Open access peer-reviewed chapter

Herbal Medicine in Uterine Fibroid

Written By

Zi-Lin Li, Tung-Yung Huang, Yih Ho, Ya-Jung Shih, Yi-Ru Chen, Heng-Yuan Tang, Hung-Yun Lin, Jaqueline Whang-Peng and Kuan Wang

Submitted: 09 July 2020 Reviewed: 18 September 2020 Published: 20 October 2020

DOI: 10.5772/intechopen.94101

From the Edited Volume


Edited by Hassan Abduljabbar

Chapter metrics overview

1,112 Chapter Downloads

View Full Metrics


Uterine fibroids, also known as uterine leiomyoma is the most common benign tumor of the uterus found in women of reproductive age. Uterine fibroids are the cause of major quality-of-life issues for approximately 25% of all women who suffer from clinically significant symptoms of uterine fibroid. Despite the prevalence of fibroid, currently, there are no effective treatment options for fibroid. The lack of understanding of the etiology of fibroid contributes to the scarcity of medical therapies available. Sex steroid hormones, dysregulation of cell signaling pathways, miRNA expression, and cytogenetic abnormalities may all implicate in fibroid etiology. Several herbal medicines have been used as anti-inflammation and antitumor agents. All of them have a common capability to inhibit expression of pro-inflammatory cytokines, proliferative genes, and pro-angiogenetic genes. Exploring herbal medicines as remedies lighten the hope of treatment. In the current review article, we discuss signal transduction pathways activated herbal medicines. We also address the possibility of using herbal medicines for uterine fibroid treatment.


  • uterine fibroids
  • herbal medicines
  • curcumin
  • resveratrol
  • THSG
  • pycnogenol
  • AFE
  • EGCG

1. Background

Uterine fibroids are common benign muscle tumors of the uterus. It affects the normal life of thousands of women of childbearing age, especially non-Caucasian women, which can be caused by genetic and environmental factors. It is not usually fatal but can produce serious clinical symptoms. The prevalence of uterine fibroids is predicted to be approximately 70% depending on the population [1]. Clinical symptoms caused by uterine fibroid include pelvic pain or compression, abnormal uterine bleeding, gastrointestinal and voiding problems. It also produces pregnancy complications as well as fertility impairment. Since there are no effective medical therapies, invasive surgeries have become a clear option for the treatment of this tumor.

Studies on the whole genome of uterine fibroid indicate that there are many new signal transduction pathways and how gene nets play a role in uterine fibroid development. Not only in its origin, the transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix are all involved in uterine fibroid growth [2]. Additionally, microRNA plays a role in regulating uterine fibroid pathogenesis [3]. Nowadays, numerous treatments for fibroids are available. Therapies include conservative medications to invasive surgeries. Up to now, the regular therapy of uterine fibroid is surgery, but its negative impact on future fertility is evidenced. Therefore, selecting appropriate individualized therapy and augmented modifications to fit patient’s expectations are readily important. However, newly developing pharmaceutical prospects have significant adverse effects, such as liver function impairment, hot flashes, bone density loss, endometrial changes, and inability to attempt conception during treatment [4].

Numbers of natural compounds are demonstrated effectively to treat uterine fibroids and to relieve their symptoms. In this review, we will discuss potential available herbal medicine compounds that may be beneficial for uterine fibroid patients, particularly those who plan to conceive during therapy or desire to preserve their future fertility. Nonetheless, there is still no significant clinic evidence available so far. Therefore, it is highly recommended to obtain more clinical trials utilizing these compounds before endorsing widespread usage [5].


2. Mechanisms and signal transductions in uterine fibroid

As the pathogenesis of uterine fibroids has not been fully elucidated, many studies have been carried out in mechanisms involved in this area and are still ongoing. The involved mechanisms affect several categories of cellular and tissue functions. The presumptive identification of progenitor stem cells of uterine fibroids has produced fibroids and maternal junctions, providing new clues about the etiology of uterine fibroids [2]. There are two hypotheses raised for the development mechanisms of uterine fibroid. However, they may cross-talk with each other intimately. The genetic hypothesis is focused primarily on the mutant mediator complex subunit 12 (MED12) genes [6], suggesting it onsets in the side population of the female reproductive system embryonic myoblasts and contributed rise to multiple small and medium fibroids later on [2]. Most studies on uterine fibroids have focused specifically on somatic mutations in the MED12 gene [6, 7]. According to the available data, this mutation has been confirmed in more than 70% of patients with uterine fibroids depending on different populations [6, 8]. Alternatively, the single and usually large-size fibroids are induced by predominantly epigenetic disorders in uterine fibroid steam cells, provoked by enhanced expression of the DNA hypomethylation in HMGA2 gene and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations (Table 1).

Curcumin Resveratrol THSG Pycnogenol Anoectochilus formosanus EGCG
ERK1/2 Inhibition [9, 10]
Activation [11]
Activation [12, 13, 14, 15] Inhibition [16]
Decrease expression levels [17]
Suppression [18]
Suppression [19] Inhibition [20]
PI3K Inhibition [21] Inhibition [22] Inhibition [23, 24] Activation [25] NA Activation [26]
Inhibition [27]
NF-κB Inhibition Inhibition Inhibition [16] Suppression [18] Activation [28]
Inhibition [19, 29]
Inhibition [20, 30]
STAT3 Inhibition Inhibition NA NA NA Inhibition [31]
AMPK Activation Activation Activation [32] Expression [33] Activation [34, 35] Activation [36, 37]
Nrf2 Activation Activation Activation
[16, 32, 38]
NA NA Activation [39]
PPAR Activation [40] NA Suppression [41] Suppression [42] Activation [36] Activation
Suppression of gene expression PD-L, IL-1, IL-6, TNF-a PD-L1, MMPs [43] PD-L1 NA PD-L1, COX-2, TNF-α, CAK, MMP-9, and TRAP [29] Proliferative genes [44]
Activation of gene expression Caspase-3, caspase-9 Caspase-3, caspase-9 Apoptotic-related protein expression [24] NA Anti-proliferative genes [45, 46] BAX, p21, MDM2, and TP53I3 [30].
Anti-oxidant Yes [47] Yes Yes [48] Yes [33, 49] Yes [19] Yes [50]
Anti-inflammation Yes Yes Yes Yes [51] Yes [45] Yes
Anti-Cancer growth Yes Yes Yes Yes [52, 53] Yes Yes
ECM production inhibition Yes [54] Yes Yes NA NA Yes [55, 56]

Table 1.

Signaling pathways, gene expressions and activities induced by natural products curcumin, resveratrol, THSG, pycnogenol, AFE and EGCG.

THSG: 2,3,5,4’-Tetrahydroxystilbene-2-O-β-glucoside; EGCG: Epigallocatechin gallate; PPAR: Peroxisome proliferator-activated receptor; ECM: Extracellular matrix.

The life cycle of uterine fibroid is divided into two stages: transformation and benign tumor development [7, 57]. Mutations are sources for normal myometrial stem cells to transform into abnormal cells. Additionally, some other factors may also cause immunological changes [58] to lead to altered DNA repair and cell mutation [59]. Finally, a mixture of early environmental exposure and hyperreactivity to estrogen may also play a role in fibroid development [60].

Reactive oxygen species (ROS) formed after exposure to oxidative stress and/or hypoxia are linked to the activation of a variety of signal molecules [61, 62, 63, 64, 65, 66]. Various enzyme systems produce ROS, including the mitochondrial electron transport chain, cytochrome P450, lipoxygenase, cyclooxygenase, NADPH oxidase complex, and peroxisomes [61]. Hypoxia triggers many key adaptive changes that enable cell survival, including inhibition of apoptosis, changes in glucose metabolism, and angiogenic phenotypes [61]. Recent studies have shown that oxygen depletion promotes mitochondria to increase more ROS production, and then activate signaling transduction pathways, such as hypoxia-inducible factor (HIF)-1α to promote cell survival and increase fibrotic growth sequentially [61].

Remarkably, ovarian sex hormones play an important role in uterine fibroid pathophysiology [7, 67, 68]. Primarily under the influences of sex hormone, myometrial stem cells transform into pathological cells and develop into uterine lesions [69]. Tumor growth occurs by a large number of cell growth and extracellular matrix (ECM) building up [70, 71]. Accumulation and remodeling of ECM are believed to be crucial for fibrotic diseases such as uterine fibroid. Indeed, ECM plays an important role in forming the bulk structure of fibroids. Rigid ECM-rich structure may cause abnormal bleeding and pelvic pain [70, 72]. Therefore, a better understanding of ECM accumulation and remodeling is critical for developing new therapeutics for uterine fibroid. The ECM is approximate twice the volume in uterine fibroid compared to those in healthy myometrium. ECM is mainly composed of different types of collagen, fibronectin, and proteoglycan [70, 71]. It has been found in ultrafiltration that different fibers forming the ECM have abnormal structures and are different from the corresponding fibers in the unchanged tissue [73].

Estrogen has been shown to stimulate proliferation in a dose- and time-dependent manner in uterine fibroid cell lines [68, 74]. Estrogen (17β-estradiol) binds to the nuclear estrogen receptor (ER)-α to modulate the expression of proto-oncogenes, cytokines, and growth factors [75, 76, 77]. Uterine fibroid cells are more accessible to actions of 17β-estradiol than normal myometrial cells [78]. Although estrogen is essential for uterine fibroid growth, progesterone now is considered the key hormone to initiate uterine fibroid pathological differentiation and growth [7]. Estradiol has a tolerant effect on the growth of uterine fibroids mediated by progesterone. Additionally, the combination of estrogen and progesterone significantly increased cellular expression of the proliferation marker Ki-67 [79] and the accumulation of ECM due to the accelerated synthesis of type 1 and type 3 collagen [80]. Studies of Ishikawa et al. have shown that combined estrogen and progesterone increased uterine fibroid size more than 3-fold higher than those treated with estradiol alone or untreated controls in a xenograft model [67]. These results highlight the significant role of progesterone in uterine fibroid growth.

Furthermore, disturbance of steroid hormone receptors may be a primary pre-requisite for development of uterine fibroid [81]. Adenovirus-mediated a dominant-negative ER-α gene delivery eliminates the expression of estrogen and progesterone-regulated genes in uterine leiomyoma cells in vitro and shrinks uterine fibroids in vivo [82, 83]. Steroid hormones can affect uterine fibroid cells by different mechanisms including paracrine [7]. Steroid hormones stimulate expression of cytokines and growth factors. Sequentially, the induced cytokines and growth factors affect signal pathways, growth, and survival of uterine fibroid cells. They also regulate angiogenesis and ECM formation [84]. Consequently, this influences uterine fibroid cells to grow and survive and ECM to accumulate. ECM may serve as a reservoir for growth factors and cytokines to increase their stability and extend their influence [70].

Different growth factors and signal pathways are involved in uterine fibroid formation processes [71, 84]. As one of the most important growth factors affect development of uterine fibroid, transforming growth factor-β (TGF-β) stimulates uterine fibroid progress [71]. TGF-β signaling connects with other different pathways such as Smad pathway, phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), the mitogen-activated protein kinases (MAPK, ERK1/2) signaling cascade, and focal adhesion kinase (FAK) [71]. Expression of TGF-β is significantly increased in myometrial cells when they are directly in contact with the uterine fibroid tumor [85]. TGF-β1 stimulates expression of metalloproteinase-2 (MMP-2), MMP-9, and membrane-associated MMP inhibitor (RECK) [86]. TGF-β also modulates ECM production via cross-talk with growth factor and integrins [87, 88].

In addition to TGF-β, insulin-like growth factor–1 (IGF-1) is another growth factor that plays a vital role in the pathogenesis of uterine fibroid [89]. Studies of Boehm et al. indicated that more IGF-1 expression increases in uterine fibroid than in normal myometrium [90]. An animal model from Eker rat also showed upregulation of IGF-1 in uterine fibroid tissue [91]. We have shown how IGF-1R accumulated in uterine fibroid primary cell lines in response to IGF-1 to regulate cell proliferation [12]. Estrogen induces ERK1/2 activation and IGF-I, cell cycle regulating transcriptional factor A-Myb accumulation to stimulate uterine fibroid cell cycle progression in human uterine leiomyoma cell lines [92]. Additionally, growth hormone stimulates IGF-1 production to promote cell proliferation and to inhibit apoptosis in uterine fibroid [93, 94].

