel, camptothecin, and artemisinin, more people are accepting herbal medicine as potential sources of clinical drugs .
Epigenetic mechanism of herbal medicine
DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are associated with the occurrence and progression of human malignancies, and DNMT and HDAC inhibitors are currently being explored as anticancer drugs in clinical trials [57, 58]. DNMTs can mediate specific DNA methyl transfer leading to epigenetic silencing of multiple genes . HDACs catalyze the deacetylation of lysine residues in the N-terminal tail of histone proteins and regulate the expression of related genes . Regulating the expression or activity of DNMT and HDAC is the most common way that herbal medicine and its bioactive components combating the disease through epigenetic regulation. In addition to these, as shown in Fig. 1, herbal medicine can also regulate the expression of related genes by affecting histone methylation, acetylation, phosphorylation, ubiquitination, as well as the demethylation modification of DNA.
There are about 120 types of brain tumors, about 45% of the primary brain tumors are glioma, and glioma or astrocytoma is one of the most common and aggressive brain tumors in children and adults . For these cancers, very few effective treatment methods, even after active surgery, chemotherapy and radiotherapy, the patient survival rate is still very low .
Since 2014, Skala and Sitarek et al. have investigated the effects of Chinese herbal medicine on glioma, and initially they found that Leonurus sibiricus transgenic roots and Rhaponticum carthamoides transformed root are able to promote glioma cell apoptosis and inhibit their viability. Poly ADP-ribose polymerase 1 (PARP1) cleavage increasing γH2A.X histone levels is necessary for the repair of DNA double-strand breaks and maintenance of genomic stability . While Ubiquitin-like with plant homeodomain and ring-finger domains 1 (UHRF1) and DNMT1 are capable of epigenetic regulation of histone ubiquitination and DNA methylation . Through further studies, they found that the cell-induced anticancer effects of Leonurus sibiricus extracts were associated with the number of γH2A.X and cleaved PARP1, and the level of UHRF1 and DNMT1 . At the same time, Rhaponticum carthamoides extract can also trigger apoptosis in glioma cells by inducing DNA damage, PARP cleavage and epigenetic modification . Topoisomerase IIβ (TopoIIβ) is a ribozyme that plays an important role in neuronal development. Yan et al.  conducted chromatin immunoprecipitation analysis and found that tetramethylpyrazine enhanced the recruitment of ac-H3 and ac-H4 in the promoter region of the TopoIIβ gene. Therefore, herbal medicine can also promote high TopoIIβ expression through epigenetic regulation and stimulate the neuronal differentiation of SH-SY5Y cells.
Thoracic malignancies include some of the most common and lethal cancers. It is expected that in the near future, the increase in cancer mortality is mainly related to smoking-induced lung cancer (including men and women), and female breast cancer . In the 2008 study, tanshinone I showed the potential as an effective adjuvant in the treatment of human breast cancer, which effectively inhibited the proliferation of breast cancer cells MCF-7 and MDA-MB-231 while promoting its apoptosis . Aurora A is a potential tumor marker, which is mainly localized to the spindle poles and the mitotic spindle, regulating the function of centrosomes, spindle bodies and kinetochores required for the normal progression of mitosis . Inhibition of Aurora A directly reshaped the immune microenvironment by removing tumor-promoted myeloid cells and enriching anticancer T lymphocytes, which established a tumor-suppressive microenvironment and significantly promoted mammary tumor regression in mice . In 2012, Gong et al.  showed that tanshinone I may downregulate Aurora A gene expression by reducing the ac-H3 associated with the primer 4-amplified area in the DNA promoter of the Aurora A gene, so inhibit the growth of breast cancer cells. In addition, herbal medicine can also affect the proliferation of breast cancer cells through the epigenetic regulation of matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases that play a key role in cancer progression and metastasis . The AKT/mTOR signaling pathway regulates the H3K27ac and H3K56ac, and Wu et al.  treated the cells with luteolin and found the levels of p-AKT and mTOR proteins were significantly reduced, thus increasing the overall occupancy levels of H3K27ac and H3K56ac in the MMP-2 and MMP-9 promoter regions, significantly inhibiting the expression of MMPs. At the same time, they also found luteolin increased the overall levels of H3K4me1 in MCF7-TamR cells, and decreased the overall levels of H3K4ac, which enhances H3K4me1 occupancy to the Ras gene family promoter and suppresses its expression . Besides, oncogenes play an important role in tumor development. After treating the breast cancer cells with cucurbitacin B isolated from the traditional herbal medicine Trichosanthes cucumerina, Dittharot et al.  found that cucurbitacin B can upregulate DNMT1 and hypermethylation in c-Myc, cyclin D1 and survivin promoters, thereby downregulating the expression of all these oncogenes. Thus, cucurbitacin B has proven to be a potential cancer therapeutic, in part through the induction of hypermethylation and silencing of oncogenic activation. Herbal medicine is also able to epigenetically regulate the development of lung cancer. Lu et al.  have used Jinfukang (JFK), a clinical medicine usually used to treat lung cancer, to investigate whether the epigenetic modification is involved in its anticancer activity. The results showed that A549 cells treated for 48 h with JFK reduced the H3K4me3 modification levels of SUSD2, PTN, GLIS2, CCND2, TM4SF4, BCL2A1, IL31RA, WISP2, TNFAIP6 and TMEM158 genes. Besides, MYC and EGFR, two genes known to have high levels of H3K4me3 in A549 cells, also showed a significantly reduced degree of H3K4me3 expression after JFK treatment. From these studies, we can see the potential of herbal medicine for therapeutic use for thoracic cancer.