Wingless-type (Wnt)/β-catenin signaling also plays a role in somatic stem-cell function in both myometrium and uterine fibroid tissue [7]. Paracrine activation of the Wnt/β-catenin pathway in uterine fibroid stem cells can stimulate tumor growth [95]. Activin A, a product of macrophages, may also play a crucial role in uterine fibroid biology. Activin A is response for different immunological actions including cell transformation to lead to tumor development [58, 96]. Interactions between Wnt/β-catenin and TGF-β pathways, as well as with steroids and growth factors, give rise to the clonal formation of uterine fibroid tumors and are believed to be the basis of modern uterine fibroid biology hypothesis [7, 97].

The genetics of uterine fibroids and the etiology of epigenetic procedures have many peculiarities at first, then become quite similar and partially overlap due to the proximity of their genetic network and epigenetic environment. Research on the etiology of uterine fibroids to elucidate new strategies for the prevention and treatment of this common disease [2].


3. Treatment of uterine fibroid

Because the natural cause of uterine fibroid is not known, it makes the myomectomy or selected conditions hysterectomy to become the mainstay of management [98]. Genetic factors, epigenetic factors, and several pathogenic factors such as sex hormones, growth factors, cytokines, chemokines, and extracellular matrix components all of them have been implicated in development and growth of uterine fibroid [99, 100]. Although surgery has been suggested, it is not an attractive choice due to its serious consequences, especially with patients desiring to preserve their fertility potential [100].

Studies of El Andaloussi et al. [101] indicate that MED12 mutation presents a potential of dysregulating Wnt4/β-catenin to transform cells [101]. The dysregulating Wnt4/β-catenin affects mTOR signaling and caused autophagy abrogation, cell proliferation, and tumorigenesis [101]. Silenced MED12 gene reduces the proliferation of uterine fibroid cells [97]. In 2020, Ali et al. also found that β-catenin nuclear translocation contributes to uterine fibroid phenotype, and β-catenin signaling is modulated by estradiol and histone deacetylases activity [102]. Additionally, the Wnt/β-catenin pathway leads to increased levels of TGF-β3 [7, 71]. As we discussed above, different isoforms of TGF-β may play a crucial role in uterine fibroid development. Studies that used anti-uterine fibroid agents cause the attenuation of this pathway by reducing TGF-β3 signal and protein expression, resulting in a reduction in TGF-β canonical signaling [103]. Therefore, canonical Wnt pathway has been suggested to be a potential therapeutic target for the treatment of uterine fibroids [104].

It has been shown the proliferation of uterine fibroid is sensitive to the GnRH agonists [105, 106] or estrogen receptor antagonists. For those patients can be applied with hormone treatment with GnRH agonists including Lupron, Synarel, and Zoladex and/or aromatase inhibitors such as anastrozole (Arimidex®), letrozole (Femara®), exemestane (Aromasin®), vorozole (Rivizor®), formestane (Lentaron®), fadrozole (Afema®), and testolactone (Teslac®). Treatment with medications such as tamoxifen may also reduce uterine fibroid size [106]. In addition, using an adenovirus-expressing dominant-negative ER-α reduces ER-α to arrest fibroid growth in a mouse model which may provide an optional treatment [107]. Besides, alternative medicine has been shown to improve the symptom of uterine fibroids [108, 109, 110].

Alternatively, several natural products have been suggested for the treatment of uterine fibroids based on their natural activities of anti-inflammation, anti-proliferation, and anti-angiogenesis. We will discuss mechanisms in the following sections.

3.1 Curcumin

Curcumin is a yellow active natural polyphenol of the perennial herb Curcuma longa, commonly known as turmeric. In addition, curcumin is commonly found as ingredients in food seasoning, cosmetics, or herbal supplements. It has traditionally been used for decades in Asian countries as a medical herb due to its anti-microbial, anti-inflammatory, anti-tumorigenic, and anti-mutagenic properties [111]. Curcumin has many medical effects such as suppression of thrombosis [112], reduction of blood cholesterol [113, 114], and reduction of myocardial infarction [115]. Evidence indicates that curcumin suppresses the growth of several tumor cell lines [116, 117]. All in all, curcumin is effective against a variety of inflammatory illnesses and modulates multiple cell signaling pathways. However, it is still not well understood which binding site or receptor for it. In vitro studies indicate that curcumin can interact with integral components of cell signaling pathways and therefore may be pharmacologically relevant. However, only limited studies have shown functional consequences of curcumin interaction [118]. The tumor suppression mechanisms of curcumin are accredited by modulation of numerous targets playing important roles in tumor growth [119, 120, 121, 122]. Those targets include transcription factors, receptors, kinases, cytokines, enzymes, and growth factors. Therefore, curcumin has been demonstrated to suppress the growth of several tumor cell lines [123]. It also inhibits the growth of uterine fibroid cells, even though there has yet to be a report describing the precise mechanism of its inhibition.

Figure 1.

Signaling pathways by which curcumin induces biological activities in cells. Curcumin binds to an unidentified cell surface binding site to activate the ERK1/2 cascade. On the other hand, in addition, to downregulate NF-κB activation, it inhibits phorbol ester-induced activation of NF-κB and ERK1/2. Curcumin also activates SAPK/JNK activation and Caspase-3 and -9-dependent apoptosis in cancer cells, may also including uterine fibroid cells. Curcumin inhibits TGF-β-induced ECM production. It also reduces inflammation and induces apoptosis.

Figure 2.

Resveratrol/THSG activates signaling pathways in uterine fibroid cells. A stilbene receptor is present on integrin αvβ3 by which resveratrol activates ERK1/2 and induces nuclear accumulation of COX-2. On the other hand, 2,3,5,4′‐tetrahydroxystilbene‐2‐O‐β‐glucoside (THSG) has a similar chemical structure and assumedly binds to integrin αvβ3 to activate the signal transduction pathway. In resveratrol-treated cancer cells, pERK1/2 also translocates to the cell nucleus and complexes with inducible COX-2. Phosphorylated ERK1/2 also translocates into the cell nucleus and forms a complex with inducible COX‐2 in resveratrol‐treated cancer cells. Resveratrol induces phosphorylation of the complexed p53 at Ser15 and p53‐dependent antiproliferation. Blocking resveratrol‐induced nuclear accumulation of COX‐2 inhibits p53 phosphorylation and antiproliferation.

Curcumin inhibits phorbol ester-induced activation of NF-κB and ERK1/2 [9, 10]. Alternatively, it induces apoptosis via activation of ERK1/2 or SAPK/JNK in cancer cells [11]. Role of ERK1/2 activation in curcumin-treated cancer cells is controversial [124]. Curcumin down-regulates endothelial cell fibrosis and inhibits uterine fibroid cell proliferation via regulation of the apoptotic pathway, and it also reduced production of the ECM component fibronectin (Figure 1). Curcumin has also been shown to attenuate TGF-β-induced endothelial-to-mesenchymal transition [125]. Extracts from Curcuma zedoaria inhibits uterine fibroid cell proliferation compared to normal myometrial cells [126]. On the other hand, it stimulates caspase-3 and caspase-9 expression in uterine fibroid cells. Curcumin provides a novel direction for uterine fibroid therapies [127].

Peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcription factor of the nuclear hormone receptor superfamily. It is expressed in a tissue-specific manner and plays an important role in the differentiation of adipocytes [128, 129]. PPARγ exerts anti-inflammatory, anticancer, and insulin sensitivity effects and participates in the control, proliferation, and differentiation of the cell cycle. Hepatic stellate cells are the type of hepatocyte responsible for fibrosis in liver damage and can lead to chronic liver damage and cirrhosis. Curcumin induces and activates PPARγ in rat hepatic stellate cells [40]. Curcumin considerably increases the proliferative inhibition of stellate cells by PPARγ. [40]. Besides, curcumin also enhances the activity of PPARγ in human colon cancer cell lines by reducing the expression of cyclin D1 and epidermal growth factor receptor (EGFR), thereby disrupting the cell cycle [130]. These two inhibitory effects depend on PPARγ activation. The study by Takashi Takeda et al. showed that uterine fibroids can share pathogenic characteristics with the development of metabolic syndrome [131]. PPARγ is also virtually involved in insulin signaling. A PPARγ agonist, thiazolidinedione, has been used to treat patients with type II diabetes [129]. Thiazolidinedione may be used to prevent the progression of atherosclerosis and metabolic syndrome [132]. On the other hand, curcumin directly inhibits fibroid proliferation, and curcumin-induced PPARγ activation can also prevent metabolic syndrome and indirectly inhibit fibroid growth [132]. However, since these findings were based on in vitro experiments, it raised concerns about the observation limitations. Later, Kenji Tsuiji et al. have developed a new in vivo uterine fibroid model to study the inhibition of rat leiomyoma (ELT-3) cells by curcumin [132]. The IC50 of curcumin-induced anti-proliferation in uterine fibroid cell lines is 20 μM, however, when patient-matched myometrial cells were exposed to equivalent concentrations of curcumin, there was no statistically significant inhibition of growth [127].

Studies indicated that curcumin absorption rate in the intestine is very low [133, 134, 135, 136]. Similar raising concerns were also in other herb medicines, such as resveratrol discussed in next section. Thus, some modifications of curcumin need to be taken to keep its high blood concentration. Some studies regarding increased absorption and bioavailability of curcumin have been reported. For instance, the co-administration of curcumin and piperine can increase the bioavailability of curcumin [135]. Another strategy is to develop new curcumin analogues with a higher cell growth inhibitory capacity. One such compound, GO-Y030, has been shown to exhibit an 8- to 40-fold greater growth inhibitory potential than curcumin in several cancer cell lines [137, 138]. It may be useful to use the compound to clinically treat uterine fibroids.

3.2 Resveratrol

Polyphenols have been attracting by their anti-oxidative effects during the past years for human chronic diseases involved in inflammation like diabetes mellitus, neurodegenerative diseases, cardiovascular diseases, and cancers [139]. Resveratrol is one of well-studied stilbenes found in peanuts, grapes, and some berries. It is a plant product in response to environmental stress, pathogen infection, and ultraviolet radiation [127]. Resveratrol has been known as chemo-preventive, serving to suppress DMBA-induced ductal breast carcinoma [140] and ultraviolet light (UV)-induced skin cancer [141] in mouse models. Resveratrol induces p53-dependent apoptosis in several human cancer cell lines, including thyroid, prostate, and breast cancer cells [13, 142, 143, 144, 145]. It also induces p53-independent anti-proliferation against cancer cells [14, 146, 147, 148]. Resveratrol has been recommended to be a reversion molecule for multiple drug-resistant breast cancer [149]. Resveratrol is safe and well-tolerated by patients, with common adverse events including nausea, diarrhea, and weight loss [150].

Although surface receptors involved in the resveratrol signal transduction remain to be identified, resveratrol binds to cell surface integrin αvβ3 to activate ERK1/2 and ant-proliferation in cancer cells [13, 145, 151] (Figure 2). Integrin αvβ3 is also involved in AKT phosphorylation [15, 152]. Resveratrol inhibits PI3K-AKT signal pathway to induce anti-proliferation [22] or other biological activities as IL-33-mediated mast cell activation [153].

Overexpression of integrin αvβ3 is observed in several types of solid tumors [154, 155] and highly growing endothelial cells [154, 155]. Our studies indicate that integrin αvβ3 overexpresses in primary uterine fibroid cell lines [12]. The integrin αvβ3 overexpresses in primary human uterine fibroid Case 016 and Case 018 compared to normal Case 003 cells [12]. Therefore, it is a perfect target for resveratrol which has been shown to bind on integrin αvβ3 receptor [13]. Integrins are not classic signaling receptors in that they possess no enzymatic activity. Integrin signaling depends on the allosteric behavior of the receptors, their ability to concentrate into adhesion zones, and the recruitment to these zones of numerous other adhesome components to form complex integrin-based cell adhesions [156, 157]. Many adhesome components are enzymes that interact with classic signaling pathways. Resveratrol regulates signal transduction via integrin αvβ3 in human uterine fibroid cells. Resveratrol attenuates expression of integrin αv and integrin β3 in primary uterine fibroid cell Case 016 and Case 018 but not in normal myometrial cells. Resveratrol induces ERK1/2 activation in uterine fibroid cells [12]. However, the constitutive phosphorylation of AKT in uterine fibroid cells was inhibited by resveratrol.

Integrin signaling and function are heavily dependent on cross-talk with other signaling pathways, especially growth factor signaling pathways [158, 159, 160]. Besides the aberrant integrin expression, IGF-1R highly expresses more in uterine fibroid compared to the normal tissues [161] indicating IGF-1 may also be involved in the abnormal proliferation [92, 162]. IGF-1 binds to IGF-1R to activate downstream AKT which is a target of resveratrol. Resveratrol did not inhibit IGF-1R phosphorylation in primary uterine fibroid cells [12]. These results suggest that the action of resveratrol on IGF-1R-dependent signal transduction is downstream IGF-1R at Akt level [12]. Resveratrol analogue, pterostilbene (3′,5′-dimethoxy-resveratrol) targets mTOR/PI3K/Akt signaling pathway to disrupt mitochondrial membrane potential, and induce apoptosis [163].

IGF-I mRNA is expressed significantly higher in leiomyoma cells than that in myometrial cells [12]. IGF-1 stimulates IGF-1R phosphorylation of but the action is blocked by resveratrol pre-treatment. Growth effect of IGF-1 can possibly reduce by resveratrol [164]. Resveratrol inhibits IGF-1-induced phosphorylated IGF-1R accumulation and proliferation consequently [12]. IGF-1 enhances leiomyoma cell proliferation and thereby accelerates uterine fibroid progression. In summary, resveratrol via a mechanism involved in crosstalk between integrin αvβ3 and IGF-1R-sensitive signal transduction pathways induces anti-proliferation in uterine fibroid.

Steroid hormones and thyroid hormone stimulate TGF-β expression [165]. Resveratrol blocks TGF-β expression and functions [166]. Cross talk among TGF-β signaling pathways, integrins, and ECM [88] is essential for uterine fibroid growth. Both Agarwal discussed the ability of resveratrol to infer with ECM formation and deposition in multiple diseases in their review article [53]. Resveratrol suppresses not only expression of fibronectin, fibromodulin, biglycan, and collagen types I and III, but also their protein levels in different cell lines [43]. Resveratrol also reduces MMP-9 protein accumulation but increases TIMP2 protein in ELT-3 cells and healthy uterine smooth muscle cells [43].

Resveratrol inhibits TGF-β signal downstream molecule AKT phosphorylation. Studies of confocal microscopy have shown resveratrol inhibits nuclear pAKT translocation in uterine fibroid cells. Alternatively, resveratrol does not interfere with pAKT nuclear translocation in normal uterine smooth muscle cells even though there are limited pAKT translocated [12]. Resveratrol reduces cellular levels of the phosphorylated/active form of anti-apoptotic kinase AKT in uterine cancer cells [167]. Sequentially, treatment of resveratrol reduces the endogenous cyclooxygenase-2 (COX-2) protein and produces PGE2 and PGF2α [167]. Evidence indicates that endogenous COX-2 is involved in inflammation, therefore, resveratrol inhibits AKT signaling pathway and COX-2 activity to induce anti-inflammation which plays vital roles in uterine fibroid cell growth.

β-catenin modulates and stimulates the stem cell renewal [168]. The regulation of the biologic functions for β-catenin is highly complex and not fully understood. Wnt proteins bind to a special cell-surface receptor, Frizzled, where it promotes activation of a cascade of proteins that leads to decreased β-catenin degradation in the cytosol and reduces nuclear β-catenin levels [7, 95]. The increased β-catenin expression is observed in uterine fibroids compared to the adjacent myometrium samples [169]. Ovarian steroids interact with the Wnt/β-catenin pathway to accelerate tumorigenesis [168]. Our studies also indicate that thyroid hormone increases nuclear β-catenin accumulation, thus β-catenin-dependent gene expression and proliferation [170, 171]. Resveratrol reduces expression and nuclear accumulation of β-catenin.

The expression of resveratrol-induced pro-apoptotic genes such as COX-2 and p21 induced in uterine fibroid cells. On the other hand, the expression of proliferative (anti-apoptotic) genes was either inhibited such as BCL2, and CDKN2 or no changed as Cyclin D1 and PCNA. The pro-apoptotic proteins such as caspase 3 and caspase 9, were also increased in resveratrol-treated cells [12]. Resveratrol-induced COX-2 facilitates p53-dependent anti-proliferation [172, 173]. Therefore, resveratrol induces anti-proliferation in uterine fibroid cells [12]. Kim et al. have also shown the extraction of herb medicine, Scutellaria barbata D. Don (Lamiaceae), down-regulates the IGF-I expression [174] and inhibits the proliferation of leiomyoma cells. Scutellaria barbata D. Don (Lamiaceae) induces the uterine smooth muscle cell differentiation markers in uterine smooth muscle cells and uterine leiomyoma smooth muscle cells, such as α smooth muscle actin (α-SMA), calreductin h1, and cyclin p27-dependent kinase inhibitor. In contrast, gene products linked to the G1 phase of the cell cycle, such as cyclin E and cdk2, are not affected by Scutellaria barbata D. Don (Lamiaceae) [175]. These observations agree with our studies. The expression of anti-apoptotic genes, such as BCL2 and CDKN2 are suppressed or unmodified Cyclin D1 and PCNA [12].

Estrogen stimulates proliferation in breast cancer cells [176, 177], endometrial cancer [178, 179] and leiomyoma cells [180]. Estrogen also stimulates cell growth in uterine fibroid cells [12]. Resveratrol can inhibit estrogen-dependent cancer growth [176] and suppresses the proliferation of six sensitive uterine fibroid cases both in the absence and presence of estradiol [12]. These results indicate the suppressing effect of resveratrol on uterine fibroid growth may not go through ER-α.

The immunomodulatory factor, checkpoint PD-1/PD-L1 has been shown to play an important role in uterine fibroid pathogenesis. They also attack attention to be therapeutic targets. Resveratrol suppresses PD-L1 expression. In the presence of thyroid hormone, resveratrol traps PD-L1 in the cytosol, meanwhile, resveratrol-induced COX-2, an inducible transcriptional co-activator [181], is trapped with thyroid hormone-induced PD-L1 in the cytosol [173].

Summarily, in the primary cell culture of patients with resveratrol-sensitive primary uterine fibroids, resveratrol can inhibit uterine fibroid proliferation, induce apoptosis, and transmit integrin-dependent signaling αvβ3. The transduction pathway promotes uterine fibroids cell cycle arrest. Additionally, resveratrol inhibits the activation of IGF-1R dependent signal transduction pathways, which play an important role in uterine fibroid proliferation. Resveratrol may or may not inhibit the expression of proliferation genes. Resveratrol also induces the expression of p21 and COX-2. Analysis of the DNA content of the PI stain indicates that resveratrol induces uterine fibroid cells cell cycle arrest at sub-G1 population [12]. Crosstalk between αvβ3 integrin and IGF-1R plays a crucial role in resveratrol-induced uterine fibroid anti-growth. In addition, resveratrol inhibits signal transduction pathways and gene expression dependent on TGF-β and β-catenin. Therefore, resveratrol can effectively prevent leiomyoma overgrowth and treat uterine fibroids.

3.3 Extract of He-Shou-Wu, 2,3,5,4′-Tetrahydroxystilbene-2-O-β-glucoside

The stilbene glucoside 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) is one of the major bioactive components of Polygonum multiflorum Thunb (He Shou Wu). It is glycosylated resveratrol and it has been used as antiaging medicine [182]. THSG suppresses experimental colitis effectively by reducing the level of oxygen and nitrogen free radicals [48]. It also has been shown to exert a protective effect on cardiotoxicity induced by doxorubicin in vitro and in vivo [183]. THSG can also diminish peroxidation levels in the brain of a mouse model with Alzheimer’s disease or cerebral ischemia–reperfusion. Administration of THSG not only prevents learning-memory deficits but also reverses the learning-memory deficit in disease-like mouse models with Alzheimer’s [184].

Mechanism involved in P. multiflorum-induced anti-atherosclerosis may be caused by THSG-induced antagonistic effects on oxidation of lipoprotein, proliferation, and decrease of nitric oxide content of coronary arterial smooth muscle cells [185] which partially explains the antiatherosclerosis mechanism of Polygonum multiflorum. Recently, the pharmacological effects of P. multiflorum on atherosclerosis have been revealed with anti-inflammation and guy microbiota regulation of THSG in ApoE−/− mice [186]. The protective effects of THSG are mediated by modulation of JNK, SirT1, and NF-κB pathways [187] (Figure 2). As resveratrol, THSG can activate signal transduction pathways as AMPK. Treatment with THSG reduces the LPS-induced neuroinflammatory response, and that the mechanism by which THSG induces anti-neuroinflammatory effects may include the Nrf2/AMPK signaling pathways [38]. Consequently, THSG treatment leads to a decrease in the level of iNOS, TNF-α, and IL-6 production [184]. THSG-induced neuroprotective effects are via Akt signaling and TrkB activity [51]. THSG possessed an anti-inflammatory effect that may also be related to the inhibition of COX-2 enzyme activity and expression [188].

As a glycosylated analogue of resveratrol, THSG has similar effects as resveratrol. Studies indicate that resveratrol significantly stimulates cell proliferation of human gingival fibroblasts at low concentration (10 μM) but inhibited cell proliferation at high concentrations (100 and 200 μM) significantly. On the other hand, THSG significantly enhances growth of human gingival fibroblasts when the concentration is over 25 μM and does not show any cytotoxic effect in human gingival fibroblasts [151]. It is evidenced that THSG may not cause cytotoxicity in normal human cells. Although there are no studies regarding effect of THSG on uterine fibroid, it should be more effective than resveratrol. THSG may not enter cells to induce superoxide which causes cytotoxicity to cells. However, studies also indicate that crude extract may cause damage in hepatocellular cells.

3.4 Pycnogenol, French maritime pine bark extract

Pycnogenol is a standardized extract of the bark of French maritime pine. Pycnogenol is composed of flavonoids, mainly proanthocyanidins, and phenolic compounds. It is a known potent antioxidant [49]. Owing to the basic chemical structure of its components, the most obvious feature of pycnogenol is its strong antioxidant activity. In fact, phenolic acids, polyphenols, and in particular flavonoids, are composed of one or more aromatic rings bearing one or more hydroxyl groups. The compositions are hence potentially able to quench free radicals by forming resonance-stabilized phenoxyl radicals [189]. Pycnogenol is a strong antioxidant that may interfere with different pathways, and it plays an important role in diseases associated with oxidative stress. Hyperglycemia is characteristic of diabetic nephropathy and induces renal tubular cell apoptosis. Pycnogenol has been demonstrated to significantly suppress the high glucose-induced morphological changes and the reduction in cell viability associated with cytotoxicity in high glucose-treated renal tubular cells [49]. Pycnogenol is able to protect high glucose-induced apoptosis increasing Bcl2/Bax protein ratio level. Combination treatment of pycnogenol and metformin improves blood glucose levels, vascular reactivity, and left ventricular hypertrophy in induced diabetic rats [33]. Furthermore, combined treatment increases expression of AMPK, glucose transporter 4 (GLUT4), and calcium/calmodulin-dependent protein kinase II (CaMKII) in left ventricle of the hearts. However, the combination of these interventions has failed to possess higher efficacy [33].

Pycnogenol has anti-oxidative and anti-inflammatory efficacy in suppressing lipid peroxidation, total reactive species, superoxide ·O2, nitric oxide NO·, peroxynitrite (ONOO), pro-inflammatory inducible nitric oxide synthase (iNOS) and COX-2 [49]. It also inhibits NF-κB nuclear translocation [49]. The safety of use of pycnogenol is demonstrated by the lack of side effects or changes in blood biochemistry and hematologic parameters. Therefore, pycnogenol has been recommended both for prevention and treatment of chronic venous insufficiency and related veno-capillary disturbances [190].

3.5 Therapeutic orchid Anoectochilus formosanus extract

Traditional herb medicine, golden thread (Anoectochilus formosanus Hayata) has been used to treat various diseases in Asia. A. formosanus extracts (AFEs) have been reported to possess hepatoprotective, anti-inflammatory, and anti-tumor activates. AFEs reduced blood glucose in hyperglycemic mice while there was no change in control group [191]. AFE and metformin at the same administrated dose of 50 mg/kg showed a similar effect on intraperitoneal glucose tolerance test in hyperglycemic mice. Free-radical scavenger capacity of AFE was concentration-dependent and 200 μg/ml of AFE was able to reduce more than 41% of the free radical [191]. The immunomodulatory protein from A. formosanus (IPAF) stimulated the TNF-α and IL-1β production, upregulated the expression of CD86, MHC II, IL-12, and Th1-associated cytokines/chemokines [28]. It also enhanced the phagocytic activity of macrophages [28]. AFE inhibited constitutive PD-L1 expression and its protein accumulation in cancer cells. AFE also induced expression of pro-apoptotic genes but inhibited proliferative and metastatic genes. Furthermore, it induced anti-proliferation in cancer cells. The results suggested that AFE not only reduced blood glucose concentration as metformin but also showed its potential use in cancer immune chemoprevention/therapy via hypoglycemic effect, ROS scavenging, and PD-L1 suppression [191]. In addition, IPAF stimulated expressions of TLR signal-related genes and the activation of NF-κB. IPAF could induce classically activated macrophage differentiation via TLR4-dependent NF-κB activation and had potential of IPAF to modulate the Th1 response [28].