Digestive system tumor
Digestive system cancer mainly consists of esophageal cancer, stomach cancer, small intestine cancer, colon–rectum cancer, liver, and pancreatic cancer. The incidence and mortality of digestive system cancer are very high, most of which are highly related to genetics and lifestyle . In 2019, Li et al.  found that oleanolic acid, widely found in oleaceae family, inhibited the proliferation of human MKN-45 and SGC-7901 cells. Through further studies, in 2021, they identified epigenetic regulation of gastric cancer. Since immunotherapy through programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade has shown benefits for gastric cancer, epigenetic DNA methylation critically modulates cancer immune checkpoints. They stimulated human gastric cancer MKN-45 cells with interleukin-1β (IL-1β) and significantly increased PD-L1 expression. After treating cells with oleanolic acid the IL-1β-increased DNA demethylase activity was abolished in MKN-45 cells, and oleanolic acid selectively reduced the expression of DNA demethylase tet methylcytosine dioxygenase 3 (TET3) induced by IL-1β, and overexpression of TET3 restored oleanolic acid-reduced PD-L1 expression. Their findings suggest the potential of oleanolic acid as an epigenetic modulator of immunotherapy or adjunctive therapy of gastric cancer . In the same year, in mice, the epigenetic regulation of herbal medicine in gastric cancer was also found. One week after subcutaneous inoculation of MKN-45 cells in nude mice and gavage with hesperetin revealed that the levels of H3K79me2 and H3K79me3 were significantly reduced after hesperetin treatment. Moreover, the DOT1-like histone lysine methyltransferase (DOT1L) expression was also significantly decreased in vivo, and DOT1L is the only known H3K79 methyltransferase and can regulate cancer metastasis. To further confirm the effect of DOT1L on gastric cancer cell metastasis in vivo, MKN-45 cells were seeded into immunodeficient mice by tail vein injection. It was observed that downregulation of the DOT1L gene significantly inhibited the ability of MKN-45 cells to metastasize within the lung . Thus, hesperetin targeting DOT1L may translate into future cancer treatment strategies. The p16 gene belongs to the INK4 gene family and consists of four members: p16 (INK4A), p15 (INK4B), p18 (INK4C), and p19 (INK4D). They all have common biological characteristics, namely cell growth suppression and tumor suppression, and p16 is the second most common tumor suppressor gene after p53 . Supercritical CO2 extract of Azadirachta indica and nimbolide inhibited the expression of HDACs and DNMTs and significantly upregulated the acetylation levels of H3K9, H3K14, H3K18 and H3K27 in the p16 promoter region in HCT116 . The p16 protein is inactivated in a variety of human cancers. Thus enhanced acetylation of the p16 promoter while reducing p16 methylation, both contribute to the restoration of p16 gene expression, thereby affecting the expression of genes associated with cancer progression or repression that may be important targets for chemoprevention or therapy.
Although cancer drugs have been evolving in recent decades, the incidence and mortality of the most prevalent urogenital cancers have not been significantly reduced . Prostate cancer is the second most common cancer in men . Since 2013, Tamgue et al.  began epigenetic studies of triptolide on prostate cancer. They treated the prostate cancer cells with triptolide and found that triptolide significantly inhibited the proliferation of prostate cancer and was also able to reduce enhancer of zeste homolog 2 (EZH2) expression. EZH2 is the enzymatic catalytic subunit of the polycomb repressor complex 2 and can alter the expression of downstream target genes by H3K27me3 . Besides, there is evidence that EZH2 plays an important role in cancer initiation, development, progression, metastasis, and drug resistance . Then, in a 2017 study, Tamgue and Lei  found that although triptolide reduced EZH2 expression in PC-3 cells, the levels of H3K27me3 and histone H3 were increased. Therefore, other regulatory mechanisms may exist in PC-3 cells. Thus, they further found that the levels of mRNA and protein of UTX (also known as KDM6A) and histone demethylase Jumonji domain-containing 3 (JMJD3), which regulate H3K27me3 demethylation , decreased significantly in a dose- and time-dependent manners. Meanwhile, triptolide significantly increases the protein levels of SUV39H1, a histone methyltransferase that catalyzes the methylation of H3K9 , and related H3K9me3. In addition, they found that triptolide-induced deposition of H3K9me3 at the target gene promoters was highly SUV39H1-dependent and that inhibition of gene expression was partly mediated by enhancing the deposition of the H3K9me3 at gene promoter and inducing heterochromatin formation. These show the great clinical application value of triptolide. Besides, it has been found that components in herbal medicine can epigenetically regulate NRF2, a master regulator of many critical anti-oxidative stress defense genes in human prostate cancer , to regain their expression . Lysine demethylase 1B (KDM1B) is a histone H3K4 demethylase required to establish maternal genomic imprints . Lee et al.  found that Oldenlandia diffusa extract, by regulating KDM1B, effectively promoted the death of cisplatin-resistant ovarian cancer cells treated with cisplatin. However, the specific mechanism is still unclear and requires further experimental exploration.
Multiple myeloma is a clonal disease of long-lived plasma cells and is the second most common hematological cancer after non-Hodgkin's lymphoma. Malignant transformation of plasma cells gives them the ability to proliferate, causing harmful lesions to the patients . The epigenetic studies on herbal medicine for myeloma were mainly conducted with triptolide by Wen et al. In 2010, using multiple myeloma cell line U266, it was found that triptolide dose-dependently reduced the genome-wide H3K4me3, H3K27me3, and H3K36me3, while also inhibiting SMYD3, EZH2 and nuclear receptor binding SET domain protein 1 (NSD1) expression . Among them, SMYD3 is a SET domain-containing protein that has histone methyltransferase activity on histone H3K4, and SMYD3 is frequently overexpressed in different cancer cell types , which is associated with advanced stage and poor survival . NSD1 is a bifunctional transcriptional regulatory protein able to participate in the regulation of mono- and dimethylation of H3K36, and targeting NSD1 may be a potential strategy for tumor therapy [96, 97]. Then, in 2012, by studying multiple myeloma (MM) cells, triptolide was demonstrated to decrease the overall H3K4me2 and H3K36me2 levels in a dose-dependent manner . It also significantly increased the expression of lysine-specific histone demethylase 1 (LSD1), a nuclear histone demethylase , and decreased the JMJD2B expression which is a histone demethylase enzyme that regulates gene expression through demethylation of H3K9me3 and H3K36me2 [100, 101]. Lastly, in 2015, Wen et al.  treated KM3 cells with triptolide, and the results showed that triptolide can downregulate the expression of the proto-oncogenes c-Myc and VEGFA, a principal angiogenic factor essential for angiogenesis , by blocking the accumulation of H3K4me3 at its promoter. These results suggest that herbal medicine may have a strong effect against MM through epigenetic mechanisms. In addition, herbal medicine can regulate epigenetic regulation of leukemia and inhibit its development. Wang et al.  found that z-ligustilide increased the level of ac-H3 (K9/14) in HL-60 cells and enriched ac-H3 (K9/14) in the promoter region of Nur77 and NOR-1. At the same time, it significantly increased p300 acetyltransferase and decreased HDAC, including HDAC1 and HDAC4/5/7 and transfer-related protein 1, recruitment to the Nur77 promoter region. Z-ligustilide also enriched p-CREB in the NOR-1 promoter region, while HDAC1 and HDAC3 decreased in the NOR-1 promoter region. Thus, herbal medicine has strong potential in treating acute leukemia through epigenetic regulation.