3.6 Epigallocatechin gallate

The green tea polyphenol epigallocatechin gallate (EGCG) has not shown cytotoxicity to normal cells but induces apoptosis and growth inhibition of cancer cells [192, 193]. EGCG inhibits uterine leiomyoma cell growth in vitro and in vivo. The use of a green tea extract with 45% EGCG content has demonstrated clinical activity without side effects in women with uterine fibroid symptoms [194]. However, there are several shortcomings of EGCG including low stability, poor bioavailability, and high metabolic transformations under physiological conditions. All present challenges for its development as a therapeutic agent [194].

The signal transduction pathway by which EGCG exerts cell cycle arrest and induction of apoptosis remains to be clarified. Several mechanisms of cell-cycle arrest by EGCG have been postulated [195]. Transcription factor, p53 regulates downstream genes important in cell cycle arrest, DNA repair, and apoptosis. Loss of p53 in many cancers leads to genomic instability, impaired cell cycle regulation, and inhibition of apoptosis [196]. EGCG-treated HuLM cells exhibited increased expression of several genes that represent p53 pathway such as BAX, p21, transformed 3 T3 cell double minute 2 (MDM2) and tumor protein p53 inducible protein 3 (TP53I3) [30]. The NF-κB signal pathway was impaired by EGCG and the expression of bcl2A1, a key factor in NF-κB pathway, was reduced 11.8-fold in 100 μM EGCG-treated uterine fibroid HuLM cells [30] compared to untreated control.

The BCL family includes proapoptotic members and antiapoptotic members, such as BAX and BCL-2, respectively. The effects of apoptosis or anti-apoptosis supplementary depend on the balance between BCL2 and BAX rather than on the BCL2 quantity alone [197]. EGCG treatment causes BCL2 to dramatically decrease while BAX up-regulates [30]. Additionally, the D-type cyclins, through the interaction with CDKs-forming cyclin d1-CDK4/6 complexes, are mainly responsible for driving the cell cycle from G1 to S phase [198]. A significant decrease was observed in the expression of CDK4 and PCNA in EGCG treated uterine fibroid HuLM cells [30].


4. Conclusion remarks

The current clinical uterine fibroid therapies are restricted to their short-term efficacy and unpleasant side effects. Unless the patients are postmenopausal, hysterectomy is generally not recommended. In terms of expanding medical options, alternative therapies for uterine fibroids have been explored. In addition to herbal medicines we discussed, natural products such as vitamin D, berberine, and others are being used for alternative uterine fibroid treatments. Moreover, it may be more effective when natural compounds combined with hormonal agents for uterine fibroid therapy. We have shown that resveratrol combined with thyroid hormone analogue, tetrac can compensate for resveratrol-induced RRM2 side effects in colorectal cancer animal xenograft model [199]. However, to search for a safe and effective medication for uterine fibroid requires further human clinical trials of these herbal compounds before promoting widespread usage.



The research described in this article from our team was supported in part by the Chair Professor Research Fund to Dr. K. Wang and Dr. J. Whang-Peng, by TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, by grants from the Ministry of Science and Technology, Taiwan (MOST107–2314-B-038-017 and MOST108–2314-B-038-050). We appreciate Miss Evelyn Yu-Chun Chen for her stunning proofreading expertise. The authors would like to extend their most sincere appreciation to Miss ABu and Miss Ya-Jung Shih for their prodigious research contributions from our group as mentioned in text.