Other chronic diseases
Herbal medicine also plays an important role in the epigenetic regulation of the development of other diseases, such as diabetes, inflammation, liver fibrosis, obesity, amnesia, and so on. In a 2015 study, the function of esculetin in diabetes was identified by Kadakol et al. . Posttranslational histone modifications (PTHMs) play a key role in the pathogenesis of diabetic complications . They found that the treatment of hearts of IR and type 2 diabetic rats with esculetin reduced the originally elevated H3K4me2, H3K36me2, H3K79me2, H3S10ph, H3S28ph, H3T3ph, H3K27ac, H3K56ac, H2AK119ub, and H2BK120ub . In 2017, it was demonstrated that esculetin treatment significantly improved vascular reactivity, increased eNos and decreased Vcam1 mRNA levels, and reduced collagen deposition in the rat thoracic aorta. At the same time, it can further improve vascular perturbation by reversing H2BK120ub to occupy the promoters of the At1, At2, Tgfβ1, and Mcp1 genes . In the same year, they also found that esculetin and telmisartan in combination therapy could improve type 2 diabetic cardiomyopathy by reversing H3, H2A, and H2B histone modifications . These studies suggest that esculetin can be used as an advanced therapeutic agent, which may be partly attributed to its ability to reverse epigenetic alterations. Liver fibrosis occurs due to the long-term injury caused by the activated myofibroblast-mediated excessive wound healing response and the excessive scar deposition in the liver parenchyma. Although genetic effects are important, epigenetic mechanisms have been shown to orchestrate many aspects of liver fibrogenesis . In 2020, by studying HSC-T6, sennoside A was demonstrated to reduce the expression of cyclin D1, CDK and c-myc and significantly inhibit the expression of p-AKT and p-ERK as well as α-smooth muscle actin and type I collagen alpha-1 protein levels. Meanwhile, sennoside A can directly bind to DNMT1 and inhibit its activity, thus significantly promoting phosphatase and tension homolog deleted on chromosome 10 (PTEN) expression in vitro . However, the dynamic expression of PTEN in rat liver tissue was negatively correlated with liver fibrosis and activated hepatic stellate cells, and positively with the reversal of fibrosis and apoptotically activated hepatic stellate cells . It thus follows that the epigenetic regulation of PTEN expression by sennoside A may be an effective new method for the treatment of liver fibrosis. In 2021, using the same cell line as with the animal model, it was shown that sennoside A consistently inhibits the expression of the liver fibrogenesis markers α-smooth muscle actin and type I collagen alpha-1 and suppresses the inflammatory response in vitro and in vivo. It can also promote SOCS1 expression in a DNMT1-dependent manner . Besides, SOCS1 helps to protect against liver injury and fibrosis and may also protect against liver carcinogenesis .
All of the above information is integrated into Table 2.
Herbal medicine has a strong capacity to regulate the occurrence and progression of chronic diseases through epigenetics. In tumors, herbal medicine can regulate the expression of tumor-related genes by influencing the methylation and acetylation of histones at the gene promoter or enhancer by controlling the expression of CBP, SUV39H1, EZH2, JMJD3, UTX, NSD1, etc. At the same time, herbal medicine can also regulate the methylation of DNA by affecting the expression of TET3, UHRF1, DNMTs, etc. In epigenetic studies of other diseases, herbal medicine shows the great potential of clinical applications in treating amnesia, allergic asthma, diabetes, inflammation, and liver fibrosis. However, the study of the specific mechanism is still quite limited. In order to provide more comprehensive information on the epigenetic impact of herbal medicine on human diseases and to fully exploit its potential in the clinic, further well-designed in vivo studies should be conducted.
Availability of data and materials
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We would like to thank members of the Lau and Xu laboratory for the critical reading of this manuscript.
This work was supported by the grants from the National Natural Science Foundation of China (Nos. 31771582 and 31271445), the Guangdong Natural Science Foundation of China (No. 2017A030313131), the “Thousand, Hundred, and Ten” Project of the Department of Education of Guangdong Province of China, the Basic and Applied Research Major Projects of Guangdong Province of China (2017KZDXM035 and 2018KZDXM036), the “Yang Fan” Project of Guangdong Province of China (Andy T. Y. Lau-2016; Yan-Ming Xu-2015), and the Shantou Medical Health Science and Technology Plan (200624165260857).
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