  1. 1. Stewart, E. A.; Cookson, C. L.; Gandolfo, R. A.; Schulze-Rath, R., Epidemiology of uterine fibroids: a systematic review. BJOG 2017, 124, (10), 1501-1512.
  2. 2. Baranov, V. S.; Osinovskaya, N. S.; Yarmolinskaya, M. I., Pathogenomics of Uterine Fibroids Development. Int J Mol Sci2019, 20, (24).
  3. 3. Jung, H. J.; Kim, H. J.; Park, K. K., Potential Roles of Long Noncoding RNAs as Therapeutic Targets in Renal Fibrosis. Int J Mol Sci2020, 21, (8).
  4. 4. Sohn, G. S.; Cho, S.; Kim, Y. M.; Cho, C. H.; Kim, M. R.; Lee, S. R.; Working Group of Society of Uterine, L., Current medical treatment of uterine fibroids. Obstet Gynecol Sci2018, 61, (2), 192-201.
  5. 5. Ciebiera, M.; Ali, M.; Prince, L.; Jackson-Bey, T.; Atabiekov, I.; Zgliczynski, S.; Al-Hendy, A., The Evolving Role of Natural Compounds in the Medical Treatment of Uterine Fibroids. J Clin Med2020, 9, (5).
  6. 6. Makinen, N.; Mehine, M.; Tolvanen, J.; Kaasinen, E.; Li, Y.; Lehtonen, H. J.; Gentile, M.; Yan, J.; Enge, M.; Taipale, M.; Aavikko, M.; Katainen, R.; Virolainen, E.; Bohling, T.; Koski, T. A.; Launonen, V.; Sjoberg, J.; Taipale, J.; Vahteristo, P.; Aaltonen, L. A., MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science2011, 334, (6053), 252-5.
  7. 7. Bulun, S. E., Uterine fibroids. N Engl J Med2013, 369, (14), 1344-55.
  8. 8. Halder, S. K.; Laknaur, A.; Miller, J.; Layman, L. C.; Diamond, M.; Al-Hendy, A., Novel MED12 gene somatic mutations in women from the Southern United States with symptomatic uterine fibroids. Mol Genet Genomics2015, 290, (2), 505-11.
  9. 9. Chun, K. S.; Keum, Y. S.; Han, S. S.; Song, Y. S.; Kim, S. H.; Surh, Y. J., Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-kappaB activation. Carcinogenesis2003, 24, (9), 1515-24.
  10. 10. Olivera, A.; Moore, T. W.; Hu, F.; Brown, A. P.; Sun, A.; Liotta, D. C.; Snyder, J. P.; Yoon, Y.; Shim, H.; Marcus, A. I.; Miller, A. H.; Pace, T. W., Inhibition of the NF-kappaB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): anti-inflammatory and anti-cancer properties. Int Immunopharmacol2012, 12, (2), 368-77.
  11. 11. Lim, W.; Jeong, M.; Bazer, F. W.; Song, G., Curcumin Suppresses Proliferation and Migration and Induces Apoptosis on Human Placental Choriocarcinoma Cells via ERK1/2 and SAPK/JNK MAPK Signaling Pathways. Biol Reprod2016, 95, (4), 83.
  12. 12. Ho, Y.; Sh Yang, Y. C.; Chin, Y. T.; Chou, S. Y.; Chen, Y. R.; Shih, Y. J.; Whang-Peng, J.; Changou, C. A.; Liu, H. L.; Lin, S. J.; Tang, H. Y.; Lin, H. Y.; Davis, P. J., Resveratrol inhibits human leiomyoma cell proliferation via crosstalk between integrin alphavbeta3 and IGF-1R. Food Chem Toxicol2018, 120, 346-355.
  13. 13. Chin, Y. T.; Hsieh, M. T.; Yang, S. H.; Tsai, P. W.; Wang, S. H.; Wang, C. C.; Lee, Y. S.; Cheng, G. Y.; HuangFu, W. C.; London, D.; Tang, H. Y.; Fu, E.; Yen, Y.; Liu, L. F.; Lin, H. Y.; Davis, P. J., Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro. Oncotarget2014, 5, (24), 12891-907.
  14. 14. Gosslau, A.; Pabbaraja, S.; Knapp, S.; Chen, K. Y., Trans- and cis-stilbene polyphenols induced rapid perinuclear mitochondrial clustering and p53-independent apoptosis in cancer cells but not normal cells. Eur J Pharmacol2008, 587, (1-3), 25-34.
  15. 15. Hwang, S.; Lee, H. J.; Kim, G.; Won, K. J.; Park, Y. S.; Jo, I., CCN1 acutely increases nitric oxide production via integrin alphavbeta3-Akt-S6K-phosphorylation of endothelial nitric oxide synthase at the serine 1177 signaling axis. Free Radic Biol Med2015, 89, 229-40.
  16. 16. Park, S. Y.; Jin, M. L.; Kang, N. J.; Park, G.; Choi, Y. W., Anti-inflammatory effects of novel Polygonum multiflorum compound via inhibiting NF-kappaB/MAPK and upregulating the Nrf2 pathways in LPS-stimulated microglia. Neurosci Lett2017, 651, 43-51.
  17. 17. Shin, N. R.; Ryu, H. W.; Ko, J. W.; Park, J. W.; Kwon, O. K.; Oh, S. R.; Kim, J. C.; Shin, I. S.; Ahn, K. S., A standardized bark extract of Pinus pinaster Aiton (Pycnogenol((R))) attenuated chronic obstructive pulmonary disease via Erk-sp1 signaling pathway. J Ethnopharmacol2016, 194, 412-420.
  18. 18. Xia, R.; Ji, C.; Zhang, L., Neuroprotective Effects of Pycnogenol Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury in Primary Rat Astrocytes via NF-kappaB and ERK1/2 MAPK Pathways. Cell Physiol Biochem2017, 42, (3), 987-998.
  19. 19. Hsieh, W. T.; Tsai, C. T.; Wu, J. B.; Hsiao, H. B.; Yang, L. C.; Lin, W. C., Kinsenoside, a high yielding constituent from Anoectochilus formosanus, inhibits carbon tetrachloride induced Kupffer cells mediated liver damage. J Ethnopharmacol2011, 135, (2), 440-9.
  20. 20. Liang, Y.; Ip, M. S. M.; Mak, J. C. W., (−)-Epigallocatechin-3-gallate suppresses cigarette smoke-induced inflammation in human cardiomyocytes via ROS-mediated MAPK and NF-kappaB pathways. Phytomedicine2019, 58, 152768.
  21. 21. Hamzehzadeh, L.; Atkin, S. L.; Majeed, M.; Butler, A. E.; Sahebkar, A., The versatile role of curcumin in cancer prevention and treatment: A focus on PI3K/AKT pathway. J Cell Physiol2018, 233, (10), 6530-6537.
  22. 22. Chai, R.; Fu, H.; Zheng, Z.; Liu, T.; Ji, S.; Li, G., Resveratrol inhibits proliferation and migration through SIRT1 mediated posttranslational modification of PI3K/AKT signaling in hepatocellular carcinoma cells. Mol Med Rep2017, 16, (6), 8037-8044.
  23. 23. Yang, X. P.; Liu, T. Y.; Qin, X. Y.; Yu, L. C., Potential protection of 2,3,5,4′-tetrahydroxystilbene-2-O-beta-D-glucoside against staurosporine-induced toxicity on cultured rat hippocampus neurons. Neurosci Lett2014, 576, 79-83.
  24. 24. Shen, J.; Zhang, Y.; Shen, H.; Pan, H.; Xu, L.; Yuan, L.; Ding, Z., The synergistic effect of 2,3,5,4’-Tetrahydroxystilbene-2-O-beta-d-glucoside combined with Adriamycin on MCF-7 breast cancer cells. Drug Des Devel Ther2018, 12, 4083-4094.
  25. 25. Lee, H. H.; Kim, K. J.; Lee, O. H.; Lee, B. Y., Effect of pycnogenol on glucose transport in mature 3T3-L1 adipocytes. Phytother Res2010, 24, (8), 1242-9.
  26. 26. Jamuna, S.; Ashokkumar, R.; Sakeena Sadullah, M. S.; Devaraj, S. N., Oligomeric proanthocyanidins and epigallocatechin gallate aggravate autophagy of foam cells through the activation of Class III PI3K/Beclin1-complex mediated cholesterol efflux. Biofactors2019, 45, (5), 763-773.
  27. 27. Gu, J. J.; Qiao, K. S.; Sun, P.; Chen, P.; Li, Q ., Study of EGCG induced apoptosis in lung cancer cells by inhibiting PI3K/Akt signaling pathway. Eur Rev Med Pharmacol Sci2018, 22, (14), 4557-4563.
  28. 28. Kuan, Y. C.; Lee, W. T.; Hung, C. L.; Yang, C.; Sheu, F., Investigating the function of a novel protein from Anoectochilus formosanus which induced macrophage differentiation through TLR4-mediated NF-kappaB activation. Int Immunopharmacol2012, 14, (1), 114-20.
  29. 29. Hsiao, H. B.; Lin, H.; Wu, J. B.; Lin, W. C., Kinsenoside prevents ovariectomy-induced bone loss and suppresses osteoclastogenesis by regulating classical NF-kappaB pathways. Osteoporos Int2013, 24, (5), 1663-76.
  30. 30. Zhang, D.; Al-Hendy, M.; Richard-Davis, G.; Montgomery-Rice, V.; Rajaratnam, V.; Al-Hendy, A., Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells. Fertil Steril2010, 94, (5), 1887-93.
  31. 31. Wang, Y.; Ren, X.; Deng, C.; Yang, L.; Yan, E.; Guo, T.; Li, Y.; Xu, M. X., Mechanism of the inhibition of the STAT3 signaling pathway by EGCG. Oncol Rep2013, 30, (6), 2691-6.
  32. 32. Park, S. Y.; Jin, M. L.; Chae, S. Y.; Ko, M. J.; Choi, Y. H.; Park, G.; Choi, Y. W., Novel compound from Polygonum multiflorum inhibits inflammatory response in LPS-stimulated microglia by upregulating AMPK/Nrf2 pathways. Neurochem Int2016, 100, 21-29.
  33. 33. Jankyova, S.; Rubintova, D.; Janosikova, L.; Panek, P.; Foltanova, T.; Kralova, E., The Effects of Pycnogenol(R) as Add-on Drug to Metformin Therapy in Diabetic Rats. Phytother Res2016, 30, (8), 1354-61.
  34. 34. Lee, Y. G.; Sue, Y. M.; Lee, C. K.; Huang, H. M.; He, J. J.; Wang, Y. S.; Juan, S. H., Synergistic effects of cAMP-dependent protein kinase A and AMP-activated protein kinase on lipolysis in kinsenoside-treated C3H10T1/2 adipocytes. Phytomedicine2019, 55, 255-263.
  35. 35. Cheng, K. T.; Wang, Y. S.; Chou, H. C.; Chang, C. C.; Lee, C. K.; Juan, S. H., Kinsenoside-mediated lipolysis through an AMPK-dependent pathway in C3H10T1/2 adipocytes: Roles of AMPK and PPARalpha in the lipolytic effect of kinsenoside. Phytomedicine2015, 22, (6), 641-7.
  36. 36. Li, B.; Takeda, T.; Tsuiji, K.; Kondo, A.; Kitamura, M.; Wong, T. F.; Yaegashi, N., The antidiabetic drug metformin inhibits uterine leiomyoma cell proliferation via an AMP-activated protein kinase signaling pathway. Gynecol Endocrinol2013, 29, (1), 87-90.
  37. 37. Ueda-Wakagi, M.; Hayashibara, K.; Nagano, T.; Ikeda, M.; Yuan, S.; Ueda, S.; Shirai, Y.; Yoshida, K. I.; Ashida, H., Epigallocatechin gallate induces GLUT4 translocation in skeletal muscle through both PI3K- and AMPK-dependent pathways. Food Funct2018, 9, (8), 4223-4233.
  38. 38. Park, S. Y.; Jin, M. L.; Wang, Z.; Park, G.; Choi, Y. W., 2,3,4′,5-tetrahydroxystilbene-2-O-beta-d-glucoside exerts anti-inflammatory effects on lipopolysaccharide-stimulated microglia by inhibiting NF-kappaB and activating AMPK/Nrf2 pathways. Food Chem Toxicol2016, 97, 159-167.
  39. 39. Pan, C.; Zhou, S.; Wu, J.; Liu, L.; Song, Y.; Li, T.; Ha, L.; Liu, X.; Wang, F.; Tian, J.; Wu, H., NRF2 Plays a Critical Role in Both Self and EGCG Protection against Diabetic Testicular Damage. Oxid Med Cell Longev2017, 2017, 3172692.
  40. 40. Xu, J.; Fu, Y.; Chen, A., Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth. Am J Physiol Gastrointest Liver Physiol2003, 285, (1), G20-30.
  41. 41. Meng, Y. K.; Li, C. Y.; Li, R. Y.; He, L. Z.; Cui, H. R.; Yin, P.; Zhang, C. E.; Li, P. Y.; Sang, X. X.; Wang, Y.; Niu, M.; Zhang, Y. M.; Guo, Y. M.; Sun, R.; Wang, J. B.; Bai, Z. F.; Xiao, X. H., Cis-stilbene glucoside in Polygonum multiflorum induces immunological idiosyncratic hepatotoxicity in LPS-treated rats by suppressing PPAR-gamma. Acta Pharmacol Sin2017, 38, (10), 1340-1352.
  42. 42. Lee, O. H.; Seo, M. J.; Choi, H. S.; Lee, B. Y., Pycnogenol(R) inhibits lipid accumulation in 3T3-L1 adipocytes with the modulation of reactive oxygen species (ROS) production associated with antioxidant enzyme responses. Phytother Res2012, 26, (3), 403-11.
  43. 43. Wu, C. H.; Shieh, T. M.; Wei, L. H.; Cheng, T. F.; Chen, H. Y.; Huang, T. C.; Wang, K. L.; Hsai, S. M., Resveratrol inhibits proliferation of myometrial and leiomyoma cells and decreases extracellular matrix-associated protein expression. Journal of Functional Foods2016, 23, 12.
  44. 44. Wang, S. I.; Mukhtar, H., Gene expression profile in human prostate LNCaP cancer cells by (−-) epigallocatechin-3-gallate. Cancer Lett2002, 182, (1), 43-51.
  45. 45. Yang, L. C.; Hsieh, C. C.; Lu, T. J.; Lin, W. C., Structurally characterized arabinogalactan from Anoectochilus formosanus as an immuno-modulator against CT26 colon cancer in BALB/c mice. Phytomedicine2014, 21, (5), 647-55.
  46. 46. Shyur, L. F.; Chen, C. H.; Lo, C. P.; Wang, S. Y.; Kang, P. L.; Sun, S. J.; Chang, C. A.; Tzeng, C. M.; Yang, N. S., Induction of apoptosis in MCF-7 human breast cancer cells by phytochemicals from Anoectochilus formosanus. J Biomed Sci2004, 11, (6), 928-39.
  47. 47. Arshad, L.; Haque, M. A.; Abbas Bukhari, S. N.; Jantan, I., An overview of structure-activity relationship studies of curcumin analogs as antioxidant and anti-inflammatory agents. Future Med Chem2017, 9, (6), 605-626.
  48. 48. Wang, X.; Zhao, L.; Han, T.; Chen, S.; Wang, J., Protective effects of 2,3,5,4′-tetrahydroxystilbene-2-O-beta-d-glucoside, an active component of Polygonum multiflorum Thunb, on experimental colitis in mice. Eur J Pharmacol2008, 578, (2-3), 339-48.
  49. 49. Kim, Y. J.; Kim, Y. A.; Yokozawa, T., Pycnogenol modulates apoptosis by suppressing oxidative stress and inflammation in high glucose-treated renal tubular cells. Food Chem Toxicol2011, 49, (9), 2196-201.
  50. 50. Pan, H.; Chen, J.; Shen, K.; Wang, X.; Wang, P.; Fu, G.; Meng, H.; Wang, Y.; Jin, B., Mitochondrial modulation by Epigallocatechin 3-Gallate ameliorates cisplatin induced renal injury through decreasing oxidative/nitrative stress, inflammation and NF-kB in mice. PLoS One2015, 10, (4), e0124775.
  51. 51. Yu, Y.; Lang, X. Y.; Li, X. X.; Gu, R. Z.; Liu, Q . S.; Lan, R.; Qin, X. Y., 2,3,5,4’-Tetrahydroxystilbene-2-O-beta-d-glucoside attenuates MPP+/MPTP-induced neurotoxicity in vitro and in vivo by restoring the BDNF-TrkB and FGF2-Akt signaling axis and inhibition of apoptosis. Food Funct2019, 10, (9), 6009-6019.
  52. 52. Huang, W. W.; Yang, J. S.; Lin, C. F.; Ho, W. J.; Lee, M. R., Pycnogenol induces differentiation and apoptosis in human promyeloid leukemia HL-60 cells. Leuk Res2005, 29, (6), 685-92.
  53. 53. Harati, K.; Slodnik, P.; Chromik, A. M.; Behr, B.; Goertz, O.; Hirsch, T.; Kapalschinski, N.; Klein-Hitpass, L.; Kolbenschlag, J.; Uhl, W.; Lehnhardt, M.; Daigeler, A., Proapoptotic effects of pycnogenol on HT1080 human fibrosarcoma cells. Int J Oncol2015, 46, (4), 1629-36.
  54. 54. Agarwal, R.; Agarwal, P., Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate? Exp Biol Med (Maywood)2017, 242, (4), 374-383.
  55. 55. Lee, J. H.; Chung, J. H.; Cho, K. H., The effects of epigallocatechin-3-gallate on extracellular matrix metabolism. J Dermatol Sci2005, 40, (3), 195-204.
  56. 56. Han, Y.; Wang, Q .; Fan, X.; Chu, J.; Peng, J.; Zhu, Y.; Li, Y.; Li, X.; Shen, L.; Asenso, J.; Li, S., Epigallocatechin gallate attenuates overloadinduced cardiac ECM remodeling via restoring T cell homeostasis. Mol Med Rep2017, 16, (3), 3542-3550.
  57. 57. McWilliams, M. M.; Chennathukuzhi, V. M., Recent Advances in Uterine Fibroid Etiology. Semin Reprod Med2017, 35, (2), 181-189.
  58. 58. Protic, O.; Toti, P.; Islam, M. S.; Occhini, R.; Giannubilo, S. R.; Catherino, W. H.; Cinti, S.; Petraglia, F.; Ciavattini, A.; Castellucci, M.; Hinz, B.; Ciarmela, P., Possible involvement of inflammatory/reparative processes in the development of uterine fibroids. Cell Tissue Res2016, 364, (2), 415-27.
  59. 59. Elhusseini, H.; Elkafas, H.; Abdelaziz, M.; Halder, S.; Atabiekov, I.; Eziba, N.; Ismail, N.; El Andaloussi, A.; Al-Hendy, A., Diet-induced vitamin D deficiency triggers inflammation and DNA damage profile in murine myometrium. Int J Womens Health2018, 10, 503-514.
  60. 60. Yang, Q .; Diamond, M. P.; Al-Hendy, A., Early Life Adverse Environmental Exposures Increase the Risk of Uterine Fibroid Development: Role of Epigenetic Regulation. Front Pharmacol2016, 7, 40.
  61. 61. Fruehauf, J. P.; Meyskens, F. L., Jr., Reactive oxygen species: a breath of life or death? Clin Cancer Res2007, 13, (3), 789-94.
  62. 62. Halliwell, B., Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med1991, 91, (3C), 14S–22S.
  63. 63. Harris, A. L., Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer2002, 2, (1), 38-47.
  64. 64. Inoue, M.; Sato, E. F.; Nishikawa, M.; Park, A. M.; Kira, Y.; Imada, I.; Utsumi, K., Mitochondrial generation of reactive oxygen species and its role in aerobic life. Curr Med Chem2003, 10, (23), 2495-505.
  65. 65. Kamata, H.; Hirata, H., Redox regulation of cellular signalling. Cell Signal1999, 11, (1), 1-14.
  66. 66. Kieran, M. W.; Folkman, J.; Heymach, J., Angiogenesis inhibitors and hypoxia. Nat Med2003, 9, (9), 1104; author reply 1104-5.
  67. 67. Ishikawa, H.; Ishi, K.; Serna, V. A.; Kakazu, R.; Bulun, S. E.; Kurita, T., Progesterone is essential for maintenance and growth of uterine leiomyoma. Endocrinology2010, 151, (6), 2433-42.
  68. 68. Borahay, M. A.; Al-Hendy, A.; Kilic, G. S.; Boehning, D., Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy. Mol Med2015, 21, 242-56.
  69. 69. Ono, M.; Qiang, W.; Serna, V. A.; Yin, P.; Coon, J. S. t.; Navarro, A.; Monsivais, D.; Kakinuma, T.; Dyson, M.; Druschitz, S.; Unno, K.; Kurita, T.; Bulun, S. E., Role of stem cells in human uterine leiomyoma growth. PLoS One2012, 7, (5), e36935.
  70. 70. Islam, M. S.; Ciavattini, A.; Petraglia, F.; Castellucci, M.; Ciarmela, P., Extracellular matrix in uterine leiomyoma pathogenesis: a potential target for future therapeutics. Hum Reprod Update2018, 24, (1), 59-85.
  71. 71. Kudo, D.; Suto, A.; Hakamada, K., The Development of a Novel Therapeutic Strategy to Target Hyaluronan in the Extracellular Matrix of Pancreatic Ductal Adenocarcinoma. Int J Mol Sci2017, 18, (3).
  72. 72. Islam, M. S.; Akhtar, M. M.; Segars, J. H.; Castellucci, M.; Ciarmela, P., Molecular targets of dietary phytochemicals for possible prevention and therapy of uterine fibroids: Focus on fibrosis. Crit Rev Food Sci Nutr2017, 57, (17), 3583-3600.
  73. 73. Sozen, I.; Arici, A., Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata. Fertil Steril2002, 78, (1), 1-12.
  74. 74. Al-Hendy, A.; Diamond, M. P.; El-Sohemy, A.; Halder, S. K., 1,25-dihydroxyvitamin D3 regulates expression of sex steroid receptors in human uterine fibroid cells. J Clin Endocrinol Metab2015, 100, (4), E572-82.
  75. 75. Curtis, S. W.; Washburn, T.; Sewall, C.; DiAugustine, R.; Lindzey, J.; Couse, J. F.; Korach, K. S., Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc Natl Acad Sci U S A1996, 93, (22), 12626-30.
  76. 76. Nilsson, S.; Makela, S.; Treuter, E.; Tujague, M.; Thomsen, J.; Andersson, G.; Enmark, E.; Pettersson, K.; Warner, M.; Gustafsson, J. A., Mechanisms of estrogen action. Physiol Rev2001, 81, (4), 1535-65.
  77. 77. Le Dily, F.; Beato, M., Signaling by Steroid Hormones in the 3D Nuclear Space. Int J Mol Sci2018, 19, (2).
  78. 78. Andersen, J.; DyReyes, V. M.; Barbieri, R. L.; Coachman, D. M.; Miksicek, R. J., Leiomyoma primary cultures have elevated transcriptional response to estrogen compared with autologous myometrial cultures. J Soc Gynecol Investig1995, 2, (3), 542-51.
  79. 79. Kim, J. J.; Kurita, T.; Bulun, S. E., Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev2013, 34, (1), 130-62.
  80. 80. Stewart, E. A.; Friedman, A. J.; Peck, K.; Nowak, R. A., Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle. J Clin Endocrinol Metab1994, 79, (3), 900-6.
  81. 81. Wei, J.; Chiriboga, L.; Mizuguchi, M.; Yee, H.; Mittal, K., Expression profile of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata. Mod Pathol2005, 18, (2), 179-88.
  82. 82. Hassan, M. H.; Salama, S. A.; Arafa, H. M.; Hamada, F. M.; Al-Hendy, A., Adenovirus-mediated delivery of a dominant-negative estrogen receptor gene in uterine leiomyoma cells abrogates estrogen- and progesterone-regulated gene expression. J Clin Endocrinol Metab2007, 92, (10), 3949-57.
  83. 83. Hassan, M. H.; Salama, S. A.; Zhang, D.; Arafa, H. M.; Hamada, F. M.; Fouad, H.; Walker, C. C.; Al-Hendy, A., Gene therapy targeting leiomyoma: adenovirus-mediated delivery of dominant-negative estrogen receptor gene shrinks uterine tumors in Eker rat model. Fertil Steril2010, 93, (1), 239-50.
  84. 84. Ciarmela, P.; Islam, M. S.; Reis, F. M.; Gray, P. C.; Bloise, E.; Petraglia, F.; Vale, W.; Castellucci, M., Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Hum Reprod Update2011, 17, (6), 772-90.
  85. 85. Arici, A.; Sozen, I., Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil Steril2000, 73, (5), 1006-11.
  86. 86. Inagaki, N.; Ung, L.; Otani, T.; Wilkinson, D.; Lopata, A., Uterine cavity matrix metalloproteinases and cytokines in patients with leiomyoma, adenomyosis or endometrial polyp. Eur J Obstet Gynecol Reprod Biol2003, 111, (2), 197-203.
  87. 87. Protic, O.; Islam, M. S.; Greco, S.; Giannubilo, S. R.; Lamanna, P.; Petraglia, F.; Ciavattini, A.; Castellucci, M.; Hinz, B.; Ciarmela, P., Activin A in Inflammation, Tissue Repair, and Fibrosis: Possible Role as Inflammatory and Fibrotic Mediator of Uterine Fibroid Development and Growth. Semin Reprod Med2017, 35, (6), 499-509.
  88. 88. Munger, J. S.; Sheppard, D., Cross talk among TGF-beta signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb Perspect Biol2011, 3, (11), a005017.
  89. 89. Baird, D. D.; Travlos, G.; Wilson, R.; Dunson, D. B.; Hill, M. C.; D’Aloisio, A. A.; London, S. J.; Schectman, J. M., Uterine leiomyomata in relation to insulin-like growth factor-I, insulin, and diabetes. Epidemiology2009, 20, (4), 604-10.
  90. 90. Boehm, K. D.; Daimon, M.; Gorodeski, I. G.; Sheean, L. A.; Utian, W. H.; Ilan, J., Expression of the insulin-like and platelet-derived growth factor genes in human uterine tissues. Mol Reprod Dev1990, 27, (2), 93-101.
  91. 91. Burroughs, K. D.; Howe, S. R.; Okubo, Y.; Fuchs-Young, R.; LeRoith, D.; Walker, C. L., Dysregulation of IGF-I signaling in uterine leiomyoma. J Endocrinol2002, 172, (1), 83-93.
  92. 92. Swartz, C. D.; Afshari, C. A.; Yu, L.; Hall, K. E.; Dixon, D., Estrogen-induced changes in IGF-I, Myb family and MAP kinase pathway genes in human uterine leiomyoma and normal uterine smooth muscle cell lines. Mol Hum Reprod2005, 11, (6), 441-50.
  93. 93. Friedman, A. J.; Rein, M. S.; Pandian, M. R.; Barbieri, R. L., Fasting serum growth hormone and insulin-like growth factor-I and -II concentrations in women with leiomyomata uteri treated with leuprolide acetate or placebo. Fertil Steril1990, 53, (2), 250-3.
  94. 94. Englund, K.; Lindblom, B.; Carlstrom, K.; Gustavsson, I.; Sjoblom, P.; Blanck, A., Gene expression and tissue concentrations of IGF-I in human myometrium and fibroids under different hormonal conditions. Mol Hum Reprod2000, 6, (10), 915-20.
  95. 95. Ono, M.; Yin, P.; Navarro, A.; Moravek, M. B.; Coon, J. S. t.; Druschitz, S. A.; Serna, V. A.; Qiang, W.; Brooks, D. C.; Malpani, S. S.; Ma, J.; Ercan, C. M.; Mittal, N.; Monsivais, D.; Dyson, M. T.; Yemelyanov, A.; Maruyama, T.; Chakravarti, D.; Kim, J. J.; Kurita, T.; Gottardi, C. J.; Bulun, S. E., Paracrine activation of WNT/beta-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proc Natl Acad Sci U S A2013, 110, (42), 17053-8.
  96. 96. Islam, M. S.; Catherino, W. H.; Protic, O.; Janjusevic, M.; Gray, P. C.; Giannubilo, S. R.; Ciavattini, A.; Lamanna, P.; Tranquilli, A. L.; Petraglia, F.; Castellucci, M.; Ciarmela, P., Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function. J Clin Endocrinol Metab2014, 99, (5), E775-85.
  97. 97. Al-Hendy, A.; Laknaur, A.; Diamond, M. P.; Ismail, N.; Boyer, T. G.; Halder, S. K., Silencing Med12 Gene Reduces Proliferation of Human Leiomyoma Cells Mediated via Wnt/beta-Catenin Signaling Pathway. Endocrinology2017, 158, (3), 592-603.
  98. 98. Donnez, J.; Dolmans, M. M., Uterine fibroid management: from the present to the future. Hum Reprod Update2016, 22, (6), 665-686.
  99. 99. Cheng, Z.; Xie, Y.; Dai, H.; Hu, L.; Zhu, Y.; Gong, J., Unequal tissue expression of proteins from the PA/PAI system, myoma necrosis, and uterus survival after uterine artery occlusion. Int J Gynaecol Obstet2008, 102, (1), 55-9.
  100. 100. Walker, C. L., Role of hormonal and reproductive factors in the etiology and treatment of uterine leiomyoma. Recent Prog Horm Res2002, 57, 277-94.
  101. 101. El Andaloussi, A.; Al-Hendy, A.; Ismail, N.; Boyer, T. G.; Halder, S. K., Introduction of Somatic Mutation in MED12 Induces Wnt4/beta-Catenin and Disrupts Autophagy in Human Uterine Myometrial Cell. Reprod Sci2020, 27, (3), 823-832.
  102. 102. Ali, M.; Shahin, S. M.; Sabri, N. A.; Al-Hendy, A.; Yang, Q ., Activation of beta-Catenin Signaling and its Crosstalk With Estrogen and Histone Deacetylases in Human Uterine Fibroids. J Clin Endocrinol Metab2020, 105, (4).
  103. 103. Lewis, T. D.; Malik, M.; Britten, J.; Parikh, T.; Cox, J.; Catherino, W. H., Ulipristal acetate decreases active TGF-beta3 and its canonical signaling in uterine leiomyoma via two novel mechanisms. Fertil Steril2019, 111, (4), 806-815 e1.
  104. 104. Ono, M.; Yin, P.; Navarro, A.; Moravek, M. B.; Coon, V. J.; Druschitz, S. A.; Gottardi, C. J.; Bulun, S. E., Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth. Fertil Steril2014, 101, (5), 1441-9.
  105. 105. Garner, C., Uses of GnRH agonists. Journal of obstetric, gynecologic, and neonatal nursing : JOGNN1994, 23, (7), 563-70.
  106. 106. Sabry, M.; Al-Hendy, A., Medical treatment of uterine leiomyoma. Reproductive sciences2012, 19, (4), 339-53.
  107. 107. Al-Hendy, A.; Salama, S., Gene therapy and uterine leiomyoma: a review. Human reproduction update2006, 12, (4), 385-400.
  108. 108. Zeng, L.; Yang, K.; Liu, H.; Zhang, G., A network pharmacology approach to investigate the pharmacological effects of Guizhi Fuling Wan on uterine fibroids. Experimental and therapeutic medicine2017, 14, (5), 4697-4710.
  109. 109. Su, S. Y.; Muo, C. H.; Morisky, D. E., Use of chinese medicine and subsequent surgery in women with uterine fibroid: a retrospective cohort study. Evidence-based complementary and alternative medicine : eCAM2012, 2012, 617918.
  110. 110. Ohara, N.; Morikawa, A.; Chen, W.; Wang, J.; DeManno, D. A.; Chwalisz, K.; Maruo, T., Comparative effects of SPRM asoprisnil (J867) on proliferation, apoptosis, and the expression of growth factors in cultured uterine leiomyoma cells and normal myometrial cells. Reproductive sciences2007, 14, (8 Suppl), 20-7.
  111. 111. Hewlings, S. J.; Kalman, D. S., Curcumin: A Review of Its Effects on Human Health. Foods2017, 6, (10).
  112. 112. Srivastava, R.; Dikshit, M.; Srimal, R. C.; Dhawan, B. N., Anti-thrombotic effect of curcumin. Thromb Res1985, 40, (3), 413-7.
  113. 113. Soudamini, K. K.; Unnikrishnan, M. C.; Soni, K. B.; Kuttan, R., Inhibition of lipid peroxidation and cholesterol levels in mice by curcumin. Indian J Physiol Pharmacol1992, 36, (4), 239-43.
  114. 114. Asai, A.; Miyazawa, T., Dietary curcuminoids prevent high-fat diet-induced lipid accumulation in rat liver and epididymal adipose tissue. J Nutr2001, 131, (11), 2932-5.
  115. 115. Venkatesan, N., Curcumin attenuation of acute adriamycin myocardial toxicity in rats. Br J Pharmacol1998, 124, (3), 425-7.
  116. 116. Aggarwal, B. B.; Kumar, A.; Bharti, A. C., Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res2003, 23, (1A), 363-98.
  117. 117. Mukhopadhyay, A.; Banerjee, S.; Stafford, L. J.; Xia, C.; Liu, M.; Aggarwal, B. B., Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Oncogene2002, 21, (57), 8852-61.
  118. 118. Gupta, S. C.; Prasad, S.; Kim, J. H.; Patchva, S.; Webb, L. J.; Priyadarsini, I. K.; Aggarwal, B. B., Multitargeting by curcumin as revealed by molecular interaction studies. Nat Prod Rep2011, 28, (12), 1937-55.
  119. 119. Anand, P.; Sundaram, C.; Jhurani, S.; Kunnumakkara, A. B.; Aggarwal, B. B., Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer Lett2008, 267, (1), 133-64.
  120. 120. Goel, A.; Kunnumakkara, A. B.; Aggarwal, B. B., Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol2008, 75, (4), 787-809.
  121. 121. Kunnumakkara, A. B.; Anand, P.; Aggarwal, B. B., Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett2008, 269, (2), 199-225.
  122. 122. Sissener, N. H.; Johannessen, L. E.; Hevroy, E. M.; Wiik-Nielsen, C. R.; Berdal, K. G.; Nordgreen, A.; Hemre, G. I., Zebrafish ( Danio rerio) as a model for investigating the safety of GM feed ingredients (soya and maize); performance, stress response and uptake of dietary DNA sequences. Br J Nutr2010, 103, (1), 3-15.
  123. 123. Houston, K. D.; Copland, J. A.; Broaddus, R. R.; Gottardis, M. M.; Fischer, S. M.; Walker, C. L., Inhibition of proliferation and estrogen receptor signaling by peroxisome proliferator-activated receptor gamma ligands in uterine leiomyoma. Cancer Res2003, 63, (6), 1221-7.
  124. 124. Lev-Ari, S.; Starr, A.; Vexler, A.; Karaush, V.; Loew, V.; Greif, J.; Fenig, E.; Aderka, D.; Ben-Yosef, R., Inhibition of pancreatic and lung adenocarcinoma cell survival by curcumin is associated with increased apoptosis, down-regulation of COX-2 and EGFR and inhibition of Erk1/2 activity. Anticancer Res2006, 26, (6B), 4423-30.
  125. 125. Chen, X.; Chen, X.; Shi, X.; Gao, Z.; Guo, Z., Curcumin attenuates endothelial cell fibrosis through inhibiting endothelial-interstitial transformation. Clin Exp Pharmacol Physiol2020, 47, (7), 1182-1192.
  126. 126. Bajracharya, P.; Lee, E. J.; Lee, D. M.; Shim, S. H.; Kim, K. J.; Lee, S. H.; Bae, J. J.; Chun, S. S.; Lee, T. K.; Kwon, S. H.; Choi, I., Effect of different ingredients in traditional Korean medicine for human uterine leiomyoma on normal myometrial and leiomyomal smooth muscle cell proliferation. Arch Pharm Res2009, 32, (11), 1555-63.
  127. 127. Malik, M.; Mendoza, M.; Payson, M.; Catherino, W. H., Curcumin, a nutritional supplement with antineoplastic activity, enhances leiomyoma cell apoptosis and decreases fibronectin expression. Fertil Steril2009, 91, (5 Suppl), 2177-84.
  128. 128. Wright, H. M.; Clish, C. B.; Mikami, T.; Hauser, S.; Yanagi, K.; Hiramatsu, R.; Serhan, C. N.; Spiegelman, B. M., A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem2000, 275, (3), 1873-7.
  129. 129. Sharma, A. M.; Staels, B., Review: Peroxisome proliferator-activated receptor gamma and adipose tissue--understanding obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metab2007, 92, (2), 386-95.
  130. 130. Chen, A.; Xu, J., Activation of PPAR{gamma} by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR. Am J Physiol Gastrointest Liver Physiol2005, 288, (3), G447-56.
  131. 131. Takeda, T.; Sakata, M.; Isobe, A.; Miyake, A.; Nishimoto, F.; Ota, Y.; Kamiura, S.; Kimura, T., Relationship between metabolic syndrome and uterine leiomyomas: a case-control study. Gynecol Obstet Invest2008, 66, (1), 14-7.
  132. 132. Tsuiji, K.; Takeda, T.; Li, B.; Wakabayashi, A.; Kondo, A.; Kimura, T.; Yaegashi, N., Inhibitory effect of curcumin on uterine leiomyoma cell proliferation. Gynecol Endocrinol2011, 27, (7), 512-7.
  133. 133. Wahlstrom, B.; Blennow, G., A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol (Copenh)1978, 43, (2), 86-92.
  134. 134. Ravindranath, V.; Chandrasekhara, N., Absorption and tissue distribution of curcumin in rats. Toxicology1980, 16, (3), 259-65.
  135. 135. Shoba, G.; Joy, D.; Joseph, T.; Majeed, M.; Rajendran, R.; Srinivas, P. S., Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med1998, 64, (4), 353-6.
  136. 136. Pan, M. H.; Huang, T. M.; Lin, J. K., Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metab Dispos1999, 27, (4), 486-94.
  137. 137. Cen, L.; Hutzen, B.; Ball, S.; DeAngelis, S.; Chen, C. L.; Fuchs, J. R.; Li, C.; Li, P. K.; Lin, J., New structural analogues of curcumin exhibit potent growth suppressive activity in human colorectal carcinoma cells. BMC Cancer2009, 9, 99.
  138. 138. Shibata, H.; Yamakoshi, H.; Sato, A.; Ohori, H.; Kakudo, Y.; Kudo, C.; Takahashi, Y.; Watanabe, M.; Takano, H.; Ishioka, C.; Noda, T.; Iwabuchi, Y., Newly synthesized curcumin analog has improved potential to prevent colorectal carcinogenesis in vivo. Cancer Sci2009, 100, (5), 956-60.
  139. 139. Costa, C.; Tsatsakis, A.; Mamoulakis, C.; Teodoro, M.; Briguglio, G.; Caruso, E.; Tsoukalas, D.; Margina, D.; Dardiotis, E.; Kouretas, D.; Fenga, C., Current evidence on the effect of dietary polyphenols intake on chronic diseases. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association2017, 110, 286-299.
  140. 140. Banerjee, S.; Bueso-Ramos, C.; Aggarwal, B. B., Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer research2002, 62, (17), 4945-54.
  141. 141. Jang, M.; Cai, L.; Udeani, G. O.; Slowing, K. V.; Thomas, C. F.; Beecher, C. W.; Fong, H. H.; Farnsworth, N. R.; Kinghorn, A. D.; Mehta, R. G.; Moon, R. C.; Pezzuto, J. M., Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science1997, 275, (5297), 218-20.
  142. 142. Lin, H. Y.; Hsieh, M. T.; Cheng, G. Y.; Lai, H. Y.; Chin, Y. T.; Shih, Y. J.; Nana, A. W.; Lin, S. Y.; Yang, Y. S. H.; Tang, H. Y.; Chiang, I. J.; Wang, K., Mechanisms of action of nonpeptide hormones on resveratrol-induced antiproliferation of cancer cells. Annals of the New York Academy of Sciences2017, 1403, (1), 92-100.
  143. 143. Ho, Y.; Lin, Y. S.; Liu, H. L.; Shih, Y. J.; Lin, S. Y.; Shih, A.; Chin, Y. T.; Chen, Y. R.; Lin, H. Y.; Davis, P. J., Biological Mechanisms by Which Antiproliferative Actions of Resveratrol Are Minimized. Nutrients2017, 9, (10).
  144. 144. Cheng, T. M.; Chin, Y. T.; Ho, Y.; Chen, Y. R.; Yang, Y. N.; Yang, Y. C.; Shih, Y. J.; Lin, T. I.; Lin, H. Y.; Davis, P. J., Resveratrol induces sumoylated COX-2-dependent anti-proliferation in human prostate cancer LNCaP cells. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association2017, 112, 67-75.
  145. 145. Chin, Y. T.; Yang, S. H.; Chang, T. C.; Changou, C. A.; Lai, H. Y.; Fu, E.; HuangFu, W. C.; Davis, P. J.; Lin, H. Y.; Liu, L. F., Mechanisms of dihydrotestosterone action on resveratrol-induced anti-proliferation in breast cancer cells with different ERalpha status. Oncotarget2015, 6, (34), 35866-79.
  146. 146. Chow, S. E.; Wang, J. S.; Chuang, S. F.; Chang, Y. L.; Chu, W. K.; Chen, W. S.; Chen, Y. W., Resveratrol-induced p53-independent apoptosis of human nasopharyngeal carcinoma cells is correlated with the downregulation of DeltaNp63. Cancer Gene Ther2010, 17, (12), 872-82.
  147. 147. Schmidt, A. H.; Solloch, U. V.; Pingel, J.; Sauter, J.; Bohme, I.; Cereb, N.; Dubicka, K.; Schumacher, S.; Wachowiak, J.; Ehninger, G., Regional HLA differences in Poland and their effect on stem cell donor registry planning. PLoS One2013, 8, (9), e73835.
  148. 148. Rasheduzzaman, M.; Jeong, J. K.; Park, S. Y., Resveratrol sensitizes lung cancer cell to TRAIL by p53 independent and suppression of Akt/NF-kappaB signaling. Life Sci2018, 208, 208-220.
  149. 149. Alamolhodaei, N. S.; Tsatsakis, A. M.; Ramezani, M.; Hayes, A. W.; Karimi, G., Resveratrol as MDR reversion molecule in breast cancer: An overview. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association2017, 103, 223-232.
  150. 150. Turner, R. S.; Thomas, R. G.; Craft, S.; van Dyck, C. H.; Mintzer, J.; Reynolds, B. A.; Brewer, J. B.; Rissman, R. A.; Raman, R.; Aisen, P. S.; Alzheimer’s Disease Cooperative, S., A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology2015, 85, (16), 1383-91.
  151. 151. Chin, Y. T.; Hsieh, M. T.; Lin, C. Y.; Kuo, P. J.; Yang, Y. C.; Shih, Y. J.; Lai, H. Y.; Cheng, G. Y.; Tang, H. Y.; Lee, C. C.; Lee, S. Y.; Wang, C. C.; Lin, H. Y.; Fu, E.; Whang-Peng, J.; Liu, L. F., 2,3,5,4’-Tetrahydroxystilbene-2-O-beta-glucoside Isolated from Polygoni Multiflori Ameliorates the Development of Periodontitis. Mediators Inflamm2016, 2016, 6953459.
  152. 152. Riaz, A.; Ilan, N.; Vlodavsky, I.; Li, J. P.; Johansson, S., Characterization of heparanase-induced phosphatidylinositol 3-kinase-AKT activation and its integrin dependence. J Biol Chem2013, 288, (17), 12366-75.
  153. 153. Nakajima, S.; Ishimaru, K.; Kobayashi, A.; Yu, G.; Nakamura, Y.; Oh-Oka, K.; Suzuki-Inoue, K.; Kono, K.; Nakao, A., Resveratrol inhibits IL-33-mediated mast cell activation by targeting the MK2/3-PI3K/Akt axis. Sci Rep2019, 9, (1), 18423.
  154. 154. Lin, H. Y.; Chin, Y. T.; Yang, Y. C.; Lai, H. Y.; Wang-Peng, J.; Liu, L. F.; Tang, H. Y.; Davis, P. J., Thyroid Hormone, Cancer, and Apoptosis. Compr Physiol2016, 6, (3), 1221-37.
  155. 155. Davis, P. J.; Lin, H. Y.; Hercbergs, A.; Keating, K. A.; Mousa, S. A., Coronaviruses and Integrin alphavbeta3: Does Thyroid Hormone Modify the Relationship? Endocr Res2020, 45, (3), 210-215.
  156. 156. Zaidel-Bar, R.; Itzkovitz, S.; Ma’ayan, A.; Iyengar, R.; Geiger, B., Functional atlas of the integrin adhesome. Nat Cell Biol2007, 9, (8), 858-67.
  157. 157. Zaidel-Bar, R.; Geiger, B., The switchable integrin adhesome. J Cell Sci2010, 123, (Pt 9), 1385-8.
  158. 158. Huveneers, S.; Danen, E. H., Adhesion signaling - crosstalk between integrins, Src and Rho. J Cell Sci2009, 122, (Pt 8), 1059-69.
  159. 159. Streuli, C. H.; Akhtar, N., Signal co-operation between integrins and other receptor systems. Biochem J2009, 418, (3), 491-506.
  160. 160. Ivaska, J.; Heino, J., Interplay between cell adhesion and growth factor receptors: from the plasma membrane to the endosomes. Cell Tissue Res2010, 339, (1), 111-20.
  161. 161. Arslan, A. A.; Gold, L. I.; Mittal, K.; Suen, T. C.; Belitskaya-Levy, I.; Tang, M. S.; Toniolo, P., Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review. Hum Reprod2005, 20, (4), 852-63.
  162. 162. Ock, S.; Ahn, J.; Lee, S. H.; Kang, H.; Offermanns, S.; Ahn, H. Y.; Jo, Y. S.; Shong, M.; Cho, B. Y.; Jo, D.; Abel, E. D.; Lee, T. J.; Park, W. J.; Lee, I. K.; Kim, J., IGF-1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH-stimulated goiter. FASEB J2013, 27, (12), 4899-908.
  163. 163. Hong Bin, W.; Da, L. H.; Xue, Y.; Jing, B., Pterostilbene (3′,5′-dimethoxy-resveratrol) exerts potent antitumor effects in HeLa human cervical cancer cells via disruption of mitochondrial membrane potential, apoptosis induction and targeting m-TOR/PI3K/Akt signalling pathway. J BUON2018, 23, (5), 1384-1389.
  164. 164. Vanamala, J.; Reddivari, L.; Radhakrishnan, S.; Tarver, C., Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer2010, 10, 238.
  165. 165. Gionfra, F.; De Vito, P.; Pallottini, V.; Lin, H. Y.; Davis, P. J.; Pedersen, J. Z.; Incerpi, S., The Role of Thyroid Hormones in Hepatocyte Proliferation and Liver Cancer. Front Endocrinol (Lausanne)2019, 10, 532.
  166. 166. Kim, K. H.; Back, J. H.; Zhu, Y.; Arbesman, J.; Athar, M.; Kopelovich, L.; Kim, A. L.; Bickers, D. R., Resveratrol targets transforming growth factor-beta2 signaling to block UV-induced tumor progression. J Invest Dermatol2011, 131, (1), 195-202.
  167. 167. Sexton, E.; Van Themsche, C.; LeBlanc, K.; Parent, S.; Lemoine, P.; Asselin, E., Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells. Mol Cancer2006, 5, 45.
  168. 168. Tanwar, P. S.; Lee, H. J.; Zhang, L.; Zukerberg, L. R.; Taketo, M. M.; Rueda, B. R.; Teixeira, J. M., Constitutive activation of Beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice. Biol Reprod2009, 81, (3), 545-52.
  169. 169. Ko, Y. A.; Jamaluddin, M. F. B.; Adebayo, M.; Bajwa, P.; Scott, R. J.; Dharmarajan, A. M.; Nahar, P.; Tanwar, P. S., Extracellular matrix (ECM) activates beta-catenin signaling in uterine fibroids. Reproduction2018, 155, (1), 61-71.
  170. 170. Nana, A. W.; Chin, Y. T.; Lin, C. Y.; Ho, Y.; Bennett, J. A.; Shih, Y. J.; Chen, Y. R.; Changou, C. A.; Pedersen, J. Z.; Incerpi, S.; Liu, L. F.; Whang-Peng, J.; Fu, E.; Li, W. S.; Mousa, S. A.; Lin, H. Y.; Davis, P. J., Tetrac downregulates beta-catenin and HMGA2 to promote the effect of resveratrol in colon cancer. Endocr Relat Cancer2018, 25, (3), 279-293.
  171. 171. Lee, Y. S.; Chin, Y. T.; Shih, Y. J.; Nana, A. W.; Chen, Y. R.; Wu, H. C.; Yang, Y. S. H.; Lin, H. Y.; Davis, P. J., Thyroid Hormone Promotes beta-Catenin Activation and Cell Proliferation in Colorectal Cancer. Horm Cancer2018, 9, (3), 156-165.
  172. 172. Lin, H. Y.; Delmas, D.; Vang, O.; Hsieh, T. C.; Lin, S.; Cheng, G. Y.; Chiang, H. L.; Chen, C. E.; Tang, H. Y.; Crawford, D. R.; Whang-Peng, J.; Hwang, J.; Liu, L. F.; Wu, J. M., Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol. J Cell Biochem2013, 114, (8), 1940-54.
  173. 173. Chin, Y. T.; Wei, P. L.; Ho, Y.; Nana, A. W.; Changou, C. A.; Chen, Y. R.; Yang, Y. S.; Hsieh, M. T.; Hercbergs, A.; Davis, P. J.; Shih, Y. J.; Lin, H. Y., Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells. Endocr Relat Cancer2018, 25, (5), 533-545.
  174. 174. Kim, D. I.; Lee, T. K.; Lim, I. S.; Kim, H.; Lee, Y. C.; Kim, C. H., Regulation of IGF-I production and proliferation of human leiomyomal smooth muscle cells by Scutellaria barbata D. Don in vitro: isolation of flavonoids of apigenin and luteolin as acting compounds. Toxicol Appl Pharmacol2005, 205, (3), 213-24.
  175. 175. Lee, T. K.; Lee, D. K.; Kim, D. I.; Lee, Y. C.; Chang, Y. C.; Kim, C. H., Inhibitory effects of Scutellaria barbata D. Don on human uterine leiomyomal smooth muscle cell proliferation through cell cycle analysis. Int Immunopharmacol2004, 4, (3), 447-54.
  176. 176. Zhang, S.; Cao, H. J.; Davis, F. B.; Tang, H. Y.; Davis, P. J.; Lin, H. Y., Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cells. Br J Cancer2004, 91, (1), 178-85.
  177. 177. Hu, C.; Liu, Y.; Teng, M.; Jiao, K.; Zhen, J.; Wu, M.; Li, Z., Resveratrol inhibits the proliferation of estrogen receptor-positive breast cancer cells by suppressing EZH2 through the modulation of ERK1/2 signaling. Cell Biol Toxicol2019, 35, (5), 445-456.
  178. 178. Chao, A.; Lin, C. Y.; Tsai, C. L.; Hsueh, S.; Lin, Y. Y.; Lin, C. T.; Chou, H. H.; Wang, T. H.; Lai, C. H.; Wang, H. S., Estrogen stimulates the proliferation of human endometrial cancer cells by stabilizing nucleophosmin/B23 (NPM/B23). J Mol Med (Berl)2013, 91, (2), 249-59.
  179. 179. Sun, Y.; Wang, C.; Yang, H.; Ma, X., The effect of estrogen on the proliferation of endometrial cancer cells is mediated by ERRgamma through AKT and ERK1/2. Eur J Cancer Prev2014, 23, (5), 418-24.
  180. 180. Jiang, X.; Ye, X.; Ma, J.; Li, W.; Wu, R.; Jun, L., G protein-coupled estrogen receptor 1 (GPER 1) mediates estrogen-induced, proliferation of leiomyoma cells. Gynecol Endocrinol2015, 31, (11), 894-8.
  181. 181. Cheng, T. M.; Chin, Y. T.; Ho, Y.; Chen, Y. R.; Yang, Y. N.; Yang, Y. C.; Shih, Y. J.; Lin, T. I.; Lin, H. Y.; Davis, P. J., Resveratrol induces sumoylated COX-2-dependent anti-proliferation in human prostate cancer LNCaP cells. Food Chem Toxicol2018, 112, 67-75.
  182. 182. Parinandi, N. L.; Maulik, N.; Thirunavukkarasu, M.; McFadden, D. W., Antioxidants in Longevity and Medicine 2014. Oxid Med Cell Longev2015, 2015, 739417.
  183. 183. Zhang, S. H.; Wang, W. Q .; Wang, J. L., Protective effect of tetrahydroxystilbene glucoside on cardiotoxicity induced by doxorubicin in vitro and in vivo. Acta Pharmacol Sin2009, 30, (11), 1479-87.
  184. 184. Zhao, Y. Y.; Zhang, L.; Feng, Y. L.; Chen, D. Q .; Xi, Z. H.; Du, X.; Bai, X.; Lin, R. C., Pharmacokinetics of 2,3,5,4′-tetrahydroxystilbene-2-O-beta-D-glucoside in rat using ultra-performance LC-quadrupole TOF-MS. J Sep Sci2013, 36, (5), 863-71.
  185. 185. Liu, Q . L.; Xiao, J. H.; Ma, R.; Ban, Y.; Wang, J. L., Effect of 2,3,5,4′-tetrahydroxystilbene-2-O-beta-D-glucoside on lipoprotein oxidation and proliferation of coronary arterial smooth cells. J Asian Nat Prod Res2007, 9, (6-8), 689-97.
  186. 186. Li, F.; Zhang, T.; He, Y.; Gu, W.; Yang, X.; Zhao, R.; Yu, J., Inflammation inhibition and gut microbiota regulation by TSG to combat atherosclerosis in ApoE(−/−) mice. J Ethnopharmacol2020, 247, 112232.
  187. 187. Wang, T.; Gu, J.; Wu, P. F.; Wang, F.; Xiong, Z.; Yang, Y. J.; Wu, W. N.; Dong, L. D.; Chen, J. G., Protection by tetrahydroxystilbene glucoside against cerebral ischemia: involvement of JNK, SIRT1, and NF-kappaB pathways and inhibition of intracellular ROS/RNS generation. Free Radic Biol Med2009, 47, (3), 229-40.
  188. 188. Zhang, Y. Z.; Shen, J. F.; Xu, J. Y.; Xiao, J. H.; Wang, J. L., Inhibitory effects of 2,3,5,4′-tetrahydroxystilbene-2-O-beta-D-glucoside on experimental inflammation and cyclooxygenase 2 activity. J Asian Nat Prod Res2007, 9, (3-5), 355-63.
  189. 189. D’Andrea, G., Pycnogenol: a blend of procyanidins with multifaceted therapeutic applications? Fitoterapia2010, 81, (7), 724-36.
  190. 190. Petrassi, C.; Mastromarino, A.; Spartera, C., PYCNOGENOL in chronic venous insufficiency. Phytomedicine2000, 7, (5), 383-8.
  191. 191. Ho, Y.; Chen, Y. F.; Wang, L. H.; Hsu, K. Y.; Chin, Y. T.; Yang, Y. S. H.; Wang, S. H.; Chen, Y. R.; Shih, Y. J.; Liu, L. F.; Wang, K.; Whang-Peng, J.; Tang, H. Y.; Lin, H. Y.; Liu, H. L.; Lin, S. J., Inhibitory Effect of Anoectochilus formosanus Extract on Hyperglycemia-Related PD-L1 Expression and Cancer Proliferation. Front Pharmacol2018, 9, 807.
  192. 192. Ahmad, N.; Gupta, S.; Mukhtar, H., Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells. Arch Biochem Biophys2000, 376, (2), 338-46.
  193. 193. Beck, S. E.; Jung, B. H.; Fiorino, A.; Gomez, J.; Rosario, E. D.; Cabrera, B. L.; Huang, S. C.; Chow, J. Y.; Carethers, J. M., Bone morphogenetic protein signaling and growth suppression in colon cancer. Am J Physiol Gastrointest Liver Physiol2006, 291, (1), G135-45.
  194. 194. Ahmed, R. S.; Liu, G.; Renzetti, A.; Farshi, P.; Yang, H.; Soave, C.; Saed, G.; El-Ghoneimy, A. A.; El-Banna, H. A.; Foldes, R.; Chan, T. H.; Dou, Q . P., Biological and Mechanistic Characterization of Novel Prodrugs of Green Tea Polyphenol Epigallocatechin Gallate Analogs in Human Leiomyoma Cell Lines. J Cell Biochem2016, 117, (10), 2357-69.
  195. 195. Beltz, L. A.; Bayer, D. K.; Moss, A. L.; Simet, I. M., Mechanisms of cancer prevention by green and black tea polyphenols. Anticancer Agents Med Chem2006, 6, (5), 389-406.
  196. 196. Kuhnel, F.; Zender, L.; Paul, Y.; Tietze, M. K.; Trautwein, C.; Manns, M.; Kubicka, S., NFkappaB mediates apoptosis through transcriptional activation of Fas (CD95) in adenoviral hepatitis. J Biol Chem2000, 275, (9), 6421-7.
  197. 197. Maldonado, V.; Melendez-Zajgla, J.; Ortega, A., Modulation of NF-kappa B, and Bcl-2 in apoptosis induced by cisplatin in HeLa cells. Mutat Res1997, 381, (1), 67-75.
  198. 198. Ahmad, N.; Cheng, P.; Mukhtar, H., Cell cycle dysregulation by green tea polyphenol epigallocatechin-3-gallate. Biochem Biophys Res Commun2000, 275, (2), 328-34.
  199. 199. Nana, A. W.; Wu, S. Y.; Yang, Y. S.; Chin, Y. T.; Cheng, T. M.; Ho, Y.; Li, W. S.; Liao, Y. M.; Chen, Y. R.; Shih, Y. J.; Liu, Y. R.; Pedersen, J.; Incerpi, S.; Hercbergs, A.; Liu, L. F.; Whang-Peng, J.; Davis, P. J.; Lin, H. Y., Nano-Diamino-Tetrac (NDAT) Enhances Resveratrol-Induced Antiproliferation by Action on the RRM2 Pathway in Colorectal Cancers. Horm Cancer2018, 9, (5), 349-360.

Written By

Zi-Lin Li, Tung-Yung Huang, Yih Ho, Ya-Jung Shih, Yi-Ru Chen, Heng-Yuan Tang, Hung-Yun Lin, Jaqueline Whang-Peng and Kuan Wang

Submitted: 09 July 2020 Reviewed: 18 September 2020 Published: 20 October 2020